A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin in Asian Subjects With T2DM and Inadequate Glycemic Control on Metformin and Saxagliptin (DS Navigation)
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: AstraZeneca

 
 
 
Clinical Study Protocol  
 
Drug Substance 
Dapagliflozin 
 
Study Code 
D1683C00008 
 
Edition Number 
5.0 
 
Date 
14 Feb 2019 
 
A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-
Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and 
Efficacy of Therapy with Dapagliflozin added to Saxagliptin in 
Combination with Metformin compared to Therapy with Placebo added to 
Saxagliptin in Combination with Metformin in Asian Subjects with Type 2 
Diabetes who have Inadequate Glycemic Control on Metformin and 
Saxagliptin  
(DS Navigation) 
 
  
 
The following Amendment(s) and Administrative Changes have been made to this protocol since the date 
of preparation: 
Amendment No. 
 Date of Amendment 
Local Amendment No: 
Date of Local 
Amendment 
Version 1.0 
 02 Jun 2015 
NA 
NA 
Version 2.0 
 16 Jan 2018 
NA 
NA 
Version 3.0 
 29 Jun 2018 
NA 
NA 
Version 4.0 
 29 Sep 2018 
NA 
NA 
Version 5.0 
 14 Feb 2019 
NA 
NA 
Administrative 
Change No. 
 Date of Administrative 
Change 
Local Administrative 
Change No. 
Date of Local 
Administrative Change 
NA  
 NA 
NA 
NA 
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. 
PPD

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
3(110) 
for subjects in China. 
4.3.1 Randomization (Day 
1) 
4.3.3 Week24/Rescue/Early 
Treatment Discontinuation 
visit 
Clarified that MTT is only applicable for subjects in China. Replaced 
‘&’ with ‘and’. 
Specified that medication after ETD will be under care and direction of 
the investigator. Clarified that MTT is only for subjects in China. 
Replaced ‘WK24’ with ‘Week24’. 
5.1 Efficacy assessments 
 
 
 
5.1.2.1 Postprandial glucose 
(PPG) at 120 minutes  
The section was updated to be consistent with section 3.6. 
Clarified that MTT is only applicable for subjects in China. 
MTT procedures were modified to reflect that administration of meal 
supply is about 10 minutes to allow some flexibility. 
Clarified that PPG is only for subjects in China. 
8.2 Sample size estimate 
8.3 Definitions of analysis 
sets 
 
8.3.1 Efficacy analysis sets 
8.5.2 Analysis of the 
secondary variable(s) 
8.5.6 Exploratory Analysis 
(if applicable) 
 
 
8.5.7 Safety analysis 
 
Modified ‘Chinese subjects’ to ‘subjects in China’ to make it clear. 
The open-label safety analysis set was modified to the open-label 
treated subjects analysis set to be consistent with section 8.3.3. Added 
that efficacy analyses will be performed. 
The definition of ITT analysis set was updated so that the ITT analysis 
set will include all randomized subjects who received at least one dose 
of double-blind study medication during the double-blind treatment 
period. 
Clarified that MTT is only applicable for subjects in China.  
The section was updated to reflect that AUC of glucose during MTT 
will be analysed based on data of subjects in China and analyses of the 
mean change from baseline for continuous endpoints will be performed 
using an MMRM or ANCOVA method depending upon the availability 
of repeated measurements for the endpoint. 
The open-label safety analysis set was modified to the open-label 
treated subjects analysis set to be consistent with section 8.3.3. 
Removed ‘by stratum’ to make it clear. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
5(110) 
 
Table 2 Lack of glycaemic 
control criteria for initiation 
of rescue medication 
4.3.2 Double-blind 
treatment period (Week 6, 
12, 18) and 4.4.3 
WK24/Rescue/Early 
Treatment Discontinuation 
Visit 
same visit. 
Excluded Week 24 for rescue medication and reworded to clear the 
boundaries of the visit labels. 
Reworded to exclude rescue in Week 24 in visit narratives. 
5.2.1.3 eGFR 
5.2.1.4 Urinalysis  
 
5.2.3 ECG 
Typo corrected in eGFR formula. 
Urine glucose deleted to avoid risk of treatment unblinding.  
 
Clarify that details of microscopic urinalyses should refer to laboratory 
manual. 
Added description on how to handle abnormal findings based on ECG. 
6.1.1 Adverse events of 
special interest 
6.3.6 Adverse events based 
on examinations and tests 
6.3.7 Hypoglycaemia 
"Fracture" added to be consistent with global pivotal study. 
Added reference instructions on AE handling and safety analyses for 
ECG. 
Replaced the wordings of “Plasma glucose concentration” with 
“glycemia level” and update “plasma glucose” to “blood glucose” since 
sources of glycemia value are not limited to plasma glucose, also 
include SMBG and CGM based on ADA guideline. 
8.2 Sample size estimate 
8.3.1 Efficacy analysis sets 
 
8.3.3 Open-label safety 
analysis sets 
8.5.3 Subgroup Analysis  
8.5.6 Exploratory Analysis 
Updated to align with synopsis. 
Clarified the description of per protocol analysis set to align with iPD 
definition in new SOP. 
Analysis set name updated to allow further efficacy analysis. 
Specify time periods for duration of T2DM. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
7(110) 
 
3.2 Exclusion Criteria 
 
 
 
 
 
3.3 Subject enrolment and 
randomization 
3.6 Methods for ensuring 
blinding 
3.10.3 Lost to follow-up 
Specify the exclusion criteria for historical use of SGLT2 inhibitors. 
Add the exclusion criteria for historical over-the-counter weight loss 
medication. 
Add the exclusion criteria for abnormal finding in ECG. 
Update the hypersensitivity reaction related to study treatment and 
their excipients based on PSSR requirement. 
 
Reword eligibility check based on microscopic hematuria urinalysis to 
allow re-test. 
Clarify the re-screening process. 
Delete duplicated wordings on HbA1c values blinding details. Remove 
the urinary glucose values and urinary glucose: creatinine ration from 
blinded procedure.  
Update unblinded FPG process for rescued subjects. 
Add “Lost to follow-up” section based on new CSP template. 
4. Study Plan and Timing of 
Procedures 
 
 
Table 1 Study Design for 
Stratum A & Stratum B 
 
 
 
 
 
 
 
Tables and footnotes updated to be consistent with the wordings from 
section 4.1 to section 4.3. 
Update hematuria urinalysis procedure. 
Update ECG and pregnancy test schedule and procedures. 
Delete Spot Urine Glucose Quantification and glucose: creatinine ratio 
as not needed for well documented products, and delete accordingly 
over the CSP. 
Split GFR from clinical chemistry as it is not part of standard 
chemistry testing. 
Split TSH from Hepatitis Screening panel and HIV testing. Add Free 
T4 reflex testing to TSH testing. 
Add extended period information for subjects with GAD antibodies 
testing to be consistent with synopsis and section 4.2. 
Add the collection of unused study medications and empty packaging 
Review concomitant medications within at least 3 months rather than 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
8(110) 
 
4.1 Screening visit (Visit 1, 
Week -18 for Stratum A and 
Week -10 for Stratum B) 
 
 
 
 
4.2 Open-label treatment 
period 
 
 
 
 
4.3 Double-blind, Double-
Dummy Treatment Period 
 
4.3.1 Randomization (Day 1) 
4.3.2 Double-blind treatment 
period (Week 6, 12, 18) 
4.3.3 Week24/Rescue/ Early 
Treatment Discontinuation 
visit 
only within 3 months from both ethical and operational perspective. 
Change urine pregnancy test to serum pregnancy test for Visit 1 to be 
consistent with table 1 and throughout the CSP. 
Add ECG testing at screening and be consistent with Table 1. 
Change the study procedure for hematuria microscopic urinalysis and 
delete sport urine glucose quantification and glucose: creatinine ratio at 
screening. 
Update the requirement for confirmation test in subjects with HCV 
antibody low positive.  
Delete pregnancy tests from visit 2 to visit 4. 
 
Delete hematuria urinalysis during open-label period. 
Specify a follow-up visit within 3-5 days following receipt of FPG 
value from central laboratory should be performed for subjects with 
FPG value > 270 mg/dl to clear potential confusions from readers. And 
apply this wording throughout the CSP when necessary. 
Add details of MTT test requirements. 
Specify urine pregnancy test will be performed locally at 
randomization visit. 
Split GFR from Chemistry and be consistent with Table 1. 
Delete sport urine glucose quantification and glucose: creatinine ratio. 
Delete haematuria urinalysis in double-blind period. 
Delete pregnancy tests for double-blind treatment period. 
Specify FPG value assessment for rescue eligibility. 
Add details of MTT test requirements and delete pregnancy test for 
Week24/Rescue/Early Treatment Discontinuation. 
Add the collection of unused study medications and empty packaging 
Specify that contact IxRS for drug dispensing and remind subjects to 
fast, bring patient diaries/glucose meter if needed. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
9(110) 
5. Study Assessments 
5.1 Efficacy assessments 
 
5.2.1.1 Hematology  
5.2.1.2 Chemistry 
5.2.1.4 Other clinical 
laboratory evaluations 
Add total blood volume of each subject over the duration of the study, 
delete the specific blood volume for each test (previous Table 3 
Volume of blood to be withdrawn from each patient) which should be 
specified in lab manual. 
 
Delete duplicated wordings on HbA1c values blinding details. Remove 
the urinary glucose values and urinary glucose: creatinine ration from 
blinded procedure.  
 
Update unblinded FPG process for rescued subjects. 
Detailed tests of hematology and chemistry assessments are deleted 
here as duplicated with Table 3. 
Split eGFR from clinical chemistry as it is not part of standard 
chemistry testing (refer to section 5.2.1.3). Following numbering in 
this section was updated accordingly. 
Update the requirement for confirmation test in subjects with HCV 
antibody low positive.  
Specify pregnancy testing to be consistent with section 4. 
5.2.3 ECG 
5.2.4 Vital Signs 
5.2.5.3 Hematuria 
 
5.2.5.5 Hepatic events 
 
5.7 Biomarker 
Clarify the ECG testing at Week 24 and delete duplicated wordings. 
Specify Alcohol/tobacco/nicotine/caffeine restrictions. 
Update the contents in hematuria. 
Delete contents in hepatic events as it is no longer applicable for this 
study. 
Delete the whole section of “Biomarker” as not applicable to this 
study. 
6.3.2 Follow-up of AEs and 
SAEs 
6.3.3 Variables 
 
6.3.7 Hypoglycaemia 
 
Add AE/SAE follow-up information based on new CSP template.  
 
Add saxagliptin into AE causality evaluation.    
 
Update the hypoglycaemia section. Remove the definition of probable 
symptomatic hypoglycaemia and relative hypoglycaemia as it's no 
longer used in ADA 2018. Correct the typo for plasma glucose 
concentration threshold for clinically significant hypoglycaemia.  
Clarify overdose definition to include saxagliptin and be consistent 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
10(110) 
6.5 Overdose 
 
6.7 Medication error 
with SOP. 
Specify the timeline of AstraZeneca response on SAE associated 
medication error, to be consistent with new CSP template. Specify the 
medication error report will be applicable for both saxagliptin and 
dapagliflozin. 
7.1 Identify of 
investigational product(s) 
7.7 Concomitant and other 
treatments 
Tables 5 Lists prohibited 
medications and the 
applicable time frames 
Re-evaluate the impact of lactose content in dapagliflozin on lactose-
intolerant individuals and update accordingly. 
Delete the strength (500mg) of Metformin as both IR and XR will be 
used. 
Delete table 5 as duplicate with prohibited medication section. 
8.2 Sample size estimate 
Rephrase the capping information to be consistent with synopsis. 
9.3 Study timetable and end 
of study 
Update study timeline to be realistic. 
Change the order of saxagliptin and dapagliflozin to be consistent with 
other dapagliflozin studies. 
11 List of References 
Add the reference of “Levey AS 2007”. 
Appendix D Algorithm for 
Microscopic Hematuria 
Delete appendix D as it's no longer applicable in dapagliflozin 
program. 
Appendix E Central 
Laboratory Assessments 
Delete appendix E as not mandatorily required in current CSP template 
and to avoid discrepancy in lab materials. 
Appendix F Actions 
Required in cases of 
increases in Liver 
Biochemistry and evaluation 
of HY’s Law 
Delete appendix F as it's not required in PSSR.  
Appendix G Algorithm on 
Management of Sustained 
Elevated Liver Safety 
Abnormalities 
Delete appendix G as it's not required in PSSR.  

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
12(110) 
2.4 Exploratory objectives   
Add details regarding Double-Dummy treatment 
3.1 Inclusion criteria: 
reproductive status 
 
3.2 Exclusion criteria 
 
 
3.3.1 Procedures for 
randomization  
Update text to make it more clear and logical 
Delete upper limit of age 75 years old to keep consistent with global 
reference study 
Update safety criteria according to dapagliflozin/saxagliptin PSSR 
including: exclude type 1 diabetes; further clarify DKA exclusion 
criteria; update renal and hepatic diseases; clarify allergies and adverse 
drug reaction criteria 
Add new arm 2: dapagliflozin 5 mg, saxagliptin 5 mg, plus metformin 
IR/XR 
Add details regarding Double-Dummy treatment 
3.5 Methods for assigning 
treatment groups 
3.6 Methods for ensuring 
blinding 
Update randomization ratio to 1:1:1 to include new arm information 
Emphasize the blinding of central laboratory assessments in protocol 
body 
4 Study plan and timing of 
procedures 
   Table 1 footnote m 
4.1.4 Screening visit (Visit 1, 
Week -18 for stratum 
A and Week -10 for 
stratum B) 
Correct information for microscopic haematuria to keep consistent 
with inclusion/exclusion criteria  
Add details regarding Double-Dummy treatment 
5 Study assessments   
5.2.1.4 Other clinical 
laboratory 
evaluations 
Update blood volume according to new request from central laboratory 
Add ‘hepatitis screening panel’ to keep consistent with the exclusion 
criteria 
6.1.1 Adverse events of 
special interest 
This section was updated to keep the consistent with ongoing 
dapagliflozin and saxagliptin studies. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
13(110) 
6.3.7 Hypoglycaemia 
6.7 Medication Error 
6.8.1.1 Diabetic 
Ketoacidosis 
Adjudication 
Committee 
Add section of hypoglycaemia to provide guidance to investigator on 
how to collect and record hypoglycaemia events 
Add information about Medication Error definition and reporting. 
This section was added to meet the requirement for dapagliflozin 
studies 
7. Investigational product 
and other Treatments 
7.1 Identity of 
investigational 
product(s) 
7.2 Dose and treatment 
regimens 
Update IMP information to include dapagliflozin 5 mg and placebo to 
match 
Add details regarding Double-Dummy treatment 
8.3 Definitions of analysis 
sets 
Add language to specify that ‘Selected safety analyses for the open-
label treatment period will be based on open-label safety analysis set’. 
8.3.1 Efficacy analysis set 
Update the definition of ITT set. Specify that for analysis based on per-
protocol set, subjects will be analysed based on randomized treatment. 
8.3.3 Open-label safety 
analysis set 
This analysis set is added because selected safety analyses will be 
performed for the open-label treatment period using the open-label 
safety analysis set 
8.5.1 Analysis of primary 
analysis set 
Add some language to specify the testing of two comparisons based on 
primary endpoint. 
Add some language to describe the model fitting and how models will 
be handled if they don’t converge. 
Make it clear that in the primary analysis, data prior to study treatment 
discontinuation and rescue will be included. 
Add details regarding Double-Dummy treatment 
8.5.5 Sensitivity analysis 
Specify missing data will be imputed by LOCF for analysis of 
proportion of subjects achieving a therapeutic glycaemic response and 
2-hr PPG. 

 
 15 (110) 
 
PROTOCOL SYNOPSIS 
 
A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-
Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and 
Efficacy of Therapy with Dapagliflozin added to Saxagliptin in 
Combination with Metformin compared to Therapy with Placebo added 
to Saxagliptin in Combination with Metformin in Asian Subjects with 
Type 2 Diabetes who have Inadequate Glycemic Control on Metformin 
and Saxagliptin  
(DS Navigation) 
 
Study site(s) and number of subjects planned 
This will be a multicenter study conducted at approximately 45 sites in Asian countries (about 
40 sites in China). Approximately 1004 subjects will be screened, and 342 randomized. 
Study period 
 
Phase of development 
Estimated date of first subject enrolled 
Q1 2019 
3 
Estimated date of last subject completed 
Q1 2021 
3 
Study design 
Study D1683C00008 is a 24-week, multicenter, randomized, double-blind, double-dummy, 
placebo-controlled, parallel-group, Phase 3 study designed to investigate if the efficacy and 
safety of triple combination of dapagliflozin 5 mg or 10 mg added to saxagliptin 5 mg plus 
metformin is superior to the dual therapy of saxagliptin 5 mg added to metformin in reducing 
hemoglobin A1c (HbA1c). 
PPD

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
16(110) 
After written informed consents have been obtained at screening visit, subjects will be 
checked for all applicable inclusion/exclusion criteria, and laboratory samples will be taken 
and submitted. In Stratum A, subjects should have a stable dose of metformin immediate 
release (IR)/extended release (XR) (≥ 1500 mg/day or a maximal tolerated dose) for at least 8 
weeks prior to screening. In Stratum B, subjects should have a stable dose of metformin 
IR/XR (≥ 1500 mg/day or a maximal tolerated dose) AND a dipeptidyl peptidase-4 (DPP-4) 
inhibitor (free form combination) at the maximum approved dose for at least 8 weeks prior to 
screening. Eligible subjects who complete the screening period will enter the lead-in period, 
which includes open-label saxagliptin 5 mg and metformin IR/XR treatment for 16 weeks in 
Stratum A or 8 weeks in Stratum B. For subjects in Stratum B, DPP-4 inhibitor will be 
switched to saxagliptin 5 mg at Week -8. Metformin treatment regimen has to be the same as 
subjects were using at study entry and keep unchanged throughout the whole study period for 
both strata. On Day 1 of randomization visit, eligible subjects will be randomized into one of 
three treatment groups (dapagliflozin 5 mg and dapagliflozin 10 mg placebo to match, 
dapagliflozin 10 mg and dapagliflozin 5 mg placebo to match or dapagliflozin 5 mg placebo to 
match and dapagliflozin 10 mg placebo to match). Thereafter subjects will receive oral 
administration of study treatments once daily for 24 weeks. Scheduled visits will occur at 
Week 6, 12, 18 and 24 during double-blind treatment period. 
Objectives 
Primary Objective: 
Outcome Measure: 
To compare the mean change from baseline in 
glycosylated hemoglobin (HbA1c) achieved with 
dapagliflozin 5 mg or dapagliflozin 10 mg added to 
saxagliptin 5 mg plus metformin versus (vs.)  placebo 
added to saxagliptin 5 mg plus metformin after 24 weeks 
of oral administration of double-blind treatment 
Mean change from baseline in HbA1c 
at Week 24 
Secondary Objective: 
Outcome Measure: 
x 
To compare the mean change from baseline achieved 
with dapagliflozin 5 mg or dapagliflozin 10 mg added 
to saxagliptin 5 mg plus metformin vs. placebo added 
to saxagliptin 5 mg plus metformin after 24 weeks of 
oral administration of double-blind treatment in the 
following: 
1) Fasting plasma glucose (FPG) 
2) 2-hour PPG from a meal tolerance test (2-hour 
MTT) 
3) Total body weight 
x 
To compare the proportion of subjects achieving a 
therapeutic glycemic response, defined as a HbA1c < 
7.0%, with dapagliflozin 5 mg or dapagliflozin 10 mg 
added to saxagliptin 5 mg plus metformin vs. placebo 
added to saxagliptin 5 mg plus metformin after 24 
weeks of oral administration of double-blind treatment 
x 
Mean change from baseline in 
fasting plasma glucose (FPG) at 
Week 24 
x 
Mean change from baseline in 2-
hour PPG during a meal tolerance 
test (2-hour MTT) at Week 24 
x 
Mean change from baseline in 
Total body weight at Week 24 
x 
Percent of subjects achieving a 
therapeutic glycaemic response, 
defined as a HbA1c < 7.0% at 
Week 24 
 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
17(110) 
Safety Objective: 
Outcome Measure: 
To evaluate the safety and tolerability of therapy with 
dapagliflozin 5 mg or dapagliflozin 10 mg added to 
saxagliptin 5 mg plus metformin vs. placebo added to 
saxagliptin 5 mg plus metformin after 24 weeks of oral 
administration of double-blind treatment 
x 
Adverse Events (AEs) /Serious 
Adverse Events (SAEs) 
x 
AEs of special interest (AESI) 
x 
Clinical laboratory tests 
x 
Physical examination 
x 
ECG 
x 
Vital signs 
Exploratory Objective: 
Outcome Measure: 
x 
To assess the percent of subjects who require rescue 
or discontinue study treatment for lack of efficacy 
with dapagliflozin 5 mg or dapagliflozin 10 mg added 
to saxagliptin 5 mg plus metformin vs. placebo added 
to saxagliptin 5 mg plus metformin up to 24 weeks of 
oral administration of double-blind treatment 
x 
To assess the time to glycemic rescue or 
discontinuation for lack of efficacy with dapagliflozin 
5 mg or dapagliflozin 10 mg added to saxagliptin 5 
mg plus metformin vs. placebo added to saxagliptin 5 
mg plus metformin during the short-term double-blind 
period 
x 
To assess the mean change from baseline in area 
under the curve (AUC) of glucose obtained during a 
MTT with dapagliflozin 5 mg or dapagliflozin 10 mg 
added to saxagliptin 5 mg plus metformin vs. placebo 
added to saxagliptin 5 mg plus metformin after 24 
weeks of oral administration of double-blind treatment 
x 
To assess the mean percent change from baseline in 
fasting serum lipids (Total-C, LDL-C, HDL-C, TG) 
with dapagliflozin 5 mg or dapagliflozin 10 mg added 
to saxagliptin 5 mg plus metformin vs. placebo added 
to saxagliptin 5 mg plus metformin after 24 weeks of 
oral administration of double-blind treatment 
x 
Percent of subjects who require 
glycemic rescue or discontinue 
study treatment for lack of 
efficacy up to Week 24 
x 
Time to glycemic rescue or 
discontinuation for lack of efficacy 
in the double-blind treatment 
period 
x 
Mean change from baseline in 
AUC of glucose obtained during a 
MTT at Week 24 
x 
Mean percent change from 
baseline in fasting lipids (Total-C, 
LDL-C, HDL-C, TG) at Week 24 
 
