Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 321
Healthy volunteers: no

Brief summary:
The purpose of this clinical research study is to determine whether dapagliflozin can improve (decrease) blood glucose values in patients with Type 2 diabetes and moderate renal impairment.This study will be conducted at approximately 100 centres from countries across North America and European regions. It is planned to randomize a total of 302 patients.

Detailed description:

Arms:
arm 1: 10 mg Tablets, Oral, Once daily, 24 weeks arm 2: Matching placebo to Dapagliflozin 10 mg tablet. Oral, Once daily, 24 weeks

Interventions: intervention 1: Dapagliflozin 10 mg intervention 2: Matching Placebo for Dapagliflozin
Intervention descriptions: intervention 1: Tablets administered orally once daily for 24 weeks. Randomization will be stratified by pre-enrolment anti-hyperglycemic therapy intervention 2: Matching Placebo for Dapagliflozin tablets administered orally once daily for 24 weeks

Protocol document:
Prot_000.pdf: 
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.
CCI


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.
CCI
CCI
CCI


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
7 (101)
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.


8 (101)
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


Clinical Study Protocol Synopsis
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
9 (101)
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


Clinical Study Protocol Synopsis
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
10 (101)
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 :
CCI


Clinical Study Protocol Synopsis
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
11 (101)
Exploratory Objective:
Outcome Measure :
CCI


Clinical Study Protocol Synopsis
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
12 (101)
Exploratory Objective:
Outcome Measure :
CCI


Clinical Study Protocol Synopsis
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
13 (101)
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 
CCI


Clinical Study Protocol Synopsis
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
14 (101)
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
15 (101)
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
16 (101)
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


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
17 (101)
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
CCI
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
18 (101)
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


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
19 (101)
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


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
20 (101)
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


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
21 (101)
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
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
22 (101)
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
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
23 (101)
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


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
24 (101)
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 


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
25 (101)
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 


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
26 (101)
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 
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
27 (101)
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 


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
28 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
29 (101)
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 


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
30 (101)
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


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
31 (101)
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 :
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
32 (101)
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
33 (101)
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
34 (101)
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. 
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
35 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
36 (101)
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).


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
37 (101)
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).


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
38 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
39 (101)
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.
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
40 (101)
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).
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
41 (101)
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 
drug, the Patient Safety data entry site and the CRO companies providing the IVRS/IWRS and 


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
42 (101)
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


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
43 (101)
!
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)


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
44 (101)

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 
schedule.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
45 (101)
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. 


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
46 (101)
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. 


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
47 (101)
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


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
48 (101)
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
CCI
CCI
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
49 (101)
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
51 (101)
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
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
52 (101)
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.
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
53 (101)
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
CCI
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
54 (101)
!
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
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
55 (101)
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 
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
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
CCI
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
59 (101)
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.
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
60 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
61 (101)
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]
CCI
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
62 (101)
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:


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
63 (101)
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.
CCI
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
64 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
65 (101)
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 


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
66 (101)
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).


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
67 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
68 (101)
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
CCI
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
69 (101)
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).


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
70 (101)
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


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
71 (101)
!
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
72 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
73 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
74 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
75 (101)
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.
CCI
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
76 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
77 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
78 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
79 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
80 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
81 (101)
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
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
82 (101)
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
83 (101)
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
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
84 (101)
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
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
85 (101)
!
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.
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
86 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
87 (101)
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 
CCI


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
88 (101)
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. 
The EC/IRB should approve all advertising used to recruit patients for the study.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
89 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
90 (101)
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.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1690C00024
Version 4.0
Date 17 January 2017
91 (101)
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.


Document Name:
                                                                   
Document Title:
                                                                                                    
                                                                                                                                     
                                                                                                                              
                                                                                                                                             
                                                                                                                 
Document ID:
                                                                                          
Version Label:
                  
 
 
 
 
 
 
 
     
            
                                          
              
Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
Signed By
Meaning of Signature
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.  
GFFVSY
'&&OLQLFDO6WXG\3URWRFROYHUVLRQ
'RF,'

$SSURYHG
&855(17
/$7(67
-DQ*07
&OLQLFDO2SHUDWLRQV
$SSURYDO
-DQ*07
%LRVWDWLVWLFV$SSURYDO
-DQ*07
&OLQLFDO'HYHORSPHQW
$SSURYDO
PPD
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D1690C00024
Edition Number2.0
Date
06NOV2017
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


PPD
PPD


PPD


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
4
TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................1
SIGNATURE OF STUDY STATISTICIAN.............................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .......................3
TABLE OF CONTENTS..........................................................................4
LIST OF ABBREVIATIONS ...................................................................8
AMENDMENT HISTORY.....................................................................12
1.
STUDY DETAILS..................................................................................15
1.1
Study Objectives.....................................................................................15
1.1.1
Primary Objective ...................................................................................15
1.1.2
Secondary Objectives..............................................................................15
1.1.3
Safety Objective......................................................................................16
1.1.4
Exploratory Objectives............................................................................16
1.1.5
Adjudication cases summarization ..........................................................19
1.2
Study Design...........................................................................................19
1.3
Treatment Group Assignment .................................................................27
1.4
Sample Size Estimate..............................................................................28
2.
ANALYSIS SETS ..................................................................................28
2.1
Definition of Analysis Sets......................................................................28
2.1.1
Enrolled Patients Set ...............................................................................28
2.1.2
Lead-in Analysis Set ...............................................................................28
2.1.3
Randomized Analysis Set........................................................................29
2.1.4
Full Analysis Set.....................................................................................29
2.1.5
Per Protocol (PP) Analysis Set ................................................................29
2.1.6
Safety Analysis Set .................................................................................29
2.2
Blinding and Unblinding.........................................................................29
2.2.1
Blinding..................................................................................................29
2.2.2
Unblinding..............................................................................................30
2.3
Protocol Deviation ..................................................................................30
2.3.1
Protocol Deviation Monitoring................................................................30
2.3.2
Protocol Deviation Reporting..................................................................31
3.
PRIMARY AND SECONDARY VARIABLES......................................31
3.1
Primary Efficacy Variable.......................................................................31
3.2
Secondary Efficacy Variables..................................................................31


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
5
3.3
Exploratory Efficacy Variables................................................................31
3.4
Safety and Tolerability Variables ............................................................33
4.
ANALYSIS METHODS.........................................................................33
4.1
General Principles...................................................................................34
4.1.1
Baseline Values.......................................................................................35
4.1.2
Change and Percent Change from Baseline .............................................35
4.1.3
Derivation of Efficacy Variable at Rescue/ Premature Discontinuation ...35
4.1.4
Analysis of Covariance ...........................................................................36
4.1.4.1
ANCOVA Model for Change from Baseline ...........................................36
4.1.4.2
ANCOVA Model for Percent Change from Baseline...............................36
4.1.5
Last Observation Carried Forward (LOCF) .............................................36
4.1.6
Longitudinal Repeated Measures Analysis ..............................................36
4.1.6.1
Longitudinal Repeated Measures Analysis for Change from Baseline .....36
4.1.6.2
Longitudinal Repeated Measures Analysis for Percent Change from 
Baseline ..................................................................................................37
4.1.7
Handling of Dropouts or Missing Data....................................................39
4.1.7.1
Multiple Imputation based on Retrieved Drop-outs (MI-RD) ..................40
4.1.7.2
Washout Imputation................................................................................41
4.1.8
Summaries of Continuous Endpoints.......................................................41
4.1.9
Proportion of Patients with Pre-Defined Characteristics ..........................42
4.1.10
Summaries of Shifts from Baseline in Categorical Variables...................42
4.1.11
Kaplan-Meier Curve and Estimates for Time-To-Event Analyses............42
4.1.12
eGFR ......................................................................................................43
4.2
Analysis Methods....................................................................................43
4.2.1
Patient Disposition..................................................................................43
4.2.2
Demographics and Baseline Characteristics ............................................43
4.2.3
Specific and General Disease Histories ...................................................46
4.2.4
Current and Concomitant Medications ....................................................46
4.2.5
Extent of Exposures ................................................................................47
4.2.5.1
Study Therapy.........................................................................................47
4.2.5.2
Treatment Compliance............................................................................48
4.2.6
Efficacy Variables...................................................................................48
4.2.6.1
Primary Efficacy Variable.......................................................................48
4.2.6.2
Sensitivity Analysis.................................................................................49
4.2.6.3
Secondary Efficacy Variables .................................................................51
4.2.6.4
Sequential Testing Procedure..................................................................51
4.2.6.5
Exploratory Efficacy Variable.................................................................51
4.2.6.6
Subgroup Analysis for Efficacy Variables...............................................55
4.2.7
Safety Variables......................................................................................58
4.2.7.1
Adverse Events.......................................................................................58
4.2.7.2
Clinical Laboratory Tests Evaluation ......................................................61
4.2.7.3
Electrocardiograms .................................................................................64
4.2.7.4
Vital Signs ..............................................................................................64
4.2.7.5
Pregnancy Test Results ...........................................................................65


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
6
4.3
Conventions............................................................................................65
4.3.1
Visit and Period Windows.......................................................................65
4.3.2
Post-Dosing Efficacy Observations .........................................................67
4.3.3
Assignment of Dates to Adverse Events and Laboratory Assessments.....67
4.3.4
Displays of Vital Signs............................................................................69
4.3.5
Calculation of Body Mass Index .............................................................69
4.3.6
Missing Dates Assessment for Concomitant Medications........................69
4.3.7
Fasting State ...........................................................................................69
4.3.8
Counting Rules for Adverse Events.........................................................70
4.3.9
Strip Sign for Selected Laboratory Data ..................................................70
4.3.10
Missing Insulin Dose ..............................................................................70
5.
INTERIM ANALYSES ..........................................................................71
6.
CHANGES OF ANALYSIS FROM PROTOCOL ..................................71
7.
REFERENCES .......................................................................................71
8.
APPENDICES........................................................................................73
LIST OF TABLES
Table 1
Exploratory objectives and outcome measures............................16
Table 2
Study Plan detailing the procedures............................................21
Table 3
Summary of the algorithm for inclusion based on HbA1c and 
eGFR .........................................................................................25
Table 4
Lack of Glycemic Control Criteria for Initiation of Open-Label 
Rescue Medication.....................................................................26
Table 5
Formulae Used to Transform Back the Results from ANCOVA 
Model or Longitudinal Model onto the Original Scale................38
Table 6
Patterns for Imputation of Missing HbA1c data at Week 24 with 
the MI-RD approach ..................................................................40
Table 7
Demographic and baseline characteristics...................................44
Table 8
Diabetes-Related Baseline Characteristics..................................44
Table 9
Baseline Renal Function Characteristics.....................................45
Table 10
Summary of Analysis to meet primary efficacy objective of 
HbA1c .......................................................................................50
Table 11
Summary of Analyses to Meet Secondary Efficacy Objectives...51
Table 12
Summary of analyses to exploratory analysis on continuous 
endpoints....................................................................................53
Table 13
Summary of exploratory analysis on categorical endpoints.........53


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
7
Table 14
Contrast Coefficients for the Example Gender-by-treatment 
Interaction..................................................................................56
Table 15
Subgroup analysis for the efficacy variables...............................56
Table 16
SI and C units.............................................................................62
Table 17
Visit Windows ...........................................................................66
LIST OF FIGURES
Figure 1
Study flow chart.........................................................................20
LIST OF APPENDICES
Appendix A
Criteria for Assessing Important Protocol Deviations .................73
Appendix B
Geographic Regions...................................................................75
Appendix C
Marked laboratory abnormalities................................................76
Appendix D
Laboratory Tests in Strip Sign Plan * .........................................78


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
8
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ACE-I
Angiotensin converting enzyme inhibitors
AE
Adverse Event
ALK-P
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
ARB
Angiotensin Receptor Blockers
AST
Aspartate Aminotransferase
AUA
American Urological Association
AZRand
AZ Randomization system 
BMI
Body Mass Index
BP
Blood Pressure
C
Conventional Units
CKD
Chronic Kidney Disease
CR
Copy Reference
CRA
Clinical Research Associate
CRF
Case Report Form 
CRO
Contract Research Organization
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTMS
Clinical Trial Management System
CV
Cardiovascular
DAE
Adverse Events Leading to Discontinuation of Study Medication
DB
Double-blind
DBP
Diastolic Blood Pressure
DILI
Drug-Induced Liver Injury
DKA
Diabetic ketoacidosis
DM
Diabetes Mellitus


