Conditions: Type 2 Diabetes Mellitus Inadequate Glycaemic Control
Keywords: Diabetes Mellitus Type 2, metformin, saxagliptin, dapagliflozin, glimepiride, inadequate glycaemic control
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 939
Healthy volunteers: no

Brief summary:
This study is being carried out to see if dapagliflozin and dapagliflozin plus saxagliptin as an addition to metformin is effective and safe in treating patients with type 2 diabetes when compared to glimepiride (sulphonylurea) as an addition to metformin treatment.

Detailed description:

Arms:
arm 1: Dapagliflozin + saxagliptin placebo + glimepiride placebo + metformin arm 2: Dapagliflozin + saxagliptin + glimepiride placebo+ metformin arm 3: Glimepiride + dapagliflozin placebo + saxagliptin placebo + metformin

Interventions: intervention 1: Dapagliflozin intervention 2: Saxagliptin intervention 3: Glimepiride intervention 4: Placebo for dapagliflozin intervention 5: Placebo for saxagliptin intervention 6: Placebo for glimepiride
Intervention descriptions: intervention 1: 10 mg, orally Green, plain, diamond-shaped, film-coated tablet intervention 2: 5 mg, orally Plain, yellow, biconvex, round, film-coated tablet intervention 3: 1, 2, or 4 mg, orally Opaque gray capsule intervention 4: Does not contain active ingredient, orally Green, plain, diamond-shaped, film-coated tablet intervention 5: Does not contain active ingredient, orally Plain, yellow, biconvex, round, film-coated tablet intervention 6: Does not contain active ingredient, orally. Opaque gray capsule

Protocol document:
Prot_001.pdf: 
 
Clinical Study Protocol (CSP), ANGEL 
Version 17.0 
Template Form Doc ID: LDMS_001_00026737 
Parent Doc ID: SOP AZDoc0018580 
 
 
 
 
 
 
 
 
 
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to 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 regulation.
 
Clinical Study Protocol  
 
Drug Substance 
Saxagliptin / Dapagliflozin 
 
Study Code 
D1689C00014 
 
Version 
4.0 
 
Date 
12 January 2017 
 
EudraCT Number 2015-002376-24 
A 52-Week, Multi-Centre, Randomised, Parallel-Group, Double-Blind, 
Active-Controlled, Phase IV Study to Evaluate the Safety and Efficacy of 
Dapagliflozin or Dapagliflozin plus Saxagliptin compared with 
Sulphonylurea all given as Add-on Therapy to Metformin in Adult Patients 
with Type 2 Diabetes Who Have Inadequate Glycaemic Control on 
Metformin Monotherapy 
Sponsor:  AstraZeneca AB, S-151 85 Södertälje, Sweden


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
2 (122) 
VERSION HISTORY 
Version 4.0, 12th January 2017 
Revision History (Version 2.0): This section was updated to correct the release date of 
Clinical Study Protocol, Version 2.0. 
Protocol Synopsis (Objectives - Other Secondary Objectives): This section was updated due 
to typo correction. 
Protocol Synopsis (Definitions of analysis set): This section was updated due to error 
correction and for further clarification of the full analysis set.  
Protocol Synopsis (Analysis of the primary variable): This section was updated to add a 
superiority test of the dapagliflozin plus saxagliptin added to metformin group versus the 
control group. 
Section 2.2 (Other secondary Objective): This section was updated due to typo correction. 
Section 6.3.8 (Hypoglycaemia): The section was updated for further clarification of 
Hypoglycaemia. 
Section 8.3 (Definition of analysis sets): This section was updated due to error correction and 
for further clarification of the full analysis set. 
Section 8.4.1.2 (Other secondary endpoints): This section was updated due to typo correction. 
Section 8.5.3 (Control of type 1 error): This section was updated to add a superiority test 
including further specifications to this test. 
Section 8.5.4 (Analysis of the primary efficacy variable): This section was updated to add a 
superiority test including further specifications to this test. 
Section 8.5.6 (Analysis of the secondary and exploratory variables): This section was updated 
due to typo correction 
Version 3.0, 01st November 2016 
Changes to the clinical study protocol are summarized below.
Protocol Synopsis (Cover page): This section was updated due to updated adress of the 
International Co-ordinating Investigator. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
3 (122) 
Protocol Synopsis (Objectives - Other Secondary Objectives): This section was updated due 
to error correction for HbA1c range and for further clarification of hypoglycaemia. 
Protocol Synopsis (Safety Objective): This section was updated for further clarification of the 
outcome measures (bullet point #1). 
Protocol Synopsis (Definition of analysis sets): This section was updated for further 
clarification of required analysis sets. 
Protocol Synopsis (Analysis of the key secondary variables): This section was updated for 
further clarification of hypoglycaemia episode. 
Section 1.2 (Choice of outcome variables): This section was updated due to error correction 
for HbA1C range. 
Section 2.2 (Other secondary Objective): This section was updated due to error correction. 
Section 2.3 (Safety Objectives - Other Secondary Objectives): This section was updated for 
further clarification of the outcome measures (bullet point #1). 
Section 4 Table 1 Study plan. Footnote A  was updated to clarify scenarios Early Termination 
visit is expected.  
Section 4.3.5 (End of Treatment period / Early Termination or Rescue visit): The section was 
updated to clarify and correct the process for handling of surveys. 
Section 5.2.5.1 (Cardiovascular events): The section was updated for further clarification of 
cardiovascular events and adjudication process. 
Section 6.4.1 (Adverse Events of Special Interest): The section was updated for further 
clarification of reporting process as this is no longer required as per FDA General Advice. 
Section 6.8.2 (Cardiovascular Adjudication Committee): The section was updated for further 
clarification of cardiovascular events and adjudication process. 
Section 8.3 (Definition of analysis sets): This section was updated for further clarification of 
required analysis sets. 
Section 8.4.1.1 (Key secondary endpoints): This section was updated for further clarification 
of hypoglycaemia episode. 
 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
4 (122) 
Section 8.4.1.2 (Other secondary endpoints): The section was updated due to error correction 
and for further clarification of hypoglycaemia. 
Section 8.5.1 (Demographic and baseline characteristics): The section was updated for further 
clarification. 
Section 8.5.3 (Control of type 1 error): The section was updated for further clarification of 
hypoglycaemia episode. 
Section 8.5.6 (Analysis of the secondary and exploratory variables): The section was updated 
due to error correction and for further clarification of secondary and exploratory variables. 
Section 8.5.8 (Safety analyses): The section was updated for further clarification. 
Appendix D (Algorithm on Management of Sustained Elevated Liver Safety Abnormalities): 
The section was updated due to error correction. 
Version 2.0, 01st February 2016 
Changes to the clinical study protocol are summarized below.
Version 1.0 of clinical study protocol transferred into new template form 
LDMS_001_00026737.  
Clinical study protocol administrative change number 1, 22nd October 2015 incorporated. 
Protocol Synopsis (Study Sites and Number of Subjects planned): The section was updated to 
reflect the updated number of sites conducting this study. 
Protocol Synopsis (Objectives - Other Secondary Objectives): This section was updated due 
to error correction. 
Protocol Synopsis (Analysis of the primary variable): This section was updated due to error 
correction. 
Protocol Synopsis (Analysis of the key secondary variables): This section was updated for 
clarification. 
Section 1.3.4 (Ketoacidosis): New section was added to follow the updated Dapagliflozin 
Investigator's Brochure Version 12, 28th November 2015. 
Section 2.2 (Secondary Objectives - Other Secondary Objectives): This section was updated 
due to error correction. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
5 (122) 
Section 3.1 Inclusion Criteria: This section was updated to correct C-peptide laboratory value. 
Section 3.9 (Discontinuation of Investigational Product): The section was updated for further 
clarification of IP discontinuation process. 
Section 3.9 (Discontinuation of Investigational Product – Study specific Discontinuation 
criteria, NN #9): Refer to clinical study protocol administrative change number 1, 22nd 
October 2015. 
Section 3.9.3 (Procedures for Discontinuation of a Subject from Investigational Product): 
Refer to clinical study protocol administrative change number 1, 22nd October 2015. 
Section 4.  (Study Plan and Timing of Procedures – Table 1): “Register actual glimepiride 
dosage in IWRS” updated as not required at EOT/Rescue visit. For further changes please 
refer to clinical study protocol administrative change number 1, 22nd October 2015. 
Section 4.1 (Screening visit): Refer to clinical study protocol administrative change number 1, 
22nd October 2015. 
Section 4.2.1 (Enrolment visit): Refer to clinical study protocol administrative change number 
1, 22nd October 2015. 
Section 4.3.3 (Dose Titration): The section was updated to precise section header and to add a 
time window of - 3days for glimepiride up-titration. 
Section 4.3.4 (Rescue Therapy): Refer to clinical study protocol administrative change 
number 1, 22nd October 2015. 
Section 4.3.5 (End of Treatment period / Early Termination or Rescue visit): The section was 
updated to clarify the process for patients who discontinue IP and agreed to follow the original 
visit schedule. 
Section 4.4 (Follow-up visit): The section was updated to clarify the process for patients who 
discontinue IP and agreed to follow the original visit schedule. 
Section 6.4.1 (Adverse Events of Special Interest): The section was updated to implement the 
requirements regarding additional safety reporting requested by the United States Food and 
Drug Administration (FDA). 
Section 6.8.1 (Hepatic Adjudication Committee): Refer to clinical study protocol 
administrative change number 1, 22nd October 2015. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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Section 7.3 (Labelling): Refer to clinical study protocol administrative change number 1, 22nd 
October 2015. 
Section 7.7 (Return of Study Drug): Refer to clinical study protocol administrative change 
number 1, 22nd October 2015. 
Section 7.8.2 (Rescue Therapy): Refer to clinical study protocol administrative change 
number 1, 22nd October 2015. 
Section 8.1 (Statistical considerations): The section was updated to be in line with study 
timelines. 
Section 8.4.1.1 (Key secondary endpoints): This section was updated for clarification. 
Section 8.4.1.2 (Other secondary endpoints): The section was updated due to error correction. 
Section 8.5.1 (Demographic and baseline characteristics): The section was updated to precise 
key baseline characteristics. 
Section 8.5.4 (Analysis of the primary efficacy variable): This section was updated due to 
error correction. 
Section 8.5.5 (Sensitivity Analysis): This section was updated based on health authority 
interactions that took place for other studies in saxa/dapa program . 
Section 8.5.6 (Analysis of the secondary and exploratory variables): The section was updated 
for further clarification. 
Section 8.5.7 (Subgroup analysis): The section was updated to precise subgroup analysis. 
Appendix B: International Airline Transportation Association (IATA) 6.2 Guidance 
Document added. 
 
Version 1.0, 22nd May 2015 
Initial creation 
 
 


 
7 (122) 
PROTOCOL SYNOPSIS 
 
A 52-Week, Multi-Centre, Randomised, Parallel-Group, Double-Blind, 
Active-Controlled, Phase IV Study to Evaluate the Safety and Efficacy of 
Dapagliflozin or Dapagliflozin plus Saxagliptin compared with 
Sulphonylurea all given as Add-on Therapy to Metformin in Adult Patients 
with Type 2 Diabetes Who Have Inadequate Glycaemic Control on 
Metformin Monotherapy 
 
 
International Co-ordinating Investigator 
 
 
 
Study site(s) and number of subjects planned 
This will be a multicentre study conducted at approximately 200 sites mainly in Germany and 
the European Union (EU).  Approximately 930 patients will be randomised. 
Study period 
Phase of development 
Estimated date of first patient enrolled 
3Q 2015 
IV 
Estimated date of last patient completed 
1Q 2017 
IV 
 
Study design 
Study D1689C00014 is a 52-week, multi-centre, randomised, parallel-group, double-blind, 
double-dummy, active-controlled Phase IV trial to study the efficacy and safety of 
dapagliflozin added to metformin and dapagliflozin plus saxagliptin added to metformin 
compared with sulphonylurea (SU [glimepiride]) added to metformin in adult patients with 
Type 2 diabetes mellitus (T2DM) who have inadequate glycaemic control on maximum 
tolerated dose (MTD) of 1500 mg of metformin monotherapy and with individual need for 
therapy escalation. 
In this study, sites will be allowed to perform a pre-study screening assessment (at Week -3) 
prior to enrolment visit to screen for HbA1c criteria.   
 
Redacted


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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All potentially eligible patients will be enrolled, provide informed consent, undergo screening 
for all applicable inclusion/exclusion criteria, and submit laboratory samples at Enrolment 
(Visit 1, 2 weeks prior to randomisation).  Patients should be treated with a stable, MTD of 
metformin immediate-release (IR) monotherapy (1500 mg/day) for at least 8 weeks prior to 
Enrolment, and remain on the same type and dose of metformin therapy for the duration of the 
study as the background therapy for all treatment arms indicated below: 
x
Dapagliflozin (10 mg orally once daily [QD]) as an add-on to metformin 
(1500 mg/day orally) 
x
Dapagliflozin (10 mg orally QD) plus saxagliptin (5 mg orally QD) as an 
add-on to metformin (1500 mg/day orally) 
x
Glimepiride (titrated from 1 to 6 mg orally QD) as an add-on to 
metformin (1500 mg/day orally) 
Objectives 
Primary Objective: 
Outcome Measure: 
To compare the absolute change from baseline 
in HbA1c at Week 52 between dapagliflozin 
plus metformin and dapagliflozin plus 
saxagliptin plus metformin with glimepiride 
plus metformin 
Change in hemoglobin A1c (HbA1c) from baseline 
(Week 0) to Week 52 
 
Key Secondary Objectives: 
Outcome Measures: 
To compare the proportion of patients 
reporting hypoglycaemia episodes during the 
52-week treatment period between 
dapagliflozin plus metformin and dapagliflozin 
plus saxagliptin plus metformin with 
glimepiride plus metformin 
Proportion of patients reporting at least one episode 
of hypoglycaemia (symptomatic + blood glucose 
50 mg/dL [2.8 mmol/L]) during the double-blind 
treatment period 
To compare the change from baseline in total 
body weight at Week 52 between dapagliflozin 
plus metformin and dapagliflozin plus 
saxagliptin plus metformin with glimepiride 
plus metformin 
Change in total body weight from baseline (Week 0) 
to Week 52 
To compare the change from baseline in 
fasting plasma glucose (FPG) at Week 52 
between dapagliflozin plus metformin and 
dapagliflozin plus saxagliptin plus metformin 
with glimepiride plus metformin 
Change in FPG from baseline (Week 0) to Week 52 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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Key Secondary Objectives: 
Outcome Measures: 
To compare the time to rescue among the 
treatment groups during the 52-week treatment 
period between dapagliflozin plus metformin 
and dapagliflozin plus saxagliptin plus 
metformin with glimepiride plus metformin 
Time to rescue during the 52-week double-blind 
treatment period 
 
Other Secondary Objectives: 
 
To compare the effects of dapagliflozin plus 
metformin and dapagliflozin plus saxagliptin 
plus metformin with glimepiride plus 
metformin at Week 52 
x Proportion of patients achieving HbA1c of  <7% 
(and <7.5%) without confirmed hypoglycaemia at 
Week 52 
x Proportion of patients achieving HbA1c of  <7% 
(and <7.5%) at Week 52 
x Proportion of patients achieving individually 
agreed HbA1c targets at Week 52 
x Proportion of patients achieving an HbA1c 
decrease of 1% with no weight gain at Week 52  
x Time spent below HbA1C target ( <7% and   < 
7.5%) during the 52-week double-blind treatment 
period 
x Change in body mass index (BMI) from baseline 
to Week 52 
x Proportion of patients achieving weight reduction 
of 5% and weight gain of 5% from baseline to 
Week 52 
x Proportion of patients reporting at least 1 episode 
of hypoglycaemia (confirmed hypoglycaemia = 
symptomatic + blood glucose 50 mg/dL, major, 
other hypoglycaemia) during the 52-week 
double-blind treatment period 
x Change in waist circumference from baseline to 
Week 52 
x Change in systolic BP from baseline to Week 52 
 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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Safety Objective: 
Outcome Measures: 
To evaluate the safety and tolerability of 
dapagliflozin and dapagliflozin plus 
saxagliptin versus glimepiride, all as add-on 
therapy to metformin, during the 52-week 
treatment period 
x Proportion of patients withdrawing from study 
medication due to hypoglycaemia 
x Adverse events (AEs)/serious AEs (SAEs) 
x AEs of special interest (AEOSI) 
x Clinical laboratory tests  
x Electrocardiogram (ECG)  
x Vital signs (pulse and blood pressure [BP]) 
x Hypoglycaemic events 
x Physical examinations, including incidence of 
oedema 
 
Exploratory Objective: 
Outcome Measures: 
To explore the mean change from baseline in 
quality of life patient reported outcomes 
(PROs) and waist:hip ratio at Week 52 
between dapagliflozin plus metformin and 
dapagliflozin plus saxagliptin plus metformin 
with glimepiride plus metformin 
x Change from baseline to Week 52 in the Short 
Form 36-item Health Survey (SF-36), 
Hypoglycaemia Fear Survey (HFS-II), and Impact 
of Weight on Quality of Life (IWQOL)-Lite 
survey 
x Change in waist:hip ratio from baseline to 
Week 52 
 
Target subject population 
Approximately 930 patients with T2DM with inadequate glycaemic control receiving 
metformin at a MTD of 1500 mg/day for at least 8 weeks prior to enrolment, will be 
randomised to 1 of 3 treatment groups. 
Duration of treatment 
Study duration will be at least 58 weeks, including a 1-week pre-study Screening period, a 
2-week enrolment period, a 52-week double-blind treatment period, and a 3-week safety 
follow-up period. 
Investigational product, dosage and mode of administration 
Dapagliflozin and matching placebo: 
Dapagliflozin 10-mg tablets or placebo matching dapagliflozin will be administered orally 
once daily for the 52-week double-blind treatment period. 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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Saxagliptin and matching placebo: 
Saxagliptin 5-mg tablets or placebo matching saxagliptin will be administered orally once 
daily for the 52-week double-blind treatment period. 
Glimepiride: 
A combination of glimepiride 1, 2, and 4 mg tablets, and matching placebo will be 
administered orally QD for a total daily dose of 1 to 6 mg of glimepiride or matching placebo 
during the entire 52-week double-blind treatment period. 
Other Treatments 
Metformin: 
For the duration of the study, patients should continue to administer the same type and dose of 
metformin therapy they were using at study entry (at a daily dose 1500 mg).  Metformin 
should be administered and stored according to product and country specific labelling.  
Rescue therapy: 
Patients who require rescue therapy will receive insulin at the discretion of the Investigator 
and in accordance with the approved product label in the applicable country. 
Statistical methods 
Sample size estimate:  
The primary objective of this study is to examine whether, after 52 weeks of oral 
administration of double-blind treatment, the absolute change from baseline in glycosylated 
HbA1c level with dapagliflozin plus metformin and dapagliflozin plus saxagliptin added to 
metformin is non-inferior to glimepiride (sulphonylurea) plus metformin in patients with 
T2DM who have inadequate glycaemic control on MTD 1500 mg/day of metformin therapy. 
To demonstrate non-inferiority of dapagliflozin or dapagliflozin plus saxagliptin to 
glimepiride for changes from baseline to Week 52 in HbA1c within a non-inferiority margin 
of 0.30%, assuming a standard deviation 1.0%, and at a 1-sided significance level of 0.025, 
290 evaluable patients will be needed in each treatment group to provide approximately 95% 
power (given a true difference of zero between dapagliflozin or dapagliflozin plus saxagliptin 
and glimepiride).  The non inferiority margin of 0.3% as well as a common standard deviation 
of 1.0% were selected based on information from earlier, similarly designed studies. 
Assuming that 5% of patients do not have a post-baseline assessment, a total of approximately 
930 patients (310 patients per treatment arm) need to be randomised.   
Assuming that approximately 30% of screened patients will fail to meet entry criteria, a total 
of approximately 1329 patients need to be enrolled. 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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Statistical Considerations 
Continuous variables will be presented with mean, median, 25th percentile, 75th percentile, 
standard deviation, minimum, maximum, and (if appropriate) the number of nonmissing 
observations.  Categorical data will be displayed via absolute and relative frequencies for each 
category, including a category labeled as ‘missing’ when appropriate.  The ‘missing’ category 
will not contribute to the denominators of relative frequencies. 
Definitions of analysis sets 
Classification into Randomized, Full Analysis (FA), Per Protocol (PP), and Safety analysis 
sets will be conducted prior to the database lock.  
The primary analysis of the primary efficacy endpoint will be performed on the FA set. A 
supportive analysis will be carried out with the PP set.  Analyses of all secondary efficacy 
endpoints will be performed using the FA set.  All safety analyses will be based on the Safety 
analysis set. 
The randomised set consists of all randomised patients. 
The FA set will be defined as all randomised patients  who receive at least one dose of study 
medication and who have a baseline and a post-baseline efficacy assessment value.  Patients 
will be analysed according to the treatment assigned. 
The PP analysis set will be defined as all FA patients without an important protocol deviation 
that might affect the primary analyses.  The criteria for important protocol deviations will be 
defined in the Statistical Analysis Plan (SAP).  Patients will be analysed according to the 
treatment assigned.  Determinations of specific deviations will made prior to unblinding of the 
data. 
The Safety analysis set will be defined as all randomised patients who received at least 1 dose 
of study medication.  Patients will be analysed according to the actual treatment received. 
Analysis of the primary variable 
The primary objective of this study is to show non-inferiority of dapagliflozin added to 
metformin and dapagliflozin plus saxagliptin added to metformin versus glimepiride added to 
metformin in terms of the primary efficacy variable change in HbA1c from baseline to 
Week 52. 
The following null hypothesis (H0) will be tested against the alternative hypothesis (HA) 
(Į=0.025, 1-sided): 
H0: 
μc - μt  -0.30%, 
HA: 
μc - μt > -0.30%, 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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where μt denotes the mean absolute change in HbA1c from baseline to Week 52 in the group 
of patients treated with dapagliflozin added to metformin or dapagliflozin plus saxagliptin 
added to metformin (test medication) and μc denotes the mean absolute change in HbA1c from 
baseline to Week 52 in the group of patients treated with glimepiride added to metformin 
(control). 
The absolute change from baseline to Week 52 in HbA1c will be analysed using a restricted 
maximum likelihood-based, Mixed-Model Repeated Measures (MMRM) model with terms 
for treatment group, baseline HbA1c, time (at relevant visits), and interactions baseline 
HbA1c-by-time and treatment group-by-time.  The model will be used to derive a 
least-squares estimate of the mean treatment difference with corresponding 2-sided 95% 
confidence interval (CI).  The primary assessments of efficacy will be a comparisons of each 
of the 2 test groups the dapagliflozin plus saxagliptin added to metformin versus the control 
group and the dapagliflozin added to metformin versus the control group using a 95% CI.  In 
particular, if the observed lower limit from a 2-sided 95% (or 1-sided 97.5%) CI for the 
difference in adjusted means is greater than -0.30%, then the test group will be considered to 
be non-inferior to the control group.  Note that multiplicity will be controlled using a 
sequential testing scheme.  The dapagliflozin plus saxagliptin added to metformin group 
versus the control group will be tested first, followed by the dapagliflozin plus metformin 
group versus the control group. A superiority test of the dapagliflozin plus saxagliptin added 
to metformin group versus the control group will also be conducted. 
Analysis of the key secondary variables 
Key secondary endpoints will be analysed using the FA set and no imputation of missing 
values will be performed.  The experiment-wise type I error will be controlled to a maximum 
of 5%.  A hierarchical closed testing procedure will be employed. 
Key secondary endpoints: 
x
Proportion of patients reporting at least 1 episode of confirmed 
hypoglycaemia  during the 52-week double-blind treatment period 
x
Change from baseline in total body weight at Week 52 
x
Change from baseline in FPG at Week 52 
x
Time to rescue during the 52-week double-blind treatment period. 
The proportion of patients experiencing at least 1 episode of confirmed hypoglycaemia will be 
analysed using logistic regression. 
The analysis of the changes from baseline to Week 52 for total body weight and FPG will be 
performed using the same MMRM  model as described for the primary efficacy endpoint.   


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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Time to rescue will be analysed using a Cox proportional hazards model.  Estimates of the 
hazard ratio and 95% CIs will be provided.  Kaplan-Meier estimates will be calculated and 
plotted by treatment group.   
Safety analyses 
The assessment of safety will be based on the analyses of AEs, vital signs, physical 
examinations, ECGs, hypoglycaemia, and clinical laboratory evaluations.  All safety analyses 
will be performed on the Safety set. 
Interim Analysis 
No interim analysis on the efficacy or safety parameters is planned for this study. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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TABLE OF CONTENTS 
PAGE
TITLE PAGE ............................................................................................................................ 1
VERSION HISTORY .............................................................................................................. 2
PROTOCOL SYNOPSIS ......................................................................................................... 7
TABLE OF CONTENTS ....................................................................................................... 15
1.
INTRODUCTION ................................................................................................. 23
1.1
Background and rationale for conducting this study ............................................. 23
1.2
Rationale for study design, doses, and control groups ........................................... 24
1.3
Benefit/risk and ethical assessment ....................................................................... 28
1.3.1
Dapagliflozin .......................................................................................................... 29
1.3.2
Saxagliptin ............................................................................................................. 29
1.3.3
Glimepiride ............................................................................................................ 29
1.3.4
Ketoacidosis ........................................................................................................... 30
1.3.5
Protection against risks .......................................................................................... 30
1.3.6
Potential benefits to patients .................................................................................. 30
1.3.7
Informed consent and alternatives to participation ................................................ 31
1.4
Study Design .......................................................................................................... 31
2.
STUDY OBJECTIVES .......................................................................................... 33
2.1
Primary objective ................................................................................................... 33
2.2
Secondary objectives ............................................................................................. 33
2.3
Safety objectives .................................................................................................... 34
2.4
Exploratory objectives ........................................................................................... 35
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 35
3.1
Inclusion criteria .................................................................................................... 35
3.2
Exclusion criteria ................................................................................................... 36
3.3
Subject enrolment and randomization ................................................................... 40
3.4
Procedures for handling incorrectly enrolled or randomized subjects ................... 40
3.5
Methods for assigning treatment groups ................................................................ 40
3.6
Methods for ensuring blinding ............................................................................... 41
3.7
Methods for unblinding .......................................................................................... 41
3.8
Restrictions ............................................................................................................ 42


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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3.9
Discontinuation of investigational product ............................................................ 43
3.9.1
Procedures for discontinuation of a subject from investigational product ............. 44
3.9.2
Down-titration of blinded study drug and/or background 
antihyperglycaemic agent during the study ........................................................... 45
3.9.3
Procedures for discontinuation of a subject from investigational product ............. 45
3.10
Criteria for withdrawal ........................................................................................... 46
3.10.1
Screen failures ........................................................................................................ 47
3.10.2
Withdrawal of the informed consent ...................................................................... 47
3.11
Discontinuation of the study .................................................................................. 47
4.
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 47
4.1
Screening visit (Visit S, Week -3) ......................................................................... 52
4.2
Enrolment Period ................................................................................................... 52
4.2.1
Enrolment Visit (Visit 1, Week -2) ........................................................................ 53
4.3
Treatment Period .................................................................................................... 55
4.3.1
Randomisation and Baseline Visit (Visit 2, Week 0) ............................................ 55
4.3.2
Treatment Period visits (Visits 3 to 11, Weeks 2, 4, 6, 8, 10, 12, 24, 36, 
and 48) ................................................................................................................... 57
4.3.3
Dose Titration ........................................................................................................ 58
4.3.4
Rescue Therapy ...................................................................................................... 59
4.3.5
End of Treatment Period Visit/Early Termination or Rescue (Visit 12, 
Week 52) ................................................................................................................ 60
4.4
Follow-up visit (Visit 13, Week 55) ...................................................................... 62
5.
STUDY ASSESSMENTS ..................................................................................... 63
5.1
Safety assessments ................................................................................................. 63
5.1.1
HbA1c .................................................................................................................... 63
5.1.2
Fasting plasma glucose .......................................................................................... 63
5.1.3
Body weight ........................................................................................................... 64
5.1.4
Body Height ........................................................................................................... 64
5.1.5
Waist and hip circumference ................................................................................. 64
5.2
Safety assessments ................................................................................................. 64
5.2.1
Laboratory safety assessments ............................................................................... 65
5.2.1.1
Volume of blood .................................................................................................... 65
5.2.1.2
Haematology .......................................................................................................... 65
5.2.1.3
Clinical Chemistry ................................................................................................. 65
5.2.1.4
Urinalysis ............................................................................................................... 66
5.2.1.5
Other clinical laboratory evaluations ..................................................................... 66
5.2.1.6
Pregnancy Testing .................................................................................................. 67
5.2.2
Physical examination ............................................................................................. 67
5.2.3
ECG ........................................................................................................................ 67
5.2.4
Vital signs .............................................................................................................. 67
5.2.5
Other safety assessments ........................................................................................ 68


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Study Code D1689C00014 
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5.2.5.1
Cardiovascular events ............................................................................................ 68
5.2.5.2
Liver function test abnormalities ........................................................................... 68
5.3
Other assessments .................................................................................................. 68
5.3.1
Hypoglycaemia ...................................................................................................... 68
5.3.2
Patient reported outcomes ...................................................................................... 69
5.3.2.1
SF-36 Health Survey .............................................................................................. 70
5.3.2.2
Hypoglycaemia Fear Survey - Worry Subscale ..................................................... 70
5.3.2.3
IWQOL-Lite .......................................................................................................... 70
5.4
Pharmacokinetics (not applicable) ......................................................................... 71
5.5
Pharmacodynamics (not applicable) ...................................................................... 71
5.6
Pharmacogenetics (not applicable) ........................................................................ 71
5.7
Biomarker analysis (not applicable) ...................................................................... 71
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 71
6.1
Definition of adverse events .................................................................................. 71
6.2
Definitions of serious adverse event ...................................................................... 71
6.3
Recording of adverse events .................................................................................. 72
6.3.1
Time period for collection of adverse events ......................................................... 72
6.3.2
Follow-up of unresolved adverse events ................................................................ 72
6.3.3
Variables ................................................................................................................ 72
6.3.3.1
Intensity rating scale .............................................................................................. 73
6.3.4
Causality collection ................................................................................................ 73
6.3.5
Adverse events based on signs and symptoms ...................................................... 74
6.3.6
Adverse events based on examinations and tests ................................................... 74
6.3.7
Hy’s Law ................................................................................................................ 75
6.3.8
Hypoglycaemia ...................................................................................................... 75
6.4
Reporting of serious adverse events....................................................................... 75
6.4.1
Adverse Events of Special Interest ........................................................................ 76
6.5
Overdose ................................................................................................................ 76
6.6
Pregnancy ............................................................................................................... 77
6.6.1
Maternal exposure .................................................................................................. 77
6.6.2
Paternal exposure ................................................................................................... 77
6.7
Management of IP related toxicities ...................................................................... 78
6.8
Study governance and oversight ............................................................................ 78
6.8.1
Hepatic Adjudication Committee .......................................................................... 78
6.8.2
Cardiovascular Adjudication Committee ............................................................... 78
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 78
7.1
Identity of investigational product(s) ..................................................................... 78
7.2
Dose and treatment regimens ................................................................................. 79


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Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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7.3
Labelling ................................................................................................................ 81
7.4
Storage ................................................................................................................... 81
7.5
Compliance ............................................................................................................ 82
7.6
Accountability ........................................................................................................ 82
7.7
Return of Study Drug ............................................................................................. 83
7.8
Concomitant and other treatments ......................................................................... 83
7.8.1
Metformin .............................................................................................................. 84
7.8.2
Rescue therapy ....................................................................................................... 84
7.8.3
Other concomitant treatment .................................................................................. 85
8.
STATISTICAL ANALYSES BY ASTRAZENECA ............................................ 85
8.1
Statistical considerations ........................................................................................ 85
8.2
Sample size estimate .............................................................................................. 85
8.3
Definitions of analysis sets .................................................................................... 86
8.4
Outcome measures for analyses ............................................................................. 86
8.4.1.1
Key secondary endpoints ....................................................................................... 86
8.4.1.2
Other secondary endpoints ..................................................................................... 87
8.4.2
Exploratory endpoints ............................................................................................ 87
8.5
Methods for statistical analyses ............................................................................. 87
8.5.1
Demographic and baseline characteristics ............................................................. 88
8.5.2
Efficacy analyses ................................................................................................... 88
8.5.3
Control of type 1 error ........................................................................................... 88
8.5.4
Analysis of the primary efficacy variable .............................................................. 89
8.5.5
Sensitivity analysis (if applicable) ......................................................................... 90
8.5.6
Analysis of the secondary and exploratory variables............................................. 90
8.5.7
Subgroup analysis .................................................................................................. 91
8.5.8
Safety analyses ....................................................................................................... 91
8.6
Interim analysis ...................................................................................................... 92
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA .......................... 92
9.1
Training of study site personnel ............................................................................. 92
9.2
Monitoring of the study ......................................................................................... 92
9.2.1
Source data ............................................................................................................. 93
9.2.2
Study agreements ................................................................................................... 93
9.2.3
Archiving of study documents ............................................................................... 93
9.3
Study timetable and end of study ........................................................................... 93
9.4
Data management by AstraZeneca or delegate ...................................................... 93
10.
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 95
10.1
Ethical conduct of the study ................................................................................... 95


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Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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10.2
Subject data protection ........................................................................................... 95
10.3
Ethics and regulatory review ................................................................................. 95
10.4
Informed consent ................................................................................................... 96
10.4.1
Screening Informed Consent .................................................................................. 97
10.5
Changes to the protocol and informed consent form ............................................. 97
10.6
Audits and inspections ........................................................................................... 97
11.
LIST OF REFERENCES ....................................................................................... 98
 
LIST OF TABLES 
Table 1  
Study Plan ................................................................................................. 48
Table 2 
Criteria for Initiation of Rescue Therapy During the Randomised 
Treatment Period ...................................................................................... 59
Table 3 
Laboratory Variables ................................................................................ 66 
Table 4 
Investigational Products for StudyD1689C00014 .................................... 76
Table 5  
Schedule of Study Medication Dispensation ............................................ 80 
Table 6 
Titrated Dose Levels and Contents of Blinded Glimepiride or 
Placebo Kit ............................................................................................... 79
 
LIST OF FIGURES 
Figure 1 
Study Design ............................................................................................ 32
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information ................................................................ 101
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ............................................................................... 103
Appendix C 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law .......................................................................... 104
Appendix D 
Algorithm on Management of Sustained Elevated Liver Safety 
Abnormalities ......................................................................................... 109
Appendix E 
Patient Reported Outcomes .................................................................... 114


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Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or special 
term
Explanation 
ADA 
American Diabetes Association 
AE 
adverse event 
AEOSI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance  
AST 
aspartate aminotransferase 
AZDD 
AstraZeneca Drug Dictionary 
ȕ-hCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
BP 
blood pressure 
CMH 
Cochran-Mantel-Haenszel 
CrCl  
creatinine clearance  
CRO 
contract research organization 
CSA 
Clinical Study Agreement 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CSRAF 
clinical supplies return authorisation form  
CV 
cardiovascular 
DDFM 
denominator degrees of freedom 
DILI 
drug-induced liver injury 
DM 
Data Management 
DPP-4 
Dipeptidyl peptidase-4 
EC 
Ethics Committee (synonymous to [IRB] and Independent Ethics 
Committee [IEC]) 
E-code 
enrolment code 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 


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Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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Abbreviation or special 
term
Explanation 
eDC 
electronic data capture  
eGFR 
estimated glomerular filtration rate 
EU 
European Union 
FA 
full analysis 
FPG 
fasting plasma glucose 
GAD 
glutamate decarboxylase 
GCP 
Good Clinical Practice 
GLP-1 
Glucagon-like peptide-1 
GMP 
good manufacturing practice 
GPV&E 
Global Pharmacovigilance & Epidemiology 
HA 
alternative hypothesis  
Hb 
haemoglobin 
HbA1c 
haemoglobin a1c 
HDL 
high-density lipoprotein 
HDPE 
high-density polyethylene 
HFS-II 
Hypoglycaemia Fear Survey 
HL 
Hy’s Law 
H0 
null hypothesis  
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IP 
investigational product  
IR 
immediate-release 
IRB 
Institutional Review Board 
IWQOL 
Impact of Weight on Quality of Life 
IWRS 
Interactive Web Response System 
LDL 
low-density lipoprotein 
LOCF 
Last-Observation-Carried-Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MoA 
mechanisms of action 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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Abbreviation or special 
term
Explanation 
MODY 
 maturity onset diabetes of the young 
MTD 
maximum tolerated dose 
OAD 
oral antidiabetic 
PHL 
Potential Hy’s Law 
PP 
Per protocol 
PPG 
postprandial glucose 
PRO 
patient reported outcome 
QD 
once daily 
SAE 
serious adverse event  
SAP 
Statistical Analysis Plan 
SCr 
serum creatinine 
SCSM 
Supply Chain Study Management 
SDV 
study data verification 
SF-36 
Short Form 36-item Health Survey 
SGLT2 
sodium glucose cotransporter 2  
SU 
sulfonylurea 
T2DM 
Type 2 diabetes mellitus 
T4 
thyroxine 
TB 
total bilirubin 
TSH 
thyroid stimulating hormone 
TZD 
thiazolidinedione 
UKPDS 
United Kingdom Prospective Diabetes Study Group 
ULN 
upper limit of normal 
US 
United States 
UTI 
urinary tract infection 
WBDC 
Web Based Data Capture 
WOCBP 
women of childbearing potential 


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Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study 
Type 2 diabetes mellitus (T2DM) is a chronic disease characterised by hyperglycaemia and an 
increased risk of microvascular and macrovascular complications.  Given the progressive 
nature of T2DM, it is challenging to achieve and maintain tight glycaemic control and 
approximately 50% of T2DM patients fail to achieve the American Diabetes Association 
(ADA) goal for glycaemic control of haemoglobin A1c (HbA1c) of <7.0%  
(Hoerger et al 2008). Typically the treatment paradigm consists of a step-wise addition of 
different classes of antihyperglycaemic drugs, as most patients eventually require 2 or more 
agents to achieve or maintain glycaemic targets.  Metformin, a biguanide, is the recommended 
drug of choice for initiating oral antidiabetic (OAD) therapy, while other classes of 
antidiabetic agents are typically added sequentially as second and third line agents.  An ideal 
add-on to metformin would provide strong HbA1c reduction through complementary 
mechanisms of action (MoA), with weight loss, and no hypoglycaemia. 
Current sequential add-on OADs include sulfonylureas (SUs), such as glimepiride.  
Glimepiride is typically used in patients with T2DM who cannot control glucose levels with 
diet and exercise alone or added to other OAD drugs.  Glimepiride stimulates the pancreatic 
beta cells to secrete insulin, which subsequently helps lower blood glucose.  Some of the key 
limitations to glimepiride are related to its effect in increasing endogenous insulin levels, 
which is associated with weight gain and increased risk of hypoglycaemia. 
Other classes of OADs include inhibitors of the human renal sodium glucose co-transporter 2 
(SGLT2), the major transporter responsible for glucose reabsorption in the kidney.  
Dapagliflozin is a potent, highly selective, and orally active SGLT2 inhibitor and its MoA 
results in the direct and insulin-independent elimination of glucose by the kidney.  
Dapagliflozin is approved in the United States (US) and the European Union (EU [trade 
names:  Farxiga™ and Forxiga™, respectively]) as an adjunct to diet and exercise to improve 
glycaemic control in adults with T2DM.  Clinical studies with dapagliflozin demonstrated the 
safety and efficacy of dapagliflozin in a wide range of patients with T2DM.  Treatment with 
dapagliflozin led to significant and clinically relevant reductions in HbA1c, fasting plasma 
glucose (FPG), and postprandial glucose (PPG) levels, and was associated with weight loss.   
Inhibitors of dipeptidyl peptidase -4 (DPP-4), the enzyme  responsible for the inactivation  of 
glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are 
another class of OADs.  Saxagliptin is a highly potent, selective, reversible, and competitive 
DPP-4 inhibitor.  By inhibiting DPP-4, saxagliptin potentiates active endogenous GLP-1 
concentrations, augmenting the physiological mechanism of insulin secretion and suppressing 
glucagon release, thereby reducing PPG and FPG levels in patients with T2DM.  Saxagliptin 
is approved by the EU for the treatment of T2DM  and in Phase III trials, has effectively 
reduced HbA1c in patients with inadequately controlled T2DM on a stable dose of metformin, 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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SUs, or thiazolidinedione, and has favorable safety and tolerability profiles  
(Del Prato et al 2011, Gomis et al 2011, Owens et al 2011, Taskinen et al 2011). 
Dapagliflozin and saxagliptin have demonstrated, both individually and added to metformin, a 
favorable safety and tolerability profile.  These OADs have demonstrated a low propensity for 
hypoglycaemia, therefore addressing a potential key concern when adding 2 glucose lowering 
agents simultaneously.  Both drugs have either demonstrated weight neutrality (saxagliptin) or 
moderate weight reduction (dapagliflozin).  Dapagliflozin has also demonstrated persistent 
effects on HbA1c over 4 years of therapy. 
Given their complementary mechanisms of action, dapagliflozin, coadministered with 
saxagliptin, has been studied to support the development of a fixed-dose combination.  A 
Phase III study (CV181169) demonstrated that early combination treatment with dapagliflozin 
and saxagliptin, added together with metformin as triple therapy, elicited superior reduction in 
HbA1c as compared to the addition of each of these individual agents to metformin alone in 
patients with inadequately controlled T2DM.  Despite larger decreases in HbA1c, this was not 
associated with an increase in hypoglycaemic event rates, which were overall low and similar 
across the different therapies tested.  While saxagliptin plus metformin has a neutral effect on 
weight, combination therapy including dapagliflozin plus metformin or dapagliflozin 
combined with saxagliptin plus metformin therapy resulted in a significant reduction of body 
weight (Rosenstock J et al).   
The aim of this present study is to test the hypothesis that dapagliflozin or dapagliflozin plus 
saxagliptin is non-inferior to glimepiride in patients with T2DM and inadequate glycaemic 
control on maximum tolerated dose (MTD) of metformin background therapy. 
1.2
Rationale for study design, doses, and control groups 
This is a Phase IV study performed as part of the clinical development program for 
saxagliptin/dapagliflozin fixed-dose combination  to improve glycaemic control as an adjunct 
to diet, exercise, and metformin treatment.  
Many medications are approved for the treatment of T2DM; however, the challenge of 
achieving and maintaining treatment goals within the current sequential therapy approach is 
linked to shortcomings of older classes of drugs.  Metformin decreases hepatic glucose output 
and subsequently, decreases fasting glucose.  Metformin is the most common initial oral 
antidiabetic therapy of choice for patients with T2DM and is recommended as the initial 
pharmacological therapy in both the US and EU because of its glycaemic efficacy, weight 
neutrality, low risk of hypoglycaemia, and beneficial cardiovascular (CV) profile. 
Current sequential add-on second and third line OADs include SUs and thiazolidinediones 
(TZDs).  However, these drugs are associated with increased risk for weight gain and 
hypoglycaemia.  Since many patients with T2DM do not reach glycaemic goals with dual 
agent therapy, many will require an additional agent with an alternate MoA.  The traditional 
third line therapy would be the initiation of insulin treatment.   


