A Multicenter, Double-Blind, Placebo-Controlled, Parallel Group, Randomized, Phase III Study to Evaluate the Glycemic Efficacy and Renal Safety of Dapagliflozin in Patients With Type 2 Diabetes Mellitus and Moderate Renal Impairment (CKD 3A) Who Have Inadequate Glycemic Control.
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: AstraZeneca

Clinical Study Protocol (CSP), ANGEL
Version 17.0
Template Form Doc ID: LDMS_001_00026737
Parent Doc ID: SOP AZDoc0018580
EudraCT Number: 2015-000804-24
Clinical Study Protocol 
Drug Substance
Dapagliflozin
Study Code
D1690C00024
Version
4.0
Date
17 January 2017
A Multicenter, Double-Blind, Placebo-Controlled, Parallel Group, 
Randomized, Phase III study to Evaluate the Glycemic Efficacy and Renal 
Safety of Dapagliflozin in Patients with Type 2 Diabetes Mellitus and 
Moderate Renal Impairment (CKD 3A) who have Inadequate Glycemic 
Control
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
VERSION HISTORY
Version 4.0, 17 January 2017
Changes to the protocol are summarised below:
Protocol Synopsis (Study site(s) and number of patients planned) and Section 9.3 
(Study timetable and end of study): The estimated date of last patient completed has been 
updated considering the extension of recruitment timelines.
List of abbreviations and definition of terms: Updated to include the acronym DKA 
(Diabetic ketoacidosis)
Section 3.2 (Exclusion criteria): Exclusion criteria number 39 has been updated to include 
rapid or short acting insulin. 
Although the inclusion criteria number 05 has clearly been stating that ‘Long acting or 
intermediate acting insulin and mixed insulins are permitted’ which means that rapid or 
short acting insulin were not allowed - this change to the exclusion criteria was made to 
provide more clarity about the exclusion of these types of insulin.
Section 5.2.5.6: This new section has been added to include information about the reporting 
and adjudication of diabetic ketoacidosis events in the study.
Version 3.0, 01 April 2016
Changes to the protocol are summarised below:
Title page: Included EudraCT number for reference.
Protocol Synopsis (Study site(s) and number of patients planned) and Section 9.3 
(Study timetable and end of study): The estimated date of last patient completed has been 
updated considering the extension of recruitment timelines.
Protocol Synopsis (Study site(s) and number of patients planned), Sections 1.2 
(Rationale for study design, doses and control groups) and 1.4 (Study Design): The 
estimated site number has been updated, as additional countries have been included in the 
study. 
Protocol Synopsis (Target patient population), Sections 1.2 (Rationale for study 
design, doses and control groups), 1.4 (Study Design), 3.10.1 (Screen failures), Table 1 
(Study Plan and Timing of Procedures), 4.2.2 (Visit 3, Lead-in), 4.3.1 (Visit 4, 
Randomization): These sections/Table have been updated appropriately, due to the 
modification of inclusion/exclusion criteria. 

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
Sections 3.1 and 3.2 (Inclusion/Exclusion criteria): 
!
HbA1c has been removed from V3 and the eGFR criterion modified, to facilitate 
randomization into the study 
!
Exclusion criteria no. 24 has been introduced in order to exclude patients with rapid 
worsening of renal function (as part of the modified eGFR criterion).
!
Exclusion criteria no. 47 (48, in the current version), has been modified to allow re-
enrolment (one single time), provided that the patient had previously not been 
randomized in the study.
Sections 3.8 (Restrictions) and 5.11 (Volume of blood): Blood volume has been updated 
(reduced by 2 mL to 61 mL) due to removal of HbA1c testing at Visit 3.
8.5.1 (Analysis of the primary variable (s)): This section is updated, to include a 
sensitivity analysis to evaluate the effect of baseline (continuous) eGFR on the results 
obtained in primary analysis.  This will be assessed by the addition of a single term for 
baseline eGFR to the primary analysis model.
Section 9.2 (Monitoring of the study): Deleted the text related to withdrawal of informed 
consent for biological samples, as it is not applicable in the study.
Version 2.0, 20 January 2016
Changes to the protocol are summarised below:
Protocol Synopsis (Study site(s) and number of patients planned), Sections 1.2 
(Rationale for study design, doses and control groups) and 1.4 (Study design): 
Additional sites and country/ies are considered to be included in the study, in order to meet 
the recruitment targets.  Hence, the number of sites is updated and the regions are 
mentioned in place of country names to avoid multiple updates to protocol due to addition 
of countries in future. 
Protocol Synopsis, Sections 2.3 and 2.4 (Safety and Exploratory Objectives): These 
sections of the protocol have been updated to clarify the objectives and definitions of 
outcomes, and to correct the typographical error of the term ‘albuminuria’.
Protocol Synopsis (Statistical Methods): Eliminated unnecessary wording.
Table of contents: 
!
The heading of section 6.3.7 (Hy’s Law) has been deleted, hence the numbers of 
subsequent sections are modified accordingly, and the table of contents is updated. 
!
Some of the section headings and all the appendices numbers are updated as per the 

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
new clinical study protocol template that has been used for authoring this document. 
Appendix A (Signatures) of the previous edition of protocol is no longer part of the 
appendices.
List of abbreviations and definition of terms: Updated to reflect the addition or deletion 
of terminologies and to rearrange the list alphabetically.
Section 1.3 (Benefit/risk and ethical assessment): Updated the section to include the 
potential risk of diabetic ketoacidosis and the action required to be taken from the 
investigator if any patients present with signs and symptoms consistent with diabetic 
ketoacidosis.
Section 3.1 (Inclusion criteria): The upper limit of BMI range has been increased to 45 
kg/m2, to enhance recruitment into the study.  The medical team cannot see any risk by 
increasing the BMI to 45 kg/m2.
Sections 3.2 (Exclusion criteria) and 7.7 (Concomitant and other treatments): 
!
The investigator’s judgement may differ from the local guidelines on the metformin 
dose range for moderate renal impairment (eGFR 30 – 59 mL/minute/1.73m2, 
MDRD formula), hence the criterion (#37) and text related to restrictions on 
metformin in section 7.7 are modified by including ‘or’ to allow this difference.
!
Criterion #38 has been updated to explicitly state that ongoing treatment with GLP-1 
agonist is an exclusion criterion.
Section 3.3 (Patient enrolment and randomization): In #3, section numbers are updated 
(Section 3.1 and 3.2) to provide reference to the specific sections (3.1 and 3.2).
Sections 3.10 (Criteria for withdrawal) and 9.2 (Monitoring of the study): Lost to 
follow-up, has been added as one of the withdrawal criteria 
 
An additional point is included under Section 9.2 to emphasise sites to be 
compliant with study procedures to avoid lost to follow up.  
Section 4 (Table 1: Study plan and timing of procedures): 
!
Day 0 has been changed to Day 1 - to be consistent with other Dapagliflozin clinical 
study protocols and industry standard.  This change (day numbers) is cascaded to the 
subsequent visits.
!
The section numbers are updated in the table, due to the deletion of heading of 
section 6.3.7 (Hy’s Law)
!
In the footnote ‘c’, ‘must’ has been changed to ‘should’ – to emphasise on the 
timing of visit.
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Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
Sections 4.2.1 (Visit 2, Start of lead-in), 5.1 (Efficacy assessments) and 5.2.5.1 (Self-
monitored FPG and hypoglycemic events): The sample specimen has been corrected to 
state ‘blood glucose’ instead of ‘fasting plasma glucose’ – as the patients are instructed to 
measure the blood glucose whenever they have symptoms suggestive of hypoglycaemia –
hypolgycemia symptoms need not always occur at fasting state.
Section 4.4 (Follow-up period, Visit 9):  The typographical error related to study period 
has been corrected from ‘treatment’ to ‘follow up’.
Section 5.2.1 (Laboratory safety assessments), Table 3: Deleted ‘U-Hb/Erythrocytes’ –
as dipstick for blood would be sufficient to confirm haematuria.
Section 5.2.5.2 (Hepatic events (Hepatic Adjudication Committee)): Corrected the 
inconsistency in limits of AST, ALT and TB, with other sections and deleted the reference 
to Appendix D (Algorithm on Management of Sustained Elevated Liver Safety 
Abnormalities.)
Section 6.3.7 (Hy’s Law): Deleted the text referring to Hy’s law, as it is not applicable for 
the study.
Section 7.7 (Concomitant and other treatments): The trade name ‘Victoza’ for liraglutide 
has been removed as it was non-relevant. The procedure for dose reduction of oral 
antidiabetics and insulin, and continued participation in the study following the dose 
reduction has been clarified.
Sections 8.3.3 (Full Analysis set), 8.3.4 (Per protocol analysis set) and 8.3.5 (Safety 
analysis set): Added details to definition of Full Analysis Set and corrected typographical 
errors. 
Sections 8.4.3 (Safety outcome variables) and 8.4.4 (Exploratory outcome variables):
Deleted time references from outcome variable descriptions
Sections 8.5 (Methods for statistical analyses), 8.5.1 (Analysis of the primary variable 
(s)) and 8.5.2 (Analysis of the secondary variable(s)): These sections are updated, to 
clarify the primary analyses and sensitivity analyses, 
 
and to simplify text.
Section 8.5.6 (Exploratory analysis): 
 
to change the analysis of proportions 
to the current analysis convention, and to simplify text.
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Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
Section 11 (List of references): Deleted the references of Tsiatis et al 2008 and Zhang et al 
2008, due to changes made in section 8.5.6.
Version 1.0, 25 March 2015
Initial creation

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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PROTOCOL SYNOPSIS
A Multicenter, Double-Blind, Placebo-Controlled, Parallel Group, 
Randomized, Phase III study to Evaluate the Glycemic Efficacy and 
Renal Safety of Dapagliflozin in Patients with Type 2 Diabetes Mellitus 
and Moderate Renal Impairment (CKD 3A) who have Inadequate 
Glycemic Control
International Co-ordinating Investigator
Study site(s) and number of patients planned
This study will be conducted at approximately 100 centres from countries across North 
America and European regions.  It is expected that approximately 302 patients will be 
randomized into the study.
Study period
Phase of development
Estimated date of first patient enrolled
Q2 2015
Phase III
Estimated date of last patient completed
Q4 2017
Study design
This is a confirmatory, phase III, randomized, double-blind, 2-arm, parallel group, placebo-
controlled, multi-national, multi-centre study to evaluate the clinical efficacy and safety of 
dapagliflozin in patients with type 2 diabetes and Chronic Kidney Disease (CKD) stage 3A.  
The study consists of 2-week screening period with a 4-week single-blind placebo lead-in 
period and a 24-week double-blind placebo-controlled treatment period followed by 3-week of 
follow-up period.
PPD

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Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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Objectives
Primary Objective:
Outcome Measure:
To compare the mean change from baseline in 
HbA1c between dapagliflozin 10 mg and 
placebo, after 24 weeks of oral administration of 
double-blind treatment in patients with type 2 
diabetes and CKD stage 3A.
Change from baseline in HbA1c at Week 24
Secondary Objective:
Outcome Measure :
To compare the percent change from baseline in 
total body weight between dapagliflozin 10 mg 
and placebo, after 24 weeks of oral 
administration of double-blind treatment.
Percent change from baseline in total body 
weight at Week 24 
To compare the change from baseline in fasting 
plasma glucose (FPG) between dapagliflozin 10 
mg and placebo, after 24 weeks of oral 
administration of double-blind treatment.
Change from baseline in FPG at Week 24
To compare the change from baseline in seated 
systolic blood pressure (SBP) between 
dapagliflozin 10 mg and placebo, after 24 weeks 
of oral administration of double-blind treatment.
Change from baseline in seated SBP at Week 24

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Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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Safety Objective:
Outcome Measure :
To examine eGFR changes during the study and 
3-week post-treatment for dapagliflozin 10 mg 
and placebo.
Change in eGFR from baseline to end of 
treatment and 3-week post-treatment
To assess the proportion of patients discontinued 
from study medication because of worsening 
renal insufficiency (defined as patients reaching 
confirmed eGFR levels <30 mL/min/1.73 m2) 
between dapagliflozin 10 mg and placebo.
Proportion of patients discontinued from study 
medication due to worsening renal insufficiency 
(<30 mL/min/1.73 m2) at the end of treatment
To evaluate the safety and tolerability of 
dapagliflozin 10 mg once daily in type 2 diabetes 
and CKD stage 3A.
AEs /Serious Adverse Events (SAEs)
Vital signs 
Physical examination
Clinical chemistry parameters
Exploratory Objective:
Outcome Measure :
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Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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Exploratory Objective:
Outcome Measure :
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Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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Exploratory Objective:
Outcome Measure :
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Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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Exploratory Objective:
Outcome Measure :
Target patient population
The target patients include, Female or male aged M18 years and <75 years:
!
With history of type 2 diabetes mellitus (T2DM) for more than 12 months with 
inadequate glycemic control, defined as HbA1c M7.0 and S11% at screening and 
stable anti-diabetic treatment during the last 12 weeks prior to randomization
!
With moderate renal impairment; CKD 3A; Estimated Glomerular Filtration Rate 
(eGFR) 45 – 59 mL/minute/1.73m2, MDRD-formula, before randomization (at Visit 
1, or Visit 2, or Visit 3)
Duration of treatment
The study will start with a 2-week screening period.  Eligible patients will enter a 4-week
single-blind placebo lead-in period and then randomized to double-blind treatment in a 1:1 
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Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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ratio to receive dapagliflozin 10 mg or matching placebo for a period of 24-week.  Patients 
will be followed up for 3-week after the double-blind treatment period. 
Investigational product, dosage and mode of administration
!
Dapagliflozin 10 mg will be administered orally once daily during the 24-week
double-blind treatment period
Comparator, dosage and mode of administration
!
Matching placebo for dapagliflozin 10 mg will be administered orally once daily 
during the 4-week single-blind placebo lead-in period and the 24-week double-blind 
treatment period 
Other treatments
!
Oral Anti-diabetic Drugs (OADs) except SGLT2 inhibitors, insulin, anti-
hypertensive drugs, lipid lowering drugs and anti-platelet drugs are allowed during 
the study and the dose should be kept constant throughout the entire 24-week
double-blind treatment period
!
Patients may receive open-label rescue medication added on to, but not as a 
replacement for their current study drug regimen. Rescue medication in this 
protocol refers to any approved, appropriate anti-diabetic agent, except SGLT2 
inhibitors, for which there is either initiation or upward titration, in accordance with 
the approved label and conventional standards of care
Statistical methods
The sample size for this study was selected to be consistent with the research hypotheses.  The 
study has a single primary endpoint for which the overall probability of a Type 1 error 
(Family-wise error rate) will be strictly controlled at no more than 0.05.  The sample size for 
this study is governed by providing adequate power for the primary comparison to achieve 
statistical significance; namely, for the change from baseline in HbA1c.  Significance levels 
are expressed in terms of two-sided alternatives; however, all tests in practice will be 
performed against one-sided alternatives using one-half the significance levels reported here. 
From post-hoc results of similar clinical studies (Study MB102029, Study D1690C00018, and 
Study D1690C00019) when patients meeting eGFR entry criteria like those in this current 
study were selected, the mean placebo-corrected change from baseline in HbA1c after 24 
weeks of treatment for the current study is estimated to be -0.3% for dapagliflozin 10 mg. 
The present study seeks to detect a treatment difference over placebo in change from baseline 
HbA1c at Week 24 of -0.3% with high statistical power (80%).  Given patients will be 
randomized with equal probability to dapagliflozin or placebo, it follows that 286 patients 
(143 per group) will provide 80% power to detect a difference in average placebo-corrected 
change from baseline in HbA1c at Week 24 of  -0.3% (T = -0.3%) at a (two-sided) 
significance level =0.05.  If 5% of randomized patients fail to qualify for inclusion in the full 

Clinical Study Protocol Synopsis
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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analysis set due to missing baseline and/or all post-randomization values for this primary 
endpoint, then a total of 151 randomized patients are required for each treatment group.  
Therefore, with respect to the primary study endpoint, 302 randomized patients in total are 
needed for the study. 
Assuming a common standard deviation (SD) of 0.9% in change from baseline HbA1c this 
sample size provides 80% power to detect a placebo-corrected difference in average change 
from baseline in HbA1c between dapagliflozin and placebo at a (two-sided) significance level 
of 0.05.  If the primary comparison in mean change from baseline in HbA1c at Week 24 does 
not achieve statistical significance at an unadjusted alpha level of 0.05, then secondary 
comparisons will not be performed.  Otherwise, secondary endpoint comparisons between 
dapagliflozin and placebo will be performed at an unadjusted alpha (Type I error) level of 
0.05, with a sequential testing procedure of secondary endpoints used to control the alpha 
level for multiplicity.
A sample size of 143 evaluable patients per treatment group (dapagliflozin and placebo) 
provides 75 percent assurance that a statistically significant difference between dapagliflozin 
and placebo in mean change from baseline to Week 24 in HbA1c will be observed for the 
primary study endpoint.
The primary endpoint of changes from baseline to Week 24 will be evaluated using a mixed 
effects model with repeated measures (MMRM). 
Changes from baseline to Week 24 in the secondary study endpoints (total body weight, FPG, 
and seated SBP) will be separately evaluated using MMRM.  
A sequential testing procedure will be employed in comparisons of primary and secondary 
efficacy parameters.  The ratio of the difference in LSM estimates (dapagliflozin versus 
placebo) to the corresponding standard error (e.g., the test statistic) will be tested first for the 
primary endpoint (HbA1c) at a two-sided alpha level of 0.05.  If statistical significance is 
achieved and the difference indicates the dapagliflozin group experienced greater 
improvement in the primary endpoint at Week 24 than placebo, then superiority of 
dapagliflozin doses to placebo will be inferred, and secondary endpoints will be sequentially 
tested at a two-sided alpha level of 0.05.  Otherwise, testing will cease.  Comparisons of 
secondary endpoints between dapagliflozin and placebo will be performed using a sequential 
test procedure.  Each test will be performed at an alpha level of 0.05, and the order of testing 
will follow the order that the secondary endpoints are listed in Section 8.4.2 of this protocol.  
Testing will cease at the first secondary endpoint for which superiority of dapagliflozin to 
placebo cannot be inferred, or the last secondary endpoint comparison is performed, 
whichever occurs first.

