Conditions: Type 2 Diabetes Mellitus Inadequate Glycaemic Control
Keywords: Diabetes Mellitus Type 2, saxagliptin, dapagliflozin, metformin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 905
Healthy volunteers: no

Brief summary:
The aim of this study is to evaluate safety and efficacy of therapy with saxagliptin 5mg co-administered with dapagliflozin 5mg, compared to therapy with saxagliptin 5mg or dapagliflozin 5mg in patients who are inadequately controlled on ≥1500mg/day of metformin monotherapy.

Detailed description:

Arms:
arm 1: 5 mg Tablets, Oral, Once daily, 24 weeks for Saxagliptin and Dapagliflozin arm 2: 5 mg Tablets, Oral, Once daily, 24 weeks for Dapagliflozin and Saxagliptin Placebo arm 3: 5 mg Tablets, Oral, Once daily, 24 weeks for Saxagliptin and Dapagliflozin placebo

Interventions: intervention 1: Dapagliflozin intervention 2: Placebo for Dapagliflozin intervention 3: Saxagliptin intervention 4: Placebo for Saxagliptin
Intervention descriptions: intervention 1: 5mg, orally, Green, plain, diamond-shaped, film-coated tablet intervention 2: Does not contain active ingredient, orally, Green, plain, diamond-shaped, film-coated tablet intervention 3: 5mg, orally, Plain, yellow, biconvex, round, film-coated tablet intervention 4: Does not contain active ingredient, orally, Plain, yellow, biconvex, round, film-coated tablet

Protocol document:
Prot_000.pdf: 
 
1 (100) 
 
Clinical Study Protocol  
 
Drug Substance 
Saxagliptin/Dapagliflozin  
 
Study Code 
D1683C00005 
 
Version 
4.0 
 
Date 
4 August 2016 
 
A Multi-Center, Randomised, Double-Blind, Active-Controlled, Parallel 
Group, Phase III Trial to Evaluate the Safety and Efficacy of Saxagliptin 
5mg Co-administered with Dapagliflozin 5mg compared to Saxagliptin 5mg 
or Dapagliflozin 5mg all given as Add-on therapy to Metformin in Patients 
with Type 2 Diabetes who have Inadequate Glycaemic Control on Metformin 
Alone 
 
Sponsor:  AstraZeneca AB, S-151 85 Södertälje, Sweden 
 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
2 (100) 
CSPVERSION HISTORY 
Version 4.0, 4 August 2016  
Changes to the protocol are summarised below. 
  
Section 1.1(Background and rationale for conducting this study) and Section 11 (List of 
references): References in the 3rd paragraph were modified. 
Section 3.1 (Inclusion criteria):   
x Fasting Plasma Glucose (FPG) in mmol/L was added to make it clear for all countries. 
x Male condom with spermicidal gel is added as an acceptable method of birth control.  
Section 3.2 (Exclusion criteria): The criteria 8 'a' was updated and mentioned as a separate 
bullet ‘b’ to exclude any exposure of DPP-4 and SGLT-2 inhibitor within 8 weeks prior to 
enrolment to be consistent with exclusion criteria 8 a on the timings for administration of any 
other antihyperglycaemic therapy.  
Section 3.7 (Methods for Unblinding): 'pharmacist' is removed as Individual treatment codes 
will only be available to the Investigator from the IVRS/IWRS.  
Section 3.9.2 (Study-specific discontinuation criteria): The note was added to withhold study 
medication when eGFR <60mL/min/1.73m2 (by MDRD) until retest eGFR result are available 
only for randomisation visit, as dapagliflozin is contraindicated in patients with eGFR 
<60mL/min/1.73m2. 
Table 1 (Study Plan):  
x The footnote 'k' was added to make it clear on rescue medication. Rescue medication 
should also be returned for rescued patients at Visit 4 and 5. 
x The footnote 'h' was updated to make it clear on pregnancy testing. Visit window for 
enrolment visit was changed to be consistent with footnote 'c'. 
x Return study medication was added to make it clear 
x Study Medication Compliance Review marked for Visit 3 to be consistent with Section 
7.6 
x Collect unused study medication/supplies was removed to make it clear 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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Section 4.2.1 (Enrolment visit): Patient diary review was removed to be consistent with Table 
1. 
Section 4.3.2 (Treatment period visits): Item 12 was updated to be consistent with Table 1. 
Study medication will be dispensed and returned at Visit 4. 
Section 6.3.1 (Time period for collection of adverse event): Discontinuation visit was deleted 
to be consistent with Table 1. 
Section 6.3.7 (Hypoglycaemia): Reference in the 3rd paragraph were updated. 
Section 6.4.1 (Adverse event of special interest): FDA has removed the post approval 
requirements for ONGLYZA (saxagliptin) for several AE’s of special interest. Specifically 
these include Liver test abnormalities accompanied by jaundice or hyperbilirubinemia, 
Opportunistic infections and Severe hypersensitivity. Therefore, all these three events were all 
removed. 
Section 7.6 (Compliance): The section is updated to be consistent with Table 1. Upper 
limitation 120% of that prescribed was added.  
Section 7.9 (Concomitant and other treatment): Typographical error where 'or chronic' was 
deleted for glucocorticosteroid therapy to be consistent with exclusion criteria 8 'e'.  
Appendix D (Algorithm on Management of Sustained Elevated Liver Safety Abnormalities): 
Patient must be discontinued from the study medication and not study is updated to be 
consistent with following paragraph and section 3.9. 
Appendix F (Actions required in cases of increases in liver biochemistry and evaluation of 
Hy’s Law): Actions required in cases of increases in liver biochemistry and evaluation of Hy’s 
Law was added and List of appendices was updated in accordance with regulatory 
requirement on reporting of FDA requested events for saxagliptin. 
Minor editorial and typographical errors are updated and not noted. 
 