Target subject population 
Approximately 342 subjects aged ≥18 years who have type 2 diabetes mellitus (T2DM) with 
inadequate glycemic control (defined as a central laboratory HbA1c ≥ 7.0 and ≤ 10.5% for 
both strata obtained at the week -2 visit) taking stable metformin IR/XR therapy and open-
label saxagliptin 5 mg will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
18(110) 
Duration of treatment 
Study duration will be at least 42 weeks (Stratum A) or 34 weeks (Stratum B), including a 2-
week screening period, a 16-week (Stratum A) or 8-week (Stratum B) lead-in period, and a 
24-week double-blind treatment period. 
Investigational product, dosage and mode of administration 
Dapagliflozin and dapagliflozin placebo to match 
Dapagliflozin 5mg tablets, dapagliflozin 10 mg tablets and dapagliflozin 5mg or 10mg 
placebo to match tablets, administered orally once daily for the 24-week double-blind 
treatment period. 
Other Treatments 
Saxagliptin: Saxagliptin 5 mg tablets, administered orally once daily for the lead-in period 
and the 24-week double-blind treatment period. 
Metformin: Throughout the study duration, subjects should continue to adhere to the same 
metformin treatment regimen as they were using at study entry. Metformin should be 
administered and stored according to product and country specific labelling. 
Rescue therapy: Subjects who require rescue therapy should receive standard of care 
treatment (insulin or any other antidiabetic agents except Glucagon-like peptide-1 (GLP-1) 
analogues, other DPP-4 inhibitors and/or SGLT2 inhibitors or metformin). 
Statistical methods 
The primary endpoint (mean change from baseline in HbA1c at Week 24) will be assessed 
comparing dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus 
metformin vs. placebo added to saxagliptin 5 mg plus metformin. Statistical significance of 
the primary endpoint will be claimed if the p-values for dapagliflozin 10 mg + saxagliptin 5 
mg + metformin vs. placebo + saxagliptin 5 mg + metformin comparison is significant at the 
2-sided, 0.05 significance level. As the success of primary endpoint on the dapagliflozin 5 mg 
+ saxagliptin 5 mg + metformin vs. placebo + saxagliptin 5 mg + metformin comparison is 
important, the sample size is planned to provide at least 90% power for primary endpoint on 
both comparisons. 
With 108 subjects per treatment group with post-baseline assessment, there is 95% power to 
detect -0.5% difference for dapagliflozin 10 mg + saxagliptin 5 mg + metformin vs. placebo + 
saxagliptin 5 mg + metformin comparison, assuming a standard deviation (SD) of 1.0% with a 
2-sided significance level of 0.05. This sample size will also provide at least 90% power to 
detect -0.5% difference for both dapagliflozin 10 mg + saxagliptin 5 mg + metformin vs. 
placebo + saxagliptin 5 mg + metformin and dapagliflozin 5 mg + saxagliptin 5 mg + 
metformin vs. placebo + saxagliptin 5 mg + metformin comparisons, assuming a SD of 1.0% 
with a 2-sided significance level of 0.05. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
19(110) 
Assuming that 5% of subjects would not have a post-baseline assessment, a total of 
approximately 342 subjects (114 subjects per treatment arm, with about 91 subjects from 
China and about 23 subjects from other countries/regions) need to be randomized. In other 
words, Chinese subjects will constitute about 80% of the total number of subjects. This study 
includes two strata, based on prior antihyperglycemic treatment. Subjects with HbA1c 
uncontrolled on a stable dose of metformin (≥ 1500 mg/day or a maximal tolerated dose) are 
enrolled into a 16-week open-label treatment period (Stratum A), adding saxagliptin 5 mg to 
metformin. Subjects with HbA1c uncontrolled on a stable dose of metformin (≥ 1500 mg/day 
or a maximal tolerated dose) AND a maximal dose of a DPP-4 inhibitor are enrolled into an 8-
week open-label treatment period (Stratum B), following treatment with saxagliptin 5 mg plus 
metformin. Subjects from two strata who remain uncontrolled HbA1C are subsequently 
randomized.  
It is desired to have approximately 33% of the randomized subjects coming from Stratum B. 
In addition, enrolment of subjects with HbA1c ≥ 8.0% and < 9.0% (Stratum A) and subjects 
with HbA1c ≥ 7.5% and ≤ 8.5% (Stratum B) into the open-label treatment period will be 
limited to approximately 171 subjects (about 50% of the randomized subjects number in each 
stratum). 
About 40% (Stratum A) and 6.5% (Stratum B) of subjects are expected to be discontinued due 
to severe lack of glycaemic control (defined as FPG > 270 mg/dL at Week -10 or Week -2 in 
Stratum A and Week -2 only in Stratum B) during the open-label treatment period. In 
addition, it is expected that 50% of screened subjects will fail to meet eligible criteria for 
open-label treatment of each stratum. This leads to a total of 1004 subjects to be screened, 
with a targeted 380 subjects in Stratum A and 122 subjects in Stratum B to enter the open-
label treatment period.  
The primary efficacy analysis will compare the change from baseline in HbA1c at Week 24 
for dapagliflozin 5 mg or dapagliflozin 10 mg + saxagliptin 5 mg + metformin treatment 
groups and the placebo + saxagliptin 5 mg + metformin group. Each comparison will be 
performed at the 0.05 significance level (2-sided) using the hierarchical testing specified in 
Section8.1. This maintains the familywise type I error rate at 0.05. 
The primary efficacy analysis of HbA1c at week 24 will be performed using a mixed-model 
repeated-measures (MMRM) model with terms for treatment group, stratum, baseline HbA1c 
value, time, the interaction of treatment and time, and the interaction of baseline HbA1c value 
and time in the model, including observations prior to rescue and study treatment 
discontinuation only, without explicitly imputing missing data. An unstructured matrix for the 
within-subject error variance-covariance will be used. The denominator degrees of freedom 
will be calculated according to the Kenward-Roger method. In case of non-convergence of the 
preferred model or memory space issue, the back-up models will be used (e.g. calculate the 
denominator degrees of freedom using other method like Satterthwaite approximation, use 
other covariance matrix like Toeplitz, AR (1), use simpler models, and etc.). Details will be 
documented in statistical analysis plan (SAP). Point estimates and 95% confidence intervals 

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will be calculated for the adjusted mean changes within each treatment group as well as for 
the differences in adjusted mean changes between treatment groups.   
Intent-to-treat (ITT) analysis set will be used for the primary efficacy analysis.  
The same MMRM approach used for HbA1c evaluation will also be used for the analysis of 
FPG and total body weight. Point estimates and 95% confidence intervals will be calculated 
for the adjusted mean changes within each treatment group as well as for the differences in 
adjusted mean changes between treatment groups.   
The analysis of covariance (ANCOVA) using last observation carried forward (LOCF) 
methodology with terms for treatment group, stratum, and baseline 2-hour postprandial 
plasma glucose (PPG) value will be used to evaluate 2-hour PPG. Point estimates and 95% 
confidence intervals will be calculated for the adjusted mean changes at Week 24 within each 
treatment group as well as for the differences in adjusted mean changes between treatment 
groups.  
The proportion of subjects achieving a therapeutic glycaemic response (defined as HbA1c < 
7.0%) at Week 24 (LOCF) will be summarized by treatment group and compared between 
treatment groups using the logistic regression based on methodology of Zhang et al (Zhang 
2008) and Tsiatis et al (Tsiatis 2008) with adjustment for baseline HbA1c and stratum. Point 
estimates and 95% confidence intervals will be calculated for the response rate within each 
treatment group as well as the difference in response rates between treatment groups.  
Safety analyses for the double-blind treatment period will be performed using the safety 
analysis set, including data after rescue. Safety analyses will include, where appropriate, 
descriptive statistics, counts, and percentages for AEs and other safety measures. No formal 
statistical tests will be performed for safety endpoints. Selected safety and efficacy analyses 
will be performed for the open-label treatment period using the open-label treated subjects 
analysis set. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
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TABLE OF CONTENTS 
TITLE PAGE ....................................................................................................... 1 
VERSION HISTORY .......................................................................................... 2 
PROTOCOL SYNOPSIS ................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................... 26 
1. 
INTRODUCTION ............................................................................................. 29 
1.1 
Background and rationale for conducting this study ........................................... 29 
1.2 
Rationale for study design, doses and control groups .......................................... 30 
1.3 
Benefit/risk and ethical assessment .................................................................... 31 
1.4 
Study design ...................................................................................................... 33 
2. 
STUDY OBJECTIVE ........................................................................................ 35 
2.1 
Primary objective ............................................................................................... 35 
2.2 
Secondary objectives .......................................................................................... 35 
2.3 
Safety objectives ................................................................................................ 35 
2.4 
Exploratory objectives ....................................................................................... 36 
3. 
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ..................... 36 
3.1 
Inclusion criteria ................................................................................................ 36 
3.2 
Exclusion criteria ............................................................................................... 38 
3.3 
Subject enrolment and randomization ................................................................. 42 
3.3.1 
Procedures for randomization ............................................................................. 42 
3.4 
Procedures for handling incorrectly enrolled or randomized subjects .................. 43 
3.5 
Methods for assigning treatment groups ............................................................. 43 
3.6 
Methods for ensuring blinding ........................................................................... 44 
3.7 
Methods for unblinding ...................................................................................... 45 
3.8 
Restrictions ........................................................................................................ 45 
3.8.1 
Prohibited and/or restricted treatments ............................................................... 45 
3.8.2 
Other restrictions ................................................................................................ 45 
3.9 
Discontinuation of investigational product ......................................................... 46 
3.9.1 
Procedures for discontinuation of a subject from investigational product ............ 46 
3.9.2 
Discontinuation guideline due to hypoglycaemic events ..................................... 47 
3.9.3 
Procedures for discontinuation of a subject from investigational product ............ 48 
3.10 
Criteria for withdrawal ....................................................................................... 48 

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3.10.1 
Screen failures ................................................................................................... 49 
3.10.2 
Withdrawal of the informed consent ................................................................... 49 
3.10.3 
Lost to follow-up ............................................................................................... 50 
3.11 
Discontinuation of the study ............................................................................... 50 
4. 
STUDY PLAN AND TIMING OF PROCEDURES........................................... 50 
4.1 
Enrolment/screening period................................................................................ 61 
4.1.1 
Screening Visit (Visit 1, Week -18 for Stratum A and Week -10 for 
Stratum B) ......................................................................................................... 61 
4.2 
Open-label treatment period ............................................................................... 62 
4.2.1 
Visit 2 (Week -16 for Stratum A and Week -8 for Stratum B) ............................ 63 
4.2.2 
Visit 3 (Week -10 for Stratum A) ....................................................................... 63 
4.2.3 
Visit 3 (Week -2 for Stratum B) ......................................................................... 64 
4.2.4 
Visit 4 (Week -2 for Stratum A) ......................................................................... 65 
4.3 
Double-blind, double-dummy treatment period .................................................. 65 
4.3.1 
Randomization (Day 1) ...................................................................................... 66 
4.3.2 
Double-blind treatment period (Week 6, 12, 18) ................................................. 68 
4.3.3 
Week24/Rescue/Early Treatment Discontinuation visit ...................................... 69 
5. 
STUDY ASSESSMENTS .................................................................................. 71 
5.1 
Efficacy assessments .......................................................................................... 71 
5.1.1 
Primary efficacy variable ................................................................................... 73 
5.1.2 
Secondary efficacy variable ............................................................................... 73 
5.1.2.1 
Postprandial glucose (PPG) at 120 minutes(China only) ..................................... 73 
5.1.2.2 
Fasting plasma glucose (FPG) ............................................................................ 73 
5.1.2.3 
Glycaemic response (HbA1c<7.0%)................................................................... 73 
5.1.2.4 
Body weight ....................................................................................................... 74 
5.1.3 
Exploratory efficacy variables ............................................................................ 74 
5.1.3.1 
Postprandial glucose AUC ................................................................................. 74 
5.1.3.2 
Fasting serum lipids ........................................................................................... 74 
5.1.3.3 
Rescue/Discontinuation ...................................................................................... 74 
5.2 
Safety assessments ............................................................................................. 74 
5.2.1 
Laboratory safety assessments ............................................................................ 74 
5.2.1.1 
Hematology ....................................................................................................... 74 
5.2.1.2 
Chemistry .......................................................................................................... 74 
5.2.1.3 
eGFR ................................................................................................................. 75 
5.2.1.4 
Urinalysis........................................................................................................... 75 
5.2.1.5 
Other clinical laboratory evaluations .................................................................. 76 
5.2.2 
Physical examination ......................................................................................... 76 
5.2.3 
ECG ................................................................................................................... 76 
5.2.4 
Vital signs .......................................................................................................... 77 
5.2.5 
Other safety assessments .................................................................................... 77 
5.2.5.1 
Self-monitoring of blood glucose (SMBG) and Hypoglycaemia events .............. 77 
5.2.5.2 
Urinary infections .............................................................................................. 78 

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5.2.5.3 
Cardiovascular events (Cardiovascular Adjudication Committee, CAC) ............. 79 
5.2.5.4 
Potential events of Diabetic Ketoacidosis (DKA Adjudication Committee) ........ 79 
5.3 
Other assessments .............................................................................................. 79 
5.3.1 
Diet and exercise counselling ............................................................................. 79 
5.3.2 
Height and body mass index (BMI) .................................................................... 79 
5.3.3 
Waist circumference .......................................................................................... 80 
5.4 
Pharmacokinetics-Not Applicable ...................................................................... 80 
5.5 
Pharmacodynamics-Not Applicable ................................................................... 80 
5.6 
Genetics-Not Applicable .................................................................................... 80 
5.7 
Biomarker-Not Applicable ................................................................................. 80 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT ............................. 80 
6.1 
Definition of adverse events ............................................................................... 80 
6.1.1 
Adverse events of special interest ....................................................................... 80 
6.2 
Definitions of serious adverse event ................................................................... 81 
6.3 
Recording of adverse events ............................................................................... 81 
6.3.1 
Time period for collection of adverse events ...................................................... 81 
6.3.2 
Follow-up of AEs and SAEs .............................................................................. 82 
6.3.3 
Variables ............................................................................................................ 82 
6.3.4 
Causality collection ............................................................................................ 83 
6.3.5 
Adverse events based on signs and symptoms .................................................... 83 
6.3.6 
Adverse events based on examinations and tests ................................................ 83 
6.3.7 
Hypoglycaemia .................................................................................................. 84 
6.3.8 
Hy’s Law-Not Applicable .................................................................................. 85 
6.4 
Reporting of serious adverse events ................................................................... 85 
6.5 
Overdose ............................................................................................................ 86 
6.6 
Pregnancy .......................................................................................................... 86 
6.6.1 
Maternal exposure .............................................................................................. 86 
6.6.2 
Paternal exposure ............................................................................................... 87 
6.7 
Medication error ................................................................................................ 87 
6.8 
Management of IP related toxicities <<Dose Reductions>> ............................... 88 
6.9 
Study governance and oversight ......................................................................... 89 
6.9.1 
Clinical Event Committee (CEC) ....................................................................... 89 
6.9.1.1 
Diabetic Ketoacidosis Adjudication Committee ................................................. 89 
6.9.1.2 
Cardiovascular Adjudication Committee ............................................................ 89 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 89 
7.1 
Identity of investigational product(s) .................................................................. 89 
7.2 
Dose and treatment regimens ............................................................................. 90 

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7.3 
Labelling ............................................................................................................ 90 
7.4 
Storage ............................................................................................................... 91 
7.5 
Compliance ........................................................................................................ 91 
7.6 
Accountability.................................................................................................... 91 
7.7 
Concomitant and other treatments ...................................................................... 92 
7.7.1 
Saxagliptin ......................................................................................................... 92 
7.7.2 
Metformin .......................................................................................................... 92 
7.7.3 
Rescue therapy ................................................................................................... 92 
7.7.4 
Other concomitant medication ............................................................................ 93 
7.8 
Post Study Access to Study Treatment ............................................................... 93 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA .......................................... 93 
8.1 
Statistical hypotheses ......................................................................................... 93 
8.2 
Sample size estimate .......................................................................................... 93 
8.3 
Definitions of analysis sets ................................................................................. 94 
8.3.1 
Efficacy analysis sets ......................................................................................... 94 
8.3.2 
Safety analysis set .............................................................................................. 95 
8.3.3 
Open-label treated subjects analysis set .............................................................. 95 
8.3.4 
PK analysis set-Not Applicable .......................................................................... 95 
8.3.5 
PRO analysis set-Not Applicable ....................................................................... 95 
8.4 
Outcome measures for analyses .......................................................................... 95 
8.4.1 
Primary efficacy variable ................................................................................... 95 
8.4.2 
Secondary efficacy variables .............................................................................. 95 
8.4.3 
Exploratory variables ......................................................................................... 95 
8.5 
Methods for statistical analyses .......................................................................... 96 
8.5.1 
Analysis of the primary variable (s) .................................................................... 96 
8.5.2 
Analysis of the secondary variable(s) ................................................................. 96 
8.5.3 
Subgroup Analysis ............................................................................................. 97 
8.5.4 
Interim analysis-Not Applicable ......................................................................... 97 
8.5.5 
Sensitivity analysis ............................................................................................. 97 
8.5.6 
Exploratory Analysis (if applicable) ................................................................... 97 
8.5.7 
Safety analysis ................................................................................................... 98 
8.5.8 
Methods for multiplicity control ......................................................................... 98 
8.6 
China cohort ...................................................................................................... 99 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ......................... 99 
9.1 
Training of study site personnel ......................................................................... 99 
9.2 
Monitoring of the study ...................................................................................... 99 
9.2.1 
Source data ...................................................................................................... 100 
9.2.2 
Study agreements ............................................................................................. 100 
9.3 
Study timetable and end of study ...................................................................... 100 

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Edition Number 5.0 
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9.4 
Data management by AstraZeneca or delegate ................................................. 100 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ..................................... 101 
10.1 
Ethical conduct of the study ............................................................................. 101 
10.2 
Subject data protection ..................................................................................... 101 
10.3 
Ethics and regulatory review ............................................................................ 102 
10.4 
Informed consent ............................................................................................. 102 
10.5 
Changes to the protocol and informed consent form ......................................... 103 
10.6 
Audits and inspections ..................................................................................... 103 
11. 
LIST OF REFERENCES ................................................................................. 104 
12. 
APPENDIX A ADDITIONAL SAFETY INFORMATION ............................. 106 
12.1 
Further guidance on the definition of a serious adverse event (SAE) ................ 106 
12.2 
A guide to interpreting the causality question ................................................... 106 
13. 
APPENDIX B INTERNATIONAL AIRLINE TRANSPORTATION 
ASSOCIATION (IATA) 6.2 GUIDANCE DOCUMENT ................................ 108 
13.1 
Labelling and shipment of biohazard samples .................................................. 108 
14. 
APPENDIX C NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASS ............................................................................................................ 110 
LIST OF TABLES 
Table 1     Study Design for Stratum A & Stratum B ........................................................... 51 
Table 2     Lack of Glycaemic Control Criteria for Initiation of Rescue Medication............. 66 
Table 3     Laboratory Safety Variables ............................................................................... 75 
LIST OF FIGURES 
Figure 1   Study Design ...................................................................................................... 34 
LIST OF APPENDICES 
APPENDIX A ADDITIONAL SAFETY INFORMATION ............................................. 106 
APPENDIX B INTERNATIONAL AIRLINE TRANSPORTATION 
ASSOCIATION (IATA) 6.2 GUIDANCE DOCUMENT ......................... 108 
APPENDIX C NEW YORK HEART ASSOCIATION FUNCTIONAL CLASS ............. 110 
 

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Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this Clinical Study Protocol (CSP). 
Abbreviation or special term 
Explanation 
ADA 
American Diabetes Association 
AE 
Adverse event 
AESI 
AEs of special interest 
ALK-P 
Alkaline phosphatase 
ALT  
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUC 
Area under the curve 
BMI  
Body mass index 
BP 
Blood Pressure 
CABG 
Coronary Artery Bypass Graft 
CAC  
Cardiovascular Adjudication Committee 
CEC 
Clinical Event Committee 
CK / CPK 
Creatine kinase 
CrCl 
Creatinine clearance 
CRF 
Case Report Form (electronic/paper) 
CRO 
Contract research organization 
CSA 
Clinical Study Agreement 
CSP 
Clinical Study Protocol 
CSR  
Clinical Study Report 
CSRAF 
Clinical Supplies Return Authorization Form 
CV 
Cardiovascular 
DBP 
Diastolic blood pressure 
DKA 
Diabetic ketoacidosis 
DPP-4 
Dipeptidyl peptidase-4 
ECG 
Electrocardiogram 
E-code 
Enrolment code 
ESRD 
End-stage renal disease 
eCRF 
Electronic Case Report Form 

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Abbreviation or special term 
Explanation 
eGFR 
Estimate glomerular filtration rate 
ETD 
Early treatment discontinuation 
EU 
European Union 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
GAD 
Glutamic acid decarboxylase 
GCP 
Good Clinical Practice 
GLP-1 
Glucagon-like peptide-1 
GMP  
Good manufacturing practice 
HAV 
Hepatitis A virus 
Hb 
Hemoglobin 
HbA1c 
Hemoglobin A1c / glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IATA 
International Airline Transportation Association 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonisation 
IP 
Investigational Product 
IR 
Immediate Release 
ITT 
Intent-to-treat 
IxRS 
Kg 
Interactive voice/web response system 
Kilogram 
LDL-C 
Low density lipoprotein cholesterol 
LOCF 
Last observation carried forward 
MCH  
Mean cell hemoglobin 
MCHC 
Mean cell haemoglobin concentration 
MCV 
Mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 

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Abbreviation or special term 
Explanation 
MMRM 
Mixed-model repeated-measures 
MOA 
Mechanism of action 
MTT 
Meal Tolerance Test 
NYHA 
PCI 
New York Heart Association 
Percutaneous coronary intervention 
PP 
Per protocol 
PPG  
Postprandial plasma glucose 
PSSR 
Project Specific Safety Requirements 
RBC  
Red blood cell 
SA 
Sickle cell anemia 
SAE 
Serious adverse event 
SAP  
Statistical analysis plan 
SBP  
Systolic blood pressure 
Scr 
Serum creatinine 
SD 
Standard deviation 
SGLT2 
Sodium glucose cotransporter 2 
SMBG 
Self-monitoring of blood glucose 
SU 
Sulfonylurea 
T2DM 
Type 2 diabetes mellitus 
T4 
Thyroxine 
TB 
Total bilirubin 
TG 
Triglyceride 
TIA 
Transient ischemic attack 
TSH  
Thyroid stimulating hormone 
TZD 
Thiazolidinedione 
ULN 
Upper limit of normal 
US 
United States  
UTI 
Urinary tract infection 
vs. 
Versus 
WBDC 
Web Based Data Capture 
WOCBP 
Women of childbearing potential 
XR 
Extended Release 