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
VERSION HISTORY..............................................................................................2
PROTOCOL SYNOPSIS.........................................................................................8
TABLE OF CONTENTS.......................................................................................16
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................21
1.
INTRODUCTION .................................................................................................24
1.1
Background and rationale for conducting this study .............................................24
1.2
Rationale for study design, doses and control groups............................................25
1.3
Benefit/risk and ethical assessment........................................................................26
1.4
Study Design..........................................................................................................29
2.
STUDY OBJECTIVES..........................................................................................30
2.1
Primary objective...................................................................................................30
2.2
Secondary objectives .............................................................................................30
2.3
Safety objectives ....................................................................................................31
2.4
Exploratory objectives ...........................................................................................31
3.
PATIENT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................34
3.1
Inclusion criteria ....................................................................................................34
3.2
Exclusion criteria ...................................................................................................35
3.3
Patient enrolment and randomization ....................................................................39
3.4
Procedures for handling incorrectly enrolled or randomized patients...................40
3.5
Methods for assigning treatment groups................................................................40
3.6
Methods for ensuring blinding...............................................................................41
3.7
Methods for unblinding..........................................................................................42
3.8
Restrictions ............................................................................................................42
3.9
Discontinuation of investigational product............................................................43
3.9.1
Study specific discontinuation criteria...................................................................43
3.9.2
Procedures for discontinuation of a patient from IP ..............................................45
3.10
Criteria for withdrawal...........................................................................................45
3.10.1
Screen failures........................................................................................................45

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Study Code D1690C00024
Version 4.0
Date 17 January 2017
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3.10.2
Withdrawal of the informed consent......................................................................45
3.10.3
Lost to follow-up....................................................................................................46
3.11
Discontinuation of the study ..................................................................................46
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................47
4.1
Enrolment/screening period (Visit 1 to Visit 2).....................................................51
4.2
Single-blind placebo lead-in period (Visit 2 to Visit 4).........................................51
4.2.1
Visit 2, Start of lead-in...........................................................................................51
4.2.2
Visit 3, Lead-in ......................................................................................................53
4.3
Treatment period....................................................................................................53
4.3.1
Visit 4, Randomization ..........................................................................................53
4.3.2
Visit 5, Treatment ..................................................................................................54
4.3.3
Visit 6, Treatment ..................................................................................................55
4.3.3.1
Rescue Medication Due to Lack of Glycemic Control in the Treatment 
Period .....................................................................................................................55
4.3.4
Visit 7, Treatment ..................................................................................................58
4.3.5
Visit 8, End of Treatment/Discontinuation/Rescue ...............................................58
4.4
Follow-up period, Visit 9.......................................................................................59
5.
STUDY ASSESSMENTS .....................................................................................59
5.1
Efficacy assessments..............................................................................................60
5.1.1
HbA1c....................................................................................................................60
5.1.2
FPG ........................................................................................................................60
5.1.3
Weight and height..................................................................................................60
5.1.4
BMI........................................................................................................................60
5.1.5
Vital signs ..............................................................................................................61
5.1.5.1
Seated blood pressure and pulse ............................................................................61
5.1.8
Insulin dose ............................................................................................................61
5.1.9
eGFR......................................................................................................................61
5.2
Safety assessments.................................................................................................62
5.2.1
Laboratory safety assessments...............................................................................62
5.2.2
Physical examination .............................................................................................64
5.2.3
ECG........................................................................................................................64
5.2.4
Vital signs ..............................................................................................................64
5.2.4.1
Blood pressure and pulse .......................................................................................64
5.2.5
Other safety assessments........................................................................................65
5.2.5.1
Self-monitored blood glucose and hypoglycemic events ......................................65
5.2.5.2
Hepatic events (Hepatic Adjudication Committee) ...............................................66
5.2.5.3
Asymptomatic bacteriuria......................................................................................66
5.2.5.4
Microscopic Hematuria..........................................................................................66
5.2.5.5
Volume Depletion..................................................................................................67
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5.2.5.6
Potential events of Diabetic Ketoacidosis..............................................................67
5.3
Other assessments – Not Applicable......................................................................67
5.4
Pharmacokinetics – Not Applicable.......................................................................67
5.5
Pharmacodynamics – Not Applicable....................................................................67
5.6
Pharmacogenetics – Not Applicable......................................................................67
5.7
Biomarker analysis – Not Applicable....................................................................67
5.8
Storage, re-use and destruction of biological samples...........................................67
5.9
Labelling and shipment of biological samples.......................................................68
5.10
Chain of custody of biological samples.................................................................68
5.11
Volume of blood ....................................................................................................68
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................69
6.1
Definition of adverse events ..................................................................................69
6.2
Definitions of serious adverse event......................................................................69
6.3
Recording of adverse events ..................................................................................70
6.3.1
Time period for collection of adverse events.........................................................70
6.3.2
Follow-up of unresolved adverse events................................................................70
6.3.3
Variables ................................................................................................................70
6.3.4
Causality collection................................................................................................71
6.3.5
Adverse events based on signs and symptoms.......................................................71
6.3.6
Adverse events based on examinations and tests...................................................72
6.3.7
Hypoglycemic events.............................................................................................72
6.4
Reporting of serious adverse events.......................................................................72
6.5
Overdose ................................................................................................................73
6.6
Pregnancy...............................................................................................................74
6.6.1
Maternal exposure..................................................................................................74
6.6.2
Paternal exposure – Not Applicable ......................................................................74
6.7
Management of IP related toxicities – Not Applicable..........................................74
6.8
Study governance and oversight ............................................................................74
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................75
7.1
Identity of investigational product(s).....................................................................75
7.2
Dose and treatment regimens.................................................................................75
7.3
Labelling ................................................................................................................76
7.4
Storage ...................................................................................................................76
7.5
Compliance ............................................................................................................76
7.6
Accountability........................................................................................................77

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Study Code D1690C00024
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7.7
Concomitant and other treatments .........................................................................77
7.7.1
Other concomitant treatment..................................................................................78
7.8
Post Study Access to Study Treatment – Not Applicable......................................79
8.
STATISTICAL ANALYSES BY ASTRAZENECA............................................79
8.1
Statistical considerations........................................................................................79
8.2
Sample size estimate..............................................................................................79
8.3
Definitions of analysis sets ....................................................................................79
8.3.1
Enrolled Patients Data Set......................................................................................79
8.3.2
Lead-in Patients Data Set.......................................................................................80
8.3.3
Full Analysis set.....................................................................................................80
8.3.4
Per Protocol Analysis Set.......................................................................................80
8.3.5
Safety Analysis Set ................................................................................................80
8.3.6
PK analysis set – Not Applicable...........................................................................81
8.3.7
PRO analysis set – Not Applicable........................................................................81
8.4
Outcome measures for analyses.............................................................................81
8.4.1
Primary outcome variable......................................................................................81
8.4.2
Secondary outcome variables.................................................................................81
8.4.3
Safety outcome variables .......................................................................................81
8.4.4
Exploratory outcome variables ..............................................................................81
8.5
Methods for statistical analyses .............................................................................83
8.5.1
Analysis of the primary variable (s).......................................................................83
8.5.2
Analysis of the secondary variable(s)....................................................................84
8.5.3
Subgroup analysis ..................................................................................................84
8.5.4
Interim analysis – Not Applicable .........................................................................85
8.5.5
Sensitivity analysis.................................................................................................85
8.5.6
Exploratory analysis...............................................................................................85
8.5.7
Analysis of safety variables ...................................................................................85
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ..........................86
9.1
Training of study site personnel.............................................................................86
9.2
Monitoring of the study .........................................................................................86
9.2.1
Source data.............................................................................................................86
9.2.2
Study agreements...................................................................................................87
9.2.3
Archiving of study documents...............................................................................87
9.3
Study timetable and end of study...........................................................................87
9.4
Data management by AstraZeneca or delegate......................................................87
10.
ETHICAL AND REGULATORY REQUIREMENTS.........................................88
10.1
Ethical conduct of the study...................................................................................88
10.2
Patient data protection............................................................................................88
10.3
Ethics and regulatory review..................................................................................88

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10.4
Informed consent ...................................................................................................89
10.5
Changes to the protocol and informed consent form.............................................90
10.6
Audits and inspections ...........................................................................................90
11.
LIST OF REFERENCES.......................................................................................90
LIST OF TABLES
Table 1
Study Plan detailing the procedures .........................................................47
Table 2
Lack of Glycemic Control Criteria for Initiation of Open-Label 
Rescue Medication ...................................................................................56
Table 3
Laboratory Safety Variables.....................................................................63
Table 4
Volume of blood to be withdrawn from each patient...............................68
Table 5
Drug Dispensing Scheme .........................................................................76
LIST OF FIGURES
Figure 1
Study flow Chart.......................................................................................29
Figure 2
Sustained elevated liver safety abnormalities flow chart .......................100
LIST OF APPENDICES
Appendix A
Additional Safety Information..................................................................93
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document .................................................................................95
Appendix C
Algorithm on Management of Sustained Elevated Liver Safety 
Abnormalities ...........................................................................................96
Appendix D
New York Heart Association (NYHA) Classification ...........................101

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse Event
ALK-P
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUA
American Urological Association
BMI
Body Mass Index
BP
Blood Pressure
CKD
Chronic Kidney Disease
CRF
Case Report Form 
CRO
Contract Research Organization
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CV
Cardiovascular
DBP
Diastolic Blood Pressure
DILI
Drug-Induced Liver Injury
DKA
Diabetic Ketoacidosis
DM
Diabetes Mellitus
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
eGFR
Estimated Glomerular Filtration Rate
EU
European Union
FPG
Fasting Plasma Glucose
FU
Follow-Up
GCP
Good Clinical Practice
GLP-1 
Glucagon-like Peptide-1
GMP
Good Manufacturing Practice
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Abbreviation or 
special term
Explanation
GRand
Global Randomization system
Hb
Haemoglobin
HbA1C
Glycosylated Haemoglobin
HF
Heart Failure
HIV
Human Immunodeficiency Virus
HN
High Normal
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
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. 
IRB
Institutional Review Board
IP
Investigational Product 
KG
Kilogram
LOCF
Last Observation Carried Forward
LSM
Least Square Mean
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MG
Milligram
MMRM
Mixed Effects Model With Repeated Measures
NOINT
No-Intercept
NYHA
New York Heart Association
OAD
Oral Anti-diabetic Drug
PI
Principal Investigator 
PPG
Post-Prandial Glucose
PTH
Parathyroid Hormone
RMM
Repeated Measures Model
RPD
Relevant Protocol Deviation
CCI
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Abbreviation or 
special term
Explanation
SAE
Serious Adverse Event 
SBP
Systolic Blood Pressure
sCr
Serum Creatinine
SD
Standard Deviation
SGLT2
Sodium Glucose Co-Transporter 2
SU
Sulfonylurea
T2DM
Type 2 Diabetes Mellitus
TB
Total Bilirubin
TIA
Transient Ischemic Attack
TZD
Thiazolidinedione
ULN
Upper Limit of Normal
US
United States
UTI
Urinary Tract Infection
WBDC
Web Based Data Capture
WOCBP
Women of childbearing potential
CCI
CCI

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Dapagliflozin (Forxiga®) is a stable, reversible, highly selective, and orally active inhibitor of 
human renal sodium glucose co-transporter 2 (SGLT2), the major transporter responsible for 
renal glucose reabsorption in the kidney (Maranghi et al 2015).  Dapagliflozin’s mechanism of 
action results in the direct and insulin-independent elimination of glucose by the kidneys.  
Traditionally, the presence of glucose in the urine has been seen as a sign of poor glycemic 
control and, thus, something to be avoided. Familial renal glucosuria in humans, however, due 
to genetic mutations that reduce the function of SGLT2, is associated with life-long glucosuria 
that is generally asymptomatic (Santer et al 2010).  Results from nonclinical- and clinical 
studies have shown that dapagliflozin can be used to promote urinary excretion of glucose as a 
safe and effective method of reducing blood glucose levels (Plosker et al 2014). 
Dapagliflozin’s mechanism of action reduces plasma glucose regardless of the patient’s 
insulin sensitivity and W-cell secretory function.  Because this mechanism is independent of 
insulin secretion or insulin action, this approach to anti-diabetic therapy provides an 
opportunity to achieve clinically important glycemic efficacy with a comparatively low risk of 
hypoglycemia.  This insulin-independent mechanism is also potentially applicable to a broad 
spectrum of patients.  In addition, the excretion of glucose may promote weight loss or 
prevent weight gain, as a consequence of calorie loss, a potential benefit for many patients 
with T2DM (Maranghi et al 2015).
The dapagliflozin clinical development program was designed to demonstrate the safety and 
efficacy of dapagliflozin in a wide range of patients with T2DM.  The program included both 
placebo-controlled and active comparator studies in drug-naïve patients at an early stage of 
disease and patients who require additional therapy after failure to reach adequate glycemic 
control with their current regimen.  Dapagliflozin’s pharmacodynamic effect of glucosuria is 
detected almost immediately (within 1 hour post-dose), is maintained through 2 years of 
treatment, and results in reductions in Fasting Plasma Glucose (FPG), Post-prandial Glucose 
(PPG), and HbA1c (glycosylated haemoglobin).  Treatment with dapagliflozin, with its unique 
mechanism of action, results in a persistent loss of glucose with associated calories in the 
urine, resulting in a consistent and maintained reduction of the total body weight, in addition 
to the improved glycemic control (Bolinder et al 2014).  The weight loss is predominantly a 
result of a reduction in fat mass, visceral adipose tissue, and subcutaneous adipose tissue in 
T2DM.  Dapagliflozin also has a mild diuretic effect, which in combination with weight loss, 
has the potential to reduce blood pressure (BP). 
Diabetic patients with moderate renal impairment are of interest because diabetic nephropathy 
affects approximately 30% of patients with diabetes (Sheen et al 2014).  In the Unites States, 
for instance, about 20% of individuals with diabetes have an eGFR lower than 60 
ml/min/1.73m2 (chronic kidney disease, CKD stage M3).  As diabetic patients progress from 
normal to diminished renal function over the natural history of their disease, there is a medical 
need for safe and effective oral anti-diabetic therapy.  Several existing anti-diabetic agents are 