Version 3.0, 18 January 2016 
Changes to the protocol are summarised below. 
Protocol Synopsis: Estimated date of last patient completed is updated from 4Q 2016 to 2Q 
2017. 
Abbreviation: Liver Function Test (LFT) is added. 
Section 3.1 (Inclusion criteria): To make it clear and consistent with Section 6.6.2 (Paternal 
exposure), “Sexually active fertile men must use effective birth control if their partners are 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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WOCBP” is removed. 
Section 3.9.1 (General discontinuation criteria): The section was updated to clearly 
differentiate treatment discontinuation from study withdrawal by removing ‘Lost to follow-
up’ since this is one of the reason for study withdrawal.  
Section 5.2.4.3 (Diabetes Ketoacidosis) and Section 6.8.3 (DKA Adjudication): These 
sections are removed and will be updated after the review from FDA regarding the relevant 
text to be added in CSP.    
Section 6.4.1 (Adverse events of special interest): The section was updated to include 
regulatory requirement on reporting of FDA requested events. 
Section 6.6.1 (Maternal exposure): To make it clear that, If a patient becomes pregnant during 
the course of study all study medication should be discontinued immediately. Patient should 
be continued in the study as per original visit schedule. Hence, “The patient should be 
withdrawn from study and continue treatment of diabetes according to the standard of care” is 
removed. 
 
Version 2.0, 08 January 2016 
Changes to the protocol are summarised below. 
Section 1.3 (Benefit/risk and ethical assessment): Per FDA request, information on 
ketoacidosis was added in the clinical study protocol. 
Section 3.10 (Criteria for Withdrawal): Per FDA request, the clinical study protocol is updated 
to clearly differentiate treatment discontinuation from study withdrawal. 
Section 3.9.1 (General discontinuation criteria): To make it clear and consistent with Section 
3.10, bullet 3 is rephrased. 
Section 3.11 (Discontinuation of the study): Additional reasons for discontinuation of the 
study are added in the clinical study protocol. 
Section 4.1 (Screening visit): Retesting of HbA1c once, at screening visit is added. 
Section 3.2 (Exclusion criteria): Bullet (f) of exclusion criteria no 12 is rephrased to be 
consistent with Section 4.1 as retesting of HbA1c is allowed under specific condition. 
Section 3.10.1 (Screen failures): The section was rephrased to be consistent with Section 4.1 
as patients are permitted to retest HbA1c once under specific condition.  
Section 4 (Study Plan and Timing of Procedures): Table 1 is updated for HbA1c, footnote is 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
5 (100) 
added to reflect the retesting of HbA1c at screening visit under specific condition. 
Section 5.7 (Biomarker analysis): Typographical error in aliquots was corrected. 
Section 7.4 (Labelling): Visit number removed as it will be added on the label when IP is 
dispensed by site personnel. 
Section 8.1 (Statistical considerations): To be more clear and specific regarding SAP and its 
further amendments 
Section 8.5.6 (Exploratory analysis): To be clear and specific on timing of collection of data 
for hypoglycaemia. 
   
Version 1.0, 23 December.2015 
Initial creation 
 
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 
 


 
6 (100) 
PROTOCOL SYNOPSIS 
 
A Multi-Center, Randomised, Double-Blind, Active-Controlled, Parallel 
Group, Phase III Trial to Evaluate the Safety and Efficacy of Saxagliptin 
5mg Co-administered with Dapagliflozin 5mg compared to Saxagliptin 5mg 
or Dapagliflozin 5mg all given as Add-on therapy to Metformin in Patients 
with Type 2 Diabetes who have Inadequate Glycaemic Control on 
Metformin Alone 
 
 
International Co-ordinating Investigator 
Study site(s) and number of patients planned 
This will be a multi-center study conducted at approximately 120 sites across North America, 
EU and ROW. Approximately 900 patients will be randomised. 
Study period 
 
Phase of development 
Estimated date of first patient enrolled 
1Q 2016 
III 
Estimated date of last patient completed 
2Q 2017 
III 
 
Study design 
Study D1683C00005 is a 24-week, double-blind, randomised, active-controlled, multi-center, 
parallel-group study to evaluate safety and efficacy of saxagliptin 5mg co-administered with 
dapagliflozin 5mg, compared with either saxagliptin 5mg or dapagliflozin 5mg in patients 
who are inadequately controlled on 1500mg/day of metformin.  After randomisation the 
patients will visit the clinic after 6, 12, and 24 weeks.  Efficacy as well as safety assessments 
will be taken before randomisation and at each visit at the clinic. 
PPD