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1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
T2DM is a chronic progressive disease, characterized by hyperglycaemia and an increased 
risk of microvascular and macrovascular complications. Despite the irrefutable evidence for 
the importance of maintaining tight glycemic control, achieving and maintaining the 
glycaemic treatment goal is still challenging. There are approximately 50% of T2DM subjects 
fail to achieve the American Diabetes Association (ADA) goal for glycemic control of HbA1c 
< 7.0% (Hoerger et al 2008). In the United States (US) according to NHANES 2004 data, 
44.3% of subjects with T2DM have HbA1c levels ≥ 7% (Hoerger et al 2008). This level of poor 
control appears not to have improved. NHANES 2006 still showed that 40% of subjects have 
HbA1c > 7% (Nguyen et al 2011). In China, among subjects with diabetes, only 25.8% (95% 
CI, 24.9%-26.8%) received treatment for diabetes, and only 39.7% of those treated had 
adequate glycemic control (Xu Y et al 2013). Progressive beta cell failure, weight gain, and 
hypoglycemia are major obstacles for the achievement of optimal glycemic control (DeFronzo 
RA et al 2009).  
Typically, the treatment paradigm consists of a step wise addition of different classes of 
antihyperglycemic drugs, as most subjects eventually require 2 or more agents to achieve or 
maintain glycemic targets. Current sequential add-on second and third line oral therapy mainly 
includes older classes of oral drugs like sulfonylureas (SUs) and thiazolidinediones (TZDs). 
Some of their key limitations are weight gain and increased risk of hypoglycaemia (SU only). 
Hypoglycaemia is a clinically important barrier to optimizing treatment and there is emerging 
evidence that hypoglycaemia is associated with negative cardiovascular (CV) outcomes. SUs 
(and insulin) are associated with a high risk of hypoglycaemia and caution is recommended 
when using combination therapy with agents causing hypoglycaemia if HbA1c is ˂ 8.5% 
(Rodbard et al 2009). Efforts by subjects to lose weight as part of a therapeutic lifestyle 
program are undermined by therapies that lead to weight gain. Over 85% of subjects with 
T2DM are overweight or obese, and additional weight gain is undesirable and often results in 
reducing treatment compliance by the subjects. TZDs, SUs and insulin, are all associated with 
a significant weight gain. 
Because of the lack of, and delay in, glucose control, the progressive nature of the disease and 
the limitations of available oral and non-oral therapies, there is a significant medical need for 
additional oral combination treatment options for T2DM. 
Saxagliptin is a DPP-4 inhibitor for the treatment of subjects with T2DM. By increasing and 
prolonging active incretin concentrations, saxagliptin increases insulin release and decreases 
glucagon concentrations in the circulation in a glucose-dependent manner. Dapagliflozin is a 
highly potent, selective, and reversible inhibitor of sodium glucose cotransporter 2 (SGLT2) 
that improves glycaemic control in subjects with T2DM by reducing renal glucose 
reabsorption, leading to urinary excretion of excess glucose (glucuresis). Therefore, both 
saxagliptin and dapagliflozin complement metformin’s mechanism of action (MOA). 
Saxagliptin and dapagliflozin have demonstrated, both individually and in combination with 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
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metformin in general a favourable safety and tolerability profile. They have shown as single 
agents, as well as in (initial and add-on) combination with metformin, a low propensity for 
hypoglycaemia consistent with their respective glucose dependent MOA. Both drugs have 
either demonstrated weight neutrality (saxagliptin) or moderate weight reduction 
(dapaglifozin). In study MB102-129, which was intended to compare the addition of 
dapagliflozin vs. placebo as add-on therapy in subjects with T2DM who are inadequately 
controlled on saxagliptin plus metformin therapy, dapagliflozin showed a significant decrease 
in HbA1c compared to placebo (-0.82%, -0.10%, respectively). Dapagliflozin also 
demonstrated significant decrease in FPG (-32.7 mg/dL vs. -5.3 mg/dL, respectively), PPG (-
73.5 mg/dL vs. -38.0 mg/dL, respectively), and weight (-1.91 kg vs. -0.41 kg, respectively), 
and more subjects achieving therapeutic glycaemic response (38.0% vs. 12.4%, respectively). 
This study also demonstrated a favourable safety and tolerability of dapagliflozin when added 
on to saxagliptin and metformin.
1.2 
Rationale for study design, doses and control groups 
This study is a Phase 3 study, performed as part of the clinical development program for both 
dapagliflozin (a SGLT2 inhibitor) and saxagliptin (a DPP-4 inhibitor) for the treatment of 
T2DM. The study is intended to compare the addition of dapagliflozin 5 mg or 10 mg vs. 
placebo as add-on therapy in subjects with T2DM who are inadequately controlled on 
saxagliptin 5 mg plus metformin therapy. 
Metformin is the oral first line gold standard agent. Metformin is a biguanide, its MOA is to 
decrease hepatic glucose output thus lowering fasting hyperglycaemia. Metformin is 
recommended as the initial pharmacological therapy because of its glycaemic efficacy, weight 
neutrality, low risk of hypoglycaemia, good tolerability and relatively low cost (Inzucchi et al 
2012). Metformin’s dose limiting side effect is gastrointestinal tolerability. However, doses≥ 
1500 mg are generally well tolerated. 
Saxagliptin is approved in many countries worldwide, including the US, Canada, China and 
countries in the European Union (EU) as an adjunct to diet and exercise to improve glycaemic 
control in adults with T2DM. The results from the 8 Phase II and Phase III clinical studies 
with saxagliptin support the oral dose of 5 mg once daily in a wide range of subjects with 
T2DM, as either monotherapy, add on combination therapy with metformin, a TZD, a SU, 
insulin, or initial combination therapy with metformin. Saxagliptin 5 mg resulted in clinically 
meaningful reductions in HbA1c, as well as FPG, PPG, insulin, C-peptide, and glucagon 
levels and is the recommended dose according to the approved drug label. 

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Dapagliflozin is approved in many countries worldwide, including the US, 
Canada, China and countries in the EU, as an adjunct to diet and exercise to improve 
glycaemic control in subjects with T2DM. The 5 mg and 10 mg doses are chosen for this 
study, because in US, Canada, Switzerland and China, the recommended starting dose is 5 mg 
once daily, and can be increased to 10 mg once daily in subjects tolerating dapagliflozin who 
require additional glycaemic control. Both strengths of dapagliflozin has demonstrated 
clinically meaningful reductions in HbA1c individually or as add on therapy with other OADs. 
Treatment with dapagliflozin, with its unique MOA, induces a persistent loss of excess 
glucose with associated calories in the urine, resulting in a consistent and maintained 
reduction of total body weight, in addition to improved glycaemic control. Dapagliflozin also 
has a mild diuretic effect, which in combination with weight loss, has the potential to reduce 
blood pressure (BP). 
The combination of dapagliflozin 10 mg and saxagliptin 5 mg has been studied initially in 3 
Phase III trials. The main study MB102-129, as mentioned above, was intended to compare 
the addition of dapagliflozin vs. placebo as add-on therapy in subjects with T2DM 
inadequately controlled on saxagliptin plus metformin therapy. In study CV181-168 
(sequential administration) 5 mg saxagliptin or placebo were added to a background of 10 mg 
dapagliflozin and metformin. In study CV181-169 (dual administration) saxagliptin 5 mg plus 
dapagliflozin 10 mg or the individual components plus placebo were given to a background of 
metformin. All of the three studies found the co-administration of dapagliflozin 10 mg and 
saxagliptin 5 mg to be well tolerated and efficacious. 
1.3 
Benefit/risk and ethical assessment 
Details regarding potential risks associated with administration of dapagliflozin and 
saxagliptin are provided in the Investigator’s Brochure (IB) for each medication. 
Prior to approval, dapagliflozin was evaluated in 5 core Phase IIb studies, 16 core Phase III 
studies, and 3 regional Phase III studies. Dapagliflozin has global market approval and based 
on global cumulative sale figures up to March 2016 it is estimated that dapagliflozin has been 
administered for >1,000,000 patient years. 
Prior to approval, saxagliptin was evaluated in 6 pivotal Phase III, randomized, double-blind 
controlled trials at doses of 2.5 mg to 10 mg. When added to standard of care in subjects with 
T2DM at high CV risk, saxagliptin neither reduced nor increased the risk of the primary 
composite endpoint of CV death, myocardial infarction (MI), or ischemic stroke (Scirica et al 
2013). 
Considering the comprehensive previous clinical experience with saxagliptin and 
dapagliflozin and the combination of dapagliflozin 10 mg and saxagliptin 5 mg has been 
studied in 3 Phase III trials, the study’s design features (including the inclusion, exclusion, and 
discontinuation criteria), planned safety procedures, and participation in this study presents a 
minimal and thus acceptable risk to the individual subjects who will be included. 
 

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Study Code D1683C00008 
Edition Number 5.0 
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Protection against risks  
The present study has been designed with appropriate measures in place to monitor and 
minimize any of the potential health risks to participating subjects. In order to ensure the 
safety of all subjects participating in this study, AstraZeneca is conducting a real-time review 
of all safety information from all ongoing clinical dapagliflozin and saxagliptin 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 and saxagliptin will be 
immediately communicated to relevant Health Authorities and appropriate actions will be 
taken regarding the clinical program as needed. In addition, all studies which include 
dapagliflozin 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 subjects in whom a potential health risk or a laboratory abnormality of clinical 
concern has been identified. Investigators are also provided guidance on appropriate 
management of potential risks such as hypoglycaemia, urinary tract infections (UTI) and 
decreased renal function and also the potential risks of saxagliptin mentioned in the Risk 
Management Plan. 
Ketoacidosis 
There have been post marketing reports of ketoacidosis, including diabetic ketoacidosis 
(DKA), in subjects with type 1 and type 2 diabetes mellitus taking dapagliflozin and other 
SGLT2 inhibitors. Dapagliflozin is not indicated for the treatment of subjects with type 1 
diabetes mellitus. 
Subjects 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 subject should be promptly evaluated. 
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from 
pancreatic disorders (e.g., type 1 diabetes, history of pancreatitis, or pancreatic surgery), 
insulin 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 subjects. 
Potential benefits to subjects 
Based on prior clinical trials experience and post-marketing information, both saxagliptin and 
dapagliflozin have a favourable benefit-risk ratio as monotherapy and add-on combination 
therapy. Integrated analyses of the safety data from the initial clinical studies demonstrated 
that the combined use of saxagliptin 5 mg and dapagliflozin 10 mg administered as either a 
dual or a sequential add-on to metformin was well tolerated in T2DM subjects who were 

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Study Code D1683C00008 
Edition Number 5.0 
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inadequately controlled on metformin alone. The combined use of saxagliptin 5 mg and 
dapagliflozin 10 mg was associated with a low risk of hypoglycaemia. Overall, the safety 
profile of administering the 2 agents together was consistent with prior clinical trials which 
evaluated the safety of these agents as monotherapy or as add-on therapy. In these 3 Phase III 
clinical studies, treatment with saxagliptin 5 mg and dapagliflozin 10 mg showed clinically 
relevant decreases in HbA1c, leading to a large proportion of subjects achieving the 
therapeutic goal of HbA1c <7%, and modest reduction in body weight in subjects with T2DM. 
In addition, saxagliptin is expected to be weight neutral and dapagliflozin to reduce weight 
moderately, while both have shown a low risk for hypoglycaemia in combination with 
metformin. Subjects are also expected to receive some benefit in the form of increased 
medical care/attention when participating in study procedures, which includes multiple clinic 
visits and physical examinations over the duration of the study. Subjects will also receive 
counselling on dietary and life-style modifications.  
Informed consent and alternatives to participation 
All prospective participants will be informed of the possible risks and benefits associated with 
this study, and their consent will be received prior to performing any study-related activity. 
When a prospective participant elects to not participate in the study or to withdraw from the 
study, other medications are available to treat their diabetes, and the subject will not be 
disadvantaged in any way. 
1.4 
Study design  
Figure 1 presents the overall design of the study. 
Study D1683C00008 is a 24-week, multicenter, randomized, double-blind, double-dummy, 
placebo-controlled, parallel-group, Phase 3 study designed to investigate if the efficacy and 
safety of triple combination of dapagliflozin 5 mg or 10 mg added to saxagliptin 5 mg plus 
metformin is superior to the dual therapy of saxagliptin 5 mg added to metformin in reducing 
HbA1c. 
After written informed consents have been obtained at screening visit, subjects will be 
checked for all applicable inclusion/exclusion criteria, and laboratory samples will be taken 
and submitted. In Stratum A, subjects should have a stable dose of metformin IR/XR (≥ 1500 
mg/day or a maximal tolerated dose) for at least 8 weeks prior to screening. In Stratum B, 
subjects should have a stable dose of metformin IR/XR (≥ 1500 mg/day or a maximal 
tolerated dose) AND a DPP-4 inhibitor (free form combination) at the maximum approved 
dose for at least 8 weeks prior to screening. Eligible subjects who complete the screening 
period will enter the lead-in period, which include open-label saxagliptin 5 mg and metformin 
IR/XR treatment for 16 weeks in Stratum A or 8 weeks in Stratum B. For subjects in Stratum 
B, DPP-4 inhibitor will be switched to saxagliptin 5 mg at Week -8. Metformin treatment 
regimen has to be the same as they were using at study entry and keep unchanged throughout 
the whole study period for both strata. On Day 1 (randomization visit), eligible subjects will 
be randomized into one of three treatment groups (dapagliflozin 5 mg and dapagliflozin 10 mg 
placebo to match, dapagliflozin 10 mg and dapagliflozin 5 mg placebo to match or 
dapagliflozin 5 mg placebo to match and dapagliflozin 10 mg placebo to match). Thereafter 

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Date 14 Feb 2019 
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subjects will receive oral administration of study treatments once daily for 24 weeks. Clinic 
visits will be scheduled at Week 6, 12, 18 and 24 during double-blind treatment period.  
Subjects with lack of glycaemic control from Week 6 up to but not including Week 24 are 
eligible to receive open-label rescue medication, in addition to their current double-blind 
treatment. All rescue decisions are based on central laboratory FPG and repeated confirmatory 
FPG. It is mandatory for subjects who meet rescue criteria in the double-blind treatment 
period to first complete the rescue visit procedures before receiving open-label rescue 
medication in order to ensure important trial endpoint measurements are collected. Following 
completion of the rescue visit, subjects will be given open-label antidiabetic rescue medication 
(insulin or other antidiabetic agents except GLP-1 analogues, other DPP-4 inhibitors and/or 
SGLT2 inhibitors or metformin) which should be initiated at the lowest starting dose and 
titrated in accordance with the approved product label in the applicable country and by their 
glycaemic response per the investigator's judgement. Titration visit will be performed either 
on-site or via telephone at the discretion of the investigator. Rescued subjects then continue in 
the double-blind treatment period according to their original study visit schedule. 
In addition, subjects who prematurely discontinue will be contacted to collect safety data. 
 
Figure 1     Study design 

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Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
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2. 
STUDY OBJECTIVE  
2.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
To compare the mean change from baseline in 
glycosylated hemoglobin (HbA1c) achieved with 
dapagliflozin 5 mg or dapagliflozin 10 mg added to 
saxagliptin 5 mg plus metformin versus (vs.)  placebo 
added to saxagliptin 5 mg plus metformin after 24 
weeks of oral administration of double-blind treatment 
Mean change from baseline in HbA1c at 
Week 24 
 
2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure: 
x 
To compare the mean change from baseline 
achieved with dapagliflozin 5 mg or dapagliflozin 
10 mg added to saxagliptin 5 mg plus metformin vs. 
placebo added to saxagliptin 5 mg plus metformin 
after 24 weeks of oral administration of double-
blind treatment in the following: 
1) Fasting plasma glucose (FPG) 
2) 2-hour PPG from a meal tolerance test (2-hour 
MTT) 
3) Total body weight 
x 
To compare the proportion of subjects achieving a 
therapeutic glycemic response, defined as a HbA1c 
< 7.0%, with dapagliflozin 5 mg or dapagliflozin 10 
mg added to saxagliptin 5 mg plus metformin vs. 
placebo added to saxagliptin 5 mg plus metformin 
after 24 weeks of oral administration of double-
blind treatment 
x 
Mean change from baseline in fasting 
plasma glucose (FPG) at Week 24 
x 
Mean change from baseline in 2-hour 
PPG during a meal tolerance test (2-
hour MTT) at Week 24 
x 
Mean change from baseline in Total 
body weight at Week 24 
x 
Percent of subjects achieving a 
therapeutic glycaemic response, 
defined as a HbA1c < 7.0% at Week 
24 
 
2.3 
Safety objectives 
Safety Objective: 
Outcome Measure: 
To evaluate the safety and tolerability of therapy with 
dapagliflozin 5 mg or dapagliflozin 10 mg added to 
saxagliptin 5 mg plus metformin vs. placebo added to 
saxagliptin 5 mg plus metformin after 24 weeks of oral 
administration of double-blind treatment 
x 
Adverse Events (AEs)/Serious 
Adverse Events (SAEs) 
x 
AEs of special interest (AESI) 
x 
Clinical laboratory tests 
x 
Physical examination 
x 
ECG 
x 
Vital signs 

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2.4 
Exploratory objectives   
Exploratory Objective: 
Outcome Measure: 
x 
To assess the percent of subjects who require rescue 
or discontinue study treatment for lack of efficacy 
with dapagliflozin 5 mg or dapagliflozin 10 mg 
added to saxagliptin 5 mg plus metformin vs. placebo 
added to saxagliptin 5 mg plus metformin up to 24 
weeks of oral administration of double-blind 
treatment 
x 
To assess the time to glycemic rescue or 
discontinuation for lack of efficacy with 
dapagliflozin 5 mg or dapagliflozin 10 mg added to 
saxagliptin 5 mg plus metformin vs. placebo added to 
saxagliptin 5 mg plus metformin during the short-
term double-blind period 
x 
To assess the mean change from baseline in area 
under the curve (AUC) of glucose obtained during a 
MTT with dapagliflozin 5 mg or dapagliflozin 10 mg 
added to saxagliptin 5 mg plus metformin vs. placebo 
added to saxagliptin 5 mg plus metformin after 24 
weeks of oral administration of double-blind 
treatment 
x 
To assess the mean percent change from baseline in 
fasting serum lipids (Total-C, LDL-C, HDL-C, TG) 
with dapagliflozin 5 mg or dapagliflozin 10 mg 
added to saxagliptin 5 mg plus metformin vs. placebo 
added to saxagliptin 5 mg plus metformin after 24 
weeks of oral administration of double-blind 
treatment 
x 
Percent of subjects who require 
glycemic rescue or discontinue 
study treatment for lack of efficacy 
up to Week 24 
x 
Time to glycemic rescue or 
discontinuation for lack of efficacy 
in the double-blind treatment period 
x 
Mean change from baseline in AUC 
of glucose obtained during a MTT 
at Week 24 
x 
Mean percent change from baseline 
in fasting lipids (Total-C, LDL-C, 
HDL-C, TG) at Week 24 
3. 
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
Each subject 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 
For inclusion in the study subjects should fulfil the following criteria: 
1. Signed Written Informed Consent  
Subjects must be willing and able to give signed and dated written informed consent 

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Edition Number 5.0 
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2. Target Population 
a. For inclusion into open-label treatment period of Stratum A 
Subjects with T2DM with inadequate glycaemic control, defined as central laboratory 
HbA1c ≥ 8.0% and ≤ 11.5% obtained at the screening visit (i.e., Week -18), on stable 
metformin therapy alone at a dose ≥ 1500 mg per day or a maximal tolerated dose for 
at least 8 weeks prior to screening visit 
b. For inclusion into open-label treatment period of Stratum B 
Subjects with T2DM with inadequate glycaemic control, defined as central laboratory 
HbA1c ≥ 7.5% and ≤ 10.5% obtained at the screening visit (i.e., Week -10), on stable 
metformin therapy at a dose ≥ 1500 mg per day or a maximal tolerated dose AND a 
DPP-4 inhibitor (free form combination) at the maximum approved dose for at least 8 
weeks prior to screening visit 
c. For inclusion into double-blind treatment period of both Stratum A and B 
Subjects with T2DM with inadequate glycaemic control, defined as central laboratory 
HbA1c ≥ 7.0 and ≤ 10.5% obtained at the Week -2 visit of the open-label treatment 
period 
d. Body mass index (BMI) ≤ 40.0 kg/m2 at the screening visit 
3. Age and Reproductive Status  
a. Men and women, aged ≥ 18 years old at time of screening visit 
b. Women of childbearing potential (WOCBP) must have a negative serum pregnancy 
test at screening and negative urine pregnancy test within 24 hours prior to the start of 
IP 
WOCBP must be using an acceptable method of contraception to avoid pregnancy 
throughout the study and for at least 4 weeks after the last dose of study medication in 
such a manner that the risk of pregnancy is minimized 
Definitions: 
Acceptable method of birth control: defined as one that results in a failure rate of <1% 
per year, when used consistently and correctly. The following are considered 
acceptable methods of contraception: total sexual abstinence; vasectomized sexual 
partner; male condom with spermicidal gel, tubal occlusion (ligation); intrauterine 
device; levonorgestrel intrauterine system; etonogestrel implants; normal and low dose 
combined oral contraceptive pills; norelgestromin/ethinyl estradiol transdermal 
system; intravaginal device (e.g., ethinyl estradiol and etonogestrel); and desogestrel. 