Clinical Study Protocol 
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Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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However, further weight gain, fluid retention, and the risk of hypoglycaemia are common 
problems with insulin therapy and present a major concern for many patients.  Furthermore, 
excessive weight gain may negatively interact with anti-hyperglycaemic treatment, by 
increasing CV risk, and reducing the ability to exercise. 
Treatment with saxagliptin and dapagliflozin, both individually and added to metformin, have 
demonstrated a favorable safety and tolerability profile.  These drugs had a low propensity for 
hypoglycaemia, therefore addressing a potential key concern when adding 2 glucose lowering 
agents simultaneously.  These drugs have demonstrated weight neutrality (saxagliptin) or 
moderate weight reduction (dapagliflozin).  Dapagliflozin has also been shown to cause a 
persistent reduction in HbA1c and weight after 4 years of therapy.   
A second-line oral dual add-on therapy with saxagliptin coadministered with dapagliflozin 
could be a new option, that includes drugs with complementary mechanisms of action, 
opposing the effects on plasma glucagon, and endogenous glucose production, increasing 
renal excretion of glucose, a low risk of hypoglycaemia, and moderate weight loss, providing 
a more effective and patient-friendly approach to the treatment of the T2DM. 
Study design, dose selection, and control groups 
The current study is designed to demonstrate the efficacy and safety of dapagliflozin 10 mg 
and dapagliflozin 10 mg plus saxagliptin 5 mg versus glimepiride in patients with inadequate 
glycaemic control on a MTD 1500 mg/day of metformin monotherapy. 
A 52-week randomised treatment period will allow for adequate information on efficacy, 
safety, and durability of a new OAD therapy. 
Control group 
This is a double-blind, active-controlled study.  The comparison of dapagliflozin alone (plus 
metformin) or the combination of dapagliflozin plus saxagliptin (plus metformin) with 
glimepiride is consistent with regulatory guidance regarding the investigation of combination 
products (CHMP 2009).  Glimepiride will be used as an active comparator because SUs are 
one of the most common classes of OADs started in patients inadequately controlled on 
metformin therapy alone (Riddle 2005).   
Background therapy 
Metformin is a biguanide; its major effect is to decrease hepatic glucose output and lower 
fasting glucose.  It is recommended as the initial pharmacological therapy in both the US and 
the EU because of its glycaemic efficacy, weight neutrality, low risk of hypoglycaemia, good 
tolerability, and relatively low cost (Inzucchi et al 2012). 
 
 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
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Dapagliflozin 
Dapagliflozin (Forxiga) is approved in the EU as an adjunct to diet and exercise to improve 
glycaemic control in patients with T2DM for whom metformin use is considered inappropriate 
due to intolerance, and in combination with other glucose-lowering medicinal products when 
these, in combination with diet and exercise do not provide adequate glycaemic control.  The 
10-mg dose was chosen for this study because it has been extensively studied in Phase III 
trials, has demonstrated consistent clinically meaningful reductions in HbA1c, and is the 
approved dose for the drug label applicable for this patient population.  Treatment with 
dapagliflozin, with its unique mechanism of action, 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.  Furthermore, dapagliflozin (10 mg) 
reduced total body weight in patients with T2DM inadequately controlled with metformin 
(Bolinder et al 2012).  Dapagliflozin also has a mild diuretic effect, which in combination with 
weight loss, has the potential to reduce blood pressure. 
Saxagliptin 
Saxagliptin (Onglyza™) is approved by the EU as an adjunct to diet and exercise to improve 
glycaemic control in adults with T2DM.  The results from the 8 Phase II and III clinical 
studies with saxagliptin support the oral dose of 5 mg once daily (QD) in a wide range of 
patients 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. 
Glimepiride 
Glimepiride is the antidiabetic drug most commonly used as a second line of therapy for 
patients who do not respond to metformin.  The choice of dose (starting with 1 mg/day and 
titrating by 1 mg every 2 weeks to a maximum dose of 6 mg/day) is per the approved product 
label. 
Choice of outcome variables 
The primary endpoint is change from baseline in HbA1c at Week 52.  HbA1c is the clinical 
and regulatory parameter used to estimate glycaemic efficacy of an OAD therapy in patients 
with T2DM.  Because of its novel, complementary mechanism of action, dapagliflozin may 
have additive or synergistic HbA1c-lowering effects when given in combination with other 
anti-hyperglycaemic agents.  Additionally, as beneficial effects on FPG and weight have been 
observed in other dapagliflozin studies, these variables have been chosen as key secondary 
objectives. 
 
 


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The rationale for selection of the secondary variables is provided below: 
x
Weight and body mass index (BMI):  More than 85% of patients with 
T2DM are overweight or obese (CDC 2004).  Weight loss is a 
fundamental goal for the majority of patients with T2DM as it has been 
shown to improve comorbid conditions such as hypertension, 
dyslipidemia, heart disease, osteoarthritis, and sleep apnea  
(NHLBI 1998). 
x
FPG is a well established measure of short-term glycaemic efficacy 
(CHMP 2012). 
x
Time until the start of rescue is an indirect measure of glucose efficacy 
and shows the durability of efficacy. 
x
Proportion achieving HbA1c <7.0%:  The target HbA1c for most patients 
with T2DM is <7.0% according to international diabetes treatment 
guidelines (Inzucchi et al 2012). 
x
Proportion achieving weight loss 5.0%: A weight loss of 5.0% in 
patients with T2DM has been associated with decreased insulin 
resistance, improved measures of glycaemia and lipemia, and reduced BP 
(Klein et al 2004). 
x
Blood pressure:  The European Association for the Study of Diabetes 
guidelines recommend a target of systolic BP <140 mmHg in patients 
with diabetes (Ryden L et al 2013). Lowering blood pressure in patients 
with diabetes has been shown to reduce the risk of coronary heart disease 
events, stroke, retinopathy and nephropathy (James et al 2014). 
x
Waist circumference:  The presence of excess fat in the abdomen out of 
proportion to total body fat is an independent predictor of risk factors and 
morbidity.  Waist circumference is positively correlated with abdominal 
fat content (NHLBI 1998). 
Choice of study population 
Subjects
Patients with T2DM with inadequate glycaemic control while being treated with MTD, at 
least 1500 mg/day, of metformin therapy. 
 
 


Clinical Study Protocol 
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Study Code D1689C00014 
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Age 
The prevalence of T2DM increases with age; it is therefore important to assess antidiabetic 
agents in adult patients.  In this study, the upper age limit (ie, 75 years) will be based on the 
dapagliflozin labelling guidelines. 
HbA1c 
The HbA1c inclusion criterion at randomisation (ie, 7.5% to 10.5%) was selected to include 
patients with poor glycaemic control, a population that would potentially achieve the greatest 
benefit from simultaneous addition of 2 antidiabetic agents. 
Pregnancy or breastfeeding 
Neither dapagliflozin nor saxagliptin have been tested in pregnant women and the risks to 
embryo, fetus, and infant are unknown.  For this reason, women who are pregnant or 
breastfeeding are excluded and women of childbearing age are instructed to take precautions 
to avoid becoming pregnant during the study. 
Other 
The purpose of the majority of the inclusion and exclusion criteria is to limit confounding 
factors that may complicate the interpretation of the study results (eg, corticosteroid-induced 
T2DM or haemoglobinopathies that would interfere with the HbA1c analyses) or to exclude 
patients whose safety could be compromised by participation in the study.  
C-peptide will be defined to ensure the patients with T2DM have some pancreatic reserve (as 
opposed to patients with Type 1 diabetics or latent auto-immune diabetes in adults who have 
had a significant loss of their pancreatic mass) and can potentially respond to non-insulin 
therapy. 
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. 
The study will provide efficacy and safety information for dapagliflozin plus metformin and 
dapagliflozin plus saxagliptin plus metformin compared with glimpiride, in patients with 
T2DM who are on metformin therapy.  Patients in the dapagliflozin plus placebo group will 
receive saxagliptin-matching placebo with metformin; and patients in the placebo group will 
receive both placebos with metformin.  All patients will be monitored throughout the study to 
ensure adequate glycaemic control. 
 


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1.3.1
Dapagliflozin 
Dapagliflozin is approved in approximately 52 countries, including the US and countries 
within the EU.  Prior to approval, dapagliflozin was evaluated in 5 core Phase IIb studies, 
16 core Phase III studies, and 3 regional Phase III studies.  These studies established that 
dapagliflozin is effective in reducing HbA1c in a broad range of patients, regardless of disease 
progression/duration or concomitant use of antidiabetic therapies.  Dapagliflozin consistently 
demonstrated statistically and clinically significant mean reductions in HbA1c versus placebo 
among the 3 doses typically studied (2.5, 5, and 10 mg).  Overall, the dose of 10 mg provided 
better efficacy than the 2 lower doses.  Effects on secondary glycaemic efficacy parameters, 
including FPG and PPG, support the primary HbA1c efficacy findings.  Dapagliflozin also 
resulted in a modest reduction in total body weight relative to placebo or comparator, largely 
attributable to a decrease in body fat mass, as well as reductions in systolic BP. Data from an 
active-controlled study for up to 4 years indicates that the beneficial effects on glycaemic and 
non-glycaemic parameters were maintained. 
Overall, dapagliflozin has been well tolerated in clinical studies.  For detailed information 
surrounding the risks associated with saxagliptin and dapagliflozin, please refer to the 
respective IBs. 
Considering the comprehensive previous clinical experience with saxagliptin and 
dapagliflozin, the study’s design features (including the inclusion, exclusion, and 
discontinuation criteria), and the planned safety procedures, participation in this study presents 
a minimal and thus acceptable risk to the individual patients who will be included.  
1.3.2
Saxagliptin 
Prior to approval, saxagliptin was evaluated in 6 pivotal Phase III, randomised, double-blind 
controlled trials.  Compared to the control, treatment with saxagliptin at doses of 2.5 to 10 mg 
resulted in clinically relevant and statistically significant improvements in HbA1c, FPG, and 
2-hour PPG.  Reductions in HbA1c were seen across subgroups, categorised by age, gender, 
race, and baseline BMI.  
Overall, the clinical safety and efficacy data accumulated to date demonstrates a positive 
benefit/risk profile for saxagliptin.  The majority of AEs reported in clinical studies have been 
of mild intensity and few have required treatment discontinuation. When added to standard of 
care in patients with T2DM at high cardiovascular (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). 
1.3.3
Glimepiride 
Glimepiride will be given according to its approved label.  Data from clinical trials indicate 
that the overall incidence of AEs associated with glimepiride is generally lower compared 
with other SUs, including a lower risk of hypoglycaemia and weight gain (Rosskamp R et al).  
Increased incidence of hypoglycaemia events has been previously noted with glimepiride 
therapy.   


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1.3.4
Ketoacidosis 
There have been postmarketing reports of ketoacidosis, including diabetic ketoacidosis, in 
patients with type 1 and type 2 diabetes mellitus taking dapagliflozin and other SGLT2 
inhibitors, although a causal relationship has not been established. Dapagliflozin is not 
indicated for the treatment of patients with type 1 diabetes mellitus.     
Patients treated with dapagliflozin who present with signs and symptoms consistent with 
ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, 
should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L (250 
mg/dL). If ketoacidosis is suspected, discontinuation or temporary interruption of 
dapagliflozin should be considered and the patient should be promptly evaluated. 
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from 
pancreatic disorders (eg, type 1 diabetes, history of pancreatitis, or pancreatic surgery), insulin 
dose reduction, reduced caloric intake, or increased insulin requirements due to infections, 
illness or surgery and alcohol abuse. Dapagliflozin should be used with caution in these 
patients. 
1.3.5
 Protection against risks 
This study has been designed with appropriate measures in place to monitor and minimise any 
of the potential health risks to participating patients.  To ensure the safety of all patients 
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, adverse event (AE) reports, preclinical data, 
epidemiological studies, and literature reports, to identify and characterise unrecognised safety 
risks or changes in those which are currently expected Adverse Drug Reactions.   
Any information that may affect the benefit-risk profile of dapagliflozin or saxagliptin will be 
immediately communicated to relevant Health Authorities and appropriate actions will be 
taken regarding the clinical program as needed.  Thus real-time, active safety surveillance will 
be conducted during the entire duration of this study.  In addition, all dapagliflozin and 
saxagliptin studies are subject to a carefully designed patient risk management plan that 
includes the temporary and if necessary permanent discontinuation of investigational product 
(IP) in individual patients in whom a potential health risk or a laboratory abnormality of 
clinical concern has been identified.  
1.3.6
Potential benefits to patients 
Based on prior clinical trials experience and postmarketing information, both saxagliptin and 
dapagliflozin have a favorable benefit-risk ratio as monotherapy and add-on combination 
therapy.  Integrated analyses of the safety data from 3 Phase III clinical studies demonstrated 
that the combined use of saxagliptin and dapagliflozin administered as either a dual or a 
sequential add-on to metformin was well tolerated in patients who were inadequately 
controlled on metformin alone.  The combined use of saxagliptin and dapagliflozin was 


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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 prior Phase III clinical studies, 
treatment with saxagliptin and dapagliflozin showed clinically relevant decreases in HbA1c, 
leading to a large proportion of patients achieving the therapeutic goal of HbA1c <7%, and 
modest reduction in body weight in patients with T2DM.  In the present study, the doses of 
saxagliptin (5 mg) and dapagliflozin (10 mg) are the most widely used clinical doses.  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.  Patients 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.  Patients will also receive 
counselling on dietary and life-style modifications.  
1.3.7
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 patient will not be 
disadvantaged in any way. 
1.4
Study Design
Figure 1 presents the overall design of the study. 
Study D1689C00014 is a 52-week, multi-centre, randomised, parallel-group, double-blind, 
double-dummy, active-controlled Phase IV study to study the efficacy and safety of 
dapagliflozin added to metformin and dapagliflozin plus saxagliptin added to metformin 
compared with sulphonylurea (glimepiride) added to metformin in adult patients with T2DM 
who have inadequate glycaemic control (HbA1c 7.5% and 10.5%) on maximum tolerated 
dose of 1500 mg of metformin monotherapy and with individual need for therapy escalation. 
In this study, sites will be allowed to perform a pre-study screening assessment (at Week -3) 
prior to enrolment visit to screen for HbA1c criteria.  All potentially eligible patients will be 
enrolled, provide informed consent, undergo screening for all applicable inclusion/exclusion 
criteria, and submit laboratory samples at Enrolment (Visit 1, 2 weeks prior to randomisation).  
Patients should be treated with a stable, maximum tolerated dose of metformin monotherapy 
(1500 mg/day) for at least 8 weeks prior to Enrolment, and remain on the same type and dose 
of metformin therapy for the duration of the study as the background therapy for all treatment 
arms as indicated below: 
x
Dapagliflozin + saxagliptin placebo + glimepiride placebo + metformin 
x
Dapagliflozin + saxagliptin + glimepiride placebo+ metformin 
x
Glimepiride + dapagliflozin placebo + saxagliptin placebo + metformin 


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Figure 1 
Study Design  
 
*Note: Glimepiride treatment will begin at 1 mg/day then be titrated (upwards or downwards) in 1 mg 
increments at subsequent visits, if needed. In the event that a subject develop recurrent hypoglycaemic episodes 
with the 1 mg dose, down-titration to 0 mg is allowed during the study. 
Abbreviations:   


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Study Code D1689C00014 
Edition 4.0 
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2.
STUDY OBJECTIVES 
Research Hypothesis: 
Treatment with dapagliflozin added to metformin and dapagliflozin plus saxagliptin added to 
metformin will be non-inferior to glimepiride (a sulphonylurea) added to metformin, within a 
margin of 0.3%, for change from baseline to Week 52 in glycosylated HbA1c. 
2.1
Primary objective 
Primary Objective: 
Outcome Measure: 
To compare the absolute change from baseline 
in HbA1c at Week 52 between dapagliflozin 
plus metformin and dapagliflozin plus 
saxagliptin plus metformin with glimepiride 
plus metformin 
Change in HbA1c from baseline (Week 0) to 
Week 52 
 
2.2
Secondary objectives 
Key Secondary Objectives: 
Outcome Measures: 
To compare the proportion of patients 
reporting hypoglycaemia episodes during the 
52-week treatment period between 
dapagliflozin plus metformin and dapagliflozin 
plus saxagliptin plus metformin with 
glimepiride plus metformin 
Proportion of patients reporting at least 1 episode of 
hypoglycaemia (symptomatic + blood glucose 
50 mg/dL [2.8 mmol/L]) during the double-blind 
treatment period 
To compare the change from baseline in total 
body weight at Week 52 between dapagliflozin 
plus metformin and dapagliflozin plus 
saxagliptin plus metformin with glimepiride 
plus metformin 
Change in total body weight from baseline (Week 0) 
to Week 52 
To compare the change from baseline in FPG 
at Week 52 between dapagliflozin plus 
metformin and dapagliflozin plus saxagliptin 
plus metformin with glimepiride plus 
metformin 
Change in FPG from baseline (Week 0) to Week 52 
To compare the time to rescue among the 
treatment groups during the 52-week treatment 
period between dapagliflozin plus metformin 
and dapagliflozin plus saxagliptin plus 
metformin with glimepiride plus metformin 
Time to rescue during the 52-week double-blind 
treatment period 
 
 


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Other Secondary Objectives: 
 
To compare the effects of dapagliflozin plus 
metformin and dapagliflozin plus saxagliptin 
plus metformin with glimepiride plus 
metformin at Week 52 
x Proportion of patients achieving HbA1c of < 7% 
(and <7.5%) without confirmed hypoglycaemia at 
Week 52 
x Proportion of patients achieving HbA1c of  <7% 
(and <7.5%) at Week 52 
x Proportion of patients achieving individually 
agreed HbA1c targets at Week 52 
x Proportion of patients achieving an HbA1c 
decrease of 1% with no weight gain at Week 52  
x Time spent below HbA1C target (<7% and  
<7.5%) during the 52-week double-blind treatment 
period 
x Change in body mass index (BMI) from baseline 
to Week 52 
x Proportion of patients achieving weight reduction 
of 5% and weight gain of 5% from baseline to 
Week 52 
x Proportion of patients reporting at least 1 episode 
of hypoglycaemia (confirmed hypoglycaemia = 
symptomatic + blood glucose 50 mg/dL, major, 
other hypoglycaemia) during the 52-week 
double-blind treatment period 
x Change in waist circumference from baseline to 
Week 52 
x Change in systolic BP from baseline to Week 52 
 
2.3
Safety objectives 
Safety Objective: 
Outcome Measures: 
To evaluate the safety and tolerability of 
dapagliflozin and dapagliflozin plus 
saxagliptin versus glimepiride, all as add-on 
therapy to metformin, during the 52-week 
treatment period 
x Proportion of patients withdrawing from study 
medication due to hypoglycaemia 
x AEs/SAEs 
x AEs of special interest (AEOSI) 
x Clinical laboratory tests  
x Electrocardiogram (ECG)  
x Vital signs (pulse and blood pressure [BP]) 
x Hypoglycaemic events 
x Physical examinations, including incidence of 
oedema 
 


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2.4
Exploratory objectives   
Exploratory Objective: 
Outcome Measures: 
To explore the mean change from baseline in 
quality of life patient reported outcomes 
(PROs) and waist:hip ratio at Week 52 
between dapagliflozin plus metformin and 
dapagliflozin plus saxagliptin plus metformin 
with glimepiride plus metformin 
x Change from baseline to Week 52 in the Short 
Form 36-item Health Survey (SF-36), 
Hypoglycaemia Fear Survey (HFS-II), and Impact 
of Weight on Quality of Life (IWQOL)-Lite 
survey 
x Change in waist:hip ratio from baseline to 
Week 52 
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.  Patients must be 
receiving metformin (1500 mg/day) for treatment of T2DM in accordance with the product 
label for their country.  Eligible patients will be enrolled and examined for all inclusion and 
exclusion criteria. 
3.1
Inclusion criteria 
For inclusion in the study patients should fulfill the following criteria: 
1.
Provision of informed consent prior to any study-specific procedures. 
2.
Is able to read, understand, and sign the Informed Consent Forms (ICFs) and, if 
applicable, an Authorisation to Use and Disclose Protected Health Information form 
(consistent with Health Insurance Portability and Accountability Act of 1996 
legislation), communicate with the Investigator, and understand and comply with 
protocol requirements, including the use of diary and glucose meter measurements. 
3.
Is male or female and 18 and <75 years old at time of informed consent. 
4.
Has a documented diagnosis of T2DM. 
5.
Has a HbA1c of 7.5% and 10.5% based on central laboratory results from 
Visit 1, with individual need for therapy escalation. 
6.
Currently treated with a stable MTD (1500 mg/day) of metformin therapy for at 
least 8 weeks prior to Enrolment visit. 
7.
Has a BMI of 45 kg/m2 at Enrolment visit. 
8.
Has a C-peptide laboratory value of 1.0 ng/mL (0.33 nmol/L; 331 pmol/L) based 
on central laboratory results from Visit 1. 


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9.
For females only: Women not of childbearing potential, or if they are women of 
childbearing potential (WOCBP), they must comply with the following: 
x
Are not pregnant or breastfeeding. 
x
Have a negative urine pregnancy test result (minimum sensitivity 25 IU/L 
or equivalent units of human chorionic gonadotropin, beta subunit 
[ȕhCG]) at Visit 1 (Enrolment) and prior to randomization. 
x
Using or willing to adopt a highly effective method of birth control (see 
below) to avoid pregnancy throughout the study and for at least 4 weeks 
after the last dosing of study medication 
Definitions: 
Women NOT of childbearing potential: Women who are permanently or surgically 
sterilised or postmenopausal.  Permanent sterilization includes hysterectomy, and/or bilateral 
oophorectomy, and/or bilateral salpingectomy. 
Postmenopausal women: Women are considered postmenopausal if they have amenorrhea 
amenorrhea for 12 months after the last menstrual period and marks the end of menstrual 
cycles. 
Highly effective 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; vasectomised sexual partner; tubal 
occlusion (ligation); intrauterine device; levonorgestrel intrauterine system (eg, Mirena®); 
etonogestrel implants (eg, Implanon®, Norplan®); normal and low dose combined oral 
contraceptive pills; norelgestromin/ethinyl estradiol transdermal system; intravaginal device 
(eg, ethinyl estradiol and etonogestrel); and desogestrel (Cerazette®). 
3.2
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
Endocrine and Metabolic Disorders 
1.
Clinically diagnosed with Type I diabetes, known diagnosis of maturity onset 
diabetes of the young (MODY), or secondary diabetes mellitus or known presence 
of glutamate decarboxylase 65 (GAD65) antibodies. 
2.
History of diabetic ketoacidosis, hyperosmolar nonketotic coma, or 
corticosteroid-induced Type 2 diabetes. 
3.
Symptoms of poorly controlled diabetes including, but not limited to, marked 
polyuria, polydipsia, and/or greater than 10% weight loss during the 3 months prior 
to Enrolment. 


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4.
FPG >270 mg/dL (>15 mmol/L) – assessed based on central laboratory results from 
Visits 1. 
5.
History of diabetes insipidus. 
6.
Patients with clinically significant thyroid disease or uncontrolled thyroid disease 
needing initiation or adjustment of thyroid treatment per Investigator’s judgement.  
Abnormal thyroid stimulating hormone (TSH) value at Enrolment will be further 
evaluated by free thyroxine (T4).  Patients with abnormal free T4 values will be 
excluded. 
Medical History and Concurrent Diseases 
7.
History of bariatric surgery or lap-band surgery, or either procedure is planned 
during the time period of the study.  History of liposuction is allowed. 
8.
History of any unstable endocrine, psychiatric, rapidly progressing or unstable renal 
disease, or rheumatic disorder, as judged by the Investigator. 
9.
Patients who, in the judgment of the Investigator, may be at risk for dehydration or 
volume depletion that may affect the patient’s safety and/or the interpretation of 
efficacy or safety data. 
10.
Has evidence of current abuse of drugs or alcohol or a history of abuse within the 
past 52 weeks that, in the Investigator’s opinion, would cause the individual to be 
noncompliant. 
Cardiovascular Conditions 
11.
Clinically significant cardiovascular disease or procedure within 3 months prior to 
Enrolment (ie, MI, cardiac surgery, coronary artery bypass surgery, coronary stent 
placement, coronary angioplasty, unstable angina, stroke, transient ischaemic 
attack, or unstable or previously undiagnosed arrhythmia) or expected to require 
coronary revascularization procedure during the course of the study. 
12.
Severe uncontrolled hypertension defined as systolic BP 180 mmHg and/or 
diastolic BP 110 mmHg at any visit up to and including Randomization (Visit 2).   
13.
Presence or history of severe congestive heart failure (New York Heart Association 
Class III and IV [CCNYHA 1994]), unstable or acute congestive heart failure, 
and/or known left ventricular ejection fraction of 40%.  
Note: eligible patients with congestive heart failure, especially those who are on diuretic 
therapy (note that use of loop diuretics is not allowed), should have careful monitoring of their 
volume status throughout the study. 


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Study Code D1689C00014 
Edition 4.0 
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Kidney Conditions 
14.
Creatinine clearance (CrCl) of <60 mL/min based on central laboratory results from 
Visit 1. 
15.
Familial renal glucosuria.  This condition is diagnosed as glucosuria (>1.0 mmol/L 
urine) in the presence of normoglycaemia in patients without the diagnosis of 
diabetes mellitus. 
Hepatic Conditions 
16.
Significant hepatic disease, including, but not limited to, severe hepatic 
insufficiency and/or significant abnormal liver function defined as aspartate 
aminotransferase (AST) and/or alanine aminotransferase (ALT) of >3x upper limit 
of normal (ULN) based on central laboratory results from Visit 1. 
17.
Serum total bilirubin (TB) of >2 mg/dL (34.2 ȝmol/L [patients with documented 
Gilbert’s syndrome will be allowed to enrol]) based on central laboratory results 
from Visit 1. 
18.
History of, or currently have, acute or chronic pancreatitis or have triglyceride 
concentrations 500 mg/dL based on central laboratory results from Visit 1. 
19.
History of severe hepatobiliary disease or hepatotoxicity with any medication. 
20.
Positive serologic evidence of current infectious liver disease, including patients 
positive for Hepatitis B viral antibody IgM, Hepatitis B surface antigen, and 
Hepatitis C virus antibody. 
Haematological/Oncological Conditions 
21.
History of malignancy within 5 years of Visit 1 (Enrolment), with the exception of 
treated in situ basal cell or squamous cell carcinoma of the skin. 
22.
Haemoglobin <10 g/dL (<100 g/L) or 6.2 mmol/L for men; haemoglobin <9.0 g/dL 
(<90 g/L) or 5.9 mmol/L for women. 
23.
History of chronic haemolytic anaemia or haemoglobinopathies (for example, sickle 
cell anaemia, thalassemia, sideroblastic anaemia).  Mild haemolysis due to artificial 
heart valves or due to sickle cell trait is not an exclusion criterion except when 
haemoglobin levels are too low (as defined in haemoglobin criteria above). 
24.
Donation or transfusion of blood, plasma, or platelets within the past 12 weeks prior 
to Enrolment, or planning to donate blood during the study. 


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Study Code D1689C00014 
Edition 4.0 
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Prohibited Medications 
25.
Concomitant treatment with loop diuretics at Visit 2 (Randomisation/baseline.) 
26.
Administration of any antihyperglycaemic therapy, other than metformin, during 
the 8 weeks prior to Visit 1 (Enrolment). 
27.
Administration of any other IP or participation in any interventional clinical studies 
30 days prior to Visit 1 (Enrolment). 
28.
Treatment with systemic glucocorticoids equivalent to oral prednisolone 10 mg 
(betamethasone 1.2 mg, dexamethasone 1.5 mg, hydrocortisone 40 mg) per day 
for >7 days within 30 days prior to enrolment.   
29.
Prescription or over-the-counter weight loss medications within 3 months prior to 
Visit 1 (Enrolment). 
Other 
30.
Has a clinically significant medical condition that could potentially affect study 
participation and compliance with the treatment and study procedures, or which 
may pose a significant risk to the patient and/or personal well-being, as judged by 
the Investigator. 
31.
Has clinically significant abnormality identified on physical examination, ECG, or 
laboratory tests (clinical chemistry, haematology, and urinalysis) as judged by the 
Investigator at Visit 1 (Enrolment) would compromise the patient’s safety or 
successful participation in the clinical study. 
32.
Has known contraindications, allergies, or hypersensitivities to any study drug or 
excipient as outlined in the IBs or local package inserts for metformin, SU, 
saxagliptin, and dapagliflozin. 
33.
Ongoing weight loss more than 5% over the last 3 months prior to Visit 1 
(Enrolment). 
34.
Known immunocompromised status, including patients who underwent organ 
transplantation. 
35.
Involvement in the planning and/or conduct of the study (applies to AstraZeneca 
staff and/or staff at the study site). 
36.
Previous screening, enrolment or randomisation in the present study. 
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4. 


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Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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3.3
Subject enrolment and randomization 
Investigators may screen potential patients prior to enrolment based on information from 
medical history and a blood sample for measurement of HbA1c.  The Investigator must obtain 
patient’s consent to this screening procedure through an abbreviated informed consent (see 
Section 10.4.1).  Investigator(s) should keep a record of patients who entered pre-study 
screening and keep it as the patient screening log.  
For patients that are enrolled into the study, the Investigators will: 
1. Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed. 
2. Assign potential patient a unique enrolment code (E-code), beginning with ‘E#’. 
3. Determine patient eligibility in accordance with inclusion/exclusion criteria. 
4. Assign an eligible patient unique randomisation code. 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. 
The E-code will be used to identify the patient throughout study participation. 
3.4
Procedures for handling incorrectly enrolled or randomized 
subjects 
Patients 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.  Patients who 
are enrolled, but subsequently found not to meet all the eligibility criteria should not be 
randomised or initiated on treatment, and should be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment.  The AstraZeneca study physician or designee must ensure all decisions are 
appropriately documented. 
3.5
Methods for assigning treatment groups 
At Visit 2 (Baseline/Week 0), enrolled patients who meet all study requirements based on 
inclusion and exclusion criteria will be randomised strictly sequentially within each center as 
patients are eligible for randomisation.  Assignment to treatment groups will be determined by 
a computer-generated random sequence.  
 


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The patients will be randomised in a 1:1:1 ratio to the following treatment groups: 
x
Dapagliflozin 10 mg + placebo for saxagliptin + placebo for glimepiride;  
x
Dapagliflozin 10 mg + saxagliptin 5 mg + placebo for glimepiride;  
x
Glimepiride (starting at 1 mg dose and titrated up to 6 mg, if needed) + 
placebo for dapagliflozin + placebo for saxagliptin (see Section 4.3.3 for 
details on glimepiride dose levels).  
If a randomisation number is allocated incorrectly, no attempt should be made to remedy the 
error once study material has been dispensed.  The patient will continue with the allocated 
number and study material.  AstraZeneca or representative should be notified as soon as the 
error is discovered.  Subsequent patients will continue using the first unallocated 
randomisation number in the original numbering sequence. 
3.6
Methods for ensuring blinding 
Blinding is ensured by using a double-blind, double-dummy technique.  Patients, the 
Investigator, study site personnel, and Sponsor personnel involved with data review and 
analysis will be blinded throughout the study until database lock.  The active tablets/capsules 
and the respective placebo tablets/capsules will be identical in size, color, smell, and taste as 
described in Table 4.  The bottles with IPs will be labelled with unique identification numbers 
allocated from the IWRS.   
No member of the study team at AstraZeneca, at study sites, or any clinical research 
organization (CRO) handling data will have access to the randomisation scheme during the 
conduct of the study, with the exception of the AstraZeneca personnel generating the 
randomisation scheme as well as AstraZeneca’s Supply Chain Study Management (SCSM), 
AstraZeneca Global Pharmacovigilance (GPV), and the CRO providing the IWRS and 
carrying out the packaging and labelling of IPs. 
3.7
Methods for unblinding  
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the Investigator(s) or pharmacists from the Interactive Web 
Response System (IWRS).  Routines for this will be described in the IWRS user manual that 
will be provided to each centre.  
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation.  The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities.  Treatment codes will not be broken for the planned analyses of data 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
42(122) 
until all decisions on the evaluability of the data from each individual patient have been made 
and documented. 
3.8
Restrictions 
Once screened and qualified for entry, patients will be instructed as follows: 
x
Fast overnight for 8 to 12 hours prior to each study site visit, ie, no food 
or beverage except water.  Allowed medications can be taken with water 
only. 
x
Continue metformin therapy at current dosage and at approximately the 
same time each day, except that the morning dose of metformin should be 
delayed on the morning of study site visits. 
x
Delay administering the IPs (as applicable) and metformin on the 
morning of the clinic visit and bring study medication and metformin to 
each study site visit. 
x
Refrain from alcohol intake and intense exercise 24 hours prior to each 
visit and recommend not to use 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 counseling and to 
the protocol visit schedule. 
x
Women must immediately contact the Investigator if they suspect they 
might be pregnant and if they have changed or plan to change their birth 
control method.  
If a patient comes to a visit without having followed the above instructions, then the patient 
should be re-scheduled for the entire visit (if possible within the allowed time-window).  The 
Sponsor or designee should be contacted if the Investigator is informed of any restriction 
violations.  
 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
43(122) 
3.9
Discontinuation of investigational product 
Patients who discontinue IP will be recommended to continue on the study and follow the 
original visit schedule without taking IP. 
Patients may be discontinued from IPs in the following situations: 
General discontinuation criteria: 
1. Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment. 
2. Patient experiences an AE or SAE that, in the Investigator’s opinion, necessitates 
discontinuation from study medication.  If this decision is made because of an SAE or 
a clinically significant abnormal laboratory value, appropriate measures are to be 
taken.  The Sponsor or its designee is to be alerted immediately (see Section 3.4). 
3. The Investigator decides the patient should discontinue study medication for reasons 
other than AE. 
4. Severe non-compliance with the study protocol as judged by the Investigator and/or 
AstraZeneca. 
5. Incorrectly enrolled patients (see Section 3.11).  
Study-specific discontinuation criteria: 
6. Use of (need for) any anti-hyperglycaemic medication other than IP or background 
metformin or study glimepiride or rescue therapy (insulin) allowed by protocol.  
Insulin use is permitted in the following situations: 
(a) For up to 14 days in total during the study and up to 7 continuous days if 
patients are unable to take oral medications (for example during a 
gastrointestinal illness). 
(b) For up to 14 days in total during the study and up to 7 continuous days if there 
is a documented illness or infection that requires additional therapy for 
maintaining glycaemic control. 
(c) For up to 14 days in total during the study and up to 7 continuous days if 
patients have to temporarily stop IP and/or metformin due to recommendations 
made in this clinical study protocol. 
(d) For up to 7 days during hospitalisation.  When the reason for hospitalisation is 
the management of the patient’s glycaemic control, treatment with insulin is 
considered a rescue and is allowed for as long as clinically necessary. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
44(122) 
7. Creatinine clearance <60 mL/min (by Cockgraft-gault) confirmed by a repeated central 
lab measurement within 1 week.  
8. Initial and repeat laboratory tests meet any of the following criteria (see Appendix C): 
x
ALT and/or AST are !3x ULN and TB !2x ULN 
x
ALT and/or AST are >5x ULN for 14 consecutive days, at any time 
after initial confirmatory results 
x
ALT and/or AST are >8x ULN 
9. One or more  major hypoglycaemic event or recurring minor events and the possibility 
of down-titration and contributing factors (eg, excessive physical activity) has been 
evaluated (as defined in Section 3.9.1). 
10. Pregnancy confirmed by a positive pregnancy test or otherwise verified. 
3.9.1
Procedures for discontinuation of a subject from investigational product  
Patients 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 patient discontinuation for hypoglycaemia. 
Clinical indications for discontinuation because of hypoglycaemia should include the 
following: 
x
Multiple occasions of episodes outlined below that, in the opinion of the 
Investigator, indicate that continued treatment with study therapy is not in 
the best interest of the patient.  This includes, but is not limited to: 

Symptoms suggestive of hypoglycaemia (eg, sweating, shakiness, increased 
heart rate, confusion, dizziness, light-headedness, or hunger) in the absence of 
environmental factors known to contribute to hypoglycaemia (ie, excess 
physical activity, concurrent illness, or missed or delayed meal)  

and/or 

Documented finger stick glucose values <54 mg/dL (<3.0 mmol/L).  