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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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 (MTD) of metformin 
monotherapy (1500mg/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: 
1. 
Dapagliflozin (5mg orally once daily [QD]) plus placebo as an add-on to metformin 
(1500mg/day orally) 
2. 
Dapagliflozin (5mg orally once daily [QD]) plus saxagliptin (5mg orally once daily 
[QD]) as an add-on to metformin (1500mg/day orally) 
3. 
Saxagliptin (5mg orally once daily [QD]) plus placebo as an add-on to metformin 
(1500mg/day orally) 
Study Objectives 
Primary Objective: 
Outcome Measure: 
To demonstrate the superiority of the change 
from baseline HbA1c achieved with the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to either agent individually 
after 24 weeks 
 
Change from baseline HbA1c to week 24 
 
Secondary Objective: 
Outcome Measure : 
To demonstrate the effect of the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to either agent individually 
on proportion of patients achieving therapeutic 
glycaemic response with after 24 weeks 
Proportion of patients achieving HbA1c < 7.0% at 24 
weeks  
 
To demonstrate the effect of the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to either agent individually 
on fasting plasma glucose after 24 weeks  
Change in fasting plasma glucose at 24 weeks. 
To demonstrate the effect of the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to saxagliptin 5mg on total 
body weight after 24 weeks  
Change in total body weight at 24 weeks 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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Safety Objective: 
Outcome Measure : 
To evaluate the safety and tolerability of the 
co-administered saxagliptin 5mg and 
dapagliflozin 5mg to either agent individually 
after 24 weeks  
Adverse Events (AEs)/ Serious AEs (SAEs) 
Vital signs 
Collection of clinical chemistry/hematology 
parameters 
 
Target patient population 
Approximately 900 patients with T2DM with inadequate glycaemic control receiving 
metformin at a MTD of 1500mg/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 27 weeks, including a 1-week pre-study Screening period, a 2- 
week enrolment period, and a 24-week double-blind treatment period. 
Investigational product, dosage and mode of administration 
Dapagliflozin and matching placebo: 
Dapagliflozin 5mg tablets or placebo matching dapagliflozin will be administered orally once 
daily for the 24-week double-blind treatment period. 
Saxagliptin and matching placebo: 
Saxagliptin 5mg tablets or placebo matching saxagliptin will be administered orally once daily 
for the 24-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 1500mg).  Metformin 
should be administered and stored according to product and country specific labelling. 
Rescue therapy: 
Patients who require rescue therapy will receive open label dapagliflozin 10mg plus 
saxagliptin 5mg as a first line treatment.  Insulin can be given as a second line treatment at 
Investigators discretion. 
Statistical methods 
Efficacy analyses will be run for the Full Analysis (FA) population and for the Per Protocol 
(PP) population (Refer section 8.3.1) if more than 10% of patients from the FA population are 
excluded from the PP population for important protocol deviations. 


Clinical Study Protocol Synopsis 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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All analyses will be done using values regardless of rescue/intensification of treatment or 
discontinuation of the study treatment.  Sensitivity analyses will be conducted for the primary 
efficacy analysis excluding the data after rescue or more than 8 days after discontinuation of 
the study treatment. 
The primary endpoint will be tested for saxagliptin plus dapagliflozin versus each of the 
individual agents simultaneously at the alpha = 0.05 level (two sided).  The secondary 
endpoints then will be tested sequentially.  Each comparison will be tested at the alpha = 0.05 
(two-sided) level. 
The primary efficacy analysis will be performed using a longitudinal repeated measures 
analysis 
for the change from baseline at Week 24, with terms for 
treatment group, baseline value, time (each relevant visit), the interaction of treatment and 
time, and the interaction of baseline value and time in the model. Point estimates and 95% 
confidence intervals will be calculated for the adjusted mean changes within each treatment 
group as well as for the differences in adjusted mean changes between treatment groups. 
A sample size of 300 patients per group will provide at least 90% power to simultaneously 
detect a difference in mean change from baseline to week 24 in HbA1c of -0.30 (%) for both 
primary endpoint comparisons of saxagliptin plus dapagliflozin vs its components at the 2-
sided alpha = 0.05 level.  This assumes a common standard deviation of 1.0% and a 3% non-
evaluability rate.  
CCI