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
9
Abbreviation or 
special term
Explanation
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) 
and Independent Ethics Committee (IEC)
E-code
 
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
Grand
Global Randomization system
Hb
Haemoglobin
HbA1c
Glycosylated Haemoglobin
HF
Heart Failure
HIV
Human Immunodeficiency Virus
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
LSM
Least Square Mean
IMPACT
Clinical Trial Management System
IVRS
Interactive Voice Response System
CCI
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
10
Abbreviation or 
special term
Explanation
IWRS
Interactive Web Response System
MAR
Missing at Random
MCMC
Markov Chain Monte Carlo
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI-RD
Multiple Imputation on Randomized Set
MMRM
Mixed-effects Model for Repeated Measures
MNAR
Missing not at Random
MG
Milligram
NYHA
New York Heart Association
OAD
Oral Anti-diabetic Drug
PI
Principal Investigator 
PPG
Post-Prandial Glucose
PTH
Parathyroid Hormone
RPD
Relevant Protocol Deviation
SAE
Serious Adverse Event 
SBP
Systolic Blood Pressure
sCr
Serum Creatinine
SD
Standard Deviation
SGLT2
Sodium Glucose Co-Transporter 2
SI
International System of Units
SU
Sulfonylurea
T2DM
Type 2 Diabetes Mellitus
TB
Total Bilirubin
TIA
Transient Ischemic Attack
TZD
Thiazolidinedione
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
11
Abbreviation or 
special term
Explanation
ULN
Upper Limit Of Normal
US
United States
UTI
Urinary Tract Infection
WBDC
Web Based Data Capture
WOCBP
Women of childbearing potential
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
12
AMENDMENT HISTORY
Version
Date
Brief description of change
1.1
15JUN2015
Removed baseline x treatment x week interaction term 
from Model 4.1.4.2
1.2
27APR2016
Added Tipping Point Analysis section, Placebo-based 
imputation and Dropout Reason-based Multiple 
Imputation for sensitivity analyses on primary efficacy 
analysis
Added proportion of patients with missing HbA1c
summary into sensitivity analysis
Moved the analysis of Repeated Measures mixed model of 
change from baseline to Week 24 (regardless of rescue, 
with an additional indicator for rescue use) from 
sensitivity analysis to exploratory analysis.
Added MMRM regardless of rescue or treatment 
discontinuation into sensitivity analysis
In section 4.3.2 Post-Dosing Efficacy Observations, added
(
SBP, eGFR, exploratory, insulin) to keep 
consistency with SAP for Dapa 23.
Modified the description for proportional analysis in 
section 4.1.9 Proportion of Patients with Pre-Defined 
Characteristics. The new approach by Zhang 2008 will be 
performed.
In Table 2, Days are adjusted to be same as the amended 
protocol.
In section of Double Blind Treatment Period (V4 to V8, 
24 weeks), changed OADs description to be aligned with 
protocol amendment v2.0.
In section of Rescue Medication Due to Lack of Glycemic 
Control, added GLP-1 agonist to exception list to be 
aligned with protocol amendment v2.0.
Removed all notations in Section 4.1; Added model 
effects description for percent change from baseline 
analysis. 
Removed summary of Creatine Clearance, as it’s not 
mentioned in the CSP. The physician confirmed eGFR 
would be used instead. 
Removed Hy’s law to be aligned with protocol 
amendment v2.0.
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
13
Version
Date
Brief description of change
Removed section of Changes of Analysis from Protocol as 
CSP has modified for those parts.
Modified Table 1 Exploratory objectives and outcome 
measures to be aligned with protocol amendment v2.0.
Removed Appendix A2 (Important Protocol Deviation 
criteria); Only keep Relevant Protocol Deviation in SAP 
which will be programmed. Important Protocol Deviation 
will be from IMPACT report and will be kept in a separate 
document.
Modified Section 2.3 Protocol Deviation accordingly.
Updated Estimands in Table 9
In section 1.1.1 Primary Objective, changed inclusion 
criteria for HbA1c from J10.5% to J11%, based on 
protocol amendment 3.0.
In section 1.2 Study Design, changed from
The study will be an international multi-centre study at 
approximately 55 centres (Canada, United States (US), 
Italy, Spain and Sweden). 
To 
The study will be an international multi-centre study at 
approximately 100 centres from countries across North 
America and European regions.
Based on protocol amendment 3.0.
The section 1.2 and Table 3 within that section have been 
updated for eGFR inclusion criteria modification based on 
protocol amendment 3.0 (remove average calculation 
between V2 and V3)
In section 2.1.1 Enrolled Patients Set, added text about 
how to handle re-screened patients due to protocol 
amendment 3.0.
In In section 4.2.6.2 Sensitivity Analysis, added a new 
sensitivity analysis with adjustment of the primary 
analysis estimand for both baseline HbA1c and baseline 
eGFR, to be aligned with protocol amendment 3.0.
In Appendix B, Geographic Regions, added new
countries.
Updated section 6, Changes analyses from protocol, as 
there are CSP amendments. 


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
14
Version
Date
Brief description of change
For Proportion of patients with pre-defined characteristics 
analyses, deleted reference of Tsiatis et al 2008 and Zhang 
et al 2008. The logistic regression model will be used for 
proportional analyses.
Updated Appendix A:
Added HbA1c criteria at Visit 1
Added Patient changed the dose of OADs, insulin anti-
hypertensive drugs, (change outside ±10%), for N7 
consecutive days during the single-blind lead-in and 
double-blind treatment period
1.3
24JUN2016
Replaces all “Relevant Protocol Deviations” to “Important 
Protocol Deviations”.
Removed Appendix B: SAS programming to perform 
sensitivity analyses using PROC MI
Demographic and Baseline Characteristics summaries 
reduced to Randomized Analysis Set.
In section 4.2.6.5, modified exploratory analysis on 
percent change from baseline in 
Changed from 
MMRM subgroup analysis to MMRM based on different 
subset population.
Added Section 4.3.10 Missing Insulin dose
19AUG2016
In section 4.2.7 AE of special interests, removed some 
items which were regarded as not necessary by the team. 
20OCT2016
Added section 1.1.5 Adjudication cases summarization
24JAN2017
Table 9, removed analysis for 
Repeated measures mixed model of QhbA1c to Week 24 
(regardless of rescue but prior to treatment 
discontinuation, with an additional indicator for rescue 
use)
30JAN2017
For proportional analysis using the logistic regression
model, the estimated odds ratio will be presented instead 
of the difference of the proportion between the treatment.
9FEB2017
Section 2.2.1: Added “Unblinding of data will be done 
between declaring “Clean File” and “Final Database 
lock”” to clarify the time point of the data unblinding.
Section 4.1.9: Added the description about pooling strata 
in logistic regression analysis.
2.0
28MAY2017
Update section 4.1.7 for sensitivity analysis for missing 
data
Added text for subgroup analysis with small strata
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
15
Version
Date
Brief description of change
09AUG2017
Removed Sections 4.1.7.1 and 4.1.7.2 for Placebo-Based 
Multiple Imputation and Tipping Point analysis from the 
SAP. 
Section 4.1.7.: Updated the seed for imputation
 
2.1
21SEP2017
Section 4.2.7.2 and Appendix C: Added 2 units (SI and C) 
for laboratory parameters where required.
2.2
27SEP2017
When only laboratory parameter unit is needed, the unit 
presented will be SI, except for 
which will be 
presented as CV- section 4.2.7.2 and appendix C
23OCT2017
Updated 4.2.7.1.6.1 Hypoglycemia to add commas to be 
explicit in the definition of events of hypoglycemia.
Updated to add ranges for conventional units in Appendix 
C.
Updated IPD 3 to remove “or beyond 40 – 65 
mL/minute/1.73 m2 at Visit 2” as agreed with AstraZeneca 
Study Physician
Updated as per the comments provided by AstraZeneca in 
“Reconciliation report for Statistical Analysis Plan Edition 
2” on 6th Oct 2017
1.
STUDY DETAILS
1.1
Study Objectives
1.1.1
Primary Objective
The primary objective is 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 who have inadequate glycemic control, defined as 
HbA1c N7.0% but J11% at Visit 1, and CKD stage 3A (eGFR 45 to 59 mL/min/1.73 m2, 
inclusive, at Visit 1, or Visit 2, or Visit 3 and eGFR 40 to 65 mL/min/1.73 m2, inclusive, at 
Visit 1).
1.1.2
Secondary Objectives
The secondary objectives are to compare dapagliflozin 10 mg and placebo after 24 weeks (or 
prior to rescue) of oral administration of double-blind therapy for the following:
!
The percent change from baseline in total body weight at Week 24
!
The change from baseline in FPG at Week 24
!
The change from baseline in seated SBP at Week 24
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
16
1.1.3
Safety Objective
The safety objectives include:
!
To examine eGFR changes during the study and 3-week post-treatment for 
dapagliflozin 10 mg and placebo.
!
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.
!
To evaluate the safety and tolerability of dapagliflozin 10 mg once daily in type 2 
diabetes and CKD stage 3A.
1.1.4
Exploratory Objectives
Exploratory objectives aim to investigate the treatment difference between dapagliflozin 
compared with placebo when added to current background therapy in patients with T2DM and 
CKD3A, for the parameters listed in Table 1.
Table 1
Exploratory objectives and outcome measures
Exploratory Objective:
Outcome Measure :
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
17
Table 1
Exploratory objectives and outcome measures
Exploratory Objective:
Outcome Measure :
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
18
Table 1
Exploratory objectives and outcome measures
Exploratory Objective:
Outcome Measure :
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
19
Table 1
Exploratory objectives and outcome measures
Exploratory Objective:
Outcome Measure :
1.1.5
Adjudication cases summarization
Pre-defined liver enzyme elevations will undergo adjudication. Adjudicated results will be 
summarized by treatment group. Liver abnormalities submitted for review  by the hepatic 
adjudication committee will be listed. 
All potential events of DKA will be recorded in the eCRF and submitted to an independent 
DKA Adjudication Committee. Adjudicated results will be summarized by treatment group.
DKA events submitted for review by the DKA adjudication committee will be listed.
1.2
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. 
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
20
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. Figure 1 illustrates details on timing of visits. Table 2
provides details on schedule of study procedures.
The study will be an international multi-centre study at approximately 100 centres from 
countries across North America and European regions.
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


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
21
Table 2
Study Plan detailing the procedures
Study Period
Screening 
period
Lead-in period
Treatment period
Follow-
up period
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
Inclusion/Exclusion Criteria
X
X
Xg,h
Allocation of E-code via 
IVRS/IWRS
X
Randomization to study treatment 
via IVRS/IWRS
X
Demographics
X
Medical and Surgical History
X
Brief Physical Examinationi
X
X
X
X
X
Complete Physical Examinationj
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
22
Study Period
Screening 
period
Lead-in period
Treatment period
Follow-
up period
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
Seated BP and Pulse
X
X
X
X
X
X
X
X
X
Orthostatic BP and Pulse
X
X
X
X
X
X
12-lead ECGk
X
Hepatitis Screen Panel
X
Blood samples for Safety 
Laboratory Panell
X
X
X
X
X
X
Blood samples for HbA1c
X
X
X
X
X
X
Blood samples for S-Creatinine 
(eGFR calculation)
X
X
X
X
X
X
X
X
Blood samples for FPG
X
X
X
X
X
Assess FPG for Rescue
X
X
 
X
X
X
X
 
X
X
X
Pregnancy testm
X
X
X
X
X
X
X
X
X
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
23
Study Period
Screening 
period
Lead-in period
Treatment period
Follow-
up period
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
Timed urine sample collection (24-
hours)
X
X
Dietary and life-style advice
X
X
X
X
X
Dispense Glucose Meter and/or 
Supplies (including diaries) 
/Provide Instructions
X
X
X
X
X
X
X
Review of diaries
X
X
X
X
X
X
X
Dispensation of Study Medication 
via IVRS/IWRS
X
X
X
X
Return of Study Medication and 
accountability
X
X
X
X
Adverse event review (AEs and 
SAEs)n
X
X
X
X
X
X
X
X
X
Hypoglycemic events review 
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
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. 