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Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
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Women NOT of childbearing potential: Women who are permanently or surgically 
sterilized or postmenopausal. Permanent sterilization includes hysterectomy, and/or 
bilateral oophorectomy, and/or bilateral salpingectomy. 
Postmenopausal women: Women are considered postmenopausal if they have 
amenorrhea for ≥12 consecutive months after the last menstrual period and marks the 
end of menstrual cycles. 
3.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Target Disease Exceptions  
a. History of diabetes insipidus or type 1 diabetes 
b. Symptoms of poorly controlled diabetes that would preclude participation in this trial 
including but not limited to marked polyuria and polydipsia with greater than 10% 
weight loss during 3 months prior to screening 
c. History of hyperosmolar nonketotic coma 
d. History of DKA requiring medical intervention (e.g. emergency room visit and/or 
hospitalization) within 1 month prior to screening 
e. Positive GAD antibodies. Only to be measured and used as exclusion criteria in 
subjects < 40 years of age 
2. Medical History and Concurrent Diseases  
a. History of bariatric surgery or lap-band procedure within 12 months prior to screening 
b. Any unstable endocrine, psychiatric or rheumatic disorders as judged by the 
investigator 
c. Subject who, in the judgment of the investigator, may be at risk for dehydration or 
volume depletion that may affect the interpretation of efficacy or safety data 
d. Subject is currently abusing alcohol or other drugs or has done so within the last 6 
months prior to screening 
CV disorders 
e. Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 160 mmHg 
and/or diastolic blood pressure (DBP) ≥ 100 mmHg 
Note: Subjects with SBP ≥ 160mmHg and < 180mmHg or a DBP ≥ 100 mmHg and < 
110mmHg will be able to enter the open-label treatment period, provided their 

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Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
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hypertension treatment is adjusted as deemed appropriate by the investigator. These 
subjects cannot be randomized if their BP remains SBP ≥ 160mmHg or DBP ≥ 100 
mmHg measured on Day 1. 
f. Any of the following CV/Vascular Disease within 3 months of the screening visit, as 
assessed by the investigator: MI, coronary revascularization (percutaneous coronary 
intervention [PCI] or coronary artery bypass grafting [CABG]), unstable angina, 
Congestive heart failure as New York Association (NYHA) class III-IV (see Appendix 
C), angioplasty, valvular disease or repair, transient ischemic attack (TIA) or 
significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia; or 
are expected to require PCI/CABG or angioplasty during the course of the study. 
Subjects with stable cardiac disease are not excluded 
Renal Diseases 
g. Subjects with moderate to severe renal impairment [defined as estimate glomerular 
filtration rate (eGFR) < 60mL/min/1.73 m2 (estimated by MDRD) or serum creatinine 
(Scr) ≥ 1.5 mg/dL in males or ≥ 1.4 mg/dL in females] or end-stage renal disease 
(ESRD) 
h. Unstable or rapidly progressing renal disease 
i. Conditions of congenital renal glucosuria 
Hepatic Diseases 
j. Significant hepatic diseases, including, but not limited to, chronic active hepatitis 
and/or severe hepatic insufficiency and/or significant abnormal liver function, 
including subjects with Alanine aminotransferase (ALT) and/or Aspartate 
aminotransferase (AST) > 3x Upper limit of normal (ULN) and/or Total Bilirubin 
(TB) > 2x ULN 
k. Subjects with severe hepatic impairment (Child-Pugh class C) 
l. Positive serologic evidence of current infectious liver disease, including subjects who 
are known to be positive for hepatitis A viral (HAV) IgM antibody, hepatitis B surface 
antigen (HBsAg), and hepatitis C virus (HCV) antibody 
Hematological/Oncological Diseases/Conditions 
m. History of hemoglobinopathy, such as sickle cell anemia (SA), thalassemia or chronic 
or recurrent hemolysis, etc. 
n. Malignancy within 5 years of the screening visit (with the exception of treated basal 
cell or treated squamous cell carcinoma) 

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o. Known immunocompromised status, including but not limited to, individuals who 
have undergone organ transplantation or who are positive for the human 
immunodeficiency virus (HIV) 
p. Donation of blood or blood products > 400mL or participation in a clinical study 
requiring withdrawal of > 400mL of blood within 6 months prior to the screening visit 
Prohibited Treatment and Therapies 
q. Administration of any anti-hyperglycemic therapy (other than metformin, or DPP-4 
inhibitors, if applicable) for more than 14 days (consecutive or not) during the 8 weeks 
prior to screening 
r. Any use of SGLT2 inhibitor within 8 weeks prior to screening 
s. Prescription and over-the-counter weight loss medications within 3 months prior to 
screening 
t. Current treatment with potent cytochrome P450 3A4/5 inhibitors (in countries where 
dose adjustment would be required by the saxagliptin label) 
u. Administration of any other investigational drug or participation in any interventional 
clinical studies within 30 days prior to screening 
3. Physical and Laboratory Test Findings  
a. Hemoglobin (Hb) ≤ 11.0g/dL (110g/L) for men; Hb ≤ 10.0g/dL (100g/L) for women 
b. For male subjects with microscopic hematuria urinalysis positive at screening and 
judged as clinically significant by the investigator will be excluded, but one re-test is 
allowed after resolution in the opinion of the investigator 
NOTE: Female subjects with hematuria can be randomized, but should be investigated 
according to local standards and best clinical practices   
c. Other central laboratory test findings  
x Abnormal free thyroxine (T4) values. Abnormal thyroid stimulating hormone 
(TSH) value at screening will be further evaluated by free T4. Subjects with 
abnormal free T4 values will be excluded  
x Any clinically significant abnormalities in any pre-randomization lab analyses or 
ECG which in the investigator’s opinion would preclude randomization 
4. Allergies and Adverse Drug Reaction  

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Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
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History of any serious allergy/hypersensitivity reaction to dapagliflozin, saxagliptin or to 
any of the excipients, including anaphylaxis or angioedema following exposure to any 
DPP-4 inhibitor 
5. Sex and Reproductive Status 
Women who are pregnant or breastfeeding 
6. Other Exclusion Criteria  
a. Prisoners or subjects who are involuntarily incarcerated 
b. Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness 
c. Subjects on a commercial weight loss program with ongoing weight loss, or on an 
intensive exercise program 
d. Employees of AstraZeneca, or their relatives 
e. Subject with any condition which, in the judgment of the investigator, may render the 
subject unable to complete the study or which may pose a significant risk to the subject 
f. Subject is a participating investigator, study coordinator, employee of an investigator 
or immediate family member of any of the aforementioned 
7. Exclusion Criteria during open-Label Treatment Period 
Note: Enrolment of subjects with HbA1c ≥ 8.0% and < 9.0% (Stratum A) and subjects 
with HbA1c ≥ 7.5% and ≤ 8.5% (Stratum B) into the open-label treatment period will 
be limited to approximately 171 subjects (about 50% of the randomized subjects 
number in each stratum) 
x For subjects in Stratum A 
At Week -10 and Week -2 a FPG qualification check will be performed. Subjects with 
a central laboratory FPG value > 270 mg/dL will be scheduled for a follow-up visit 
(within 3 - 5 days following receipt of FPG value from central laboratory) to obtain a 
second central laboratory FPG value. If the mean of the originally scheduled central 
laboratory FPG and the repeat central laboratory FPG value is > 270 mg/dL, the 
subject cannot be randomized and must be discontinued 
x For subjects in Stratum B 
At Week -2 a FPG qualification check will be performed. Subjects with a central 
laboratory FPG value > 270 mg/dL will be scheduled for a follow-up visit (within 3 - 5 
days following receipt of FPG value from central laboratory) to obtain a second central 
laboratory FPG value. If the mean of the originally scheduled central laboratory FPG 

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Date 14 Feb 2019 
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and the repeat central laboratory FPG value is > 270 mg/dL, the subject cannot be 
randomized and must be discontinued 
3.3 
Subject enrolment and randomization 
Randomization codes will be assigned strictly sequentially as subjects become eligible for 
randomization via interactive voice/web response system (IxRS). 
Investigator(s) should keep a record, the subject screening log, of subjects who entered 
screening. 
The investigator(s) will: 
1. Obtain signed informed consent from the potential subject before any study specific 
procedures are performed. 
2. Assign (using IxRS) potential subject a unique enrolment code (E-code), beginning 
with ‘E + 4-digit site number + 3-digit subject number starting with 001’. For example, 
the first subject at site 9999 would be assigned the subject number: E9999001. This E-
code will be used for identification throughout the study and will not be used for any 
other participant. 
3. Determine subject eligibility. See Section 3.1 and Section 3.2. 
At the time of entry into open-label treatment period, the site will contact the IxRS in order 
that open-label medication saxagliptin 5 mg can be assigned and dispensed. 
Subject who does not meet the eligibility criteria is considered as screen failure in the study. 
These subjects will be terminated from the study and registered as Screen Failure by using 
IxRS. Re-screening is allowed one single time considering that the subject was not assigned 
with open-label treatment. The same E-code that the subject received at the first enrolment 
will be used. All screening assessments and procedures, including re-signing the informed 
consent form (ICF), should be performed again.  
Following completion of the open-label treatment period, subjects who meet all study 
requirements based on inclusion and exclusion criteria will be randomly assigned by the IxRS 
at randomization visit (Day 1). Centralized block randomization (not stratified by site) will be 
used within each stratum. 
If a subject withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused. 
3.3.1 
Procedures for randomization 
Subjects who meet all study requirements based on inclusion and exclusion criteria will be 
randomized to 1 of 3 treatment groups in a 1:1:1 ratio: 

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Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
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x 
Arm 1: Dapagliflozin 10 mg, dapagliflozin 5 mg placebo to match, saxagliptin 5 mg, 
plus metformin IR/XR 
x 
Arm 2: Dapagliflozin 5 mg, dapagliflozin 10 mg placebo to match, saxagliptin 5 mg, 
plus metformin IR/XR 
x 
Arm 3: Dapagliflozin 5 mg placebo to match and dapagliflozin 10 mg placebo to 
match, saxagliptin 5 mg, plus metformin IR/XR 
If a subject is discontinued from the study treatment, his/her randomization or enrolment code 
will not be reused, and the subject will not be allowed to re-enter the study. Randomized 
subjects who discontinue early from the study will not be replaced. 
If a randomization number is allocated incorrectly, no attempt should be made to remedy the 
error once study material has been dispensed. The subject will continue with the allocated 
number and study material. AstraZeneca or representative should be notified as soon as the 
error is discovered. Subsequent subjects will continue using the first unallocated 
randomization number in the original numbering sequence. 
3.4 
Procedures for handling incorrectly enrolled or randomized 
subjects 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Subjects 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 subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the subject from 
treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented. 
3.5 
Methods for assigning treatment groups 
After written informed consent has been obtained, the subject will be assigned an E-code that 
is country, centre, and subject specific. The E-code will be used to identify the subject 
throughout study participation. Subject eligibility will be established before treatment 
randomization. Subjects who meet all criteria for this study will be randomized to double-
blind treatment with a 1:1:1 ratio on Day 1 of randomization visit. Assignment to treatment 
groups will be determined by a computer-generated random sequence using IxRS. 
The number and size of tablets will be identical for the IPs for the 3 treatment arms. Clinical 
supplies will be identified by randomization kit numbers, where each kit number is specific to 
a treatment arm. If a subject discontinues from the study, the subject’s E-code and 

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Date 14 Feb 2019 
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randomization number will not be reused, and the subject will not be allowed to re-enter the 
study. 
The permutation block size will be generated by the study statistician and will be known only 
by a minimum number of AstraZeneca personnel. 
3.6 
Methods for ensuring blinding 
This is a double-blind study. Subjects, investigators, and all other personnel involved in the 
conduct of the study are blinded to individual treatment assignments for the duration of the 
study. 
To preserve the blinding of the study, a minimum number of AstraZeneca personnel will see 
the randomization table and treatment assignments before the study is complete. e.g., 
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 contract 
research organization (CRO) companies providing the IxRS and carrying out the packaging 
and labelling of IPs. 
At the screening visit, each subject will be assigned a unique sequential subject number by the 
IxRS. This number will be used for identification throughout the study and will not be used 
for any other participant. 
Subjects who meet the criteria will be randomly assigned by IxRS to one of three double-blind 
treatment groups in a 1:1:1 ratio using a centralized blocked randomization schedule ratio (not 
stratified by site) within each stratum. 
Randomization schedules for all subject treatment and containers will be generated and kept 
by AstraZeneca and stored in a secure location with restricted access. 
At all study visits when study medication is dispensed, each subject will be assigned a kit 
number by the IxRS. Kit numbers will be assigned randomly and will correspond to the 
numbers printed on the packages and kits containing study drug. 
During the double-blind treatment period, the HbA1c, FPG and plasma glucose MTT 
values(China only) will be masked to the investigator and to the Sponsor. These values can be 
provided to the investigator after the study has been completed through CSR. FPG will be 
unblinded if the value meets the defined rescue criteria or during following visits after ETD 
and confirmed with investigator/monitor. In addition, if rescue medication is initiated during 
double blinded phase, the central laboratory FPG value will be reported to the investigator to 
ensure proper follow-up of the rescued subject. 
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency or pregnancy in an individual subject, in which knowledge of the IP is critical to 
the subject's management, the blind for that subject may be broken by the treating physician. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
45(110) 
3.7 
Methods for unblinding  
Individual treatment codes, indicating the treatment randomization for each randomized 
subject, will be available to the investigator(s) or pharmacists from the IxRS. Routines for this 
will be described in the IxRS 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 subject requires knowledge of the treatment randomization. The 
investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to subject 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 subject have been made 
and documented. 
3.8 
Restrictions 
3.8.1 
Prohibited and/or restricted treatments 
Once enrolled, subjects may not receive any of the following for the duration of the screening, 
open-label, double-blind treatment periods: 
x 
Antihyperglycemic medication (other than protocol required medication and/or 
protocol-allowed open-label rescue medication). 
x 
Treatment with any stable replacement or chronic corticosteroid therapy at the time of 
screening is permitted. During the trial (beginning with screening), newly initiation of 
treatment with any systemic corticosteroid therapy that will involve ≥ 5 days of 
therapy is not permitted (inhaled and topical are allowed). The AstraZeneca study 
physician should be consulted prior to the beginning of therapy for subjects who 
require systemic corticosteroid treatment. 
x 
In countries where dose adjustment would be required by the local saxagliptin label: if 
initiation of treatment with any potent cytochrome P450 3A4/5 inhibitor during the 
trial is required, the AstraZeneca study physician should be consulted prior to 
beginning therapy with any potent cytochrome P450 3A4/5 inhibitor. 
3.8.2 
Other restrictions 
Once screened and qualified for entry, subjects will be instructed as follows: 
x 
Fast overnight for at least 8 hours prior to each study site visit, i.e., no food or 
beverage except water.  Allowed medications can be taken with water only. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
46(110) 
x 
Continue metformin therapy at current dosage and at approximately the same time 
each day, except that any morning dose of metformin should be delayed on the 
morning of study site visits.  
x 
Delay administering the IPs, saxagliptin and metformin on the morning of the clinic 
visit and bring study medications to each study site visit. 
x 
Refrain from alcohol intake and intense exercise 24 hours prior to each visit and 
recommend not using tobacco/nicotine within 12 hours prior to each visit. 
x 
Do not donate blood for the duration of the study and for 3 months following the last 
study visit. 
x 
Comply with prescribed dosing regimen to preserve study integrity and ensure patient 
safety.  
x 
Discuss any new prescriptions and over-the-counter or herbal/nutritional therapies with 
the investigator, as concomitant use could result in alterations to their glycaemic 
control and may place them at risk for significant hypoglycaemic episodes. 
x 
Make every attempt to adhere to the diet and exercise counselling and to the protocol 
visit schedule. 
x 
Women must immediately contact the investigator if they suspect they might be 
pregnant or if they have changed or plan to change their birth control method. 
If a subject comes to a visit without following above instructions, the subject should be re-
scheduled for the required visit (if possible within the allowed time-window). The Sponsor or 
designee should be contacted if the investigator is informed of any restriction violations. 
3.9 
Discontinuation of investigational product 
3.9.1 
Procedures for discontinuation of a subject from investigational product  
Subjects MUST discontinue IP for any of the following reasons: 
x 
Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment 
x 
Subject experiences an AE or SAE that, in the investigator’s opinion, necessitates 
discontinuation from study medication 
x 
Pregnancy confirmed by a positive pregnancy test or otherwise verified 
x 
Serious hypersensitivity reaction 
x 
Acute pancreatitis 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
47(110) 
x 
Severe non-compliance with the study protocol  
x 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness 
x 
eGFR < 60mL/min/1.73m2 for sustained period of time (16 weeks) 
Note: Dapagliflozin based on its MOA has been shown to reduce eGFR by up to 
10% with initiation of therapy; however, this has in general been reversible and 
not resulted in renal failure and eGFR values returned to baseline within 12 - 24 
weeks of continued therapy. 
x 
Initial and repeat laboratory tests meet any of the following criteria: 
- ALT and/or AST are >3 x ULN and TB >2 x ULN 
- ALT and/or AST are >5 x ULN for ≥14 consecutive days, at any time after initial 
confirmatory results 
- ALT and/or AST are >8 x ULN 
x 
Consider to temporary interrupt dapagliflozin if DKA is suspected. The subject should 
be promptly evaluated. If DKA is confirmed, dapagliflozin should be discontinued 
permanently. 
x 
Hypoglycaemia events as defined in Section 3.9.2. 
Note: Discontinuation of non-IP at the discretion of the investigator should be reported to 
Sponsor and recorded in eCRF. 
3.9.2 
Discontinuation guideline due to hypoglycaemic events 
Subjects will be recommended to continue on the study and not discontinue from treatment 
based on single episodes of hypoglycaemia or symptoms of hypoglycaemia unless clinically 
indicated. The assessment of a single finger stick or central laboratory glucose value should 
not be the sole assessment used to determine subject discontinuation due to hypoglycaemia. 
Clinical indications for discontinuation due to hypoglycaemia 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 subject. This 
includes, but is not limited to: 
x 
Multiple symptomatic episodes of hypoglycaemia (e.g., sweating, shakiness, increased 
heart rate (HR), confusion, dizziness, light-headedness, or hunger) in the absence of 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
48(110) 
environmental factors known to contribute to hypoglycaemia (i.e., excess physical 
activity, concurrent illness, or missed or delayed meal) 
            OR 
x 
More than 1 episode of severe hypoglycaemia as defined by the ADA. (See Section 
6.3.7 for ADA definition of severe hypoglycaemia.)  
Down titration of blinded IP and/or background antihyperglycemic agent will not be allowed 
at any time during the study.  
If finger stick glucose values are discordant from glycaemia control assessed by the central 
laboratory or with clinical symptoms, the subject’s glucose meter should be tested and the 
procedure for using it reviewed with the subject. 
Section 5.2.5.1 provides additional guidance on management and reporting of hypoglycaemia. 
3.9.3 
Procedures for discontinuation of a subject from investigational product 
At any time, subjects are free to discontinue IP or withdraw from the study (i.e., IP and 
assessments – see Section 3.10), without prejudice to further treatment. A subject that decides 
to discontinue IP will always be asked about the reason(s) and the presence of any AEs. If 
possible, they will be seen and assessed by an investigator(s). AEs will be followed up (See 
Section 6.3.2); diary cards and all study medications should be returned by the subject. 
Subjects who discontinue the IP and/or study early will have Early treatment discontinuation 
(ETD) procedures performed as shown in the Study Schedule (refer to Section 4). 
Subjects that discontinue IP should continue in the study returning on their next regularly 
scheduled visits. At their next regularly scheduled visits all protocol specified visits and 
procedures should be performed with the exception of IP management. Medication for the 
management of subject’s diabetes would be under care and direction of the investigator. The 
only exception to this requirement is when a subject 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 subject is withdrawn from study, see Section 3.10. 
3.10 
Criteria for withdrawal  
Every effort should be made to conduct all protocol-required procedures to complete the 
study. Subjects may be removed from the study for the following reasons. 
x 
Screen failures: see Section 3.10.1. 
x 
Withdrawal by subject: see Section 3.10.2. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
49(110) 
x 
AE: Subject experiences an AE that, in the investigator’s opinion, necessitates 
withdrawal from the study. 
x 
Investigator Decision: investigator feels it is in the subject's best interest to terminate 
participation for reasons other than an AE. 
x 
Protocol Violation: Subject is noncompliant with protocol procedures, becomes 
pregnant, violates study entry criteria, or starts an exclusionary concomitant 
medication. 
x 
Lost to Follow-Up: Subject fails to return for study visits and cannot be reached with 
reasonable, repeated attempts. 
x 
Study Terminated by Sponsor:  The Sponsor discontinues the study protocol. 
x 
Administrative Reasons: Regulatory authority discontinues the study protocol or the 
clinical study site discontinues participation. 
Any withdrawal must be fully documented in the subject’s source records and recorded in the 
electronic Case Report Form (eCRF). The documentation must include the reason for the 
withdrawal and details of any sequelae (followed until symptoms resolve or improve, as 
appropriate).  
If a subject is withdrawn from the study during double-blind treatment period, they must 
complete the procedures outlined in Section 4 and Sponsor should be contacted. 
3.10.1 
Screen failures  
Screening failures are subjects who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomized. These subjects should have the reason for study withdrawal 
recorded as ‘Screen failure’ (i.e., subject does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (not randomized 
subjects). 
3.10.2 
Withdrawal of the informed consent 
Subjects are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment. 
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AE. The investigator will follow up AEs outside of the clinical study.  
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn subjects will not be replaced.  