Recurrent episodes of hypoglycaemia (see Section 6.3.8 for definitions) that did 
not resolve after appropriate glimepiride down-titration. 
x
A patient may also be discontinued from the study because of severe 
hypoglycaemia, as determined by the Investigator. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
45(122) 
If finger stick glucose values are discordant from glycaemic control assessed by the laboratory 
or with clinical symptoms, the patient’s glucose meter should be tested and the instructions for 
use reviewed with the patient. 
3.9.2
Down-titration of blinded study drug and/or background antihyperglycaemic 
agent during the study 
Blinded glimepiride/placebo dose can be down-titrated at any time during the study to a dose 
as low as medically necessary, including a dose of 0 mg/day.  The  treatment  may  thereafter  
be  up-titrated again if no hypoglycaemia occured.  Down-titration of other blinded study drug 
and/or background antihyperglycaemic agent will not be allowed at any time during the study. 
3.9.3
Procedures for discontinuation of a subject from investigational product  
At any time, patients are free to discontinue IP or withdraw from the study (ie, IP and 
assessments – see Section 3.10), without prejudice to further treatment.  A patient who decides 
to discontinue IP will always be asked about the reason(s) and the presence of any AEs.  If 
possible, the patient will be seen and assessed by an Investigator.  Any AEs will be followed 
up (see Section 6.3.5); patient diaries and all study drugs should be returned by the patient. 
Patients who discontinue from the study medication will have an Early Termination Visit 
equivalent to the Visit 12 (Week 52/End of Treatment) assessments immediately following 
discontinuation of  study medication (see Section 4.3.5). The following data will be collected 
and entered onto the clinical database:  
x
Concomitant medication 
x
AEs 
In the case of a decision to discontinue treatment, the Investigator will follow the patient until 
the event has resolved or stabilised. 
For patients who discontinue IP between visit 3 & visit 8 and agree to follow the original visit 
schedule a Follow up visit is not required since those patients will continue in accordance with 
the study plan and then visits take place each second week. 
For patients who discontinue IP after Visit 8 and agree to follow the original visit schedule a 
Follow up visit should be performed as advised by the study plan – approximately 3 weeks 
after the Early Discontinuation visit. The next visits and the following ones have to be planned 
in accrodance to the original visit schedule.  
If a patient is withdrawn from study, see Section 3.10. 
If a patient is discontinued from the study, his/her randomisation or enrolment number will not 
be reused, and the patient will not be allowed to re-enter the study.  Randomised patients who 
discontinue early from the study will not be replaced. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
46(122) 
3.10
Criteria for withdrawal  
Every reasonable effort should be made to conduct all protocol-required procedures to 
complete the study.  Patients may be removed from the study for the following reasons: 
1. Screen failures: see Section 3.10.1. 
2. Withdrawal by patient:  see Section 3.10.2. 
3. Adverse event:  Patient experiences an AE that, in the Investigator’s opinion, 
necessitates withdrawal from the study. 
4. Investigator decision:  Investigator feels it is in the patient's best interest to terminate 
participation for reasons other than an AE. 
5. Protocol violation:  Patient is noncompliant with protocol procedures, becomes 
pregnant, violates study entry criteria, or starts an exclusionary concomitant 
medication. 
6. Lost to Follow-Up:  Patient fails to return for study visits and cannot be reached with 
reasonable, repeated attempts. 
7. Study terminated by Sponsor:  The Sponsor discontinues the study protocol. 
8. Administrative reasons:  The EU or other regulatory authority discontinues the study 
protocol or the clinical study site discontinues participation. 
Every effort will be made to ensure that the subject continues to return to the clinic for study 
visits and to avoid “lost to follow-up” during the conduct of the study.  The study staff should 
make diligent attempts to contact patients who fail to return for study visits by using 
institutional databases, patients’ health professionals, and any other means that comply with 
country and local laws and regulations.  After the first missed visit, patients who are 
considered temporarily lost to follow-up will have 2 documented telephone contact attempts 
and 1 certified letter in an effort to contact patients. 
Any withdrawal must be fully documented in the patient’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 patient is withdrawn from the study, they must complete the procedures outlined in 
Section 3.10.2 and Sponsor should be contacted. 
 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
47(122) 
3.10.1
Screen failures  
Screening failures are patients who do not fulfill the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 
recorded as ‘Eligibility Criteria not fulfilled’ (ie, patient does not meet the required 
inclusion/exclusion criteria).  This reason for study withdrawal is only valid for screen failures 
(not randomised patients).  Patients can only be enrolled 1 time into this study and no second 
attempts to screen the same patient will be allowed.  
3.10.2
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment. 
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs.  The Investigator will follow-up AEs outside of the clinical study.   
All attempts should be made to determine the underlying reason for the withdrawal and, where 
possible, the primary underlying reason should be recorded (eg, withdrawal due to an AE or 
lack of efficacy should not be recorded in the “voluntary withdrawal” category). 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.  Withdrawn subjects will not be replaced. 
3.11
Discontinuation of the study 
The study may be stopped if, in the judgment of AstraZeneca, trial patients 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 IP  
x
Are not considered to be consistent with continuation of the study. 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation 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 patients’ interests. 
4.
STUDY PLAN AND TIMING OF PROCEDURES  
Table 1 presents the schedule of assessments for this study


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
48(122) 
Table 1  
Study Plan 
Visit 
Screening 
Enrolment 
52-week Double-blind Treatment Period 
Safety 
Follow-up  
R/
Baseline
 
 
 
 
 
 
 
 
EOT/ 
Rescuea
Sb 
1 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Weeks 
-3 
-2 
0 
2 
4 
6 
8 
10 
12 
24 
36 
48 
52 
55 
Visit window (days)d
±3 
±3
- 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
±7 
±7 
Informed consent 
Xe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assign E-code 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography and medical 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
criteria 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Brief physical examination 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
Complete physical 
examination 
 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Vital signs (BP, pulse) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Waist and hip 
circumference 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant medicationsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
49(122) 
Visit 
Screening
Enrolment 
52-week Double-blind Treatment Period 
Safety
Follow-up  
R/
Baseline
 
 
 
 
 
 
 
 
EOT/ 
Rescuea
Sb 
1 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Weeks 
-3 
-2 
0 
2 
4 
6 
8 
10 
12 
24 
36 
48 
52 
55 
Visit window (days)d
±3 
±3
- 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
±7 
±7 
Clinical chemistryg 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Haematology 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
HbA1c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Haemoglobin 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine (to calculate 
CrCl and eGFR) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FPG (local laboratory) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
FPG (central laboratory) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipidsh 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Triglycerides 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
C-peptide 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis screening paneli 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (urine, 
WOCBP only) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypoglycaemic events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
50(122) 
Visit 
Screening
Enrolment 
52-week Double-blind Treatment Period 
Safety
Follow-up  
R/
Baseline
 
 
 
 
 
 
 
 
EOT/ 
Rescuea
Sb 
1 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Weeks 
-3 
-2 
0 
2 
4 
6 
8 
10 
12 
24 
36 
48 
52 
55 
Visit window (days)d
±3 
±3
- 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
±7 
±7 
Discuss individual targets 
for glucose control (FPG 
and HbA1c) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diet and lifestyle advice 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense glucometer 
and/or supplies; provide 
instructions 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense patient diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense study medication 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Register actual glimepiride 
dosage in IWRS 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Patient diary review for 
glucometer values/ 
hypoglycaemic events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Perform SF-36 survey 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Perform Hypoglycaemia 
Fear Survey-Worry Scale 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Perform IWQOL-Lite  
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Collect unused study 
medication/supplies 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
51(122) 
Visit 
Screening
Enrolment 
52-week Double-blind Treatment Period 
Safety
Follow-up  
R/
Baseline
 
 
 
 
 
 
 
 
EOT/ 
Rescuea
Sb 
1 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Weeks 
-3 
-2 
0 
2 
4 
6 
8 
10 
12 
24 
36 
48 
52 
55 
Visit window (days)d
±3 
±3
- 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
±7 
±7 
Dispense rescue 
medication (if necessary) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations:  AE adverse event, Base baseline, BP blood pressure, BMI body mass index, CrCl creatinine clearance, E-code enrolment code, ECG  electrocardiogram, eGFR 
estimated glomerular filtration rate, EOT end of treatment, FPG fasting plasma glucose, HbA1c haemoglobin A1c, HDL high-density lipoprotein, IWQOL Impact of 
Weight on Quality of Life, IWRS Interactive Web Response System, LDL low-density lipoprotein, R randomisation, SAE serious adverse event, SF short form, 
TSH  thyroid stimulating hormone, WOCBP women of child-bearing potential. 
a 
Early Termination procedures are to be completed for all patients who terminate the study, discontinue from IP or are rescued before Visit 12 (Week 52) of the Treatment 
Period.  
b 
An optional Screening visit (Visit S) may occur within 1 week prior to Enrolment (Visit 1) to screen for eligibility based on a non-fasting sample of HbA1c in patients that 
do not have a recent HbA1c value (within 2 months). 
c  
Visit 2 (Randomisation/Baseline) should be performed within 14 days after Enrolment visit, when laboratory results from Visit 1 are available. 
d 
Once a patient is randomised at Visit 2, all visits should be scheduled relative to Visit 2. 
e 
An abbreviated informed consent form will be signed at Screening visit. 
f 
Review of concomitant medications includes over the counter drugs and herbal/nutritional therapies  
g 
Specifications of clinical chemistry laboratory parameters are detailed in Section 5.2.1.3.  Visits 1 and 8 to 11 have the same parameters; Visits 2, 12, and 13 have the 
same parameters; and no clinical chemistry is performed at Visits 3 through 7.  CrCl and eGFR will be calculated at all visits. 
h 
Serum lipid panel will include LDL-cholesterol, HDL-cholesterol, triglycerides, and total cholesterol. 
i 
Hepatitis panel includes hepatitis B viral antibody IgM, Hepatitis B surface antigen, and hepatitis C virus antibody. 
 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
52(122) 
4.1
Screening visit (Visit S, Week -3) 
Failure to meet the HbA1c inclusion criterion is the main reason for screening failure in 
diabetes treatment studies.  Therefore, in this study, sites will be allowed to perform a 
pre-study screening assessment (at Week -3) within 1 week prior to enrolment visit, which 
will comprise of a collection of 1 non-fasting blood sample to determine HbA1c at the central 
laboratory.  Investigators will screen only patients who are potentially eligible for the study 
based on their medical conditions and existing therapies, and only those who are expected to 
meet all entry criteria at Enrolment (Visit 1).  Patients without a recent (within 2 months) local 
laboratory HbA1c result that allows to assess whether the patient may qualify for this study 
should attend the Screening visit to verify their HbA1c. 
In order to be considered for screening, patients must: 
x
Be 18 and <75 years old at time of informed consent. 
x
Have a documented diagnosis of T2DM. 
x
Currently treated with a stable MTD (1500 mg/day) of metformin 
therapy and not have received any other antihyperglycaemic therapy 
within 8 weeks from the expected date of Enrolment (Visit 1). 
At this Screening visit, the following will be performed: 
x
Abbreviated informed consent to the pre-screening procedures will be 
obtained (see Section 10.4) 
x
A blood sample will be collected for measurement of HbA1c by a central 
laboratory.  Fasting is not required. 
x
Verification of current metformin therapy 
Patients with HbA1c result of 7.0% and 11.0% at Screening will be scheduled for an 
enrolment visit within 7 days.  Patients should be fasting at the next visit (Enrolment, Visit 1) 
and a full ICF will be obtained before any assessments at that visit are initiated.  
All patients who are screened should be listed on a patient screening log.  A screening code 
will be created for all screened patients by the Investigator.  This code will identify screening 
laboratory results together with date of birth and gender. 
Patients are not allowed to be rescreened. 
4.2
Enrolment Period 
Procedures will be performed according to the Study Plan (Table 1).  Patients will be 
instructed to arrive in the morning for each scheduled visit.  Prior to each study visit, patients 
are required to have fasted overnight for 8 to 12 hours (no food or beverage, except water).   


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
53(122) 
Patients are advised to refrain from alcohol intake and intense exercise 24 hours prior to each 
visit and recommend not to use tobacco/nicotine within 12 hours prior to each visit.  Patients 
should delay administering their morning dose of metformin on the morning of the enrolment 
visit (Visit 1).   
In case it is not usual practice for the site to ask all patients to come to regular visits having 
fasted, the patients will first sign informed consent then perform the other enrolment 
assessments, but will need to return at least 1 day later to collect enrolment laboratory 
assessments while in a fasted state. 
4.2.1
Enrolment Visit (Visit 1, Week -2) 
Patients on a stable, MTD of metformin IR monotherapy 1500 mg/day for the last 8 weeks 
with an HbA1c 7.5 and 10.5% and with an individual need for therapy escalation will be 
eligible to enter the study.  The patient should maintain the prescribed stable dose of 
metformin for the duration of the study.  Visit 1 (Enrolment) should take place approximately 
1 week after Screening visit (Visit S; if performed).  Prior to this visit, patients are to have 
fasted overnight (8 to 12 hours).  At Enrolment, informed consent for Protocol D1689C00014 
will be obtained prior to performing any protocol-required procedures.  Patients will be 
assessed to ensure that they meet eligibility criteria.  Patients who do not meet these criteria 
must not be enrolled in the study and will be considered screen failures.   
Enrolment (Visit 1) procedures should be scheduled for at least 1 day later than the day of 
informed consent signature if the patient is not in a fasting state on the consent date.   
The following will be performed during this visit: 
x
Informed consent will be obtained. 
x
E-code will be assigned from IWRS. 
x
The patient’s demography and complete medical history will be recorded. 
x
Inclusion and exclusion criteria will be verified. 
x
A complete physical exam will be conducted (see Section 5.2.2). 
x
Vital signs (sitting systolic and diastolic BP and pulse) will be measured 
(see Section 5.2.4). 
x
Body weight and height will be measured (see Section 5.1.3 and 5.1.4). 
x
BMI will be calculated. 
x
12-lead ECG will be performed. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
54(122) 
x
All prior medications (prescription medications within 3 months) and 
concomitant medications (including over the counter and 
herbal/nutritional supplements) will be reviewed. 
x
Blood samples will be collected for the following laboratory assessments: 
x
Clinical chemistry (see Section 5.2.1.3) 
x
HbA1c 
x
Haemoglobin 
x
Serum creatinine (calculated creatinine clearance [Cockcroft-Gault 
formula] and eGFR) 
x
FPG (samples for central laboratory testing, see Section 5.2.1) 
x
C-peptide 
x
Hepatitis screening (hepatitis B surface antigen, antibody to 
hepatitis B core antigen IgM, and hepatitis C virus antibody) 
x
Thyroid function (TSH) 
x
Triglycerides 
x
Urine will be collected for urinalysis. 
x
Urinary pregnancy test for beta human chorionic gonatropin (ȕhCG) for 
female patients (WOCBP only) 
x
Hypoglycaemic events history will be recorded. 
x
SAEs will be reviewed. 
x
Diet and life-style advice will be provided. 
x
Glucose meter and/or supplies and instructions will be provided. 
x
Patient diary and instructions will be provided. 
Individuals will be screen failed if results of any laboratory test are abnormal and clinically 
significant as judged by the Investigator or medical monitor.   


Clinical Study Protocol 
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Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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4.3
Treatment Period 
4.3.1
Randomisation and Baseline Visit (Visit 2, Week 0) 
Visit 2 (Randomisation/Baseline) should take place approximately 2 weeks after Visit 1.  Prior 
to this visit, patients are to have fasted overnight (8 to 12 hours).  Patients are advised to 
refrain from alcohol intake and intense exercise 24 hours prior to each visit and recommend 
not to use tobacco/nicotine within 12 hours prior to each visit.  Patients should delay 
administering their morning dose of metformin on the morning of the study site visit. 
The following will be performed during this visit: 
x
Inclusion/exclusion and randomisation criteria will be verified. 
x
A complete physical examination will be conducted (refer to 
Section 5.2.2). 
x
Vital signs (sitting systolic and diastolic BP and pulse) will be assessed. 
x
Body weight will be measured. 
x
BMI will be calculated. 
x
Waist and hip circumference will be measured. 
x
12-lead ECG will be performed. 
x
Concomitant medications (including over the counter and 
herbal/nutritional supplements) will be reviewed. 
x
Blood samples will be collected prior to administration of study 
medication for the following assessments: 
x
Clinical chemistry (see Section 5.2.1.3) 
x
Haematology 
x
HbA1c 
x
Serum creatinine (calculated creatinine clearance [Cockcroft-Gault 
formula] and eGFR) 
x
FPG (by local and central laboratories) 
x
Lipids (low-density lipoprotein [LDL]-cholesterol, high-density 
lipoprotein [HDL]-cholesterol, triglycerides, total cholesterol) 
x
Urine will be collected for urinalysis  


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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x
Urinary pregnancy test (ȕhCG) for female patients (WOCBP only) will 
be performed. 
x
AEs and SAEs will be reviewed. 
x
Hypoglycaemic events will be reviewed. 
x
Investigator will discuss and agree with the patient on the individual 
goals for glucose control (based on FPG and HbA1c). 
x
Diet and life-style advice will be provided. 
x
Patients will be randomly assigned to 1 of 3 treatment groups (while 
continuing on metformin therapy):  
x
Dapagliflozin 10 mg + saxagliptin 5 mg + placebo for glimepiride;  
x
Dapagliflozin 10 mg + placebo for saxagliptin + placebo for 
glimepiride;  
x
Glimepiride (Level 1 dose; 1 mg/day) + placebo for dapagliflozin + 
placebo for saxagliptin (see Section 4.3.3 for details on glimepiride 
dose levels).  
x
Glucose meter and/or supplies and instructions will be provided. 
x
Patient diary and instructions will be provided. 
x
Study medication will be dispensed.  Study site personnel will monitor 
administration of study medication and morning dose of metformin with 
food. 
x
Patient diary will be reviewed for hypoglycaemic events/check 
glucometer values. 
Prior to performing any assessments at this visit, the following surveys will be completed: 
x
SF-36 questionairre will be performed (see Section 5.3.2.1) 
x
Hypoglycaemia Fear Survey (Worry Scale) will be performed (see 
Section 5.3.2.2). 
x
IWQOL-Lite survey will be performed (see Section 5.3.2.3). 


Clinical Study Protocol 
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Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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4.3.2
 Treatment Period visits (Visits 3 to 11, Weeks 2, 4, 6, 8, 10, 12, 24, 36, and 48) 
After the randomisation visit (Visit 2), patients will complete study visits at 2- to 12-week 
intervals according to Study Plan (Table 1) until the end of the randomised treatment period 
(Visit 12, Week 52).  Prior to these visits, patients are required to have fasted overnight (8 to 
12 hours).  Patients are advised to refrain from alcohol intake and intense exercise 24 hours 
prior to each visit and recommend not to use tobacco/nicotine within 12 hours prior to each 
visit.   
Patients should delay administering their morning dose of metformin and study medication on 
the morning of the study site visits.  Patients should bring their metformin and study 
medication with them to the study site and will self-administer study medication as directed 
by study-site personnel.   
The following will be performed during these visits: 
x
A brief physical examination will be conducted, except at Visit 9, where 
a complete exam will be performed (refer to Section 5.2.2). 
x
Vital signs (sitting systolic and diastolic BP and pulse) will be assessed. 
x
Body weight will be measured. 
x
Concomitant medications (including over the counter and 
herbal/nutritional supplements) will be reviewed.  
x
Blood samples will be collected prior to administration of study 
medication for the following assessments: 
x
Clinical chemistry (Visits 8 to 11; see Section 5.2.1.3) 
x
HbA1c 
x
Serum creatinine (for calculated creatinine clearance 
[Cockcroft-Gault formula] and eGFR) 
x
FPG (samples for local on site evaluation and for testing by central 
laboratories at all visits) 
x
Urine will be collected for urinalysis (Visits 3 to 11) 
x
Urinary pregnancy test (ȕhCG) for female patients (WOCBP only) will 
be performed. 
x
Hypoglycaemic events will be reviewed. 
x
AEs and SAEs will be reviewed. 


Clinical Study Protocol 
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Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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x
Diet and life-style advice will be provided. 
x
Glucose meter and/or supplies and instructions will be provided. 
x
Patient diary will be provided. 
x
Study medication will be dispensed (see Table 5) 
x
Study medication compliance will be reviewed by drug accountability. 
x
Actual glimepiride dosage will be registered in IWRS. 
x
Patient diary will be reviewed for hypoglycaemic events/check 
glucometer values.  
x
Rescue medication will be dispensed (as necessary, see Table 2). 
Prior to performing any assessments at the specified visit, the following surveys will be 
completed: 
x
SF-36 questionairre will be performed (Visit 9 only). 
x
Hypoglycaemia Fear Survey (Worry Scale) will be performed (Visit 9 
only). 
x
IWQOL-Lite survey will be performed (Visit 9 only). 
Study site personnel will instruct patients to take IP and metformin (with food) after study 
visit complete. 
4.3.3
Dose Titration 
During theTreatment Period, the blinded glimepiride/placebo dose will be slowly titrated in a 
stepwise fashion depending on glycaemic control at every visit.  For the duration of the study, 
FPG will be measured at the study centre using a glucose analyser provided by AstraZeneca.  
The Investigator’s decision on dose titration (either upwards or downwards) will take the 
plasma glucose measurements (measured at home in the days prior to the visit), and the 
Investigator’s measurements at the study visits, as well as the occurrence of hypoglycaemia 
into account.  The glimepiride/placebo dose should be titrated to achieve the individual target 
FPG of the patient (a target of approximately 110 mg/dL [6.1 mmol/L] is recommended).  
Up-titration should not be done in case of a recent hypoglycaemia episode.   
The starting dose for glimepiride/placebo is 1 mg QD, which can be further increased by 
increments of 1 mg at 2-week intervals (- 3 days) to a maximum of 6 mg/day (maximum 
recommended dose as per the Summary of Product Characteristics and thus the maximum 
dose to be used in this study).  The titration dose levels will be 1, 2, 3, 4, 5, and 6 mg QD.   


Clinical Study Protocol 
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Edition 4.0 
Date 12 January 2017 
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In patients for whom titration is not medically indicated at a specific week, reassessment for 
titration will occur at the following visit. 
The glimepiride/placebo dose can be down-titrated at any time during the study to mitigate 
recurrent hypoglycaemic events.  If necessary, glimepiride/placebo will be allowed to be 
down-titrated to 0 mg (ie, 2 placebo capsules).  The treatment can thereafter be up-titrated 
again during the treatment period.   
4.3.4
Rescue Therapy 
During the entire Treatment Period, patients may be eligible for treatment with open-label 
rescue medication (insulin) in addition to their blinded treatment regimen in order to treat 
ongoing hyperglycaemia.  For patients who have not reached their MTD of 
glimepiride/placebo, up-titration of glimepiride/placebo should be attempted first before 
rescue is initiated. 
Investigators may increase glimepiride/placebo dose or should initiate rescue insulin treatment 
based on progressively stricter glycaemic criteria according to Table 2.  Assessment of 
glycaemic parameters (ie, based on FPG and HbA1c results from central laboratory) will be 
done at each visit to determine if criteria for rescue medication are met during the randomised 
treatment period. 
Table 2 
Criteria for Initiation of Rescue Therapy During the Randomised 
Treatment Period 
Visit Period 
Central Laboratory glycaemic 
parameters 
Week 0 to 16 (after Visit 2 and including Visit 8) 
FPG >240 mg/dL (13.3 mmol/L) 
Week 16 to 24 (after Visit 8 and including day of 
Visit 9) 
FPG >200 mg/dL (11.1 mmol/L) 
Week 24 to 52 (after Visit 9 and including Visit 12) 
HbA1c >8.0% 
Abbreviations: FPG fasting plasma glucose; HbA1c haemoglobin A1c. 
 
Patients with a laboratory value meeting the rescue criteria at a pre-specified visit will be 
scheduled for a follow-up visit (within 3 to 5 days) to obtain a second laboratory value and 
review the patient’s glucose meter readings.  If the repeat laboratory value still meets the 
rescue criterion, the patient should be rescued with insulin.  Patients will continue receiving 
blinded study medication while receiving rescue therapy.  Patients who meet rescue criteria in 
the double-blind treatment period must complete the Rescue visit which includes assessments 
indicated at Visit 12, prior to initiation of rescue therapy. 
Rescued patients will be given open-label insulin 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 patients will then continue in the double-blind 
treatment period according to their original visit schedule.  Rescue therapy will be prescribed 
by the Investigator. 


Clinical Study Protocol 
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Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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4.3.5
End of Treatment Period Visit/Early Termination or Rescue (Visit 12, 
Week 52) 
Visit 12 (End of Treatment Visit) should occur 4 weeks after Visit 11 or if the patient 
discontinued early from IP or is rescued.  Prior to this visit, patients are required to have fasted 
overnight (8 to 12 hours).  Patients are advised to refrain from alcohol intake and intense 
exercise 24 hours prior to each visit and recommend not to use tobacco/nicotine within 
12 hours prior to each visit.  Patients should delay administering the morning dose of 
metformin and study medication on the morning of the visit and bring metformin and study 
medication to the study site visit.   
The following procedures will be conducted: 
x
A complete physical exam will be conducted. 
x
Vital signs (sitting systolic and diastolic BP and pulse) will be assessed. 
x
Body weight will be measured. 
x
BMI will be calculated. 
x
Waist and hip circumference will be measured. 
x
12-lead ECG will be performed. 
x
Concomitant medications (including over the counter and 
herbal/nutritional supplements) will be reviewed. 
x
Blood samples will be collected prior to administration of study 
medication for the following assessments: 
x
Clinical chemistry (see Section 5.2.1.3) 
x
Haematology 
x
HbA1c 
x
Creatinine (calculated creatinine clearance [Cockcroft-Gault 
formula] and eGFR) 
x
FPG (samples collected for analysis by local on site laboratory and 
central laboratory) 
x
Lipids (low-density lipoprotein [LDL]-cholesterol, high-density 
lipoprotein [HDL]-cholesterol, triglycerides, total cholesterol) 
x
Urine will be collected for urinalysis.  


Clinical Study Protocol 
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Study Code D1689C00014 
Edition 4.0 
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x
Urinary pregnancy test (ȕhCG) for female patients (WOCBP only) will 
be performed. 
x
Hypoglycaemic events will be reviewed. 
x
AEs and SAEs will be reviewed. 
x
Diet and life-style advice will be provided. 
x
Study medication compliance will be reviewed. 
x
Actual glimepiride dosage will be registered in IWRS. 
x
Patient diary will be reviewed for hypoglycaemic events/check 
glucometer values and collected. 
x
Patient diary will be collected (not applicable for rescue visit, for end of 
treatment only).  
x
Unused study medication/supplies will be collected (not applicable for 
rescue visit). 
x
Glucose meter and/or supplies and instructions will be collected. 
For patients who discontinue IP and agree to follow the original visit schedule, patient diary, 
study supplies and glucose meter will be not collected. Next visit(s) will be scheduled 
according to the original visit schedule. 
Prior to performing any assessments at the specified visit, the following surveys will be 
completed: 
x
SF-36 questionnaire will be performed for: End of treatment visit/Early 
termination visit and  Rescue visit .  
x
Hypoglycaemia Fear Survey (Worry Scale) will be performed for: End of 
treatment visit/Early termination visit and Rescue visit.   
x
IWQOL-Lite survey will be performed for: End of treatment visit/Early 
termination visit and Rescue visit.  
For those patients who performed either IP discontinuation visit (Visit 12, End of 
treatment) or Rescue visit, there is no need to complete the surveys at any other 
study visit until the end of study. 
 


Clinical Study Protocol 
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Study Code D1689C00014 
Edition 4.0 
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4.4
Follow-up visit (Visit 13, Week 55) 
Visit 13 (Safety Follow-up Visit) should occur approximately 3 weeks after Visit 12.  Prior to 
this visit, patients are required to have fasted overnight (8 to 12 hours).  Patients are advised to 
refrain from alcohol intake and intense exercise 24 hours prior to each visit and recommend 
not to use tobacco/nicotine within 12 hours prior to each visit.  
The following procedures will be conducted: 
x
A brief physical exam will be conducted (refer to Section 5.2.2). 
x
Vital signs (sitting systolic and diastolic BP and pulse) will be assessed. 
x
Body weight will be measured. 
x
Concomitant medications (including over the counter and 
herbal/nutritional supplements) will be reviewed. 
x
Blood samples will be collected for the following assessments: 
x
Clinical chemistry (see Section 5.2.1.3) 
x
Haematology 
x
Creatinine (calculated creatinine clearance [Cockcroft-Gault 
formula] and eGFR) 
x
FPG (central laboratory only) 
x
Lipids (low-density lipoprotein [LDL]-cholesterol, high-density 
lipoprotein [HDL]-cholesterol, triglycerides, total cholesterol) 
x
Urine will be collected for urinalysis.  
x
Urinary pregnancy test (ȕhCG) for female patients (WOCBP only) will 
be performed. 
x
Hypoglycaemic events will be reviewed. 
x
AEs and SAEs will be reviewed. 
x
Unused study medication/supplies will be collected. 
For patients who discontinue IP between visit 3 & visit 8 and agree to follow the original visit 
schedule, Follow up visit is not required since those patients will continue in accordance with 
the study plan and then visits take place each second week. 


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Edition 4.0 
Date 12 January 2017 
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For patients who discontinue IP after visit 8 and agree to follow the original visit schedule, 
Follow up visit should be performed as advised by the study plan – approximately 3 weeks 
after the Early Discontinuation visit. The next visits and the following ones have to be planned 
in accordance to the original visit schedule.  
5.
STUDY ASSESSMENTS 
A Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The Investigator will ensure that data are recorded on the eCRFs as specified in the 
Clinical Study Protocol (CSP) 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. 
5.1
Safety assessments 
Study outcome measures are summarised in Section 8.4. 
5.1.1
HbA1c 
Blood samples for measurement of HbA1c will be collected according to the schedule 
presented in the Study Plan (Table 1).  The instructions for collection, processing, packaging, 
and shipping of the samples will be detailed in the laboratory manual. 
The results from baseline and onwards will not be reported to the Investigator unless the 
values meet the defined rescue criteria.  In addition, if rescue medication is initiated, the 
central laboratory HbA1c value will be reported to the Investigator to ensure proper follow-up 
of the rescued patient. 
5.1.2
Fasting plasma glucose 
Blood samples for measurement of FPG will be collected according to the schedule presented 
in the Study Plan (Table 1).  The instructions for collection, processing, packaging and 
shipping of the samples to central laboratory will be detailed in the laboratory manual. 
The results from baseline and onwards will not be reported to the Investigator unless the 
values meet the defined rescue criteria.  In addition, if rescue medication is initiated, the 
central laboratory FPG value will be reported to the Investigator to ensure proper follow-up of 
the rescued patient. 
Fasting plasma glucose will also be measured by local on-site laboratory within 5௘ minutes 
after vein puncture in venous EDTA blood according to a standardised protocol, using a 
patient-near electronic device. 


Clinical Study Protocol 
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5.1.3
Body weight 
Body weight will be measured according to the schedule presented in the Study Plan 
(Table 1).  The study site staff should use a digital precision scale if possible, and record the 
weight in kilograms to the first decimal point (eg, 95.3 kg).  The same scale should be used 
and the patient should wear a standard hospital-type gown or equivalent light clothing and no 
shoes for the body weight measurement at each visit. 
5.1.4
Body Height 
Body height will be measured according to the schedule presented in the Study Plan (Table 1).  
The study site staff should record the height in centimetres.  The patient should remove their 
footwear and head gear and stand with feet together, heels against the back board, and knees 
straight. 
5.1.5
Waist and hip circumference 
For waist and hip circumference measurement, the study site personnel must ensure that: 
x
The patient stands and the examiner places a measuring tape in a horizontal plane 
midway between the lowest rib and the iliac crest for waist circumference and at the 
maximum circumference of the buttocks for hip circumference. 
x
The measuring tape is snug, but does not compress the skin, is parallel to the floor, and 
is not twisted. 
x
The measurement is taken at the end of a normal respiratory expiration. 
x
The measurement is recorded in centimeters to the first decimal point. 
x
Waist and hip circumference will be measured according to the schedules presented in 
the Study Plan (Table 1). 
Waist-hip ratio is a calculated ratio between waist circumference and hip circumference (waist 
circumference / hip circumference, measured in centimetres) and will be computed by 
AstraZeneca. 
5.2
Safety assessments 
The Investigator will evaluate all Enrolment and safety laboratory reports and will sign and 
date the review.  Any out of range laboratory results should be assessed for clinical 
significance and reported as AEs accordingly.  The Investigator should follow all clinically 
significant laboratory abnormalities occurring during the study that were not present at 
baseline.  These abnormalities should be evaluated with additional tests, if necessary, until the 
underlying cause is diagnosed or resolution occurs.  The diagnosis and resolution date must be 
reported to the Sponsor. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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Samples will be collected according to the schedules presented in the Study Plan (Table 1).  
The instructions for collection, processing, packaging, and shipping of the samples will be 
detailed in the laboratory manual. 
5.2.1
Laboratory safety assessments 
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the Study Plan (Table 1).   
The date and time of sampling will be recorded on the laboratory requisition form.  The 
samples will be processed by a central laboratory and results will be reported back to the 
clinic within 72 hours. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  
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
Volume of blood 
The total blood drawn from each patient over the course of the study will not exceed 450 mL. 
 
5.2.1.2
Haematology 
Haematology assessments at Visits 2, 12, and 13 will include the following: red blood cell 
count, leukocyte count, haemoglobin (Hb), haematocrit, and platelets (see Table 3).  
5.2.1.3
Clinical Chemistry 
Chemistry assessments (see Table 3) will include the following:  
x
Visits 1 (Enrolment) and 8 to 11: creatinine, TB, AST, and ALT. 
x
Visits 2 (Randomisation), 12, and 13: creatinine, TB, AST, ALT, alkaline 
phosphatase (ALP), uric acid, potassium, calcium, sodium, chloride, 
bicarbonate, magnesium, and phosphorus (or other routine chemistry 
panels as approved by the Sponsor). 
Visits 3 to 7: No clinical chemistry will be performed.  A separate blood 
sample for measurement of serum creatinine will be collected to calculate 
CrCl [Cockcroft Gault formula] and eGFR [MDRD]. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
66(122) 
 
Table 3 
Laboratory Variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Red blood cell count 
S/P-Creatinine 
B-Leukocyte count 
S/P-Bilirubin, total (TB) 
B-Haemoglobin (Hb) 
S/P-Alkaline phosphatase (ALP) 
B-Haematocrit
S/P-Aspartate transaminase (AST) 
B-Platelet count 
S/P-Alanine transaminase (ALT) 
S/P-Uric acid 
 
S/P-Potassium 
 
S/P-Calcium, total 
 
S/P-Sodium 
 
S/P-Chloride  
 
S/P-Bicarbonate 
 
S/P-Magnesium 
 
S/P-Phosphorus 
Abbreviations:  AST aspartate transaminase, ALP alkaline phosphatase, ALT alanine transaminase, B blood, Hb 
haemoglobin, P plasma, S serum, TB total bilirubin. 
 
5.2.1.4
Urinalysis 
Urinalysis assessments will be performed according to Study Plan (Table 1) and will include 
the following: haemoglobin, erythrocytes, blood, protein, albumin, glucose, and creatinine (or 
other routine urinalysis as approved by the Sponsor).  
5.2.1.5
Other clinical laboratory evaluations 
Blood samples will be collected for the measurement of TSH as presented in the Study Plan 
(Table 1).  Patients with abnormal TSH values will be further evaluated by free T4.  Patients 
with abnormal free T4 will be excluded (see Section 3.2). 
Other measures will include: 
x
C-peptide 
x
Lipids (LDL-cholesterol, HDL-cholesterol, triglycerides, total 
cholesterol) 
x
Creatinine (for calculated creatinine clearance [Cockcroft-Gault formula] 
and eGFR) 


Clinical Study Protocol 
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Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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x
Hepatitis screening (hepatitis B surface antigen, antibody to hepatitis B 
core antigen IgM, and hepatitis C virus antibody) 
5.2.1.6
Pregnancy Testing 
All female patients, unless postmenopausal (amenorrhea for 12 months after the last menstrual 
period and marks the end of menstrual cycles) or has been surgically sterilised, will provide 
urine samples for pregnancy tests according to the schedule presented in the Study Plan 
(Table 1).  The first dose of study medication or any other in-clinic dose of study medication 
will not be administered until a negative result is obtained. 
5.2.2
Physical examination 
A complete physical examination will be performed according to the schedule presented in the 
Study Plan (Table 1).  The complete physical examination includes an assessment of the 
following: general appearance including skin inspection (including injection site), respiratory, 
cardiovascular, lymph nodes, thyroid, musculoskeletal/extremities, lungs, abdomen, and 
reflexes.  Baseline physical examination data are collected at Week 0 and new findings at the 
following physical examinations are recorded as change from baseline. 
 
A physical examination, either complete or brief, could be performed at any of the other visits 
at the Investigator’s discretion.  
Clinically significant abnormalities in physical examination findings at Study Termination 
must be followed up by the Investigator and evaluated with additional tests if necessary, until 
the underlying cause is diagnosed or resolution occurs.  As appropriate, the diagnosis and 
resolution date physical examination abnormalities must be reported as AEs. 
Refer to Section 6.1 for reporting AEs. 
5.2.3
ECG 
A 12-lead ECG will be performed 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 
patient in a supine position.  If the ECG must be performed with the patient in another 
position (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. 
5.2.4
Vital signs 
Vital sign measurements in this study will include sitting systolic and diastolic BP and pulse.  
Vital signs should be measured at every visit after the patient rests for approximately 
5 minutes and with the patient in a sitting position. 


Clinical Study Protocol 
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Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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Blood pressure measurement with a properly calibrated and validated instrument should be 
used.  Patients 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 3 measurements should be made at least 30 seconds apart.  The 
average of 3 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. 
Vital sign measurements must be performed in the seated position. 
5.2.5
Other safety assessments 
5.2.5.1
Cardiovascular events 
Deaths (including cause of death [CV related vs. non-CV]) and CV events (including MI, 
stroke, acute coronary syndrome, ventricular fibrillation/tachycardia, and congestive heart 
failure requiring hospitalisation) considered to be SAEs should be reported to the safety data 
entry site within 24 hours (refer to Section 6.2). 
Adjudication for hospitalization for heart failure will be performed according to the respective 
charter.  
5.2.5.2
Liver function test abnormalities 
Please see Appendix D, ‘Algorithm on Management of Sustained Elevated Liver Safety 
Abnormalitites’, for further guidance. 
5.3
Other assessments  
5.3.1
Hypoglycaemia 
Patients will receive a hypoglycaemia/blood glucose diary when a glucometer is dispensed.  
Patients will be asked to measure their fasting blood glucose 2 to 3 days prior to each site visit 
during the treatment period and document results in their patient diary. Patients will be asked 
to also check their blood glucose when: 
x
The subject experiences signs or symptoms of hypoglycaemia. 
x
At additional time points at the Investigator’s discretion which may 
include change of dose of standard of care medications or any other 
relevant signs or symptoms. 
Patients will be instructed to contact the study team any time they experience a 
hypoglycaemic event.  Patients will also be instructed to document any hypoglycaemia events 
that have occurred since their last visit.  Hypoglycaemic events must be recorded in the diary 
anytime a subject experiences either of the following: 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
69(122) 
x
Signs and symptoms of hypoglycaemia (regardless of blood glucose 
value by finger stick) 
x
Blood glucose value by finger stick 70 mg/dL (3.9 mmol/L) (regardless 
of symptoms). 
For these hypoglycaemic events, patients must record the following information in the diary: 
x
Date and time of hypoglycaemic event 
x
Symptoms 
x
Blood glucose value by finger stick and time of finger stick 
x
Whether the subject experienced incoherence, unconsciousness, or 
required assistance of another person to recover 
x
Treatments administered 
Patients should be instructed to document exact date and time of last dose of study medication 
prior to each event.  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.  Patients will also be 
requested to document any AEs and any concomitant medications they have taken since the 
last visit, and to contact the site with any questions about AEs and/or concomitant 
medications.  The investigator should ensure these are transcribed onto the source documents 
during AE review. 
Hypoglycaemia events will be summarised descriptively.  Summaries will be provided overall 
for all events of hypoglycaemia as well as the subcategories as defined in Section 6.3.8. 
5.3.2
Patient reported outcomes 
All patients will complete the SF-36 Health Survey, HFS-II-Worry Scale, and the 
IWQOL-Lite survey according to the schedule presented in the Study Plan (Table 1) prior to 
performing any other assessments at that visit. 
The instruments/questions will be self-administered using paper and pencil questionnaires.  It 
is important to administer the questionnaire and questions according to recommendation for 
standardised administration.  The patient should be informed about how important his/her 
participation is.  The patients should complete the questionnaire/questions before any other 
study related procedures take place and before any communication with the study personnel. 
The questionnaire/questions should be completed in a quiet place without influence from 
study personnel or accompanied family or friend.  The staff at the clinic should never help the 
patient to choose an answer and must be neutral in their response to the patient’s questions.  
The staff at the clinic is not allowed to interpret or rephrase the questions for the patient.  