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
24
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 CSP, 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 CSP, Section 5.2.1, Table 3.
m
Only for WOCBP. Blood sample will be collected for serum XHCG 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).


Screening Period (V1 to V2, 2 weeks)
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.
Placebo Lead-in Period (V2 to V4, 4 weeks)
At Visit 2 (start of lead-in), patients will be examined for HbA1c, and eGFR level, from blood 
sample obtained from Visit 1. If the HbA1c is N7.0% and J11% 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, the eGFR 
value within the range of 45-59 mL/min/1.73 m2 at Visit 1, or Visit 2, or Visit 3, and the 
standard lab values (from Visit 2) will be randomized to the 24-week double-blind treatment 
period. 
Table 3
Summary of the algorithm for inclusion based on HbA1c and eGFR
Visit
Algorithm
Sample obtained at Visit 1:
HbA1c N7.0% and J11%
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
At randomization, patients will be stratified according to pre-enrolment anti-hyperglycemic 
therapy. The 5 strata are listed in Section 1.3.
Double Blind Treatment Period (V4 to V8, 24 weeks)
Following completion of the lead-in phase, eligible patients will enter the 24-week double-
blind treatment phase. 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 24-week double-blind 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.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
26
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 the study 
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. 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 (see Table 4 below), 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.
Table 4
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.
Irrespective of study visit number, patients who meet rescue criteria in the treatment period 
must first complete the Week 24 visit’s procedures before receipt of open-label anti-diabetic 
rescue medication to ensure that important study endpoint measurements are collected.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
27
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 4 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.
Follow-up Period (V8 to V9, 3 weeks)
After completion of the treatment period, patients will enter a 3-week 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. Patients who discontinue study drug will remain in the study 
for follow-up 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, but will complete all scheduled study visits and 
procedures.
The total planned study duration from Visit 1 to the safety follow-up (Visit 9) will be 33 
weeks.
1.3
Treatment Group Assignment
The randomization codes will be computer generated by AstraZeneca R&D using the AZ 
Randomization system (AZRand) and loaded into the IVRS/IWRS database. Randomization 
codes will be generated to ensure approximate balance (1:1) between the two treatment arms 
(dapagliflozin 10 mg or matching placebo, once daily).
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


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
28
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.
1.4
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.
2.
ANALYSIS SETS
2.1
Definition of Analysis Sets
2.1.1
Enrolled Patients Set
The Enrolled Patients Data Set includes data collected from all patients who signed informed
consent. For this study, per change to the inclusion/exclusion criteria in Amendment 3, 
patients can be re-enrolled a single time, but they cannot be re-randomized. Re-enrolled 
patients will be assigned new Ecode and will be counted only once in the Enrolled Patients 
Data Set.
2.1.2
Lead-in Analysis Set
For the summary of patients enrolled in the lead-in period, all patients with an E-code and who 
took at least one dose of lead-in medication (Placebo) will be included in the analysis set.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
29
2.1.3
Randomized Analysis Set
For the summary of demographic and baseline characteristics, all patients assigned a 
randomization code by the IVRS/IWRS system will be included in the analysis set.
2.1.4
Full Analysis Set 
The primary efficacy analysis will be performed on the Full Analysis Set (FAS) which will 
consist of all randomized patients who took at least one dose of double-blind study drug and 
have a non-missing baseline value and at least one post-baseline on any of the efficacy 
variables (HbA1c, total weight, FPG and SBP). 
When the Full Analysis Set is used, patients will be presented in the treatment group to which 
they were randomized regardless of the treatment actually received.
2.1.5
Per Protocol (PP) Analysis Set
The PP Analysis Set is a subset of the Full Analysis Set and will consist of patients who do 
not deviate from the terms specified in Appendix A (important protocol deviation), which may 
affect the study outcome significantly and interpretation of the study results. All decisions to 
exclude patients from the primary data set will be made prior to the unblinding of the study. 
The PP Analysis set will only be applied if the PP Analysis set has a minimum of 10% fewer 
patients than the Full Analysis Set due to important protocol deviations. In that case, only the 
primary efficacy endpoint of change from baseline in HbA1c will be analyzed using the PP 
Analysis set. Demographics, and baseline diabetes characteristics will be summarized using 
the PP Analysis set if necessary. 
2.1.6
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 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.
2.2
Blinding and Unblinding
2.2.1
Blinding
The investigator, AstraZeneca personnel, and patients will remain blinded to treatment 
allocation throughout the entire study period. The database used for the analysis of the double-


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
30
blind data of the study will be locked after all patients have terminated the study. In order to 
protect the integrity of the treatment period of the study, the patients and investigators will not 
have access to the individual treatment assignments until the study has completed.
Unless otherwise specified, to maintain integrity of the study, HbA1c and urinary glucose 
values will be masked to AZ as well as on laboratory reports to investigators during the
double-blind study period. See protocol for further details.
2.2.2
Unblinding
Blinding is critical to the integrity of this clinical trial. However, in the event of a medical 
emergency or pregnancy, during which knowledge of the identity of the investigational 
product is critical to the patient's management, procedures are in place to have the blind 
broken for an individual patient. A separate procedure is in place for unblinding in case of 
expedited safety reporting to regulatory authorities.
Unmasked HbA1c and urinary glucose values will be transferred from the Central Lab 
between “Clean File” and “Database Lock”. Unblinding of treatment data will also occur after 
“Clean File” and before “Database Lock”. The locked database will be unblinded for reporting 
purposes.
2.3
Protocol Deviation
AstraZeneca uses ICH E3 terminology for protocol deviations, which are all important 
deviations related to study inclusion or exclusion criteria, conduct of the trial, patient
managements or patient assessment.
2.3.1
Protocol Deviation Monitoring
During study conduct, protocol deviations will be closely monitored and identified from two 
sources:
!
IMPACT monitoring – deviations will be automatically derived from the database via 
edit checks and must be reported as a protocol deviation in IMPACT by the Site 
Monitor. Some protocol deviations which do not have corresponding data checks must 
be manually checked in the clinical database (i.e. Rave) and must be reported as a 
protocol deviation in IMPACT by the Site Monitor.
!
Statistical programmed protocol deviation – These are deviations generated by 
execution of programs written using the predefined deviator descriptions in the SAP 
Appendix A. 
The reports or information collected from IMPACT monitoring report will be reviewed and 
assessed periodically during study conduct by AZ/vendor study team and documented in 
EXCEL spreadsheet, with study id, patient id, PD collection date, PD free text term, PD coded 
term, PD source, major or minor criteria, and comments.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
31
In the case of a discrepancy (e.g. statistical programming shows patient is 100% compliant 
with study drug but IMPACT monitoring report shows patient is non-compliant), the 
statistical programming from the clinical database will be considered as the definitive source. 
A decision will be made prior to unblinding the study to determine which protocol deviations 
may significantly affect the study outcome and should be excluded completely or partially 
from the Per Protocol Analysis.
2.3.2
Protocol Deviation Reporting
The criteria for all major and minor protocol deviations will be provided in a separate protocol 
deviation document from the SAP. Protocol deviations that the study team considers to be 
important will be tabulated or listed in CSR.
Protocol deviations that may affect the study outcome significantly and the interpretability of 
the study results are defined as important protocol deviations (IPD). The criteria for important
protocol deviations are given in Appendix A of the SAP. 
Patients having IPD (Appendix A) will be summarized by treatment group and overall. 
Separate listings of all patients with important protocol deviations will also be produced.
The details of instruction of programming for IPD would be described in a separate document 
from the SAP. 
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Primary Efficacy Variable
The primary outcome variable will be the change from baseline in HbA1c (%).
3.2
Secondary Efficacy 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).
3.3
Exploratory Efficacy Variables
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
32
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
33
3.4
Safety and Tolerability Variables
No formal statistical testing of the safety and tolerability variables will be carried out. The 
safety and tolerability variables will be individually summarized. The safety and tolerability 
variables are:
!
Incidence of AEs (including SAEs, other significant AEs, and AEs of special
interest).
!
Laboratory parameters (including marked abnormalities in clinical laboratory tests)
!
eGFR
!
Vital signs
4.
ANALYSIS METHODS
The primary analysis of the change in HbA1c from baseline to Week 24 will be based on a 
mixed model repeated measures (MMRM) analysis using the FAS, and will include all 
available data following randomization up to and including Week 24. For all patients that are 
administered rescue therapy or discontinue treatment during the double-blind treatment 
period, only those measurements made on or prior to rescue or treatment discontinuation, 
(whichever occurs first) will be included in analysis.
All statistical comparisons of primary and secondary efficacy variables will be based on 
2-sided test procedures with an alpha level of significance of 0.05 required to infer statistical 
significance, unless otherwise specified. All analyses will report nominal p-values. No other 
correction to the reported p-values will be made for the analysis of secondary measures.
Where appropriate, interval estimates at a nominal 95% level of confidence will be presented.
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
34
An additional analysis to support primary analysis will be repeated with the primary variable 
(change from baseline in HbA1c using MMRM) at week 24 on the per-protocol analysis set. 
The sensitivity analysis in the Per Protocol Set will be applied to primary efficacy endpoints 
only if there will be more than 10% difference in number of patients from Full Analysis Set.
Additional sensitivity analyses (including Multiple Imputation based on Retrieved Dropouts 
(MI-RD) and the Washout Imputation) will be performed to address the impact of missing 
data or initiation of rescue. 
Exploratory analyses of continuous exploratory endpoints that undergo multiple assessments 
over the 24 week double-blind treatment period will be performed either using MMRM
analyses as described for the primary analyses, or using analysis of covariance (ANCOVA), 
logistic regression, or descriptive summaries as warranted. Exploratory subgroup analysis will 
include additional covariates and interaction terms for the subgroup variables when warranted.
4.1
General Principles
The SAS System Version 9.4 will be used to perform the statistical analyses. All statistical 
evaluations, summaries, and tabulations will be performed by qualified personnel at Quintiles. 
Before unblinding of the study following clean file declaration, all decisions on the 
evaluability of the data for each individual patient will be made and documented and each 
patient will be assigned to the appropriate analysis data set.
All efficacy analyses will be based on the Full Analysis Set. The Safety Analysis Set will be 
used for analysis of all safety and tolerability variables.
Descriptive statistics for continuous data will include n, mean, median, standard deviation, 
minimum and maximum value. Descriptive data for categorical data will include n, frequency, 
and percentage.
The day of first dose of double-blind study medication (Day 1) will be defined as the 
reference start date for the randomized treatment period and will appear in the listings where 
an assessment date or event date appears when appropriate. 
!
If the date of the event is on or after the reference date then: 
Study Day = (date of event – reference date) + 1.
!
If the date of the event is prior to the reference date then: 
Study Day = (date of event – reference date).
A windowing convention will be used to determine the analysis value for a given study 
visit for observed data analyses. The window definitions as outlined in Section 4.3.1 will 
be used for the efficacy and safety analyses.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
35
4.1.1
Baseline Values
For all efficacy variables summarized for the FAS, the baseline value will be the last non-
missing value on or prior to the date of the first dose of double-blind study drug. For the 
sensitivity analyses on primary efficacy variable when summarized for the Randomized 
Analysis Set, if a patient is randomized but is not administered double-blind study medication 
then the baseline value will be the last non-missing value on or prior to the randomization 
date.
The baseline value of each safety laboratory test or ECGs or physical exam endpoint is 
defined as the last assessment (either numerical or character value) on or prior to the date of 
the first dose of double-blind study drug.
4.1.2
Change and Percent Change from Baseline
Change from baseline to any randomized treatment period Week t is defined as follows:
	 = 			  		   		
Percent change from baseline to any randomized treatment period Week t is defined as 
follows:
		 	 = 			  		   		
Baseline
× 100
The “Week t” to which a measurement belongs is determined using the conventions described 
in Section 4.3.
4.1.3
Derivation of Efficacy Variable at Rescue/ Premature Discontinuation
In efficacy analyses, the glycemic parameters will only include measurements obtained prior 
to or on the date of rescue medication administration or discontinuation of double-blind 
medication (whichever is earlier). An exception would be in sensitivity analysis, where the 
analysis is performed on data regardless of rescue (see more details in Section 4.2.6.2).
For secondary efficacy variables of body weight (kg), seated SBP (mmHg) and remaining
exploratory variables, measurements after rescue medication will not be excluded from the 
analyses.
Patients not completing the treatment period should have all Week 24 visit procedures done at 
the time of study discontinuation or rescue.
Patients who meet the pre-specified rescue criteria, at the specified visit described in Table 4, 
will be scheduled for a follow-up visit (within 3-5 days) to obtain a confirmatory central lab 
FPG value. If the confirmatory FPG value still meets the criteria, the patient will be rescued.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
36
4.1.4
Analysis of Covariance
4.1.4.1
ANCOVA Model for Change from Baseline
Unless otherwise specified, when an analysis of covariance (ANCOVA) model is used to 
analyze a continuous variable, the model will include the fixed main effects of treatment 
group, anti-diabetic treatment strata at randomization, and the baseline measurement as a 
covariate.
The ANCOVA will present least squares (LS) mean estimates and 2-sided 95% confidence 
intervals (CIs) for mean changes from baseline by treatment group and differences in LS mean 
estimates, the corresponding 2-sided 95% Cis and nominal p-values.
4.1.4.2
ANCOVA Model for Percent Change from Baseline 
Unless otherwise specified, for analyses of parameters in terms of percent change from 
baseline at Week t, ANCOVA analysis will be performed on the difference between natural 
logarithmically transformed value at the end of treatment and at baseline [loge(post) –
loge(baseline)], and will include terms for treatment, the log-transformed baseline value and 
anti-diabetic treatment strata at randomization.
Least squares estimates and differences and the corresponding 95% confidence intervals 
obtained from the model output will be used to generate estimates of (geometric) mean 
percent change. Where applicable, the t-statistic corresponding to the Type III sums of squares
for the differences in the least squares means will be used to obtain p-values for treatment 
group comparisons.
Table 5 details the formulae that will be used to transform back the results from the ANCOVA 
model to obtain the values reported in the tables.
4.1.5
Last Observation Carried Forward (LOCF)
Unless otherwise specified, when an analysis of covariance (ANCOVA) model is used to 
analyze a continuous variable, analyses will be based on measurements at the time point Week 
24, if no measurement is available at that time point Week 24 (patient has discontinued before 
Week 24, or measurement not taken at Week 24 though patient was not discontinued), the last 
available post-baseline measurement will be carried forward (LOCF). For glycemic 
parameters for patients who started rescue medication or discontinued double-blind 
medication prior to Week 24, their last post-baseline measurement taken prior to or on the 
date of the first dose of rescue medication or the discontinuation date (whichever is earlier) 
will be used.
4.1.6
Longitudinal Repeated Measures Analysis
4.1.6.1
Longitudinal Repeated Measures Analysis for Change from Baseline
For changes from baseline to Week 24 in all efficacy parameters (e.g. HbA1c, FPG, and 
seated SBP etc.) and exploratory analysis on continuous endpoints (e.g. eGFR, 
 