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
PROTOCOL SYNOPSIS ......................................................................................... 6 
TABLE OF CONTENTS ....................................................................................... 10 
1. 
INTRODUCTION ................................................................................................. 19 
1.1 
Background and rationale for conducting this study ............................................. 19 
1.2 
Rationale for study design, doses and control groups ............................................ 20 
1.3 
Benefit/risk and ethical assessment........................................................................ 23 
1.4 
Study Design .......................................................................................................... 25 
2. 
STUDY OBJECTIVES .......................................................................................... 27 
2.1 
Primary objective ................................................................................................... 27 
2.2 
Secondary objectives ............................................................................................. 27 
2.3 
Safety objectives .................................................................................................... 27 
2.4 
Exploratory objectives ........................................................................................... 27 
3. 
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 29 
3.1 
Inclusion criteria .................................................................................................... 29 
3.2 
Exclusion criteria ................................................................................................... 30 
3.3 
Patient enrolment and randomisation ..................................................................... 34 
3.4 
Procedures for handling incorrectly enrolled or randomised patients ................... 34 
3.5 
Methods for assigning treatment groups ................................................................ 35 
3.6 
Methods for ensuring blinding ............................................................................... 35 
3.7 
Methods for unblinding .......................................................................................... 36 
3.8 
Restrictions ............................................................................................................ 36 
3.9 
Discontinuation of investigational product ............................................................ 37 
3.9.1 
General discontinuation criteria: ............................................................................ 37 
3.9.2 
Study-specific discontinuation criteria: ................................................................. 37 
3.9.3 
Discontinuation guidelines for protocol-defined severe hypoglycaemia 
episodes or recurrent non-severe hypoglycaemia episodes ................................... 38 
3.9.4 
Procedures for discontinuation of a patient from investigational product ............. 39 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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3.10 
Criteria for withdrawal ........................................................................................... 39 
3.10.1 
Screen failures ........................................................................................................ 40 
3.10.2 
Withdrawal of the informed consent ...................................................................... 40 
3.11 
Discontinuation of the study .................................................................................. 40 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 41 
4.1 
Screening Visit ....................................................................................................... 45 
4.2 
Enrolment Period ................................................................................................... 46 
4.2.1 
Enrolment visit (Visit 1, Week -2) ......................................................................... 46 
4.3 
Treatment period .................................................................................................... 47 
4.3.1 
Randomisation and baseline visit (Visit 2, Week 0) .............................................. 47 
4.3.2 
Treatment period visits (Visits 3 and 4; Weeks 6 and 12) ..................................... 49 
4.4 
Rescue therapy ....................................................................................................... 50 
4.5 
End of treatment period visit/ Early Termination or Rescue (Visit 5, Week 
24) .......................................................................................................................... 51 
5. 
STUDY ASSESSMENTS ..................................................................................... 52 
5.1 
Efficacy assessments .............................................................................................. 52 
5.1.1 
HbA1c .................................................................................................................... 52 
5.1.2 
Fasting plasma glucose .......................................................................................... 53 
5.1.3 
Body weight ........................................................................................................... 53 
5.1.4 
Body height ............................................................................................................ 53 
5.2 
Safety assessments ................................................................................................. 53 
5.2.1 
Laboratory safety assessments ............................................................................... 53 
5.2.2 
Physical examination ............................................................................................. 56 
5.2.3 
Vital signs .............................................................................................................. 57 
5.2.4 
Other safety assessments ........................................................................................ 57 
5.2.4.1 
Cardiovascular events ............................................................................................ 57 
5.2.4.2 
Liver function test abnormalities ........................................................................... 57 
5.3 
Other assessments .................................................................................................. 58 
5.3.1 
Self-monitored blood glucose and hypoglycaemic events ..................................... 58 
5.3.2 
Diet and exercise counseling ................................................................................. 59 
5.4 
Pharmacokinetics (Not Applicable) ....................................................................... 59 
5.5 
Pharmacodynamics (Not Applicable) .................................................................... 59 
5.6 
Pharmacogenetics (Not Applicable) ...................................................................... 59 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 61 
CCI


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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6.1 
Definition of adverse events .................................................................................. 61 
6.2 
Definitions of serious adverse event ...................................................................... 61 
6.3 
Recording of adverse events .................................................................................. 62 
6.3.1 
Time period for collection of adverse events ......................................................... 62 
6.3.2 
Follow-up of unresolved adverse events ................................................................ 62 
6.3.3 
Variables ................................................................................................................ 62 
6.3.3.1 
Intensity rating scale .............................................................................................. 63 
6.3.4 
Causality collection ................................................................................................ 63 
6.3.5 
Adverse events based on signs and symptoms....................................................... 63 
6.3.6 
Adverse events based on examinations and tests ................................................... 64 
6.3.7 
Hypoglycaemia ...................................................................................................... 64 
6.4 
Reporting of serious adverse events....................................................................... 65 
6.4.1 
Adverse events of special interest .......................................................................... 66 
6.5 
Overdose ................................................................................................................ 66 
6.6 
Pregnancy ............................................................................................................... 67 
6.6.1 
Maternal exposure .................................................................................................. 67 
6.6.2 
Paternal exposure ................................................................................................... 67 
6.7 
Management of IP related toxicities ...................................................................... 67 
6.8 
Study governance and oversight ............................................................................ 68 
6.8.1 
Hepatic Adjudication Committee .......................................................................... 68 
6.8.2 
Cardiovascular Adjudication Committee ............................................................... 68 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 69 
7.1 
Identity of investigational product(s) ..................................................................... 69 
7.2 
Dose and treatment regimens ................................................................................. 70 
7.3 
Identity of Open Label Rescue Medications .......................................................... 70 
7.4 
Labelling ................................................................................................................ 71 
7.5 
Storage ................................................................................................................... 71 
7.6 
Compliance ............................................................................................................ 71 
7.7 
Accountability ........................................................................................................ 72 
7.8 
Return of study drug .............................................................................................. 73 
7.9 
Concomitant and other treatments ......................................................................... 73 
7.9.1 
Metformin .............................................................................................................. 74 
7.9.2 
Open label Rescue Medications ............................................................................. 74 
7.9.3 
Other concomitant treatment .................................................................................. 75 
7.10 
Post Study Access to Study Treatment (Not Applicable) ...................................... 75 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA ............................................ 75 
8.1 
Statistical considerations ........................................................................................ 75 