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contraindicated in this population, are associated with increased risk of hypoglycemia, or have 
not been adequately studied in these patients (SDCD 2014).  Safety and efficacy data in 
patients with normal, mildly, and moderately impaired renal function have been collected in 
previous studies in the dapagliflozin development program.
Notably, dapagliflozin’s ability to inhibit renal glucose reabsorption declines with decreasing 
eGFR.  Urinary glucose excretion is about 50% lower in patients with T2DM treated with 
dapagliflozin having CKD stage 3, as compared with patients with normal or mildly impaired 
renal function.  Such eGFR dependence is expected given the fall in filtered glucose load with 
worsening CKD stage.  In a previous study, dapagliflozin did not have a significant impact on 
glycemic control in patients with more advanced CKD, although there was a modest decrease 
in HbA1c and FPG in patients with a GFR of 45–59 ml/min (Kohan et al 2014). However, that 
study suffered from several limitations.  The use of insulin-based regimens in almost two-
thirds of patients, often with sliding scale administration, made accurate capture of insulin 
dosing difficult.  Unmeasured differential behaviour with respect to sliding scale and other 
adjustments of insulin between placebo and dapagliflozin could have blunted the apparent 
efficacy of dapagliflozin.  A second limitation was the relatively small size of the study, which 
was powered for a 0.6% change in HbA1c, and therefore limited in its ability to demonstrate 
smaller glycemic effects and thus, the study may be considered underpowered and subject to 
type 2 error.  Other factors such as a very short placebo lead-in period and a relatively large 
placebo effect in this study could potentially also have affected and obscured the interpretation 
of the data.  In other clinical studies, which did not suffer from the limitations described 
above, SGLT2-inhibitors have been shown to be safe and effective in T2DM patients with 
moderate renal impairment lending support to further studies in this specific patient segment 
(Yale et al 2013, Barnett et al 2014).
1.2
Rationale for study design, doses and control groups
This study will be performed as part of the clinical development program for dapagliflozin for 
the treatment of T2DM.  This study intends to compare efficacy and safety of dapagliflozin 
with placebo in the treatment of patients with T2DM who have inadequate glycemic control, 
defined as HbA1c M7.0% and S11%, and moderate renal impairment (eGFR 45 to 59 
ml/min/1.73 m2).  SGLT2-inhibition has been shown to improve glycaeimic control in T2DM 
patients with renal impairment.  Based on these results, it is anticipated that after 24 weeks of 
daily oral administration of dapagliflozin 10 mg or placebo, there will be a greater mean 
reduction from baseline in HbA1c achieved with dapagliflozin compared to placebo in 
patients with T2DM and moderate renal impairment who have inadequate glycemic control on 
their current anti-diabetic regimen.  A standard dapagliflozin dose for treatment of T2DM (10 
mg dapagliflozin once daily) has been selected for this study and is expected to provide 
efficacy in reducing hyperglycemia while mitigating the potential for AEs, based on previous 
clinical experience. In addition to improved glycemic control in patient treated with 
dapagliflozin 10 mg, it is anticipated that a decrease in body weight and BP will provide 
additional benefit to the patients. 
This is a confirmatory, phase III, randomized, double-blind, 2-arm, parallel group, placebo-
controlled, multi-national, multi-centre study to evaluate the clinical efficacy and safety of 

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dapagliflozin in patients with type 2 diabetes and CKD stage 3A (eGFR 45-59 mL/min/1.73 
m2). Patients will be randomized to 24 weeks’ treatment with dapagliflozin 10 mg or matching 
placebo. The study will be an international multi-centre study at approximately 100 centres 
from countries across North America and European regions.  It is planned to randomize a total 
of 302 patients (151 patients per treatment arm).  The study is powered to detect a change of 
0.3% in HbA1c between active treatment and placebo following 24 weeks of treatment.
Dapagliflozin 10 mg once daily or matching placebo will be added to usual care of patients 
who have inadequate glycemic control on their existing therapies.  This double-blind 
randomized phase III study requires a placebo group to determine efficacy of dapagliflozin in 
a specific patient segment in order to discriminate effects caused by the study treatment from 
effects caused by other factors.  All patients in the study are protected from harm by rescue 
criteria, which call for withdrawal from the study if the patient shows evidence of 
inadequately controlled disease. 
Randomization will be stratified by pre-enrolment anti-hyperglycemic therapy 
(long/intermediate-acting and mixed insulin regimen, metformin-based regimen, sulfonylurea 
(SU)-based regimen, thiazolidinedione (TZD)-based regimen, and other regimen). Any 
patients on metformin treatment need to have a dose suitable according to local guidelines or 
investigator’s judgement for the full CKD 3 segment (i.e., eGFR 30 - 60 ml/min/1.73 m2, 
calculated using the MDRD formula).
The study consists of 2-week screening period, a 4-week single-blind placebo lead-in period, a 
24-week double-blind placebo-controlled treatment period, and a 3-week follow-up (FU) 
period.  The study drug is taken once daily in the morning.
The main efficacy assessments will be performed at regular intervals and will include HbA1c, 
weight,
FPG, seated BP and heart rate. During the double-blind 
treatment period, HbA1c and urinary glucose values will be blinded to the Investigator and to 
the Sponsor.  These values will be provided to the Investigator after the study has been 
completed.  FPG value will be reported as an un-blinded value throughout the study.
The main safety assessments will be performed at regular intervals and will include physical 
examination, vital signs, renal function (change in eGFR), safety laboratory test, and AE 
monitoring.
1.3
Benefit/risk and ethical assessment
Risk category
Dapagliflozin has global market approval and has been administered to thousands of T2DM 
patients globally.  Details regarding potential risks associated with administration of 
dapagliflozin once daily are provided in the Investigator’s Brochure.
Considering dapagliflozin’s mechanism of action, the previous clinical experience with 
dapagliflozin, the study’s design features (including the inclusion, exclusion, and 
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discontinuation criteria), and the planned safety procedures, participation in this study presents 
a minimal, and thus acceptable, risk to the individual patients that will be included.
Potential risks
Inhibition of SGLT2 results in increased urinary glucose excretions, which is commonly 
believed to increase the risk of urinary tract infections (UTIs).  In some of the global Phase III 
studies, events of UTI were reported in a slightly higher proportion of dapagliflozin-treated 
patients than the placebo group.  Increased urinary glucose excretion may also lead to an 
increased risk of developing genital infections.  In global Phase III studies, the proportions of 
patients treated with dapagliflozin who reported AEs that matched a predefined list of Medical 
dictionary for regulatory activities (MedDRA) preferred terms that were indicative of genital 
infection were higher than those seen for placebo.
Based on the mechanism of action of dapagliflozin and results of animal and clinical studies, 
there may be a potential risk for this compound to cause hypovolaemia or electrolyte 
imbalance.  As a precaution, patients who, in the judgment of the Investigator, may be at risk 
for dehydration or volume depletion due to co-existing conditions or concomitant 
medications, such as loop diuretics, should have careful monitoring of their volume status.  In 
patients already receiving dapagliflozin who develop conditions that may cause hypovolaemia 
or electrolyte imbalance, decisions to interrupt or discontinue dapagliflozin therapy and 
management of patients should be based on clinical judgment.
Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia 
were reported in dapagliflozin vs. placebo but the clinical meaning of this is unclear.
Hepatic laboratory markers were assessed in all the clinical studies with dapagliflozin.  In the 
pooled analyses, the proportion of patients with elevated liver function tests was similar in the 
dapagliflozin and comparator groups and no clinically meaningful or consistent mean changes 
from baseline in liver function tests were observed in the dapagliflozin and placebo groups 
across the Phase IIb and III clinical studies.  One patient had a SAE reported as drug-induced 
acute hepatitis that was later diagnosed as most comparable with autoimmune hepatitis.
There have been postmarketing reports of ketoacidosis, including diabetic ketoacidosis 
(DKA), in patients with type 1 and type 2 diabetes mellitus taking dapagliflozin and other 
SGLT2 inhibitors, although a causal relationship has not been established. Dapagliflozin is not 
indicated for the treatment of patients with type 1 diabetes mellitus.
Patients treated with dapagliflozin who present with signs and symptoms consistent with 
ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, 
should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L (250 
mg/dL). If ketoacidosis is suspected, discontinuation or temporary interruption of 
dapagliflozin should be considered and the patient should be promptly evaluated.
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from 
pancreatic disorders (eg, type 1 diabetes, history of pancreatitis, or pancreatic surgery), insulin 

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dose reduction, reduced caloric intake, or increased insulin requirements due to infections, 
illness or surgery and alcohol abuse. Dapagliflozin should be used with caution in these 
patients.
No study procedure will put patients at a risk beyond those ordinarily encountered during the 
performance of routine medical examinations or routine tests.
Protection against risks
This study has been designed with appropriate measures in place so as to monitor and 
minimize any of the potential health risks to participating patients.  In order to ensure the 
safety of all patients participating in this study, AstraZeneca will conduct a real-time review of 
all safety information from all ongoing clinical dapagliflozin studies as they become available.  
Safety signal detection will include the integration of all available sources of safety 
information, including clinical study data, AE reports, pre-clinical data, epidemiological 
studies and literature reports, to identify and characterize unrecognized safety risks or changes 
in those which are currently expected Adverse Drug Reactions.  Any information that may 
affect the benefit-risk profile of dapagliflozin will be immediately communicated to relevant 
Health Authorities and appropriate actions will be taken regarding the clinical program as 
needed.  Thus real-time, active safety surveillance will be conducted during the entire duration 
of this study.  In addition, all dapagliflozin studies are subject to a carefully designed patient 
risk management plan that includes the temporary and if necessary permanent discontinuation 
of investigational product (IP) in individual patients in whom a potential health risk or a 
laboratory abnormality of clinical concern has been identified.
Potential benefits to patients
All patients will receive counselling on dietary and life-style modifications.  Global phase II 
and phase III studies have established the effect of dapagliflozin therapy.  This phase III study 
will evaluate these effects of dapagliflozin in T2DM patients with moderate renal impairment 
(CKD3A).  In this study, the dose of dapagliflozin (10 mg) was chosen to provide efficacy in 
reducing hyperglycemia while mitigating the risk for AEs, based on previous clinical 
experience.  In addition, dapagliflozin is expected to help decrease body weight (or prevent 
weight gain) as well as help lower BP especially in patients with elevated baseline BP.  
Patients are also expected to receive some benefit in the form of increased medical 
care/attention when participating in study procedures, which includes at least 9 clinical visits.
Informed consent and alternatives to participation
All prospective participants will be fully informed of the possible risks and benefits associated 
with this study, and their consent will be obtained prior to performing any study-specific 
activity.  Should a prospective participant elect to not participate in the study or to withdraw 
from the study, other medications are available to treat their diabetes, and the patient will not 
be disadvantaged in any way.

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Conclusion
Considering the pre-clinical and clinical experience with dapagliflozin and the precautions 
included in the study protocol, participation in this study presents a minimal and thus 
acceptable risk to patients who meet the inclusion/exclusion criteria and consent to take part in 
the study. 
1.4
Study Design 
This is a confirmatory, phase III, randomized, double-blind, 2-arm, parallel group, placebo-
controlled, multi-national, multi-centre study to evaluate the clinical efficacy and safety of 
dapagliflozin in patients with type 2 diabetes and CKD stage 3A.  The study consists of 2-
week screening period, a 4-week single-blind placebo lead-in period, a 24-week double-blind 
placebo-controlled treatment period, and a 3-week follow-up period.  Patients will be 
randomized to 24 weeks treatment with dapagliflozin 10 mg or matching placebo after the 
placebo lead-in period.  The study will be an international multi-centre study at approximately 
100 centres from countries across North America and European regions.
The study comprises of 9 visits: enrolment visit (Visit 1), Start of lead-in (Visit 2), Lead-in 
(Visit 3), randomization visit (Visit 4), Treatment period (Visit 5-7), end of treatment visit 
(Visit 8), and a follow-up visit (Visit 9). For details on timing of visits, see Figure 1 below.
Figure 1
Study flow Chart
4wk
2wk
24wk
3wk
Dapagliflozin 10 mg
Matching Placebo
Screening
Double-blind treatment
Single-blind placebo 
lead-in
Follow-Up
R
(1:1)
DB
Continue usual care medication
V1, 
Wk -6
V2, 
Wk -4
V3, 
Wk -1
V4, 
Wk 0
V5, 
Wk 1
V6, 
Wk 4
V7, 
Wk 12
V8, 
Wk 24
V9, 
Wk 27
R = Randomization, DB = Double-blind, V = Visit, Wk = Week
At Visit 1, all potentially eligible patients will provide informed consent, undergo screening 
for HbA1c, eGFR level and other applicable inclusion/exclusion criteria. Visit 1, can be 
completed over multiple visits, provided all procedures have been completed, with the results 
reviewed, prior to Visit 2.  Patients at risk for volume depletion due to co-existing conditions 
or concomitant medications, such as loop diuretics should have careful monitoring of their 
volume status.  At Visit 2 (start of lead-in), patients will be examined for HbA1c, and eGFR 

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level, from blood sample obtained from Visit 1. If the HbA1c is M7.0% and S11% and the 
eGFR value is within the range of 40-65 mL/min/1.73 m2 (MDRD-formula), patients will 
enter a 4-week single-blind placebo lead-in period. Blood samples will be collected for 
standard lab values (and eGFR level).  At Visit 2 and Visit 3, eGFR will be measured.  At 
Visit 4, patients who meet all of the inclusion and none of the exclusion criteria, including the 
eGFR value within the range of 45-59mL/min/1.73 m2 at Visit 1, or Visit 2, or Visit 31, and 
the standard lab values (from Visit 2) will be randomized to the 24 weeks double-blind 
treatment period.  The dose of Oral Anti-diabetic Drugs (OADs), insulin, anti-hypertensive 
drugs, lipid lowering drugs and anti-platelet drugs should be kept constant throughout the 
entire 24-week treatment period.  At randomization, patients will be stratified according to 
pre-enrolment anti-hyperglycemic therapy.
After either completion of the treatment period or discontinuation from treatment, patients will 
enter a 3 weeks safety follow-up period without study drug.  At the follow-up visit (Visit 9 
(FU)) any changes in physical signs, renal function (i.e., changes in eGFR), symptoms or 
laboratory parameters that may be related to dapagliflozin will be evaluated.  The total 
planned study duration from Visit 1 to the safety follow-up (Visit 9) will be 33 weeks.
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To compare the mean change from baseline in 
HbA1c between dapagliflozin 10 mg and placebo, 
after 24 weeks of oral administration of double-
blind treatment in patients with type 2 diabetes 
and CKD stage 3A.
Change from baseline in HbA1c at Week 24
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :
To compare the percent change from baseline in 
total body weight between dapagliflozin 10 mg 
and placebo, after 24 weeks of oral administration 
of double-blind treatment.
Percent change from baseline in total body 
weight at Week 24 
                                                
1 Summary of the algorithm for inclusion based on HbA1c and eGFR:
Sample obtained at Visit 1:
HbA1c M7.0% and S11%
eGFR 40-65 mL/min/1.73 m2, MDRD-formula
Samples obtained at Visit 1, or Visit 2, or Visit 3:
eGFR 45-59 mL/min/1.73 m2, MDRD-formula

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To compare the change from baseline in FPG 
between dapagliflozin 10 mg and placebo, after 24 
weeks of oral administration of double-blind 
treatment.
Change from baseline in FPG at Week 24
To compare the change from baseline in seated 
SBP between dapagliflozin 10 mg and placebo, 
after 24 weeks of oral administration of double-
blind treatment.
Change from baseline in seated SBP at Week 
24
2.3
Safety objectives
Safety Objective:
Outcome Measure :
To examine eGFR changes during the study and 
3-week post-treatment for dapagliflozin 10 mg 
and placebo.
Change in eGFR from baseline to end of 
treatment and 3-week post-treatment 
To assess the proportion of patients discontinued 
from study medication because of worsening 
renal insufficiency (defined as patients reaching 
confirmed eGFR levels <30 mL/min/1.73 m2) 
between dapagliflozin 10 mg and placebo.
Proportion of patients discontinued from study 
medication due to worsening renal 
insufficiency (<30 mL/min/1.73 m2) at the end 
of treatment
To evaluate the safety and tolerability of 
dapagliflozin 10 mg once daily in type 2 diabetes 
and CKD stage 3A.
AEs /SAEs
Vital signs 
Physical examination
Clinical chemistry parameters
2.4
Exploratory objectives  
Exploratory objectives are to determine whether treatment with dapagliflozin compared with 
placebo when added to current background therapy in patients with T2DM and CKD3A will 
have effect on the following parameters.
Exploratory Objective:
Outcome Measure :
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CCI

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CCI

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3.
PATIENT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
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.
3.1
Inclusion criteria
Patients should meet all inclusion criteria at the time of randomization.  If at the time of 
enrolment (Visit 1) or start of lead-in (Visit 2) it is known that the patient will not meet 
criteria after a successful lead-in period, they should not be entered into single-blind placebo 
lead-in.
For inclusion in the study, patients should fulfil the following criteria:
1.
Provision of informed consent prior to any study specific procedures.
2.
Female or male aged M18 years and <75 years.
3.
History of T2DM for more than 12 months. 
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4.
Inadequate glycemic control, defined as HbA1c M7.0% and S11% measured at 
screening (value from blood sample obtained at Visit 1) for patient to be 
randomized. 
5.
Stable anti-diabetic treatment regimen, defined as stable diet and exercise therapy 
alone or in combination with any or both of the two following alternatives:
!
A regimen of any approved oral anti-diabetic medication (except SGLT2-
inhibitors) where no dose-changes have occurred during 12 weeks before 
randomization.
!
Long acting or intermediate acting insulin and mixed insulin permitted as long 
as the dose is stable during last 12 weeks before randomization, changes ± 10% 
are allowed (in relation to number of units at randomization).  For example, if 
the patient is taking 50 units/day of insulin at randomization, the total daily 
doses in the past 12 weeks should not have exceeded 55 units, or been less than 
45 units.  However, occasional exceptions (S one day/week) during this time 
period are permitted.
6.
Renal impairment: CKD 3A 
!
eGFR* 40 – 65 mL/minute/1.73 m2 at Visit 2 (value from blood sample 
obtained at Visit 1) to enter the lead-in period.
!
eGFR* 45 – 59 mL/minute/1.73 m2 at Visit 1, or Visit 2, or Visit 3 for 
randomization.
*according to the re-expressed abbreviated (four-variable) MDRD Study equation, using central laboratory 
measurements of serum creatinine (sCr). [eGFR (mL/min/1.73m2) = 175 x (standardized sCr)-1.154 x (Age)-0.203 x (0.742 
if female) x (1.212 if Black)] [Note: sCr reported in mg/dL]
7.
Body mass index (BMI) between 18 and 45 kg/m2, inclusive at Visit 1.
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
Sex and Reproductive Status
1.
Women of childbearing potential (WOCBP) who are unwilling or unable to use an 
acceptable method to avoid pregnancy for the entire study period.
2.
Women who are pregnant or breastfeeding.
3.
Women with a positive pregnancy test on enrolment or prior to study drug 
administration.