etc.), analyses will be based on a longitudinal repeated measures 
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
37
(MMRM) analysis using “direct likelihood”. The SAS procedure PROC MIXED will be used. 
The preferred model for this analysis 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 covariance structure will be used to model the within-patient error. The 
Kenward-Roger approximation (Kenward and Roger, 1997) will be used to estimate 
denominator degrees of freedom. 
In case of non-convergence of the preferred model or memory space issues, the following 
back-up models are defined:
!
The first backup model is the same as the preferred model but the Kenward-Roger
method will be replaced by Satterthwaite approximation.
!
The second backup model is the same as the preferred model but without the term for
baseline measurement-by-week interaction.
The second back-up model will only be provided if the first back-up model does not converge 
or has memory issues.
The mixed model will provide least-squares mean estimates, standard errors and 2-sided 95%
confidence intervals within each treatment group. The differences in least-squares means, 2-
sided 95% confidence intervals and p-value of the differences in week 24 visit estimates 
between dapagliflozin and placebo will be presented as well.
4.1.6.2
Longitudinal Repeated Measures Analysis for Percent Change from Baseline
Unless otherwise specified, for all percent changes from baseline to Week 24 in efficacy 
parameters (e.g. percent change from baseline in body weight (kg), percent change from 
baseline in 
 analyses will use the longitudinal repeated measures analysis; as the 
difference between the natural logarithmically transformed Week 24 and baseline values.
The difference between the natural logarithm of Week 24 values and the natural logarithm of 
baseline values will be used as response variable for this analysis model. The preferred 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 natural logarithm of baseline measurement and natural 
logarithm of baseline measurement-by-week interaction. 
Exponentiation of estimates based on differences on a natural logarithmic scale will be 
performed prior to reporting, and geometric values (e.g., estimates, standard errors, 
differences and standard errors, and 95% confidence limits) will be converted to percentages 
prior to reporting, and reported on a percentage scale. See Table 5 for more details.
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
38
Table 5
Formulae Used to Transform Back the Results from ANCOVA Model 
or Longitudinal Model onto the Original Scale.
Quantity
Computation method
Geometric mean of the Week t to baseline
ratio
exp(mean change from baseline in natural
logarithm)
Mean percent change from baseline
100 x [exp(mean change from baseline in natural 
logarithm) – 1]
Standard error of mean percent change
from baseline
100 x exp(mean change from baseline in
natural logarithm) x standard error of mean
change from baseline in natural logarithm
– or, equivalently –
100 x Geometric mean of the Week t to
baseline ratio x standard error of mean
change from baseline in natural logarithm
Lower confidence limit for mean percent
change from baseline
100 x [exp(lower confidence limit for mean
change from baseline in natural logarithm)
– 1]
Upper confidence limit for mean percent
change from baseline
100 x [exp(upper confidence limit for mean
change from baseline in natural logarithm)
– 1]
Adjusted geometric mean of the Week t to
baseline ratio
exp(Adjusted mean change from baseline in
natural logarithm)
Adjusted mean percent change from
baseline
100 x [exp(Adjusted mean change from
baseline in natural logarithm) – 1]
Standard error of adjusted mean percent
change from baseline
100 x exp(Adjusted mean change from
baseline in natural logarithm) x standard
error of mean change from baseline in
natural logarithm
– or, equivalently –
100 x adjusted geometric mean of the Week
t to baseline ratio x standard error of mean
change from baseline in natural logarithm
Lower confidence limit for adjusted mean
percent change from baseline
100 x [exp(lower confidence limit for
adjusted mean change from baseline in
natural logarithm) – 1]
Upper confidence limit for adjusted mean
percent change from baseline
100 x [exp(upper confidence limit for
adjusted mean change from baseline in
natural logarithm) – 1]


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
39
Table 5
Formulae Used to Transform Back the Results from ANCOVA Model 
or Longitudinal Model onto the Original Scale.
Quantity
Computation method
Adjusted geometric mean of the Week t to
baseline ratio achieved with each
dapagliflozin treatment arm relative to that
achieved with Control, expressed as a
percent difference.
Please note that for the SAS output, a
shorter text will be used:
Adjusted GM of Week t/Baseline for each
dapagliflozin treatment arm relative to
Control, in % difference.
100 x (((adjusted mean percent change for
dapagliflozin treatment arm
+100)/(adjusted mean percent change for
Control +100)) – 1)
– or, equivalently –
100 x (exp(difference in adjusted mean
change from baseline between dapagliflozin
treatment arm and Control in natural
logarithm) – 1)
4.1.7
Handling of Dropouts or Missing Data
The primary estimand will be the treatment difference at Week 24 if all subjects had remained 
in the trial and received treatment as planned without rescue medication. In order to address 
the impact of missing data, initiation of rescue therapy, and premature treatment 
discontinuation on the primary efficacy analysis, the analysis of the primary efficacy endpoint 
will be repeated in sensitivity analyses.
For the assessment of efficacy, interpretation of results in the presence of missing data 
depends on the missing data mechanism assumptions as well as on the use of data collected 
after initiation of rescue therapy or premature study treatment discontinuation in the analysis.
In this study, the primary efficacy analysis is performed using an MMRM which assumes 
MAR, and based on data collected up to initiation of rescue or premature study treatment 
discontinuation, whichever occurs first.
Two additional methods of sensitivity analyses will be performed.  These are Multiple 
Imputation based on Retrieved Dropouts (MI-RD) and Washout Imputation based on 
Randomized Set.
In multiple imputation a common (fixed) seed value of 29653, and 1000 simulations will be 
performed. The detailed analysis plan and implementation of these methods are described in 
Sections 4.1.7.1 and 4.1.7.2 to, respectively.
To address the impact of missing data on primary efficacy analysis, the amount of missing 
data, the distribution of missing data among treatment groups, and the reasons for missing 
data will be examined. The proportion of patients with missing HbA1c assessments will be 
summarized by treatment group, scheduled time point during the double-blind treatment 
period, and categories of missing causes if applicable. In addition, spaghetti plots of mean 
HbA1c profiles over time will be provided for each treatment to assess the patterns of missing 
HbA1c assessments, with patients grouped according to the time of the last assessment prior 
to rescue or discontinuation.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
40
4.1.7.1
Multiple Imputation based on Retrieved Drop-outs (MI-RD)
In MI-RD, all patients in the randomized set who have a baseline assessment (regardless of 
rescue or treatment discontinuation) will be included in the analysis. Based on status of 
whether the patients have early treatment discontinuation and whether the assessment is 
available at Week 24, the population will be categorized as 4 subpopulations described in 
Table 6. 
The main steps of the implementation of MI-RD are described below. 
Step 1: Impute missing data for patients without HbA1c at Week 24 using a regression model 
imputation based on data from patients who discontinued treatment but had HbA1c 
assessment at Week 24 within that treatment group. The HbA1c baseline will be used as 
explanatory variable for imputation. If, for each (protocol-defined) visit where there is at least 
1 patient with a last on-treatment assessment and is missing a Week 24 HbA1c value, there are 
(at that same visit) sufficient numbers of patients with a last on-treatment assessment that 
subsequently discontinued treatment but have a Week 24 HbA1c value, then the missing 
Week 24 HbA1c values will be imputed from the non-missing Week 24 HbA1c values by 
“last on-treatment visit” within each treatment group. Otherwise, if there are sufficient 
numbers of patients that discontinued treatment but have a Week 24 HbA1c value (regardless 
of last protocol-defined visit “on-treatment”) then missing Week 24 HbA1c values will be 
imputed from the patients that have discontinued treatment but have Week 24 HbA1c values 
within each treatment group. The imputation population and process are described in Table 6. 
Imputation will be done within each treatment group.
Step 2: Analyze the multiple imputed HbA1c change from baseline at Week 24 using 
ANCOVA model. Combine estimates obtained from multiple imputed datasets based on 
Rubin’s combination rules (Little R., Rubin D.B. 2002).
The MI-RD approach requires a sufficient number of patients who discontinued treatment but 
had HbA1c assessment at Week 24 in each treatment. If there is not a sufficient number of 
patients to do the analysis, then this approach will not be implemented.
Table 6
Patterns for Imputation of Missing HbA1c data at Week 24 with the 
MI-RD approach
Subpopulations (patterns) considered in the imputation 
process
Imputation at Week 24
Subpopulation 1: Patients who were on treatment with HbA1c 
at Week 24.
No action
Subpopulation 2: Patients who discontinued treatment by 
Week 24 but had HbA1c assessments at Week 24.
No action 