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Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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8.2 
Sample size estimate .............................................................................................. 75 
8.3 
Definitions of analysis sets .................................................................................... 76 
8.3.1 
Efficacy analysis set ............................................................................................... 76 
8.3.2 
Safety analysis set .................................................................................................. 76 
8.3.3 
PK analysis set (Not Applicable) ........................................................................... 76 
8.3.4 
PRO analysis set (Not Applicable) ........................................................................ 76 
8.4 
Outcome measures for analyses ............................................................................. 76 
8.5 
Methods for statistical analyses ............................................................................. 77 
8.5.1 
Analysis of the primary variable (s) ....................................................................... 78 
8.5.2 
Analysis of the secondary variable(s) .................................................................... 78 
8.5.3 
Subgroup analysis (if applicable) ........................................................................... 78 
8.5.4 
Interim analysis (Not Applicable) .......................................................................... 79 
8.5.5 
Sensitivity analysis (if applicable) ......................................................................... 79 
8.5.6 
Exploratory analysis (if applicable) ....................................................................... 79 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA .......................... 80 
9.1 
Training of study site personnel ............................................................................. 80 
9.2 
Monitoring of the study ......................................................................................... 80 
9.2.1 
Source data ............................................................................................................. 80 
9.2.2 
Patients study agreements ...................................................................................... 81 
9.2.3 
Archiving of study documents ............................................................................... 81 
9.3 
Study timetable and end of study ........................................................................... 81 
9.4 
Data management by AstraZeneca or delegate ...................................................... 81 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 82 
10.1 
Ethical conduct of the study ................................................................................... 82 
10.2 
Subject data protection ........................................................................................... 82 
10.3 
Ethics and regulatory review.................................................................................. 82 
10.4 
Informed consent ................................................................................................... 83 
10.4.1 
Screening informed consent ................................................................................... 83 
10.5 
Changes to the protocol and informed consent form ............................................. 84 
10.6 
Audits and inspections ........................................................................................... 84 
11. 
LIST OF REFERENCES ....................................................................................... 85 
 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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LIST OF TABLES 
Table 1 
Study Plan ................................................................................................. 42 
Table 2 
Criteria for Initiation of Rescue Therapy During the Randomised 
Treatment Period ...................................................................................... 50 
Table 3 
Volume of blood to be withdrawn from each patient ............................... 54 
Table 4 
Laboratory Safety Variables ..................................................................... 55 
Table 5 
Investigational Products for Study D1683C00005 ................................... 69 
Table 6 
Open label Rescue Medication for Study D1683C00005 ........................ 70 
 
LIST OF FIGURES 
Figure 1 
Study Design ............................................................................................ 26 
Figure 2 
Sustained Elevated Liver Safety Abnormalities Flow Chart .................... 94 
Figure 3 
Algorithm for Protocol Specified Tests for Hematuria after 
Enrollment ................................................................................................ 96 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information .................................................................. 87 
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ................................................................................. 89 
Appendix C 
New York Heart Association (NYHA) Classification ............................. 90 
Appendix D 
Algorithm on Management of Sustained Elevated Liver Safety 
Abnormalities ........................................................................................... 91 
Appendix E 
Algorithm for Microscopic Hematuria ..................................................... 95 
Appendix F 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................ 97 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
ADA 
American Diabetes Association 
ALK-P 
Alkaline Phosphatase 
ALT 
Alanine transaminase 
ALP 
Alkaline phosphatase 
ANA 
Antinuclear Antibody 
ANCOVA 
Analysis of covariance 
Anti-LKM 
Anti-Liver/Kidney Microsomal Antibody 
AST 
Aspartate transaminase 
ȕ-HCG 
ȕ- human chorionic gonadotrophin 
BMI 
Body mass index 
BP 
Blood pressure 
CDT 
Carbohydrate deficient transferrin 
CABG 
Coronary Artery Bypass Grafting 
CK 
Creatine Kinase 
CMV 
Cytomegalovirus 
CRO 
Clinical Research Organization 
CrCl 
Creatinine Clearance 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CSP 
Clinical Study Protocol 
CTCAE 
Common Terminology Criteria for Adverse Event 
CV 
Cardiovascular 
DAE 
Discontinuation of Investigational Product due to Adverse Event 
DBP 
Diastolic blood pressure 
DGR 
Dangerous Goods Regulations 
DILI 
Drug Induced Liver Injury 
DNA 
Deoxyribonucleic acid  