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
70(122) 
After the patient has completed the questionnaire and questions, the study personnel will 
review the questionnaire/questions for completeness only. 
5.3.2.1
SF-36 Health Survey 
The Short Form 36-item Health Survey addresses 8 health concepts including: physical 
functioning, bodily pain, role limitations due to physical health problems, role limitations due 
to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, 
and general health perceptions.  The survey also includes a single item that provides an 
indication of perceived change in health. 
Scoring the SF-36 Health Survey consists of 8 scaled scores, which are the weighted sums of 
the questions in their section.  Each scale is directly transformed into a 0 to 100 scale on the 
assumption that each question carries equal weight.  The lower the score the more disability.  
The higher the score the more favourable health state (ie, a score of zero is equivalent to 
maximum disability and a score of 100 is equivalent to no disability).   
5.3.2.2
Hypoglycaemia Fear Survey - Worry Subscale  
The HFS-II is a reliable and valid measure of the fear of hypoglycaemia in adults with T2DM 
that measures the behavioural and affective dimensions of fear of hypoglycaemia, using 
modern test-theory methods, including item-response theory (Appendix E).  Items in the 
HFSII-Worry scale describes specific concerns that patients may have about their 
hypoglycaemic episodes (eg, being alone, episodes occurring during sleep, or having an 
accident). 
5.3.2.3
IWQOL-Lite 
The IWQOL-Lite survey is a 31-item, self-reported assessment of quality of life in 
overweight/obese individuals (Appendix E).  The measure consists of scores on 5 dimensions: 
physical function (11 items), self-esteem (7 items), sexual life (4 items), public distress 
(5 items), and work (4 items).  In addition, there is a global score (sum of scale scores).  
Participants are asked to rate items with respect to the past week on this instrument (from 
never true to always true).  Scores on the IWQOL-Lite (domains and global score) range from 
0 to 100.  Higher scores indicate poorer quality of life.  The IWQOL-Lite has demonstrated 
excellent psychometric properties in overweight persons seeking treatment, in a community 
setting and in persons with and without diabetes (Kolotkin et al 2003).  IWQOL-Lite is 
included for exploratory purposes and the questions will be assessed at baseline, after 
24 weeks, and after 52 weeks of treatment. 
Translations of the questions into local languages have or will be performed according to a 
linguistic validation process. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
71(122) 
5.4
Pharmacokinetics (not applicable) 
5.5
Pharmacodynamics (not applicable) 
5.6
Pharmacogenetics (not applicable) 
5.7
Biomarker analysis (not applicable) 
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The 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 (eg, nausea and chest pain), signs (eg, tachycardia and enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, ECG).  In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event 
An SAE is an AE occurring during any study phase (ie, treatment or follow-up) that fulfills 
1 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 patient or may 
require medical intervention to prevent one of the outcomes listed above. 
 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
72(122) 
Any event of cancer, drug dependency/abuse, laboratory abnormalities fulfilling the Hy’s law 
definition (ALT/AST >3x ULN and total bilirubin >2x ULN) or overdose (defined as the 
accidental or intentional ingestion of any dose of the IP that is considered both excessive and 
medically important), should be reported as an SAE using the most relevant SAE criteria, as 
judged by the Investigator. 
For further guidance on the definition of an SAE, see Appendix B, ‘Additional Safety 
Information’. 
6.3
Recording of adverse events 
6.3.1
Time period for collection of adverse events 
AEs will be collected from time of signature of informed consent, Enrolment, Randomisation, 
and throughout the treatment period and including the follow-up period (Visit 13). 
SAEs will be recorded from the time of informed consent. 
All AEs/SAEs will be recorded on source documents and the eCRFs. 
6.3.2
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the patient’s last visit 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 patient with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary. 
 
6.3.3
Variables  
The following variables will be collect for each AE: 
x
AE (verbatim) 
x
The date when the AE started and stopped 
x
Maximum intensity or intensity or changes in intensity 
x
Whether the AE is serious or not 
x
Investigator causality rating against the IP (yes or no) 
x
Action taken with regard to IP 
x
AE caused subject’s withdrawal from study (yes or no) 
x
Outcome. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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In addition, the following variables will be collected for SAEs: 
x
Date AE met criteria for SAE 
x
Date Investigator became aware of SAE 
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 
x
Causality assessment in relation to Study procedure(s) 
x
Description of AE. 
 
6.3.3.1
Intensity rating scale 
The maximum intensity of an AE will be rated according to the following definition: 
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 an 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 an SAE when it satisfies the criteria 
shown in Section 6.2. 
6.3.4
Causality collection 
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’ 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
74(122) 
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure, the causal relationship 
is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol. 
6.3.5
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient 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, ECG, and vital signs should therefore only be reported as AEs if they fulfill 
any of the SAE criteria or are the reason for discontinuation of treatment with the IP. 
If deterioration in a laboratory values or 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 (eg, anaemia versus low 
haemoglobin value).  In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as an AE. 
Hyperglycaemia due to insufficient clinical response is not necessarily considered an 
AE/SAE, unless the Investigator does not consider it expected for that patient, based on an 
increased frequency or severity in relation to the patient’s usual clinical course.     
Hypoglycaemic episodes should only be reported on the AE eCRF page if the event fulfils 
protocol criteria for a SAE (see Section 6.2).  In this case, a SAE must be reported in addition 
to the hypoglycaemia eCRF pages for hypoglycaemia.  A separate section in the eCRF will be 
used to document all reported episodes of hypoglycaemia (see Section 6.3.8). 
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. 
 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
75(122) 
6.3.7
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT 3x ULN together with total bilirubin 2x ULN may need to 
be reported as SAEs.  Please refer to Appendix C and D for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law.    
6.3.8
Hypoglycaemia 
Patients 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 patient diary (see 
Section 5.3.1 for detailed instructions).   
Study site personnel must obtain accurate information for the patient’s file and for the 
hypoglycaemia page of the eCRF.  If the hypoglycaemic episode intensity is classified as 
severe, the Investigator is required to contact the Sponsor. 
Hypoglycaemia events will be summarised descriptively.  Summaries will be provided overall 
for all events of hypoglycaemia as well as by the following subcategories: 
Major hypoglycaemic events, defined as symptomatic events requiring external assistance 
due to severe impairment in consciousness or behaviour, with a capillary or plasma glucose 
value <54 mg/dL (<3.0 mmol/L), and prompt recovery after glucose or glucagon 
administration. 
Hypoglycaemia: Typical symptoms of hypoglycaemia accompanied by blood glucose 
70 mg/dL (3.9 mmol/L). 
Other episodes of hypoglycaemia: Symptoms of hypoglycaemia without a blood glucose 
reading or symptoms of hypoglycaemia accompanied by blood glucose level >70 mg/dL (3.9 
mmol/L). 
Confirmed hypoglycaemia: Typical symptoms of hypoglycaemia accompanied by blood 
glucose 50 mg/dL (2.8 mmol/L). 
Asymptomatic hypoglycaemia: An event not accompanied by typical hypoglycaemia 
symptoms but with measured plasma glucose 70 mg/dL (3.9 mmol/L). 
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 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the safety data entry site within 1 calendar day of initial 
receipt for fatal and life threatening events and within 3 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 1 calendar day ie, 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 an SAE to the appropriate AstraZeneca representative by designated back-up 
procedures.  AstraZeneca will provide appropriate local contact information for safety 
reporting to the Investigator during site initiation. 
The AstraZeneca representative will advise investigators/study site personnel how to proceed. 
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug and the EU Summary of Product Characteristics for the active comparator product 
(including any AstraZeneca comparator).  
6.4.1
Adverse Events of Special Interest 
Event categories of special interest for this study may include, but are not limited to, 
hypoglycaemia, hypersensitivity reactions, severe cutaneous adverse reactions, all infections, 
decreased lymphocyte count, pancreatitis, all malignancies, confirmed adjudicated 
hospitallizations for cardiac failure events, cardiac failure, renal impairment/renal failure, 
volume depletion (hypotension, dehydration, and hypovolemia), and liver injury, including 
confirmed adjudicated hepatic events. 
6.5
Overdose 
Overdose is defined as the accidental or intentional ingestion of any dose of IP that is 
considered both excessive and medically important.  For the purpose of this study, an 
overdose is defined as a dose of study medication in excess of that specified in the CSP (ie, 
more than 1 tablet per day of either study drug).   
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. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
77(122) 
x
An overdose without associated symptoms is only reported on the 
Overdose eCRF module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
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 an SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.  
 
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
6.6.1
Maternal exposure 
If a patient becomes pregnant during the course of the study all study medication should be 
discontinued immediately.  The patient should be withdrawn from study and continue 
treatment of diabetes according to the standard of care.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day ie, 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 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. 
6.6.2
Paternal exposure  
There is no restriction on fathering children or donating sperm during the study. 
 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
78(122) 
6.7
Management of IP related toxicities 
Dose reductions are not permitted in this study. 
6.8
Study governance and oversight 
6.8.1
Hepatic Adjudication Committee 
An independent Hepatic Adjudication Committee, blinded to the treatment of the patients, will 
determine the probability that drug-induced liver injury (DILI) is the cause of liver-related 
abnormalities, including, but not limited to: 
x
Hepatic events timely related to death (within 30 days before death)  
x
AST and/or ALT >3x ULN and TB >2x ULN (within 14 days of the AST 
and/or ALT elevation; see Appendix D 
x
AST and/or ALT >10x ULN  
A separate Adjudication Manual will define and describe the procedure for the handling, 
reporting and classification of these cases. 
6.8.2
Cardiovascular Adjudication Committee 
Adjudication for hospitalization for heart failure will be performed according to the respective 
charter using pre-specified criteria by an adjudication committee composed of independent 
cardiologists blinded to study treatment.  The adjudication committee operations and criteria 
will be described in a separate charter. 
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1
Identity of investigational product(s) 
Table 4 
Investigational Products for Study D1689C00014 
Blinded Investigational 
product 
Dosage, route, form and strength 
Manufacturer 
Dapagliflozin  
10 mg, orally 
Green, plain, diamond-shaped,  
film-coated tablet 
AstraZeneca 
Placebo for dapagliflozin  
Does not contain active ingredient, orally 
Green, plain, diamond-shaped,  
film-coated tablet 
AstraZeneca 
Saxagliptin 
5 mg, orally 
Plain, yellow, biconvex, round,  
film-coated tablet 
AstraZeneca 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
79(122) 
Blinded Investigational 
product 
Dosage, route, form and strength 
Manufacturer 
Placebo for 
saxagliptin 
Does not contain active ingredient, orally 
Plain, yellow, biconvex, round,  
film-coated tablet 
AstraZeneca 
Glimepiride (comparator) 
1, 2, or 4 mg, orally 
Opaque gray capsule 
AstraZeneca  
Placebo for glimepiride 
Does not contain active ingredient, orally. 
Opaque gray capsule 
AstraZeneca  
 
The IPs will be supplied by Astrazeneca.  Primary packaging of the IP will be carried out by 
AstraZeneca or their designee in accordance with Good Manufacturing Practice (GMP).   
It is the responsibility of the Investigator to ensure that IP is only dispensed to study patients.  
The IP must be dispensed only from official study sites by authorised personnel according to 
local regulations. 
In this protocol, the identity of the IPs are described in Table 4. 
The formulation number and batch number will be recorded in the electronic Trial Master File 
and identified in the CSR. 
Dapagliflozin, saxagliptin, glimepiride and their matching placebo tablets will be packed in 
bottles and provided as individual patient kits at Visit 2.  The tablets may contain lactose, 
which may cause discomfort in lactose-intolerant individuals.  For additional information refer 
to the prescribing information for saxagliptin and dapagliflozin.  
Non IP medications: Rescue medication (insulin) and metformin will not be provided by the 
Sponsor, since it is part of patient’s standard of care. 
7.2
Dose and treatment regimens 
The study consists of an Enrolment visit (Visit 1), a Randomisation visit (Visit 2), followed by 
a 52 week randomised, double-blind, double-dummy treatment period.   
AstraZeneca or a designated representative will provide all IPs.  In the event the patient loses 
her/his study medication, the study centre should notify the Investigator immediately in order 
to receive a replacement kit via the IWRS. 
At Visit 2, patients will be randomly assigned to 1 of the 3 treatment arms and randomised 
study medication will be dispensed in kits as dapagliflozin 10 mg tablets, saxagliptin 5 mg 
tablets, glimepiride 1 to 6 mg capsules (see Section 4.3.3), and matching placebo tablets.  
Study medication will be dispensed according to the schedule presented in Table 5. 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
80(122) 
Every day during the treatment period, patients will take 4 tablet/capsules:  1 from the 
dapagliflozin bottle, 1 from the saxagliptin/placebo bottle, 1 from each of the 
glimepiride/placebo bottles (Bottle A and Bottle B; see Table 6). 
The first doses of study medication will be taken at the study site.  Patients will subsequently 
self administer saxagliptin, dapagliflozin, glimepiride, and matching placebos QD orally for 
the 52-week treatment period. 
On days of scheduled study visits, patients should bring their study medication with them to 
the study site and will take that daily dose as directed by study site personnel. 
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 patients should skip the missed dose and take the medicine at the 
next regularly scheduled time. 
Table 5  
Schedule of Study Medication Dispensation 
Enrolment 
Blinded Study Medication during Randomised Treatment Period 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Study Week 
W-2 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W24 
W36 
W48 
W52 
Dapagliflozin 
or placebo 
(tablets) 
- 
X 
- 
- 
- 
- 
- 
X 
X 
X 
X 
- 
Saxagliptin or 
placebo 
(tablets) 
- 
X 
- 
- 
- 
- 
- 
X 
X 
X 
X 
- 
Glimepiride  
or placebo 
(capsules)a 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Note: A dash denotes no dispensation of the drug and X denotes that drug will be dispensed at the specified 
visit. 
a 
Glimepiride will be dispensed in 2 bottles, see Table 6. 
Abbreviations: W week. 
 
Table 6 
Titrated Dose Levels and Contents of Blinded Glimepiride or Placebo Kit 
Dose levels 
Total Dosage 
Bottle A 
Bottle B 
0 
0 mg 
Placebo 
Placebo 
1 
1 mg
1 mg 
Placebo 
2 
2 mg
2 mg 
Placebo 
3 
3 mg
1 mg 
2 mg 
4 
4 mg
2 mg 
2 mg 
5 
5 mg
1 mg 
4 mg 


Clinical Study Protocol 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
81(122) 
Dose levels 
Total Dosage 
Bottle A 
Bottle B 
6 
6 mg
2 mg 
4 mg 
7 
Placebo
Placebo 
Placebo 
 
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements for labelling.  
Label text will be translated into local language. 
The label will include at least the following information: 
1. Name of Sponsor 
2. Pharmaceutical dosage form, route of administration, and quantity of dosage units 
3. Code number to identify the contents and packaging operation 
4. Study code 
5. Enrolment code (to be added on the label when IP is dispensed)    
6. Directions for use  
7. “For clinical trial use only” 
8. Storage conditions 
9. Period of use, eg, expiration date 
10. “Keep out of the reach of children” 
11. The name of the Investigator, where applicable (to be added on the label when IP 
is dispensed)  
12. Visit date 
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. 
 


Clinical Study Protocol 
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Study Code D1689C00014 
Edition 4.0 
Date 12 January 2017 
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7.5
Compliance 
The patient will be asked about compliance at each study visit.  When study medication is 
returned, compliance will be assessed based upon subject’s interview and a count of the 
tablets returned.  Compliance should be between 80% and 120% of that prescribed.  The 
Investigator (or designee) will record the amounts of study medication dispensed and returned 
at each visit, 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 80% compliant with recording study drug 
doses during the study, then the period of non compliance should be noted as a protocol 
deviation and the sponsor should be notified.  Patients judged to be non-compliant may 
continue in the study, but should be counselled on the importance of taking their study 
medication and applicable ancillary medications as prescribed. 
The administration of all study medications (including IPs) should be recorded in the 
appropriate sections of the eCRF.   
7.6
Accountability 
The study drug provided for this study will be used only as directed in the CSP. 
The study personnel will account for all study drugs dispensed and returned from the patient. 
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.  
For this study, study drugs (those supplied by AstraZeneca or sourced by the Investigator) 
such as partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met: 
x
On-site disposal practices must not expose humans to risks from the drug. 
x
On-site disposal practices and procedures are in agreement with  
applicable laws and regulations, including any special requirements for 
controlled or hazardous substances. 
x
Written procedures for on-site disposal are available and followed.  The 
procedures must be filed with the site’s standard operating procedures 
(SOPs) and a copy provided to AstraZeneca upon request. 


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x
Records are maintained that allow for traceability of each container, 
including the date disposed of, quantity disposed, and identification of the 
person disposing the containers.  The method of disposal (ie, incinerator, 
licensed sanitary landfill, or licensed waste disposal vendor) must be 
documented. 
x
Accountability and disposal records are complete, up-to-date, and 
available for the Monitor to review throughout the clinical trial period. 
 
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug. 
It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local, and institutional guidelines and procedures, and provided that appropriate records 
of disposal are kept 
7.7
Return of Study Drug 
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by AstraZeneca must be returned to 
AstraZeneca or designee. The return of study drug will be arranged by the responsible Study 
Monitor. 
Arrangements for the return of study drug will be made by the responsible Study Monitor. 
7.8
Concomitant and other treatments  
Patients must follow the medication restrictions outlined in the inclusion and exclusion criteria 
(Sections 3.1 and 3.2, respectively) during the study.  Dosages of concomitant medications 
should be maintained constant during the study, unless instructed otherwise by the 
Investigator or a treating physician in accordance to the standard of care.  Use of restricted 
medication must be reported to the Sponsor.  Any change in regimen for any concomitant 
medication must the be documented in source documents and entered into the eCRF.  
Concomitant herbal or nutritional therapies must also be entered into the eCRF. 
The table below lists prohibited medications during the study and the applicable time frames. 
Restricted Medication/Class of drug: 
Usage 
Sulfonylureas, pioglitazone, rosiglitazone, 
GLP-1 receptor agonists, any DPP-4 and 
SGLT2 inhibitors other than IP 
Prohibited during the study.   
Insulin therapy (with the exception of insulin 
therapy during a hospitalisation or use in 
gestational diabetes). 
Use of insulin during the study is only acceptable if 
given as a rescue treatment as allowed per the protocol 
(Section 7.8.2) for any duration as clinically 


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Restricted Medication/Class of drug: 
Usage 
necessary, or for a temporary use in the following 
situations: 
- For up to 14 days in total and up to 7 consecutive 
days if patient is unable to take oral medications 
- For up to 14 days in total and up to 7 cconsecutive 
days if there is a documented illness or infection that 
requires additional therapy to maintain glycaemic 
control 
- For up to 14 days in total and up to 7 cconsecutive 
days if patients have to temporarily stop study 
medication or metformin due to recommendations 
made in this protocol 
- For up to 7 days during hospitalization.  When the 
reason for hospitalisation is the management of the 
patient’s glycaemic control, treatment with insulin is 
considered a rescue and is allowed for as long as 
clinically necessary 
Other investigational drugs or participation in 
any interventional clinical study 
Prohibited during the study. 
Treatment with systemic glucocorticoids 
equivalent to oral prednisolone 10 mg 
(betamethasone 1.2 mg, dexamethasone 
1.5 mg, hydrocortisone 40 mg) per day 
Newly initiation of treatment with any systemic 
corticosteroid therapy that will involve 5 days of 
therapy (inhaled and topical are allowed).  The 
Medical Monitor should be consulted prior to 
beginning therapy with corticosteroids for patients 
who require systemic corticosteroid treatment. 
Prescription or over-the-counter weight loss 
medications 
Prohibited during the study. 
 
7.8.1
Metformin 
Patients will remain on their pre-study stable, maximum tolerated metformin doses 
1500 mg/day, during the 52-week double-blind treatment period of the study.  Metformin 
should be administered and stored according to product and country-specific labelling. 
Metformin will not be provided in pre-packaged kits by the Sponsor as it is the usual care 
prior to study participation. 
7.8.2
Rescue therapy 
Patients may be eligible for rescue therapy (see Section 4.3.4) with open-label rescue 
medication (Insulin) in order to treat ongoing hyperglycaemia.  Patients should continue 
receiving blinded 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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Rescue therapy will be prescribed by the Investigator and not provided by the Sponsor, 
however could be supplied/prescribed according to local requirements. 
7.8.3
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF. 
8.
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1
Statistical considerations 
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violators identified at the end of the 52-week randomised treatment period. 
 
Due to the large number of centres and the expected low number of patients per centre, data 
from all sites will be pooled together and centre effects will not be investigated.  
All collected data will be listed.  A comprehensive Statistical Analysis Plan (SAP) and any 
subsequent amendments will be documented, with final amendments completed prior to 
unblinding of the data. 
8.2
Sample size estimate 
The primary objective of this study is to examine whether, after 52 weeks of oral 
administration of double-blind treatment, the absolute change from baseline in HbA1c levels 
with dapagliflozin plus metformin and dapagliflozin plus saxagliptin added to metformin is 
non-inferior to glimepiride plus metformin in patients with T2DM who have inadequate 
glycaemic control on 1500 mg/day metformin therapy. 
To demonstrate non-inferiority of dapagliflozin and dapagliflozin plus saxagliptin to 
glimepiride for changes from baseline to Week 52 in HbA1c within a non-inferiority margin 
of 0.30%, assuming a standard deviation 1.0%, and at a 1-sided significance level of 0.025, 
290 evaluable patients will be needed in each treatment group to provide approximately 95% 
power (given a true difference of zero between dapagliflozin or dapagliflozin plus saxagliptin 
and glimepiride).  The non -inferiority margin of 0.3% as well as a common standard 
deviation of 1.0% were selected based on information from earlier, similarly designed studies. 
Assuming that 5% of patients do not have a post-baseline assessment, a total of approximately 
930 patients (310 patients per treatment arm) need to be randomised.   
Assuming that 30% of screened patients will fail to meet screening criteria, a total of 
1329 patients need to be screened. 
Redacted


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8.3
Definitions of analysis sets 
Classification into Full Analysis (FA), Per Protocol (PP), and Safety sets will be conducted 
prior to the database lock.  
The primary efficacy analysis will be performed on the FA set. A supportive analysis will be 
carried out with the PP analysis set.  Analyses of all secondary efficacy endpoints will be 
performed using the FA analysis set.  All safety analyses will be based on the Safety set. 
Randomised set 
The randomised set will be defined as all randomised patients. 
Full analysis set 
The FA set will be defined as all randomised patients who receive at least one dose of study 
medication and who have a baseline and a post-baseline efficacy assessment value.  Patients 
will be analysed according to the treatment assigned. 
Per protocol analysis set 
The PP analysis set will be defined as all FA patients without an important protocol deviation 
that might affect the primary efficacy analyses.  The criteria for important protocol deviations 
will be defined in the statistical analysis plan.  Patients will be analysed according to the 
treatment assigned. 
A complete list of protocol violations will be provided in the SAP.  
Safety analysis set 
The safety analysis set will be defined as all randomised patients who received at least 1 dose 
of study medication.  Patients will be analysed according to the actual treatment received. 
8.4
Outcome measures for analyses 
8.4.1.1
Key secondary endpoints 
x
Proportion of patients reporting at least 1 episode of confirmed 
hypoglycaemia during the double-blind treatment period. 
x
Change in total body weight from baseline at Week 52. 
x
Change in FPG from baseline at Week 52. 
x
Time to rescue during the 52-week double-blind treatment period. 


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8.4.1.2
Other secondary endpoints 
x
Proportion of patients achieving HbA1c of  <7% (and <7.5%) without 
confirmed hypoglycaemia at Week 52. 
x
Proportion of patients achieving HbA1c of  <7% (and <7.5%) at 
Week 52. 
x
Proportion of patients achieving individually agreed HbA1c targets at 
Week 52. 
x
Proportion of patients achieving an HbA1c decrease of 1% with no 
weight gain at Week 52. 
x
Time spent below HbA1C target (<7% and <7.5%) from baseline until 
Week 52. 
x
Change in BMI from baseline to Week 52. 
x
Proportion of patients achieving weight reduction of 5% and weight 
gain of 5% from baseline to Week 52. 
x
Proportion of patients reporting at least 1 episode of any hypoglycaemia 
during the treatment period. 
x
Change in waist circumference from baseline to Week 52. 
x
Change in systolic BP from baseline to Week 52 
8.4.2
Exploratory endpoints 
x
Change from baseline to Week 52 in SF-36, Worry Scale of the 
Hypoglycaemia Fear Survey, and IWQOL-Lite survey. 
x
Change in waist:hip circumference ratio from baseline to Week 52. 
 
8.5
Methods for statistical analyses 
Continuous variables will be presented with mean, median, 25th percentile, 75th percentile, 
standard deviation, minimum, maximum, and (if appropriate) the number of nonmissing 
observations.  Categorical data will be displayed via absolute and relative frequencies for each 
category, including a category labeled as ‘missing’ when appropriate.  The ‘missing’ category 
will not contribute to the denominators of relative frequencies. 


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8.5.1
Demographic and baseline characteristics 
Demographic and baseline characteristics will be summarised using frequency distributions 
and descriptive statistics using the randomized set, for each treatment group as well as for all 
patients combined.  Key baseline characteristics that will be summarised include: age, gender, 
race, ethnicity, country, body weight, BMI, eGFR, duration of T2DM, baseline FPG, and 
baseline HbA1c.  Baseline is defined as the last measurement prior to the first dose of 
double-blind study medication or as the last non-missing value of the visit 1 or visit 2 
assessment for those subjects without first dose start date. No statistical tests will be 
performed to compare treatment groups at baseline. 
8.5.2
Efficacy analyses 
All efficacy analyses will be performed using the FA set.  A sensitivity analysis will also be 
conducted using the PP set. 
All analyses will be done using values prior to rescue of treatment.  Values collected after this 
time will be excluded from analyses.  Sensitivity analyses will be conducted for the primary 
endpoint using all available data.  For the endpoint of the proportion of patients achieving 
therapeutic glycaemic response at Week 52, all available data will be used but patients rescued 
prior to Week 52 will be treated as non-responders. 
8.5.3
Control of type 1 error 
The experiment-wise type I error will be controlled to a maximum of 5%.  A hierarchical 
closed testing procedure will be employed such that key secondary endpoints will be 
considered for statistical significance (in terms of superiority) only if non-inferiority of the 
primary endpoint is concluded and that a key secondary endpoint will be considered for 
statistical significance only if test ordered before it is found to be statistically significant.  At 
each step, dapagliflozin plus saxagliptin added to metformin versus glimepiride added to 
metformin will be tested first followed by the test for dapagliflozin added to metformin versus 
glimepiride added to metformin except for the superiority tests of the primary endpoint and 
the endpoint of total BW.  The test of superiority for HbA1c will include only the comparison 
of dapagliflozin plus saxagliptin added to metformin vs glimepiride added to metformin.  For 
total BW, dapagliflozin added to metformin versus glimepiride will be tested first followed by 
dapagliflozin plus saxagliptin added to metformin versus glimepiride added to metformin. 
The following testing order will be followed for the overall type I error control: 
1. Change from baseline in HbA1c at Week 52 (test for non-inferiority) 
2. Proportion of patients reporting at least 1 episode of confirmed hypoglycaemia at 
Week 52 (test for superiority) 
3. Change in total body weight from baseline to Week 52 (test for superiority) 
4.
Change from baseline in HbA1c at Week 52 (test for superiority of dapagliflozin plus 
saxagliptin added to metformin to control only) 


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5.
Change in FPG from baseline to Week 52 (test for superiority) 
6.
Time to rescue at Week 52 (test for superiority) 
The statistical comparisons will be done using a comparison-wise type I error of 5% (2-sided). 
For all other secondary variables and exploratory variables, nominal p-values will be reported 
without significance testing. 
 
8.5.4
Analysis of the primary efficacy variable 
The primary objective of this study is to show non-inferiority of dapagliflozin added to 
metformin and dapagliflozin plus saxagliptin added to metformin versus glimepiride added to 
metformin in terms of the primary efficacy variable change in HbA1c from baseline to 
Week 52. 
The following null hypothesis (H0) will be tested against the alternative hypothesis 
(HA) (Į=0.025, 1-sided): 
H0: 
μc - μt  -0.30%, 
HA: 
μc - μt > -0.30%, 
where μt denotes the mean absolute change in HbA1c from baseline to Week 52 in the group 
of patients treated with dapagliflozin added to metformin or dapagliflozin plus saxagliptin 
added to metformin (test medication) and μc denotes the mean absolute change in HbA1c from 
baseline to Week 52 in the group of patients treated with glimepiride added to metformin 
(control). 
The absolute change from baseline to Week 52 in HbA1c will be analysed using a restricted 
maximum likelihood-based (REML), Mixed-Model Repeated Measures (MMRM) model with 
terms for treatment group, baseline HbA1c, time (at relevant visits), and interactions baseline 
HbA1c-by-time and treatment group-by-time.  The model will be used to derive a 
least-squares estimate of the mean treatment difference with corresponding 2-sided 95% 
confidence interval (CI).  The primary assessments of efficacy will be a comparisons of each 
of the 2 test groups the dapagliflozin plus saxagliptin added to metformin versus the control 
group and the dapagliflozin added to metformin versus the control group using a 95% CI.   
In particular, if the observed lower limit from a 2-sided 95% (or 1-sided 97.5%) CI for the 
difference in adjusted means is greater than -0.30%, then the test group will be considered to 
be non-inferior to the control group.  Note, that multiplicity will be controlled using a 
sequential testing scheme as described above.  The dapagliflozin plus saxagliptin added to 
metformin group will be tested versus the control group first, followed by the dapagliflozin 
plus metformin group versus the control group. 


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A superiority test of the dapagliflozin plus saxagliptin added to metformin group versus the 
control group will also be conducted using the same modelling approach as for the primary 
non-inferiority analysis.  
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
(DDFM).  An unstructured variance will be used to model the within-patient errors.   
8.5.5
Sensitivity analysis (if applicable) 
Sensitivity analyses will be performed to assess the impact of assumptions on the results of the 
analyses by using other statistical methods. 
Following sensitivity analyses will be performed: 
x
The primary analysis will be repeated with patients from the Per-Protocol analysis set 
x
The primary analysis will be repeated including all values according to the ITT 
principle (regardless of rescue or treatment or discontinuation) 
x
ANCOVA analysis using values prior to rescue at week 52. If Week 52 value is not 
available the LOCF value will be used 
8.5.6
Analysis of the secondary and exploratory variables 
All secondary endpoints will be analysed using the FA set.  In order to protect the overall type 
I error rate, the interpretation of the statistical significance of treatment comparisons for key 
secondary efficacy endpoints will be done using a procedure as outlined in Section 8.5.3. 
The analysis of the changes from baseline to Week 52 for FPG, total body weight and and 
systolic Blood Pressure (SBP) will be performed using the same MMRM model as described 
for the primary efficacy endpoint.  Point estimates and 95% CI will be calculated for the 
adjusted mean changes from baseline within each treatment group as well as for each 
comparison versus control in adjusted mean changes together with the p-values corresponding 
to testing the hypotheses of no difference between dapagliflozin added to metformin and 
dapagliflozin plus saxagliptin added to metformin compared to glimepiride added to 
metformin. 
The time spent below HbA1C target (<7% and <7.5%) from baseline until Week 52 as well as 
the change from baseline at Week 52 in BMI and waist circumference will be analysed using 
an analysis of covariance (ANCOVA) model that will include terms for treatment groups and 
the baseline respective covariate.   
The ANCOVA model will be used to derive a least squares estimate of the contrasts of each 
test combination versus the control with 95% CI and a corresponding 2-sided p-value.  
Furthermore, a 2-sided 95% CI for the mean change within each treatment group will be 
calculated. 
Time to rescue will be analysed using a Cox proportional hazards model.  Estimates of the 
hazard ratio and 95% CI will be provided.  Kaplan-Meier estimates will be calculated and 


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plotted by treatment group.  For the analysis during 52 weeks, all patients will be censored at 
the final visit if rescue has not occurred by then. 
The proportion of patients achieving a therapeutic glycaemic response at Week 52 and  
reporting hypoglycaemia during the double-blind treatment period will be summarised by 
treatment group and compared between treatment groups using logistic regression with 
baseline HbA1c as a covariate.    
The proportion of patients achieving a weight reduction/gain at Week 52 will be summarised 
by treatment group and compared between treatment groups using logistic regression with 
baseline weight as a covariate. 
The proportion of patients achieving composite endpoints will be summarised by treatment 
group and comparisons between treatment groups (contrasts of each test combination versus 
the control) will be done using a Chi-Square test. 
All exploratory endpoints will be analysed only in a descriptive fashion (no inferential 
procedure will be applied). 
8.5.7
Subgroup analysis 
Subgroup analyses for age, gender, race, eGFR and baseline HbA1c for continuous endpoints 
will be analysed as was done for the original analysis but for the applicable subset of patients.  
Interaction tests will be performed for time to event and continuous endpoints using the 
original model with treatment interaction terms added. 
8.5.8
Safety analyses 
The assessment of safety will be based on the analyses of AEs, vital signs, physical 
examinations, ECGs, hypoglycaemia, and clinical laboratory evaluations.  All safety analyses 
will be performed on the Safety Set. 
The number and percent of patients with at least 1 AE will be summarised for each treatment 
group, including summaries of AEs, SAEs, AEs leading to discontinuation of study 
medication, and AEOSI.  Summaries will include the number of patients with events by 
specified system organ classes and preferred terms. 
Additionally, the incidence and frequency of AEs will be summarised for each treatment 
group for both frequent events (occurring in at least 5% of patients) and for selected AEOSI. 
Summary statistics will be presented at each assessment visit for the continuous laboratory 
parameters.  Descriptive statistics of changes from baseline by study visits will also be 
presented. 
A frequency table of results of categorical laboratory parameters will be produced.  
Furthermore, laboratory abnormalities will be analysed by shift tables where each patient will 
be counted only once with the worst grade in the summary tables.  The number and percent of 


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patients with laboratory values meeting marked abnormality criteria will be summarised for 
each treatment group. 
All laboratory data will be listed with abnormal values flagged. 
Vital signs will be listed and summarised over time by treatment group.  Changes from 
baseline will also be summarised.  Notable values and changes will be tabulated. 
The normality/abnormality of the ECG tracing (as determined by the investigator) at baseline 
versus week 52 of the double-blind treatment period will be summarised.  
The number of patients with hypoglycaemic events and the percentage of patients 
withdrawing from the study medication due to hypoglycaemia will be presented descriptively 
by treatment group. 
8.6
Interim analysis 
No interim analysis on the efficacy or safety parameters is planned for this study. 
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the CSP and related documents with the investigational staff and 
also train them in any study specific procedures and the WBDC system utilised. 
The 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 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 CRO and 
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 accordance with the Laboratory Manual and that 
study drug accountability checks are being performed 


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x
Perform source data verification including verification of informed 
consent of participating patients.  This will require direct access to all 
original records for each patient (eg, clinic charts) 
x
Ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the patient. 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
9.2.1
Source data 
Refer to the CSA for location of source data. 
9.2.2
Study agreements 
The Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this CSP and the CSA, the terms of CSP shall prevail with respect to the conduct of 
the study and the treatment of patients and in all other respects, not relating to study conduct 
or treatment of patients, the terms of the CSA shall prevail. 
Agreements between AstraZeneca or representative and the Investigator should be in place 
before any study-related procedures can take place, or patients are enrolled. 
9.2.3
Archiving of study documents 
The Investigator follows the principles outlined in the CSA. 
9.3
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study’. 
The first patient is expected to be enrolled 3rd Quarter of 2015.  The study is expected to 
complete 1st Quarter 2017. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with saxagliptin or dapagliflozin.
9.4
Data management by AstraZeneca or delegate 
Data management will be performed by AstraZeneca or representative, according to the Data 
Management Plan.  AEs and medical/surgical history will be classified according to the 
terminology of the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA).  Medications will be classified according to the AstraZeneca Drug Dictionary 


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(AZDD).  Classification coding will be performed by the Medical Coding Team at 
AstraZeneca or representative. 
Data entered in the electronic data capture (eDC) system will be immediately saved to a 
central database and changes tracked to provide an audit trail.  When the Principal Investigator 
has signed the eCRF electronically as per eCRF instructions, then the patient’s data will be 
locked. 
Electronic case report forms 
The eCRF and the protocol are both confidential.  The eCRF will be created by AstraZeneca 
or representative and programmed into the eDC system.  All study centres will need internet 
access to access the eCRFs and will only have access to data for patients at their own study 
centres.  Data Management (DM) and other coordinator teams will have access to data at all 
study centres.  All eCRFs are to be completed by an authorised member of the study centre 
staff and reviewed and signed by the Investigator.  All entries, corrections, and alterations are 
to be made by the responsible Investigator or an authorised member of the study centre staff.  
All eCRFs are to be completed in a manner that ensures accurate interpretation of data.  It is 
each Investigator’s responsibility to ensure that all discontinued orders or changes in the study 
or other medications entered on the patient’s eCRF correspond to the entries on the patient’s 
medical records. 
The eCRFs for any patient leaving the study should be completed at the time study medication 
is terminated or a patient discontinues study participation for whatever reason.  The eCRFs 
must accurately reflect data contained in the patient’s records (eg, source). 
Dataflow 
After the data are entered into the eCRF by study centre, auto-queries that are generated by the 
eDC system should be addressed by the study centre.  Data queries will be raised for 
inconsistent, impossible, or missing data.   
At the monitoring visit, the Study Monitor must perform the study data verification (SDV) of 
the required fields on completed forms, and if there are no open queries, freeze the form.  Data 
management will run manual consistency checks outside of the eDC system and will raise 
manual queries for study centres to address; if the form is frozen, DM will unfreeze it to allow 
study centres to amend data.  The same process is to be followed by any other groups creating 
manual queries in the eDC system (eg, for SAE reconciliation).  Once all data are entered, 
SDV complete on required fields, manual queries and electronic data reconciliation complete, 
and all queries closed, then the casebook can be signed.  Once the casebook is signed, DM 
will then lock the casebook so that no amendments can be made. 
Database lock 
Once all patient casebooks are locked, the final data transfer can be sent to statistics.  A 
database lock checklist will also be completed by DM and the programmer to confirm all 


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applicable quality control checks were performed.  When all data have been coded, validated, 
and locked, clean file will be declared.  Any treatment revealing data may thereafter be added 
and the final database will be locked 
Coding 
All AEs and Medical Histories recorded in the eCRF will be classified according to the 
terminology of the latest version of the MedDRA.  Medications will be classified according to 
the AZDD.  The coding will occur outside of the eDC system and will be merged with the 
clinical datasets sent to statistics. 
The data collected through third party sources will be obtained and reconciled against study 
data. 
The data will be validated as defined in the DM 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 DM Plan will also clarify the roles and responsibilities of the various 
functions and personnel involved in the data management process. 
Serious Adverse Event (SAE) Reconciliation 
AstraZeneca or representative will perform SAE reconciliation between the clinical study 
database and the safety data entry site clinical patient safety database.  
Data associated with human biological samples 
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca. 
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 global standard: Human 
Biological Samples.
10.2
Subject data protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
10.3
Ethics and regulatory review 
An Ethics Committee (EC) should approve the final study protocol, including the final version 
of the ICF and any other written information and/or materials to be provided to the patients.  