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
41
Table 6
Patterns for Imputation of Missing HbA1c data at Week 24 with the 
MI-RD approach
Subpopulations (patterns) considered in the imputation 
process
Imputation at Week 24
Subpopulation 3: Patients who discontinued treatment by 
Week 24 without HbA1c assessments at Week 24. 
Use data from Subpopulation 2 
patients to estimate imputation 
model. 
Subpopulation 4: Patients who did not discontinue treatment 
prematurely but without HbA1c assessments at Week 24
(patients lost to follow-up).
Use data from Subpopulation 2 
patients to estimate imputation 
model. 
4.1.7.2
Washout Imputation
In washout-imputation, all patients in the randomized set who have a baseline assessment 
(regardless of rescue or treatment discontinuation) will be included in the analysis. This 
imputation method will only impute the time point at Week 24 for the active treatment using 
multiple imputation regression with randomization strata and baseline HbA1c as the 
predictors. This approach ignores any post-baseline changes in the HbA1c values when 
predicting missing Week 24 values and will impute all patients similar to an average placebo 
patient. ANCOVA will be used as the analysis method.
The main steps of the implementation of the washout imputation are described below. 
Step 1: Impute Week 24 missing data for patients in the active treatment using regression 
model multiple imputation based on data from the placebo arm. For patients in placebo arm 
missing data at any time point will be imputed assuming MAR mechanism. The variables used 
as explanatory variables for imputation include Randomization strata and HbA1c baseline.
Step 2: Analyze the multiple imputed data at Week 24 using ANCOVA model. Combine 
estimates obtained from multiple imputed datasets based on Rubin’s combination rules (Little
R., Rubin D.B. 2002).
4.1.8
Summaries of Continuous Endpoints
Descriptive statistics will be used to present efficacy and safety variables. For continuous 
variables, n, mean, standard deviation (or standard error), median, minimum, and maximum 
will be presented by visit when applicable.
The changes from baseline will be summarized for relevant efficacy and safety parameters and 
will include 95% CIs for means. The percent changes from baseline will be summarized for 


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
42
selected lab parameters and will include 95% CIs for means. Summaries for continuous 
endpoints will also include quartiles.
4.1.9
Proportion of Patients with Pre-Defined Characteristics 
Exploratory analyses of variables that represent proportions of patients (e.g. proportions of 
patients achieving response in 
 at Week 24 LOCF) will be performed using the 
logistic regression model when there are at least 5 responders in each treatment group. For 
proportion of responders 
, estimates, confidence intervals, and 
tests will be obtained using logistic regression model with adjustment for baseline variable(s)
and pooled randomization strata to accommodate composite endpoints (e.g, adjustment for 
baseline 
and pooled randomization strata). 
For analysis using the logistic regression model, the pooled randomization strata will be used 
as the adjustment factor. Patients with randomization strata in Metformin-based regimen, 
SU-based regimen, TZD-based regimen, and Other regimen will be pooled together as in one 
strata group called as “oral antidiabetic medications”. For the analysis on the proportion of 
patients initiating insulin therapy in patients not on insulin at the start of the study, since all 
patients would be in strata of “oral antidiabetic medications”, strata will be excluded in model
in this analysis.
The estimated odds ratio of dapagliflozin treatment group to the placebo group will be 
displayed along with standard error and the 95% confidence intervals. P-values will be 
calculated if applicable. Raw proportions will also be displayed by treatment group. When 
there are less than 5 responders in each treatment group, the unadjusted (and difference) 
proportions, exact 95% confidence interval, and p-values from the Fisher’s exact test (when 
applicable) will be provided. Although p-values will be generated for exploratory endpoints, 
statistical significance will not be inferred and claims will not be made.
4.1.10
Summaries of Shifts from Baseline in Categorical Variables
Changes from baseline in certain categorical variables will be summarized using shift tables. 
Frequencies and percents of patients within each treatment group will be generated for levels 
of cross-classifications of baseline and the on-treatment value of the variable. The on-
treatment value can be either the value at a certain time point, (for example, laboratory tests)
or the minimum/maximum value in the direction of toxicity, which has been observed during 
a study period. Treatment group differences will not be assessed in summaries of shifts.
4.1.11
Kaplan-Meier Curve and Estimates for Time-To-Event Analyses
Kaplan-Meier plots (Kaplan EL and Meier P 1958) will be used to generate product-limit 
estimates of probabilities for 
 
 by treatment for the 24-week double-blind period. Estimated probabilities will be 
displayed by treatment group as “overlay curves”. Probabilities will be connected to form a 
“survival curve” across rescue times and the last rescue will be carried-forward to Week 24. 
Additionally, a summary table will accompany the plot and will display the Kaplan-Meier 
estimates of the cumulative proportion (with 95% CI calculated based on Greenwood’s 
CCI
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
43
method when applicable (Greenwood M 1926)) of patients with event at specific time points 
by treatment group. If the estimated lower bound of 95% CI is below 0 or the estimated upper 
bound of 95% CI is over 1, then it will be restricted to 0 or 1 respectively. Unless otherwise 
specified, the plot will be presented only when there are at least 5 events in one treatment 
group.
4.1.12
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].
4.2
Analysis Methods
4.2.1
Patient Disposition
All patients enrolled (who signed informed consent) will be summarized. The disposition of 
patients for the lead-in period, the double-blind treatment period and the whole study which 
include follow-up period will be summarized. 
The summary of status in the lead-in period will include all patients receiving at least one dose 
of study drug (placebo) during the lead-in period. The summary of status in the double-blind 
treatment period will include all patients in Randomized Data Set. The number and percent of 
patients who entered, completed and discontinued, with the reasons for discontinuation will be 
summarized for each period (lead-in, double-blind treatment and the whole study which 
includes follow-up period). Summaries of double-blind and the whole study which includes 
follow-up period will be made by treatment group and overall.
A listing of patients who discontinued from the lead-in period and from the double-blind 
treatment period will be provided.
Patients enrolled, randomized, and treated will be summarized by country and study site.
4.2.2
Demographics and Baseline Characteristics
Demographic and other baseline characteristics, including diabetes-related characteristics and 
renal function characteristics will be summarized by treatment group and overall, using the 
Randomized Data Set.
Demographic and baseline characteristics are listed in Table 7. Diabetes related baseline 
characteristics are listed in Table 8. Common renal function baseline characteristics are listed 
in Table 9.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
44
Table 7
Demographic and baseline characteristics
Characteristic
Summarized as
Categories
Gender
Categorical
Male, Female
Age
Categorical and Continuous
<65 yrs
N65 yrs
Female Age
Categorical
J50 yrs
>50 yrs
Race
Categorical
White
Black or African American
Asian
Native Hawaiian or Other Pacific
Islander
American Indian or Alaska Native
Other
Ethnicity
Categorical
Hispanic or Latino
Not Hispanic or Latino
Body weight
Continuous
--
Continuous
--
Body Mass Index
Categorical and Continuous
<25 kg/m2 
N25 kg/m2 
N27 kg/m2 
N30 kg/m2 
Geographic Region
Categorical
As defined in Appendix B
Table 8
Diabetes-Related Baseline Characteristics
Characteristic
Summarized as
Categories
Duration of type 2 diabetes
Categorical and Continuous
<3 yrs
N3 and J10 yrs
>10 yrs
HbA1c
Categorical and Continuous
<8%
N8-<9%
N9-<10%
N10%
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
45
Table 8
Diabetes-Related Baseline Characteristics
Characteristic
Summarized as
Categories
FPG
Categorical and Continuous
<110 mg/dL
110 - <150 mg/dL
150 - <200 mg/dL
200 - <240 mg/dL
240 - <300 mg/dL
300 mg/dL
pre-enrolment anti-
hyperglycemic therapy
Categorical
Insulin-based regimen
SU-based regimen
TZD-based regimen
Metformin-based regimen
other regimen
Table 9
Baseline Renal Function Characteristics
Characteristic
Summarized as 
Categories
eGFR (MDRD)
Categorical and Continuous
<30 mL/min/1.73 m2
30 and <45 mL/min/1.73 m2
45 and <60 mL/min/1.73 m2
60 and < 90 mL/min/1.73 m2
90 mL/min/1.73 m2
All summaries of continuous characteristics will be based on non-missing observations. 
Summary statistics including mean, median, SD, the first and third quartiles will be calculated. 
For categorical characteristics, percents will be calculated out of the total number of patients 
in the data set, overall and by treatment group (ie, each denominator includes the number of
patients with missing/unknown values for the endpoint).
Duration of Type 2 diabetes is calculated as the number of years from Type 2 diabetes
diagnosis date to informed consent date:
(consent date - diagnosis date + 1) / 365.25.
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
46
The duration of diabetes will be included in the baseline diabetes characteristics listing. If the 
date Type 2 diabetes was diagnosed is partially missing, the following rules will take effect:
!
Missing day, but month and year are present: the day will be imputed as the 15th day 
of the month.
!
Missing day and month, but year is present: the day and month will be imputed as 30 
June of the year.
!
Missing year, but day and month are present: No imputations will occur, and the 
patient will be excluded from all summaries related to duration of Type 2 diabetes.
!
Missing day, month and year: No imputations will occur, and the patient will be 
excluded from all summaries related to duration of Type 2 diabetes.
If any such imputed date falls after the consent date, then the diagnosis date will be taken as 
equal to the consent date.
Demographic and baseline diabetes characteristics will be presented in listings for each patient
in the Randomized analysis set.
4.2.3
Specific and General Disease Histories
The numbers and percents of patients with diabetes history, general medical history findings 
and surgical history will be summarized by body system for each treatment group and overall
using the Randomized Analysis Set.
For these displays, percents will be calculated out of the total number of patients in the data
set, overall and by treatment group (i.e., each denominator includes the number of patients
with missing/unknown values for the endpoint).
The specific disease history and general medical history will be presented in listings for each 
patient in the Randomized Analysis Set.
4.2.4
Current and Concomitant Medications
Current and concomitant medications will be summarized using the Safety analysis set by 
drug class (anatomic class and therapeutic class), generic drug name and treatment group, as 
defined by the AstraZeneca Drug Dictionary most current at time of database lock. A 
summary will be produced for each of the following:
!
all current medication
!
all concomitant medication
!
all concomitant diuretic medication
!
all concomitant ARB and/or ACE-I medication
!
all concomitant anti-hypertensive medication
Current medications are defined as medications with a start date prior to the first day of
double-blind treatment period and without a stop date prior to the consent date, i.e. current 