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
16 (100) 
Abbreviation or 
special term 
Explanation 
DPP-4 
Dipeptidyl peptidase -4 
EBV 
Epstein-Barr Virus 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
E-code 
Enrolment code 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EOT 
End of Treatment 
FA 
Full Analysis 
FDC 
Fixed Dose Combination 
FPG 
Fasting plasma glucose 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl-transpeptidase 
GLP-1 
Glucagon-like peptide-1 
GMP 
Good Manufacturing Practice 
GPV 
AZ Global Pharmacovigilance 
AZRand 
AZ Randomisation system 
Hb 
Haemoglobin 
HbA1c 
Haemoglobin A1c 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HSV 
Herpes Simplex Virus 
IATA 
International Airline Transportation Association 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
International 
Co-ordinating 
investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally.  
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IP 
Investigational Product  
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
17 (100) 
Abbreviation or 
special term 
Explanation 
LADA 
Latent Autoimmune Diabetes of Adults 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
LOCF 
Last-Observation-Carried-Forward 
LIMS 
Laboratory information management system 
LSLV 
Last Subject Last Visit 
MCH 
Mean Cell Haemoglobin 
MCHC 
Mean Cell Haemoglobin concentration 
MCV 
Mean Cell Volume 
MAR 
Missing at random 
MDRD 
Modification in Diet and Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MoA 
Mechanisms of action 
MTD 
Maximum Tolerated Dose 
NYHA 
New York Heart Association 
OAD 
Oral antidiabetic 
OAE 
Other Significant Adverse Event 
PGx 
Pharmacogenetic research 
PI 
Principal Investigator  
PP 
Per Protocol 
PPG 
Postprandial glucose 
PCI 
Percutaneous Coronary Intervention 
PT/INR 
Prothrombin time 
QD 
Once daily 
SA 
Sickle cell trait 
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SCSM 
AZ Supply Chain Study Management 
SGLT2 
Sodium glucose co-transporter 2 
SMA 
Anti-Smooth Muscle Antibody 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
18 (100) 
Abbreviation or 
special term 
Explanation 
SOPs 
Standard operating procedures 
SU 
Sulphonylurea 
T2DM 
Type 2 diabetes mellitus 
TB 
Bilirubin, total 
TIA 
Transient ischemic attack 
TIBC 
Total iron binding capacity 
TSH 
Thyroid Stimulating Hormone 
TZD 
Thiazolidinediones 
U/A 
Urinalyses 
ULN 
Upper Limit of Normal 
Vs 
Versus 
WBDC 
Web Based Data Capture 
WOCBP 
Women of childbearing potential 
 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
19 (100) 
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. 
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 US and 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, 
SUs, or thiazolidinedione, and has favorable safety and tolerability profiles (A. R. Chacra et al 
2009, Jaime A. Davidson 2014, Priscilla L Hollander et al 2011, Ralph A. Defronzo et al 
2009). 
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 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
20 (100) 
moderate weight reduction (dapagliflozin).  Dapagliflozin has also demonstrated persistent 
effects on HbA1c over 4 years of therapy. 
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 either saxagliptin OR dapagliflozin to metformin 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 
bodyweight (Rosenstock J et al 2015).  
The recommended starting dose of dapagliflozin is 5mg in a few countries.  The dose can be 
increased to 10mg in patients tolerating dapagliflozin 5mg who require additional glycaemic 
control. The aim of this study is thus to provide relevant clinical data regarding the efficacy 
and short term safety of saxagliptin 5mg co-administered with dapagliflozin 5mg after 24 
weeks. 
This is a double-blind, randomised, active-controlled, multi-center, 24 week, parallel-group 
study to evaluate safety and efficacy of saxagliptin 5mg co-administered with dapagliflozin 
5mg, compared with either saxagliptin 5mg or dapagliflozin 5mg all given as add-on therapy 
to metformin in patients who are inadequately controlled on metformin alone.  After 
randomisation the patients will visit the clinic after 6, 12, and 24 weeks.  Efficacy as well as 
safety assessments will be taken before randomisation and at each visit at the clinic. 
1.2 
Rationale for study design, doses and control groups 
This is a Phase III study, performed as part of the clinical development program for 
saxagliptin plus dapagliflozin fixed dose combination (FDC) therapy to improve glycaemic 
control as an adjunct to diet and exercise and metformin when treatment with both saxagliptin 
and dapagliflozin is appropriate. 
Study design, dose selection, and control groups 
The current study is designed to evaluate safety and efficacy of therapy with saxagliptin 5mg 
co-administered with dapagliflozin 5mg, compared to therapy with saxaglipgtin 5mg or 
dapagliflozin 5mg in patients who are inadequately controlled on 1500mg/day of metformin 
monotherapy. 
A 24-week randomised, double-blinded treatment period will allow for adequate information 
on efficacy and safety of the studied doses. 
Active control group 
This is a double-blind, active-controlled study.  All three study arms, saxagliptin 5mg plus 
dapagliflozin 5mg, saxagliptin 5mg plus placebo and dapagliflozin 5mg plus placebo, contain 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
21 (100) 
at least one approved, oral anti-diabetic medication added to the background of metformin. 
Therefore all patients are anticipated to benefit from better glycaemic control during the study. 
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). 
Dapagliflozin 
Dapagliflozin (Farxiga™) is approved in many countries worldwide, including the US, 
Canada, and countries 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 5mg 
dose was chosen for this study because it is the starting dose in the US, Canada and 
Switzerland, has demonstrated clinically meaningful reductions in HbA1c, and is used at that 
dose in the combination under evaluation in this study.  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.  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 in many countries worldwide, including the US, Canada 