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Central Laboratory Test Findings (from blood samples obtained at Visit 2)
4.
Aspartate Aminotransferase (AST) >3X ULN.
5.
Alanine Aminotransferase (ALT) >3X ULN.
6.
Total Bilirubin (TB) >2 mg/dL (35 ]mol/L).
7.
Serum Potassium (K) >5.5 meq/L (5.5 mmol/L).
8.
Serum Calcium (Ca) <8 mg/dL or > ULN (<1.99 mmol/L or > ULN).
9.
Positive for hepatitis B surface antigen.
10.
Positive for anti-hepatitis C virus antibody.
11.
Hemoglobin S9.0 g/dL (90 g/L).
Target Disease Exceptions
12.
History of diabetes insipidus.
13.
Symptoms of poorly controlled diabetes that would preclude participation in this 
study including but not limited to marked polyuria and polydipsia with greater than 
10% weight loss during the three months prior to signing the consent at visit 1, or 
other signs and symptoms.
14.
History of diabetic ketoacidosis or hyperosmolar nonketotic coma.
15.
History of M2 major hypoglycemic events in the 3 months prior to enrolment, 
defined as symptomatic events requiring external assistance due to severe 
impairment in consciousness or behaviour, with blood glucose level <3.0 mmol/L, 
<54 mg/dL (plasma glucose level <3.5 mmol/L, <63 mg/dL) and prompt recovery 
after glucose or glucagon administration.
Medical History and Concurrent Diseases
CV/Vascular diseases:
16.
Severe uncontrolled hypertension defined as SBP M180 mmHg and/or DBP M110 
mmHg at any visit up to randomization.
Any of the following CV/Vascular Diseases within 3 months of prior to signing the 
consent at visit 1:
17.
Myocardial infarction.
18.
Cardiac surgery or revascularization (CABG/PTCA).

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19.
Unstable angina.
20.
Unstable heart failure (HF).
21.
HF New York Heart Association (NYHA) Class IV.
22.
Transient ischemic attack (TIA) or significant cerebrovascular disease.
23.
Unstable or previously undiagnosed arrhythmia.
Renal Diseases:
24.
Rapid worsening of renal function from Visit 1 to Visit 3 defined as >25% decrease 
in eGFR* from Visit 1 to Visit 3.
*according to the re-expressed abbreviated (four-variable) MDRD Study equation, using central laboratory measurements of 
serum creatinine (sCr). [eGFR (mL/min/1.73m2) = 175 x (standardized sCr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if 
Black)] [Note: sCr reported in mg/dL]
25.
History of any biopsy or imaging verifying intercurrent kidney disease (such as 
glomerular nephritis or sign of renal artery stenosis) other than diabetic nephropathy 
or diabetic nephropathy with nephrosclerosis.
26.
History of renal transplant.
27.
Hemodialysis, ultrafiltration therapy, or peritoneal dialysis within 6 months prior to 
signing the consent at visit 1.
Hepatic Diseases:
28.
Significant hepatic disease, including, but not limited to, chronic active hepatitis 
and/or severe hepatic insufficiency.
29.
Documented history of hepatotoxicity with any medication.
30.
Documented history of severe hepatobiliary disease.
Hematological and Oncological Diseases/Conditions:
31.
History of hemoglobinopathy, or chronic or recurrent hemolysis.
32.
Donation of blood or blood products to a blood bank, blood transfusion, or 
participation in a clinical study requiring withdrawal of > 400 mL of blood during 
the 6 weeks prior to signing the consent at visit 1.
33.
Malignancy within 5 years of the enrolment visit (with the exception of treated 
basal cell or treated squamous cell carcinoma).

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34.
Known immunocompromised status, including but not limited to, individuals who 
have undergone organ transplantation or who are positive for the human 
immunodeficiency virus (HIV).
35.
History of unexplained microscopic or gross hematuria, or microscopic hematuria at 
visit 2.  
Allergies and Adverse Drug Reactions:
36.
Known allergies or contraindication to the contents of dapagliflozin or placebo 
tablets. The tablets contain lactose and may cause discomfort in some individuals.
Prohibited Treatments and/or Therapies:
37.
Long term treatment with glucocorticoids (two temporary periods of no longer than 
10 days each are allowed during the study); topical or inhaled corticosteroids are 
allowed.   
38.
A metformin dose which is outside the specified dose range for moderate renal 
impairment (eGFR 30– 59 mL/minute/1.73m2, MDRD formula) according to local 
guidelines or investigator’s judgement.
39.
Ongoing treatment with any SGLT2-inhibitor, GLP-1 analogue, or rapid/short 
acting insulins at screening.
40.
History of bariatric surgery or lap-band procedure.
41.
Administration of sibutramine, phentermine, orlistat, rimonabant, benzphetamine, 
diethylpropion, methamphetamine, liraglutide indicated for anti-obesity treatment, 
and/or phendimetrazine, within 30 days prior to signing the consent at visit 1.
Other Exclusion Criteria:
42.
Any unstable endocrine, psychiatric, or rheumatic disorders as judged by the 
Investigator.
43.
Patient is, in the judgment of the Investigator, unlikely to comply with the protocol 
or has any severe concurrent medical or psychological condition that may affect the 
interpretation of efficacy or safety data.
44.
Patient who, in the judgment of the Investigator, may be at risk for dehydration or 
volume depletion due to co-existing conditions.
45.
Patient with any condition which, in the judgment of the Investigator, may render 
the patient unable to complete the study or which may pose a significant risk to the 
patient.

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46.
Patient is currently abusing alcohol or other drugs or has done so within the last 6 
months prior to signing the consent at visit 1.
47.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
48.
Previous randomization in the present study.
Note: Re-enrolment of a patient who has not previously been randomized to double-
blind treatment in the study is allowed one single time only.
49.
Participation in another clinical study with an IP during the last 30 days prior to 
signing the consent at visit 1.
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study patients and to ensure that the results of the study can be used. It is imperative that 
patients fully meet all eligibility criteria.
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomization
Investigator(s) should keep a record, the patient screening log, of patient who entered pre-
study screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed.  Patient is considered enrolled in the study after she/he 
has signed the informed consent form (ICF).
3.
Determine patient eligibility. See Section 3.1 and 3.2
4.
Assign eligible patient unique randomization code, by accessing IVRS or IWRS, 
see Section 3.5.  Patient is considered randomized in the study after this assignment.
Patients entering the single-blind placebo lead-in period
At the time of entry into the single-blind placebo lead-in period, the site will contact the 
IVRS/IWRS in order that lead-in medication can be assigned and dispensed.
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Patient who does not meet the eligibility criteria is considered as screen failure in the study.  
These patients will be terminated from the study and registered as Screen Failure by using 
IVRS/IWRS. See section 3.10.1.
Patients entering the double-blind treatment period
Following completion of the single-blind lead-in period, patients eligible for double-blind 
treatment will be randomly assigned to one of the two treatment arms by the IVRS/IWRS in a 
1:1 ratio (dapagliflozin 10 mg: matching placebo) using a randomization schedule.
If a patient discontinues/withdraws from the study, then his/her enrolment/randomization code 
cannot be reused.
3.4
Procedures for handling incorrectly enrolled or randomized 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study drug.  There can be no exceptions to this rule.  Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be randomized 
or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the following steps to be taken: 
(a)
The Investigator or monitor should inform the AstraZeneca study physician
immediately, ensuring patient safety must always be the number one priority.
(b)
Study Treatment must be discontinued in all cases where continued treatment is 
deemed to pose a safety risk to the patient.  A discussion should occur between the 
AstraZeneca study physician and the investigator, a decision may be reached 
whether to continue or discontinue the patient from study treatment.  The 
AstraZeneca study physician must ensure all decisions are appropriately 
documented.  
(c)
In those cases where continuation of study therapy is judged not to present a 
concern related to safety and disease management, the rationale for continuing 
study therapy must be clearly documented.  The patient should continue follow up 
in accordance with defined study procedures.
3.5
Methods for assigning treatment groups
Randomization codes will be generated to ensure approximate balance (1:1) between the two 
treatment arms (dapagliflozin 10 mg or matching placebo, once daily).
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Randomization will be done via IVRS/IWRS at Visit 4.  The IVRS/IWRS will allocate 
randomization codes sequentially through central randomization as patients become eligible 
for randomization. 
Randomization will be stratified by pre-enrolment anti-hyperglycemic therapy.  The following 
5 strata will be defined:
1.
Insulin-based regimen: Patients receiving insulin alone or in combination with any 
other anti-hyperglycemic medication
2.
Metformin-based regimen: Patients receiving metformin alone or in combination 
with any other anti-hyperglycemic medication except insulin
3.
SU-based regimen: Patients receiving a SU alone or in combination with any other 
anti-hyperglycemic medication except insulin and metformin
4.
TZD-based regimen: Patients receiving a TZD alone or in combination with any 
other anti-hyperglycemic medication except insulin, metformin, or a SU
5.
Other regimen: Patients receiving either any anti-hyperglycemic medication(s) not 
described by strata 1-4, or no background anti-hyperglycemic medication.
For each patient randomized the IVRS/IWRS will provide the investigator with a unique Kit 
ID number matching the treatment arm assigned to the patient.  Following randomization, the 
first dose of study drug will be administered to the patient after completion of study visit 
procedures.  At randomization and subsequent dispensing visit the patient should always be 
provided medication with the Kit ID(s) allocated by the IVRS/IWRS.  If a patient receives the 
incorrect randomized treatment at any time during the study, the centre must immediately 
notify the AstraZeneca representative and IVRS/IWRS contact and this must be corrected as 
soon as discovered after discussing with study physician.
3.6
Methods for ensuring blinding
The study has a single-blind placebo lead-in period of 4 weeks from Visit 2, where patients 
will be blinded to treatment. Other members at AstraZeneca, investigational centres or any 
Contract Research Organization (CRO) handling data will be aware of the placebo treatment 
during this period.
The study will be conducted in a double-blind fashion.  The dapagliflozin 10 mg tablet and its 
matching placebo will be identical in size, colour, smell, taste, packaging and labelling.
Until the completion of the 24-week randomized treatment period, no member of the study 
team at AstraZeneca, at the investigational centres or any CRO handling data will have access 
to the randomization scheme, with the exception of AstraZeneca personnel generating the 
randomization scheme as well as relevant persons at Pharmaceutical Development Supply 
Chain at AstraZeneca or their designee, where the information is needed to package study 
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carrying out the packaging and labelling of investigational products. Patients and investigators 
will remain blinded past the 24-week randomized treatment period.
The treatment codes and results will be kept strictly within AstraZeneca to safeguard the 
integrity of the blind of the investigators and patients, and hence to minimize any possible bias 
in data handling.
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomization for each randomized
patient, will be available to the Investigator(s) or pharmacists from the IVRS/IWRS. Routines 
for this will be described in the IVRS/IWRS user manual that will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomization.  The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities.  Treatment codes will not be broken for the planned analyses of data 
until all decisions on the evaluability of the data from each individual patient have been made 
and documented.
3.8
Restrictions
!
All patients will visit the clinic fasting in the morning (except for Visits 1 and 5),
between 6 a.m. to 10 a.m.
!
Patients will be instructed to abstain from all food and beverages for 8 hours prior 
to each clinic visit (except for Visits 1 and 5). Drinking water is allowed
!
Patients should not drink alcohol within 24 hours prior to each visit and should not 
use tobacco/nicotine within 12 hours prior to each visit
!
Patients should bring all their medications and IP to the site
!
Anti-hypertensive medication can be taken with a glass of water after completion of 
BP and body weight measurements
!
Medications including IP should be taken after visit samples and examinations have 
been performed.  Anti-hyperglycemic drugs should be taken in connection with a 
meal
!
Antiepileptic drugs and antibiotics shall be taken as required

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!
Women must immediately contact the Investigator if they suspect they might be 
pregnant and if they have changed or plan to change their birth control method.
If a patient arrives for a visit without having followed the above instructions, the entire visit 
should be rescheduled (within the allowed time-window, if possible).
As up to approximately 61 mL of blood will be drawn from each patient during the entire 
duration of the clinical study (excluding extra blood samples taken at unscheduled, specialized 
liver/liver discontinuation visits, serum pregnancy test), patients should be instructed to 
abstain from donating any blood during the clinical study and for 12 weeks following their last 
study visit.
Prohibited and restricted concomitant medications are listed in Section 7.7.
3.9
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 treatment, without 
prejudice to further treatment. Patients who choose to discontinue study treatment 
are expected to continue in the study until the end of the study
!
AEs, ie, any clinical AE, laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not 
in the best interest of the patient
!
Severe non-compliance with the study protocol as judged by the investigator and/or 
AstraZeneca
!
Pregnancy
!
Incorrectly enrolled patients (see Section 3.4)
!
Lost to FU, patient fails to return for study visits and cannot be reached with 
reasonable, repeated attempts.
!
Termination of the study by AstraZeneca.
!
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g., infectious
disease) illness.
3.9.1
Study specific discontinuation criteria 
!
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)

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
ALT and/or AST >5 times ULN confirmed at the central laboratory and sustained 
over a period of 14 days or more
(See Appendix C Algorithm on Management of Sustained Elevated Liver Safety 
Abnormalities for further details)
!
Protocol-defined recurrent major hypoglycemia episodes 
!
Acute renal insufficiency or worsened chronic renal insufficiency based on repeat 
eGFR values (eGFR<30 mL/minute/1.73m2). The re-test should be scheduled 
within 4 days, whenever possible.
Discontinuation guidelines for protocol-defined major hypoglycemia episodes  
Patients should not be discontinued from any treatment phase based on single episodes of 
hypoglycemia or symptoms of hypoglycemia unless clinically indicated.  The assessment of a 
single finger stick or laboratory glucose value should not be the sole assessment used to 
determine patient discontinuation for hypoglycemia.
Clinical indications for discontinuation because of hypoglycemia may include the following:
!
Multiple occasions of episodes outlined below that, in the opinion of the 
Investigator, indicate that continued treatment with study therapy is not in the best 
interest of the patient.  This includes, but is not limited to:

Symptoms suggestive of hypoglycemia (e.g., sweating, shakiness, 
increased heart rate, confusion, dizziness, light-headedness, or hunger) in 
the absence of environmental factors known to contribute to 
hypoglycemia (i.e., excess physical activity, concurrent illness, or missed 
or delayed meal) and/or

Documented finger stick glucose values <54 mg/dL (<3.0 mmol/L). 
!
A patient may also be discontinued from the study because of severe hypoglycemia, 
as determined by the Investigator.
Discontinuation Guidelines for Acute Renal Insufficiency or Worsened Chronic Renal 
Insufficiency
For patients with signs of deteriorating renal function, additional monitoring needs to be 
conducted.  Any patients with a calculated eGFR<30 mL/minute/1.73m2 will be scheduled for 
a re-test within 4 days whenever possible.  The eGFR is calculated based on the re-expressed 
abbreviated (four-variable) MDRD Study equation, using central laboratory measurements of 
sCr. [eGFR (mL/min/1.73m2) = 175 x (standardized sCr)-1.154 x (Age)-0.203 x (0.742 if female) 
x (1.212 if Black)] [Note: sCr reported in mg/dL]
If, at the re-test, the eGFR M30 mL/minute/1.73m2, the patient can resume normal visit 
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If, at the re-test, the eGFR <30 mL/minute/1.73m2, the patient should be discontinued from IP 
and the patient’s renal function should continue to be monitored according to the judgment of 
the Investigator.
3.9.2
Procedures for discontinuation of a patient from IP
A patient that decides to discontinue IP will always be asked about the reason(s) and the 
presence of any AEs.  Diaries and all study drugs should be returned by the patient.
All patients who discontinue study drug will be asked to remain in the study for FU and 
complete all scheduled study visits through Week 27.  At the time of discontinuation the 
Week 24 procedures will be performed.  Patients will not receive double-blind study drug 
during this follow-up period (and use of SGLT2-inhibitors should be restricted), but will 
complete all scheduled study visits and procedures.  Patients unable or unwilling to return for 
scheduled visits as part of follow-up will have the opportunity to receive follow-up via 
telephone calls placed by the site mainly to review safety and concomitant medications.  The 
only exception to this procedure is when a patient withdraws consent for all study procedures 
or loses the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness).
If a patient is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomized.  These patients should have the reason for study 
withdrawal recorded as ‘Eligibility criteria not fulfilled’ (i.e., patient does not meet the 
required inclusion/exclusion criteria).  This reason for study withdrawal is only valid for 
screen failures (not randomized patients).  Patients can be re-enrolled one single time, but they 
cannot be re-randomized.
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE the reason for withdrawal must be entered on the appropriate electronic case report 
form (eCRF) page.  If possible, they will be seen and assessed by an Investigator(s).  The 
Investigator will follow up AEs outside of the clinical study.  The patient will return diaries 
and all study drugs. 
If a patient withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused.  Withdrawn patients will not be replaced. 