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
47
medication will be any medication with at least 1 dose taken on or after the day of consent 
date up to the day prior to the first dose of study medication.
Concomitant medication during the double-blind treatment period is defined a medication 
with either
!
a recorded medication start date falling within the double-blind treatment period, or
!
a recorded medication start date prior to the first day of study medication during the 
double-blind treatment period without any recorded medication stop date prior to the 
start of the double-blind treatment period.
This means that concomitant medications for the double-blind treatment period will be any 
medication taken from start of the double-blind treatment period up to the end of the double-
blind treatment period.
Missing and partial date handling of start and stop dates of previous, current and concomitant 
medications, is described in Section 4.3.6. 
4.2.5
Extent of Exposures
4.2.5.1
Study Therapy
Extent of exposure is defined as the number of days between the start and the end dates of 
study therapy, where the start date of study therapy is the date of the first dose of investigative 
or comparator treatment, and the end date of study therapy is the last known dose of 
investigative or comparator treatment during the double-blind randomized treatment period,
ie, 
Extent of exposure=Last dosing date - First dosing date + 1.
Extent of exposure to the investigational product will be summarized using Safety analysis set 
for the double-blind treatment period regardless of rescue and prior to rescue respectively, 
presenting the numbers and percents of patients with an extent of exposure within the 
following day ranges by treatment group: 1 to 14, 15 to 28, 29 to 42, 43 to 56, 57 to 84, 85 to 
112, 113 to 168, and N169 days. Also the mean, SD, median and range of extent of exposure 
to study medication will be presented by treatment group.
Extent of exposure for the investigational product during the double-blind treatment period 
will be summarized and listed by patient. Additionally, a listing of randomization scheme and 
a listing of patients by batch number of investigational product will be produced.
Also, rescue medication usage (number of patients taking rescue medication or insulin) will be 
summarized by treatment group based on CRF records. A by patient listing for rescue 
medication usage will be presented for all rescued patients during double-blind treatment 
period.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
48
4.2.5.2
Treatment Compliance
Percent treatment compliance is calculated during the double-blind treatment period for the
blinded study medication. Percent compliance is defined as the number of tablets taken, 
divided by the number of tablets that should have been taken. A patient is considered 
compliant if percent compliance is between 80% and 120%, inclusive. The number of tablets 
that should have been taken is calculated as (date of the last investigational dose - date of 1st 
investigational dose during randomized treatment period + 1), times the prescribed daily dose. 
Total number of tablets taken is the difference between total number of tablets dispensed 
minus total number of tablets returned over the entire randomized treatment period. All dates 
and tablets counts data are to be taken from the “Drug Accountability” or DA module in CRF.
The number and percent of patients compliant with double-blind study drug during the 
double-blind treatment period will be summarized for the safety analysis set.
4.2.6
Efficacy Variables
4.2.6.1
Primary Efficacy Variable
The primary objective of this study is 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. The primary estimand will 
be the treatment difference at Week 24 if all patients had remained in the trial and received 
treatment as planned without rescue medication. The analysis of the primary estimand will 
include all available data up to Week 24 or premature discontinuation of randomized 
treatment, whichever occurs first.
The null and alternative hypotheses of interest are:
H0: #$ = #% VS Ha: #$ & #%, 
Where #$ and #% are mean change from baseline to week 24 in HbA1c for study medication 
dapagliflozin and placebo groups respectively.
For rescued patients, measurements obtained after rescued medication or rescued insulin will 
be excluded.  For patients discontinuing double-blind medication, measurements obtained 
after discontinuation will be excluded.
The primary analysis for the change in HbA1c from baseline at Week 24 will be based on 
longitudinal repeated measures analysis as described in Section 4.1.6.1. For all patients that 
are administered rescue therapy or discontinue treatment during the double-blind treatment 
period, only those measurements made on or prior to rescue or treatment discontinuation, 
(whichever occurs first) the will be included in analysis. For the primary efficacy analysis, the 
additional 3-way interaction term Baseline*Week*Treatment will be used as a model check to 
assess if there is statistically significant treatment effect across visits which differs in 
dependency on baseline values.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
49
Point estimates and 95% confidence intervals for the mean change within each treatment 
group as well as for the differences in mean change between dapagliflozin 10 mg treatment 
group and the placebo treatment group will be calculated. P-value will be calculated to 
compare the treatment effect in the dapagliflozin 10 mg treatment group to that in the placebo 
treatment group.
4.2.6.2
Sensitivity Analysis
To assess the robustness of the primary efficacy analysis, and to compare the results with 
previous studies, the sensitivity analyses on the primary efficacy endpoints will be carried out 
using the following approaches:
!
Repeat of the primary analyses for the Per Protocol Set (if warranted) which is a subset 
of the Full Analysis Set and will consist of patients who do not deviate from the terms 
of the protocol, utilizing the longitudinal repeated measures methodology described in 
Section 4.1.6.1, only include measurements prior to rescue and treatment 
discontinuation.
Note the sensitivity analysis using the Per Protocol Set will be applied to primary 
efficacy endpoints only if there the Per Protocol Set has a minimum of 10% fewer 
patients for any treatment group than the Full Analysis Set.
!
Repeat of the primary analyses for the Full Analysis Set who have a baseline 
assessment and any post-baseline double-blind treatment period HbA1c assessment 
utilizing longitudinal repeated measures methodology described in Section 4.1.6.1, 
with adjustment for baseline eGFR and baseline eGFR-by-week interaction, in 
addition to adjustment for baseline HbA1c and baseline HbA1c-by-week interaction,
only include measurements prior to rescue and treatment discontinuation.
!
Repeat of the primary analyses for the Randomized Set who have a baseline 
assessment regardless of rescue or treatment discontinuation utilizing ANCOVA at 
Week 24 within the framework of MI-RD imputation described in Section 4.1.7.3.
!
Repeat of the primary analyses for the Randomized Set who have a baseline 
assessment regardless of rescue or treatment discontinuation utilizing ANCOVA at 
Week 24 within the framework of Washout-imputation described in Section 4.1.7.4.
Summaries and analyses supporting the primary efficacy objective are:


Table 10
Summary of Analysis to meet primary efficacy objective of HbA1c
Analysis type
Estimand
Missing Data 
Assumption
Imputation 
Method
Analysis set
Repeated measures mixed model of QHbA1c
to Week 24 (prior to rescue and treatment 
discontinuation)a
Difference in outcome 
improvement at Week 24 without 
rescue and without treatment 
discontinuation.
MAR
No imputation
FASa
Repeated measures mixed model of QHbA1c
to Week 24 (prior to rescue and treatment 
discontinuation)b
Difference in outcome 
improvement at Week 24 without 
rescue and without treatment 
discontinuation. For PP analysis set 
only.
MAR
No imputation
PPb
Repeated Measures mixed model of QHbA1c
to Week 24 with adjustment for baseline 
eGFR in addition to adjustment for baseline 
HbA1c (prior to rescue and treatment 
discontinuation)
Difference in outcome 
improvement at Week 24 without 
rescue and without treatment 
discontinuation.
MAR
No imputation
FAS
ANCOVA of QHbA1c to Week 24 from MI-
RD imputation
Difference in outcome 
improvement at Week 24 regardless 
of rescue or treatment 
discontinuation.
MNAR
Observed and 
Imputed values
RAND
ANCOVA of QHbA1c to Week 24 from 
washout imputation
Difference in outcome 
improvement at Week 24 regardless 
of rescue or treatment 
discontinuation.
MNAR
Observed and 
Imputed values
RAND
QHbA1c=change from baseline in HbA1c; PP=Per Protocol; FAS = Full analysis set
a The primary analysis
b The sensitivity analysis on PP will be applied to primary efficacy endpoint only if there will be more than 10% difference in number of patients from FAS


4.2.6.3
Secondary Efficacy Variables
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, will be analyzed using a longitudinal repeated 
measures analysis, similar to the one used for the primary analysis of the primary endpoint.
Summaries and analyses supporting the secondary efficacy objectives are:
Table 11
Summary of Analyses to Meet Secondary Efficacy Objectives
Analysis type
LOCF or Observed 
values
Analysis set
Repeated measures mixed model of percent 
change from baseline to Week 24 in body weight 
(kg) (prior to treatment discontinuation)
Observed values
FAS
Repeated measures mixed model of change from 
baseline to Week 24 in FPG (mg/dL (prior to 
rescue and treatment discontinuation)
Observed values
FAS
Repeated measures mixed model of change from 
baseline to Week 24 in seated SBP (mmHg) 
(prior to treatment discontinuation)
Observed values
FAS
LOCF = Last Observation carried Forward; FAS = Full analysis set
4.2.6.4
Sequential Testing Procedure
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 Table 
11. 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. If either the testing procedure is stopped or superiority to placebo is 
not demonstrated, then nominal p-values will be provided.
4.2.6.5
Exploratory Efficacy Variable
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
52
Table 12 lists the summary of exploratory analyses on continuous endpoints.
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
53
Table 12
Summary of analyses to exploratory analysis on continuous endpoints
Analysis Type
LOCF or observed 
values
Analysis Set
ANCOVA = Analysis of Covariance; LOCF = Last Observation carried Forward; FAS = Full analysis set
Exploratory analyses of variables that represent proportions of patients will be performed 
using the methodology as described in Section 4.1.9.
Table 13 lists the summary of exploratory proportion analyses.
Table 13
Summary of exploratory analysis on categorical endpoints
Analysis Type
LOCF or observed 
values
Analysis Set
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
54
Table 13
Summary of exploratory analysis on categorical endpoints
Analysis Type
LOCF or observed 
values
Analysis Set
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
55
Table 13
Summary of exploratory analysis on categorical endpoints
Analysis Type
LOCF or observed 
values
Analysis Set
4.2.6.6
Subgroup Analysis for Efficacy Variables
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
56
Table 14
Contrast Coefficients for the Example Gender-by-treatment 
Interaction
Gender
Male
Male
Female
Female
Treatment group
Dapa 10 mg
Placebo
Dapa 10 mg
Placebo
Contrast 
coefficient
-1
1
1
-1
Table 15 lists the subgroup variables with the efficacy endpoints. 
Subgroup analysis for other efficacy and safety variables will be conducted as deemed 
appropriate and necessary.
Table 15
Subgroup analysis for the efficacy variables
Analysis endpoints
Grouping 
Variable
Category
Analysis 
set used
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
57
Table 15
Subgroup analysis for the efficacy variables
Analysis endpoints
Grouping 
Variable
Category
Analysis 
set used
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
58
4.2.7
Safety Variables
The Safety Analysis Set will be used for all safety analyses, including all data after rescue 
during the double-blind treatment period. Sensitivity analyses on data collected prior to rescue 
during the double-blind treatment period will be performed for selected Adverse Events (AEs) 
as described in multiple sub-sections under Section 4.2.7.1.
Safety analyses will be conducted on the double-blind treatment period and follow-up period. 
AEs within 4 days or SAEs within 30 days post last double-blind study medication, which are 
considered in the double-blind treatment period, will not be counted as AEs or SAEs during 
the follow-up period. 
Unless otherwise specified, the safety analyses of changes from baseline to a specific time 
point in safety variables (e.g., laboratory parameters and vital signs) will only include patients 
from the Safety Analysis Set who have data available for both the baseline and the time point 
under consideration. 
Safety data that collected before randomization will not contribute to summaries but will be 
listed.
4.2.7.1
Adverse Events
Adverse Events (AEs) will be classified by Primary System Organ Class (SOC) and Preferred 
Term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA). All 
adverse events will be coded using the latest available version of MedDRA by the database 
lock. 
Unless otherwise specified, no statistical tests will be performed to compare AE rates between 
treatment groups. This policy was adopted to recognize the lack of power and the potential for 
misleading interpretation based on repeated statistical tests which increase the family wise 
Type I error level.
Counting rules for adverse events are described in Section 4.3.8.
In summaries by system organ class (SOC) and preferred term (PT), AEs will be sorted by
decreasing frequency of each PT and SOC, within SOC, according to the Dapagliflozin 10 mg 
group. In summaries by PT, AEs will be sorted by decreasing frequency of PT according to 
the Dapagliflozin 10 mg group.
Missing AE dates will be imputed as defined in Section 4.3.3.
Separate pages to capture events of hypoglycemia and to capture all potential events of DKA 
are contained within the CRF. Discontinuation due to hypoglycemia would not be reported on 
an AE CRF page unless the event fulfilled criteria for an SAE in which case an SAE form 
would be completed. Hypoglycemia and DKA events that are reported as SAEs will be 
included in all summaries of AEs or SAEs (see Section 4.2.7.1.1). Separate summaries will be 