and countries in 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 5mg once daily (QD) in a wide range of patients with T2DM, as either 
monotherapy, add on combination therapy with metformin, a Thiazolidinediones(TZD), a 
Sulphonylurea (SU), insulin, or initial combination therapy with metformin.  Saxagliptin 5mg 
resulted in clinically meaningful reductions in HbA1c, as well as Fasting Plasma Glucose 
(FPG), Post Prandial Glucose (PPG), insulin, C-peptide, and glucagon levels and is the 
recommended dose according to the approved drug label. 
Combination of saxagliptin and dapagliflozin 
The combination of saxagliptin 5mg and dapagliflozin 10mg has been studied in 3 phase III 
trials.  The main study CV181-169, was a double blind randomised trial has compared dual 
add on saxagliptin 5mg/ dapagliflozin 10mg FDC to both of the components and found the 
FDC to be safe and superior to each of the components.  The treatment was given on the 
background of metformin and lasted for 24 weeks. 
Two other studies were sequential add on of saxagliptin 5mg to a background of dapagliflozin 
10mg and metformin (study CV181-168) and add on dapagliflozin 10mg to a background of 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
22 (100) 
saxagliptin 5mg and metformin (study MB102-129).  Both studies found the co-administration 
of saxagliptin 5mg and dapagliflozin 10mg to be well tolerated and efficacious. 
Choice of outcome variables 
The primary endpoint is change from baseline in HbA1c at Week 24.  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. 
The rationale for selection of the secondary variables and exploratory variables is provided 
below: 
1. 
Proportion of patients achieving HbA1c <7.0%: The target HbA1c for most patients 
with T2DM is <7.0% according to international diabetes treatment guidelines. 
2. 
FPG is a well-established measure of short-term glycaemic efficacy (CHMP 2012). 
3. 
Weight: 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).  
4. 
The start of rescue is an indirect measure of glucose efficacy and shows the 
durability of efficacy. 
Choice of study population 
Patients 
Patients with T2DM with inadequate glycaemic control while being treated with at least 
1500mg/day, of metformin therapy. 
HbA1c 
The HbA1c inclusion criterion at randomisation (i.e., 7.5% to 10.0%) 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, foetus, 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. 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
23 (100) 
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 (e.g., 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. 
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 5mg plus saxagliptin 
5mg added to metformin compared to dapagliflozin 5mg added to metformin or saxagliptin 
5mg added to metformin, 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 saxagliptin group will receive dapagliflozin matching placebo 
with metformin.  All patients will be monitored throughout the study to ensure adequate 
glycaemic control. 
Dapagliflozin and Saxagliptin 
Prior to approval, dapagliflozin was evaluated in 5 core Phase IIb studies, 16 core Phase III 
studies, and 3 regional Phase III studies. 
Prior to approval, saxagliptin was evaluated in 6 pivotal Phase III, randomised, double-blind 
controlled trials at doses of 2.5 to 10mg.  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). 
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. 
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 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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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. 
Ketoacidosis 
There have been post-marketing 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 (e.g, type 1 diabetes, history of pancreatitis, or pancreatic surgery), 
insulin dose reduction, reduced caloric intake, or increased insulin requirements due to 
infections, illness or surgery and alcohol abuse. Dapagliflozin should be used with caution in 
these patients. 
Potential benefits to Patients 
Based on prior clinical trials experience and post-marketing 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 5mg and dapagliflozin 10mg 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 
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, a lower than 
commonly used dose of dapagliflozin (5mg) is used in combination with the standard dose of 
saxagliptin (5mg) so the risks of adverse events (AEs) are further reduced.  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 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
25 (100) 
examinations over the duration of the study.  Patients will also receive counselling on dietary 
and life-style modifications. 
Informed consent and alternatives to participation 
All prospective participants will be informed of the possible risks and benefits associated with 
this study, and their consent will be received prior to performing any study-related activity.  
When a prospective participant elects to not participate in the study or to withdraw from the 
study, other medications are available to treat their diabetes, and the patient will not be 
disadvantaged in any way. 
1.4 
Study Design  
Figure 1 presents the overall design of the study. 
Study D1683C00005 is a 24-week, multi-center, randomised, parallel-group, double-blind, 
active-controlled Phase III study to evaluate safety and efficacy of therapy with saxagliptin 
5mg co-administered with dapagliflozin 5mg added to metformin, compared to therapy with 
saxaglipgtin 5mg or dapagliflozin 5mg added to metformin in adult patients with T2DM who 
have inadequate glycaemic control (HbA1c 7.5% to 10.0%) on maximum tolerated dose of 
1500mg/day of metformin monotherapy. 
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 
(1500mg/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: 
1. 
Dapagliflozin 5mg + saxagliptin 5mg + metformin 
2. 
Dapagliflozin 5mg + saxagliptin placebo + metformin 
3. 
Saxagliptin 5mg + dapagliflozin placebo + metformin 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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Figure 1 
Study Design 
 