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3.10.3
Lost to follow-up
Patient fails to return for study visits and cannot be reached with reasonable, repeated 
attempts.
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.  Every effort will be made to ensure that the patient continues to return 
to the clinic for study visits and to avoid “lost to follow-up” during the conduct of the study. 
The study staff should make diligent attempts to contact patients who fail to return for study 
visits by using institutional databases, patient’s health professionals, and any other means that 
comply with country and local laws and regulations.  After the first missed visit, patients who 
are considered temporarily lost to follow-up will have 2 documented telephone contact 
attempts and 1 certified letter in an effort to contact patients
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings that:
!
meet individual stopping criteria or are otherwise considered significant 
!
are assessed as causally related to study drug 
!
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation must be recorded in the eCRF.  All reasons for discontinuation of treatment 
must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests. 

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4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 1
Study Plan detailing the procedures 
Study Period
Screening 
period
Lead-in period
Treatment period
Follow-
up period
For details 
see 
Protocol 
Section
Visit
Enrolment
Start of 
lead-in
Lead-in
Random-
ization
Treat-
ment
Treat-
ment
Treat-
ment
End of 
Treatment/ 
Discontinuat-
ion/Rescue
Follow-
up
Visit Number
(Fasting/Non-fasting)
1a
Non-fasting
2b
Fasting
3c
Fasting
4c,d
Fasting
5 c,d,e
Non-
fasting
6 c,d,e
Fasting
7 c,d,e
Fasting
8 c,d,e
Fasting
9
Fasting
Week
-6
-4
-1
0
1
4
12
24
27
Day
-42 to -29
-28
-7
1
8
29
85
169
190
Visit Window
± 3
± 3
± 0
± 5
± 5
± 5
± 5
± 5
Signed and Dated Informed 
consentf
X
10.4
Inclusion/Exclusion Criteria
X
X
Xg,h
3.1 and 3.2
Allocation of E-code via 
IVRS/IWRS
X
3.3
Randomization to study treatment 
via IVRS/IWRS
X
3.3 and 3.5
Demographics
X
4.1
Medical and Surgical History
X
4.1
Brief Physical Examinationi
X
X
X
X
X
5.2.2
Complete Physical Examinationj
X
X
5.2.2
Height
X
5.1.3
Weight
X
X
X
X
X
X
X
X
X
5.1.3

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Study Period
Screening 
period
Lead-in period
Treatment period
Follow-
up period
For details 
see 
Protocol 
Section
Visit
Enrolment
Start of 
lead-in
Lead-in
Random-
ization
Treat-
ment
Treat-
ment
Treat-
ment
End of 
Treatment/ 
Discontinuat-
ion/Rescue
Follow-
up
Visit Number
(Fasting/Non-fasting)
1a
Non-fasting
2b
Fasting
3c
Fasting
4c,d
Fasting
5 c,d,e
Non-
fasting
6 c,d,e
Fasting
7 c,d,e
Fasting
8 c,d,e
Fasting
9
Fasting
Week
-6
-4
-1
0
1
4
12
24
27
Day
-42 to -29
-28
-7
1
8
29
85
169
190
Visit Window
± 3
± 3
± 0
± 5
± 5
± 5
± 5
± 5
X
X
X
X
X
5.1.6
Seated BP and Pulse
X
X
X
X
X
X
X
X
X
5.1.5.1
Orthostatic BP and Pulse
X
X
X
X
X
X
5.2.4.1
12-lead ECGk
X
5.2.3
Hepatitis Screen Panel
X
5.2.1
Blood samples for Safety 
Laboratory Panell
X
X
X
X
X
X
5.2.1
Blood samples for HbA1c
X
X
X
X
X
X
5.1.1
Blood samples for S-Creatinine 
(eGFR calculation)
X
X
X
X
X
X
X
X
5.1.9
Blood samples for FPG
X
X
X
X
X
5.1.2
Assess FPG for Rescue
X
X
4.3.3.1
 
X
X
X
X
5.1.10
 
X
X
X
5.2.1
Pregnancy testm
X
X
X
X
X
X
X
X
X
5.2.1
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Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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Study Period
Screening 
period
Lead-in period
Treatment period
Follow-
up period
For details 
see 
Protocol 
Section
Visit
Enrolment
Start of 
lead-in
Lead-in
Random-
ization
Treat-
ment
Treat-
ment
Treat-
ment
End of 
Treatment/ 
Discontinuat-
ion/Rescue
Follow-
up
Visit Number
(Fasting/Non-fasting)
1a
Non-fasting
2b
Fasting
3c
Fasting
4c,d
Fasting
5 c,d,e
Non-
fasting
6 c,d,e
Fasting
7 c,d,e
Fasting
8 c,d,e
Fasting
9
Fasting
Week
-6
-4
-1
0
1
4
12
24
27
Day
-42 to -29
-28
-7
1
8
29
85
169
190
Visit Window
± 3
± 3
± 0
± 5
± 5
± 5
± 5
± 5
Urinalysis (dipstick and spot urine 
collection)
X
X
X
X
X
X
5.2.1
Timed urine sample collection (24-
hours)
X
X
5.1.7
Dietary and life-style advice
X
X
X
X
X
4.2.1
Dispense Glucose Meter and/or 
Supplies (including diaries) 
/Provide Instructions
X
X
X
X
X
X
X
5.1.8 and 
5.2.5.1
Review of diaries
X
X
X
X
X
X
X
5.1.8 and 
5.2.5.1
Dispensation of Study Medication 
via IVRS/IWRS
X
X
X
X
7
Return of Study Medication and 
accountability
X
X
X
X
7.5 and 7.6
Adverse event review (AEs and 
SAEs)n
X
X
X
X
X
X
X
X
X
6
Hypoglycemic events review 
X
X
X
X
X
X
X
X
5.2.5.1 and 
6.3.7
Concomitant medication
X
X
X
X
X
X
X
X
X
7.7

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
50 (101)
a
Screening procedures, indicated under Visit 1, can be completed over multiple visits, provided all procedures have been completed, with the results 
reviewed, prior to Visit 2. 
b
Patients must have their Visit 2 completed within 14 days following Visit 1. Visit window of ±3 for Visit 2 corresponds to the randomization visit (Visit 
4). Note: The single-blind lead-in study medication and the central laboratory results from Visit 1 must have been received at the site prior to completing 
the entry into Visit 2.
c
Central Laboratory samples must be collected in a fasting state (at least 8 hours of fasting prior to the study visit) except visit 5, and patients should be 
seen between 6 a.m. and 10 a.m.  Patients must refrain from tobacco/nicotine for 12 hours and alcohol for 24 hours, respectively prior to study visits. 
Ensure to collect all fasting blood samples prior to the morning dose(s) of blinded study medication. Doses of study medication and other concomitant 
medications on the day of the visits must be taken upon completion of study visit procedures. (See Section 3.8)
d
Double-blind treatment period visits must be scheduled according to the randomization visit date (Day 1), with a protocol-allowed visit window of ±5 
days. Patients will bring their glucose meter and study supplies to the site at all visits. Any slippage in time from one visit must not accumulate to affect 
other visits.
e
Randomized patients discontinuing study medication or requiring rescue should have Week 24 procedures done at the time of anti-diabetic  rescue or 
study medication discontinuation.  All patients who discontinue study medication will be asked to continue ordinary visit schedule, unless they entirely 
withdraw consent from the study.  In patients discontinuing the study due to AE/SAE, the Investigator will follow the patients until the event has 
resolved or stabilized.
f
The signature of the ICF by the prospective patient should be obtained at Visit 1.  When only the Informed Consent is signed, and all other screening 
visit procedures are completed. 
g
eGFR value for inclusion is based on eGFR value between 45 – 59 mL/minute/1.73 m2 at Visit 1, or Visit 2, or Visit 3.
h
Lab values for inclusion will be based on results from Visit 2 and Visit 3. Lab values from Visit 4 will be used as baseline values for study entry.
i
A brief physical examination should include cardiovascular (CV), lungs, abdomen, and extremities; and any organ systems pertinent to the patient’s 
signs, symptoms, or AEs.
j
A complete physical examination should include general appearance, head, eyes, ears, nose, throat, neck, CV, lungs, abdomen, lymph nodes, extremities, 
neurological, skin, and musculoskeletal.
k
The 12-lead ECG must be performed at Visit 2. The results from this ECG must be available, assessed, and initialed and dated by the Investigator prior 
to Visit 4.
l
Includes Hematology and Clinical chemistry.  Please refer to Table 3
m
Only for WOCBP. Blood sample will be collected for serum WHCG test, only if urine test is positive.
n
SAEs will be collected from the time of informed consent and AEs will be collected from the start of the placebo lead-in (Visit 2).

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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4.1
Enrolment/screening period (Visit 1 to Visit 2)
Procedures will be performed according to the Study Plan Table 1. 
At enrolment, obtain written informed consent prior to any study procedure or change in 
medical therapy required by the protocol.  Consenting patients are assessed to ensure that they 
meet eligibility criteria.  Patients who do not meet these criteria must not be enrolled in the 
study.
The below assessments to be performed for all consented patients at Visit 1:
!
Contact IVRS/IWRS to obtain unique patient enrolment number
!
Review and confirm the patient’s eligibility for the study by assessing inclusion and 
exclusion criteria listed in Sections 3.1 and 3.2.
!
A standard patient medical, medication and surgical history will be obtained with 
the review of selection criteria
!
Record demography (including sex, age, race and ethnic group)
!
Perform brief physical examination
!
Obtain vital signs (seated BP and pulse), body weight and height
!
Obtain specimen (blood) for HbA1c
!
Obtain specimens (blood) for S-Creatinine for eGFR calculation
!
Perform urine pregnancy test for women of child bearing potential.  Serum 
pregnancy test (WhCG) is performed, if urine pregnancy test result is positive
!
Review concomitant medications 
!
Schedule the entry into lead-in visit between 06.00 a.m. and 10.00 a.m.
!
Remind patient to be fasting and withhold anti-diabetic medications, insulin, anti-
hypertensive drugs, lipid lowering drugs and anti-platelet drugs, the morning of 
their next visit and to refrain from tobacco/nicotine for 12 hours and alcohol for 24 
hours, respectively prior to next visit
4.2
Single-blind placebo lead-in period (Visit 2 to Visit 4)
4.2.1
Visit 2, Start of lead-in
At visit 2 patients will be examined for HbA1c and eGFR level from blood sample obtained 
from Visit 1.  If the HbA1c M7.0 and S11.0% and the eGFR value is within the range 40-65 
mL/min/1.73 m2 (MDRD-formula), then patients will enter a 4-week single-blind placebo 

Clinical Study Protocol
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Study Code D1690C00024
Version 4.0
Date 17 January 2017
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lead-in period.  At the lead-in visit, the patient’s current dietary and life-style will be 
reviewed.  Patients will be instructed on diet and life-style in accordance with the local 
Diabetes guidelines or ADA guidelines by a qualified member of the study staff beginning 
with the lead-in visit.  The below procedures will be performed during the visit for the eligible 
patients:
!
Review and confirm the patient’s eligibility for the study by assessing inclusion and 
exclusion criteria listed in Sections 3.1 and 3.2.
!
Perform complete physical examination and body weight
!
Obtain vital signs (seated BP and pulse)
!
Perform 12-lead ECG. ECG must be obtained and reviewed with no significant
abnormalities prior to Randomization
!
Obtain specimens (blood) for hepatitis screen panel, safety laboratory panel 
including S-Creatinine for eGFR calculation,
!
Perform urine pregnancy test for women of child bearing potential.  Serum 
pregnancy test (WhCG) is performed, if urine pregnancy test result is positive
!
Obtain specimen for urinalysis (dip stick and spot urine collection)
!
Contact IVRS/IWRS to register visit and obtain study drug dispensing bottle 
assignment number and dispense study drug bottle
!
Have patient to take their first dose of lead-in period study drug
!
Provide instruction on diet and life-style
!
Dispense blood glucose meter and supplies, provide instruction on their use and 
self-monitoring of blood glucose (see Section 5.2.5.1)
!
Provide instruction on recording daily insulin doses and glucose values (when 
symptoms suggestive of hypoglycaemia) in the patient diary
!
Remind patient to be fasting and withhold study drug and other anti-diabetic 
medications, insulin, anti-hypertensive drugs, lipid lowering drugs and anti-platelet 
drugs, the morning of their next visit and to refrain from tobacco/nicotine for 12 
hours and alcohol for 24 hours, respectively prior to next visit
!
Remind patient to bring study drug, diary and glucose meter to the next scheduled 
visit
!
Review concomitant medications and SAEs from Visit 1.
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Clinical Study Protocol
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Study Code D1690C00024
Version 4.0
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4.2.2
Visit 3, Lead-in
!
Obtain vital signs (seated BP and pulse) and body weight
!
Obtain specimens (blood) for S-Creatinine for eGFR calculation
!
Perform urine pregnancy test for women of child bearing potential.  Serum 
pregnancy test (WhCG) is performed, if urine pregnancy test result is positive
!
Dispense blood glucose meter supplies and diary (if required)
!
Review diary and calculate mean total daily dose of insulin (see Section 5.1.8)
!
Review concomitant medications
!
Assess AEs including hypoglycemic events (see Section 6.3.7)
!
Remind patient to be fasting and withhold study drug and other anti-diabetic 
medications, insulin, anti-hypertensive drugs, lipid lowering drugs and anti-platelet 
drugs, the morning of their next visit and to refrain from tobacco/nicotine for 12 
hours and alcohol for 24 hours, respectively prior to next visit
4.3
Treatment period
Descriptions of the procedures for this period are included in the Study Plan Table 1.  The 
specific requirements for the treatment period are mentioned below: 
4.3.1
Visit 4, Randomization
At Visit 4, patients who meet all of the inclusion and none of the exclusion criteria, including 
the eGFR value between 45-59 mL/min/1.73 m2 at Visit 1, or Visit 2, or Visit 3 - will be 
randomized to the 24 weeks double-blind treatment period.
!
Perform brief physical examination
!
Measure body weight and
!
Obtain vital signs (seated and orthostatic BP and pulse)
!
Obtain specimen (blood) for safety laboratory panel including S-Creatinine for 
eGFR calculation
!
Perform urine pregnancy test for women of child bearing potential. Serum 
pregnancy test (WhCG) is performed, if urine pregnancy test result is positive
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Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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!
Obtain specimen for urinalysis (dip stick and spot urine collection)
!
Timed urine sample collection (24-hours) (see Section 5.1)
!
Contact IVRS/IWRS to randomize patient and obtain study drug dispensing bottle 
assignment number and dispense the study drug bottle
!
Patient will be administered his/her first dose of the double-blind treatment at site
!
Provide dietary and life-style advice
!
Dispense glucose meter supplies and diary (if required)
!
Review diary and calculate mean total daily dose of insulin for baseline (see Section
5.1.8)
!
Collect and assess compliance with lead-in period study drug based on tablet count 
(see Section 7.5)
!
Review concomitant medications and AEs including hypoglycemic events
!
Remind patient to withhold study drug and other anti-diabetic medications, insulin, 
anti-hypertensive drugs, lipid lowering drugs and anti-platelet drugs, the morning of 
their next visit and to refrain from tobacco/nicotine for 12 hours and alcohol for 24 
hours, respectively prior to next visit
4.3.2
Visit 5, Treatment
!
Measure body weight 
!
Obtain vital signs (seated and orthostatic BP and pulse)
!
Perform urine pregnancy test for women of child bearing potential.  Serum 
pregnancy test (WhCG) is performed, if urine pregnancy test result is positive
!
Dispense glucose meter supplies and diary (if required)
!
Review diary and calculate mean total daily dose of insulin (see Section 5.1.8)
!
Review concomitant medications and AEs including hypoglycemic events
!
Remind patient to be fasting and withhold study drug and other anti-diabetic 
medications, insulin, anti-hypertensive drugs, lipid lowering drugs and anti-platelet 
drugs, the morning of their next visit and to refrain from tobacco/nicotine for 12 
hours and alcohol for 24 hours, respectively prior to next visit
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Clinical Study Protocol
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Study Code D1690C00024
Version 4.0
Date 17 January 2017
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4.3.3
Visit 6, Treatment
!
Perform brief physical examination
!
Measure body weight and
!
Obtain vital signs (seated and orthostatic BP and pulse)
!
Obtain specimens (blood) for safety laboratory panel including S-Creatinine for 
eGFR calculation
!
Obtain specimen (blood) for HbA1c and FPG
!
Assess FPG for rescue (see Section 4.3.3.1 for details)
!
Perform urine pregnancy test for women of child bearing potential. Serum 
pregnancy test (WhCG) is performed, if urine pregnancy test result is positive
!
Obtain specimen for urinalysis (dip stick and spot urine collection)
!
Contact IVRS/IWRS and obtain study drug dispensing bottles assignment number
and dispense the study drug bottles
!
Collect and assess compliance with study drug based on tablet count (see Section
7.5)
!
Provide dietary and life-style advice
!
Dispense glucose meter supplies and diary (if required)
!
Review diary and calculate mean total daily dose of insulin (see Section 5.1.8)
!
Review concomitant medications and AEs including hypoglycemic events
!
Remind patient to be fasting and withhold study drug and other anti-diabetic 
medications, insulin, anti-hypertensive drugs, lipid lowering drugs and anti-platelet 
drugs, the morning of their next visit and to refrain from tobacco/nicotine for 12 
hours and alcohol for 24 hours, respectively prior to next visit
4.3.3.1
Rescue Medication Due to Lack of Glycemic Control in the Treatment Period
Patients with lack of glycemic control during the 24-week treatment period may be eligible to 
receive open-label rescue medication in addition to their blinded treatment in order to treat 
ongoing hyperglycemia. Patients may receive open-label rescue medication added on to, but 
not as a replacement for, their current study drug regimen. Rescue medication in this protocol 
refers to any approved, appropriate anti-diabetic agent, except SGLT2-inhibitors, for which 
there is either initiation or upward titration, in accordance with the approved label and 
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Clinical Study Protocol
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Study Code D1690C00024
Version 4.0
Date 17 January 2017
56 (101)
conventional standards of care. Open-label rescue medication is to be titrated as needed to 
obtain adequate glycemic control. Patients who received a first rescue medication, who 
subsequently fulfil lack of glycemic control criteria, may have other rescue medications added 
or substituted, according to Investigator judgment.
During the 24-week double-blind treatment period, all rescue decisions will be based on 
central laboratory FPG and confirmatory FPG results.  If patients meet the protocol-specified 
glycemic criteria based on FPG, they will be recommended for open-label rescue medication.
Between scheduled visits, the patients will be asked to check their blood glucose if they 
develop symptoms suggestive of hyperglycemia.  The sections and tables listed below define 
the lack of glycemic control criteria.  Glucometers will be provided by AstraZeneca.  The 
patients will receive instructions for the use of the glucometer according to the manufacturer’s 
instructions.  Patients will be instructed to contact the investigator if they experience a 
hyperglycemic event in order to schedule an extra visit for central laboratory FPG and if 
needed, a confirmatory, repeat FPG.
Patients in the follow-up phase will not need to adhere to the protocol defined rescue criteria, 
and may have their anti-diabetic regimen adjusted at the Investigator’s discretion.
The sections and tables listed below define the lack of glycemic control criteria for initiation 
of open-label rescue medication.
Protocol-Defined Lack of Glycemic Control Criteria for Initiation of Open-Label Rescue 
Medication
Pre-specified glycemic criteria (see Table 2 below), based upon central laboratory FPG and 
confirmatory, repeat FPG, have been established during the 24-week double-blind treatment 
period, from Week 4 and up to Week 24 visits, to determine eligibility for open-label rescue 
medication initiation/titration.
Table 2
Lack of Glycemic Control Criteria for Initiation of Open-Label Rescue 
Medication
Visit Label
Central Laboratory FPG
From Week 4 (Visit 6) to Week 12 (Visit 7) 
(excluding Week 12)
FPG >240 mg/dL (13.3 mmol/L)
From Week 12 (Visit 7) to Week 24 (Visit 8) 
(excluding Week 24)
FPG >200 mg/dL (11.1 mmol/L)
Patients with a central laboratory FPG value meeting the lack of glycemic control criterion at 
a pre-specified visit will be scheduled for a follow-up visit (within 3 - 5 days) to obtain a 
second central laboratory FPG value and review the patient’s glucose meter readings.  If the 
repeat central laboratory FPG value still meets the criterion, the patient will receive rescue 
medication.