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
59
provided including hypoglycemia events reported on the hypoglycemia CRF pages (see 
Section 4.2.7.1.6 Adverse Events of Special Interest).
4.2.7.1.1
All Adverse Events 
All adverse events (serious and non-serious) with onset during the double-blind treatment 
period will be summarized by system organ class, preferred term and treatment group, for 
both the primary and sensitivity safety analyses. 
The patient incidence of Related AEs, Deaths, SAEs and AEs Leading to Discontinuation of 
Study Medication (DAEs) will be summarized. Hypoglycemic and DKA events that are 
reported on separate eCRF pages will be summarized separately.
In addition, following summaries will be provided for the double-blind treatment period. 
These summaries will exclude hypoglycemic AEs: 
!
Proportion of patients with adverse events in subgroups of patients defined by age 
category (< 65 and N65 yrs), gender, race and female age category (J50 and >50 
yrs).
!
Most common adverse events by preferred term and treatment group (reported by 
N2% and N5% of patients in any treatment group).
!
Adverse events by system organ class, preferred term, intensity and treatment 
group.
!
Adverse events related to study medication by system organ class, preferred term 
and treatment group.
All AEs occurring during the study (including the placebo lead-in period, double-blind 
treatment and the follow-up period) will be listed. 
4.2.7.1.2
Deaths
All deaths recorded on the status page, the AE page, or SAE page (with a death date, cause of 
death, outcome or SAE categorization present) of the CRF will be considered a death in the 
analyses. Any deaths that occur during the study will be described in depth as narrative in the 
CSR. A listing of all deaths that occur during the study will be produced.
4.2.7.1.3
Serious Adverse Events
SAEs (including hypoglycemic and DKA events) with an onset from Day 1 of double-blind 
treatment up to and including 30 days after the last dose date in the double-blind treatment 
period will be considered as occurring during the double-blind treatment period.
SAEs (including hypoglycemic and DKA events) occurring during the double-blind treatment 
period will be summarized by SOC, PT and treatment group. In addition, the proportion of 
patients with related SAEs will be presented by SOC, PT and treatment group.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
60
A listing of all SAEs will be produced, displaying all SAEs (including pre-treatment events) 
that occurred during the study.
4.2.7.1.4
Related Adverse Events
The patient incidence of related AEs will be presented by SOC, PT and treatment group. 
4.2.7.1.5
Adverse Events Leading to Discontinuation (DAE)
AEs with an onset during the double-blind treatment period reported with an action taken of 
discontinuation of study medication will be summarized by SOC, PT and treatment group. 
When summarizing AEs leading to discontinuation, no upper cutoff day windows (i.e. 4 days
and 30 days from last dosing date in double-blind treatment period for AEs and SAEs 
respectively) are applied. For double-blind period analyses, the only upper cutoff date is the 
last date of the double-blind treatment period.
In addition, a patient listing of discontinuation due to AEs will be provided, displaying all 
events that led to discontinuation that occurred during the study.
4.2.7.1.6
Adverse Events of Special Interest
Separate summaries will be provided for the following adverse events of special interest. To 
identify each type of adverse event of special interest in this section, a list of preferred terms
will be selected, reviewed and finalized prior to the database lock and unblinding of the 
database. 
!
Genital Infection
!
Urinary-tract Infection
!
Volume depletion (including hypotension, dehydration, and hypovolemia)
!
Renal Impairment/Renal Failure
!
Bone Fractures
Unless otherwise specified, AEs and SAEs of special interest with an onset from Day 1 of 
double-blind treatment up to and including 4 days and 30 days respectively, after the last dose 
date in the double-blind treatment period will be considered as occurring during the double-
blind treatment period.
4.2.7.1.6.1
Hypoglycemia
Separate pages to capture events of hypoglycemia are contained within the CRF. 
Hypoglycemic events with an onset from Day 1 of the double-blind treatment period up to and 
including 4 days (30 days for SAE) after the last dose date in the double-blind treatment 
period will be considered as occurring during the double-blind treatment period. The 


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
61
proportion of patients with hypoglycemic events will be tabulated by treatment group in the 
double-blind treatment period. Both primary and sensitivity safety analyses will be performed. 
Hypoglycemic events will be categorized using the following classes:
!
Major episodes of hypoglycemia - defined as symptomatic episodes requiring 
external (3rd party) assistance due to severe impairment in consciousness or 
behaviour, with a capillary or plasma glucose value <3 mmol/L (<54 mg/dL), and 
prompt recovery after glucose or glucagon administration,
!
Minor episodes of hypoglycemia - defined as either a symptomatic episode with a 
capillary or plasma glucose measurement below 3.5 mmol/L (63 mg/dL) regardless 
of need for external assistance, or an asymptomatic capillary or plasma glucose 
measurement below 3.5 mmol/L (63 mg/dL), that does not qualify as a major 
episode, 
!
Other episodes of hypoglycemia - defined as episodes reported by the investigator 
that are suggestive of hypoglycemia but do not meet the above criteria. 
When summarizing hypoglycemic events leading to discontinuation no upper cutoff day 
windows are applied. 
A listing of patients will be produced and it will display all hypoglycemic events with an onset 
on or after the start date of double-blind treatment period.
4.2.7.1.6.2
DKA
Separate pages to capture all potential events of DKA, signs and symptoms, and risk factors
are contained within the CRF. 
DKA events with an onset from Day 1 of the double-blind treatment period up to and 
including 4 days (30 days for SAE) after the last dose date in the double-blind treatment 
period will be considered as occurring during the double-blind treatment period. DKA events 
will be adjudicated, and the proportion of patients with DKA events overall as well as by 
adjudicated result will be tabulated by treatment group in the double-blind treatment period. 
A listing will display all adjudicated DKA events as well as the corresponding signs and 
symptoms and risk factors with an onset on or after the start date of double-blind treatment 
period.
4.2.7.2
Clinical Laboratory Tests Evaluation
Unless otherwise specified, laboratory data obtained after the start of study medication dosing 
up to and including 4 days (30 days for liver function laboratory test) after the last double-
blind dosing date will be considered as obtained during the double-blind treatment period. 
Laboratory data obtained from the day after the last study medication +4 days (30 days for 
liver function laboratory test) up to the last visit date of the follow-up period will be 
considered as obtained during the follow-up period.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
62
For liver safety, a summary of proportion of patients with elevated liver test (see Appendix C 
for definition) will be provided for the double-blind treatment period. In addition, a summary 
of proportion of patients with elevated liver test and/or reported AE of hepatic disorder will 
also be provided for the double-blind treatment period.
All scheduled laboratory evaluations are performed by central laboratories. All laboratory 
evaluations performed by central laboratories will be included in summary tables. 
Laboratory parameters will be presented in international system units, except for those listed 
in Table 16, which will be presented in conventional units (C) and international system units
(SI).
Table 16
SI and C units
Test name
SI unit
C unit
FPG
mmol/L
mg/dL
Total Bilirubin
umol/L
mg/dL
Serum creatinine
umol/L
mg/dL
Urine creatinine
mmol/L
mg/dL
Phosphate
mmol/L
mg/dL
4.2.7.2.1
Marked Laboratory Abnormalities
Laboratory abnormalities will be evaluated based on marked abnormality (MA) criteria.
Appendix C (Laboratory Abnormality Criteria) lists the pre-defined criteria for MAs. If both
the baseline and on-treatment values of a parameter are beyond the same MA limit for that
parameter, then the on-treatment value will be considered a MA only if it is more extreme
(farther from the limit) than was the baseline value. If the baseline value is beyond the low,
and the on-treatment value is beyond the high MA limit (or vice-versa), then the on-treatment 
value will be considered a MA. If the baseline value is not beyond either MA limit, and the 
post-baseline value is beyond either MA limit, then the post-baseline value will be considered 
MA.
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
63
Laboratory MAs occurring during the double-blind treatment period will be summarized by
treatment group for primary and sensitivity safety analysis. The directions of changes (high or
low) in MAs will be indicated in the tables. 
Additionally, for each patient with a MA for a parameter, all the patient’s values of that 
parameter over the double-blind treatment period and the follow-up period will be listed.
4.2.7.2.2
Changes from Baseline Values for Selected Laboratory Parameters over 
Time
All analyses of laboratory data will use observed data regardless of rescue. Visit windows are 
provided in Section 4.3.1 in order to link each laboratory test to a scheduled visit. Change 
from baseline during the double-blind treatment period and the follow-up period for selected 
laboratory parameters will be summarized by treatment group, presenting n’s, means, 
medians, minimum, maximum, SEs:
Hematology parameters:
!
hemoglobin 
!
hematocrit 
!
red blood cell (RBC) count 
!
white blood cell (WBC) count 
!
platelet count
Serum Chemistry parameters:
!
aspartate aminotransferase (AST) 
!
alanine aminotransferase (ALT) 
!
alkaline phosphatase 
!
total bilirubin 
!
blood urea nitrogen (BUN) 
!
electrolytes - sodium, potassium, bicarbonate, chloride, magnesium, calcium
!
total protein and albumin 
!
creatinine, serum (Scr) 
!
Estimated eGFR (mL/min/1.73m2) using MDRD equation


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
64
Urine parameters:
!
Creatinine 
4.2.7.2.3
Additional Laboratory Data Summaries
Shift Tables for Electrolytes (Sodium, Potassium, Calcium, Phosphate, and Magnesium) 
Categories
Shift tables of Safety Data Set patients with electrolytes values in categories of low, normal, 
and high (based on normal range of central laboratory) will be summarized by treatment group 
using the highest (for sodium, calcium, phosphate, and magnesium) and lowest (for sodium, 
potassium, and calcium) values (regardless of rescue) obtained during the double-blind 
treatment period. 
will be summarized by treatment group using the Week 24 values (the last observation 
regardless of rescue prior to Week 24 will be used if no Week 24 measurement is available). 
4.2.7.3
Electrocardiograms
The 12-lead ECG is performed at Visit 2 only. Listings of ECG interpretations will be 
generated on request.
4.2.7.4
Vital Signs
Unless otherwise specified, vital signs and other physical data obtained after the start of study 
medication dosing up to 4 days (inclusive) after the last double-blind dosing date will be 
considered as obtained during the double-blind treatment period. Vital signs and other 
physical data obtained from the day after the last study medication +4 days (exclusive) up to 
the last visit date of the follow-up period will be considered as obtained during the follow-up 
period.
Visit windows are provided in Section 4.3.1 in order to link each vital sign measurement to a 
scheduled visit. 
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
65
The values and changes from baseline for systolic and diastolic blood pressures and heart rate
will be summarized by treatment group at each scheduled visit using descriptive statistics 
(using available data regardless of rescue for patients in Safety Data Set). 
Number and percentages of patients with orthostatic hypotension (fall in systolic blood 
pressure of >20 mmHg or diastolic blood pressure of >10 mmHg (supine to standing)) will be 
summarized by treatment group at each scheduled visit using available data regardless of 
rescue in Safety Data Set. All observations regardless of distance to the target in each 
scheduled visit window will be used for the summary of orthostatic hypotension.
Changes from baseline in weight, BMI, 
will be summarized 
presenting n’s, means, medians, minimums, maximums, and SEs, at each scheduled visit 
during the double-blind treatment period and the follow-up period.
4.2.7.5
Pregnancy Test Results
A by-patient listing of pregnancy test results will be provided using Safety Data Set. 
4.3
Conventions
4.3.1
Visit and Period Windows
Patients do not always adhere strictly to the visit timing in the protocol. Therefore the 
designation of visits during the double-blind treatment period and follow-up period will be 
based on the day of evaluation relative to the reference start date rather than the nominal visit 
recorded in the CRF.
To assign a measurement to a Week t during a study period, the first step consists of selecting
all measurements falling within this study period as defined below. To further determine the
Week t measurement, mutually exclusive relative day windows are used.
The day windows are defined to provide derived visits that correspond to the post-baseline
time points specified in the protocol. As already stated, some restrictions may exist on some
laboratory assessments to be included in efficacy analyses. These restrictions will be reflected
in the day ranges. For example, since no HbA1c is to be collected at Week 1, the windows for
HbA1c will only start at Week 4. No Week 1 windowing will be defined.
For each visit, a window will be defined such that the lower and upper bounds of each 
window is generally the midpoint between 2 consecutive study visits. The visit windows and 
applicable study day ranges are presented below in Table 17.
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
66
Table 17
Visit Windows
Visit
Target Day
Adjusted windows for analyses
A1C
FPG
Safety Laboratory
Vital Signs
Weight
BMI
 
 
Baseline
1
J1
J1
J1
Week 1
8
2-18*
Week 4
29
2-57*
19-57*
Week 12
85
58-127*
58-127*
Week 24
169
128-Last day of DB 
period
128- Last day of DB 
period
2- Last day of DB 
period
Follow-up Week 
27
190
Day 1 of FU period--
Last day of FU period
Day 1 of FU period--
Last day of FU 
period
Day 1 of FU 
period--
Last day of FU 
period
*: before the last day of DB period.
For some efficacy parameters, the use of double-blind treatment observations is specified in 
Section 4.3.2. This section defines the last day after treatment for which these observations are 
included in the visit window.
For assignment of data to time points using the visit windows, study day will be defined as 
follows:
(Date of assessment - Date of first dosing) + 1. 
In case of multiple observations within a single visit window, the following rules apply:
!
If there are two or more observations within the same visit window, the observation 
closest to the target day will be used in the analysis
!
If two observations are equidistant from the target day and the ties are on different 
sides of the target day, the observation with the earlier assessment date will be used 
in the analysis
!
If two observations are equidistant from the target day and the ties located on the 
same sides of the target day (i.e. more than one observation for the same day but 
different time), the observation with the earlier (if the assessment day is equal or 
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
67
larger than the target day) or later (if the assessment day is smaller than the target 
day) assessment time will be used in the analysis
!
If two or more observations are collected on the same day, all non-missing but with 
no collection time associated with at least one of them, the average of the 
observations will be used in the analysis.
!
If two or more observations are collected on the same day and time, and they are 
same closest to the target day, the average of the observations will be used in the 
analysis.
If a visit window does not contain any observation, then the data will be missing for that visit. 
 