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The Investigator will ensure the distribution of these documents to the applicable EC, and to 
the study site staff. 
The opinion of the EC should be given in writing.  The Investigator should submit the written 
approval to AstraZeneca before enrolment of any patient into the study.  
The EC should approve all advertising used to recruit patients for the study. 
AstraZeneca or designee should approve any modifications to the ICF that are needed to meet 
local requirements. 
If required by local regulations, the CSP should be re-approved by the EC annually. 
Before enrolment of any patient into the study, the final CSP, 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 or designee will handle the distribution of any of these documents to the national 
regulatory authorities. 
AstraZeneca or designee will provide Regulatory Authorities, ECs, and Investigators with 
safety updates/reports according to local requirements. 
Each Principal Investigator is responsible for providing the EC/ Institutional Review Board 
(IRB) 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 Investigator so that 
he/she can meet these reporting requirements. 
10.4
Informed consent 
The Investigator(s) at each centre will: 
x
Ensure each patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study 
x
Ensure each patient is notified that they are free to discontinue from the 
study at any time 
x
Ensure that each patient is given the opportunity to ask questions and 
allowed time to consider the information provided 
x
Ensure each patient 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 


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x
Ensure a copy of the signed ICF is given to the patient 
x
Ensure that any incentives for patients who participate in the study as 
well as any provisions for patients harmed as a consequence of study 
participation are described in the informed consent form that is approved 
by an EC. 
10.4.1
Screening Informed Consent 
The screening informed consent is an abbreviated document that explains the risks associated 
with the screening laboratory test (HbA1c) performed to assess qualification to the study.  
This document will provide only general information about the study, without the need to 
provide any specific details about the study procedures, and risks or benefits from study 
participation.  The screening ICF will also document the patient’s consent to return to the 
enrolment visit in a fasting state, in case they are considered eligible for the study.  For any 
patient that undergoes the screening procedure and is considered eligible to participate in the 
study, the full informed consent will be provided at the enrolment visit. 
10.5
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International 
Coordinating Investigator, the Investigator, and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a CSP Amendment and where required in a new version of the study protocol 
(Revised CSP). 
The CSP Amendment is to be approved by the relevant EC 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 CSP to each 
Investigator(s).  For distribution to EC see Section 10.3. 
If a protocol amendment requires a change to a centre’s ICF, AstraZeneca and the centre’s EC 
are to approve the revised ICF before the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each EC. 
10.6
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an EC may perform 
audits or inspections at the centre, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 


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any applicable regulatory requirements.  The Investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the centre. 
11.
LIST OF REFERENCES 
Bolinder et al 2012 
Bolinder J, et. al, Effects of dapagliflozin on body weight, total fat mass, and regional 
adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic 
control on metformin. JCEM 2012 Mar;97(3):1020-31 
CCNYHA 1994 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, Brown & Co. 
1994; 253-256. 
CDC 2004 
Centers for Disease Control and Prevention (CDC): Prevalence of overweight and obesity 
among adults with diagnosed diabetes-United States, 1988-1994 and 1999-2002. MMWR 
Morb Mortal Wkly Rep 2004; 53:1066-8.   
CHMP 2009 
European Medicines Agency (EMA) Committee for Medicinal Products for Human Use 
(CHMP). Guideline on Clinical Development of Fixed Combination Medicinal Products. 
CHMP/EWP/240/95 Rev. 1. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00003686.pdf. Published 19 February 2009. Accessed 19 June 2014. 
CHMP 2012 
European Medicines Agency (EMA) Committee for Medicinal Products for Human Use 
(CHMP). Guideline on clinical investigation of medicinal products in the treatment or 
prevention of diabetes mellitus. CPMP/EWP/1080/00 Rev. 1. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC5
00129256.pdf. Published 14 May 2012. Accessed 19 June 2014. 
Del Prato et al 2011 
Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of 
saxagliptin monotherapy on glycaemic control and markers of ȕ-cell function in patients with 
inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab.  
2011; 13:258-267. 
Dicker 2011 
Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. 
Diabetes Care. 2011; 34 (Suppl) 2:S276-8. 


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Study Code D1689C00014 
Edition 4.0 
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Gomis et al 2011 
Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial 
combination therapy with saxagliptin and pioglitazone in patients with inadequately controlled 
type 2 diabetes: a randomized, double-blind, placebo controlled study. Diabetes Obes Metab. 
2011; 13:653-661.  
Hoerger et al 2008 
Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? 
Diabetes Care. 2008; 31:81-86.  
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. 
James et al 2014 
James P, Oparil S, Carter B, Cushman W, Dennison-Himmelfarb C, Handler J, et al. 2014 
Evidence-Based Guideline for the Management of High Blood Pressure in Adults, Report 
from the panel memebers appointed to the Eigth joint National Committee (JNC 8), JAMA. 
2014; 311 (5) 507-520. 
Klein et al 2004 
Klein S, Sheard NF, Pi-Sunyer X, Daly A, Wylie-Rosett J, Kulkarni K, et al. Weight 
management through lifestyle modification for the prevention and management of type 2 
diabetes: rationale and strategies. A statement of the American Diabetes Association, the 
North American Association for the Study of Obesity, and the American Society for Clinical 
Nutrition. Diabetes Care 2004; 27(8):2067-2073. 
Kolotkin et al 2003 
Kolotkin RL, Crosby RD, Pendleton R, Strong M, Gress RE, Adams T. Health-related quality 
of life in patients seeking gastric bypass surgery vs non-treatment-seeking controls. Obes Surg 
2003;13(3):371-7. 
NHLBI 1998 
National Heart, Lung, and Blood Institute (NHLBI) Clinical Guidelines on the Identification, 
Evaluation, and Treatment of Overweight and Obesity in Adults. NIH publication No. 
98-4083. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm. Published 
September 1998. Accessed 19 June 2014. 
Owens et al 2011 
Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of saxagliptin in persons 
with Type 2 diabetes inadequately controlled by a combination of metformin and 
sulphonylurea: a 24 week randomized study. Diabet Med. 2011; 28:1352-1361. 


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Study Code D1689C00014 
Edition 4.0 
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Riddle 2005  
Riddle MC. Glycemic management of type 2 diabetes: an emerging strategy with oral agents, 
insulins, and combinations. Endocrinol Metab Clin North Am 2005; 34: 77–98. 
Rosenstock J 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 randomized double-blind 
trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or 
dapagliflozin to metformin. Diabetes Care. 2015; 38(3): 376-83. 
Rosskamp R et al 1996  
Rosskamp R, et. al, Clinical profile of the novel sulfonylurea glimepiride, Diabetes res Clin 
Pract. 1996 Jul; 31 Suppl: S33-42 
Ryden L et al 2013 
Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, et al. ESC Guidelines on 
diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: 
the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society 
of Cardiology (ESC) and developed in collaboration with the European Association for the 
Study of Diabetes (EASD). Eur Heart J. 2013; 34(39):3035-87.  
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. 
Taskinen et al 2011 
Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, et al. Safety and 
efficacy of saxagliptin as add-on therapy to metformin in patients with type 2 diabetes: a 
randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011; 13:65-74.  
UKPDS 1998 
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications in 
patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837-853. 
UKPDS 1998b 
UK Prospective Diabetes Study Effect of intensive blood-glucose control with metformin on 
complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998b; 
352:854-865.  


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Appendix A 
Additional Safety Information 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
‘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 (eg, 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 (eg, 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 (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation 
Development of drug dependency or drug abuse 
 


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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. 
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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Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus: 
x
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 
x
UN 3373 – Biological Substance, Category B 
x
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
x
Clinical trial samples will fall into Category B or exempt under IATA regulations 
x
Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging  
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 
containment standards are encouraged wherever possible when road or rail transport is 
used.


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Appendix C 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
TABLE OF CONTENTS 
PAGE
 
TABLE OF CONTENTS ..................................................................................... 104
1.
INTRODUCTION ............................................................................................... 105
2.
DEFINITIONS ..................................................................................................... 105
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES ............................... 106
4.
FOLLOW-UP ...................................................................................................... 107
4.1
Potential Hy’s Law Criteria not met .................................................................... 107
4.2
Potential Hy’s Law Criteria met .......................................................................... 107
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES ........... 107
6.
REFERENCES .................................................................................................... 108
 


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1.
INTRODUCTION 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  Specific guidance on the managing liver abnormalities can 
be found in Section 5.2.5.2 of the protocol. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes. 
2.
DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)  3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TB)  2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP).  
Hy’s Law (HL) 
AST or ALT  3x ULN  together with TB  2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TB, but there is no specified timeframe within which the elevations 
in transaminases and TB must occur. 


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3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
x
ALT  3xULN 
x
AST  3xULN 
x
TB  2xULN 
 
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative).  
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will: 
x
Notify the AstraZeneca representative 
x
Request a repeat of the test (new blood draw) by the central laboratory 
x
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay: 
x
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits (including 
both central and local laboratory results) 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
x
Notify the AstraZeneca representative 
x
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits 
x
Promptly enter the laboratory data into the laboratory CRF 


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4.
FOLLOW-UP 
4.1
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
x
Inform the AstraZeneca representative that the patient has not met PHL criteria. 
x
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
4.2
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
x
Notify the AstraZeneca representative who will then inform the central Study Team  
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will: 
x
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated  
x
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests available 
in the Hy’s law lab kit should be used.  
x
Complete the three Liver CRF Modules as information becomes available  
x
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.   


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According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TB elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
x
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
x
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes 
If it is agreed that there is no explanation that would explain the ALT or AST and TB 
elevations other than the IMP: 
x
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
x
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
x
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review 
6.
REFERENCES 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 


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Appendix D 
Algorithm on Management of Sustained Elevated Liver 
Safety Abnormalities 
ALGORITHM ON MANAGEMENT OF SUSTAINED ELEVATED 
LIVER SAFETY ABNORMALITIES 
The monitoring for liver safety will be performed using the serum levels of AST, ALT, and 
TB (see Figure 2 
Sustained elevated liver safety abnormalities flow chartError! 
Reference source not found. - algorithm flow chart). 
Patients with a central laboratory ALT and/or AST >3X ULN will be scheduled for a 
follow-up visit within 3 days following receipt of the initial laboratory results, to obtain repeat 
central laboratory ALT, AST, TB and Alkaline Phosphatase (ALK-P). In the event that the 
repeat laboratory assessments cannot be obtained within 3 days, the Investigator is encouraged 
to discuss possible alternatives with the Sponsor. Patients should remain on study medication 
until confirmatory results are obtained, unless otherwise contraindicated. 
x
If the repeat ALT and AST are d3X ULN, patient should continue double-blind 
treatment according to their original visit schedule unless otherwise contraindicated. 
x
If the repeat ALT and/or AST are >3X ULN but d8X ULN and TB d2X ULN, 
the patient’s medical history, including details of risk factors for liver diseases, 
should be evaluated for potential underlying aetiologies. In addition, specialized 
blood sampling will be performed to evaluate liver function as well as identify 
potential causes of laboratory elevation(s). The Investigator should continue to 
monitor the patient’s liver tests every 3 days following receipt of the prior 
laboratory results until the ALT and AST are d2X ULN or until ALT and AST are 
at or below baseline levels. The frequency of retesting can decrease to once a week 
or less if abnormalities stabilize and the patient is asymptomatic. Patients should 
remain on study medication unless confirmatory results indicate that a criterion for 
discontinuation has been met or continuing study medication would be otherwise 
contraindicated. 
Patients must be discontinued from the study if an initial and repeat confirmatory
laboratory tests meet any of the following criteria: 
x
ALT and/or AST are !3 x ULN and TB !2 x ULN 
x
ALT and/or AST are >5 x ULN for t14 consecutive days, at any time after initial 
confirmatory results 
x
ALT and/or AST are >8 x ULN 
 


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In each of these situations, study medication will be discontinued, the Sponsor notified and the 
End of Treatment Visit performed within 3 days of the confirmed laboratory results (see 
Section 4.3.5). At the End of Treatment Visit, medical history including details of risk factors 
for liver diseases (if not previously assessed) will be requested and additional blood sampling 
performed (Specialized Liver Panel and Liver Discontinuation Panel, see detailed below). 
Patient should also be scheduled for a Follow-up Visit 3 weeks after discontinuation of 
investigational product. A referral consultation to a hepatologist or gastroenterologist 
(specializing in liver abnormalities) should be obtained. 
Any additional tests and/or examinations should be carried out at the discretion of the 
Investigator. Any further investigations and laboratory results for patients with abnormal 
laboratory values at the Follow-up Visit should be made available to the Sponsor upon 
request. 
Additional information, including but not limited to completion of supplemental eCRFs may 
be requested for certain adverse events and/or laboratory abnormalities which are 
reported/identified as part of the hepatic safety surveillance. 
Following the End of Treatment Visit, the Investigator should continue to monitor the 
subject’s liver tests every 3 days following receipt of the prior laboratory results until the ALT 
and AST are 2 x ULN or until ALT and AST are at or below baseline levels. The frequency 
of retesting can decrease to once a week or less if abnormalities stabilize and the subject is 
asymptomatic. 
Guidance on Assessment of Hepatic Laboratory Abnormalities 
The following is presented to assist in the evaluation and management of hepatic laboratory 
values. It is not intended to supplant Investigators’ clinical judgment. 
Patients who experience ALT and/or AST values >3 x ULN confirmed with a repeated test 
will have the following performed within 3 days of the confirmed laboratory results: 
x
AE assessment 
x
Physical Examination for jaundice and other signs of liver diseases  
x
Review of relevant risk factors and current history focusing on possible causes of 
the increased ALT and/or AST and/or TB, including: 

Use of suspect concomitant medication [including over-the-counter (ie, 
acetaminophen/paracetamol), herbal and vitamin preparations] 

Recent alcohol consumption or recreational drug/narcotic use 

Recent unaccustomed physical exertion 

Occupational or environmental exposure to hepatotoxins  


Clinical Study Protocol Appendix D 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
111(122) 

Other conditions which may cause liver diseases or which may cause abnormal 
test results 
x
Specialized Liver Laboratory Panel (see below) 
Specialized Liver Panel 
For patients who are being monitored frequently as a result of confirmed AST and/or ALT 
>3X ULN, additional central laboratory tests will be performed within 3 days of receipt of 
confirmatory results. These laboratory tests will study the possible causes of the increased 
ALT and/or AST and/or TB, and may include, but are not limited to, the following tests: 
x
Hepatitis A IgM 
x
Hepatitis BsAg 
x
Hepatitis B Core Ab IgM 
x
Hepatitis C virus RNA 
x
Hepatitis C Ab 
x
Hepatitis E IgM 
x
Epstein-Barr Virus (EBV) IgM Ab 
x
Lactate Dehydrogenase (LDH) 
x
Gamma-glutamyl-transpeptidase (GGT) 
x
Carbohydrate deficient transferrin (CDT) 
x
Prothrombin time (PT/INR) 
x
Iron Panel - iron, ferritin, total iron binding capacity (TIBC) 
x
Immunology Panel including Antinuclear Antibody (ANA), Anti-Smooth Muscle 
Antibody (SMA) and Anti-Liver/Kidney Microsomal Antibody (Anti-LKM) 
x
Anti-tissue Transglutaminase Antibody 
Liver Discontinuation Panel 
For patients who are discontinued from the study as a result of sustained elevated liver safety 
abnormalities, additional central laboratory tests will be performed at the time of End of 
Treatment Visit. Similar to the Specialized Liver Panel, these laboratory tests will study the 
possible causes of the increased ALT and/or AST and/or TB, and may include, but are not 
limited to, the following tests: 


Clinical Study Protocol Appendix D 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
112(122) 
x
Cytomegalovirus (CMV) IgM Ab 
x
Herpes Simplex Virus (HSV) 1 and 2 
x
Ceruloplasmin 
x
Toxoplasmosis 
x
Alpha-1 antitrypsin 
For specific details regarding the Specialized Liver Panel or the Liver Discontinuation Panel 
laboratory tests, refer to the Central Laboratory Manual for this study. 
 


Clinical Study Protocol Appendix D 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
113(122) 
Figure 2 
Sustained elevated liver safety abnormalities flow chart 
 
Obtain confirmatory repeat AST, ALT, ALK-P and TB 
within 3 days. Do NOT hold study medication. 
Step 1: Central Laboratory Alert Criteria 
ALT and/or AST > 3x ULN 
a In patients with repeat ALT or AST > 3x ULN but d 8x ULN, only patients with TB d 2x ULN at Step 1 should be followed according to Step 2b. Patients with an initial TB and 
confirmatory repeat TB > 2x ULN should be followed according to Step 2d. 
b
Please see text above in the Appendix for details on additional assessments to be performed (AE assessment, PE, review of current medical history including focused review of 
current medical history including focused review of risk factors for liver diseases and collection of blood samples [specialized liver panel or liver discontinuation panel]). 
c Confirmatory repeat AST, ALT, ALK-P and TB should be obtained every 3 days following receipt of prior laboratory results, until the ALT and AST are d 2x ULN or until ALT and 
AST are at or below baseline levels. The frequency of retesting can decrease to once a week or less if abnormalities stabilize and the patient is asymptomatic. 
If repeat ALT and/or AST > 5x ULN for t 14 consecutive days, at 
any time after initial confirmatory results 
Each time AST, ALT, ALK-P and TB results are received, go 
back to Step 2 to review and implement the appropriate follow-up
Step 2d: 
If repeat ALT and/or AST 
> 3x ULN with a second 
confirmed TB > 2x ULNª 
Step 2e: 
If repeat ALT and/or 
AST > 8x ULN 
Step 2c: 
If repeat ALT and/or AST 
> 5x ULN BUT d 8x ULN 
and TB d 2x ULN 
Step 2b: 
If repeat ALT and/or AST ! 3x 
ULN BUT d5x ULN and TB 
d2x ULN 
Step 2a: 
If first repeat ALT and
AST d 3x ULN  
OR after additional 
repeat testing ALT and 
AST 2x ULN or at/or  
below baseline 
Continue the patient 
in the double-blind 
treatment according 
to the original visit 
schedule, unless 
otherwise 
contraindicated. 
-
Continue study medication 
-
Perform additional 
assessments, including the 
specialized liver panelb 
-
Obtain confirmatory 
repeat AST, ALT, ALK-P 
and TB every 3 days.c 
-
Continue study medication 
-
Perform additional 
assessments, including the 
specialized liver panelb 
-
Obtain confirmatory 
repeat AST, ALT, ALK-P 
and TB every 3 days.c 
-
Discontinue the patient immediately 
-
Notify the Sponsor
-
Perform the End of Treatment visit and 
additional assessments, including the liver 
discontinuation panelb 
-
Obtain confirmatory repeat AST, ALT, 
ALK-P and TB every 3 days.c 


 
114 (122) 
Appendix E 
Patient Reported Outcomes 
 
SF-36 HEALTH SURVEY      
Your Health and Well-Being 
This survey asks for your views about your health.  This information will 
help keep track of how you feel and how well you are able to do your usual 
activities.  Thank you for completing this survey! 
For each of the following questions, please mark an 
 in the one box that 
best describes your answer. 
1. In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 
 
  
1 
 
2 
 
3 
 
4 
 
5 
 
2. Compared to one year ago, how would you rate your health in general 
 
now? 
Much better 
now than one 
year ago 
Somewhat 
better now 
than one year 
ago 
About the 
same as one 
year ago 
Somewhat 
worse now 
than one year 
ago 
Much worse 
now than one 
year ago 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 


Clinical Study Protocol Appendix E 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
 
115(122) 
3. The following questions are about activities you might do during a 
typical day.  Does your health now limit you in these activities?  If so, 
how much? 
Yes, 
limited 
a lot 
Yes, 
limited 
a little 
No, not 
limited 
at all 
 
 
 
 
a  Vigorous activities, such as running, lifting  
 heavy objects, participating in strenuous  
 sports  .................................................................... 
1 ................... 
2 .................. 
3 
 
b   Moderate activities, such as moving a table,  
  pushing a vacuum cleaner, bowling, or  
 playing golf ........................................................... 
1 ................... 
2 .................. 
3 
 
c   Lifting or carrying groceries .................................. 
1 ................... 
2 .................. 
3 
 
d  Climbing several flights of stairs ............................ 
1 ................... 
2 .................. 
3 
 
e  Climbing one flight of stairs ................................... 
1 ................... 
2 .................. 
3 
 
Redacted


Clinical Study Protocol Appendix E 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
 
116(122) 
f  Bending, kneeling, or stooping ............................... 
1 ................... 
2 .................. 
3 
 
g Walking more than a mile ...................................... 
1 ................... 
2 .................. 
3
 
h Walking several hundred yards .............................. 
1 ................... 
2 .................. 
3
 
i Walking one hundred yards .................................... 
1 ................... 
2 .................. 
3
 
j  Bathing or dressing yourself ................................... 
1 ................... 
2 .................. 
3
 
4. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
 
All of 
the time
Most of 
the time 
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
a  Cut down on the amount of time you spent  
on work or other activities ........................................ 
1 .......... 
2 ......... 
3 .......... 
4 ......... 
5 
b Accomplished less than you would like .................. 
1 .......... 
2 ......... 
3 .......... 
4 ......... 
5 
 
c  Were limited in the kind of work or other  
    activities .................................................................. 
1 .......... 
2 ......... 
3 .......... 
4 ......... 
5 
d  Had difficulty performing the work or other  
  activities (for example, it took extra effort)  ........... 
1 .......... 
2 ......... 
3 .......... 
4 ......... 
5 
 
Redacted


Clinical Study Protocol Appendix E 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
 
117(122) 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)? 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
 
a  Cut down on the amount of time you spent  
 on work or other activities .................................... 
1 ......... 
2 ......... 
3 .......... 
4 ......... 
5 
b Accomplished less than you would like ............... 
1 ......... 
2 ......... 
3 .......... 
4 ......... 
5 
 
c  Did work or other activities less carefully  
 than usual .............................................................. 
1 ......... 
2 ......... 
3 .......... 
4 ......... 
5 
 
6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
 
1 
 
2 
 
3 
  
4 
 
5 
7. How much bodily pain have you had during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very Severe 
 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
Redacted


Clinical Study Protocol Appendix E 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
 
118(122) 
8. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
9. These questions are about how you feel and how things have been with 
you during the past 4 weeks.  For each question, please give the one 
answer that comes closest to the way you have been feeling.  How much 
of the time during the past 4 weeks... 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
 
 
b Have you been very nervous?..............................
1..........
2.......... 
3 ......... 
4..........
5
 
c  Have you felt so down in the dumps  
 that nothing could cheer you up? ......................... 
1 .......... 
2 .......... 
3 ......... 
4 .......... 
5
d Have you felt calm and peaceful?........................ 
1 .......... 
2 .......... 
3 ......... 
4 .......... 
5
e Did you have a lot of energy? .............................. 
1 .......... 
2 .......... 
3 ......... 
4 .......... 
5
f Have you felt downhearted and  
 depressed? ............................................................ 
1 .......... 
2 .......... 
3 ......... 
4 .......... 
5
g Did you feel worn out? ........................................ 
1 .......... 
2 .......... 
3 ......... 
4 .......... 
5
h Have you been happy? ......................................... 
1 .......... 
2 .......... 
3 ......... 
4 .......... 
5
i Did you feel tired? ............................................... 
1 .......... 
2 .......... 
3 ......... 
4 .......... 
5
 
Redacted


Clinical Study Protocol Appendix E 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
 
119(122) 
10.
 During the past 4 weeks, how much of the time has your physical 
health  or emotional problems interfered with your social activities 
(like visiting friends, relatives, etc.)? 
All of the 
time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
 
 
 
 
 
1 
 
2 
 
3 
  
4 
 
5 
 
11.
How TRUE or FALSE is each of the following statements for you? 
 
Definitely 
true 
Mostly 
true 
Don't 
know 
Mostly 
false 
Definitely 
false 
 
a  I seem to get sick a little easier  
 than other people .................................... 
1 ............ 
2 ........... 
3 ........... 
4 ........... 
5 
b I am as healthy as anybody I know......... 
1 ............ 
2 ........... 
3 ........... 
4 ........... 
5 
c  I expect my health to get worse .............. 
1 ............ 
2 ........... 
3 ........... 
4 ........... 
5 
d  My health is excellent ............................. 
1 ............ 
2 ........... 
3 ........... 
4 ........... 
5
THANK YOU FOR COMPLETING THESE QUESTIONS! 
Redacted


Clinical Study Protocol Appendix E 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
 
120 (122) 
HYPOGLYCAEMIA FEAR SURVEY – WORRY SUBSCALE 
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Clinical Study Protocol Appendix E 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
 
121 (122) 
IMPACT OF WEIGHT ON QUALITY OF LIFE QUESTIONNAIRE – 
LITE VERSION (IWQOL-LITE) 
Please answer the following statements by circling the number that best 
applies to you in the past week. Be as open as possible. There are no right 
or wrong answers. 
Physical Function
ALWAYS
TRUE
USUALLY
TRUE
SOMETIMES
TRUE
RARELY
TRUE
NEVER 
TRUE 
1. 
Because of my weight I have trouble 
picking up objects.
5
4
3
2
1
2. 
Because of my weight I have trouble tying 
my shoes.
5
4
3
2
1
3. 
Because of my weight I have difficulty 
getting up from chairs.
5
4
3
2
1
4. 
Because of my weight I have trouble using 
stairs.
5
4
3
2
1
5. 
Because of my weight I have difficulty 
putting on or taking off my clothing.
5
4
3
2
1
6. 
Because of my weight I have trouble with 
mobility.
5
4
3
2
1
7. 
Because of my weight I have trouble 
crossing my legs.
5
4
3
2
1
8. 
I feel short of breath with only mild exertion.
5
4
3
2
1
9. 
I am troubled by painful or stiff joints.
5
4
3
2
1
10. 
My ankles and lower legs are swollen at
the end of the day.
5
4
3
2
1
11. 
I am worried about my health.
5
4
3
2
1
Self-esteem
ALWAYS
TRUE
USUALLY
TRUE
SOMETIMES
TRUE
RARELY
TRUE
NEVER 
TRUE 
1. 
Because of my weight I am self-conscious.
5
4
3
2
1
2. 
Because of my weight my self-esteem is
not what it could be.
5
4
3
2
1
3. 
Because of my weight I feel unsure of 
myself.
5
4
3
2
1
4. 
Because of my weight I don’t like myself.
5
4
3
2
1
5. 
Because of my weight I am afraid of being 
rejected.
5
4
3
2
1
6. 
Because of my weight I avoid looking in 
mirrors or seeing myself in photographs.
5
4
3
2
1
7. 
Because of my weight I am embarrassed to 
be seen in public places.
5
4
3
2
1
 
 
IWQOL-Lite – English (US). 
Redacted


Clinical Study Protocol Appendix E 
Drug Substance Saxagliptin / Dapagliflozin  
Study Code D1689C00014 
Version 4.0 
Date 12 January 2017 
 
122 (122) 
Sexual Life
ALWAYS
TRUE
USUALLY
TRUE
SOMETIMES
TRUE
RARELY
TRUE
NEVER 
TRUE 
1. 
Because of my weight I do not enjoy sexual 
activity.
5
4
3
2
1
2. 
Because of my weight I have little or no
sexual desire.
5
4
3
2
1
3. 
Because of my weight I have difficulty with 
sexual performance.
5
4
3
2
1
4. 
Because of my weight I avoid sexual 
encounters whenever possible.
5
4
3
2
1
 
Public Distress
ALWAYS 
TRUE 
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I experience ridicule, 
teasing, or unwanted attention.
5
4
3
2
1
2.
Because of my weight I worry about fitting 
into seats in public places (e.g. theaters, 
restaurants, cars, or airplanes).
5
4
3
2
1
3.
Because of my weight I worry about fitting 
through aisles or turnstiles.
5
4
3
2
1
4.
Because of my weight I worry about finding 
chairs that are strong enough to hold my
weight.
5
4
3
2
1
5.
Because of my weight I experience 
discrimination by others.
5
4
3
2
1
Work (Note: For homemakers and 
retirees, answer with respect 
ALWAYS 
TRUE
USUALLY 
TRUE
SOMETIMES 
TRUE 
 
RARELY 
TRUE 
 
NEVER 
TRUE
1.
Because of my weight I have trouble getting 
things accomplished or meeting my
responsibilities.
5
4
3
2
1
2.
Because of my weight I am less productive 
than I could be.
5
4
3
2
1
3.
Because of my weight I don’t receive 
appropriate raises, promotions or 
recognition at work.
5
4
3
2
1
4.
Because of my weight I am afraid to go on 
job interviews.
5
4
3
2
1
 
 
 
 
 
 
 
IWQOL-Lite – English (US). 
Redacted


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SAP_000.pdf: 
Statistical Analysis Plan
Study Code
D1689C00014
Statistical Analysis Plan
Edition Number
3.0
Date
21 Mar 2017
A 52-Week, Multi-Centre, Randomised, Parallel-Group, Double-Blind, 
Active-Controlled, Phase IV Study to Evaluate the Safety and Efficacy of 
Dapagliflozin or Dapagliflozin plus Saxagliptin compared with Sulphonylurea all 
given as Add-on Therapy to Metformin in Adult Patients with Type 2 Diabetes 
Who Have Inadequate Glycaemic Control on Metformin Monotherapy


Redacted


Redacted


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
4
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
SIGNATURE OF STUDY STATISTICIAN ..........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN....................................3
TABLE OF CONTENTS.........................................................................................4
LIST OF ABBREVIATIONS..................................................................................8
AMENDMENT HISTORY ...................................................................................11
1.
STUDY DETAILS.................................................................................................12
1.1
Study objectives.....................................................................................................12
1.1.1
Primary objective...................................................................................................12
1.1.2
Secondary objectives .............................................................................................12
1.1.3
Other secondary objectives....................................................................................12
1.1.4
Safety objectives ....................................................................................................13
1.1.5
Exploratory objectives ...........................................................................................13
1.2
Study design...........................................................................................................13
1.2.1
Inclusion and exclusion criteria .............................................................................19
1.2.2
Treatment assignment ............................................................................................19
1.2.3
Blinding and unblinding ........................................................................................20
1.2.4
Double-blind treatment period...............................................................................20
1.2.4.1
Randomisation and baseline visit (visit 2, week 0):...............................................21
1.2.4.2
Treatment period visits (visits 3 to 11; weeks 2, 4, 6, 8, 10, 12, 24, 36, and 
48): .........................................................................................................................21
1.2.4.3
End of treatment period visit/early termination visit/ rescue visit (visit 12; 
week 52):................................................................................................................24
1.2.5
Adjudication committees .......................................................................................24
1.3
Number of patients.................................................................................................24
2.
ANALYSIS SETS .................................................................................................24
2.1
Enrolled patients set...............................................................................................24
2.2
Randomised patients set.........................................................................................25
2.3
Full Analysis Set....................................................................................................25
2.4
Per Protocol Analysis Set.......................................................................................25
2.5
Safety Analysis Set ................................................................................................25


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
5
2.6
Protocol Deviations................................................................................................25
2.6.1
Protocol deviation monitoring ...............................................................................26
2.6.2
Protocol deviation reporting ..................................................................................26
3.
PRIMARY AND SECONDARY VARIABLES...................................................28
3.1
Primary efficacy variable.......................................................................................28
3.2
Key secondary efficacy variables ..........................................................................28
3.3
Other secondary efficacy variables........................................................................29
3.4
Safety variables......................................................................................................29
3.5
Pharmacokinetics ...................................................................................................30
3.6
Patient reported outcomes (PROs).........................................................................30
3.7
Additional exploratory endpoints ..........................................................................30
3.8
Health economics...................................................................................................30
4.
ANALYSIS METHODS .......................................................................................31
4.1
General principles ..................................................................................................31
4.2
Primary analysis.....................................................................................................31
4.2.1
Objectives and hypotheses.....................................................................................31
4.3
Secondary analysis.................................................................................................32
4.3.1
Control of Type I error...........................................................................................32
4.4
Sensitivity analyses................................................................................................33
4.5
Definitions..............................................................................................................33
4.5.1
Baseline values.......................................................................................................33
4.5.2
Derived data...........................................................................................................34
4.5.3
Change from baseline ............................................................................................34
4.5.4
Longitudinal repeated measures analysis...............................................................34
4.5.4.1
Adjustment for baseline imbalances ......................................................................35
4.5.4.2
Assessment of Treatment-by-Baseline interaction ................................................35
4.5.4.3
Subgroup Analyses and Assessment of Treatment-by-Subgroup interaction........36
4.5.5
Analysis of covariance (ANCOVA) for change from baseline .............................36
4.5.6
Kaplan-Meier curve and estimates for time-to-event analysis...............................37
4.5.7
Analysis of proportions..........................................................................................37
4.5.8
Time spent below target HbA1c (<7% and <7.5%)...............................................37
4.6
Missing data...........................................................................................................38
4.6.1
Handling missing demographic and baseline characteristics data.........................38
4.6.2
Handling missing efficacy data..............................................................................38
4.7
Analysis methods...................................................................................................39
4.7.1
Study population ....................................................................................................39
4.7.1.1
Patient disposition..................................................................................................39
4.7.1.2
Demographic and baseline characteristics.............................................................39


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
6
4.7.1.3
Specific and general disease histories....................................................................40
4.7.2
Extent of exposure .................................................................................................41
4.7.2.1
Study medication ...................................................................................................41
4.7.2.2
Interruption of study medication............................................................................41
4.7.2.3
Dose titrations of Glimepiride................................................................................41
4.7.3
Current and Concomitant medications...................................................................41
4.7.3.1
Other Treatments ...................................................................................................42
4.7.4
Treatment compliance............................................................................................43
4.8
Efficacy analyses....................................................................................................44
4.8.1
Primary Efficacy Analysis .....................................................................................45
4.8.2
Analysis of secondary and exploratory variables ..................................................46
4.8.3
Exploratory Variables ............................................................................................48
4.8.3.1
SF-36v2..................................................................................................................48
4.8.3.2
HFS II – Worry subscale........................................................................................48
4.8.3.3
IWQOL-Lite ..........................................................................................................48
4.8.3.4
Waist:Hip ratio.......................................................................................................48
4.8.4
Sensitivity analysis.................................................................................................49
4.8.5
Subgroup analyses .................................................................................................49
4.9
Safety analysis .......................................................................................................49
4.9.1
Adverse events.......................................................................................................50
4.9.2
Serious adverse events ...........................................................................................51
4.9.3
Adverse events leading to discontinuation of study medication............................51
4.9.4
Adverse events of special interest..........................................................................51
4.9.5
Deaths ....................................................................................................................52
4.9.6
Hypoglycaemia ......................................................................................................52
4.9.7
Laboratory evaluation ............................................................................................53
4.9.7.1
Marked laboratory abnormalities...........................................................................53
4.9.7.2
Additional laboratory data summaries...................................................................54
4.9.8
Vital signs ..............................................................................................................54
4.9.9
Electrocardiograms ................................................................................................54
4.9.10
Pregnancy test results.............................................................................................55
4.10
Figures and graphs .................................................................................................55
4.11
Conventions ...........................................................................................................55
4.11.1
Study Day...............................................................................................................55
4.11.2
Visit Windows .......................................................................................................56
4.11.3
Post-Dosing Observations......................................................................................57
4.11.4
Duration of Type 2 Diabetes and Missing Dates...................................................57
4.11.5
Missing Dates for Adverse Events.........................................................................58
4.11.6
Counting Rules for Adverse Events.......................................................................59
4.11.7
Strip Sign for Selected Laboratory Data................................................................60
5.
CHANGES OF ANALYSIS FROM THE PROTOCOL.......................................60
6.
REFERENCES ......................................................................................................61


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
7
7.
APPENDICES .......................................................................................................62
7.1
Appendix I .............................................................................................................62
7.1.1
List of Planned Tables ...........................................................................................62
7.1.2
List of Planned Figures ..........................................................................................65
7.1.3
List of Planned Listings .........................................................................................66
7.2
Appendix II – Inclusion and Exclusion Criteria ....................................................67
7.3
Appendix III – Laboratory Parameters and Marked Abnormalities ......................70
7.4
Appendix IV – Missing data pattern for HbA1c....................................................72
7.5
Appendix V – IWQOL-Lite Scoring .....................................................................73


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
8
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ADA
American Diabetes Association
AE
adverse event
AEOSI
adverse events of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AZDD
AstraZeneca Drug Dictionary
β-hCG
beta human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
CI
confidence interval
CrCl 
creatinine clearance 
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CSRAF
clinical supplies return authorisation form
CV
cardiovascular
DDFM
denominator degrees of freedom
DILI
drug-induced liver injury
E-code
enrolment code
ECG
electrocardiogram
eCRF
electronic Case Report Form
eGFR
estimated glomerular filtration rate
FPG
fasting plasma glucose
GAD
glutamate decarboxylase
GLP-1
Glucagon-like peptide-1
HA
alternative hypothesis 
Hb
haemoglobin
HbA1c
haemoglobin a1c
HDL
high-density lipoprotein


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
9
Abbreviation or 
special term
Explanation
HDPE
high-density polyethylene
HFS-II
Hypoglycaemia Fear Survey
H0
null hypothesis 
HR
heart rate
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IP
investigational product
IR
immediate-release
IRB
Institutional Review Board
IWQOL
Impact of Weight on Quality of Life
IWRS
Interactive Web Response System
LDL
low density lipoprotein
LOCF
Last-Observation-Carried-Forward
MAR
missing at random
MCS
Mental Health Component Summary
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MMRM
Mixed Model Repeated Measures
MODY
maturity onset diabetes of the young
MTD
maximum tolerated dose
OAD
oral antidiabetic
PCS
Physical Health Component Summary
PP
Per protocol
PPG
postprandial glucose
PRO
patient reported outcome
PT
Preferred Term
QD
once daily
RPD
Relevant Protocol Deviation
SAE
serious adverse event 
SAP
Statistical analysis plan
SBP
Systolic Blood Pressure


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
10
Abbreviation or 
special term
Explanation
SCr
serum creatinine
SD
standard deviation
SF-36
Short Form 36-item Health Survey
SGLT2
sodium glucose cotransporter 2 
SOC
system organ class
SU
sulfonylurea
T2DM
Type 2 diabetes mellitus
T4
thyroxine
TB
total bilirubin
TZD
thiazolidinedione
UACR
Urinary Albumin to Creatinine Ratio
ULN
upper limit of normal
US
United States
UTI
Urinary Tract Infection
WBDC
Web Based Data Capture
WOCBP
Women of childbearing potential
N
Total sample size
NA
Not applicable
Variable
A characteristic or a property of a patient that may vary e.g. from time to
time or between patients


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
11
AMENDMENT HISTORY
Date
Brief description of change
30Jan2017
SAP updated in alignment with Protocol Amendment 3 (issued 01Nov2016) and 
Protocol Amendment 4 (issued 12Jan2017).
20Mar2017
Further clarification of RPDs, addition of a secondary efficacy variable and 
addition of summary tables over time for Glimepiride dose levels and 
hypoglycaemic events.


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
12
1.
STUDY DETAILS
The present Statistical Analysis Plan (SAP) outlines the variables and methods used for 
evaluating the safety and efficacy of dapagliflozin or dapagliflozin plus saxagliptin compared
with sulphonylurea (glimepiride) as add-on therapies to metformin in adults with type 2 
diabetes who have inadequate glycaemic control on maximum tolerated dose (MTD) of ≥1500 
mg of metformin monotherapy.
1.1
Study objectives
1.1.1
Primary objective
To compare the absolute change from baseline in HbA1c at week 52 between dapagliflozin 
plus metformin and dapagliflozin plus saxagliptin plus metformin with glimepiride plus 
metformin. 
1.1.2
Secondary objectives
!
To compare the proportion of patients reporting confirmed hypoglycaemia episodes during 
the 52-week treatment period between dapagliflozin plus metformin and dapagliflozin plus 
saxagliptin plus metformin with glimepiride plus metformin
!
To compare the change from baseline in total body weight at week 52 between 
dapagliflozin plus metformin and dapagliflozin plus saxagliptin plus metformin with 
glimepiride plus metformin
!
To compare the change from baseline in FPG at week 52 between dapagliflozin plus 
metformin and dapagliflozin plus saxagliptin plus metformin with glimepiride plus 
metformin
!
To compare the time to rescue treatment among the treatment groups during the 52 week 
treatment period between dapagliflozin plus metformin and dapagliflozin plus saxagliptin 
plus metformin with glimepiride plus metformin
1.1.3
Other secondary objectives
To compare the effects of dapagliflozin plus metformin and dapagliflozin plus saxagliptin plus 
metformin with glimepiride plus metformin on the:
!
Proportion of patients achieving HbA1c of <7% (and <7.5%) without confirmed 
hypoglycaemia at week 52
!
Proportion of patients achieving HbA1c of <7% (and <7.5%) at week 52
!
Proportion of patients achieving individually agreed HbA1c targets at week 52
!
Proportion of patients achieving an HbA1c decrease of ≥1% with no weight gain at 
week 52
!
Time spent below HbA1C target (<7%) (and <7.5%) during the 52-week double-
blind treatment period
!
Change in body mass index (BMI) from baseline to week 52


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
13
!
Proportion of patients achieving weight reduction of ≥5% from baseline to week 52
!
Proportion of patients with weight gain ≥5% from baseline to week 52
!
Proportion of patients reporting at least 1 episode of hypoglycaemia (confirmed 
hypoglycaemia = symptomatic + blood glucose ≤50 mg/dL, major, other 
hypoglycaemia) during the 52 week double-blind treatment period
!
Change in waist circumference from baseline to week 52
!
Change in systolic BP from baseline to week 52
1.1.4
Safety objectives
To evaluate the safety and tolerability of dapagliflozin and dapagliflozin plus saxagliptin 
versus glimepiride, all as add-on therapy to metformin, during the 52-week treatment period
on the:
!
Proportion of patients withdrawing from study treatment due to hypoglycaemia
!
AEs/SAEs
!
AEs of special interest (AEOSI)
!
Clinical laboratory tests 
!
Electrocardiogram (ECG) 
!
Vital signs (pulse and blood pressure [BP])
!
Hypoglycaemic events
!
Physical examinations, including incidence of oedema
1.1.5
Exploratory objectives
To explore the mean change from baseline to week 52 in quality of life patient reported 
outcomes (PROs) and waist-to-hip ratio at week 52 between dapagliflozin plus metformin and 
dapagliflozin plus saxagliptin plus metformin with glimepiride plus metformin.
1.2
Study design
This is a 52-week, multi-centre, randomised, parallel-group, double blind, double-dummy, 
active-controlled phase IV trial to study the efficacy and safety of dapagliflozin added to 
metformin and dapagliflozin plus saxagliptin added to metformin compared with 
sulphonylurea (SU [glimepiride]) added to metformin in adult patients with Type 2 diabetes 
mellitus (T2DM) - who have inadequate glycaemic control on maximum tolerated dose 
(MTD) of ≥1500 mg of metformin monotherapy.
The study’s duration will be at least 58 weeks, including a 1 week non-obligatory pre-study 
screening period; a 2-week enrolment period; a 52-week double blind treatment period and a 
3-week safety follow-up period.
Figure 1 and Table 1 show the study’s flow chart and the detailed study plan respectively.