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition Number 5.0 
Date 14 Feb 2019 
50(110) 
3.10.3 
Lost to follow-up 
A subject will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
x The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule.  
x Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject or next of kin by e.g. repeat telephone 
calls, certified letter to the subject´s last known mailing address or local equivalent 
methods. These contact attempts should be documented in the subject’s medical 
record.  
x Efforts to reach the subject should continue until the end of the study. Should the 
subject be unreachable at the end of the study the subject should be considered to be 
lost to follow up with unknown vital status at end of study. 
3.11 
Discontinuation of the study 
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that: 
x meet individual stopping criteria or are otherwise considered significant  
x are assessed as causally related to study drug 
x are not considered to be consistent with continuation of the study 
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up 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 subjects’ interests. 
4. 
STUDY PLAN AND TIMING OF PROCEDURES  

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
51(110) 
Table 1 
Study design for Stratum A & Stratum B 
Procedural Outline - Stratum A 
Procedure 
Screening 
Period  
Open-Label Treatment 
Period  
(visit windows ± 2 days) c 
Double-Blind, Double Dummy Treatment Period  
(visit windows ± 5 days) e 
WK 
(-18) 
WK  
(-16) 
WK 
(-10) 
WK 
(-2) 
Day 
1 
WK 
6 
WK 
12 
WK 
18 
WK 24 
Rescue/
ETD 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
/ 
Obtain informed consent a 
X 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
Review medical history  
X 
 
 
 
 
 
 
 
 
 
Review eligibility criteria 
X 
X b 
 
 
X d 
 
 
 
 
 
Brief physical examination 
 
 
 
X 
X 
X 
X 
X 
 
 
Complete physical 
examination 
X 
 
 
 
 
 
 
 
X 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP and HR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height  
X 
 
 
 
 
 
 
 
 
 
BMI 
X 
 
 
 
 
 
 
 
 
 
Waist circumference 
 
X 
 
 
X 
 
 
 
X 
X 
12-Lead ECG 
X 
 
 
 
X 
 
 
 
X 
X 
Provide diet and exercise 
counselling 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
52(110) 
Procedural Outline - Stratum A 
Procedure 
Screening 
Period  
Open-Label Treatment 
Period  
(visit windows ± 2 days) c 
Double-Blind, Double Dummy Treatment Period  
(visit windows ± 5 days) e 
WK 
(-18) 
WK  
(-16) 
WK 
(-10) 
WK 
(-2) 
Day 
1 
WK 
6 
WK 
12 
WK 
18 
WK 24 
Rescue/
ETD 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
/ 
Provide glucose meter/ 
Supplies/Instructions/Patient 
diaries 
 
X 
X 
X 
X 
X 
X 
X 
 
X v 
Review patient diaries 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Review concomitant 
medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess adverse events, 
Hypoglycaemia events f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
(WOCBP only) g 
X 
(Serum) 
 
 
 
X 
(Urine) 
 
 
 
 
 
Clinical chemistry h, 
hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
eGFR i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematuria microscopic 
urinalysis j 
X  
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
FPG 
X 
X 
X k 
X k 
X l 
X 
X 
X 
X l 
X l 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
53(110) 
Procedural Outline - Stratum A 
Procedure 
Screening 
Period  
Open-Label Treatment 
Period  
(visit windows ± 2 days) c 
Double-Blind, Double Dummy Treatment Period  
(visit windows ± 5 days) e 
WK 
(-18) 
WK  
(-16) 
WK 
(-10) 
WK 
(-2) 
Day 
1 
WK 
6 
WK 
12 
WK 
18 
WK 24 
Rescue/
ETD 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
/ 
Assess FPG for rescue m 
 
 
 
 
 
X 
X 
X 
  
X 
MTT (glucose) n 
 
 
 
 
X 
 
 
 
X 
X 
GAD antibodies o 
X 
 
 
 
 
 
 
 
 
 
Hepatitis screening panel p, 
HIV test 
X 
 
 
 
 
 
 
 
 
 
TSH, free T4 q 
X 
 
 
 
 
 
 
 
 
 
Fasting serum lipids (Total-C, 
LDL-C, HDL-C, TG) r 
 
 
 
 
X 
 
 
 
X 
X 
Contact IxRS 
X 
X 
X 
X 
X 
X 
X 
X 
X s 
X t 
Dispense open-label study 
medication u 
 
X 
X 
X 
X 
X 
X 
X 
 
X v 
Dispense blinded study 
medication 
 
 
 
 
X 
X 
X 
X 
 
X v 
Collect unused study 
medication and empty 
packaging  
 
 
X 
X 
X 
X 
X 
X 
X 
X v 
Review study medication 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BP = Blood pressure, HR = Heart rate, BMI = Body Mass index, ETD = Early treatment discontinuation, WOCBP = Women of childbearing 
potential 
 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
54(110) 
Note for Stratum A 
a. 
Informed consent must be completed before any study related procedures performed. 
b. 
Visit 2 (WK -16) cannot be performed until all laboratory results from the screening period have been received and reviewed to confirm eligibility. The 
lead-in period should start within 2 weeks (± 2 days) after completion of the screening visit, and may start as late as 6 weeks after completion of 
screening visit for subjects who need to test GAD antibodies to make sure all laboratory results have been received. 
c. 
Visit 3 (WK -10) and Visit 4 (WK -2) can be performed 6 weeks and 14 weeks after administration of open-label treatment (Visit 2) separately, with ± 2 
days visit windows.  
d. 
Visit 5 (Day 1) can be performed after the completion of open-label treatment, with ± 5 days visit window. All applicable inclusion/exclusion/ 
randomization criteria must be verified by investigator before dosing on Day 1.  
e. 
After the randomization visit (Day 1), subjects will be scheduled for study visits at 6-week intervals, with ± 5 days visit window.  
Subjects who discontinue IP should perform ETD visit first, and then continue in the study original visits and procedures with the exception of blinded 
IP management, and medication after ETD will be under care and direction of the investigator (see Section 3.9.3).  
Rescued subjects must first complete the Rescue visit procedures before receiving rescue medication, and then continue in the double-blind treatment 
period according to their original visit schedule (see Section 4.3). 
f. 
Assess and record adverse event (SAE will be recorded from the time of signing informed consent, AE will be recorded from the time of first 
administration of open-label study medication throughout the open-label and double-blind treatment period and including the last visit). Signs and 
symptoms of hypoglycaemia, hypoglycaemia episode or discontinuation due to hypoglycaemia should not be reported on the AE eCRF page, unless the 
event fulfils protocol criteria for a SAE (see Section 6.3). 
g. 
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (performed in central laboratory) at screening and negative urine 
pregnancy test (performed locally) within 24 hours prior to the first administration of double-blind treatments. 
h. 
Refer to Table 3 for detailed tests. If CK>400 IU/L, Troponin I test is required. 
i. 
Glomerular Filtration Rate will be calculated by the central laboratory using the re-expressed abbreviated (four-variable) Modification in Diet and Renal 
Disease (MDRD) formula and results will be reported to the sites and the Sponsor (see Section 5.2.1.3). 
j. 
For male subjects with microscopic hematuria urinalysis positive at screening and judged as clinically significant by the investigator will be excluded, 
but one re-test is allowed after resolution in the opinion of the investigator (see Section 5.2.1.4).  
k. 
FPG must be ≤ 270 mg/dL to be eligible (see Section 3.2 for more details) 
l. 
Blood collection for FPG will not be required at Visit 5 (Day 1), WK 24/ETD or rescue if MTT was performed at the same visit since the sampling of 
FPG would be covered in MTT. For subjects in Vietnam and Thailand, and those without MTT performed, blood samples should be collected for FPG. 
m. 
During blinded-treatment period of WK 6 up to but not including WK 24, subjects may be eligible for the addition of open-label rescue medication 
(insulin or any other antidiabetic agents except GLP-1 analogues, other DPP-4 and/or SGLT2 inhibitors or metformin) to their blinded treatment 
regimen in order to treat ongoing hyperglycaemia, based upon central laboratory FPG values and repeated confirmatory FPG criteria. Rescued subjects 
will then continue in the double-blind treatment period according to their original visit schedule (see Section 4.3). 
n. 
For subjects in China, maximum of 2 MTTs will be performed per subject: one at Day 1 and the other one at either WK 24 or Rescue/ETD visit, 
whichever occurs first. Subject must be fasted for at least 8 hours prior to the MTT and consume at least 150 grams of carbohydrate per day for the three 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
55(110) 
days prior to MTT. In addition, subjects must abstain from tobacco, alcohol and caffeine for at least 24 hours prior to the MTT. There are 5 samples 
collected per MTT visit at Day 1 (draw at time 0 pre-meal, 30, 60 120, 180 mins post meal), and 6 samples collected per MTT visit at Week 
24/Rescue/ETD visit (draw at time -60 mins pre-meal, 0 pre-meal, 30, 60, 120, 180 mins post meal), refer to Section 5.1. 
o. 
GAD antibodies will only to be measured and used as an exclusion criterion in subjects < 40 years of age. Results must be reviewed by investigator prior 
to the entry into the open-label period. 
p. 
After reviewed all applicable inclusion and exclusion criteria, potential eligible subjects, in the opinion of the investigator, with HCV antibody low 
positive results should have unscheduled visit as soon as possible to collect additional blood sample for HCV confirmation test in central laboratory 
during screening period (see Section 5.2.1.5). 
q. 
Abnormal thyroid stimulating hormone (TSH) value at screening will be further evaluated by free T4. Subjects with abnormal free T4 values will be 
excluded (see Section 5.2.1.5). 
r. 
Reflex testing will occur for Direct LDL-C if TG > 400 mg/dL (4.52mmol/L), refer to Section 5.1.3.2. 
s. 
Contact IxRS to register study completion at WK 24. 
t. 
Contact IxRS if drug dispensing required  
u. 
Dispensing of open-label study medication: Saxagliptin 5 mg is dispensed by IxRS. Metformin will be prescribed by site investigator. Subjects should 
continue to receive the same metformin treatment regimen as they were using at study entry and keep unchanged throughout the whole study period.  
v. 
Open-label study medication and/or glucose meter/supplies/Instructions/patient diaries could be dispensed at rescue/ETD visit if needed. Blinded study 
medication could be dispensed at rescue visit if needed. Collect unused study medication and empty packaging if needed. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
56(110) 
 
Procedural Outline - Stratum B 
Procedure 
Screening 
Period  
Open-Label Treatment 
Period  
(visit windows ± 2 days) 3 
Double-Blind, Double Dummy Treatment Period  
(visit windows ± 5 days) 5 
WK 
(-10) 
WK  
(-8) 
WK 
(-2) 
Day 
1 
WK 
6 
WK 
12 
WK 
18 
WK 24 
Rescue/
ETD 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
/ 
Obtain informed consent 1 
X 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
Review medical history  
X 
 
 
 
 
 
 
 
 
Review eligibility criteria 
X 
X 2 
 
X 4 
 
 
 
 
 
Brief physical examination 
 
 
X 
X 
X 
X 
X 
 
 
Complete physical 
examination 
X 
 
 
 
 
 
 
X 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP and HR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height  
X 
 
 
 
 
 
 
 
 
BMI 
X 
 
 
 
 
 
 
 
 
Waist circumference 
 
X 
 
X 
 
 
 
X 
X 
12-Lead ECG 
X 
 
 
X 
 
 
 
X 
X 
Provide diet and exercise 
counselling 
 
X 
X 
X 
X 
X 
X 
X 
X 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
57(110) 
Procedural Outline - Stratum B 
Procedure 
Screening 
Period  
Open-Label Treatment 
Period  
(visit windows ± 2 days) 3 
Double-Blind, Double Dummy Treatment Period  
(visit windows ± 5 days) 5 
WK 
(-10) 
WK  
(-8) 
WK 
(-2) 
Day 
1 
WK 
6 
WK 
12 
WK 
18 
WK 24 
Rescue/
ETD 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
/ 
Provide glucose meter/ 
Supplies/Instructions/Patient 
diaries 
 
X 
X 
X 
X 
X 
X 
 
X 22 
Review patient diaries 
 
 
X 
X 
X 
X 
X 
X 
X 
Review concomitant 
medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess adverse events, 6 
Hypoglycaemia events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
(WOCBP only) 7 
X 
(Serum) 
 
 
X 
(Urine) 
 
 
 
 
 
Clinical chemistry 8, 
hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
eGFR 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematuria microscopic 
urinalysis 10 
X  
 
 
 
 
 
 
 
 
HbA1c 
X 
 
X 
X 
X 
X 
X 
X 
X 
FPG 
X 
X 
X 11 
X 12 
X 
X 
X 
X 12 
X 12 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
58(110) 
Procedural Outline - Stratum B 
Procedure 
Screening 
Period  
Open-Label Treatment 
Period  
(visit windows ± 2 days) 3 
Double-Blind, Double Dummy Treatment Period  
(visit windows ± 5 days) 5 
WK 
(-10) 
WK  
(-8) 
WK 
(-2) 
Day 
1 
WK 
6 
WK 
12 
WK 
18 
WK 24 
Rescue/
ETD 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
/ 
Assess FPG for rescue 13 
 
 
 
 
X 
X 
X 
  
X 
MTT (glucose) 14 
 
 
 
X 
 
 
 
X 
X 
GAD antibodies 15 
X 
 
 
 
 
 
 
 
 
Hepatitis screening panel 16, 
HIV test 
X 
 
 
 
 
 
 
 
 
TSH, free T4 17 
X 
 
 
 
 
 
 
 
 
Fasting serum lipids (Total-C, 
LDL-C, HDL-C, TG) 18 
 
 
 
X 
 
 
 
X 
X 
Contact IxRS 
X 
X 
X 
X 
X 
X 
X 
X 19 
X 20 
Dispense open-label study 
medication 21 
 
X 
X 
X 
X 
X 
X 
 
X 22 
Dispense blinded study 
medication 
 
 
 
X 
X 
X 
X 
 
X 22 
Collect unused study 
medications and empty 
packaging 
 
 
X 
X 
X 
X 
X 
X 
X 22 
Review study medication 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BP = Blood pressure, HR = Heart rate, BMI = Body Mass index, ETD = Early treatment discontinuation, WOCBP = Women of childbearing 
potential 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
59(110) 
 
Note for Stratum B 
1 
Informed consent must be completed before any study related procedures performed. 
2 
Visit 2 (WK -8) cannot be performed until all laboratory results from the screening period have been received and reviewed to confirm eligibility. The 
lead-in period should start within 2 weeks (± 2 days) after completion of the screening visit, and may start as late as 6 weeks after completion of 
screening visit for subjects who need to test GAD antibodies to make sure all laboratory results have been received. 
3 
Visit 3 (WK -2) can be performed 6 weeks after administration of open-label treatment (Visit 2), with ± 2 days visit windows.  
4 
Visit 4 (Day 1) can be performed after the completion of open-label treatment, with ± 5 days visit window. All applicable inclusion/exclusion/ 
randomization criteria must be verified by investigator before dosing on Day 1.  
5 
After the randomization visit (Day 1), subjects will be scheduled for study visits at 6-week intervals, with ± 5 days visit window.  
Subjects who discontinue IP should perform ETD visit first, and then continue in the study original visits and procedures with the exception of blinded 
IP management, and medication after ETD will be under care and direction of the investigator (see Section 3.9.3).  
Rescued subjects must first complete the Rescue visit procedures before receiving rescue medication, and then continue in the double-blind treatment 
period according to their original visit schedule (see Section 4.3). 
6 
Assess and record adverse event (SAE will be recorded from the time of signing informed consent, AE will be recorded from the time of first 
administration of open-label study medication throughout the open-label and double-blind treatment period and including the last visit). Signs and 
symptoms of hypoglycaemia, hypoglycaemia episode or discontinuation due to hypoglycaemia should not be reported on the AE eCRF page, unless the 
event fulfils protocol criteria for a SAE (see Section 6.3). 
7 
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (performed in central laboratory) at screening and negative urine 
pregnancy test (performed locally) within 24 hours prior to the first administration of double-blind treatments. 
8 
Refer to Table 3 for detailed tests. If CK>400 IU/L, Troponin I test is required. 
9 
Glomerular Filtration Rate will be calculated by the central laboratory using the re-expressed abbreviated (four-variable) Modification in Diet and Renal 
Disease (MDRD) formula and results will be reported to the sites and the Sponsor (see Section 5.2.1.3). 
10 
For male subjects with microscopic hematuria urinalysis positive at screening and judged as clinically significant by the investigator will be excluded, 
but one re-test is allowed after resolution in the opinion of the investigator (see Section 5.2.1.4). 
11 
FPG must be ≤ 270 mg/dL to be eligible (see Section 3.2 for more details). 
12 
Blood collection for FPG will not be required at Visit 5 (Day 1), WK 24/ETD or rescue if MTT was performed at the same visit since the sampling of    
FPG would be covered by MTT. For subjects in Vietnam and Thailand, and those without MTT performed, blood samples should be collected for FPG. 
13 
During blinded-treatment period of WK 6 up to but not including WK 24, subjects may be eligible for the addition of open-label rescue medication 
(insulin or any other antidiabetic agents except GLP-1 analogues, other DPP-4 and/or SGLT2 inhibitors or metformin) to their blinded treatment 
regimen in order to treat ongoing hyperglycaemia, based upon central laboratory FPG values and repeated confirmatory FPG criteria. Rescued subjects 
will then continue in the double-blind treatment period according to their original visit schedule (see Section 4.3). 
14 
For subjects in China, maximum of 2 MTTs will be performed per subject, one at Day 1 and the other one at either WK 24 or Rescue/ETD visit, 
whichever occurs first. Subject must be fasted for at least 8 hours prior to the MTT and consume at least 150 grams of carbohydrate per day for the three 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
60(110) 
days prior to MTT. In addition, subjects must abstain from tobacco, alcohol and caffeine for at least 24 hours prior to the MTT. There are 5 samples 
collected per MTT visit at Day 1 (draw at time 0 pre-meal, 30, 60 120, 180 mins post meal), and 6 samples collected per MTT visit at Week 
24/Rescue/ETD visit (draw at time -60 mins pre-meal, 0 pre-meal, 30, 60, 120, 180 mins post meal), refer to Section 5.1. 
15 
GAD antibodies will only to be measured and used as an exclusion criterion in subjects < 40 years of age. Results must be reviewed by investigator prior 
to the entry into the open-label period. 
16 
After reviewed all applicable inclusion and exclusion criteria, potential eligible subjects, in the opinion of the investigator, with HCV antibody low 
positive results should have unscheduled visit as soon as possible to collect additional blood sample for HCV confirmation test in central laboratory 
during screening period (see Section 5.2.1.5). 
17 
Abnormal thyroid stimulating hormone (TSH) value at screening will be further evaluated by free T4. Subjects with abnormal free T4 values will be 
excluded (see Section 5.2.1.5).  
18 
Reflex testing will occur for Direct LDL-C if TG > 400 mg/dL (4.52mmol/L), refer to Section 5.1.3.2. 
19 
Contact IxRS to register study completion at WK 24.  
20 
Contact IxRS if drug dispensing required  
21 
Dispensing of open-label study medication: Saxagliptin 5 mg is dispensed by IxRS. Metformin will be prescribed by site investigator. Subjects should 
continue to receive the same metformin treatment regimen as they were using at study entry and keep unchanged throughout the whole study period.  
22 
Open-label study medication and/or glucose meter/supplies/Instructions/patient diaries could be dispensed at rescue/ETD visit if needed. Blinded study 
medication could be diepensed at rescue visite if needed. Collect unused study medication and empty packaging if needed.  
 
 
 
 
 
 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
61(110) 
4.1 
Enrolment/screening period 
Procedures will be performed according to the Study Plan (Table 1).  
Informed consent for protocol D1683C00008 will be obtained in written form prior to 
performing any protocol-required procedures. In order to assess eligibility during screening 
visit, subjects are required to fast overnight for at least 8 hours (no food or beverage, except 
water), to refrain from alcohol intake and intense exercise for 24 hours, and are recommended 
not using tobacco/nicotine/caffeine within 12 hours prior to the screening visit. Subjects 
should delay administering their morning dose of anti-diabetes drugs on the morning of 
screening visit as well (see Section 3.8.2).  
4.1.1 
Screening Visit (Visit 1, Week -18 for Stratum A and Week -10 for Stratum B) 
Subjects will be assessed to ensure that they meet eligibility criteria. Subjects who do not meet 
these criteria must not be enrolled into the study.  
The following will be performed during this visit: 
x 
The subject’s demography, completed medical and surgical history will be recorded 
x 
Inclusion and exclusion criteria will be verified 
x 
A complete physical examination will be conducted  
x 
Body weight and height will be measured 
x 
BMI will be calculated 
x 
Vital signs (sitting systolic and diastolic BP and HR) will be measured.  
Note: Subjects with SBP ≥ 160mmHg and < 180mmHg or a DBP ≥ 100 mmHg and < 
110mmHg will be able to enter the open-label treatment period, provided their 
hypertension treatment is adjusted as deemed appropriate by the investigator. These 
subjects cannot be randomized if their BP remains SBP ≥ 160mmHg or DBP ≥ 100 
mmHg measured on Day 1. 
x 
All prior medications within at least 3 months and concomitant medications (including 
prescription medications over the counter and herbal / nutritional supplements) will be 
reviewed 
x 
Contact IxRS to obtain unique subject enrolment number 
x 
12-lead ECG will be performed 
x 
Blood samples will be collected for the following assessments: 
- Chemistry and Hematology  

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
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- eGFR (calculated according to the Glomerular Filtration Rate, MDRD formula) 
- HbA1c 
- FPG  
- Hepatitis screening panel, refer to Section 5.2.1.5. 
- HIV 
- TSH, and free T4 will be evaluated if TSH is abnormal, refer to Section 5.2.1.5. 
- GAD antibodies. Only to be measured and used as exclusion criteria in subjects ˂ 
40 years age (GAD antibodies results must be reviewed by investigator prior to 
entry into open-label treatment period) 
- Perform serum pregnancy test for WOCBP in central laboratory 
x 
Urine samples will be collected for the following assessments: 
- Urinalysis  
- Hematuria microscopic urinalysis    
x 
Review and record SAE if necessary (SAE will be recorded from the time of signing 
informed consent, see Section 6.3) 
x 
Schedule the entry into open-label treatment visit to occur in the morning and remind 
subjects to be fasting for next visit 
Note: For male subjects with microscopic hematuria urinalysis positive at screening and 
judged as clinically significant by the investigator will be excluded, but one re-test is allowed 
after resolution in the opinion of the investigator. Female subjects with hematuria can be 
randomized, but should be investigated according to local standards and best clinical practices 
(see Section 5.2.1.4).  
4.2 
Open-label treatment period 
Eligible subjects who complete the screening period will enter the open-label treatment 
period, which included open-label saxagliptin 5 mg and metformin IR/XR treatment for 16 
weeks in Stratum A or 8 weeks in Stratum B. The DPP-4 inhibitor will be switched to 
saxagliptin 5 mg at Week -8 in Stratum B. Subjects will continue to receive the same 
metformin treatment regimen as they were using at study entry and keep unchanged 
throughout the whole study period for both strata. Metformin will be prescribed by site 
investigators. Subjects will be instructed on using of a diary to record self-monitored glucose, 
study medication and hypoglycaemia. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
63(110) 
Prior to each visit, subjects are required to fast overnight (at least 8 hours), to refrain from 
alcohol intake and intense exercise for 24 hours, and are recommended not using 
tobacco/nicotine/caffeine within 12 hours prior to each visit. Subjects should delay 
administering their morning dose of anti-diabetes drugs on the morning of the study site visit. 
Refer to Section 3.8.2 for other restrictions.  
4.2.1 
Visit 2 (Week -16 for Stratum A and Week -8 for Stratum B) 
The below procedures will be performed during the visit for the eligible subjects: 
x 
Review concomitant medications, AEs and hypoglycaemia episodes  
x 
Inclusion and exclusion criteria will be further verified 
x 
Body weight and waist circumference will be measured 
x 
Vital signs (sitting systolic and diastolic BP and HR) will be measured 
x 
Provide diet and exercise counselling  
x 
Blood samples will be collected for the following assessments: 
- Chemistry and Hematology 
- eGFR (calculated according to the Glomerular Filtration Rate, MDRD formula) 
- FPG 
x 
Urine sample will be collected for the following assessment: 
- Urinalysis     
x 
Dispense glucose meter and supplies, provide instruction on their use, and instruct the 
subjects to self-monitor their blood glucose at least one time per day (see Section 
5.2.5.1) 
x 
Dispense patient diaries and provide instruction on recording hypoglycaemia episodes, 
and study medication intake 
x 
Contact IxRS to dispense open-label study medication saxagliptin 5 mg and instruct 
subjects to take saxagliptin and metformin at site 
x 
Remind subjects to be fasted, to withhold study medication and bring study 
medication, patient diaries and glucose meter to the next scheduled visit. 
4.2.2 
Visit 3 (Week -10 for Stratum A) 
The following will be performed during this visit: 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
64(110) 
x 
Review concomitant of medications, AEs and hypoglycaemia episodes  
x 
Body weight will be measured 
x 
Vital signs (sitting systolic and diastolic BP and HR) will be measured 
x 
Provide diet and exercise counselling  
x 
Blood samples will be collected for the following assessments: 
- Chemistry and Hematology 
- eGFR (calculated according to the Glomerular Filtration Rate, MDRD formula) 
- FPG. Subjects with a central laboratory FPG value > 270 mg/dL will be scheduled 
for a follow-up visit (within 3 - 5 days following receipt of FPG value from central 
laboratory) to obtain a second central laboratory FPG value. If the mean of the 
originally scheduled central laboratory FPG and the repeat central laboratory FPG 
value is > 270 mg/dL, the subject cannot be randomized and must be discontinued 
x 
Urine sample will be collected for the following assessment: 
- Urinalysis  
x 
Collect unused study medications and empty packaging 
x 
Review patient diaries from previous visit to assess study medication compliance and 
dispense patient diaries as needed  
x 
Re-dispense glucose meter, supplies and provide instructions as needed 
x 
Contact IxRS to dispense open-label study medication saxagliptin 5 mg and instruct 
subjects to take saxagliptin and metformin at site 
x 
Remind subjects to be fasting, withhold study medication and to bring study 
medication, patient diaries and glucose meter to the next scheduled visit 
4.2.3 
Visit 3 (Week -2 for Stratum B) 
The following will be performed during this visit: 
x 
Review concomitant medications, AEs and hypoglycaemia episodes  
x 
Brief physical examination will be performed 
x 
Body weight will be measured 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
65(110) 
x 
Vital signs (sitting systolic and diastolic BP and HR) will be measured 
x 
Provide diet and exercise counselling  
x 
Blood samples will be collected for the following assessments: 
- Chemistry and Hematology  
- eGFR (calculated according to the Glomerular Filtration Rate, MDRD formula) 
- HbA1c. This will be used to evaluate subjects’ eligibility at randomization (see 
Section 3.1) 
- FPG. Subjects with a central laboratory FPG value > 270 mg/dL will be scheduled 
for a follow-up visit (within 3 - 5 days following receipt of FPG value from central 
laboratory) to obtain a second central laboratory FPG value. If the mean of the 
originally scheduled central laboratory FPG and the repeat central laboratory FPG 
value is > 270 mg/dL, the subject cannot be randomized and must be discontinued 
x 
Urine sample will be collected for the following assessment: 
- Urinalysis  
x 
Collect unused study medications and empty packaging 
x 
Review patient diaries from previous visit to assess study medication compliance and 
dispense patient diaries as needed 
x 
Contact IxRS to dispense open-label study medication saxagliptin 5 mg and instruct 
subjects to take saxagliptin and metformin at site 
x 
Re-dispense glucose meter, supplies and provide instructions as needed 
x 
Remind subjects to be fasting, withhold study medication and to bring study 
medication, patient diaries and glucose meter to the next scheduled visit 
4.2.4 
Visit 4 (Week -2 for Stratum A) 
Perform the same procedures as detailed in Visit 3 of Stratum B (Section 4.2.3). 
4.3 
Double-blind, double-dummy treatment period 
After the randomization visit (Day 1), subjects will complete study visits at 6-week intervals 
according to Study Plan (Table 1) until the end of the randomized treatment period (Week 24). 
During Week 6 to 24 of the double-blind treatment period of the trial, subjects may be eligible 
for the addition of open-label rescue medication (insulin or any other antidiabetic agents 
except GLP-1 analogues, other DPP-4 and/or SGLT2 inhibitors or metformin) to their blinded 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
66(110) 
treatment regimen in order to treat ongoing hyperglycaemia, based upon central laboratory 
FPG values and repeated confirmatory FPG criteria (see Table 2). 
Table 2 
Lack of glycaemic control criteria for initiation of rescue medication 
Visit Label 
Central Laboratory FPG 
Week 6 
FPG > 270 mg/dL (15.0 mmol/L) 
After Week 6 up to but not including Week 12 
FPG > 240 mg/dL (13.3 mmol/L) 
From Week 12 up to but not including Week 24  
FPG > 200 mg/dL (11.1 mmol/L) 
 