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
57 (101)
Irrespective of study visit number, patients who meet rescue criteria in the treatment period 
must first complete the Week 24 visit procedures before receipt of open-label anti-diabetic 
rescue medication to ensure that important study endpoint measurements are collected.
Following completion of the Week 24 “Rescue” visit, rescued patients will be administered 
open-label rescue medication in addition to their blinded study drug.  Rescued patients will 
then continue in the treatment period according to their original visit schedule.  Patients who 
received a first open-label anti-diabetic rescue medication, who subsequently fulfill lack of 
glycemic control criteria described in the Table 2 above, may have other rescue medications 
added or substituted, according to Investigator judgment, without repetition of rescue visits.
Patients with a central laboratory FPG value >200 mg/dL (11.1 mmol/L) at Week 24 (Visit 8), 
will not be considered as rescued for efficacy analysis.
Guidelines with regard to changes in insulin dose
Each patient’s baseline insulin therapy should remain unchanged wherever possible 
throughout the double-blind treatment period.  The stable insulin regimen aims to continue 
insulin as it was being used by the patient at enrollment and lead-in, with no changes to 
insulin type and with as few changes in insulin dosage as possible.  A stable insulin regimen is 
pivotal, because it makes it possible for the study to measure any differences in glycemic 
control between the dapagliflozin treatment arm and the matching placebo arm.  Down-
titration of insulin will be allowed only as necessary to prevent low blood glucose or 
hypoglycemia. During the double-blind treatment period, a few patients will experience poor 
glycemic control, as measured by increased FPG measurements from the central laboratory 
during study visits. When glucose measurements exceed certain limits (as specified in Table 2
above), the patient will be ‘‘rescued’’. 
During the double-blind treatment period, if up-titration of insulin dose is >10% (lasting more 
than 7 consecutive days) in comparison to the mean daily insulin dose at baseline, the patient 
shall be handled as administration of anti-diabetic rescue medication (i.e., the patient must 
complete the Week 24 visit procedures, as outlined in section 4.3.5) and the patient will 
continue in the treatment period according to their original visit schedule.  Patients must 
record the daily dose of insulin in the diary provided (minimum of 80% of days with a value) 
and review any changes in insulin doses with their investigator, either at regularly scheduled 
visits, or via telephone calls between visits.  Patients required to be rescued, shall be called for 
an unscheduled visit within 5 days, to complete the Week 24 procedures.
Any insulin dose changes (even if more than ±10% of the mean daily insulin dose at baseline) 
is not considered as an up or down titration as long the insulin dose change is not for a period 
of more than 7 consecutive days.  For example, dose changes due to known changes in 
physical activity or food intake will not be registered as up or down titration as long as the 
insulin dose is back to the previous dose after the change.  Similarly, if insulin requirement 
has increased temporarily, e.g., due to an infection, it will not be considered an up-titration 
even if the insulin dose increase is more than 10% of the baseline mean daily insulin dose, as 

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
58 (101)
long as such an increase is for a period of not more than 7 consecutive days and the insulin 
dose is expected to return to the baseline level once the precipitating condition has resolved. 
4.3.4
Visit 7, Treatment
Perform the same assessments as detailed in visit 6 (see Section 4.3.3). 
4.3.5
Visit 8, End of Treatment/Discontinuation/Rescue
Randomized patients discontinuing study drug or requiring rescue should have Visit 8 (Week 
24) procedures done at the time of rescue or study drug discontinuation.  All patients who 
discontinue study drug will be asked to continue ordinary visit schedule, unless they entirely 
withdraw consent from the study.
!
Perform complete physical examination
!
Measure body weight 
!
Obtain vital signs (seated and orthostatic BP and pulse)
!
Obtain specimen (blood) for safety laboratory panel including S-Creatinine for 
eGFR calculation
!
Perform urine pregnancy test for women of child bearing potential. Serum 
pregnancy test (WhCG) is performed, if urine pregnancy test result is positive
!
Obtain specimen for urinalysis (dip stick and spot urine collection)
!
Timed urine sample collection (24-hours) (see Section 5.1)
!
Collect and assess compliance with study drug based on tablet count
!
Provide dietary and life-style advice
!
Dispense glucose meter supplies and diary (if required)
!
Review diary and calculate mean total daily dose of insulin
!
Review concomitant medications and AEs including hypoglycemic events
!
Remind patient to be fasting and withhold anti-diabetic medications, insulin, anti-
hypertensive drugs, lipid lowering drugs and anti-platelet drugs, the morning of 
their next visit and to refrain from tobacco/nicotine for 12 hours and alcohol for 24 
hours, respectively prior to next visit
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Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
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4.4
Follow-up period, Visit 9
Descriptions of the procedures for this period are included in the Study Plan Table 1.  The 
specific requirements for the follow up period are mentioned below: 
After completion of Week 24 visit, patients will enter a 3-week safety follow-up period 
without study drug.  The follow-up visit (Visit 9) provides the opportunity to further evaluate 
changes in physical signs, renal function (i.e., changes in eGFR), symptoms or laboratory 
parameters that may be related to dapagliflozin.
!
Perform brief physical examination
!
Measure body weight 
!
Obtain vital signs (seated and orthostatic BP and pulse)
!
Obtain specimen (blood) for safety laboratory panel including S-Creatinine for 
eGFR calculation
!
Perform urine pregnancy test for women of child bearing potential.  Serum 
pregnancy test (WhCG) is performed, if urine pregnancy test result is positive
!
Obtain specimen for urinalysis (dip stick and spot urine collection)
!
Review diary and calculate mean total daily dose of insulin
!
Review concomitant medications and AEs including hypoglycemic events
5.
STUDY ASSESSMENTS  
The Rave® Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.
The investigator will ensure that data on the observations, tests, and assessments specified in 
the protocol are recorded on the eCRF provided by AstraZeneca as specified in the study 
protocol and in accordance with the instructions provided.  The CRF will be accompanied 
with “Instructions for the investigator”, which should be followed.  These instructions provide 
guidance for the recording of study data in the CRF including how to change data incorrectly 
recorded.
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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Study Code D1690C00024
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Date 17 January 2017
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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.
5.1
Efficacy assessments
Blood and urine samples will be obtained at specified time points for laboratory evaluations.  
The central laboratory for this study will perform the analysis of all scheduled laboratory tests 
and will provide reference ranges for these tests.  The detailed methods for specimen 
collection, handling, processing, shipping, and storage will be supplied in the Investigator’s 
Laboratory Manual provided by the Central Laboratory.  All clinical laboratory tests will be 
performed by the Central Laboratory or designated reference laboratory.
During the double-blind treatment period, HbA1c and urinary glucose values will be blinded 
to the Investigator and to the Sponsor.  These values will be provided to the Investigator after 
the study has been completed.  FPG value will be reported as an un-blinded value throughout 
the study.
All glycemic efficacy objectives will be based on values measured by central laboratory.  Any 
self-monitored blood glucose measured by the patient and FPG measured by the site using 
glucometer will be used only for safety purposes. [Note: The patients will be asked to check 
their blood glucose only if they develop symptoms suggestive of hypoglycemia or 
hyperglycemia and to record hypoglycemia symptoms in the patient diary.]
5.1.1
HbA1c
HbA1c is the primary assessment for the determination of glycemic efficacy and will be 
analysed by a central laboratory according to the procedures described in the Laboratory 
Manual which will be distributed to each study site during site initiation. 
5.1.2
FPG
FPG is a well established measure of glycemic efficacy and considered to be an acceptable 
secondary endpoint.  FPG will be analysed by a central laboratory according to the procedures 
described in the Laboratory Manual which will be distributed to each study site during site 
initiation.
5.1.3
Weight and height 
The patient’s weight will be recorded in kilogram (kg) to one decimal place, with light 
clothing and no shoes.  All readings should be recorded as accurately as possible and the same 
scale should be used for all assessments for a given patient.  The patient’s height will be 
recorded in centimetres, with no shoes.
5.1.4
BMI 
BMI is a calculated ratio between weight and height (weight / height2, where weight is 
measured in kg, and height in metres) and will be computed by AstraZeneca.

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Study Code D1690C00024
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5.1.5
Vital signs
5.1.5.1
Seated blood pressure and pulse
Pulse and BP measurements must be taken consistently throughout the study.  Pulse and BP 
should be recorded using the same equipment at each visit.  Use only the right or the left arm 
when measuring these parameters.  Document which arm was used, along with the observer’s 
initials.  The same arm should be used at all visits for each position.  At each study visit, BP 
and pulse measurements should be obtained prior to blinded study drug administration.  Pulse 
and BP will be measured thrice (1 minute apart) before any blood sampling is done after the 
patient has been sitting and resting for least 5 minutes.  BP readings should be taken while the 
patient is in a comfortable seated position with the arm supported at the level of the heart.  All 
three readings must be recorded in eCRF.  For study analyses, the average of the three BP and 
pulse readings will be used.
5.1.8
Insulin dose 
The daily insulin dose will be recorded in patient diary by patient and the mean daily dose is 
calculated by investigator.  The calculated mean daily insulin dose is an average daily insulin 
use from the last visit.
5.1.9
eGFR
eGFR is calculated according to the MDRD formula): GFR (mL/min/1.73m2) = 175 x 
(standardized sCr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if Black)] [Note: sCr reported 
in mg/dL]
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5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the Study Plan (see Section 4). Additional safety 
samples may be collected for analysis at local laboratory, if clinically indicated at the 
discretion of the investigator. 
The detailed methods for specimen collection, handling, processing, shipping, and storage will 
be supplied in the Investigator’s Laboratory Manual provided by the Central Laboratory.
The following laboratory variables will be measured:

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Table 3
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry [serum (S) or plasma 
(P)]
B-Haemoglobin (Hb)
S-Aspartate transaminase (AST)
B-Hematocrit
S-Alanine transaminase (ALT)
B-Red blood cell count
S-Alkaline phosphatase (ALK-P)
B-White blood cell count
S-Bilirubin, total
B-Platelet count
S-Blood Urea Nitrogen
S-Creatinine
Urine analysis (dipstick)
S-Albumin
Blood (Microscopy if dipstick positive for blood)
S-Total protein
Pregnancy test (Urine HCG pregnancy test for 
WOCBP (HCG minimum sensitivity of 25 IU/L), 
dipstick analyzed at the study centre)
S-Potassium
Urine analysis (spot urine) 
S-Calcium, total
Creatinine
S-Sodium
Albumin
S- Bicarbonate
S- Chloride
Glucose (The quantitative urinary glucose values 
must not be disclosed during the double-blind 
phase (i.e., Visit 4 to 8) to maintain the blindness.)
S- Magnesium
S- Phosphorus
P- Parathyroid Hormone (PTH)
S- 25-hydroxy-vitamin D
S- WHCG, if urine pregnancy test result is 
positive 
Hepatitis Screen Panel (Includes Hepatitis B 
viral antibody IgM, Hepatitis B surface 
antigen and Hepatitis C virus antibody).
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.  For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.
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NB. In case a patient shows an AST and/or ALT M3xULN and TB M 2xULN, please refer to 
Appendix C “Algorithm on Management of Sustained Elevated Liver Safety Abnormalities”, 
for further instructions.
5.2.2
Physical examination
A brief physical examination should include the CV system, lungs, abdomen, and extremities, 
and any organ system pertinent to the patient’s signs, symptoms, or AEs.  The patient should 
always be evaluated for the presence of oedema.  A complete physical examination should 
include general appearance, head, eyes, ears, nose, throat, neck, CV system, lungs, abdomen, 
lymph nodes, extremities, neurological system, skin, and musculoskeletal system.  The patient 
should always be evaluated for the presence of oedema.
5.2.3
ECG
A 12-lead ECG will be taken after the patient has been lying down resting for at least 5 
minutes.  The ECG will be evaluated by the investigator and entered as ‘Normal’ or 
‘Abnormal’ in the eCRF.  If the ECG is evaluated as “Abnormal” the investigator should 
document the specific abnormality.
5.2.4
Vital signs
5.2.4.1
Blood pressure and pulse
As BP is both efficacy and safety variable in this study, measurement of seated BP is 
described in Sections 5.1.5.
Orthostatic BP: At selected visits where orthostatic BP and pulse are collected, supine and 
standing measurements should be made after the seated BP and pulse measurements have 
been made, using the same arm that was used for the seated BP measurements.  All readings 
should be recorded in eCRF. Ideally, BP should be measured with the same equipment, at the 
same time of day, and by the same personnel at each visit.
The supine BP and pulse must be measured prior to the standing BP and pulse.  After the 
patient rests in the supine position for at least 5 minutes, supine BP and pulse will be 
determined from three replicate measurements obtained at least 1 minute apart.  All three 
readings must be recorded in eCRF. For study analyses, the average of the three BP and pulse 
readings will be used.
After the supine BP and pulse measurements are obtained, the patient will stand for 2 to 3 
minutes.  After this time, the BP will be measured with the arm supported at the level of the 
heart. Standing BP and pulse will be determined from three replicate measurements obtained 
at least 1 minute apart.  All 3 readings must be recorded in eCRF.  For study analyses, the 
average of the three BP and pulse readings will be used.