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
14
Figure 1. Flow chart of patients
*Note: Glimepiride treatment will begin at 1 mg/day then be titrated (upwards or downwards) in 1 mg 
increments at subsequent visits, if needed. In the event that a subject develop recurrent hypoglycaemic episodes 
with the 1 mg dose, down-titration to 0 mg is allowed during the study
Abbreviations:  HbA1c haemoglobin A1c, MTD maximum tolerated dose, T2DM Type 2 diabetes mellitus.


Table 1. Study plan
Visit
Screening
Enrolment
52-week Double-blind Treatment Period
Safety 
Follow-up 
R/
Baseline
EOT/ Rescuea
Sb
1
2c
3
4
5
6
7
8
9
10
11
12
13
Weeks
-3
-2
0
2
4
6
8
10
12
24
36
48
52
55
Visit window (days)d
±3
±3
-
±3
±3
±3
±3
±3
±3
±4
±4
±4
±7
±7
Informed consent
Xe
X
Assign E-code
X
Demography and medical 
history
X
Inclusion/ exclusion 
criteria
X
X
Randomisation
X
Brief physical 
examination
X
X
X
X
X
X
X
X
X
Complete physical 
examination
X
X
X
X
Vital signs (BP, pulse)
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
BMI
X
X
X
Waist and hip 
circumference
X
X
12-lead ECG
X
X
X
Concomitant medicationsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
16
Visit
Screening
Enrolment
52-week Double-blind Treatment Period
Safety 
Follow-up 
R/
Baseline
EOT/ Rescuea
Sb
1
2c
3
4
5
6
7
8
9
10
11
12
13
Weeks
-3
-2
0
2
4
6
8
10
12
24
36
48
52
55
Visit window (days)d
±3
±3
-
±3
±3
±3
±3
±3
±3
±4
±4
±4
±7
±7
Clinical chemistryg
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine (to calculate 
CrCl and eGFR)
X
X
X
X
X
X
X
X
X
X
X
X
X
FPG (local laboratory)
X
X
X
X
X
X
X
X
X
X
X
FPG (central laboratory)
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipidsh
X
X
X
X
C-peptide
X
Hepatitis screening paneli
X
TSH
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test (urine, 
WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic events
X
X
X
X
X
X
X
X
X
X
X
X
X
Discuss individual targets 
for glucose control (FPG 
and HbA1c)
X
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
17
Visit
Screening
Enrolment
52-week Double-blind Treatment Period
Safety 
Follow-up 
R/
Baseline
EOT/ Rescuea
Sb
1
2c
3
4
5
6
7
8
9
10
11
12
13
Weeks
-3
-2
0
2
4
6
8
10
12
24
36
48
52
55
Visit window (days)d
±3
±3
-
±3
±3
±3
±3
±3
±3
±4
±4
±4
±7
±7
Diet and lifestyle advice
X
X
X
X
X
X
X
X
X
X
X
X
Dispense glucometer 
and/or supplies; provide 
instructions
X
X
X
X
X
X
X
X
X
X
X
Dispense patient diary
X
X
X
X
X
X
X
X
X
X
X
Dispense study 
medication
X
X
X
X
X
X
X
X
X
X
Register actual 
glimepiride dosage in 
IWRS
X
X
X
X
X
X
X
X
X
X
Patient diary review for 
glucometer values/ 
hypoglycaemic events
X
X
X
X
X
X
X
X
X
X
X
Perform SF-36 survey
X
X
X
Perform Hypoglycaemia 
Fear Survey-Worry Scale
X
X
X
Perform IWQOL-Lite 
X
X
X
Collect unused study 
medication/supplies
X
X
Dispense rescue 
medication (if necessary)
X
X
X
X
X
X
X
X
X


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
18
Abbreviations:  AE adverse event, Base baseline, BP blood pressure, BMI body mass index, CrCl creatinine clearance, E-code enrolment code, ECG  
electrocardiogram, eGFR estimated glomerular filtration rate, EOT end of treatment, FPG fasting plasma glucose, HbA1c haemoglobin A1c, HDL high-
density lipoprotein, IWQOL Impact of Weight on Quality of Life, IWRS Interactive Web Response System, LDL low-density lipoprotein, R randomisation, 
SAE serious adverse event, SF short form, TSH  thyroid stimulating hormone, WOCBP women of child-bearing potential.
aEarly Termination procedures are to be completed for all patients who terminate the study or are rescued before Visit 12 (Week 52) of the Treatment Period. 
bAn optional Screening visit (Visit S) may occur within 1 week prior to Enrolment (Visit 1) to screen for eligibility based on a non-fasting sample of HbA1c 
in patients that do not have a recent HbA1c value (within 30 days).
cVisit 2 (Randomisation/Baseline) should be performed within 14 days after Enrolment visit, when laboratory results from Visit 1 are available.
dOnce a patient is randomised at Visit 2, all visits should be scheduled relative to Visit 2.
eAn abbreviated informed consent form will be signed at Screening visit.
fReview of concomitant medications includes over the counter drugs and herbal/nutritional therapies 
gSpecifications of clinical chemistry laboratory parameters are detailed in CSP Section 5.2.1.3.  Visits 1 and 8 to 11 have the same parameters; Visits 2, 12, 
and 13 have the same parameters; and no clinical chemistry is performed at Visits 3 through 7.  CrCl and eGFR will be calculated at all visits.
hSerum lipid panel will include LDL-cholesterol, HDL-cholesterol, triglycerides, and total cholesterol.
iHepatitis panel includes hepatitis B viral antibody IgM, Hepatitis B surface antigen, and hepatitis C virus antibody.


Study Code D1689C00014
Statistical Analysis Plan
Edition Number 3.0 
Date  21 Mar 2017
19
Visit windows for the analysis of efficacy and safety variables are described in detail in 
Section 4.11.2.
The study will be run at approximately 250 sites mainly in Germany and European Union 
(EU). Approximately 930 patients (310 patients per treatment group) are planned for 
randomisation to ensure that at least 290 patients per treatment group are evaluable in the Full 
Analysis Set (assuming 5% exclusion rate from Full Analysis Set). Assuming however that 
approximately 30% of screened patients will fail the entry criteria, a total of (approximately)
1329 patients will be enrolled.  
Sites will be allowed to perform a pre-study screening assessment (at Week -3) prior to 
enrolment visit to screen for HbA1c criteria.  All potentially eligible patients will be enrolled, 
provide informed consent, undergo screening for all applicable inclusion/exclusion criteria, 
and submit laboratory samples at Enrolment (Visit 1, 2 weeks prior to randomisation).  
Patients should be treated with a stable, maximum tolerated dose of metformin monotherapy 
(≥1500 mg/day) for at least 8 weeks prior to Enrolment, and remain on the same type and dose 
of metformin therapy for the duration of the study as the background therapy for all treatment 
arms, as indicated in Section 1.2.2. 
1.2.1
Inclusion and exclusion criteria
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances should there be exceptions to this rule.  Patients must be 
receiving metformin (≥1500 mg/day) for treatment of T2DM in accordance with the product 
label for their country.  Eligible patients will be enrolled and examined for all inclusion and 
exclusion criteria. A full list of the inclusion/exclusion criteria is presented in Appendix II.
1.2.2
Treatment assignment 
Patients who meet the study’s inclusion and exclusion criteria will be randomised with a 1:1:1 
ratio to the following treatment groups:
!
Dapagliflozin 10 mg + placebo for saxagliptin + placebo for glimepiride; 
!
Dapagliflozin 10 mg + saxagliptin 5 mg + placebo for glimepiride; 
!
Glimepiride (starting at 1 mg dose and titrated up to 6 mg, if needed) + placebo for 
dapagliflozin + placebo for saxagliptin
The randomisation codes will be computer generated by AstraZeneca R&D using the AZ 
Global Randomisation system (GRand) and loaded into the IVRS/IWRS database. 
Randomisation will be done via IVRS/IWRS at Visit 2. The IVRS/IWRS will allocate 
randomisation codes centrally as patients become eligible for randomisation. 
If a randomisation number is allocated incorrectly, no attempt should be made to remedy the 
error once study material has been dispensed; the patient will continue with the allocated 


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number and study material.  AstraZeneca or representative should be notified as soon as the 
error is discovered and subsequent patients will continue using the first unallocated 
randomisation number in the original numbering sequence. 
1.2.3
Blinding and unblinding
A double-blind, double dummy technique is used for blinding. Patients, investigator, study 
site personnel and sponsor personnel involved with data review and analysis will be blinded 
throughout the study until database lock. The tablets/capsules of both the active control and 
the placebo will be identical in size, colour, smell and taste while the bottles with the IPs will 
be labelled with unique identification numbers allocated from the IWRS.
The database will be locked after all patients have completed the study (or have prematurely 
discontinued) and all outstanding data queries are resolved. The locked database will be 
unblinded for reporting purposes. In order to protect the integrity of the study, the patients and 
investigators will not have access to the individual treatment assignments until the study has 
been completed.
In addition, no member of the study team (either at AstraZeneca, study sites or any clinical 
research organisation (CRO)) handling data will have access to the randomisation scheme 
during the conduct of the study – except AstraZeneca personnel generating the randomisation 
scheme as well as AstraZeneca’s Supply Chain Study Management (SCSM), AstraZeneca 
Global Pharmacovigilance (GPV), and the CRO providing the IWRS and carrying out the 
packaging and labelling of IPs.   
Unless otherwise specified, to maintain the integrity of the study, HbA1c values and urinary 
glucose values will be masked on laboratory reports to investigators during at least the double-
blind treatment period.
The treatment code - indicating the treatment randomisation for each randomised patient -
should not be broken except in medical emergencies when the appropriate management of the 
patient requires knowledge of the treatment randomisation.  The Investigator documents and 
reports the action to AstraZeneca, without revealing the treatment given to patient to the 
AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities.  Treatment codes will not be broken for the planned analyses of data 
until all decisions on the evaluability of the data from each individual patient have been made 
and documented. 
1.2.4
Double-blind treatment period
The double-blind treatment period consists of the following visits:


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1.2.4.1
Randomisation and baseline visit (visit 2, week 0):
During this visit the inclusion/exclusion criteria will be verified and a number of 
assessments/measurements will be carried out (or calculated) including:
o
A complete physical examination
o
Vital signs (sitting systolic and diastolic BP and pulse)
o
Body weight
o
Body Mass Index (BMI)
o
Waist and hip circumference
o
12-lead ECG
o
Review of concomitant medications (including over the counter and 
herbal/nutritional supplements)
o
Blood samples (including clinical chemistry; haematology; HbA1c; serum 
creatinine (calculated creatinine clearance [Cockcroft Gault formula] and 
eGFR); FPG (by local and central laboratories); lipids (low-density lipoprotein 
[LDL]-cholesterol, high-density lipoprotein [HDL]-cholesterol, triglycerides, 
total cholesterol)
o
Urinalysis
o
Urinary pregnancy test (βhCG) for female patients (WOCBP only)
o
AEs and SAEs
o
Hypoglycaemic events
o
Glucose control (based on FPG and HbA1c)
Diet and life-style advice will be provided and patients will be randomly assigned to 1 of 3 
treatment groups as described in Section 1.2.2.  In addition, the following surveys will be 
completed, prior to any assessment at this visit:
o
SF-36 questionnaire
o
Hypoglycaemia Fear Survey (Worry Scale)
o
IWQOL-Lite survey
These surveys are described in detail in Section 3.6.
1.2.4.2
Treatment period visits (visits 3 to 11; weeks 2, 4, 6, 8, 10, 12, 24, 36, and 48):
Prior to these visits, patients are required to have fasted overnight (8 to 12 hours), refrain from 
alcohol intake, intense exercise (24 hours prior to each visit) and tobacco/nicotine use (within 
12 hours prior to each visit). Also patients should bring their metformin and study medication 
and self-administer the latter as directed by study-site personnel. 
During these visits, the study medication and when necessary the rescue medication will be 
dispensed (Table 2) and assessments of all of the previously listed (baseline) parameters will 
be performed.  


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Table 2. Schedule of study medication dispensation
Enrolment
Blinded Study Medication during Randomised Treatment Period
Visit #
1
2
3
4
5
6
7
8
9
10
11
12
Study Week
W-2
W0 W2
W4
W6
W8
W10
W12
W24
W36
W48
W52
Dapagliflozin 
or placebo 
(tablets)
-
X
-
-
-
-
-
X
X
X
X
-
Saxagliptin or 
placebo 
(tablets)
-
X
-
-
-
-
-
X
X
X
X
-
Glimepiride 
or placebo 
(capsules)a
-
X
X
X
X
X
X
X
X
X
X
-
Note: A dash denotes no dispensation of the drug and X denotes that drug will be dispensed at the specified 
visit.
a
Glimepiride will be dispensed in 2 bottles; see Table 5
Abbreviations: W week.
Every day during the treatment period, patients will take 4 tablet/capsules: 1 from the
dapagliflozin bottle, 1 from the saxagliptin/placebo bottle, and 1 from each of the
glimepiride/placebo bottles (Bottle A and Bottle B; see Table 3).
Dose titration
During the treatment period, the blinded glimepiride/placebo dose will be slowly titrated in a 
stepwise fashion (Table 3) depending on glycaemic control at every visit.  It should be titrated 
to achieve the individual target FPG of the patient (a target of approximately 110 mg/dL [6.1 
mmol/L] is recommended). Up titration should not be done in cases of a recent hypoglycaemia
episode while down-titration can be done to mitigate recurrent hypoglycaemic events or at any 
time during the study.  If necessary, glimepiride/placebo will be allowed to be down-titrated to 
0 mg (i.e., 2 placebo capsules).  The treatment can thereafter be up-titrated again during the 
treatment period.
Down-titration of other blinded study drug and/or background antihyperglycaemic agent will 
not be allowed at any time during the study. 
The other two treatment groups will be given placebo bottles to maintain the study blind. 


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Table 3. Titrated dose levels and contents of blinded glimepiride or placebo kit
Dose levels
Total Dosage
Bottle A
Bottle B
0
0 mg
Placebo
Placebo
1
1 mg
1 mg
Placebo
2
2 mg
2 mg
Placebo
3
3 mg
1 mg
2 mg
4
4 mg
2 mg
2 mg
5
5 mg
1 mg
4 mg
6
6 mg
2 mg
4 mg
7
Placebo
Placebo
Placebo
Rescue therapy
During the treatment period, patients may be eligible for treatment with open-label rescue 
medication (insulin) in addition to their blinded treatment regimen to treat ongoing 
hyperglycaemia. For patients who have not reached their MTD of glimepiride/placebo, up-
titration of glimepiride/placebo should be attempted first before rescue is initiated.
Investigators may increase glimepiride/placebo dose or should initiate rescue insulin treatment 
based on progressively stricter glycaemic criteria according to Table 4:
Table 4. Criteria for rescue therapy during the randomised treatment period
Visit Period
Central Laboratory glycaemic 
parameters
Week 0 to 12 (after Visit 2 and including Visit 8)
FPG >240 mg/dL (13.3 mmol/L)
Week 12 to 24 (after Visit 8 and including day of 
Visit 9)
FPG >200 mg/dL (11.1 mmol/L)
Week 24 to 52 (after Visit 9 and including Visit 12)
HbA1c >8.0%
Abbreviations: FPG fasting plasma glucose; HbA1c haemoglobin A1c.
Rescued patients will be given open-label insulin in accordance with the approved product 
label in the applicable country at the discretion of the Investigator, in addition to their double-
blind study medication. Rescued patients will then continue in the double-blind treatment 
period according to their original visit schedule. 


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1.2.4.3
End of treatment period visit/early termination visit/ rescue visit (visit 12; 
week 52):
During this visit, all the previously listed (baseline and at each treatment period visit)
parameters will be re-assessed (see Table 1).
1.2.5
Adjudication committees
Two independent adjudication committees, blinded to study treatment, will oversee the study: 
a) the hepatic adjudication committee and b) the cardiovascular adjudication committee. 
The former will determine the probability that drug-induced liver injury (DILI) is the cause of 
liver-related abnormalities including (but not limited) to hepatic events timely related to death 
(within 30 days before death); AST and/or ALT >3x ULN and TB >2x ULN (within 14 days 
of the AST and/or ALT elevation; AST and/or ALT >10x ULN. 
The latter committee will use pre-specified criteria – composed of independent cardiologists 
blinded to study treatment - for performing adjudication for hospitalisation for heart failure. 
Further details of these adjudication committees can be found in their respective charters.
1.3
Number of patients
To demonstrate non-inferiority of dapagliflozin plus metformin or dapagliflozin plus 
saxagliptin plus metformin to glimepiride plus metformin for changes from baseline to week 
52 in HbA1c within a non-inferiority margin of 0.30% - assuming a standard deviation 1.0%, 
and at a 1-sided significance level of 0.025 - 290 evaluable patients will be needed in each 
treatment group to provide approximately 95% power (given a true difference of zero between 
dapagliflozin or dapagliflozin plus saxagliptin and glimepiride).  The non-inferiority margin 
of 0.3% as well as a common standard deviation of 1.0% were selected based on information 
from earlier, similarly designed studies. Assuming that 5% of patients do not have a post-
baseline assessment, a total of approximately 930 patients (310 patients per treatment arm) 
need to be randomised.  Moreover, if 30% of screened patients fail to meet screening criteria, 
a total of 1329 patients need to be screened.
A hierarchical testing procedure will be followed to control type 1 error rate of 0.05.  
Dapagliflozin plus saxagliptin plus metformin will be tested for non-inferiority first. If 
dapagliflozin plus saxagliptin plus metformin is non-inferior to glimepiride plus metformin 
then dapagliflozin plus metformin will be tested for non-inferiority.
2.
ANALYSIS SETS
2.1
Enrolled patients set
This consists of all patients who signed informed consent. 


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2.2
Randomised patients set
This consists of all randomised patients. It is also known as the intention to treat (ITT) 
population. Patients will be analysed according to the treatment they were originally assigned
(based on the ITT principle).
2.3
Full Analysis Set
The Full Analysis Set will include all randomised patients who receive at least one dose of 
study medication and who have a non-missing baseline value and at least one post-baseline 
efficacy value (i.e., HbA1c, FPG, weight). Patients will be analysed according to the treatment 
they were originally assigned (based on the ITT principle).
The Full Analysis set will be used for addressing the non-inferiority claim for the primary 
efficacy objective and also for the analysis of all secondary objectives.  
2.4
Per Protocol Analysis Set
The Per Protocol Analysis Set will be a subset of the Full Analysis Set consisting of patients
who do not violate the terms of the protocol (patients who do not have relevant protocol 
deviations (RPDs, see section 2.6.2). All decisions to exclude patients and/or data from the 
Full Analysis Set to form the Per Protocol Analysis Set will be made prior to un-blinding the 
study and agreed by the study team.
The Per Protocol Analysis Set will be used to re-analyse the primary efficacy variable (as a 
sensitivity analysis).
2.5
Safety Analysis Set
The safety analysis set is defined as all randomised patients who received at least one dose of 
study medication.  Patients will be analysed according to the actual treatment received. If, at 
any point during the treatment period, a patient received treatment which was different from 
which they were randomised to, they will be included in the treatment arm which they 
received for the majority of the treatment period.
The Safety Analysis Set will be used to analyse all safety related variables: adverse events; 
serious adverse events; adverse events of special interest; discontinuation of study medication 
due to hypoglycaemia; clinical laboratory tests; electrocardiogram (ECG); vital signs; 
hypoglycaemic events.
2.6
Protocol Deviations
AstraZeneca uses ICH E3 terminology for protocol deviations, which are all important 
deviations related to study inclusion or exclusion criteria, conduct of the trial, patient 
managements or patient assessment.


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2.6.1
Protocol deviation monitoring
During study conduct, protocol deviations will be closely monitored and identified from two 
sources:
!
IMPACT monitoring – These are manually entered protocol deviations identified by 
the CRA during study conduct.
!
Programmed protocol deviations – These are deviations generated by execution of 
programs written using the predefined deviator descriptions in the SAP and protocol.
2.6.2
Protocol deviation reporting
Protocol deviations will be reviewed in a blinded fashion by the study team prior to database 
lock. All decisions to exclude patients and/or data from the Full Analysis Set (to form the Per-
Protocol Analysis Set) will be made prior to the unblinding of the study and agreed by the 
study team.
Protocol deviations that are determined to affect the primary efficacy results are deemed 
relevant protocol deviations (RPDs). A full list of RPDs is described in Table 5.
Table 5. List of Relevant Protocol Deviations (RPDs)
Number 
RPD criteria
Exclusion level
1
Randomised patients without type 2 diabetes, or with 
corticosteroid-induced Type 2 diabetes, or with maturity onset 
diabetes in young (MODY), or with diabetes insipidus.
Complete exclusion
2*
Randomised patients without a central laboratory
HbA1c obtained at the Enrolment visit (Visit 1), or with
central laboratory HbA1c <7.5% or >10.5% as
measured from sample collected either at Enrolment visit 
(Visit 1) or at an unscheduled visit prior to visit 2
Complete exclusion
3
Randomised patients who meet one of the following
criteria:
a) received a metformin dose <1500 mg, or
>3000 mg during the 8 weeks prior to enrolment (Visit 1), b) 
not treated with metformin alone at any time during the 8 
weeks prior to enrolment (Visit 1), c) metformin dose was 
changed during the 8 weeks prior to enrolment (Visit 1)
Complete exclusion
4
Randomised patients who were treated with
glucocorticoids equivalent to oral prednisolone
≥10 mg (betametasone ≥1.2 mg, dexametasone ≥
1.5 mg, hydrocortisone ≥40 mg)/day for more than
7 days within 30 days prior to enrolment (topical or inhaled 
corticosteroids are allowed)
Complete exclusion
5a
Randomised patients who took antihyperglycaemic 
medication other than protocol required 
Partial exclusion (exclusion 
would start from the day when 


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dapagliflozin/saxagliptin or dapagliflozin or glimepiride in 
addition to IP (i.e. other antihyperglycaemic medications 
started after discontinuation of IP are not classed as an RPD)
other than CSP required 
antihyperglycaemic medicine was 
started)
Partial exclusion (exclusion 
would start from 8th consecutive 
day of insulin therapy or 15th day 
of non-consecutive therapy, 
whichever is first).
5b
Or
insulin is used longer than permitted by the CSP and violates 
the following situations where insulin use is allowed:
-
For up to 14 days in total during the study and up to 7 
consecutive days if patient is unable to take oral 
medications
-
For up to 14 days in total during the study and up to 7 
consecutive days if there is a documented illness or 
infection that requires additional therapy for 
maintaining glycaemic control; 
-
For up to 14 days in total during the study and up to 7 
consecutive days if patients have to temporarily stop 
IP or metformin due to recommendations made in the 
clinical study protocol
-
For up to 7 days during hospitalisation.  When the 
reason for hospitalisation is the management of the 
patient’s glycaemic control, treatment with insulin is 
considered a rescue and is allowed for as long as 
clinically necessary
5c
6a
Or
Metformin dose was changed for patients who were 
randomised and still taking the double-blind study medication.
Patients who received incorrect investigational product at any 
time during the study
Partial exclusion (exclusion 
would start from the date when 
Metformin dose was changed).
Partial exclusion (exclusion 
would start from the date when 
the incorrect IP was taken)
6b
Randomised patients who are judged to be noncompliant in 
terms of overall compliance, i.e., who took less than 80% or 
more than 120% of their prescribed dose of study medication 
during the double-blind treatment period.
Complete exclusion
7
Randomised patients who receive no double-blind medication 
for ≥2 consecutive weeks
Partial exclusion (exclusion 
would start from the 14th
consecutive day the medication 
was not taken in an interruption)
8
Treatment with systemic glucocorticoids equivalent to oral 
prednisolone ≥10 mg (betamethasone ≥1.2 mg, 
dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day for 
≥5 consecutive days of therapy. 
Partial exclusion (exclusion starts 
from the 5th day of therapy with 
the oral steroids provided in the 
doses higher than equivalent to 
oral prednisolone). 
9a*
If TSH is abnormal and free T4 is missing or abnormal at visit 
1 or at an unscheduled visit prior to visit 2
Complete exclusion
9b
TSH was not performed at visit 1 or at an unscheduled visit 
Complete Exclusion


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prior to visit 2
10
Known condition of congenital renal glucosuria
Complete exclusion
11
Previous randomisation to treatment in the present
study (as assessed by exclusion criteria 36)
Complete exclusion
12*
Creatinine clearance (CrCl) of <60 mL/min or missing CrCl 
result, based on central laboratory results from Visit 1 or at an 
unscheduled visit prior to visit 2.
Complete exclusion
13*
C-peptide laboratory value of <1.0 ng/mL (0.33 nmol/L; 331
pmol/L) or missing C-peptide result, based on central 
laboratory results from Visit 1 or at unscheduled visit prior to 
visit 2.
Complete exclusion
14*
FPG >270 mg/dL (>15 mmol/L) or missing FPG result, based 
on central laboratory results from Visit 1 or at an unscheduled 
visit prior to visit 2
Complete exclusion
* If a patient has an unacceptable/missing value at Visit 1 but then has an unscheduled visit prior to Visit 2 with 
an acceptable value, the patient will not be considered an RPD.
Patients having relevant protocol deviations will be summarised and listed (by treatment 
group and overall). 
Protocol deviations attributed to the GCP violations will be reported in the CSR according to
the following definitions: 
Table 6. List of GCP violations
Number 
GCP criteria 
Exclusion level
1
Delay in SAE reporting 
NA 
2. 
Delay in pregnancy reporting 
NA
3,
Delay in overdose reporting 
NA
4. 
Incorrect ICF handling, not in accordance to the CSP 
Complete exclusion 
In the unlikely case that a patient did not provide signed and dated written informed consent, 
he/she will be excluded from all summaries.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Primary efficacy variable
The primary efficacy variable is the change in HbA1c from baseline (week 0) to week 52. Its 
calculation is described in Section 4.5.3.
3.2
Key secondary efficacy variables
The key secondary efficacy variables are:


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1. Proportion of patients reporting at least one episode of confirmed hypoglycaemia 
(symptomatic + blood glucose ≤50 mg/dL [2.8 mmol/L]), see section 4.9.6) during the 
double-blind treatment period
2. Change in total body weight from baseline to week 52 
3. Change in FPG from baseline to week 52 
4. Time to rescue (start of insulin or discontinuation due to lack of glycaemic control) 
during the 52-week double-blind treatment period. Its calculation is described in 
Section 4.5.6.
3.3
Other secondary efficacy variables
Other secondary efficacy variables are:
!
Proportion of patients achieving HbA1c of <7% (and <7.5%) without confirmed 
hypoglycaemia at week 52
!
Proportion of patients achieving HbA1c of <7% (and <7.5%) at Week 52
!
Proportion of patients achieving individually agreed HbA1c targets at Week 52
!
Proportion of patients achieving an HbA1c decrease of ≥1% with no weight gain at 
week 52
!
Time spent below HbA1C target (<7%) (and <7.5%) during the 52-week double-blind 
treatment period
!
Change in body mass index (BMI) from baseline to week 52
!
Proportion of patients achieving weight reduction of ≥5% from baseline to week 52
!
Proportion of patients with weight gain ≥5% from baseline to week 52
!
Proportion of patients reporting at least 1 episode of any hypoglycaemia (confirmed = 
symptomatic + blood glucose ≤50 mg/dL, major, other hypoglycaemia) during the 52-
week double-blind treatment period
!
Change in waist circumference from baseline to week 52
!
Change in systolic BP from baseline to week 52
!
Proportion of patients reporting at least one episode of hypoglycaemia (symptomatic + 
blood glucose ≤70 mg/dL [3.9 mmol/L]), see section 4.9.6) during the double-blind 
treatment period
3.4
Safety variables
The following safety variables (defined in Section 4.9) will be analysed:
!
Incidence of adverse events (AEs) (including serious adverse events (SAEs), 
Hypoglycaemic AEs and AEs of special interest (AEOSI))
!
Proportion of patients withdrawing from study treatment due to hypoglycaemia
!
Change from baseline in clinical laboratory parameters
!
Change from baseline in vital signs (pulse and blood pressure)


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3.5
Pharmacokinetics
NA
3.6
Patient reported outcomes (PROs)
All patients will complete the SF-36v2 Health Survey, HFS-II Worry Scale and the IWQOL-
Lite survey. The SF-36 addresses 8 health concepts: physical functioning; role - physical;
bodily pain; general health; vitality; social functioning; role - emotional; and mental health.  
SF-36 also includes a single item that provides an indication of perceived change in health. Its 
score ranges from 0 to 100 with higher scores indicating better health.
The HF-II measures the fear of hypoglycaemia in adults with T2DM. Items in the HFS-II 
Worry scale describe the concerns that patients may have about their hypoglycaemic episodes 
(e.g., being alone, episodes occurring during sleep, or having an accident). Each is measured 
on a 5 point scale (Never to Always).
The IWQOL-Lite is a 31-item self-reported assessment of quality of life in overweight or 
obese individuals. It scores on 5 dimensions: physical function (11 items); self-esteem (7 
items); sexual life (4 items); public distress (5 items); and work (4 items).  A global score 
(sum of scale scores) is also included.  Participants are asked to rate items with respect to the 
past week on this instrument (from never true to always true).  Scores on the IWQOL-Lite 
(domains and global score) range from 0 to 100 with higher scores indicating poorer quality of 
life.
The following exploratory endpoints related to patient reported outcomes will be summarised:
!
Change in the short form 36-item health survey (SF-36) scores from baseline to week 
52
!
Change in the Hypoglycaemia Fear Survey (HFS-II) Worry scores from baseline to 
week 52
!
Change in the Impact of Weight on Quality of Life (IWQOL)-Lite survey scores from 
baseline to week 52
3.7
Additional exploratory endpoints
!
Change in waist:hip ratio from baseline to week 52
3.8
Health economics
NA


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4.
ANALYSIS METHODS
4.1
General principles
Continuous variables will be presented with mean; median; 25th and 75th percentiles; standard 
deviation (SD); minimum; maximum; and (if appropriate) the number of non-missing 
observations.  Categorical data will be displayed via absolute and relative frequencies for each 
category, including a category labelled as ‘missing’ when appropriate.  The ‘missing’ category 
will not contribute to the denominators of relative frequencies.
Demographic and baseline characteristics will be summarised using frequency distributions 
and descriptive statistics using the Randomised patients set, for each treatment group as well 
as for all patients combined.  Key baseline characteristics that will be summarised include: 
age; gender; race; ethnicity; country; body weight; BMI; duration of T2DM; baseline FPG;
baseline HbA1c and baseline eGFR.  Baseline is defined as the last measurement prior to the 
first dose of double blind study medication or as the last non-missing value of the visit 1 or 
visit 2 assessment for those subjects without a first dose start date.  No statistical tests will be 
performed to compare treatment groups at baseline. 
4.2
Primary analysis
The primary analysis will be carried out for the primary objective using data from the Full 
Analysis set. It will use values prior to rescue treatment or discontinuation (more than 8
consecutive days off treatment, see section 4.6.2).
4.2.1
Objectives and hypotheses
The combination of metformin and a sulphonylurea (glimepiride) is a standard therapy in the 
treatment of type 2 diabetes and has been shown to reduce HbA1c. 
The primary objective of this study is to demonstrate the non-inferiority of dapagliflozin and 
dapagliflozin plus saxagliptin as add-on therapies to metformin compared to glimepiride as 
add-on therapy to metformin for the primary efficacy variable (change in HbA1c from 
baseline to week 52). 
The null hypothesis H0 (given below) will be tested against the alternative hypothesis HA (α = 
0.025, one-sided):
H0: μt – μc  ≥ 0.30%,
HA: μt – μc  < 0.30%
where μt denotes the mean absolute change in HbA1c from baseline to week 52 in patients 
treated with dapagliflozin added to metformin and dapagliflozin plus saxagliptin added to 
metformin (test medication); μc denotes the mean absolute change in HbA1c from baseline to 
week 52 in patients treated with glimepiride added to metformin (active control). The non-
inferiority margin is determined to be 0.30% (in absolute terms). A difference of 0.30% or 


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less, in HbA1c change from baseline to week 52 between the treatment groups, is considered 
clinically equivalent (from a medical point of view). Non-inferiority will be assessed using the 
2-sided 95% Confidence Interval (CI) of the adjusted mean difference between dapagliflozin 
or dapagliflozin plus saxagliptin and glimepiride. If the upper limit of the 2-sided 95% CI is 
less than 0.30% then dapagliflozin or dapagliflozin plus saxagliptin will be considered to be 
non-inferior to glimepiride.
To preserve the Type I error ≤ 0.025 (one-sided), a hierarchical testing procedure will be used 
as follows: 
∀
First test dapagliflozin plus saxagliptin versus glimepiride 
∀
If non-inferiority is achieved then test dapagliflozin versus glimepiride 
4.3
Secondary analysis
Four key secondary endpoints have been identified:
1. Proportion of patients reporting at least 1 episode of confirmed hypoglycaemia
(symptomatic + blood glucose ≤50 mg/dL) during the double-blind treatment period
2. Change in total body weight from baseline to week 52
3. Change in FPG from baseline to week 52
4. Time to rescue during the 52 week treatment period
The hypotheses of the above four key secondary endpoints will test for superiority of 
dapagliflozin and dapagliflozin plus saxagliptin over glimepiride when used as add-on therapy 
to metformin - where superiority implies smaller proportions of patients experiencing at least 
one episode of hypoglycaemia, greater reductions in body weight and FPG; and a longer time 
to rescue treatment.  
A superiority test of the dapagliflozin plus saxagliptin added to metformin group versus the 
glimepiride added to metformin group will also be conducted for the primary efficacy variable 
of change in HbA1c from baseline to week 52.
4.3.1
Control of Type I error
The experiment-wise type I error will be controlled to a maximum of 5%. A hierarchical
closed testing procedure will be employed such that key secondary endpoints will be
considered for statistical significance (in terms of superiority) only if non-inferiority of the
primary endpoint is concluded and that a key secondary endpoint will be considered for
statistical significance only if the test ordered before it is found to be statistically significant. 
At each step, dapagliflozin plus saxagliptin added to metformin versus glimepiride added to 
metformin will be tested first followed by the test for dapagliflozin added to metformin versus 
glimepiride added to metformin except for the superiority tests of the primary endpoint and 
the endpoint of total body weight. The test of superiority for HbA1c will include only the 
comparison of dapagliflozin plus saxagliptin added to metformin vs glimepiride added to 
metformin. For total body weight, dapagliflozin added to metformin versus glimepiride will


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be tested first followed by dapagliflozin plus saxagliptin added to metformin versus
glimepiride added to metformin.
The following testing order will be followed for the overall type I error control:
1. Change from baseline in HbA1c at Week 52 (test for non-inferiority)
2. Proportion of patients reporting at least 1 episode of confirmed hypoglycaemia at 
Week 52 (test for superiority)
3. Change in total body weight from baseline to Week 52 (test for superiority)
4. Change from baseline in HbA1c at Week 52 (test for superiority of dapagliflozin plus 
saxagliptin added to metformin vs glimepiride added to metformin only)
5. Change in FPG from baseline to Week 52 (test for superiority)
6. Time to rescue at Week 52 (test for superiority)
The statistical comparisons will be done using a comparison-wise type I error of 5% (2-sided).
For all other secondary variables and exploratory variables, nominal p-values will be reported
without multiplicity controlled significance testing.
4.4
Sensitivity analyses
Sensitivity analyses will be carried out for the primary efficacy endpoint (change in HbA1c 
from baseline (week 0) to week 52) only. These sensitivity analyses will be as follows
!
Mixed Model Repeated Measures (MMRM) using the Per-Protocol analysis set, 
!
ANCOVA using values prior to rescue treatment (LOCF will be used if the week 52 
value is not available)
!
The MMRM model will be repeated including all values according to the ITT principle 
(i.e. all values will be included regardless of use of rescue treatment or treatment 
discontinuation)
Further details of these sensitivity analyses is provided in Section 4.8.4.  
4.5
Definitions
4.5.1
Baseline values
For all efficacy variables, the baseline value will be the last non-missing value on or prior to 
the first dose of the double-blind study drug date or the last non-missing value of the visit 1 or 
visit 2 assessment for those subjects without a first dose start date.
The baseline value of each safety laboratory test or physical exam endpoint is defined as the 
last assessment (either numerical or character value) on or prior to the first dose of double-
blind study drug date or the last non-missing value of the visit 1 or visit 2 assessment for those 
subjects without a first dose start date.


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4.5.2
Derived data
The waist:hip ratio is calculated as: waist circumference (cm) / hip circumference (cm).
To convert HbA1c from mmol/mol to % the following conversion factor will be used:
HbA1c (%) = (0.09148*HbA1c (mmol/mol) ) + 2.152
4.5.3
Change from baseline
Change from baseline to any week t in the double-blind treatment period is defined as follows:
  = 
  −
, 
where a)   is the change from baseline at week t, b) 
  is the measurement at week 
t, and c) 
 is the measurement at baseline.
4.5.4
Longitudinal repeated measures analysis
A longitudinal repeated measures analysis using restricted maximum likelihood (REML) will 
be performed for the primary efficacy endpoint and three of the secondary endpoints (change 
in weight from baseline to week 52, change in FPG from baseline to week 52 and change in 
SBP from baseline to week 52). The SAS procedure PROC MIXED will be used. The 
preferred model will include the fixed categorical effects of treatment, week and treatment-by-
week interaction as well as the continuous fixed covariates of baseline measurement and 
baseline measurement-by-week interaction. 
This method involves implementing a linear mixed effects model of the form:
 =  + 
, +   + ! + (!  ) + (! 
) + $
where
!
 is the change from baseline for patient j in treatment group i at time k.
!
 is the slope coefficient for the baseline measurement
!