Subjects with a central laboratory FPG value meeting the lack of glycaemic control criterion 
at a pre-specified visit will be scheduled for a follow-up visit (within 3 - 5 days following 
receipt of FPG value from central laboratory) to obtain a second central laboratory FPG value 
and review the subject’s glucose meter readings. If the repeat central laboratory FPG value 
still meets the criterion, the subject must be rescued. Subjects should continue receiving study 
medication while receiving rescue therapy. Subjects who meet rescue criteria in the double-
blind treatment period must first complete the Rescue Visit procedures before receiving open-
label rescue medication to ensure that important trial endpoint measurements are collected 
(See Section 4.3.3). Following completion of the Rescue Visit, rescued subjects will be given 
open-label rescue medication to be initiated at the lowest starting dose and titrated in 
accordance with the approved product label in the applicable country at the discretion of the 
investigator, in addition to their double-blinded study medication. Rescued subjects will then 
continue in the double-blind treatment period according to their original visit schedule. 
Following initiation of open-label rescue antidiabetic medication, rescued subjects should be 
scheduled for titration visits (either on site visits or telephone visits are determined by 
investigators) to increase their antidiabetic medication dose, as tolerated and in accordance 
with the approved product label for that country and by their glycaemic response and as per 
the investigator’s judgment. Adjustment of study medication (includes metformin) will not be 
allowed at any time during the study.  
Note: Rescue medication will not be provided by Sponsor in this study.  
All of the procedures of treatment period listed below are for both Stratum A and B. Prior to 
each visit (except MTT related visits), subjects are required to fast overnight (at least 8 hours), 
refrain from alcohol intake and intense exercise for 24 hours, and are recommended not using 
tobacco/nicotine/caffeine within 12 hours prior to each visit. Subjects should delay 
administering their morning dose of anti-diabetes drugs on the morning of the study site visit. 
Please see Section 5.1 for restrictions on MTT related visit. 
4.3.1 
Randomization (Day 1) 
Only for subjects in China, prior to visit assessment on Day 1, investigator should confirm that 
subjects’ dietary intake for the three days prior to MTT included at least 150 grams of 
carbohydrate per day, subject fasted for at least 8 hours prior to the visit except water 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
67(110) 
(including abstaining from tobacco, alcohol and caffeine for 24 hours, and subject did not take 
their morning dose of IPs, saxagliptin, and metformin. Otherwise the visit should be 
rescheduled within 3 days (see refer to Section 5.1 for detailed MTT related procedures and 
requirements).  
The following will be performed during this visit: 
x 
Inclusion/exclusion and randomization criteria will be verified 
x 
Body weight will be measured 
x 
Vital signs (sitting systolic and diastolic BP and HR) will be assessed 
x 
Waist circumference will be measured  
x 
12-lead electrocardiogram (ECG) will be performed 
x 
Review concomitant medications, AEs and hypoglycaemia episodes  
x 
Perform brief physical examination 
x 
Blood samples will be collected prior to administration of study medications for the 
following assessments: 
- Chemistry and Hematology  
- eGFR (calculated according to the Glomerular Filtration Rate, MDRD formula) 
- HbA1c 
- FPG. Blood collection for FPG will not be required if MTT was performed at the 
same visit 
- For subjects in China, perform MTT and obtain blood samples as described in 
Section 5.1. The study medications (including IPs, saxagliptin and metformin) 
should be given within 2 hours AFTER MTT is completed (refer to Section 5.1)  
- Fasting serum lipid concentrations (total cholesterol, low density lipoprotein 
cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and 
triglycerides (TG)) 
x 
Urine samples will be collected for the following assessments: 
- Urinalysis     
- Perform urine pregnancy test for WOCBP locally 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
68(110) 
x 
Collect unused study medications and empty packaging 
x 
Review patient diaries from previous visit to assess study medication compliance and 
dispense patient diaries as needed  
x 
Contact IxRS to randomize subject and obtain study medication dispensing kit and 
bottle assignment number 
x 
Dispense open-label saxagliptin 5 mg and double-blind, double dummy study 
medication and instruct subjects to take open-label and double-blind study medications 
at site 
x 
Provide diet and exercise counselling (see Section 5.3.1) 
x 
Re-dispense glucose meter, supplies and provide instructions as needed 
x 
Remind subjects to be fasting, withhold study medications and to bring study 
medications, patient diaries and glucose meter to the next scheduled visit 
4.3.2 
Double-blind treatment period (Week 6, 12, 18) 
The following will be performed during this visit: 
x 
Review concomitant medications, AEs and hypoglycaemia episodes  
x 
Body weight will be measured 
x 
Vital signs (sitting systolic and diastolic BP and HR) will be assessed 
x 
Perform brief physical examination 
x 
Blood samples will be collected prior to administration of study medications for the 
following assessments: 
- Chemistry and Hematology  
- eGFR (calculated according to the Glomerular Filtration Rate, MDRD formula) 
- HbA1c 
- FPG  
x 
Urine sample will be collected for the following assessment: 
- Urinalysis     
x 
During blinded-treatment period of WK 6 up to but not including WK 24, once the 
FPG value is available from the central laboratory, check whether the FPG is over 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
69(110) 
rescue limits. If so, bring subject back within 3-5 days following receipt of FPG value 
from central laboratory for an unscheduled confirmatory visit to confirm the high FPG 
and assess eligibility for rescue during the double-blind treatment period as listed in 
Section 4.3. 
x 
Collect unused study medications and empty packaging as needed 
x 
Review patient diaries from previous visit to assess study medication compliance and 
dispense patient diaries as needed  
x 
Contact IxRS to dispense open-label saxagliptin 5 mg and double-blind, double 
dummy study medications 
x 
Provide diet and exercise counselling (see Section 5.3.1) 
x 
Re-dispense glucose meter, supplies and provide instructions as needed 
x 
Remind subjects to be fasting, withhold study medications and to bring study 
medications, patient diaries and glucose meter to the next scheduled visit 
4.3.3 
Week24/Rescue/Early Treatment Discontinuation visit  
Only for subjects in China, prior to the visit assessment if MTT to be performed, investigator 
should confirm that subjects’ dietary intake for the three days prior to MTT included at least 
150 grams of carbohydrate per day, subject fasted for at least 8 hours except water (including 
abstaining from tobacco, alcohol and caffeine for 24 hours, and subject did not take their 
morning dose of IPs, saxagliptin, and metformin. Otherwise, the visit should be rescheduled 
within 3 days (refer to Section 5.1 for detailed MTT related procedures and requirements).  
Randomized subjects completing the 24 weeks double-blind treatment period, ETD or 
requiring rescue should have the following procedures completed: 
x 
Review concomitant medications, AEs and hypoglycaemia episodes  
x 
Body weight will be measured 
x 
Vital signs (sitting systolic and diastolic BP and HR) will be assessed 
x 
Waist circumference will be measured  
x 
12-lead ECG will be performed  
x 
Perform complete physical examination 
x 
Blood samples will be collected prior to administration of study medications for the 
following assessments: 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
70(110) 
- Chemistry and Hematology  
- eGFR (calculated according to the Glomerular Filtration Rate, MDRD formula) 
- HbA1c 
- FPG. Blood collection for FPG will not be required if MTT was performed at the 
same visit. 
- For subjects in China, perform MTT and obtain blood samples as described in 
Section 5.1. The study medication should be given 1 hour BEFORE administration 
of the meal supplement. MTT will not be conducted at Week 24 if subject has been 
rescued or discontinued from treatment prior to Week 24. In the event an MTT is 
performed during the course of a rescue visit, first dose of rescue medication should 
be taken after completion of the MTT.  
- Fasting serum lipid concentrations (total cholesterol, LDL-C, HDL-C, and TG) 
x 
Urine sample will be collected for the following assessment: 
- Urinalysis     
x 
Once the FPG value is available from the central laboratory at ETD visit after WK 6 of 
double-blind treatment, check whether the FPG is over rescue limits. If so, bring 
subject back within 3-5 days following receipt of FPG value from central laboratory 
for an unscheduled confirmatory visit to confirm the high FPG and assess eligibility 
for rescue during the double-blind treatment period as listed in Section 4.3. 
x 
Collect unused study medications and empty packaging as needed 
x 
Review patient diaries from previous visit to assess study medication compliance and 
dispense patient diaries as needed  
x 
Provide diet and exercise counselling (see Section 5.3.1) 
x 
Re-dispense glucose meter, supplies and provide instructions if needed (only for 
rescue visit or ETD visit) 
x 
Contact IxRS to register study completion at Week 24 
x 
Dispense open-label saxagliptin 5 mg and/or double-blind, double dummy study 
medications if needed 
x 
Remind subjects to be fasting, bring patient diaries and glucose meter to the next 
scheduled visit if needed. 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
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Subjects who discontinue IP should perform ETD visit first, and then continue in the study 
original visits and procedures with exception of blinded IP management, and medication after 
ETD will be under care and direction of the investigator (see Section 3.9.3).  
Rescued subjects must first complete the Rescue visit procedures before receiving rescue 
medication, and then continue in the double-blind treatment period according to their original 
visit schedule (see Section 4.3). 
5. 
STUDY ASSESSMENTS   
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling. The investigator will ensure that data are recorded on the eCRFs as specified 
in the study protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
The investigator will sign the completed eCRFs. A copy of the completed eCRFs will be 
archived at the study site. 
Volume of blood 
The total volume of blood that will be drawn for each subject over the duration of the study 
will be approximately 88 mL in Stratum A and 81.5 mL in Stratum B. For subjects who are 
eligible for rescue or perform additional ETD visit in any of stratum, there will be additional 
blood sample with approximately 6.5 mL required. The collection of additional samples 
performed locally or for unscheduled visit is at the discretion of the investigator and should be 
recorded appropriately, thus requiring additional sample volumes. Detailed instruction for 
blood sample collection will be described in central laboratory manual.  
5.1 
Efficacy assessments 
Blood and urine samples will be obtained at specified time points for laboratory evaluations. 
The central laboratory or designated reference laboratory for this study will perform the 
analysis of all scheduled laboratory tests (except urine pregnancy test which will be performed 
locally at randomization visit), and will provide reference ranges for these tests. All samples 
for clinical laboratory testing must be collected in the morning after the subject has fasted for 
at least 8 hours prior to collection. 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.  
During the double-blind treatment period, the HbA1c, FPG and plasma glucose MTT values 
(China only) will be blinded to the investigator and to the Sponsor. These values can be 
provided to the investigator after the study has been completed through CSR. FPG will be 
unblinded if the value meets the defined rescue criteria or during following visits after ETD 
and confirmed with investigator/monitor. In addition, if rescue medication is initiated during 

Clinical Study Protocol 
Drug Substance Dapagliflozin  
Study Code D1683C00008 
Edition5.0 
Date 14 Feb 2019 
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double blinded phase, the central laboratory FPG value will be reported to the investigator to 
ensure proper follow-up of the rescued subject. 
All glycaemic efficacy objectives will be based on values measured by central laboratory. Any 
self-monitored plasma glucose measured by the subject and FPG measured by the site using 
glucometer will be used only for safety purposes. 
Meal Tolerance Test (MTT), only for subjects in China 
A maximum of 2 MTTs will be performed per subject: one at Day 1 and the other one at either 
Week 24 or Rescue/ETD visit, whichever occurs first.  
If the administration of study drug is contraindicated (e.g., discontinuation due to AE, 
pregnancy, or decreased creatinine clearance (CrCl)), the MTT should NOT be performed. 
The MTT visit should be rescheduled within 3 days if the subject did not comply with all of 
the following: 
x 
Confirm that the subjects’ dietary intake for the three days prior to MTT included at 
least 150 grams of carbohydrate per day 
x 
Confirm that the subject fasted for at least 8 hours prior to the visit except water 
(including abstaining from tobacco, alcohol and caffeine for 24 hours prior to the 
MTT)  
x 
Confirm that the subject did not take their morning dose of study medications, 
saxagliptin, dapagliflozin and metformin prior to the visit 
Note: In the event more than 2-time points are missing from randomization visit (Day 1) 
MTT, the investigator should contact study physician prior to proceeding with the Week 24 or 
Rescue/ETD visit, as there might be situations where the analysis cannot be performed in the 
absence of key time point expected to be obtained at randomization visit (Day 1). In these 
situations, conducting a MTT at Week 24 or Rescue/ETD visit may not be required.  
MTT procedures for Day 1: 
x 
Insert saline lock, if appropriate 
x 
Draw Time 0 blood sample for glucose 
x 
Start timer immediately AFTER drawing Time 0 blood sample 
x 
Administer the meal supplement for about 10 minutes, start immediately after Time 0 
blood sample is drawn 
x 
Draw specimen for post-meal glucose at 30, 60, 120, 180 minutes 
x 
Give study medications within 2 hours AFTER MTT is completed 

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At Week 24 or Rescue/ETD, 
x 
Insert saline lock, if appropriate 
x 
Draw Time -60 minutes blood sample BEFORE taking study medications for glucose 
x 
Give study medications 1 hour BEFORE administration of the meal supplement 
x 
Draw Time 0 blood sample for glucose 
x 
Administer the meal supplement for about 10 minutes, start immediately after Time 0 
blood sample is drawn 
x 
Draw specimen for post-meal glucose at 30, 60, 120, 180 minutes 
x 
Remove saline lock 
In the event an MTT is performed during the course of a rescue visit, first dose of rescue 
medication should be taken after completion of the MTT. 
5.1.1 
Primary efficacy variable 
HbA1c is the primary assessment for the determination of glycaemic 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 
Secondary efficacy variable 
5.1.2.1 
Postprandial glucose (PPG) at 120 minutes(China only) 
The change from baseline to Week 24 in the 120-minute postprandial glucose value during an 
MTT. PPG 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. 
5.1.2.2 
Fasting plasma glucose (FPG) 
FPG is a well-established measure of glycaemic 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. 
5.1.2.3 
Glycaemic response (HbA1c<7.0%) 
The proportion of subjects achieving a therapeutic glycaemic response at Week 24, defined as 
HbA1c <7.0%, will be assessed using information gathered from the eCRF and the central 
laboratory. 

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5.1.2.4 
Body weight 
The subject’s body 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 subject. The same scale should be used 
throughout the study, and calibrated on a regular basis as recommended by the manufacturer. 
5.1.3 
Exploratory efficacy variables 
5.1.3.1 
Postprandial glucose AUC 
The change from baseline to Week 24 in the postprandial glucose AUC from 0 to 180 minutes 
in response to an MTT. PPG 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. 
5.1.3.2 
Fasting serum lipids 
Fasting serum lipids (TC, LDL-C, HDL-C and TG) will be analysed by a central laboratory in 
accordance with procedures mentioned in the Laboratory Manual [Reflex testing will occur 
for Direct LDL-C if TG > 400 mg/dL (4.52mmol/L)]. 
5.1.3.3 
Rescue/Discontinuation 
The proportion of subjects require glycaemic rescue or discontinue study treatment for lack of 
efficacy and time to glycaemic rescue or discontinuation for lack of efficacy will be assessed 
using information gathered from the eCRF and the central laboratory. 
5.2 
Safety assessments 
5.2.1 
Laboratory safety assessments 
Laboratory safety assessments will be performed as presented in the Study Plan (Table 1). 
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection, and results (including values, units, and reference 
ranges) will be recorded on the appropriate eCRF. 
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. 
5.2.1.1 
Hematology 
Hematology assessments refer to Table 3. 
5.2.1.2 
Chemistry  
Chemistry assessments refer to Table 3. If CK>400 IU/L, Troponin I test is required. 

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5.2.1.3 
eGFR  
eGFR is calculated according to the MDRD formula: 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]. 
Table 3 
Laboratory safety variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
Haemoglobin (Hb) 
Aspartate transaminase (AST) 
Hematocrit 
Alanine transaminase (ALT) 
Red blood cell (RBC) 
ALK-P 
Mean cell volume (MCV) 
Creatine kinase (CK/CPK). If CK>400 IU/L, 
test Troponin I. 
Mean cell hemoglobin (MCH) 
Total bilirubin 
Mean cell haemoglobin concentration (MCHC) 
Creatinine 
White blood cell count and differential 
Sodium 
Platelet count 
Potassium 
 
Chloride 
 
Calcium 
 
Magnesium 
 
Phosphorus 
 
Total Protein 
 
Uric acid 
 
Bicarbonate 
 
5.2.1.4 
Urinalysis  
x 
Urinalysis assessments will be performed according to Study Plan (Table 1) and will 
include the following: blood, protein, albumin, urine ketones, creatinine, and 
calculated urinary albumin: creatinine ratio.  
x 
At screening visit, microscopic urinalyses will be tested at Central Laboratory as 
detailed in the laboratory manual, and hematuria result must be evaluated. One re-test 
of microscopy for hematuria urinalysis after resolution is allowed in subjects with 
positive result of hematuria at screening period in the opinion of investigators.  
 