visit date, then the average of the available non-missing measurements with that same visit 
date will be used in summary and analysis. 
4.3.2
Post-Dosing Efficacy Observations
While double blind treatment period efficacy observations will be listed regardless of whether
the patient was taking blinded study drug. Observations will be included in summarizes of the 
FAS only if the following rules are satisfied:
!
HbA1c, body weight, BMI and
will be summarized only if 
measured on or before the 8th day after the last double-blind drug dosing date.
!
FPG, 
SBP, eGFR and Insulin initiation will be summarized only if 
measured on or before the 1st day after the last randomized, double-blind drug dose 
date.
!
Lipids and other exploratory parameters (if available) will be summarized only if 
measured on or before the 4th day after the last randomized, double-blind drug dose 
date.
!
The efficacy measurements of HbA1c and FPG will be summarized/analysed only 
if measured on or prior to the first dose of rescue medication.
4.3.3
Assignment of Dates to Adverse Events and Laboratory Assessments
In case of missing dates and/or times, imputation rules will be applied as follows:
For AEs, a missing or incomplete onset date will be imputed according to the following 
conventions: 
1. If the onset date for an AE is missing or incomplete, an imputed date will be derived to 
slot the event to an appropriate analysis period. This derived date will not be reported 
in summary tables or listings. 
CCI
CCI
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
68
Exception: No dates will be imputed for SAEs. Every effort will be made to determine
the actual onset date for the event or to obtain a reliable estimate for the onset date 
from the investigator.
2. If an onset date is missing, the derived onset date will be calculated as the first non-
missing valid date from the following list (in order of precedence):
!
First active study medication date
!
Consent date
!
Visit date corresponding to the visit at which the event was reported.
!
If a valid non-missing date is not available for any of these dates, the derived onset 
date will be set to missing.
3. If an onset date is incomplete, the derived onset date will be calculated using the 
following algorithm:
!
Calculate a surrogate date as the first non-missing valid date from the following list (in 
order of precedence):

First active study medication date

Consent date

Visit date corresponding to the visit at which the event was reported

If a valid non-missing date is not available for any of these dates, the surrogate 
date will be set to missing.
!
Based on the information provided, set the derived date to the earliest possible date. If 
only a year is provided, set the derived date to January first of that year. If a year and 
month is provided, set the derived date to the first day of that month.
!
If the surrogate date is non-missing then:

If the derived date is on or after the surrogate date use the derived date as 
calculated

If the derived date is before the surrogate date and the surrogate date is 
consistent with the partial data provided for the onset date, use the surrogate 
date as the derived date 

If the derived date is before the surrogate date and the surrogate date is not 
consistent with the partial data provided for the onset date then set the derived 
onset date to be the latest possible date based on the partial onset date 
information provided. If only a year is provided, set the derived date to 
December 31st of that year. If a year and month is provided, set the derived 
date to the last day of that month.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
69
!
If all three dates used to determine the surrogate date are missing, then based on the 
information provided, set the derived date to the earliest possible date. If only a year is 
provided, set the derived date to January first of that year. If a year and month is 
provided, set the derived date to the first day of that month.
4.3.4
Displays of Vital Signs
At each applicable visit, vital signs systolic and diastolic blood pressures and pulse rate are to
be measured three times. Only the means of the individual values, rather than the values
themselves, will be summarized.
4.3.5
Calculation of Body Mass Index
The BMI is defined as:
BMI = (weight in kilograms)/(height in meters)2
BMI values will not be rounded to whole integers.
4.3.6
Missing Dates Assessment for Concomitant Medications
Start and stop dates for all concomitant medications are collected on the CRF. However, in
case of missing or partial information in these dates, the following rules will be used:
If start date is missing or partial:
!
if month is missing, use January (01)
!
if day is missing, use the 1st (01)
!
if year is missing, use year of the entry visit (consent date for those missing entry visit)
!
if entire date is missing, use consent date
If stop date is missing, partial or “continuing:”
!
if month is missing, use December (12)
!
if day is missing, use the last day of the month under consideration
!
if year or the entire date is missing or if “continuing”, we leave the date as missing.
Imputed dates will not appear on the tables of non-study medication.
Imputed dates will be reviewed within the study team and agreed by the study team prior to 
the study being unblinded.
4.3.7
Fasting State
 fasting plasma glucose, only assessments documented 
with the patient in fasting state will be summarized and listed. The patient will be determined 
to be fasting using the response to the question “Was the patient fasting?” in the Central Lab 
Data Transfer Specification. If the response is not marked, the patient is assumed not fasting.
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
70
4.3.8
Counting Rules for Adverse Events
1) Where a patient has the same AE, based on preferred terminology, reported multiple times 
in a single analysis period, the patient will only be counted once at the preferred terminology 
level in AE frequency tables.
2) When a patient has the same AE, based on preferred terminology, reported multiple times
in a single analysis period, the following criteria, in order of precedence, will be used to select 
the event to be included in summary tables:
!
Relationship to study medication: Related events will take precedence over unrelated 
events in determining the event to include in summary tables.
!
Intensity of event: More intense events will take precedence over less intense events 
in determining the event to include in summary tables. Missing intensity will be 
considered the least intense event.
!
Onset date and time: Earlier onset date-time events will take precedence over later 
onset date-time events in determining the event to include in summary.
3) When reporting AEs by intensity, in addition to providing a summary table based on the
event selection criteria detailed above, summary tables will also be provided based on the 
most intense event during the analysis period - independent of relationship to study 
medication. For these tables, the following criteria, in order of precedence, will be used to 
select the event to be included in summary tables:
!
Intensity of event
!
Onset date and time
4.3.9
Strip Sign for Selected Laboratory Data
For selected laboratory test values that have been received with an operator sign as a part of 
the result (>, N, <, or J), a process to strip the operator sign will be applied and the resulting 
numeric values will be used for data analysis. The raw value with operator will remain as such 
on the CRF (or in the electronic record) and in the database. 
The applicable laboratory tests and applicable operator signs are listed in Appendix D.
Additional laboratory parameters can be approved to be added in strip sign plan later along the 
progress of this study. Unless otherwise specified, for laboratory parameters not included in 
any statistical analyses, operator signs will not be stripped and the value will counted as 
missing.
4.3.10
Missing Insulin Dose
For patients who took insulin before or during the study, the mean total insulin dose should be 
collected in the CRF which includes the dosing values with start and end dosing date. If there 
are missing dosing values or date gaps during the insulin treatment period, linear interpolation 
will be used to fill in the missing doses or missing days. The interpolated values will be used 
to determine if the increase of N10% increase in insulin occurred for those patients.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
71
5.
INTERIM ANALYSES
No interim analysis was planned.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
No changes of analysis from the latest version of protocol.
7.
REFERENCES
Carpenter, J. R. and Kenward, M. G. 2013
Carpenter, J. R. and Kenward, M. G. (2013), Multiple Imputation and Its Application, New 
York: John Wiley & Sons.
Diggle, Liang and Zeger 1994
Diggle, P.J., Liang, K.Y., and Zeger, S.L. (1994), Analysis of Longitudinal Data, Oxford: 
Clarendon Press. 
Greenwood M 1926
Greenwood M. The natural duration of cancer. Reports on public health and medical patients. 
1926;33:1-26.
Kaplan EL and Meier P 1958
Kaplan EL and Meier P. Nonparametric Estimation From Incomplete Observations. Journal of 
the American Statistical Association 53:457-481, 1958.
Kenward et al 1997
Kenward, M.G. and Roger, J.H. Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood, Biometrics 1997, 53: 983 - 997. 
Little, R. J.A. 1993
Little, R.J.A. (1993), “Patten-Mixture Models for Multivariate Incomplete Data”, Journal of 
the American Statistical Association, 88, 125-134.
Ratitch B, O'Kelly M, Tosiello R 2013
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat 2013 Nov-Dec; 12(6):337-47.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
72
Little R., Rubin D.B. 2002
Roderick J. A. Little, Donald B. Rubin, Statistical Analysis with Missing Data, 2nd Edition, 
John Wiley & Sons
van Buuren, S. 2012
van Buuren, S. (2012), Flexible Imputation of Missing Data, Boca Raton, FL: Chapman & 
Hall/CRC.


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
73
8.
APPENDICES
Appendix A
Criteria for Assessing Important Protocol Deviations 
Number
Important Protocol Deviations (IPD) Criteria
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
74
Number
Important Protocol Deviations (IPD) Criteria
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
75
Appendix B
Geographic Regions
Geographic Region 
Countries
North America
Canada
United States
Europe
Italy
Spain
Sweden
Bulgaria
Poland
Czech


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
76
Appendix C
Marked laboratory abnormalities
Clinical laboratory variables will be summarized and listed using the units listed here. The 
criteria for marked abnormality for each variable are listed in the following table. Note that a 
post-baseline lab value will be considered a MA only if it satisfies the specified criteria and is 
more extreme (farther from the limit) than is the baseline value.
Some parameters units are presented in SI and C, indicating that analyses will be done with
both units.
Marked Abnormality Criteria
Clinical Laboratory variables
Units
Low
High
Hematology
HCT males/females
RATIO
<0.2 RATIO
>0.55 RATIO
HCT males/females
RATIO
>0.6 RATIO
Hemoglobin males/females
g/L
<60 g/L
>180 g/L
Hemoglobin males/females
g/L
>200 g/L
Blood Chemistry
Albumin
g/L
20 g/L
>60 g/L
Total protein
g/L
>100 g/L
ALP
U/L
>3X ULN
ALT
U/L
>3X ULN
AST
U/L
>3X ULN
ALT
U/L
>5X ULN
AST
U/L
>5X ULN
ALT
U/L
>10X ULN
AST
U/L
>10X ULN
ALT
U/L
>20X ULN
AST
U/L
>20X ULN
Total Bilirubin
umol/L (SI)
mg/dL (C)
>2X ULN if 
PreRx ULN; 
>3X ULN if 
PreRx >ULN
Glucose, Plasma Unspecified
mmol/ L (SI)
mg/dL (C)
<2.997 mmol/L (SI)
<54 mg/dL (C)
>19.425 
mmol/L (SI)
>350 mg/dL (C)
Na (Sodium)
mmol/L
<130 mmol/L
>150 mmol/L


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
77
Marked Abnormality Criteria
Clinical Laboratory variables
Units
Low
High
Na (Sodium)
mmol/L
<120 mmol/L
K (Potassium)
mmol/L
2.5 mmol/L
6.0 mmol/L
HCO3 (Bicarbonate)
mmol/L
13 mmol/L
BUN 
UREA
mmol/L
>21.42 mmol/L
Creatinine
umol/L (SI)
mg/dL (C)
1.5X PreRx 
CREAT
Creatinine
umol/L (SI)
mg/dL (C)
221 umol/L 
(SI)
2.5 mg/dL 
(C)
CK (Creatine Kinase)
U/L
>5X ULN
CK (Creatine Kinase)
U/L
>10X ULN
Calcium
mmol/L
<1.87125mmol/L
0.2495 
mmol/L from 
ULN and 
0.12475 
mmol/L from 
PreRx CA
Magnesium
mmol/L
<0.5mmol/L
>2mmol/L
PO4 (Phosphate)
mmol/L (SI)
mg/dL (C)
Age 17-65: 0.58122 
mmol/L (C)
1.8 mg/dL (SI)
Age 66: # 0.67809 
mmol/L (C)
# 2.1 mg/dL (SI)
Age 17-65: 
1.80824 
mmol/L (C)
 5.6 mg/dL 
(SI)
Age 66: 
1.64679 
mmol/L (C)
  5.1 mg/dL 
(SI)
Urine
CCI


Statistical Analysis Plan 
Study Code D1690C00024
Edition Number 2.0
Date 06NOV2017
78
Appendix D
Laboratory Tests in Strip Sign Plan *
Lab tests in strip sign plan
Test Code
Operator Sign & Limit of 
Quantification
CCI