, is the baseline measurement for patient j in treatment group i
!
  is the mean effect for treatment group i
!
! is the mean effect at time k
!
(!  ) is the interaction term between treatment group i and time k
!
(! 
)ijk is baseline measurement-by-week interaction term for patient j in 
treatment group i at time k
!
$ is the error term for patient j in treatment group i at time k


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The above model incorporates repeated measures (where measurements are taken repeatedly 
on the same patient i.e., at baseline, week 2, week 4 up to week 52). Hence, the primary model 
is a mixed model repeated measures (MMRM). The model will be used to derive a least-
squares estimate of the mean treatment difference with corresponding 2-sided 95% CI.
An unstructured matrix for the within-subject error variance-covariance will be used. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
(DDFM).
In case of non-convergence of the preferred model or memory space issues, the following 
back-up models will be defined:
!
The first backup model is the same as the preferred model but the Kenward-Roger 
method will be replaced by Satterthwaite approximation
!
The second backup model is the same as the preferred model but without the term for 
baseline measurement-by-week interaction
The second back-up model will only be provided if the first back-up model does not converge 
or has memory issues.
4.5.4.1
Adjustment for baseline imbalances
Clinically important imbalances between treatment groups with respect to baseline 
characteristics will be identified using summaries of baseline data by treatment group. Any 
imbalances will be assessed from a clinical perspective (without performing statistical 
testing). If clinically important imbalances are found (e.g., between countries), they may be 
adjusted for in the analysis by including the corresponding baseline characteristics as 
additional covariates in the model, e.g., a fixed effect for country may be added to the MMRM 
model. 
4.5.4.2
Assessment of Treatment-by-Baseline interaction
Treatment-by-baseline interaction will be assessed for the analyses of the primary efficacy
endpoint. In the repeated measures model, the interaction will be tested by including the 
additional terms for the treatment-by-baseline interaction (treatment-by-baseline HbA1c and 
treatment-by-baseline HbA1c-by-week).
The treatment-by-baseline HbA1c-by-week interaction will be assessed using contrasts of the 
treatment effect by baseline HbA1c at Week 52. The test for interaction will be performed at 
the 0.10 level of significance. If the interaction is not significant, the original model will be 
used (see section 4.5.4). Otherwise, the interaction will be assessed as qualitative or 
quantitative. Assessment of the interaction type will be based on regression lines plotted for 
each treatment group. The intercepts and slopes for these regression plots will be obtained 
from the analysis model including the interaction term. The intercepts will be estimated by the 


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least squares treatment means. The horizontal axis of the plots will range from the minimum 
baseline value from all subjects included in the analysis to the maximum baseline value.
If the regression lines do not cross, or the crossing is judged not severe (i.e., the crossing
occurs near the boundary or beyond the range of baseline values), then the interaction will be
considered quantitative and this does not compromise the validity of the treatment
comparisons. In this case, the treatment comparisons will be made using the original model 
without the interaction term.
Otherwise, the interaction will be considered qualitative and treatment comparisons will not
be presented as a result of the original model. In this case, the impact of the baseline value on 
treatment effect will be investigated by summarizing the data in subsets defined by baseline 
categories.
4.5.4.3
Subgroup Analyses and Assessment of Treatment-by-Subgroup interaction
Treatment effects will be assessed across the following sub-groups: baseline HbA1c (<8%, 
≥8% - <9%, ≥9%), age group (<65, ≥65 - <75, ≥75 yrs), gender, female age group (≤50, >50 
yrs), race, country, and baseline eGFR (<30, ≥30 - <45, ≥45 - <60, ≥60 - <90, ≥90 
mL/min/1.73m2). The analyses will be based on the primary model (see section 4.5.4). The 
estimates within each baseline HbA1c subgroup will come from the model with terms for 
treatment, week, baseline HbA1c category, treatment-by-week, treatment-by-baseline HbA1c 
category, time-by-baseline HbA1c category and treatment-by-time-by-baseline HbA1c 
category. Adjusted mean change from baseline and its difference from the control group will 
be given for each subgroup at week 52. The model to assess the treatment-by-baseline HbA1c 
interaction will include baseline HbA1c as a continuous variable (as per section 4.5.4.2).
Treatment effects within the remaining subgroups will come from the model including the 
fixed categorical effects of treatment, week, subgroup, treatment-by-week, treatment-by-
subgroup, time-by-subgroup and treatment-by-time-by-subgroup as well as the continuous 
fixed covariates of baseline HbA1c and baseline HbA1c-by-week interaction. Tests of the 
treatment by subgroup interaction will be assessed using contrasts of the treatment effect by 
subgroups at Week 52. The model to assess the treatment-by-age interaction, the treatment-
by-female age interaction and the treatment-by-baseline eGFR interaction will include 
age/baseline eGFR as a continuous variable.
4.5.5
Analysis of covariance (ANCOVA) for change from baseline
Analysis of covariance (ANCOVA) is used for endpoints examining the change from baseline 
to week t (See Section 4.8.2 and Table 11 for details of endpoints). In this model, the change 
from baseline (at time point t) is a function of the treatment group (fixed effect) and the 
baseline measure (covariate). The following model will be used:
%, =  +  &', +   + $


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where,  %, = &, −&',, the week t change from the baseline of subject j in treatment 
group i;  &', is the baseline measure of subject j in treatment group i; &, is the week t
measure of subject j in treatment group i;   is the mean effect of treatment group i; intercept, 
β and   are unknown parameters to be estimated from the data.
Ordinary least squares (OLS) will be used to estimate the model’s parameters along with two-
sided 95% Confidence Intervals (CIs). 
4.5.6
Kaplan-Meier curve and estimates for time-to-event analysis
Kaplan-Meier plots of time to rescue will be displayed by treatment group. Unless otherwise 
specified, the plot will be presented only when there are at least 5 events in one treatment 
group. Additionally, a table will accompany the plot and will display the Kaplan-Meier 
estimates of the cumulative proportion (with 95% confidence interval based on Greenwood’s 
method when applicable) of patients with event at specific time points by treatment group. If 
the estimated lower bound of 95% confidence interval is below 0 or the estimated upper 
bound of 95% confidence interval is over 1, then it will be restricted to 0 or 1 respectively.
Time to rescue is defined as the time (in days) from the first dose date after randomisation to 
the date at which the patient first meets the following rescue criterion: (which is confirmed), 
i.
FPG > 240 mg/dL (13.3 mmol/L) for the period after Visit 2 to and including Visit 8 
(Week 0 to 12) OR
ii.
FPG > 200 mg/dL (11.1 mmol/L) for the period after Visit 8 to and including day of 
Visit 9 (Week 12 to 24) OR
iii.
HbA1c > 8% for the period after Visit 9 to and including Visit 12 (Week 24 to 52) 
Time to rescue will be censored at the earliest of discontinuation of study medication/study, or 
study completion, or time of insulin start (for those subjects who received rescue treatment 
without confirmed rescue criteria).
4.5.7
Analysis of proportions
Proportions endpoints will be analysed using logistic regression with the baseline measure as a 
covariate. The adjusted percentage with 95% CI, Odds Ratio with 95% CI and nominal p-
values for the comparison of dapagliflozin or dapagliflozin plus saxagliptin vs glimepiride
will be presented. The confidence intervals will be based on the profile likelihood method. 
When there are less than 5 responders in any treatment group, the unadjusted proportions 
(and difference), exact 95% confidence interval, and p-values from the Fisher’s exact test 
(when applicable) will be provided.
4.5.8
Time spent below target HbA1c (<7% and <7.5%)
In order to calculate the time spent below HbA1c target (<7% and <7.5%), linear interpolation 
will be used to create a profile for the HbA1c values over time for each patient. The amount of 
time spent <7% (or <7.5%) will then be calculated (in days) from this profile. If there is more 


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than 1 segment where the patient is below target and then rebounds, the individual segment 
times will be added together. 
Missing intermediate HbA1c values will not be imputed, the interpolation will proceed from 
the last available value to the next available value. If the week 52 value is missing, there will 
be no extrapolation of data to this timepoint. 
Actual visit dates will be used to determine times between all visits. No time below target will 
be counted beyond 365 days (52 weeks).
Values recorded after rescue (for those who used rescue medication) or values collected more 
than 8 days after the last dose date (for patients who stayed more than 8 consecutive days off 
treatment) will be excluded from these calculations. 
4.6
Missing data
4.6.1
Handling missing demographic and baseline characteristics data
For demographic and baseline characteristics, each variable will be analysed and/or
summarized using the available data i.e. patients with missing data will be excluded from the 
summaries.
4.6.2
Handling missing efficacy data
Missing data can result from patients discontinuing the study prematurely or by missing 
intermediate visits or selected assessments while remaining in the study. To eliminate missing 
data, every effort will be made to obtain the protocol-required data for all scheduled study 
assessments for all enrolled patients. For efficacy analyses, the MMRM model assumes
missing observations are missing at random (MAR). MAR means that the tendency of a data 
value to be missing depends only on the observed data, and not on the missing data. For 
example, if an HbA1c value is missing, it assumes this is not related to the missing data but to 
some of the observed data (response and covariates) (Ref (1)).
For the change in HbA1c and weight analyses using MMRM, values recorded after rescue 
treatment for those patients who used rescue medication or values collected more than 8 days 
after the last dose date for patients who stayed more than 8 consecutive days off treatment are 
excluded from the analysis. For the change in FPG analysis using MMRM, values recorded 
after rescue treatment for those patients who used rescue medication or values collected more 
than 1 day after the last dose date for patients who stayed more than 1 consecutive days off 
treatment are excluded from the analysis. For the change in SBP analysis using MMRM, 
values recorded after rescue treatment for those patients who used rescue medication or values 
collected more than 4 days after the last dose date for patients who stayed more than 4 
consecutive days off treatment are excluded from the analysis.
The MMRM model assumes the time course of the endpoint values for patients who 
discontinue double-blind treatment or are rescued at a specific time point is consistent with the 
time course for patients ongoing at that time point.


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Summaries of missing data by visit for HbA1c will be provided in order to explore this 
assumption (see Table 16 provided in Appendix IV).
When performing ANCOVA, the Last Observation Carried Forward (LOCF) method will be 
used for dealing with missing values i.e. if no Week 52 measurement is available, the last 
available earlier post-baseline measurement will be used except for the efficacy variable time 
spent below HbA1c target. For patients who started rescue medication prior to Week 52, their 
last post-baseline measurement taken prior to the date of the first dose of rescue medication 
will be used.
For the proportions endpoints regarding glycaemic control at week 52, all available data will 
be used but patients rescued prior to week 52 will be treated as treatment failures (non-
responders). Subjects with missing information at week 52 (e.g. HbA1c, weight) will be 
counted as treatment failures. For the endpoints ‘the proportion of patients with at least one 
episode of confirmed hypoglycaemia’ and ‘the proportion of patients with at least one episode 
of hypoglycaemia (symptomatic with blood glucose ≤70mg/dL [3.9mmol/L]), if the blood 
glucose value is missing for a patient with hypoglycaemia, they will not be counted as having 
a confirmed hypoglycaemic event.
Section 4.11 provides additional information regarding handling of missing or partial dates, 
inclusion of values, visit windowing, and values obtained post treatment.
4.7
Analysis methods
4.7.1
Study population
4.7.1.1
Patient disposition
The disposition of patients for the pre-treatment period and the double-blind treatment period 
will be summarised. This involves all patients enrolled (who signed informed consent) in the 
pre-treatment period; all patients randomised to the double-blind treatment period (and those 
not randomised and reason for not randomised); all patients completing (and discontinuing 
and reasons for discontinuing) the double-blind treatment period.
4.7.1.2
Demographic and baseline characteristics
Demographic and other baseline characteristics, including diabetes-related characteristics and 
renal function characteristics, will be summarised and listed by treatment group and overall, 
using the Randomised Patients Set. 
Table 7 describes the demographic and baseline characteristics; Table 8 describes the 
diabetes-related common baseline characteristics and Table 9 describes the common renal 
function baseline characteristics. 
Table 7. Demographic and baseline characteristics
Characteristic
Type
Categories
Gender
Categorical
Male, Female
Age
Continuous and categorical
< 65 yrs; ≥65 - <75 yrs; ≥75 yrs


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Female age
Categorical 
≤50 yrs; >50 yrs
Race
Categorical
White; Black or African 
American; Asian; Other
Ethnicity 
Categorical
Hispanic/Latino, Not 
Hispanic/Latino 
Body weight
Continuous
Height
Continuous
Waist circumference
Continuous
Body Mass Index
Continuous and categorical
<25kg/m2; ≥25kg/m2; ≥27kg/m2; 
≥30kg/m2
Country
Categorical
Germany; Slovakia; Hungary; 
Poland; Czech Republic
Table 8. Diabetes-related baseline characteristics
Characteristic
Type
Categories
Duration of type 2 diabetes
Continuous and categorical
< 3 yrs; ≥3 - ≤10 yrs; >10yrs
HbA1c
Continuous and categorical
<8%; ≥8% - <9%; ≥9%
FPG
Continuous
C-Peptide
Continuous
Table 9. Baseline renal function and other characteristics
Characteristic
Type
Categories
eGFR (MDRD)
Categorical and continuous 
<30 mL/min/1.73 m2; ≥30 - <45 
mL/min/1.73 m2; ≥45 - <60 
mL/min/1.73 m2; ≥60 - <90 
mL/min/1.73 m2;
≥90 mL/min/1.73 m2
4.7.1.3
Specific and general disease histories
The number (percent) of patients with diabetes and diabetes-related disease histories will be 
summarised and listed by treatment group, and overall using the Randomised Patients Set.
The number (percent) of patients with abnormal general medical history findings will be 
summarised by treatment group and overall by System Organ Class (SOC) and Preferred 
Term (PT) using the Randomised Patients Set. Medical History will be coded using the 
MedDRA dictionary (version 19.1 or later).


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4.7.2
Extent of exposure
4.7.2.1
Study medication
The extent of exposure to study medication (investigational products) during the double-blind 
treatment period is defined as the difference between the last and the first dose of study 
medication of the double-blind treatment period plus 1 day. 
The extent of exposure to study medication will be summarised using the Safety Analysis Set. 
The number and percent of patients with an extent of exposure within pre-specified day ranges 
will be presented for the double-blind treatment period by treatment group as follows: 1-6; 7-
14; 15-28; 29-42; 43-56; 57-70; 71-84; 85-168; 169-252; 253-336; 337-371, ≥372 days. The 
mean, standard deviation (SD), median and range of the number of days of exposure will also 
be presented.
A listing of patients by batch number of study medication will be generated. 
Dose levels of metformin at randomisation (visit 2) will be summarised for each treatment 
group (Safety Analysis Set). Dose levels of glimepiride at week 52 and over time will be 
summarised for this treatment group (Safety Analysis Set).
4.7.2.2
Interruption of study medication
Dates for any interruptions of study drug will be captured on the Exposure (EX) CRF page. 
Dose interruptions will be summarised for each treatment group (Safety Analysis Set). Down 
titrations to 0mg glimepiride will be included as interruptions (for the purposes of this 
summary table only).
4.7.2.3
Dose titrations of Glimepiride
The number of patients with a down-titration will be summarised for the glimepiride plus 
metformin treatment group (Safety Analysis set).
4.7.3
Current and Concomitant medications
Current and concomitant medications will be summarised using the Safety analysis set by 
drug class (anatomic class and therapeutic class), generic drug name and treatment group, as 
defined by the AstraZeneca Drug Dictionary most current at time of database lock (version 
16.2 or later). A summary will be produced for each of the following:
!
all current medication
!
all concomitant medication
Current medications are defined as medications with a start and stop date prior to the first day 
of double-blind treatment, i.e. current medication will be any medication with at least 1 dose 
taken on or after the day of consent date up to the day prior to the first dose of study 
medication and stopped prior to the first dose of study medication.
Concomitant medications are defined as a medication with either:


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!
a recorded medication start date falling within the double-blind treatment period (i.e. a 
medication started during the double-blind phase), or
!
a recorded medication start date prior to the first day of study medication during the 
double-blind treatment period without any recorded medication stop date prior to the 
start of the double-blind treatment period (i.e. a medication started prior to double-
blind medication and continued in the double-blind phase).
If missing or partial dates of medication start/stop dates occur, the medication will be assumed 
to be taken during the double-blind treatment period unless there is convincing evidence to the 
contrary, i.e. it will be included in the summary table of concomitant medications.
4.7.3.1
Other Treatments
A list of the prohibited medications during the study (and their corresponding time frames) is 
presented in Table 10.
Table 10.    List of prohibited medications
Restricted Medication/Class of drug:
Usage
Sulfonylureas, pioglitazone, rosiglitazone, 
GLP-1 receptor agonists, any DPP-4 and 
SGLT2 inhibitors other than IP.
Prohibited during the study.  
Insulin therapy (with the exception of insulin 
therapy during a hospitalisation or use in 
gestational diabetes).
Use of insulin during the study is only acceptable if 
given as a rescue treatment as allowed per the protocol 
(CSP Section 7.8.2) for any duration as clinically 
necessary, or for a temporary use in the following 
situations:
-
For up to 14 days in total and up to 
7 consecutive days if patient is unable to take oral 
medications
-
For up to 14 days in total and up to 
7 consecutive days if there is a documented illness or 
infection that requires additional therapy to maintain 
glycaemic control
-
For up to 14 days in total and up to 
7 cconsecutive days if patients have to temporarily 
stop study medication or metformin due to 
recommendations made in this protocol
-
For up to 7 days during hospitalization.  When 
the reason for hospitalisation is the management of the 
patient’s glycaemic control, treatment with insulin is 
considered a rescue and is allowed for as long as 
clinically necessary


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Restricted Medication/Class of drug:
Usage
Other investigational drugs or participation in 
any interventional clinical study
Prohibited during the study.
Treatment with systemic glucocorticoids 
equivalent to oral prednisolone ≥10 mg 
(betamethasone ≥1.2 mg, dexamethasone 
≥1.5 mg, hydrocortisone ≥40 mg) per day
Newly initiation of treatment with any systemic 
corticosteroid therapy that will involve ≥5 days of 
therapy (inhaled and topical are allowed).  The 
Medical Monitor should be consulted prior to 
beginning therapy with corticosteroids for patients
who require systemic corticosteroid treatment.
Prescription or over-the-counter weight loss 
medications
Prohibited during the study.
Other treatments include:
!
Metformin
Patients will remain on their pre-study stable, maximum tolerated metformin doses ≥1500 
mg/day, during the 52-week double-blind treatment period of the study.  Metformin should be 
administered and stored according to product and country-specific labelling.
Metformin will not be provided in pre-packaged kits by the Sponsor as it is the usual care 
prior to study participation.
!
Rescue therapy
Patients may be eligible for rescue therapy with open-label rescue medication (Insulin) for 
treating ongoing hyperglycaemia.  Patients should continue receiving blinded study 
medication while receiving rescue therapy.  If rescue therapy fails, further therapy will be 
given at the discretion of the Investigator.
Rescue therapy will be prescribed by the investigator (and not provided by the Sponsor).
!
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the investigator and recorded 
in the appropriate sections of the CRF.
4.7.4
Treatment compliance
Percent treatment compliance will be calculated during the double-blind treatment period for 
each treatment group. For each patient, percent compliance is defined as the number of tablets 
taken divided by the number of tablets that should have been taken, multiplied by 100.


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The number of tablets that should have been taken will be calculated as the double-blind 
treatment stop date – double-blind treatment start date + 1, multiplied by 4 (since each patient 
should take 1 tablet per day from each of the 4 bottles).
The number of tablets taken will be calculated as the total number of tablets dispensed minus 
the total number of tablets returned (i.e. the totals for all 4 bottles).
A patient is considered compliant if percent compliance is ≥ 80% and ≤ 120%. The number 
and percent of patients considered compliant will be summarised for each treatment group 
using the Safety Analysis Set.
4.8
Efficacy analyses
The following table provides a summary of how each efficacy variable will be analysed:
Table 11
Statistical analyses to be conducted and sensitivity analyses
Efficacy Variable
Analyses
Primary:
Change in HbA1c from baseline to week 52 
Primary analysis:
MMRM (Full Analysis Set)
Sensitivity analyses:
MMRM (Per Protocol Analysis Set)
ANCOVA using values prior to rescue treatment 
(LOCF used if the week 52 value is not 
available)
MMRM primary model repeated including all 
values regardless of whether patient used rescue 
treatment or discontinued treatment
Subgroup analyses: 
MMRM with covariates for each of the 
following: age group, gender, race, country,
baseline HbA1c and baseline eGFR
Key Secondary:
Proportion with at least one episode of 
confirmed hypoglycaemia
Logistic regression 
Change in body weight from baseline to week 52
MMRM
Change in FPG from baseline to week 52
MMRM
Time to rescue 
Cox PH model
Other Secondary:
Proportion achieving HbA1c <7% (and <7.5%) 
without confirmed hypoglycaemia at week 52
Logistic regression 


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Note: Each analysis is based on the Full Analysis Set unless otherwise stated.
4.8.1
Primary Efficacy Analysis
The primary efficacy variable is the change in HbA1c from baseline to week 52 in the double-
blind treatment period. The primary efficacy analysis will be based on the Full Analysis Set
including values prior to rescue treatment or discontinuation. Values recorded after rescue 
treatment for those patients who used rescue medication or values collected more than 8 days 
after last dose date for patients who stayed more than 8 consecutive days off treatment are 
excluded from the analysis. 
The primary efficacy variable will be analysed using the MMRM model (Section 4.5.4) with 
fixed effects for treatment group and covariates (baseline HbA1c; week (week 2 to week 52), 
and interactions baseline HbA1c-by-week and treatment group-by-week). Point estimates and 
95% CIs will be calculated for the adjusted mean changes from baseline within each treatment 
group as well as for each comparison versus control in adjusted mean changes. The Kenward-
Roger approximation will be used to estimate denominator degrees of freedom (DDFM) while 
an unstructured variance will be used to model the within-patient errors.  
The primary assessments of efficacy will be a comparison of each of the 2 test groups: the 
dapagliflozin plus saxagliptin added to metformin versus the control group (glimepiride added 
to metformin) - and the dapagliflozin added to metformin versus the control group - using a 2-
sided 95% CI.  In particular, if the observed upper limit from a 2-sided 95% CI for the 
Proportion achieving HbA1c <7% (and <7.5%) 
at week 52
Logistic regression 
Proportion achieving individually agreed HbA1c 
targets at week 52
Logistic regression 
Proportion with an HbA1c decrease of ≥1% with 
no weight gain at week 52
Pearson’s Chi-square test
Time spent below HbA1c target (<7% and 
<7.5%)
ANCOVA
Change in BMI from baseline to week 52
ANCOVA (LOCF)
Proportion with a weight reduction ≥5% or a 
weight gain ≥5% at week 52
Logistic regression 
Proportion with at least 1 episode of any 
hypoglycaemia
Logistic regression 
Change in waist circumference from baseline to 
week 52
ANCOVA (LOCF)
Change in systolic BP from baseline to week 52
MMRM
Proportion with at least one episode of 
hypoglycaemia (symptomatic with blood 
glucose ≤70 mg/dL [3.9mmol/L])
Logistic regression


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difference in adjusted means is less than 0.30%, then the test group will be considered to be 
non-inferior to the control group.  
Multiplicity will be controlled using a sequential testing scheme: the dapagliflozin plus 
saxagliptin added to metformin group will be tested versus the glimepiride group first, 
followed by the dapagliflozin plus metformin group versus the glimepiride group. If the first 
comparison is non-inferior the second comparison will be tested. Otherwise, significance 
testing will stop at the first comparison and the second comparison will be reported 
descriptively. See Section 4.2.1 for details. A superiority test of the dapagliflozin plus 
saxagliptin added to metformin group versus the glimepiride added to metformin group will 
also be conducted using the same modelling approach as for the primary non-inferiority 
analysis.
4.8.2
Analysis of secondary and exploratory variables
All secondary endpoints will be analysed using the Full Analysis set including values prior to 
rescue treatment or discontinuation. For HbA1c, weight, BMI and waist circumference, values 
recorded after rescue treatment for those patients who used rescue medication or values 
collected more than 8 days after the last dose date for patients who stayed more than 8 
consecutive days off treatment are excluded from the analysis. For FPG, values recorded after 
rescue treatment for those patients who used rescue medication or values collected more than 
1 day after the last dose date for patients who stayed more than 1 consecutive day off 
treatment are excluded from the analysis. For SBP, values recorded after rescue treatment for 
those patients who used rescue medication or values collected more than 4 days after the last 
dose date for patients who stayed more than 4 consecutive days off treatment are excluded 
from the analysis.
The statistical testing of the primary and key secondary efficacy variables will proceed in a 
sequential manner. If for the primary comparison between dapagliflozin or dapagliflozin plus 
saxagliptin (added to metformin) treatment group and the glimepiride (added to metformin) 
treatment group, the upper limit from a 2-sided 95% CI for the difference in adjusted means is 
less than 0.30%, then the dapagliflozin or dapagliflozin plus saxagliptin will be non-inferior to 
glimepiride and all four key secondary efficacy variables will be tested for superiority at a 
0.05 level (two-sided) as well as the superiority test of the primary efficacy variable. To 
protect the type I error rate of the hierarchical testing procedure, the interpretation of the 
statistical significance of treatment comparisons for each key secondary efficacy variable and 
the superiority test of the primary efficacy variable will be done using a step-wise procedure 
(described in Section 4.3.1).
A summary of each efficacy variable and associated analysis is provided in Table 11.
The analysis of the changes from baseline to week 52 for a) total body weight, b) FPG and c) 
SBP will be performed using the MMRM model (as described for the primary efficacy 
endpoint).  Point estimates and 2-sided 95% CI will be calculated for the adjusted mean 
changes from baseline within each treatment group and between treatment groups together 
with the p-values corresponding to testing the hypotheses of no difference between 


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dapagliflozin added to metformin and dapagliflozin plus saxagliptin added to metformin 
compared to glimepiride added to metformin.
The time spent below HbA1C target (<7% and <7.5%) from baseline to week 52 will be 
analysed using an analysis of covariance (ANCOVA) model with fixed effects for treatment 
group and baseline HbA1c (see section 4.5.5). The change from baseline at week 52 in a) BMI
and b) waist circumference will be analysed using an ANCOVA model with fixed effects for 
treatment groups and respective baseline covariates (see section 4.5.5). LOCF will be applied 
as detailed in section 4.6.2 for the latter two analyses. The ANCOVA model will be used to 
derive a least squares estimate of each test drug combination versus the control with 95% CI 
and (a corresponding 2-sided) p-value.  In addition, a 2-sided 95% CI for the mean change 
within each treatment group will be calculated. 
Time to rescue will be analysed using a Cox proportional hazards model with the Efron 
method (Ref 2) for handling ties (i.e., same rescue times).  Estimates of the hazard ratio and 
95% CI will be provided.  Kaplan-Meier estimates will be calculated and plotted by treatment 
group.  Median time to rescue and their 95% CIs (derived from the Kaplan-Meier estimates) 
will also be reported. Patients will be censored at the final visit (Visit 12; week 52) if rescue 
has not occurred by then (Section 4.5.6), or will be censored at the time of insulin start (for 
those subjects who received rescue treatment without confirmed rescue criteria). The 
proportional hazards (PH) assumption of the Cox model will be visually checked (e.g., the 
survival curves should not cross for the PH to hold). If the PH assumption is not met, the time 
to rescue will be analysed using a Wilcoxon test (using SAS proc lifetest).
The proportion of patients with at least one episode of confirmed hypoglycaemia, the 
proportion achieving HbA1c <7% (and <7.5%) without confirmed hypoglycaemia at week 52,
the proportion achieving HbA1c <7% (and <7.5%) at week 52, the proportion achieving their 
individually agreed HbA1c targets at week 52, the proportion with at least one episode of any 
hypoglycaemia and the proportion with at least one episode of hypoglycaemia (symptomatic 
with blood glucose ≤70mg/dL [3.9mmol/L]) will be summarised by treatment group and 
compared between treatment groups using logistic regression with baseline HbA1c as a 
covariate (see section 4.5.7). The adjusted percentage with 95% CI, Odds Ratio with 95% CI 
and nominal p-values for the comparison of dapagliflozin or dapagliflozin plus saxagliptin vs
glimepiride will be presented. The confidence intervals will be based on the profile likelihood 
method.
The proportion of patients achieving a ≥5% weight reduction or ≥5% weight gain will be 
summarised by treatment group and compared between treatment groups using logistic 
regression with baseline weight as a covariate.
The proportion of patients with an HbA1c decrease ≥1% with no weight gain at week 52 will 
be summarised by treatment group and comparisons between treatment groups (contrasts of 
each test combination vs the control) will be performed using a Pearson’s Chi-Square test. 
Nominal p-values and asymptotic 95% CIs will be presented.


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Descriptive summaries of change from baseline in HbA1c, FPG, weight, BMI, waist 
circumference and systolic BP over time (observed values), will be presented in addition to 
the analyses described above.
4.8.3
Exploratory Variables
The summaries described below will be based on the Full Analysis Set including values prior 
to rescue treatment or discontinuation. Values recorded after rescue treatment for those 
patients who used rescue medication or values collected more than 8 days after last dose date 
for patients who stayed more than 8 consecutive days off treatment are excluded from the 
analyses.
4.8.3.1
SF-36v2
The SF-36v2 questionnaire contains 36 items and covers 8 health domain scales and 2 
psychometrically based physical and mental component summary measures. The 8 health 
domain scales are referred to as follows: physical functioning (PF); role - physical (RP);
bodily pain (BP); general health (GH); vitality (VT); social functioning (SF); role - emotional 
(RE); mental health (MH). The 2 summary measures are referred to as the physical component 
score (PCS) and mental component score (MCS).
Standardised scores will be generated using the validated scoring software package 
(QualityMetric Health OutcomesTM Scoring Software 4.5 (or later version)) for the 8 health 
domain scales and 2 summary measures using the raw data entered in the eCRFs.
The scores for each of the 8 health domain scales along with the PCS and MCS summary 
measures will be summarised by absolute values and changes from baseline at week 24 and 
week 52. 
4.8.3.2
HFS II – Worry subscale
A mean summary score will be calculated by summing the responses to the 18 questions and 
dividing by the number of answered questions. If < 50% of the questions are answered, the 
mean score will not be calculated. Absolute values and changes from baseline in this mean
score will be summarised by treatment group at week 24 and week 52.
4.8.3.3
IWQOL-Lite
A score for each of the 5 domains (physical function, self-esteem, sexual-life, public distress 
and work) and a total score will be calculated as detailed in Appendix V. The raw scores will 
be converted to transformed scores (ranging from 0 to 100) as described in Appendix V.  
Absolute values and change from baseline in the transformed scores will be summarised by 
treatment group at week 24 and week 52.
4.8.3.4
Waist:Hip ratio
Change from baseline in waist:hip ratio will be summarised at week 52.


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4.8.4
Sensitivity analysis
To assess the robustness of the primary efficacy results, sensitivity analyses will be carried out 
as follows for change from baseline in HbA1c to week 52:
!
The primary MMRM model will be repeated using the Per-Protocol analysis set
!
An ANCOVA analysis will be performed using values prior to rescue treatment at 
week 52. If the Week 52 value is missing or post rescue treatment/discontinuation, the 
last post-baseline measurement prior to week 52 and prior to rescue treatment will be 
used.
!
The primary MMRM model will be repeated including all values according to the ITT 
principle (i.e. all values will be included regardless of use of rescue treatment or 
treatment discontinuation)
In addition, as noted in section 4.6.2, summaries of missing data by visit will be used to assess 
the missing data assumptions (See example in Table 16 in Appendix IV). A spaghetti plot to 
show drop-out patterns over time will also be provided.
4.8.5
Subgroup analyses
The primary efficacy analysis will be repeated to summarize HbA1c within subgroups based 
on: age group (<65, ≥65 - <75, ≥75 yrs), gender, female age group (≤50, >50 yrs), race, 
country, baseline HbA1c (<8%, ≥8% - <9%, ≥9%), and baseline eGFR (<30, ≥30 - <45, ≥45 -
<60, ≥60 - <90, ≥90 mL/min/1.73m2). The primary MMRM model will be repeated as 
described in Section 4.5.4.3. The nominal p-value for the subgroup-by-treatment interaction at 
week 52 will be presented.
If the value of the grouping variable cannot be determined, the patient will be excluded from 
the corresponding subgroup analysis. For each subgroup analysis, if, in any treatment group, 
the number of patients is less than 10 for a subgroup, this subgroup will not be included in the 
interaction model and descriptive summaries only will be displayed. If there are problems 
with the convergence of the MMRM model, descriptive summaries within subgroups will be 
provided.
4.9
Safety analysis
All safety analyses will be performed on the Safety Analysis Set. Summaries of safety data 
will be produced for the double-blind (DB) treatment period (on-treatment) only, while
listings will include all events, i.e., listings will include values during the pre-treatment period, 
during the DB treatment period and during the follow-up period.
A separate page to capture events of hypoglycaemia is contained within the CRF (AZ module 
HYPOE). Hypoglycaemia (or discontinuation due to hypoglycaemia) will not be reported on 
an AE CRF page unless the event fulfilled criteria for SAE (in which case a SAE form will be 
completed). Hypoglycaemia events that are reported as SAEs will be included in all 


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summaries of AEs or SAEs. Separate summaries will be provided including hypoglycaemia 
events reported on that special CRF page (see Section 4.9.6).
Analysis of changes from baseline to a specific time point (e.g., laboratory parameters and
vital signs) will only include patients from the Safety Analysis set who have data available for 
both the baseline and the time point under consideration unless otherwise specified.
SAEs and the lab measurements for the liver function tests will be included in the summaries 
only if they occurred or were measured on or prior to the 30th day after the last blinded drug 
treatment date. All other safety events (non-severe AEs, hypoglycaemia, etc.) and 
measurements (safety labs, vital signs etc.) will be included in the summaries only if they 
occurred or were measured on or prior to the 4th day after the last blinded drug treatment date.
No formal statistical testing will be performed for safety analyses; only descriptive summaries
will be provided. A dot plot (showing relative risk) will be produced for the most common 
adverse events.
4.9.1
Adverse events
Adverse events will be classified by Primary System Organ Class (SOC) and Preferred Term 
(PT) according to the MedDRA (version 19.1 or later). Summaries of AEs will be produced 
by SOC, PT and treatment group. In summaries by SOC and PT, AEs will be sorted by 
decreasing frequency within each SOC and PT according to the dapagliflozin + metformin 
dose group. In summaries by PT, AEs will be sorted by decreasing frequency within PT 
according to the dapagliflozin + metformin dose group.
Summaries of AEs will report the number (and percentage of patients) of the following:
!
All AEs (including AEs, SAEs, death, hypoglycaemia, treatment-related events and 
events leading to the discontinuation of study medication)
a) using data obtained prior to rescue medication only
b) repeated to contain all data regardless of use of rescue medication
!
AEs by SOC and PT
a) using data obtained prior to rescue medication only
b) using all data regardless of use of rescue medication
The following summaries will be provided using all data regardless of use of rescue 
medication:
!
AEs by SOC and PT by age categories
!
AEs by SOC and PT by gender
!
AEs by SOC and PT by female age categories
!
AEs by SOC and PT by race
!
Most common AEs (i.e., occurring in at least 2% of patients in any treatment group)
by PT
!
AEs by SOC, PT and intensity


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!
Treatment-related AEs by SOC and PT
!
Most common AEs (i.e., occurring in at least 5% of patients in any treatment group) 
by PT
AEs will be summarised for the double-blind treatment period only; listings of AEs will 
include all events throughout the study period (i.e. pre-treatment period, double-blind 
treatment period and follow-up).
A dot plot (showing relative risk) will be produced for the most common adverse events (by 
preferred term).
4.9.2
Serious adverse events
All serious adverse events (SAEs) will be described in narratives, regardless of investigator 
assessment of causality.
Summaries of SAEs will be produced for the double-blind treatment period (using all data 
regardless of use of rescue medication) and will consist of:
!
SAEs by SOC and PT
!
SAEs related to study medication by SOC and PT
Listings of SAEs will include all events throughout the study period i.e. pre-treatment period, 
double-blind treatment period and follow-up.
4.9.3
Adverse events leading to discontinuation of study medication
AEs with an onset during the double-blind treatment period reported with an action taken of 
permanent discontinuation of study medication will be summarised by SOC and PT (using all 
data regardless of use of rescue medication). This summary will include hypoglycaemia 
events that were reported as SAEs.  
In addition to a narrative description, a patient listing of discontinuation due to AEs will be 
provided - displaying all events that led to discontinuation of study medication with an onset 
date prior to the double-blind treatment period and up to the follow-up period, if any.
4.9.4
Adverse events of special interest
Adverse events of special interest (AEOSI) will be defined based on lists of preferred terms.  
These lists will be reviewed and finalized prior to database lock and unblinding of the 
database.  
The following summaries and listings of AEOSI will include all data regardless of use of 
rescue medication:
!
AEs of genital infection
!
AEs of genital infection by gender


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!
AE of antimicrobial treatment for genital infection by gender 
!
AEs of Urinary Tract Infection (UTI)
!
AEs of UTI by gender
!
AEs of antimicrobial treatment for UTI by gender
!
AEs of renal impairment/failure
!
AEs of volume depletion
!
AEs of fracture
!
AEs of hepatic disorder
!
AEs of hypersensitivity reactions
!
AEs of severe cutaneous adverse reactions
!
AEs of gastroenteritis and upper respiratory tract infections
!
AEs of decreased lymphocyte count
!
AEs of pancreatitis
!
AEs of all malignancies
!
AEs of confirmed adjudicated hospitalisations for cardiac failure events
!
AEs of cardiac failure
!
AEs of DKA
Details of the summaries to be provided for events of Hypoglycaemia can be found in Section 
4.9.6. 
4.9.5
Deaths
All deaths recorded on the AE page of the CRF will be considered a death in the analyses. 
Any deaths that occur during the study will be described in depth as narrative in the CSR. 
Deaths with an onset from day 1 of the double-blind treatment period up to and including 30 
days after the last dose date will be considered as occurring during the double-blind treatment 
period.
Summaries of deaths will include data regardless of use of rescue medication; listing of deaths 
will also include all data regardless of use of rescue medication (Enrolled population).
4.9.6
Hypoglycaemia
Hypoglycaemic events occurring after the start of double blind study medication up to and 
including 4 days after the last double-blind dosing date will be considered as obtained during 
the double-blind treatment period and included in the summaries described below.
The proportion of patients with hypoglycaemic events and the number of hypoglycaemic 
events per patient will be summarised by treatment group. Hypoglycaemic events will also be 
categorised as follows:
!
Major hypoglycaemic events: symptomatic events requiring external assistance due to 
severe impairment in consciousness or behaviour, with a capillary or plasma glucose 


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value <54 mg/dL (<3.0 mmol/L), and prompt recovery after glucose or glucagon 
administration
!
Hypoglycaemia: Typical symptoms of hypoglycaemia accompanied by blood glucose 
≤70 mg/dL (3.9 mmol/L)
!
Other episodes of hypoglycaemia: Symptoms of hypoglycaemia without a blood 
glucose reading or symptoms of hypoglycaemia accompanied by blood glucose >70 
mg/dL (3.9 mmol/L)
!
Confirmed hypoglycaemia: Typical symptoms of hypoglycaemia accompanied by 
blood glucose ≤50 mg/dL (2.8 mmol/L)
!
Asymptomatic hypoglycaemia: An event not accompanied by typical hypoglycaemia 
symptoms but with measured plasma glucose ≤70 mg/dL (≤3.9 mmol/L)
Hypoglycaemic events leading to discontinuation of study medication will be summarised by 
treatment. A summary of hypoglycaemic events over time by treatment will also be provided.
Summaries will be produced using data obtained prior to rescue medication only then repeated 
using all data regardless of use of rescue medication for patients in the Safety Analysis Set. A 
listing of patients will be produced for all hypoglycaemic events. 
4.9.7
Laboratory evaluation
Unless otherwise specified, laboratory data obtained after the start of study medication and up 
to and including 4 days (or 30 days for liver function laboratory test) after the last dose of the 
double-blind treatment period, will be considered as obtained during the double-blind 
treatment period.
Laboratory data (including haematology, clinical chemistry, creatinine and lipids; Appendix 
III) will be summarised by visit using the analysis windows defined in Table 12. Values and 
changes from baseline for laboratory data will be summarised by treatment group at each 
scheduled visit during the double blind treatment period using descriptive statistics (using all
available data regardless of use of rescue medication) for patients in Safety Analysis Data Set. 
Summaries of laboratory data will be produced for the double-blind treatment period, while
listings will include values from the follow-up visit.
4.9.7.1
Marked laboratory abnormalities
Laboratory abnormalities will be evaluated based on marked abnormality values (MA). The 
pre-defined criteria for marked abnormalities are detailed in Appendix III, Table 15. If both 
the baseline and on-treatment values of a parameter are beyond the same MA limit for the 
parameter, then the on-treatment value will be considered an MA only if it is more extreme 
(farther from the limit) than was the baseline value. If the baseline value is beyond the low 
MA limit, and the post-baseline value is beyond the high MA limit (or vice-versa), then the 
post-baseline value will be considered a MA.