Interpretable microscopic hematuria is defined as ≥ 3 RBC/HPF without the presence 
of epithelial cells. Urine samples that are positive for hematuria WITH the presence of 
epithelial cells are not interpretable and must be repeated. For this study, the presence 

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of epithelial cells is defined as ≥ 1+ as reported by the central laboratory. It is the 
responsibility of investigators to estimate based on the result whether the sample is 
interpretable or not. 
5.2.1.5 
 Other clinical laboratory evaluations 
Thyroid Hormones 
Blood samples will be collected for the measurement of TSH at Visit 1 (Screening), as 
presented in the Study Plan (Table 1). Abnormal TSH value at screening will be further 
evaluated by free T4. Subjects with abnormal free T4 values will be excluded. 
Hepatitis Screening Panel 
x 
HAV IgM antibody  
x 
HBsAg 
x 
HCV antibody 
Note: After reviewed all applicable inclusion and exclusion criteria, potential eligible subjects, 
in the opinion of the investigator, with HCV antibody low positive results should have 
unscheduled visit as soon as possible to collect additional blood sample for HCV confirmation 
test in central laboratory during screening period. 
Pregnancy Testing 
All WOCBP will provide samples for pregnancy tests (serum test in central laboratory during 
screening and urine test locally on Day 1) according to the schedule presented in the Study 
Plan (Table 1). Subjects must be not enrolled or randomized or must be discontinued if 
confirmed pregnancy (see Section 3.9.1).  
5.2.2 
Physical examination 
A brief physical examination should include CV, lungs, abdomen and extremities, and any 
organ systems pertinent to the subject’s signs, symptoms or AEs. 
A complete physical examination should include general appearance, head, eyes, ears, nose, 
throat, neck, CV, lungs, abdomen, lymph nodes, extremities, neurological, skin, and 
musculoskeletal. 
5.2.3 
ECG 
A 12-lead ECG will be performed at Screening, Day 1, Week 24/ETD and/or rescue, 
according to the schedule presented in the Study Plan (Table 1).  
Standard 12-lead ECGs will be performed after approximately 5 minutes of quiet rest with the 
subject in a supine position. If the ECG must be performed with the subject in another position 

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(sitting, standing, etc.), the investigator should record the alternate position. The investigator 
should date and sign the ECG tracing and record the clinical significance of any abnormal 
result on the tracing. ECGs will be interpreted by a qualified physician (the investigator or 
qualified designee) at the clinical study site and entered as ‘Normal’ or ‘Abnormal’ in the 
eCRF. If the ECG is evaluated as “Abnormal”, the investigator should document the specific 
abnormality. All clinically significant abnormalities should be recorded as AEs on eCRF. 
5.2.4 
 Vital signs 
Vital sign measurements in this study will include sitting systolic and diastolic BP and HR. 
Vital signs should be measured at every visit after the subject rests for approximately 5 
minutes and with the subject in a sitting position. 
BP measurement with a properly calibrated and validated instrument should be used. Subjects 
should be seated quietly for at least 5 minutes in a chair rather than on an examination table, 
with feet on the floor and arm supported at heart level. An appropriate sized cuff (cuff bladder 
encircling at least 80% of the arm) should be used to ensure accuracy. At least 2 
measurements should be made at least 30 seconds apart. The average of 2 readings is to be 
entered in the eCRF. This will be documented in the source documents at the investigative 
site. The same arm should be used for all BP measurements during the study. 
Refrain from alcohol intake and intense exercise 24 hours prior to each visit and recommend 
not using tobacco/nicotine/caffeine within 12 hours prior to each visit.  
It is critical that the BP and HR measurements be obtained prior to the administration of 
blinded study medication. 
5.2.5 
Other safety assessments 
5.2.5.1 
Self-monitoring of blood glucose (SMBG) and Hypoglycaemia events 
Glucose meters will be supplied to each study site. At the entry into Open-Label Treatment 
Period (Week -16 visit for subjects in Stratum A and Week -8 for subjects in Stratum B), 
subjects will receive a glucose meter, supplies and instruction on their use. Supplies will be 
provided to allow for approximately 60 blood glucose assessments per month for duration of 
the study. The investigator may require more frequent readings based on local clinical 
practice. Subjects should bring their glucose meter with them to each study visit to ensure that 
it is functioning properly. The glucose meters should be calibrated according to instructions 
given in the package leaflet. Subjects may keep the glucose meters at the end of the study.  
The Sponsor recommends instructing the subjects to self-monitor their blood glucose at least 
one time per day, and in the occurrence of hypoglycaemic symptoms, and to contact the 
investigator in the event of an unusually high or low blood glucose value. In addition, subjects 
should comply with site’s instructions with regard to SMBG and should promptly report to the 
site blood glucose values and/or signs and symptoms suggestive of a hypoglycaemia episode.  
The memory of the glucose meter should be reviewed to compare with the patient diary, as 
applicable. The glucose values should be reviewed by the site to identify any unusual high or 

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low values, and to confirm that the values were obtained for the subject. If finger stick glucose 
values are discordant from glycaemic control assessed by central laboratory or with clinical 
symptoms, the subject’s glucose meter should be tested and procedure for using it reviewed 
with the subject. 
Hypoglycaemia Events 
Hypoglycaemia may be an expected event in subjects who are treated for diabetes. Subjects 
and their family members must be aware of the possibility that hypoglycaemia may occur and 
the dangers associated with low blood sugar. 
Study subjects must be properly instructed on the recognition and management of 
hypoglycaemia. Subjects should record in their diaries any hypoglycaemic symptoms. They 
should be encouraged to measure, when possible, their blood glucose values when they have 
symptoms of hypoglycaemia. Subjects should carry with them easily ingestible forms of 
carbohydrate at all times in order to treat an event of hypoglycaemia should it occur. 
During clinical trials, subjects frequently report symptoms of hypoglycaemia when asked, 
even when treated with placebo or medications not otherwise associated with hypoglycaemia. 
As hypoglycaemia is an important event associated with diabetes therapy, all episodes which 
could be consistent with the clinical definition of hypoglycaemia as assessed by the 
investigator should be documented and reported on the appropriate eCRF page. 
Hypoglycaemia eCRF pages will be used to document all reported episodes of 
hypoglycaemia. The investigator is responsible for questioning the subject about all 
symptoms reported on the hypoglycaemia log and for determining if they meet the 
clinical definition of hypoglycaemia. Only symptoms and/or blood glucose values deemed 
by the investigator to meet the definition of hypoglycaemia should be reported on the 
hypoglycaemia eCRF pages. Signs and symptoms of hypoglycaemia, hypoglycaemia episode 
or discontinuation due to hypoglycaemia should not be reported on the AE eCRF page, unless 
the event fulfils protocol criteria for a SAE (see Section 6.2), in which case an SAE form must 
be completed in addition to the hypoglycaemia eCRF pages for hypoglycaemia.
The diary will be returned by the subject and reviewed by site personnel at every subsequent 
visit. Completed diary pages will be added to the subject’s source record, and data from the 
diary will be entered in the appropriate eCRF. A new diary for the next period will be handed 
over to the subject if needed.  
5.2.5.2 
Urinary infections  
The following is presented to assist in the classification and management of UTI. It is not 
intended to supplant investigators’ clinical judgement: 
IP should be withheld in subjects with clinical evidence of upper tract UTIs (e.g. 
pyelonephritis) or presumed urosepsis until the course of treatment of the infection has been 
completed and clinical recovery has occurred.  

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It is recommended that a follow-up urine culture should be obtained within 7 days of clinical 
recovery from all UTIs. Whether or not additional therapy is prescribed because of culture 
results should be determined by investigator judgement, after consultation with AstraZeneca 
study physician.  
It is the investigator’s responsibility to report, as applicable based on investigator’s judgement 
and subject’s medical history, related AEs as defined in Section 6. Additional information, 
including but not limited to completion of supplemental eCRFs may be requested for certain 
AEs and/or laboratory abnormalities which are reported/identified during the course of the 
study. 
5.2.5.3 
Cardiovascular events (Cardiovascular Adjudication Committee, CAC) 
An independent Adjudication Committee, blinded to the treatment of the subjects, will 
adjudicate cardiac failure events requiring hospitalization reported in the study. CAC 
adjudication manual/charter of operations further defines and describes the procedure for the 
handling, reporting and classification of these events. 
5.2.5.4 
 Potential events of Diabetic Ketoacidosis (DKA Adjudication Committee) 
All potential events of DKA will be recorded in the eCRF and submitted to an independent 
DKA Adjudication Committee. The DKA Committee will assess available information on 
each potential DKA event and will classify the event in accordance with the definitions in the 
DKA Adjudication Charter. 
The DKA Adjudication Committee will be kept blinded to the study drug treatment received 
by each subject 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 
5.3.1 
Diet and exercise counselling 
Starting at the lead-in period, subjects will be instructed on a diet and exercise program in 
accordance with the ADA or similar local guidelines to be followed for the study duration.  
A registered dietitian, registered nurse, physician, certified diabetes educator, nutritionist, or 
other qualified member of the study team who has appropriate documented training will 
provide this counselling. 
In addition, as part of the diet and exercise program, the investigator or designee should 
ensure that each subject receives an adequate daily intake of minerals and vitamins, in 
accordance with the National Academy of Sciences or similar local guidelines. 
5.3.2 
Height and body mass index (BMI) 
Measurement of height should be performed with the subject’s shoes removed. The subject’s 
knee should be straightened, head held erect, and eyes forward. 

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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. 
5.3.3 
Waist circumference  
The waist circumference should be measured in the standing position at the natural waist 
(smallest waist circumference). If there is no natural waist, the measurement should be made 
at the level of the umbilicus. Measurements should be made at the end of a normal inspiration. 
5.4 
Pharmacokinetics-Not Applicable 
5.5 
Pharmacodynamics-Not Applicable 
5.6 
Genetics-Not Applicable  
5.7 
Biomarker-Not Applicable 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
6.1 
Definition of adverse events 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product. An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, 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. 
6.1.1 
Adverse events of special interest 
The following AEs are classified as AEs that should be given special attention. They include: 
hypoglycaemia, volume depletion, cardiac failure (including confirmed adjudicated 
hospitalization due to cardiac failure events), hypersensitivity reactions, pancreatitis, severe 
cutaneous adverse reactions, malignancies (including pancreatic cancer, breast cancer and 
bladder cancer), genital infections, UTIs, liver injury, renal impairment/renal failure, DKA, 
AEs leading to amputation and potential risk factor AEs for amputations affecting lower limbs 
(“preceding events”) and fracture. 
AEs leading to amputation and potential risk factor AEs for amputations affecting lower 
limbs (“preceding events”)   

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To ensure that data on amputations is systematically collected, amputations and underlying 
conditions relevant to amputation will be recorded on a specific eCRF page. The AE leading 
to amputation should be recorded in the eCRF as AE/SAE. 
In addition to amputation, non-serious and serious events potentially placing the subject at risk 
for a lower limb amputation (“preceding events”) should also be recorded in the eCRF as 
AE/SAE, whether or not an amputation has taken place. The lower limb “preceding events” of 
interest include diabetic foot related conditions, vascular, wounds/injury/trauma, infection and 
neuropathy. If any of these or other potentially relevant event have occurred, relevant 
information must be provided (this will be collected on a dedicated eCRF page - for details 
see eCRF instruction). 
6.2 
Definitions of serious adverse event 
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria: 
x 
Results in death 
x 
Is immediately life-threatening 
x 
Requires in-patient hospitalisation or prolongation of existing hospitalisation  
x 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
x 
Is a congenital abnormality or birth defect 
x 
Is an important medical event that may jeopardise the subject 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 CSP. 
6.3 
Recording of adverse events 
6.3.1 
Time period for collection of adverse events 
AEs will be collected from the time of first administration of open-label study medication 
saxagliptin 5 mg throughout the Open-label and Double-blind, double dummy treatment 
period and including the last visit. 
SAEs will be recorded from the time of signing informed consent throughout the Open-label 
and Double-blind, double dummy treatment period and including the last visit. 
All AEs will be recorded on source documents and the eCRF. 

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6.3.2 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts. All SAE/non-serious AEs, will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up. 
Any AEs that are unresolved at the subject's last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically indicated, 
but without further recording in the eCRF. AstraZeneca retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary. 
6.3.3 
Variables  
The following variables will be collect for each AE; 
x 
AE (verbatim) 
x 
The date when the AE started and stopped 
x 
Maximum intensity  
x 
Whether the AE is serious or not  
x 
Investigator causality rating against the dapagliflozin and saxagliptin (yes or no) 
x 
Action taken with regard to dapagliflozin and saxagliptin 
x 
Outcome. 
In addition, the following variables will be collected for SAEs: 
x 
Date AE met criteria for serious AE 
x 
Date investigator became aware of serious AE 
x 
AE is serious due to 
x 
Date of hospitalisation 
x 
Date of discharge 
x 
Probable cause of death 
x 
Date of death 
x 
Autopsy performed 

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x 
Causality assessment in relation to study procedure(s) 
x 
Description of AE. 
Maximum intensity will be graded according to the following rating scale: 
x 
Mild (awareness of sign or symptom, but easily tolerated) 
x 
Moderate (discomfort sufficient to cause interference with normal activities) 
x 
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 IP?’ 
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 subject 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 eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately. 
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 
clinical study report (CSR). Deterioration as compared to baseline in protocol-mandated 
laboratory values, vital signs and other safety variables should therefore only be reported as 

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AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of treatment 
with the IP. 
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 haemoglobin 
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. 
For instructions how to handle AE based on ECG see section 5.2.3 and safety analyses for 
ECG recording see section 8.5.7. 
6.3.7 
Hypoglycaemia 
Subjects will be asked to test their blood glucose if they experience symptoms suggestive of 
hypoglycaemia and to record specific symptoms and glucose values in the subject diary. 
Study site personnel must obtain accurate information for the subject’s file and for the 
hypoglycaemia page of the eCRF.  
Hypoglycemia episodes will be classified in the CSR according to 2018 ADA Criteria as 
follows (ADA 2018).  
Severe hypoglycaemia:  
An event requiring assistance of another person to actively administer carbohydrate, glucagon, 
or other resuscitative actions. These episodes may be associated with sufficient 
neuroglycopenia to induce seizure or coma. Glycaemia level may not be available during such 
an event, but neurological recovery attributable to the restoration of blood glucose to normal is 
considered sufficient evidence that the event was induced by a low blood glucose 
concentration. 
In summary, hypoglycaemia event will be considered as severe hypoglycaemia if it meets all 
of the following criteria: 
x 
Require third party assistance 
x 
Prompt recovery after carbohydrate or glucagon administration 
x 
Include symptoms of neuroglycopenia (such as dizziness, confusion, lethargy, 
headache, visual disturbances, difficulty concentrating, speech difficulty, 
somnolence/prolonged sleep etc.) 

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x 
Glycaemia level, if available, of less than or equal to 70 mg/dL (3.9 mmol/L) 
Clinically significant hypoglycaemia: Glycaemia level < 54 mg/dL (3.0 mmol/L).  
Hypoglycemia alert value: Glycaemia level ≤ 70 mg/dL (3.9 mmol/L) 
Since the glycaemic threshold for activation of glucagon and epinephrine secretion as glucose 
levels decline is normally 65 to 70mg/dL (3.6 to 3.9mmol/L) and since antecedent blood 
glucose concentrations of less than or equal to 70mg/dL (3.9mmol/L) reduce sympathoadrenal 
responses to subsequent hypoglycaemia, this hypoglycaemia alert value of ≤ 70 mg/dL (3.9 
mmol/L) can be important for therapeutic dose adjustment of glucose-lowering drugs. 
If any episodes of probable symptomatic hypoglycaemia (episodes for which symptoms of 
hypoglycaemia are not accompanied by a blood glucose determination, but which were 
presumably caused by a blood glucose concentration less than or equal to 70 mg/dL [3.9 
mmol/L]) are reported by subjects, the investigator should evaluate and properly record as 
such in the subject’s source records and follow them according to clinical practice. But this 
category of hypoglycaemia is not considered as clinically significant and will be not recorded 
in eCRF or reported in CSR. 
6.3.8 
Hy’s Law-Not Applicable 
6.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate 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 telephone. 

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The AstraZeneca representative will advise the investigator/study site personnel how to 
proceed. 
6.5 
Overdose 
Overdose is defined as the accidental or intentional ingestion of any dose of study medication 
provided by Sponsor that is considered both excessive and medically important. For the 
purpose of this study, an overdose is defined as a dose of dapagliflozin or saxagliptin in excess 
of that specified in the CSP (i.e., take more than 1 tablet per day for any of dapagliflozin or its 
placebo to match or saxagliptin).  
For other non-IP (metformin or rescue therapy), overdose will not be collected unless 
overdose in those medications associated with SAE. 
If an overdose is suspected, monitoring of vital functions as well as treatment as appropriate 
should be performed: 
x 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
x 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
If an overdose on an AstraZeneca study medication 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. 
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. 
In the event of an overdose, appropriate supportive treatment should be initiated as dictated by 
the subject’s clinical status. Saxagliptin and its active metabolite are removed by hemodialysis 
(23% of dose over 4 hours). The removal of dapagliflozin by hemodialysis has not been 
studied. 
6.6 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
6.6.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study, IP should be discontinued 
immediately. 

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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 subject 
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  
There is no restriction on fathering children or donating sperm during the study.  
6.7 
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for saxagliptin or dapagliflozin that either causes harm to the subject or 
has the potential to cause harm to the subject. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject. 
Medication error includes situations where an error 
x 
Occurred 
x 
Was identified and intercepted before the subject received the drug 
x 
Did not occur, but circumstances were recognized that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 
x 
Drug name confusion 
x 
Dispensing error e.g. medication prepared incorrectly, even if it was not actually given 
to the subject 

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x 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
x 
Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a 
solid tablet 
x 
Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature 
x 
Wrong subject received the medication (excluding IxRS errors) 
x 
Wrong drug administered to subject (excluding IxRS errors) 
Examples of events that do not require reporting as medication errors in clinical studies: 
x 
Errors related to or resulting from IxRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 
x 
Subject accidentally missed drug dose(s) e.g. forgot to take medication 
x 
Accidental overdose (will be captured as an overdose) 
x 
Subject failed to return unused medication or empty packaging 
x 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 6.4) and within 30 days for all other 
medication errors. 
6.8 
Management of IP related toxicities <<Dose Reductions>> 
Dose reductions are not permitted in this study. 

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6.9 
Study governance and oversight 
6.9.1 
Clinical Event Committee (CEC) 
6.9.1.1 
Diabetic Ketoacidosis Adjudication Committee  
All potential events of DKA will be submitted to an independent DKA Adjudication 
Committee.  The committee will be kept blinded to the treatment codes.  A separate DKA 
Adjudication Manual will define and describe the procedures for the collection of DKA 
information, handling, adjudication criteria and reporting of these events. Please also refer to 
Section 5.2.5.4. 
6.9.1.2 
Cardiovascular Adjudication Committee 
An independent CAC blinded to the treatment of the subjects, will adjudicate heart failure 
events requiring hospitalization reported in the study. A separate Adjudication Manual will 
define and describe the procedure for the handling, reporting and classification of these 
events. Please also refer to Section 5.2.5.3. 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
IP will be packaged in bottles. The tablets contain lactose, in quantities not likely to cause 
discomfort in lactose-intolerant individuals. Primary packaging of the IP will be carried out by 
AstraZeneca or their designee in accordance with Good Manufacturing Practice (GMP). 
Investigational 
product 
Dosage, route, form and strength 
Manufacturer 
Dapagliflozin 10 mg 
10 mg, orally,Green, plain, diamond-shaped, film-coated 
tablet 
AstraZeneca 
Dapagliflozin 5 mg 
5 mg, orally,Green, plain, diamond-shaped, film-coated 
tablet 
AstraZeneca 
Dapagliflozin 10 mg 
placebo to match 
Does not contain active ingredient, orally, Green, plain, 
diamond-shaped, film-coated tablet 
AstraZeneca 
Dapagliflozin 5 mg 
placebo to match 
Does not contain active ingredient, orally, Green, plain, 
diamond-shaped, film-coated tablet 
AstraZeneca 
 
Non-IP: 
Saxagliptin (Onglyza®): 5 mg tablets. Sourced by Sponsor. * 
Metformin: Not sourced by Sponsor. To be prescribed by Investigator.   
* Onglyza® to be used in China. Saxagliptin to be used in all countries outside China. 

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7.2 
Dose and treatment regimens 
The study medications include investigational drugs (dapagliflozin 5 mg, dapagliflozin 10 mg 
and dapagliflozin placebo to match) and non-IPs (saxagliptin 5 mg, metformin and rescue 
therapy). Study medication should be taken in the morning and should be taken at 
approximately the same time of the day during the study period. Subjects should be instructed 
to abstain from all food for 8 hours prior to each clinical visit; however, drinking water is 
allowed. For all visits, the subjects should visit the study centre in the morning without taking 
the IPs, saxagliptin 5 mg, metformin. In the morning prior to each visit, acceptable 
concomitant medications can be taken with water only. 
x 
Open-label saxagliptin 5 mg tablets will be administered orally once daily for the 
open-label treatment period and the 24-week double-blind treatment period  
x 
Open-label metformin IR/XR will be administered orally with food at doses ≥ 1500 
mg/day or a maximal tolerated dose and keep unchanged for the open-label treatment 
period and the 24-week double-blind treatment period 
x 
Subjects randomized to the 5 mg treatment arm will receive one tablet of dapagliflozin 
5 mg and one tablet of dapagliflozin 10 mg placebo to match, to be administered orally 
once daily for the 24-week double-blind treatment period 
Subjects randomized to the 10 mg treatment arm will receive one tablet of 
dapagliflozin 10 mg and one tablet of dapagliflozin 5mg placebo to match, to be 
administered orally once daily for the 24-week double-blind treatment period 
Subjects randomized to the placebo arm, will receive one tablet of dapagliflozin 5 mg 
placebo to match and one tablet of dapagliflozin 10 mg placebo to match, to be 
administered orally once daily for the 24-week double blind treatment period 
If any dose is missed, it should be taken as soon as noticed, unless it is almost time for the 
next dose, in which case subjects should skip the missed dose and take the medicine at the 
next regularly scheduled time. Advise subjects not to take 2 doses of dapagliflozin at the same 
time. 
7.3 
Labelling 
Single panel labels or booklet labels will be prepared in accordance with GMP and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. Label 
text will be translated into local language. 
The label will include at least the following information: 
x 
Name of sponsor 
x 
IP/study drug dosage form, route of administration, and quantity of dosage units 

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x 
Storage conditions 
x 
Study code 
x 
Enrolment code (to be added on the label when IP is dispensed) 
x 
Directions for use 
x 
The name of Principal Investigator, where applicable (to be added on the label when IP 
is dispensed) 
x 
The period of use e.g., expiry date 
x 
“For clinical study use only” 
x 
“Keep out of reach of children” 
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 dapagliflozin and saxagliptin should be recorded in the appropriate 
sections of the eCRF. 
Each time for the dispensing of saxagliptin and/or dapagliflozin, compliance will be 
reinforced. When saxagliptin and/or dapagliflozin is returned, compliance will be assessed 
based on returned tablet counts. Compliance should be between ≥80% and ≤120%. The 
investigator (or designee) will record the amounts of study medication dispensed and returned 
at each site, as well as document reasons for non-compliance, in the source document. The 
dates of all study medication dosing, including interruptions, missed doses or overdose, must 
be recorded on the eCRF. If the subject is not compliant with recording study drug doses 
during the study period, non-compliance should be noted as a protocol deviation and the 
Sponsor should be notified. The subject may continue in the study, but should be counselled 
on the importance of taking their study medication and applicable ancillary medications as 
prescribed. 
Metformin should be administered according to product and country specific labelling and 
monitored by investigator. 
7.6 
Accountability 
The study drugs 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 
subject. 

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Study site personnel will account for all study medications received at the site, unused study 
medications and for appropriate destruction. Certificates of delivery, destruction, and return 
should be signed.  
A drug disposition form will be provided to record all study medication dispensed to or 
returned from each subject. Upon completion of the study, all unused study medication, and 
copies of completed drug disposition forms should be returned to the Sponsor (or designee). 
Used study medication kits may be disposed at study sites after accountability has been 
verified by the Sponsor (or designee) and may not be returned to the Sponsor (or designee).  
For unused study medication, a clinical supplies return authorization form (CSRAF) will be 
completed by the clinical research associate at the closeout visit. The completed CSRAF 
should be enclosed with each return drug shipment to the Sponsor (or designee). The study 
site personnel must maintain documentation of any missing, damaged, or unreturned study 
medication. 
7.7 
Concomitant and other treatments  
Subjects must follow the medication restrictions outlined in the inclusion and exclusion 
criteria (Sections 3.1and 3.2, respectively) during the study. Dosages for certain concomitant 
medications should be maintained constant during the study, unless instructed otherwise by 
the investigator or a treating physician. Any change in regimen for any concomitant 
medication, including restricted concomitant medications, must be reported to the Sponsor. 
Concomitant herbal or nutritional therapies must also be entered into the eCRF.   
7.7.1 
Saxagliptin 
Saxagliptin 5 mg tablets, administered orally once daily for the open-label period and the 24-
week double-blind treatment period, and will be provided by the Sponsor. 
7.7.2 
Metformin 
Up to Week 24, subjects should continue to administer the same type and dose of metformin 
therapy they were using at study entry. Metformin should be administered and stored 
according to product and country-specific labelling. 
Metformin will not be provided by the Sponsor. 
7.7.3 
Rescue therapy 
Subjects must first complete rescue procedures before receiving open-label rescue therapy. 
Subjects who require rescue therapy (i.e., FPG rescue criteria met) should receive standard of 
care treatment. Subjects should continue receiving study medication while receiving rescue 
therapy.  
If rescue therapy fails, further therapy will be given at the discretion of the investigator. 