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5.2.5
Other safety assessments
5.2.5.1
Self-monitored blood glucose and hypoglycemic events
The patients will be asked to check their blood glucose when they develop symptoms 
suggestive of hypoglycemia and to record specific symptoms in a hypoglycemia/blood 
glucose diary.  Any results collected in the diary will be reviewed by the investigator at each 
visit.  The investigator is responsible for questioning the patient about all symptoms reported 
in the diary and for determining if they meet the clinical definition of hypoglycemia.  Only 
symptoms and/or blood glucose values that meet the definition of hypoglycemia should be 
reported on the hypoglycemia eCRF pages see Section 6.3.7.  Glucometers will be provided 
by AstraZeneca. 
Patients will be instructed to contact the investigator anytime they experience a hypoglycemic 
event.  Hypoglycemic events must be recorded in the diary anytime a patient experiences 
either of the following:
!
Signs and symptoms of hypoglycemia (regardless of blood glucose value by finger 
stick)
!
Blood glucose value by finger stick <63 mg/dL (3.5 mmol/L) (regardless of 
symptoms).
Data to be collected for each hypoglycemic event:
!
Date and time of episode (start and stop)
!
Whether symptoms were present, and list of symptoms
!
Possible contributing factors
!
Whether a finger stick value was obtained, and if so, the blood glucose value
!
Whether intervention was needed for recovery
!
How the episode was treated
!
Whether recovery was prompt after treatment
!
Time of last anti-diabetic agents administration
!
Time of last meal and its contents
The patient diary will be reviewed and added to the patient’s source record. A new diary for 
the next period will be handed over to the patient if needed 

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5.2.5.2
Hepatic events (Hepatic Adjudication Committee)
An independent Hepatic Adjudication Committee, blinded to the treatment of the patients, will 
determine the probability that drug-induced liver injury (DILI) is the cause of liver-related 
abnormalities, including, but not limited to:
!
Hepatic events timely related to death (within 30 days before death) 
!
AST and/or ALT >3x ULN and TB >2x ULN (within 14 days of the AST and/or 
ALT elevation 
!
AST and/or ALT >10x ULN 
A separate Adjudication Manual will define and describe the procedure for the handling, 
reporting and classification of these cases.
5.2.5.3
Asymptomatic bacteriuria
The following is presented to assist in the classification and management of asymptomatic 
bacteriuria in studies with dapagliflozin.  It is not intended to supplant investigators’ clinical 
judgement.
During enrolment, treatment and follow up of patients in this study, the investigator may 
discover a patient with asymptomatic bacteriuria.  Asymptomatic bacteriuria is defined as the 
presence of M105 colony forming units/mL of bacteria, in a properly collected voided urine 
specimen, without signs or symptoms typically attributed to urinary tract infection (UTI).  
Asymptomatic bacteriuria is prevalent among diabetic women, and is associated with pyuria 
in 70% of cases.  Neither guidelines from the US (Nicolle et al 2005, USPSTF 2008) nor 
Europe (EAU 2014) recommend screening for, or treatment of, asymptomatic bacteriuria in 
non-pregnant diabetic patients.  In this study, the central laboratory will report urinary dipstick 
test results for hemoglobin but will not routinely report the results of urinary dipstick tests for 
leukocyte esterase as a screening test for pyuria in surveillance urine examinations.
5.2.5.4
Microscopic Hematuria
In the event that hematuria is observed during a patient’s participation, the sponsors 
recommend standard of care in diagnosing the cause of the hematuria.  This section presents 
references and an example of standard of care evaluation of microscopic hematuria.  Local 
standards of care should be followed.
Patients with repeated reports of microscopic hematuria in 2 or more properly collected urine 
samples need to have follow-up for this result according to standard of care.  The American 
Urological Association defines microscopic hematuria as three or more red blood cells per 
high-power microscopic field in urinary sediment from two or more properly collected 
urinalysis specimens (AUA, Grossfeld et al 2001).  These Best Practice guidelines have been 
evaluated by Jung in a study of 772000 patients (Jung et al 2011).

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Patients who show microscopic hematuria that is accompanied by significant proteinuria, red 
blood cell casts, or dysmorphic red blood cells in the sediment should be evaluated for the 
presence of primary renal disease and need to be referred to a nephrologist (AUA, Grossfeld 
et al 2001).
Patients who lack other explanation for their hematuria, or who have risk factors for 
significant urologic disease, will need a urological evaluation and should be referred to an 
urologist.  Risk factors for significant urological disease include unexplained microscopic 
hematuria as well as smoking history, occupational exposure to dyes or chemicals (such as 
benzenes or aromatic amines), visible hematuria, age >40 years, previous urologic history, 
history of irritative voiding symptoms, history of UTI, analgesics or phenacetin abuse, history 
of pelvic irradiation, or cyclophosphamide use (AUA, Greenwood M 1926).  Results from any 
procedure or investigations should be reported on the eCRF.
5.2.5.5
Volume Depletion
The risk of electrolyte abnormalities, volume depletion, and impaired renal function is 
enhanced when two diuretics are used in combination.  For this reason, caution should be 
exercised when administering dapagliflozin, which has a modest diuretic effect, to patients 
who are taking loop diuretics.  These patients should have careful monitoring of electrolytes, 
volume status, and renal function.  Loop diuretic dose adjustments should be made if 
clinically indicated.
5.2.5.6
Potential events of Diabetic Ketoacidosis
All potential events of DKA will be recorded in the eCRF and submitted to an independent 
DKA Adjudication Committee. The DKA Committee T2DM will assess available 
information on each potential DKA event and will classify the event in accordance with the 
definitions in the DKA Adjudication Charter T2DM. 
The DKA Adjudication Committee will be kept blinded to the study drug treatment received 
by each patient with a potential DKA event in the clinical study. A separate DKA 
Adjudication Manual will define and describe the procedures for the collection of DKA 
information, handling, adjudication criteria and reporting of these events/cases.
5.3
Other assessments – Not Applicable
5.4
Pharmacokinetics – Not Applicable
5.5
Pharmacodynamics – Not Applicable
5.6
Pharmacogenetics – Not Applicable
5.7
Biomarker analysis – Not Applicable
5.8
Storage, re-use and destruction of biological samples
After the analyses are complete the samples will be either completely consumed during the 
analytical process or disposed of after the analysis.

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5.9
Labelling and shipment of biological samples
The Principal Investigator (PI) ensures that samples are labelled and shipped in accordance 
with the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix B ‘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 
labelling, shipment and containment provisions are approved.
5.10
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The PI at each centre keeps full traceability of collected biological samples from the patients 
while in storage at the centre 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.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
5.11
Volume of blood
The total volume of blood that will be drawn for each patient in this study is listed in the Table 
4 below.  The collection of additional samples is performed locally at the discretion of the 
investigator and recorded appropriately, thus requiring additional sample volumes.
Table 4
Volume of blood to be withdrawn from each patient
Assessment
Sample Volume 
(mL)
No. of samples
Total volume 
(mL)
Clinical chemistry
2.5
8
20
2.5
3
7.5
Haematology
HbA1c
2
7
14
FPG
2
5
10
Hepatitis screen panel
3.5
1
3.5
                                                
2 Combined in 1 sample with Clinical Chemistry
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Assessment
Sample Volume 
(mL)
No. of samples
Total volume 
(mL)
Parathyroid Hormone (PTH)
2
3
6
Total
61
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The PI is responsible for ensuring that all staff involved in the study is familiar with the 
content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product.  An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, 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.
6.2
Definitions of serious adverse event
A SAE is an AE occurring during any study phase (i.e., lead-in, treatment, washout, FU), that 
fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
!
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the patient or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol (CSP).

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6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs will be collected from the start of the placebo lead-in period throughout the treatment 
period (Visit 2 to 8) and including the follow-up period (Visit 9).
SAEs will be recorded from the time of informed consent is obtained until the end of the study 
(Visit 9).
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last AE assessment visit in the study are followed 
up by the Investigator for as long as medically indicated, but without further recording in the 
CRF.  AstraZeneca retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collect for each AE;
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity
!
Whether the AE is serious or not
!
Investigator causality rating against the IP (yes or no)
!
Action taken with regard to investigational product
!
Outcome.
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
AE is serious due to
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death

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!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Description of AE.
Maximum intensity will be graded according to the following rating scale:
!
Mild (awareness of sign or symptom, but easily tolerated)
!
Moderate (discomfort sufficient to cause interference with normal activities)
!
Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
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 A to the CSP.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study personnel: “Have you had any health problems since the 
previous visit/you were last asked?”, or revealed by observation will be collected and recorded 
in the CRF.  When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.

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6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values, vital 
signs, and other safety variables should therefore only be reported as AEs if they are clinically 
significant, fulfil any of the SAE criteria or are the reason for discontinuation of treatment 
with the investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (e.g., anaemia versus low Hb value).  In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
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.
Pre-defined liver enzyme elevations will undergo adjudication.  The definitions of the events 
to be adjudicated are provided in the Hepatic Adjudication Manual.  For all events identified 
for adjudication, the Investigator will complete the appropriate eCRF pages and provide 
source documentation as detailed in the Hepatic Adjudication Manual. See also Section 
5.2.5.2.
6.3.7
Hypoglycemic events
A separate section in the eCRF will be used to document all reported episodes of 
hypoglycaemia (see Section 5.2.5.1).  Hypoglycemic episodes should also be reported on the 
AE eCRF page if the event fulfils protocol criteria for a SAE (see Section 6.2).
!
Major hypoglycemic events, defined as symptomatic events requiring external 
assistance due to severe impairment in consciousness or behaviour, with a 
capillary or plasma glucose value <54 mg/dL (<3.0 mmol/L), and prompt recovery 
after glucose or glucagon administration. 
!
Minor hypoglycemic event, defined as either a symptomatic episode with a 
capillary or plasma glucose measurement <63 mg/dL (<3.5 mmol/L) regardless of 
need for external assistance or an asymptomatic capillary or plasma glucose 
measurement below 63 mg/dL (3.5 mmol/L), that does not qualify as a major 
episode.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF.

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If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by designated back-up 
procedures.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
6.5
Overdose
Overdose is defined as more than 100 mg of dapagliflozin per day.  Dapagliflozin has been 
well tolerated at doses of up to 500 mg per day in single dose testing in healthy volunteers and 
up to 100 mg per day in repeat dose testing for 14 days in healthy volunteers and patients with 
T2DM.  If an overdose is suspected, monitoring of vital functions as well as treatment as 
appropriate should be performed
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on 
the relevant AE modules in the CRF and on the Overdose CRF module.
!
An overdose without associated symptoms is only reported on the Overdose CRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.

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The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
6.6.2
Paternal exposure – Not Applicable
6.7
Management of IP related toxicities – Not Applicable
Dose reductions of IP are not permitted in the study.
6.8
Study governance and oversight
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance this could involve amendments to the study protocol and letters to 
Investigators.

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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Investigational product
Dosage form and strength
Manufacturer
Dapagliflozin 10 mg
Green, plain, diamond shaped, 
film coated 10 mg tablet
Matching placebo for 
dapagliflozin 10 mg
Green, plain, diamond shaped, 
film coated tablet
Dapagliflozin and its matching placebo will be supplied in bottles, each containing 35 tablets.  
The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals.
7.2
Dose and treatment regimens
The study consists of a 4-week single-blind placebo lead-in period, a 24-week double-blind 
placebo-controlled treatment period, and a 3-week follow-up period.  The study drug is taken 
orally once daily in the morning.  Doses of study drug on the day of the visits must be taken 
upon completion of study visit procedures.
Treatment during single-blind lead-in period
During the 4-week (Visit 2 to Visit 4) single-blind lead-in period eligible patients will receive
1 bottle containing 35 tablets of placebo matching dapagliflozin 10 mg.  First dose of lead-in 
period study drug will be administered at the clinic by site staff. Subsequent doses should be 
taken once daily in the morning.
Treatment during double-blind randomization period
At Visit 4, eligible patients will be randomized to double-blind treatment of dapagliflozin 10 
mg or matching placebo.  The study drug should be taken once daily in the morning and at 
approximately the same time of the day during the study period.  Nevertheless prior to each 
clinical visit patients should be instructed not to take any medication at morning and to abstain 
from all food and beverages for 8 hours; however, drinking water is allowed.  On the day of 
study visit, study drug and other concomitant medications will be taken, after completion of 
study visit procedures.  Except anti-hypertensive medication (see Section 3.8)
First dose of study drug will be administered at the clinic by site staff.
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Table 5
Drug Dispensing Scheme
Visit ID
No. of bottles to dispense of dapagliflozin 10 mg or matching 
placeboa
Visit 1 (Enrolment)
N/A
Visit 2 (Start of Lead-in)
1 bottle (placebo)
Visit 3 (Lead-in)
N/A
Visit 4 (Randomization)
1 bottle (dapagliflozin or placebo)
Visit 5 (Treatment)
N/A
Visit 6 (Treatment)
2 bottles (dapagliflozin or placebo)
Visit 7 (Treatment)
3 bottles (dapagliflozin or placebo)
Visit 8 (Study Completion)
N/A
Visit 9 (Study Follow-Up)
N/A
a
Each bottle contains 35 tablets.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the bottle specifies the appropriate storage.
7.5
Compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the CRF.
Each time study drug is dispensed, compliance will be reinforced.  When study drug is 
returned, compliance will be assessed based on returned tablet counts. Tablet counts will be 
recorded in the eCRF.  Patients should demonstrate good compliance with the administration 
of study drug (M70% and S130%) during the lead-in period. For patients with compliance 
between M70% and < 80% or > 120% and S130%, the Investigator should ensure that there are 
no systematic factors which may result in unacceptable compliance with study drug during the 
treatment period of the study.  Such cases should be discussed with the study physician prior 
to randomization.  During double-blind treatment period, patients judged to be non compliant 
(defined as taking less than 80% or more than 120% of the prescribed dose of study drug) may 
continue in the study, but should be counselled on the importance of taking their study 
medication and applicable concomitant medications as prescribed.

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7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to and returned from the 
patient.
The investigator is responsible for making sure:
!
That the IP is handled and stored safely and properly (see Section 7.4).
!
That the IP is only dispensed to study patients in accordance with this protocol.
Patients should return all unused IP and empty containers to the investigator.
At the termination of the Clinical Study or at the request of AstraZeneca, the investigator will 
either return any unused IP to AstraZeneca or its designate, or destroy IP 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 AstraZeneca or its 
designate, the study site personnel or the AstraZeneca monitor will account for all received IP 
received at the site, unused IP and for appropriate destruction.  Certificates of delivery, 
destruction and return should be signed and archived.
7.7
Concomitant and other treatments 
Changes in concomitant medication should be avoided during study participation, with the 
exception of situations defined in this protocol, but medication, which is considered necessary 
for the patient’s safety and well-being, may be given at the discretion of the investigators, who
must decide if the patient should remain in study or need to be dismissed from study due to 
patient’s safety or interference with study objectives.
The administration of all medication must be recorded in the appropriate sections of the 
electronic CRF.  The specific type of medication (trade or generic name), the indication for 
use, dosages, and the dates of usage should be reported.
After having completed or discontinued the study, patients will receive usual care and anti-
diabetic agents according to the investigator's judgment and according to local medical 
practice.
Restricted Medication/Class of drug:
Usage:
Metformin
A metformin dose which is outside the specified 
dose range for moderate renal impairment (eGFR 
30– 59 mL/minute/1.73m2, MDRD formula) 
according to local guidelines or investigator’s 
judgment, is not allowed.