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Laboratory abnormalities during the double-blind treatment period will be summarised using 
all data regardless of use of rescue medication.
Additionally, patients with MA will be listed.
4.9.7.2
Additional laboratory data summaries
Shift tables will be produced for the following parameters (including all data regardless of use 
of rescue medication):
!
Sodium, calcium, phosphorus and magnesium baseline to highest category of Low, 
Normal or High
!
Sodium, potassium and calcium baseline to lowest category of Low, Normal or High
!
Urinary Albumin to Creatinine Ratio (UACR) for categories of albuminuria (normal
(0-<30mg/g), micro(30-,300 mg/g), macro(≥ 300 mg/g))
For liver safety, a summary of the proportion of patients with elevated liver tests including 
elevated AT (ALT and/or) AST) and total bilirubin will be provided. The following three 
criteria will be summarised:
!
(AST or ALT > 3XULN) and (Bilirubin > 1.5XULN within 14 days on or after AT 
elevation)
!
(AST or ALT > 3XULN) and (Bilirubin > 2XULN within 14 days on or after AT 
elevation)
!
(AST or ALT > 3XULN) and {(Bilirubin > 2XULN and no ALP >= 2XULN) within 
14 days on or after AT elevation)}
4.9.8
Vital signs
Vital signs data obtained after the start of study medication dosing up to and including 4 days 
after the last double-blind dosing date will be considered as obtained during the double-blind 
treatment period. 
Vital sign measurements include systolic and diastolic blood pressure and pulse are measured 
with the patient in a sitting position.
Vital signs data will be summarised by visit using the visit windows defined in Table 12.
Values and changes from baseline for vital sign measurements will be summarised by 
treatment group at each scheduled visit during the double-blind treatment period using 
descriptive statistics (using all available data regardless of use of rescue medication) for 
patients in Safety Analysis Data Set.
4.9.9
Electrocardiograms
The normality/abnormality of the ECG tracing (as determined by the investigator) will be 
summarised using frequency tables on number of patients with a normal/abnormal ECG 


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tracing at baseline versus week 52 of the double-blind treatment period. When the data at 
week 52 is not available for a patient, the last observation prior to week 52 of that patient will 
be used in the summary.
A listing of patients will be produced which will display all ECG findings up to week 52 in 
patients with abnormal ECGs (as determined by the investigator).
4.9.10
Pregnancy test results
A by-patient listing of pregnancy test results will be provided using the Safety Analysis Set.
4.10
Figures and graphs
The following figures will be presented by treatment group.
!
Longitudinal plots
o
HbA1c adjusted mean change from baseline over time
o
Total body weight adjusted mean change from baseline over time
o
FPG adjusted mean change from baseline over time
!
Forest plots
o
HbA1c adjusted mean change from baseline to week 52
o
Total body weight adjusted mean change from baseline to week 52
o
Proportion of patients reporting at least one episode of confirmed 
hypoglycaemia from baseline until week 52
!
Kaplan-Meier curves for:
o
Time to rescue
o
Time to discontinuation of study medication
!
Spaghetti plot
o
Mean HbA1c over time grouped by last available visit on treatment
!
Dot plot (showing relative risk) for:
o
Most common Adverse Events, by preferred term
4.11
Conventions
4.11.1
Study Day
If the date of assessment is prior to first dose of study medication then study day will be
calculated as:
Study day = Date of assessment – Date of first dosing.
If the date of assessment is on or after the day of first dose then study day will be calculated 
as:
Study day = Date of assessment – Date of first dosing + 1


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Day 1 of the double-blind treatment period is the start date of double-blind study medication.
4.11.2
Visit Windows
Deviations are to be expected between patients in the actual number of study days from 
randomisation to when planned visits are carried out.  To handle these deviations in tables, 
figures, listings, and analyses, visit assessments will be slotted according to visit windows.  
Data will be assigned to the visit windows using study day. For the efficacy and safety data, 
the data will be listed and summarised by visit as listed in Table 12 below:
Table 12. Visit windows for efficacy and safety data 
Visit
Target 
Day
Adjusted windows for analyses (Days)
HbA1c
Vital Signs, sBP
Body Weight,
FPG*, urinalysis
hypoglycaemic 
events 
Waist 
circumference,
BMI,  ECG, 
complete 
physical 
examination**
Laboratory
parameters***, 
Serum lipids
Baseline
1
≤1
≤1
≤1
≤1
Week 2
15
2 - 21
2 - 21
Week 4
29
22 - 35
22 - 35
Week 6
43
36 - 49
36 - 49
Week 8
57
50 - 63
50 - 63
Week 10
71
64 - 77
64 - 77
Week 12
85
78 - 126
78 - 126
Week 24
169
127 - 210
127 - 210
Week 36
253
211 - 294
211 - 294
Week 48
337
295 - 348
295 - 348
Week 52
365
349 - Last 
dosing date¥ + 7
349 - Last dosing 
date¥ + 4*
2 – Last dosing
date of the DB 
period + 4 
2 – Last dosing 
date of the DB 
period + 4
Follow-up
Week 55
386
(Last dosing 
date¥ + 7) –
Last visit date
(Last dosing date¥
+ 4*) – Last visit 
date
(Last dosing 
date¥ + 4) – Last 
visit date
*: For FPG, week 52 and week 55 windows use last dosing date +1. 
**: also assessed at Week 24; **: clinical chemistry parameters also assessed at Weeks 12, 24, 36, 48.
¥: Last dosing date ≥ Day 349


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In case of multiple observations within a single visit window, the following rules apply:
!
If there are two or more observations within the same visit window, the non-
missing observation closest to the target day will be used in the analysis
!
If two observations are equidistant from the target day, the non-missing 
observation with the later collection date will be used in the analysis
!
If two observations are collected on the same day and have a collection time 
associated with them, the non-missing observation with the later collection time 
will be used in the analysis
!
If two or more observations are collected on the same day, all non-missing but with 
no collection time associated with at least one of them, the average of the 
observations will be used in the analysis.
If a visit window does not contain any observations, the data will be missing for that visit. 
4.11.3
Post-Dosing Observations
While double blind treatment period efficacy and safety observations will be listed regardless 
of whether the patient was taking blinded study drug, observations will be summarised only 
when the following rules are satisfied:
For efficacy parameters
!
HbA1C, body weight, BMI and waist circumference will be summarised only if 
measured on or before the 8th day after the last double-blind drug dosing date.
!
FPG, will be summarised only if measured on or before the first day after the last 
randomised, double-blind drug dose date.
!
SBP will be summarised only if measured on or before the 4th day after the last 
double-blind drug dosing date.
For safety parameters
!
SAEs and the lab measurements for the liver function tests will be included in the 
summaries only if occurred/measured on or prior to the 30th day after the last blinded 
drug treatment date.
!
All other safety events (non-severe AEs, hypoglycaemia, etc.) and measurements
(safety lab, vital signs, etc.) will be included in the summaries only if
occurred/measured on or prior to the 4th day after the last blinded drug treatment date.
4.11.4
Duration of Type 2 Diabetes and Missing Dates
Duration of Type 2 diabetes is calculated as the number of years from Type 2 diabetes 
diagnosis date to informed consent date:
(1 + consent date - diagnosis date) / 365.25


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If the date Type 2 diabetes was diagnosed is partially missing, the following rules will take 
effect:
!
Missing day, but month and year are present: the day will be imputed as the 15th day of 
the month.
!
Missing day and month, but year is present: the day and month will be imputed as 30 
June of the year (provided that the imputed date is less than the consent date).
!
Missing year, but day and month are present: No imputations will occur, and the 
patient will be excluded from all summaries related to duration of Type 2 diabetes.
!
Missing day, month and year: No imputations will occur, and the patient will be 
excluded from all summaries related to duration of Type 2 diabetes
!
If any such imputed date falls after the consent date, then the diagnosis date will be 
taken as equal to the consent date.
These durations, even if partially imputed, will be listed. However, only the portion of the date 
of diagnosis actually observed, rather than imputed dates, will be displayed in listings.
4.11.5
Missing Dates for Adverse Events 
If missing or partial dates of AE onset occur, a conservative approach will be followed and 
events will be assumed to be during the Double-Blind treatment period unless there is 
convincing evidence to the contrary. For AEs, a missing or incomplete onset date will be 
imputed according to the following conventions: 
!
If the onset date for an AE is missing or incomplete, an imputed date will be derived to 
slot the event to an appropriate analysis period (pre-treatment, during DB treatment or
follow-up). This derived date will not be reported in summary tables or listings. Every 
effort will be made to determine the actual onset date for the event or to obtain a 
reliable estimate for the onset date from the investigator.
!
If an onset date is missing, the derived onset date will be calculated as the first non-
missing valid date from the following list (in order of precedence):
o
First active study medication date
o
Visit date corresponding to the visit at which the event was reported.
o
If a valid non-missing date is not available for any of these dates, the derived onset 
date will be set to missing.
!
If an onset date is incomplete, the derived onset date will be calculated using the 
following algorithm:
o
Calculate a surrogate date as the first non-missing valid date from the 
following list (in order of precedence):
∀
First active study medication date
∀
Visit date corresponding to the visit at which the event was reported
∀
If a valid non-missing date is not available for any of these dates, the 
surrogate date will be set to missing.


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o
Based on the information provided, set the derived date to the earliest possible 
date. If only a year is provided, set the derived date to January first of that year. If a 
year and month is provided, set the derived date to the first day of that month.
o
If the surrogate date is non-missing then:
∀
If the derived date is on or after the surrogate date use the derived date as 
calculated
∀
If the derived date is before the surrogate date and the surrogate date is 
consistent with the partial data provided for the onset date, use the 
surrogate date as the derived date 
∀
If the derived date is before the surrogate date and the surrogate date is not 
consistent with the partial data provided for the onset date then set the 
derived onset date to be the latest possible date based on the partial onset 
date information provided. If only a year is provided, set the derived date 
to December 31st of that year. If a year and month is provided, set the 
derived date to the last day of that month.
o
If all three dates used to determine the surrogate date are missing, then based on 
the information provided, set the derived date to the earliest possible date. If only a 
year is provided, set the derived date to January first of that year. If a year and 
month is provided, set the derived date to the first day of that month.
4.11.6
Counting Rules for Adverse Events
Where a patient has the same AE, based on preferred terminology, reported multiple times in a 
single analysis period, the patient will only be counted once at the preferred terminology level 
in AE frequency tables.
Where a patient has multiple adverse events within the same system organ class in a single
analysis period, the patient will only be counted once at the system organ class level in
adverse event frequency tables.
When a patient has the same AE, based on preferred terminology, reported multiple times in a 
single analysis period, the following criteria, in order of precedence, will be used to select the 
event to be included in summary tables:
!
Relationship to study medication: Related events will take precedence over unrelated 
events in determining the event to include in summary tables.
!
Intensity of event: More intense events will take precedence over less intense events 
in determining the event to include in summary tables. Missing intensity will be 
considered the least intense event.
!
Onset date: Earlier onset date events will take precedence over later onset date-time 
events in determining the event to include in summary.
When reporting AEs by intensity, in addition to providing a summary table based on the event 
selection criteria detailed above, summary tables will also be provided based on the most 


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intense event during the analysis period - independent of relationship to study medication. For 
these tables, the following criteria, in order of precedence, will be used to select the event to 
be included in summary tables:
!
Intensity of event
!
Onset date 
4.11.7
Strip Sign for Selected Laboratory Data
For selected laboratory test values that have been received with an operator sign as a part of 
the result (>, #, <, or ∃), a process to strip the operator sign will be applied  and the resulting 
numeric values will be used for data analysis. The raw value with operator will remain as such 
on the CRF (or in the electronic record) and in the database. 
5.
CHANGES OF ANALYSIS FROM THE PROTOCOL
1. The protocol text for the analysis of the primary efficacy variable specifies the null and 
alternative hypotheses in terms of ‘control minus test’ as follows:
The null hypothesis H0 (given below) will be tested against the alternative hypothesis HA (α = 
0.025, one-sided):
H0: μc – μt  ≤-0.30%,
HA: μc – μt  > -0.30%
If the observed lower limit from a 2-sided 95% (or 1-sided 97.5%) CI for the difference in 
adjusted means is greater than -0.30%, then the test group will be considered to be non-
inferior to the control group.
In order to be consistent with previous AZ studies of this nature and to aid comparisons across 
studies, this SAP refers to this in terms of ‘test minus control’ as follows:
The null hypothesis H0 (given below) will be tested against the alternative hypothesis HA (α = 
0.025, one-sided):
H0: μt – μc  ≥ 0.30%,
HA: μt – μc  < 0.30%
If the upper limit of the 2-sided 95% CI is less than 0.30% then dapagliflozin or dapagliflozin 
plus saxagliptin will be considered to be non-inferior to glimepiride.


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6.
REFERENCES
1. The prevention and treatment of missing data in clinical trials. Washington, DC: National 
Academies Press. National Research Council 2010
2. Efron B. The efficacy of Cox’s Likelihood function for censored data. Journal of the 
American Statistical Association. 1977; 72, 557-565.


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7.
APPENDICES
7.1
Appendix I
7.1.1
List of Planned Tables
Demography
1. Patient disposition (All patients)
2. Analysis sets (All patients)
3. Relevant protocol deviations (Full analysis set)
4. Demographic characteristics (Randomised patients set)
5. Patient characteristics (Randomised patients set)
6. Diabetes-related and renal baseline characteristics (Randomised patients set)
7. Patient recruitment by country and centre (Randomised patients set)
8. Diabetes-related disease history (Randomised patients set)
9. Medical and surgical history (Randomised patients set)
10. All current medications (Safety analysis set)
11. All concomitant medications (Safety analysis set)
Extent of Exposure
12. Extent of exposure to Investigational Product (Safety analysis set)
13. Metformin dose at randomisation (Safety analysis set)
14. Dose levels of Glimepiride (Safety analysis set)
15. Dose levels of Glimepiride over time (Safety analysis set)
16. Dose titrations of Glimepiride (Safety analysis set)
17. Treatment interruptions (Safety analysis set) 
18. Study treatment compliance (Safety analysis set)
Efficacy
19. Primary efficacy endpoint - change from baseline in HbA1c at week 52 (Full analysis 
set)
20. Key Secondary efficacy endpoints (Full analysis set)
21. Change from baseline in HbA1c  - MMRM summary over time (Full analysis set)
22. Sensitivity analysis - change from baseline in HbA1c at week 52 (Per Protocol analysis 
set)
23. Sensitivity analysis - change from baseline in HbA1c at week 52, LOCF ANCOVA 
(Full analysis set)
24. Sensitivity analysis - change from baseline in HbA1c at week 52 including all values 
regardless of use of rescue treatment or treatment discontinuation (Full analysis set)
25. Change from baseline in HbA1c - Assessment of missing data patterns  (Full analysis 
set)
26. Primary efficacy analysis - MMRM summary (Full analysis set)
27. Change from baseline in HbA1c at week 52 by baseline HbA1c (Full analysis set)
28. Change from baseline in HbA1c at week 52 by age (Full analysis set)
29. Change from baseline in HbA1c at week 52 by gender (Full analysis set)
30. Change from baseline in HbA1c at week 52 by female age group (Full analysis set)
31. Change from baseline in HbA1c at week 52 by race (Full analysis set)
32. Change from baseline in HbA1c at week 52 by country (Full analysis set)


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33. Change from baseline in HbA1c at week 52 by baseline eGFR (Full analysis set)
34. Change from baseline in weight - MMRM summary over time (Full analysis set)
35. Change from baseline in FPG - MMRM summary over time (Full analysis set)
36. Time to rescue - Kaplan Meier estimates (Full analysis set)
37. Proportion meeting HbA1c criteria without confirmed hypoglycaemia at week 52 (Full 
analysis set)
38. Proportion meeting HbA1c criteria at week 52 (Full analysis set)
39. Proportion achieving individually agreed HbA1c targets at week 52 (Full analysis set)
40. Proportion with a HbA1c decrease >=1% with no weight gain (Full analysis set)
41. Time spent below HbA1c target (<7% and <7.5%) (Full analysis set)
42. Change in BMI from baseline to week 52 (LOCF) (Full analysis set)
43. Proportion with a weight reduction >=5%  or a weight gain >=5% (Full analysis set)
44. Proportion with at least 1 episode of any hypoglycaemia (Full analysis set)
45. Change in waist circumference from baseline to week 52 (LOCF) (Full analysis set)
46. Change in systolic blood pressure from baseline to week 52 (MMRM) (Full analysis 
set)
47. Proportion with at least one episode of hypoglycaemia (symptomatic + blood glucose 
≤70 mg/dL [3.9 mmol/L]) (Full analysis set)
48. Change from baseline over time in efficacy variables (observed values) (Full analysis 
set)
Exploratory
49. SF-36v2 scores and change from baseline (Full analysis set)
50. HFS-II worry scale - mean score and change from baseline (Full analysis set)
51. IWQOL-Lite scores and change from baseline (Full analysis set)
52. Waist-to-hip ratio (Full analysis set)
Adverse Events
53. Overall adverse events summary (Safety analysis set) - with data prior to rescue 
treatment only
54. Overall adverse events summary (Safety analysis set) - including all data regardless of 
rescue
55. Adverse events by SOC and PT (Safety analysis set) - with data prior to rescue 
treatment only
56. Adverse events by SOC and PT (Safety analysis set) - including all data regardless of 
rescue
57. Adverse events by SOC and PT by age categories (Safety analysis set) - including all 
data regardless of rescue
58. Adverse events by SOC and PT by gender (Safety analysis set) - including all data 
regardless of rescue
59. Adverse events by SOC and PT by female age categories (Safety analysis set) -
including all data regardless of rescue
60. Adverse events by SOC and PT by race (Safety analysis set) - including all data 
regardless of rescue
61. Most common adverse events (frequency >=5% in any treatment group) (Safety 
analysis set) - including all data regardless of rescue


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62. Most common adverse events (frequency >=2% in any treatment group) (Safety 
analysis set) - including all data regardless of rescue
63. Adverse events by SOC and PT by maximum intensity (Safety analysis set) - including 
all data regardless of rescue
64. Causally related Adverse events by SOC and PT (Safety analysis set) - including all 
data regardless of rescue
65. Adverse events with an outcome of death by SOC and PT (Safety analysis set) -
including all data regardless of rescue
66. Adverse events with outcome of death - key patient information (Safety analysis set) -
including all data regardless of rescue 
67. Serious adverse events by SOC and PT (Safety analysis set) - including all data 
regardless of rescue
68. Serious adverse events causally related to study medication by SOC and PT (Safety 
analysis set) – including all data regardless of rescue
69. Adverse events leading to discontinuation of study medication by SOC and PT (Safety 
analysis set) – including all data regardless of rescue
70. Adverse events of special interest, preferred terms
71. Adverse events of special interest,  genital infection (Safety analysis set)
72. Adverse events of special interest, genital infection by gender (Safety analysis set)
73. Adverse events of special interest, antimicrobial treatment for genital infection by 
gender (Safety analysis set)
74. Adverse events of special interest, urinary tract infection (Safety analysis set)
75. Adverse events of special interest, urinary tract infection by gender (Safety analysis 
set)
76. Adverse events of special interest, antimicrobial treatment for urinary tract infection 
by gender (Safety analysis set)
77. Adverse events of special interest, renal impairment/failure (Safety analysis set)
78. Adverse events of special interest, volume depletion (Safety analysis set)
79. Adverse events of special interest, fracture (Safety analysis set)
80. Adverse events of special interest, hepatic disorder (Safety analysis set)
81. Adverse events of special interest, hypersensitivity reactions (Safety analysis set)
82. Adverse events of special interest, severe cutaneous adverse reactions (Safety analysis 
set)
83. Adverse events of special interest, gastroenteritis and upper respiratory tract infections 
(Safety analysis set)
84. Adverse events of special interest, decreased lymphocyte count (Safety analysis set)
85. Adverse events of special interest, pancreatitis (Safety analysis set)
86. Adverse events of special interest, all malignancies (Safety analysis set)
87. Adverse events of special interest, confirmed adjudicated hospitalisations for cardiac 
failure events (Safety analysis set)
88. Adverse events of special interest, cardiac failure (Safety analysis set)
89. Adverse events of special interest, DKA (Safety analysis set)
90. Non-serious adverse events occurring in greater than 5% of patients (Safety analysis 
set)
91. Hypoglycaemic events (Safety analysis set) - with data prior to rescue treatment only


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92. Hypoglycaemic events (Safety analysis set) - including all data regardless of rescue
93. Hypoglycaemic events over time (Safety analysis set) - with data prior to rescue 
treatment only
94. Hypoglycaemic events over time (Safety analysis set) - including all data regardless of 
rescue
Laboratory Data, Vital Signs and ECG
95. Haematology and clinical chemistry laboratory variables over time (Safety analysis 
set)
96. Lipid parameters over time (Safety analysis set)
97. Marked Laboratory Abnormalities (Safety analysis set)
98. Proportion of subjects with elevated liver tests (Safety analysis set)
99. Patients with combined ALT or AST, and bilirubin, elevations - individual patient data 
(Safety analysis set)
100.
Sodium, Calcium Phosphorous and Magnesium, baseline to maximum value 
during treatment (Safety analysis set)
101.
Sodium, Calcium Phosphorous and Magnesium, baseline to minimum value 
during treatment (Safety analysis set)
102.
Urine Albumin to Creatinine Ratio shift table Baseline to Week 52 value 
(Safety analysis set
103.
Urinalysis, baseline versus maximum value on treatment, shift table (Safety 
analysis set)
104.
Vital signs variables over time (Safety analysis set)
105.
ECG baseline versus week 52 (Safety analysis set)
7.1.2
List of Planned Figures
1. HbA1c - adjusted mean change from baseline over time (Full analysis set)
2. Weight - adjusted mean change from baseline over time (Full analysis set)
3. FPG - adjusted mean change from baseline over time (Full analysis set)
4. HbA1c - difference in adjusted mean change from baseline to week 52, Forest Plot 
(Full analysis set)
5. Weight - difference in adjusted mean change from baseline to week 52, Forest Plot 
(Full analysis set)
6. Proportion of patients reporting at least one episode of confirmed hypoglycaemia from 
baseline to week 52, Forest Plot (Full analysis set)
7. Kaplan-Meier plot of Time to rescue(Full analysis set)
8. Kaplan-Meier plot of Time to discontinuation of study medication (Full analysis set)
9. HbA1c - adjusted mean change from baseline over time by baseline HbA1c (Full 
analysis set)
10. Spaghetti plot of mean HbA1c over time (observed) grouped by last available visit on 
treatment – Excluding data after rescue (Full analysis set)
11. Most common adverse events (>=2%), by preferred term, dot plot showing relative 
risk (Safety analysis set)


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7.1.3
List of Planned Listings
1. Study medication batch numbers
2. Randomisation scheme and codes (Randomised patients set)
3. Patient disposition I (Enrolled patients)
4. Patient disposition II (Randomised patients set)
5. Relevant protocol deviations (Full analysis set)
6. Analysis sets
7. Exclusions from analysis sets
8. Demographic Characteristics (Randomised patients)
9. Baseline characteristics (Randomised patients)
10. Medical and surgical history (Randomised patients set)
11. All current medications (Safety analysis set)
12. All concomitant medications (Safety analysis set)
13. Metformin treatment details (Safety analysis set)
14. Insulin Treatment details (Safety analysis set)
15. Study Drug Accountability (Safety analysis set)
16. Exposure Data (Safety analysis set)
17. Titration data (Safety analysis set)
18. Efficacy parameters over time (Full analysis set)
19. Efficacy parameters I (Full analysis set)
20. Efficacy parameters II (Full analysis set)
21. SF-36 raw data (Full analysis set)
22. SF-36 derived data (Full analysis set)
23. HFS-II Worry Scale (Full analysis set)
24. IWQOL-Lite raw data (Full analysis set)
25. IWQOL-Lite derived data (Full analysis set)
26. Adverse Events (Safety analysis set)
27. Serious adverse events (Safety analysis set)
28. Adverse Events leading to discontinuation of study medication (Safety analysis set)
29. Adverse Events of special interest (Safety analysis set)
30. Events of hypoglycaemia I (Safety analysis set)
31. Events of hypoglycaemia II (Safety analysis set)
32. Laboratory data (Safety analysis set)
33. Marked Laboratory Abnormalities data (Safety analysis set)
34. Liver Function Tests (Safety analysis set)
35. Vital Signs (Safety analysis set)
36. Abnormal ECG Findings (Safety analysis set)
37. Pregnancy Data (Safety analysis set)


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7.2
Appendix II – Inclusion and Exclusion Criteria
Table 13. Patient inclusion and exclusion criteria
Inclusion criteria
1.
Provision of informed consent prior to any study-specific procedures
2.
Is able to read, understand, and sign the Informed Consent Forms (ICFs) and, if applicable, an 
Authorisation to Use and Disclose Protected Health Information form, communicate with the 
Investigator, understand and comply with protocol requirements (including the use of diary 
and glucose meter measurements)
3.
Is male or female of ≥18 and <75 years old at time of informed consent
4.
Has a documented diagnosis of T2DM
5.
Has a HbA1c of ≥7.5% and ≤10.5% based on central laboratory results from Visit 1, with 
individual need for therapy escalation
6.
Currently treated with a stable MTD (≥1500 mg/day) of metformin therapy for at least 8 
weeks prior to Enrolment visit
7.
Has a BMI of ≤45 kg/m2 at enrolment visit
8.
Has a C-peptide laboratory value of ≥1.0 ng/mL (0.33 nmol/L; 333.3 pmol/L) based on 
central laboratory results from Visit 1
9.
For females only: women not of childbearing potential, or if they are women of childbearing 
potential (WOCBP), they must comply with the following:
o
Are not pregnant or breastfeeding
o
Have a negative urine pregnancy test result (minimum sensitivity 25 IU/L or 
equivalent units of human chorionic gonadotropin, beta subunit [βhCG]) at Visit 1 
(Enrolment) and prior to randomisation.
o
Using or willing to adopt a highly effective method of birth control to avoid 
pregnancy throughout the study and for at least 4 weeks after the last dosing of study 
medication
Exclusion criteria
1.
Clinically diagnosed with Type I diabetes, known diagnosis of maturity onset diabetes of the 
young (MODY), or secondary diabetes mellitus or known presence of glutamate 
decarboxylase 65 (GAD65) antibodies
2.
History of diabetic ketoacidosis, hyperosmolar nonketotic coma, or corticosteroid induced 
Type 2 diabetes
3.
Symptoms of poorly controlled diabetes including, but not limited to, marked polyuria,
polydipsia, and/or greater than 10% weight loss during the 3 months prior to Enrolment


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4.
FPG >270 mg/dL (>15 mmol/L) – assessed based on central laboratory results from Visits 1
5.
History of diabetes insipidus
6.
Patients with clinically significant thyroid disease or uncontrolled thyroid disease needing 
initiation or adjustment of thyroid treatment per Investigator’s judgement.  Abnormal thyroid 
stimulating hormone (TSH) value at Enrolment will be further evaluated by free thyroxine 
(T4).  Patients with abnormal free T4 values will be excluded
7.
History of bariatric surgery or lap-band surgery, or either procedure is planned during the time 
period of the study.  History of liposuction is allowed.
8.
History of any unstable endocrine, psychiatric, rapidly progressing or unstable renal disease, 
or rheumatic disorder, as judged by the Investigator.
9.
Patients who, in the judgment of the Investigator, may be at risk for dehydration or volume 
depletion that may affect the patient’s safety and/or the interpretation of efficacy or safety 
data
10. Has evidence of current abuse of drugs or alcohol or a history of abuse within the past 52 
weeks that, in the Investigator’s opinion, would cause the individual to be noncompliant
11. Clinically significant cardiovascular disease or procedure within 3 months prior to Enrolment 
(ie, MI, cardiac surgery, coronary artery bypass surgery, coronary stent placement, coronary 
angioplasty, unstable angina, stroke, transient ischaemic attack, or unstable or previously 
undiagnosed arrhythmia) or expected to require coronary revascularization procedure during 
the course of the study
12. Severe uncontrolled hypertension defined as systolic BP ≥180 mmHg and/or diastolic BP 
≥110 mmHg at any visit up to and including Randomization (Visit 2)
13. Presence or history of severe congestive heart failure (New York Heart Association Class III 
and IV [CCNYHA 1994]), unstable or acute congestive heart failure, and/or known left 
ventricular ejection fraction of ≤40%
14. Creatinine clearance (CrCl) of <60 mL/min based on central laboratory results from Visit 1
15. Familial renal glucosuria.  This condition is diagnosed as glucosuria (>1.0 mmol/L urine) in 
the presence of normoglycaemia in patients without the diagnosis of diabetes mellitus
16. Significant hepatic disease, including, but not limited to, severe hepatic insufficiency and/or 
significant abnormal liver function defined as aspartate aminotransferase (AST) and/or 
alanine aminotransferase (ALT) of >3x upper limit of normal (ULN) based on central 
laboratory results from Visit 1
17. Serum total bilirubin (TB) of >2 mg/dL (34.2 μmol/L [patients with documented Gilbert’s 
syndrome will be allowed to enrol]) based on central laboratory results from Visit 1
18. History of, or currently have, acute or chronic pancreatitis or have triglyceride concentrations 
≥500 mg/dL based on central laboratory results from Visit 1.
19. History of severe hepatobiliary disease or hepatotoxicity with any medication
20. Positive serologic evidence of current infectious liver disease, including patients positive for 


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Hepatitis B viral antibody IgM, Hepatitis B surface antigen, and Hepatitis C virus antibody
21. History of malignancy within 5 years of Visit 1 (Enrolment), with the exception of treated in 
situ basal cell or squamous cell carcinoma of the skin
22. Haemoglobin <10 g/dL (<100 g/L) or 6.2 mmol/L for men; haemoglobin <9.0 g/dL (<90 g/L) 
or 5.9 mmol/L for women
23. History of chronic haemolytic anaemia or haemoglobinopathies (for example, sickle cell 
anaemia, thalassemia, sideroblastic anaemia).  Mild haemolysis due to artificial heart valves 
or due to sickle cell trait is not an exclusion criterion except when haemoglobin levels are too 
low (as defined in haemoglobin criteria above)
24. Donation or transfusion of blood, plasma, or platelets within the past 12 weeks prior to 
Enrolment, or planning to donate blood during the study
25. Concomitant treatment with loop diuretics at Visit 2 (Randomisation/baseline.
26. Administration of any antihyperglycaemic therapy, other than metformin, during the 8 weeks 
prior to Visit 1 (Enrolment)
27. Administration of any other IP or participation in any interventional clinical studies 30 days 
prior to Visit 1 (Enrolment)
28. Treatment with systemic glucocorticoids equivalent to oral prednisolone ≥10 mg 
(betamethasone ≥1.2 mg, dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day for >7 
days within 30 days prior to enrolment
29. Prescription or over-the-counter weight loss medications within 3 months prior to Visit 1 
(Enrolment)
30. Has a clinically significant medical condition that could potentially affect study participation 
and compliance with the treatment and study procedures, or which may pose a significant risk 
to the patient and/or personal well-being, as judged by the Investigator
31. Has clinically significant abnormality identified on physical examination, ECG, or laboratory 
tests (clinical chemistry, haematology, and urinalysis) as judged by the Investigator at Visit 1 
(Enrolment) would compromise the patient’s safety or successful participation in the clinical 
study
32. Has known contraindications, allergies, or hypersensitivities to any study drug or excipient as 
outlined in the IBs or local package inserts for metformin, SU, saxagliptin, and dapagliflozin
33. Ongoing weight loss more than 5% over the last 3 months prior to Visit 1 (Enrolment)
34. Known immunocompromised status, including patients who underwent organ transplantation
35. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or 
staff at the study site)
36. Previous screening, enrolment or randomisation in the present study


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7.3
Appendix III – Laboratory Parameters and Marked Abnormalities
Table 14. Laboratory parameters
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Red blood cell count
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total (TB)
B-Haemoglobin (Hb)
S/P-Alkaline phosphatase (ALP)
B-Haematocrit
S/P-Aspartate transaminase (AST)
B-Platelet count
S/P-Alanine transaminase (ALT)
S/P-Uric acid
S/P-Potassium
S/P-Calcium, total
S/P-Sodium
S/P-Chloride 
S/P-Bicarbonate
S/P-Magnesium
S/P-Phosphorus
Table 15. Marked abnormality criteria for safety laboratory variables 
Marked abnormality criteria
Clinical laboratory 
variables
Units
Low
High
Haematology
HCT males/females
%
< 20%
> 55%
HCT males/females
%
> 60%
Hemoglobin 
males/females
g/L
< 60 g/L
> 180 g/L
Hemoglobin 
males/females
g/L
> 200 g/L
Blood chemistry
ALP
U/L
> 3X ULN
ALT
U/L
> 3X ULN
AST
U/L
> 3X ULN
ALT
U/L
> 5X ULN
AST
U/L
> 5X ULN


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Date  21 Mar 2017
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Marked abnormality criteria
Clinical laboratory 
variables
Units
Low
High
ALT
U/L
> 10X ULN
AST
U/L
> 10X ULN
ALT
U/L
> 20X ULN
AST
U/L
> 20X ULN
Total Bilirubin
umol/L
> 2X ULN if PreRx ≤ULN;    
> 3X ULN if PreRx > ULN
Glucose, Plasma 
Unspecified
mmol/L
< 3 mmol/L
> 19.425 mmol/L
Na (Sodium)
mmol/L
< 130 mmol/L
> 150 mmol/L
Na (Sodium)
mmol/L
< 120 mmol/L
K (Potassium)
mmol/L
≤ 2.5 mmol/L
≥ 6.0 mmol/L
HCO3 (Bicarbonate)
mmol/L
≤ 13 mmol/L
Creatinine
umol/L
≥1.5X PreRx CREAT
Creatinine
umol/L
≥ 221 umol/L
Calcium
mmol/L
< 1.871 mmol/L
≥ 0.25 mmol/L from ULN and 
≥ 0.125 mmol/L from PreRx 
CA
Magnesium
mmol/L
< 0.5 mmol/L
> 2 mmol/L
PO4 (Phosphate)
mmol/L
Age 17-65: ≤
0.581mmol/L
Age 17-65: ≥ 1.808 mmol/L
Magnesium
Age ≥ 66: ≤ 0.678 
mmol/L
Age ≥ 66: ≥ 1.647 mmol/L
Urine
UACR (Urinary 
Albumin-to-
Creatinine Ratio)
mg/g
> 1800 mg/g


Study Code D1689C00014
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Date  21 Mar 2017
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7.4
Appendix IV – Missing data pattern for HbA1c
Table 16. Assessment of missing data patterns by visit and treatment group (Full analysis set)
Visit
Change from Baseline in HbA1c 
Assessments
DAPA + MET
(N = XXX)
DAPA + SAXA + MET
(N = XXX)
GLIM + MET
(N = XXX)
Week X
Available at Week X
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
No baseline assessment available
X (X.X%)
X (X.X%)
X (X.X%)
Missed Visit
X (X.X%)
X (X.X%)
X (X.X%)
Lost to Follow-up
X (X.X%)
X (X.X%)
X (X.X%)
Discontinued Study Medication
X (X.X%)
X (X.X%)
X (X.X%)
Rescued
X (X.X%)
X (X.X%)
X (X.X%)
Cumulative Patients Excluded:
   Primary Efficacy Analysis 
X (X.X%)
X (X.X%)
X (X.X%)
  Sensitivity Analysis*
X (X.X%)
X (X.X%)
X (X.X%)
Week Y
Available at Week Y
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
No baseline assessment available
X (X.X%)
X (X.X%)
X (X.X%)
Missed Visit
X (X.X%)
X (X.X%)
X (X.X%)
Lost to Follow-up
X (X.X%)
X (X.X%)
X (X.X%)
Discontinued Study Medication
X (X.X%)
X (X.X%)
X (X.X%)
Rescued
X (X.X%)
X (X.X%)
X (X.X%)
Cumulative Patients Excluded:
   Primary Efficacy Analysis
X (X.X%)
X (X.X%)
X (X.X%)
  Sensitivity Analysis*
X (X.X%)
X (X.X%)
X (X.X%)
Missed Visit = Patient has an HbA1c at a visit before and an HbA1c at a visit after the Missed Visit.
Lost to Follow-up (e.g., Right Censored) = Patient has an HbA1c at a visit before but no HbA1c assessments 
after the visit.
Discontinued Study Medication = Patient has discontinued study medication prior to that visit (will result in 
exclusion from Primary Efficacy analysis; may or may not have an HbA1c available).
Rescued = Patient has received rescue medication prior to that visit (will result in exclusion from Primary 
Efficacy analysis; may or may not have an HbA1c available).
* Sensitivity analysis re-running MMRM including all values regardless of use of rescue medication or treatment 
discontinuation
Cumulative number (%) patients excluded from the primary efficacy analysis is the distinct patients within 
(LTFU + Discontinued Study Med + Rescued + No baseline available)
Cumulative number (%) patients excluded from the sensitivity analysis is the distinct patients within (LTFU + 
No baseline available)


Study Code D1689C00014
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Date  21 Mar 2017
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7.5
Appendix V – IWQOL-Lite Scoring
The IWQOL-Lite is a 31-item self-reported assessment of quality of life in overweight or 
obese individuals. It scores on 5 dimensions: physical function (11 items); self-esteem (7 
items); sexual life (4 items); public distress (5 items); and work (4 items).  Raw scores for 
each scale will be computed for each of the five scales only if a minimum of 50% of the items 
for that scale are answered, and for the total score only if 75% of the answers for all items are 
completed. (The required number of minimum responses is: Physical Function=6 of 11; Self-
Esteem =4 of 7; Sexual Life=2 of 4; Public Distress=3 of 5; Work=2 of 4; Total=24 of 31.) In 
computing raw scores, a pro-rated system for handling missing data will be used. To calculate 
the raw score for any scale or total score, the procedures are as follows:
1. Determine if the minimum number of items are answered for that scale. The required 
number of minimum responses is: Physical Function=6 of 11; Self- Esteem =4 of 7; 
Sexual Life=2 of 4; Public Distress=3 of 5; Work=2 of 4; Total=24 of 31.
Example 1: If an individual answered 5 of 11 Physical Function questions, the Physical 
Function score would be considered missing and coded as 999.
Example 2: If an individual answered 26 items on the entire scale, a valid score would be
calculated for the IWQOL-Lite total.
2. Take the average of the valid items for that scale. Compute the average for the valid 
responses to items for that scale where 1=”Never True” and 5=”Always True”. The 
average must be a number between 1 and 5. For example, if the respondent answered “3” 
on every item of the Physical Function scale, the mean would be 3.
Example 3: An individual answered the 11 Physical Function questions as follows (9 indicates 
missing question): 2, 3, 2, 4, 9, 2, 2, 3, 4, 9, 5. The individual answered 9 of 11 questions, with 
an average of 3.0 (27/9).
Example 4: An individual answered the 5 Public Distress questions as follows: 3, 1, 3, 4, 3. 
The individual answered 5 of 5 questions with an average of 2.8 (14/5).
3. Multiply that average by the total number of items for that scale. The total number of 
items on IWQOL-Lite scales are as follows: Physical Function=11, Self-Esteem=7, Sexual 
Life=4, Public Distress=5, Work=4, Total=31). Round to the nearest whole integer. For 
example, if the mean of the Physical Function scale is 3.0, then you would multiply 3.0 X 
11 = 33.
Example 5: From the Physical Function answers in Example 3, multiply the average (3.0) 
times the number of total questions in the Physical Function scale (11) and round to the 
nearest whole integer: 3 X 11 = 33 (no need to round). This is the Physical Function Raw 
Score.


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Date  21 Mar 2017
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Example 6: From the Public Distress answers in Example 4, multiply the average (2.8) times 
the number of total questions in the Public Distress scale (5) and round to the nearest whole 
integer: 2.8 X 5 = 14 (no need to round). This is the Public Distress Raw Score.
In order to convert the IWQOL-Lite raw scores to the more familiar 0 (worst) to 100 (best) 
scoring using the following formulae:
1. Subtract the raw score (as calculated above) from the maximum score for each scale 
(Physical Function=55, Self-Esteem=35, Sexual Life=20, Public Distress=25, Work=20, 
Total=155).
2. Divide that difference by the range for each scale (Physical Function=44, Self-Esteem=28, 
Sexual Life=16, Public Distress=20, Work=16, Total=124).
3. Multiply that total by 100.
Example 7: From the Physical Function answers in Example 5, subtract the raw score (33) 
from the maximum score for Physical Function (55) and divide that result by the range for 
Physical Function (44) and multiply the result by 100: (55 - 33)/44 = .50 X 100 = 50.
Example 8: From the Public Distress answers in Example 6, subtract the raw score (14) from 
the maximum score for Public Distress (25) and divide that result by the range for Public 
Distress (20) and multiply by 100: (25 - 14)/20 = .55 X 100= 55.
An easy way to check the scoring is to enter a record with all 1's and a second record with all 
5's. The first record should have all transformed scores equal to 100 and the second record 
should have all transformed scores equal to 0.