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7.7.4 
Other concomitant medication 
Other medication other than that described above, which is considered necessary for the 
subject’s safety and well-being, may be given at the discretion of the investigator and recorded 
in the appropriate sections of the eCRF. 
7.8 
Post Study Access to Study Treatment 
At the end of the study, the Sponsor will not continue to supply study drug to 
subjects/investigators unless the Sponsor chooses to extend the study. The investigator should 
ensure that the subject receives appropriate standard of care therapy. 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1 
Statistical hypotheses 
The primary hypothesis in this study is that the mean change from baseline in HbA1c at Week 
24 achieved with dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin is superior to 
that achieved with placebo added to saxagliptin 5 mg plus metformin.  
The secondary hypotheses will be tested only if dapagliflozin 10 mg added to saxagliptin 5 mg 
plus metformin is found to be superior to placebo added to saxagliptin 5 mg plus metformin in 
mean change from baseline in HbA1c at Week 24. 
The secondary hypothesis in this study is that the mean change from baseline in HbA1c at 
Week 24 achieved with dapagliflozin 5 mg added to saxagliptin 5 mg plus metformin is 
superior to that achieved with placebo added to saxagliptin 5 mg plus metformin.  
8.2 
Sample size estimate 
The primary endpoint (mean change from baseline in HbA1c at Week 24) will be assessed 
comparing dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus 
metformin versus (vs.) placebo added to saxagliptin 5 mg plus metformin. Statistical 
significance of the primary endpoint will be claimed if the p-values for dapagliflozin 10 mg + 
saxagliptin 5 mg + metformin vs. placebo + saxagliptin 5 mg + metformin comparison is 
significant at the 2-sided, 0.05 significance level. As the success of primary endpoint on the 
dapagliflozin 5mg + saxagliptin 5 mg + metformin vs. placebo + saxagliptin 5 mg + 
metformin comparison is important, the sample size is planned to provide at least 90% power 
for primary endpoint on both comparisons. 
With 108 subjects per treatment group with post-baseline assessment, there is 95% power to 
detect -0.5% difference for dapagliflozin 10mg + saxagliptin 5 mg + metformin vs. placebo + 
saxagliptin 5 mg + metformin comparison, assuming a standard deviation (SD) of 1.0% with a 
2-sided significance level of 0.05. This sample size will also provide at least 90% power to 
detect -0.5% difference for both dapagliflozin 10mg + saxagliptin 5 mg + metformin vs. 
placebo + saxagliptin 5 mg + metformin and dapagliflozin 5mg + saxagliptin 5 mg + 

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metformin vs. placebo + saxagliptin 5 mg + metformin comparisons, assuming a standard 
deviation (SD) of 1.0% with a 2-sided significance level of 0.05. 
Assuming that 5% of subjects would not have a post-baseline assessment, a total of 
approximately 342 subjects (114 subjects per treatment arm, with about 91 subjects from 
China and about 23 subjects from other countries/region) need to be randomized. In other 
words, subjects in China will constitute about 80% of the total number of subjects. This study 
includes two strata, based on prior antihyperglycemic treatment. Stratum A includes subjects 
whose HbA1c is uncontrolled on a stable dose of metformin and are enrolled into a 16-week 
open-label treatment period, adding saxagliptin 5 mg to metformin. Subjects in stratum A who 
remain uncontrolled are subsequently randomized. Stratum B includes subjects whose HbA1c 
is uncontrolled on a stable dose of metformin and a maximal dose of a DPP-4 inhibitor who 
are randomized following treatment with saxagliptin 5 mg during an 8-week open-label 
treatment period.  
It is desired to have approximately 33% of the randomized subjects coming from Stratum B. 
In addition, Enrolment of subjects with HbA1c ≥ 8.0% and < 9.0% (Stratum A) and subjects 
with HbA1c ≥ 7.5% and ≤ 8.5% (Stratum B) into the open-label treatment period will be 
limited to approximately 171 subjects (about 50% of the randomized subjects number in each 
stratum). 
About 40% (Stratum A) and 6.5% (Stratum B) of subjects are expected to be discontinued due 
to severe lack of glycaemic control (defined as FPG > 270 mg/dL at Week -10 or Week -2 in 
Stratum A and Week -2 only in Stratum B) during the open-label treatment period. In 
addition, it is expected that 50% of screened subjects will fail to meet eligible criteria for each 
stratum. This leads to a total of 1004 subjects to be screened, with a targeted 380 subjects in 
Stratum A and 122 subjects in Stratum B to enter the open-label treatment period.  
8.3 
Definitions of analysis sets 
The primary efficacy analysis will be performed based on ITT analysis set. Safety analysis for 
double-blind treatment period will be performed based on the safety analysis set. Selected 
safety and efficacy analyses for the open-label treatment period will be based on open-label 
treated subjects analysis set. 
8.3.1 
Efficacy analysis sets 
The ITT analysis set will include all randomized subjects who received at least one dose of 
double-blind study medication during the double-blind treatment period. Subjects will be 
analyzed according to the treatment groups to which they are randomized.  
The per protocol (PP) analysis set is a subset of the ITT set that includes subjects without 
important protocol deviations that could potentially affect the primary efficacy interpretability 
of the study results. Subjects will be analyzed according to the treatment groups to which they 
are randomized. The criteria for PP relevant important protocol deviations will be established 
after protocol deviation reviews, before the data has been unblinded.  

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8.3.2 
Safety analysis set 
The safety analysis set will include all randomized subjects who have received at least 1 dose 
of double-blind study medication during the double-blind treatment period. Subjects will be 
analyzed according to treatment actually received. Subject receiving different treatment as 
assigned by randomization during the entire course of study, will be analyzed based on the 
first treatment the subject actually received. 
8.3.3 
Open-label treated subjects analysis set 
The open-label treated subjects analysis set will consist of all subjects who receive at least one 
dose of open-label study medication during the open-label treatment period. 
8.3.4 
PK analysis set-Not Applicable 
8.3.5 
PRO analysis set-Not Applicable  
8.4 
Outcome measures for analyses 
8.4.1 
Primary efficacy variable 
Mean change from baseline in HbA1c at Week 24 will used as primary efficacy variable 
8.4.2 
Secondary efficacy variables 
x 
Mean change from baseline in FPG at Week 24 
x 
Mean change from baseline in 2-hour PPG during a 2-hour MTT at Week 24 
x 
Mean change from baseline in total body weight at Week 24 
x 
Proportion of subject achieving a therapeutic glycaemic response, defined as a HbA1c 
< 7.0% at Week 24 
8.4.3 
Exploratory variables 
x 
The proportion of subjects who require glycaemic rescue or discontinue study 
treatment for lack of efficacy up to Week 24 
x 
Time to glycaemic rescue or discontinuation for lack of efficacy in the double-blind 
treatment period 
x 
Mean change from baseline in AUC glucose obtained during MTT at Week 24 
x 
Mean percent change from baseline in fasting serum lipids (Total-C, LDL-C, HDL-C, 
TG) during the double-blind treatment period 

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8.5 
Methods for statistical analyses 
All personnel involved with the analysis of the study will remain blinded until database lock. 
Analyses will be performed by AstraZeneca or its representatives. The SAP will be finalized 
prior to unblinding of data. 
8.5.1 
Analysis of the primary variable (s) 
The primary efficacy analysis compared the change from baseline in HbA1c at Week 24 for 
each of dapagliflozin 5 mg or dapagliflozin 10 mg + saxagliptin 5 mg + metformin treatment 
groups and the placebo + saxagliptin 5 mg + metformin group. Each comparison was 
performed at the 0.05 significance level (2-sided) using the hierarchical testing specified in 
Section 8.1. This maintains the familywise type I error rate at 0.05. 
The primary efficacy analysis of HbA1c at Week 24 will be performed using a mixed-model 
repeated-measures (MMRM) model with terms for treatment group, stratum, baseline HbA1c 
value, time, the interaction of treatment and time, and the interaction of baseline HbA1c value 
and time in the model, including observations prior to rescue and study treatment 
discontinuation only, without explicitly imputing missing data. Point estimates and 95% 
confidence intervals will be calculated for the adjusted mean changes within each treatment 
group as well as for the differences in adjusted mean changes between treatment groups. 
An unstructured matrix for the within-subject error variance-covariance will be used. The 
denominator degrees of freedom will be calculated according to the Kenward-Roger method. 
In case of non-convergence of the preferred model or memory space issue, the back-up 
models will be used [e.g. calculate the denominator degrees of freedom using other method 
like Satterthwaite approximation, use other covariance matrix like Toeplitz, AR (1), use 
simpler models, and etc.]. Details will be documented in SAP. 
ITT analysis set will be used for the primary efficacy analysis.  
8.5.2 
Analysis of the secondary variable(s) 
The same MMRM approach used for HbA1c evaluation will be also used for the analysis of 
FPG and total body weight. Point estimates and 95% confidence intervals will be calculated 
for the adjusted mean changes within each treatment group as well as for the differences in 
adjusted mean changes between treatment groups.   
For subjects in China, the ANCOVA using last observation carried forward (LOCF) 
methodology with terms for treatment group, stratum, and baseline 2-hour PPG value will be 
used to evaluate 2-hour PPG. Point estimates and 95% confidence intervals will be calculated 
for the adjusted mean changes at Week 24 within each treatment group as well as for the 
differences in adjusted mean changes between treatment groups.  
The proportion of subjects achieving a therapeutic glycaemic response (defined as HbA1c < 
7.0%) at Week 24 (LOCF) will be summarized by treatment group and compared between 
treatment groups using the logistic regression based on methodology of Zhang et al (Zhang 

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2008) and Tsiatis et al (Tsiatis 2008) with adjustment for baseline HbA1c and stratum. Point 
estimates and 95% confidence intervals will be calculated for the response rate within each 
treatment group as well as the difference in response rates between treatment groups will be 
calculated.  
8.5.3 
Subgroup Analysis   
Specifically, the treatment effect on the adjusted mean change from baseline in HbA1c will be 
examined in the following subgroups:  
x 
Baseline HbA1c (< 8.0%, 8.0% to <9.0%, t 9.0%) 
x 
Gender (male, female) 
x 
Age (<65, t 65 years) 
x 
Female/Age (female d 50 years, female > 50 years) 
x 
Duration of T2DM (< 3 years,3-10 years, > 10 years) 
8.5.4 
Interim analysis-Not Applicable 
8.5.5 
Sensitivity analysis 
Two separate sensitivity analyses for HbA1c will be performed based on ITT analysis set:  
1. The MMRM approach with terms for treatment group, stratum, baseline HbA1c value, 
time, the interaction of treatment and time, and the interaction of baseline HbA1c 
value and time in the model, including data after rescue and/or study treatment 
discontinuation.  
2. ANCOVA (LOCF) model, with terms for treatment group, stratum, and baseline 
HbA1c value, including observations prior to rescue and study treatment 
discontinuation only, where last post-baseline observation carried forward (LOCF) 
will be used for missing value at Week 24.  
The third sensitivity analyses for HbA1c is to repeat the primary analysis for HbA1c based on 
per protocol analysis set. 
Sensitivity analyses for FPG and total body weight will consist of ANCOVA analyses using 
LOCF methodology based on ITT analysis set. 
8.5.6 
Exploratory Analysis (if applicable)  
The percent of subjects who require glycaemic rescue or discontinue study for lack of efficacy 
up to Week 24 will be assessed by summarizing the difference in percentages between 
treatment groups and analyze the variable of time to glycaemic rescue or discontinuation for 
lack of efficacy in the double-blind treatment period using the Kaplan-Meier methodology. 

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Analyses of the mean change from baseline for continuous endpoints will be performed using 
an MMRM or ANCOVA method depending upon the availability of repeated measurements 
for the endpoint. Among them, AUC of glucose during MTT will only be analyzed based on 
data of subjects in China. 
For lipids (Total-C, LDL-C, HDL-C, TG), the natural logarithms of the post- to pre-treatment 
ratios, and the natural logarithm (Ln) of the baseline lipid measurement, will be used in the 
model. 
ITT analysis set will be used for the exploratory analysis. 
8.5.7 
Safety analysis 
Safety analyses for the double-blind treatment period will be performed using the Safety 
analysis set, including data after rescue. Safety analyses will include, where appropriate, 
descriptive statistics, counts and percentages for AEs and other safety measures. No formal 
statistical tests will be performed.  
The number and percent of subjects with at least one AE will be summarized for each 
treatment group, including summaries of AEs, SAEs, AEs leading to discontinuation, and AEs 
of special interest. Summaries will include the number of subjects with events by specified 
system organ classes and preferred terms. 
Additionally, the incidence of AEs and frequency of recurring AEs will be summarized for 
each treatment group for both frequent events and for selected AEs of special interest.  
Values and changes from baseline at each scheduled time point for clinical laboratory 
parameters and vital signs, including seated BP and HR, will be summarized by treatment 
group using descriptive statistics. The normality/abnormality of ECG tracings, as determined 
by the investigator, will be summarized by shift tables overall and by ECG tracing at baseline. 
The number and percent of subjects with laboratory values meeting marked abnormality 
criteria will be summarized for each treatment group. Other safety assessments including Scr 
and eGFR by MDRD, will be summarized by treatment group using descriptive statistics of 
values and changes from baseline at each scheduled time point. 
Additional analyses for AEs and laboratory marked abnormalities may be performed 
excluding data after rescue and study treatment discontinuation. The primary analyses of 
events of hypoglycaemia will be performed excluding data after rescue and study treatment 
discontinuation. 
Selected safety analyses will be performed for the open-label treatment period using the Open-
label treated subjects analysis set. 
8.5.8 
Methods for multiplicity control 
The primary efficacy analysis compared the change from baseline in HbA1c at Week 24 for 
each of dapagliflozin 5 mg or dapagliflozin 10 mg + saxagliptin 5 mg + metformin treatment 

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groups and the placebo + saxagliptin 5 mg + metformin group. Each comparison was 
performed at the 0.05 significance level (2-sided) using the hierarchical testing specified in 
Section 8.1. This maintains the familywise type I error rate at 0.05. 
 
8.6 
China cohort 
Per China Regulatory Authority guidance, in addition to the evaluation of global cohort data 
for primary, secondary and selected exploratory objectives plus safety objectives, evaluation 
of consistency in efficacy and safety in China is required to facilitate the benefit-risk 
assessment for  subjects in China sites (China cohort). Hence, the efficacy and safety data in 
China cohort will be analysed separately where the same endpoint definitions and the same 
analysis methods (as detailed in Section 8.5) are applied. 
 
Definition of analysis sets in section 8.3 will be applied in China cohort. 
 
Details of China cohort analysis will be specified in SAP, which is to be finalized before data 
lock. 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1 
Training of study site personnel 
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the CSP and related documents with the investigational staff 
and also train them in any study specific procedures and the WBDC system(s) utilised. 
The Principal Investigator 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 Principal Investigator 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: 
x 
Provide information and support to the investigator(s) 
x 
Confirm that facilities remain acceptable 
x 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 

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accordance with the Laboratory Manual and that study drug accountability checks are 
being performed 
x 
Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (e.g., clinic charts) 
x 
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, 
and the action is documented, and reported to the subject 
The AstraZeneca representative will be available between visits if the investigators(s) or other 
staffs at the centre need information and advice about the study conduct. 
9.2.1 
Source data 
Refer to the CSA location of source data. 
9.2.2 
Study agreements 
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 subject undergoing the study’. 
The study is expected to start in Q4 2018 and continues to Q4 2020. 
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 and/or saxagliptin. 
9.4 
Data management by AstraZeneca or delegate 
Data management will be performed by AstraZeneca Data Management Centre staff 
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. 
The data collected through third party sources will be obtained and reconciled against study 
data. 

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AEs and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA). Medications will be 
classified according to the AstraZeneca Drug Dictionary. All coding will be performed by the 
Medical Coding Team at the AstraZeneca Data Management Centre. 
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process. 
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked. 
SAE Reconciliation 
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational sit.  
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 IxRS 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 International Conference on Harmonisation 
(ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and 
Human Biological Samples. 
10.2 
Subject data protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 

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10.3 
Ethics and regulatory review 
An Ethics Committee 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 subjects. The 
investigator will ensure the distribution of these documents to the applicable Ethics 
Committee, and to the study site staff. 
The opinion of the Ethics Committee should be given in writing. The investigator should 
submit the written approval to AstraZeneca before enrolment of any subject into the study.  
The Ethics Committee should approve all advertising used to recruit subjects for the study. 
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 Ethics Committee 
annually. 
Before enrolment of any subject 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, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements. 
Each Principal Investigator is responsible for providing the Ethics Committees with reports of 
any serious and unexpected adverse drug reactions from any other study conducted with the 
IP. AstraZeneca will provide this information to the Principal Investigator so that he/she can 
meet these reporting requirements. 
10.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
x 
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study 
x 
Ensure each subject is notified that they are free to discontinue from the study at any 
time 
x 
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided 

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x 
Ensure each subject provides signed and dated informed consent before conducting 
any procedure specifically for the study 
x 
Ensure the original, signed ICF(s) is/are stored in the investigator’s Study File 
x 
Ensure a copy of the signed ICF is given to the subject 
x 
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an Ethics Committee. 
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 and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a new version of the study protocol. 
The amendment is to be approved by the relevant Ethics Committee 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 Principal Investigator(s). For distribution to Ethics Committee see Section 10.3. 
If a protocol amendment requires a change to a centre’s ICF, AstraZeneca and the centre’s 
Ethics Committee are to approve the revised ICF before the revised form is used.  
10.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
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 ICH, and any applicable regulatory requirements. The investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the centre. 

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11. 
LIST OF REFERENCES 
DeFronzo RA et al 2009 
DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of 
type 2 diabetes. [Banting Lecture]. Diabetes. 2009; 58:773-795.  
Hoerger et al 2008 
Hoeger TJ, et al., Is Glycemic Control Improving in U.S. Adults? Diabetes Care 31(1):81-86, 
2008. 
Rodbard et al 2009 
Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of 
Clinical Endocrinologists/American College of Endocrinology consensus panel on Type 2 
Diabetes Mellitus: An Algorithm for Glycemic Control.  American Association of Clinical 
Endocrinologists (AACE/ACE) Consensus Statement, Endocr Pract. 2009; 15:540-559. 
Nguyen et al 2011 
Nguyen, NT, at al., Relationship Between Obesity and Diabetes in a US Adult Population: 
Findings from the National Health and Nutrition Examination Survey, Obes Surg 21:351-355, 
2011. 
Inzucchi et al 2012 
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach, Position 
Statement of the American Diabetes Association (ADA) and the European Association for the 
Study of Diabetes (EASD). Diabetes Care. 2012; 35(6):1364-79. 
Rosenstock et al 2015 
Rosenstock J, Hansen L, Zee P, Li Y, Cook W, Hirshberg B, et al. Dual add-on therapy in 
type 2 diabetes poorly controlled with metformin monotherapy: a randomised double-blind 
trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or 
dapagliflozin to metformin. Diabetes Care. 2015; 38(3): 376-83. 
Scirica et al 2013 
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al (SAVOR-TIMI 
53 Steering Committee and Investigators). Saxagliptin and cardiovascular outcomes in 
patients with type 2 diabetes mellitus. N Engl J Med. 2013; 369:1317-1326. 
Tsiatis 2008 
Tsiatis A, Davidian M, Zhang M, et al. Covariate adjustment for two-sample treatment 
comparisons in randomized clinical trials: a principled yet flexible approach. Statistics in 
Medicine. 2008 Oct 15; 27(23): 4658–4677.  
Xu Y et al 2013 
Prevalence and control of diabetes in Chinese adults JAMA. 2013 Sep 4; 310(9):948-59. 

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Zhang 2008 
Zhang M, Tsiatis A, Davidian M. Improving efficiency of inference in randomized clinical 
trials using auxiliary covariates. Biometrics. 2008 Sep; 64(3): 707–715.  
ADA 2018 
Standards of Medical Care in Diabetes 2018. Diabetes Care 2018 Jan; 41 (Supplement 1): S1-
S2 
Levey AS 2007 
Levey AS, Coresh J, Greene T, et al. Expressing the Modification of Diet in Renal Disease 
Study Equation for Estimating Glomerular Filtration Rate with Standardized Serum Creatinine 
Values. Clinical Chemistry 2007; 53:766-72 
 

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12. 
APPENDIX A ADDITIONAL SAFETY INFORMATION 
12.1 
Further guidance on the definition of a serious adverse event (SAE) 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious. Simply stopping the suspect drug does not 
mean that it is an important medical event; medical judgement must be used. 
x 
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment 
x 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine 
x 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
x 
Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
x 
Development of drug dependency or drug abuse 
12.2 
A guide to interpreting the causality question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 

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

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13. 
APPENDIX B INTERNATIONAL AIRLINE 
TRANSPORTATION ASSOCIATION (IATA) 6.2 GUIDANCE 
DOCUMENT 
13.1 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are e.g., Ebola, Lassa fever 
virus: 
x 
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 
x 
UN 3373 – Biological Substance, Category B 
x 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
x 
Clinical trial samples will fall into Category B or exempt under IATA regulations 
x 
Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging  
x 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
x 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
x 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 

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containment standards are encouraged wherever possible when road or rail transport is 
used. 

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14. 
APPENDIX C NEW YORK HEART ASSOCIATION 
FUNCTIONAL CLASS 
I. 
Subjects without limitation of physical activity. Ordinary activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
II. 
Subjects with slight limitation of physical activity who are comfortable at rest. 
Ordinary activity results in palpitation, dyspnea, or fatigue. 
III. 
Subjects with marked limitation of physical activity. Although subjects are 
comfortable at rest, less than ordinary activity will lead to symptoms. 
IV. 
Subjects with inability to carry on any physical activity without discomfort. Symptoms 
may be present at rest.