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Teriparatide, bisphosphonates and/or 
calcitonin
Treatment with teriparatide, bisphosphonates and/or 
calcitonin are allowed provided the dose has not 
changed within 30 days prior to enrolment.
Prohibited Medication/Class of drug:
Usage:
Antiviral drugs
Treatment for HIV and/or use of antiviral drugs 
(delavirdine, indinavir, nelfinavir, ritonavir, 
saquinavir) is not allowed
Glucocorticoids (long term treatment)
Long term treatment with glucocorticoids 
(equivalent to oral prednisolone M10 mg 
(betamethasone M1.2 mg, dexamethasone M1.5 mg, 
hydrocortisone M40 mg) is not allowed, (two 
temporary periods of no longer than 10 days each 
are allowed during the study); topical or inhaled 
corticosteroids are allowed.
Weight loss medication
Use of weight loss medication, including but not 
limited to sibutramine, phentermine, orlistat, 
rimonabant, benzphetamine, diethylpropion, 
methamphetamine, liraglutide indicated for anti-
obesity treatment, and/or phendimetrazine, within 
30 days of the enrolment visit, is not allowed.
Rescue/Supportive Medication/Class of 
drug:
Usage:
Open label rescue medication
See Section 4.3.3.1
Guidelines with regard to standard of care and other therapy
During the duration of the study period, standard of care for each patient should be kept 
unchanged to the largest extent as possible, according to the judgment of the Investigator.  
Specifically, the dose of OADs, insulin, anti-hypertensive drugs, lipid lowering drugs and 
anti-platelet drugs should be kept constant throughout the entire 24-week treatment period.
If dose of OADs and insulin is reduced according to the investigator discretion, patient should 
still continue in the study with double blind treatment and the dose changes must be recorded 
in the appropriate sections of the electronic CRF.
7.7.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the CRF.

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7.8
Post Study Access to Study Treatment – Not Applicable
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
!
All personnel involved with the analysis of the study will remain blinded until 
database lock and protocol violators identified.
!
Analyses will be performed by AstraZeneca or its representatives.
!
Refer to SAP for details.
!
All personnel involved with the analysis of the study will remain blinded until 
database lock and protocol violators are identified. Analyses will be performed by 
AstraZeneca or its representatives.  
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first patient 
randomized and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data (this is the expectation for the pivotal studies).
8.2
Sample size estimate
The primary endpoint is the change from baseline in HbA1c at Week 24.  From post-hoc 
results of similar clinical studies (Study MB102029, Study D1690C00018, and Study 
D1690C00019) when patients meeting eGFR entry criteria like those in this current study 
were selected, the mean placebo-corrected change from baseline in HbA1c after 24 weeks of 
treatment for the current study is estimated to be -0.3% for dapagliflozin 10 mg. 
Assuming a common standard deviation (SD) of 0.9% in the primary endpoint, 143 patients 
per treatment group with both baseline and at least one post-baseline HbA1c measurement
will provide 80% power to detect a treatment difference of 0.3% in the primary endpoint  at a 
two-sided significance level =0.05, using a two-sample t-test.  Assuming that 5% of 
randomized patients fail to qualify for inclusion in the full analysis set due to missing baseline 
and/or all post-randomization values for this primary endpoint, a total of 302 randomized 
patients (151 per treatment group) are needed for the study. 
8.3
Definitions of analysis sets
8.3.1
Enrolled Patients Data Set
The Enrolled Patients Data Set includes data collected from all patients who signed informed 
consent.

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8.3.2
Lead-in Patients Data Set
The Lead-in Patients Data Set includes data collected from all patients who took at least one 
dose of lead-in medication.
8.3.3
Full Analysis set
The primary efficacy analysis will be performed on the Full Analysis Set, which will consist 
of all randomized patients who took at least one dose of double-blind study drug during the 
short term double-blind period and have a non-missing baseline value and at least one post-
baseline efficacy value (HbA1c, total body weight, FPG, and SBP).
When the Full Analysis Set is used, patients will be presented in the treatment group to which 
they were randomized at the start of the short term double-blind treatment period (even if the 
treatment they received was different).
8.3.4
Per Protocol Analysis Set
The per-protocol analysis set is a subset of the Full Analysis Set consisting of patients who do 
not violate the terms of the protocol which may affect the primary efficacy endpoint 
significantly.  All decisions to exclude patients from the primary data set will be made prior to 
the un-blinding of the study.
Relevant Protocol Deviations (RPDs), used to determine complete or partial data exclusion for 
the short term double-blind treatment period due to prohibited concomitant treatment, are 
listed in section 7.7.  Any further protocol deviations for a particular study will be specified in 
the study-specific SAP.
8.3.5
Safety Analysis Set
The Safety Analysis Data Set will consist of all patients who received at least one dose of 
double-blind study drug during the short term double-blind treatment period.  The Safety 
Analysis Data Set will include any patient who accidentally received double-blind study drug 
but was not randomized in the study. 
All analyses using the Safety Analysis Data Set will be presented by randomized treatment 
group, except in cases where information was available which indicated that a patient received 
a different treatment for the entire course of their participation in the double-blind treatment 
period of the study.  In this case, the safety data for those patients will be presented by the 
treatment actually received.  In case a patient never received the treatment as assigned by 
randomization, then the safety data for that patient will be presented by the first treatment 
received.

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8.3.6
PK analysis set – Not Applicable
8.3.7
PRO analysis set – Not Applicable
8.4
Outcome measures for analyses
8.4.1
Primary outcome variable 
The primary outcome variable will be the change in HbA1c (%).   
8.4.2
Secondary outcome variables 
Secondary outcome variables will be:
!
Percent change from baseline in body weight (kg).
!
Change from baseline in FPG (mg/dL).
!
Change from baseline in seated SBP (mmHg).
8.4.3
Safety outcome variables 
Safety outcome variables will be:
!
Numbers and proportions of patients experiencing AEs and, separately, marked 
laboratory abnormalities.
!
Changes from baseline in eGFR (mL/min)  
!
Proportions of patients discontinued from study drug due to worsening renal 
insufficiency (eGFR<30 mL/min/1.73m2) during treatment.
!
Changes from baseline in SBP (mmHg), DBP (mmHg), and heart rate (bpm).
!
Changes from baseline in the findings from physical examination.
!
Changes from baseline in clinical laboratory test results.
8.4.4
Exploratory outcome variables
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8.5
Methods for statistical analyses
Unless otherwise specified, analyses of efficacy endpoints will only include measurements 
prior to the administration of rescue medication.
8.5.1
Analysis of the primary variable (s)
The primary endpoint is the changes from baseline in HbA1c at Week 24. The primary 
analysis of the primary endpoint will be based on a mixed effects model with repeated 
measures (MMRM) using ‘direct likelihood’, including patients in the Full Analysis Set who 
have a baseline measurement and at least one post-baseline measurement. The primary 
analysis will only include measurements prior to the administration of rescue medication. 
Measurements made following rescue administration will not be included in analysis. 
The SAS procedure PROC MIXED will be used for the primary analysis. The primary 
analysis model will include the fixed categorical effects of treatment, week, randomization 
stratification factor (i.e. anti-diabetic treatment strata) and treatment-by-week interaction as 
well as the continuous fixed covariates of baseline measurement and baseline measurement-
by-week interaction. An unstructured matrix for the within-patient error variance-covariance 
will be used. The denominator degrees of freedom will be calculated according to the 
Kenward-Roger method. A number of back-up models will be defined in the statistical 
analysis plan in case of non-convergence of the preferred model or other issues. Point 
estimates and 95% confidence intervals for the mean change within each treatment group as 
well as the difference in mean change between the dapagliflozin and placebo will be 
calculated. P-value of the differences in week 24 visit estimates between dapagliflozin and 
placebo will be calculated. 
A variety of sensitivity analyses will be specified in the Statistical Analysis Plan to assess the 
robustness of the primary analysis results, including a sensitivity analysis of the effect of 
baseline eGFR on the results obtained in primary analysis as well as sensitivity analyses 
which include all data pre- and post-rescue.  In order to assess the robustness of the primary 
analysis results on the missing data assumptions, the amount of missing data, the distribution 
of missing data among treatment groups, and the reasons for missing data will be examined.  
If substantial amount of missing data is observed or if imbalance occurs amongst the treatment
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groups, additional sensitivity analyses, including those based on alternative missing data 
assumptions, may be performed.
8.5.2
Analysis of the secondary variable(s)
A sequential testing procedure will be employed among the primary endpoint and secondary 
endpoints in order to control the type I error rate at the 0.05 level. The tests for the secondary 
efficacy endpoints will be performed only if the test for the primary endpoint is significant, in 
which case the secondary endpoints will be tested in the order that they appear in the 
objectives section of the protocol synopsis. Statistical tests will be only performed for a given 
secondary endpoint if all previous sequential tests for that comparison between dapagliflozin 
and placebo are also significant. Otherwise, the testing procedure will stop at the secondary 
endpoint that does not reach statistical significance. 
The secondary endpoints, i.e, percent change from baseline in total body weight (using 
logarithmic transformation) at Week 24, change from baseline in FPG at Week 24, change 
from baseline in seated SBP at Week 24, and percent change from baseline in total body 
weight (using logarithmic transformation) at Week 24, will be analyzed using a MMRM, 
similar to the one used for the primary analysis of the primary endpoint. 
 
MRM analysis will performed on the difference between natural 
logarithmically transformed values at end of treatment and at baseline, and will include terms 
for treatment, week, and the interaction between treatment and week, as well as the log-
transformed baseline value and the interaction between week and log-baseline value. 
8.5.3
Subgroup analysis 
As part of the exploratory objectives, subgroup analyses for the primary endpoint and key 
secondary endpoints (percent change from baseline in body weight at Week 24 and change 
from baseline in seated SBP) will be performed for the following subgroups:
!
Baseline HbA1c #8.5%, #7.5% and <8.5%, and <7.5%,
!
Baseline BMI <25 kg/m2, and #65 yrs
Additionally, subgroup analyses of the primary endpoints may be performed for the following 
subgroups. Further details will be provided in the SAP.   
!
Race of Black or African American, White, Asian, Other
!
Age of <65, and #65 yrs
!
Gender of Male, Female
!
Anti-diabetic therapy of long/intermediate-acting and mixed insulin regimen, SU-
based regimen, TZD-based regimen, metformin-based regimen and other regimen
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!
Country/region
!
Other subgroups
8.5.4
Interim analysis – Not Applicable
8.5.5
Sensitivity analysis
Refer to section 8.5.1
8.5.6
Exploratory analysis 
Exploratory analysis on continuous exploratory endpoints will be evaluated using a MMRM, 
similar to the one used for the primary analysis of the primary endpoint.  Exploratory 
subgroup analysis will include additional covariates and interaction terms for the subgroup 
variables.
Exploratory analyses of variables that represent proportions of patients will be performed 
using the logistic regression with adjustment for randomization strata and baseline 
measurement.
Exploratory analyses of time-to-event variables will be performed using Kaplan-Meier plots 
accompanied by a tabular summary.
8.5.7
Analysis of safety variables
Safety analyses will be performed using descriptive statistics. Dichotomous safety variables 
will be summarized by treatment as counts and percentages. Categorical safety variables will 
be separately summarized by treatment as counts and percentages by category. Continuous 
safety variables will be summarized by treatment using descriptive statistics.  Comparisons 
between dapagliflozin 10 mg and matching placebo will not be made for safety variables, and 
inferential testing will not be performed.
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9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the CSP and related documents with the investigational staff and 
also train them in any study specific procedures and the WBDC system utilised.
The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved.
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data are 
being accurately and timely recorded in the CRFs, that biological samples are 
handled in accordance with the Laboratory Manual and that study drug 
accountability checks are being performed
!
Perform source data verification (a comparison of the data in the CRFs with the 
patient's medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. 
This will require direct access to all original records for each patient (e.g., clinic 
charts)
!
Ensure site is compliant with study procedures to avoid “lost to follow-up” as 
listed in Section 3.10
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the CSA for location of source data.

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9.2.2
Study agreements
The PI at each/the centre 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 CSP and the 
CSA, the terms of CSP 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 AstraZeneca and the PI should be in place before any study-related 
procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study is expected to start in Q2 2015 and to end by Q4 2017.
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with dapagliflozin.
9.4
Data management by AstraZeneca or delegate
Data management will be performed by 
 the AZ Data Management Centre, 
according to the Data Management Plan.
Data will be entered into the WBDC system Rave at the study site.  Trained site staff will be 
entering the data as specified in the protocol and according to the eCRF instructions.  Data 
entered into the WBDC system will be immediately saved to a central database and changes 
tracked to provide an audit trail.  The data will then be Source Data Verified, reviewed, 
queried and updated as needed
AEs and medical/surgical history will be classified according to the terminology of the latest 
version the MedDRA.  Medications will be classified according to the AstraZeneca Drug 
Dictionary.  All coding will be performed by the Medical Coding Team at the Data 
Management Centre.
The PI is responsible for signing the eCRF and this may be delegated to a trained Investigator.
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.  The Data Management Plan will also clarify the roles and 
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responsibilities of the various functions and personnel involved in the data management 
process. 
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.  A 
copy of the eCRF will be archived at the study site when the study is completed.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
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 the clinical database.  Data Management will assure that the 
data collection tool for IVRS are tested and validated. External data reconciliation will be 
done with the clinical database as defined in the Data Management Plan.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the AstraZeneca policy on Bioethics and Human Biological Samples.
10.2
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.
10.3
Ethics and regulatory review
An Ethics Committee (EC)/Institutional Review Board (IRB) should approve the final study 
protocol, including the final version of the ICF and any other written information and/or 
materials to be provided to the patients.  The Investigator will ensure the distribution of these 
documents to the applicable EC/IRB, and to the study site staff.
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrolment of any patient into the study. 
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AstraZeneca 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 EC/IRB annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, EC/IRB and PIs with safety updates/reports 
according to local requirements.
Each PI is responsible for providing the EC/IRB with reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the investigational product.  
AstraZeneca will provide this information to the PI so that he/she can meet these reporting 
requirements.
10.4
Informed consent
The PI(s) at each centre will:
!
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study
!
Ensure each patient is notified that they are free to discontinue from the study at any 
time
!
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided
!
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study
!
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File
!
Ensure a copy of the signed ICF is given to the patient
!
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC/IRB.

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10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca.
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 CSP).
The amendment is to be approved by the relevant EC/IRB and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed 
for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each PI.  For distribution to EC/IRB see Section 10.3.
If a protocol amendment requires a change to a centre’s ICF, AstraZeneca and the centre’s 
EC/IRB 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 EC/IRB.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an EC may perform 
audits or inspections at the centre, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, GCP, guidelines of the 
International Conference on Harmonisation (ICH), and any applicable regulatory 
requirements.  The Investigator will contact AstraZeneca immediately if contacted by a 
regulatory agency about an inspection at the centre.
11.
LIST OF REFERENCES
AUA
American Urological Association website, www.auanet.org
Barnett et al 2014
Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al. Efficacy and safety 
of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and 
chronic kidney disease: a randomized, double-blind, placebo-controlled trial. Lancet Diabetes 
Endocrinol. 2014;2:369-84.

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Bolinder et al 2014
Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al. 
Dapagliflozin maintains glycemic control while reducing weight and body fat mass over 2 
years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes 
Obes Metab. 2014;16:159-69.
EAU 2014
European Association of Urology guidelines 2014. Available at http://www.uroweb.org/.
Greenwood M 1926
Greenwood M. The natural duration of cancer. Reports on public health and medical subjects. 
1926;33:1-26.
Grossfeld et al 2001
Grossfeld GD, Wolf JS Jr, Litwin MS, Hricak H, Shuler C, Agerter DC, et al. Asymptomatic 
Microscopic Hematuria in Adults: Summary of the AUA Best Practice Policy 
Recommendations. Am Fam Physician. 2001;63:1145-1154.
Jung et al 2011
Jung H, Gleason JM, Loo RK, Patel HS, Slezak JM, Jacobsen SJ. Association of hematuria on 
microscopic urinalysis and risk or urinary tract cancer. The Journal of Urology 2011; 
185:1698-703.
Kohan et al 2014
Kohan DE, Fioretto P, Tang W, List JF.  Long-term study of patients with type 2 diabetes and 
moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but 
does not improve glycemic control. Kidney Int. 2014;85:962-71.
Maranghi et al 2015
Maranghi M, Carnovale A, Durante C, Tarquini G, Tiseo G, Filetti S. Pharmacokinetics, 
pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 
diabetes.”Expert Opin Drug Metab Toxicol. 2015;11:125-37.
Nicolle et al 2005
Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM. Infectious diseases 
society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in 
adults. Clin Infect Dis 2005;40:643-54.
Plosker et al 2014
Plosker GL. Dapagliflozin: a review of its use in patients with type 2 diabetes. Drugs. 
2014;74:2191-209.
Santer et al 2010
Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a 
therapeutic target. Clin J Am Soc Nephrol. 2010;5:133-41.

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
92 (101)
SDCD 2014
Standards of Medical Care in Diabetes 2014. Diabetes Care Volume 37, Supplement 1, 
January 2014.
Sheen et al 2014
Sheen YJ, Sheu WH. Risks of rapid decline renal function in patients with type 2 diabetes. 
World J Diabetes. 2014;5:835-46.
USPSTF 2008
US Preventative Services Taskforce (USPSTF). Screening for Asymptomatic Bacteriuria in 
Adults: US Preventative Services Taskforce Reaffirmation Recommendation Statement. Ann 
Intern Med 2008;149:43-47.
Yale et al 2013
Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al. Efficacy and safety of 
canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes 
Metab. 2013;15:463-73.

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