 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
To demonstrate the superiority of the change 
from baseline HbA1c achieved with the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to either agent individually 
after 24 weeks 
Change from baseline HbA1c to week 24 
2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure : 
To demonstrate the effect of the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to either agent individually 
on proportion of patients achieving therapeutic 
glycaemic response with after 24 weeks 
Proportion of patients achieving HbA1c <7.0% at 24 
weeks  
 
To demonstrate the effect of the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to either agent individually 
on fasting plasma glucose after 24 weeks  
Change in fasting plasma glucose at 24 weeks 
To demonstrate the effect of the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to saxagliptin 5mg on total 
body weight after 24 weeks  
Change in total body weight at 24 weeks 
2.3 
Safety objectives 
Safety Objective: 
Outcome Measure : 
To evaluate the safety and tolerability of the 
co-administered saxagliptin 5mg and 
dapagliflozin 5mg to either agent individually 
after 24 weeks 
 
AEs/SAEs 
Vital signs 
Collection of clinical chemistry/hematology 
parameters 
 
2.4 
Exploratory objectives   
Exploratory Objective: 
Outcome Measure : 
CCI


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
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CCI


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
29 (100) 
3. 
PATIENT 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. 
3.1 
Inclusion criteria 
For inclusion in the study patients should fulfil the following criteria: 
1. 
Signed written informed consent: Patients must be willing and able to give signed 
and dated written informed consent. 
2. 
Target population:  
(a) 
Patients with T2DM with inadequate glycaemic control, defined as a central 
laboratory HbA1c 7.5% to 10.0% obtained at the screening visit. 
(b) 
Fasting Plasma Glucose (FPG)  270mg/dl (15.0mmol/L) at the enrolment visit. 
Note: At Week -2 (Visit 1), a qualification check will be performed and patients will be 
excluded, if their FPG is >270mg/dl.  A re-test will be permitted within 7 days if the initial 
result was >270mg/dl but <300mg/dl (16.7mmol/L). Patients will be excluded if the mean 
value of the Week -2 result and the re-test result is >270mg/dl. 
(c) 
Stable metformin therapy for at least 8 weeks prior to enrolment at a dose of 
1500mg per day. 
(d) 
BMI 45.0kg/m2 at Enrolment visit. 
3. 
Age and reproductive status: 
(a) 
Men and women, aged 18 years old at time of screening visit. 
(b) 
For Females Only: Women of childbearing potential (WOCBP) must be using an 
acceptable method of contraception to avoid pregnancy throughout the study and 
CCI


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
30 (100) 
for at least 4 weeks after the last dose of study medication in such a manner that the 
risk of pregnancy is minimized. 
 
WOCBP must have a negative urine pregnancy test (minimum sensitivity 
25IU/L or equivalent units of HCG) within 24 hours prior to the start of 
investigational product. 
 
Women are not pregnant or breastfeeding. 
 Definitions 
Women NOT of childbearing potential: Women who are permanently or surgically 
sterilized or postmenopausal.  Permanent sterilization includes hysterectomy, and/or bilateral 
oophorectomy, and/or bilateral salpingectomy. 
Postmenopausal women: Women are considered postmenopausal if they have amenorrhea 
for 12 consecutive months after the last menstrual period and marks the end of menstrual 
cycles. 
Acceptable method of birth control: defined as one that results in a failure rate of <1% per 
year, when used consistently and correctly. The following are considered acceptable methods 
of contraception: total sexual abstinence; vasectomized sexual partner; male condom with 
spermicidal gel, tubal occlusion (ligation); intrauterine device; levonorgestrel intrauterine 
system (eg, Mirena®); etonogestrel implants (eg, Implanon®, Norplan®); normal and low 
dose combined oral contraceptive pills; norelgestromin/ethinyl estradiol transdermal system; 
intravaginal device (e.g., 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: 
1. 
Target disease exceptions: 
(a) 
History of diabetes insipidus. 
(b) 
Symptoms of poorly controlled diabetes that would preclude participation in this 
trial including but not limited to marked polyuria and polydipsia with greater than 
10% weight loss during the 3 months prior to Enrolment (Visit 1), or other signs 
and symptoms. 
(c) 
Type 1 diabetes or Latent Autoimmune Diabetes of Adults (LADA). 
(d) 
History of diabetic ketoacidosis or hyperosmolar nonketotic coma. 
2. 
Medical history and concurrent diseases: 


Clinical Study Protocol 
Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
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(a) 
History of bariatric surgery or lap-band procedure within 12 months prior to 
Enrolment.  
(b) 
History of any clinically significant disease or disorder which, in the opinion of the 
investigator, may put the patient at risk because of participation in the study, may 
influence the results, or may limit the patient's ability to participate in or complete 
the study. 
(c) 
Patient who, in the judgment of the Investigator, may be a risk for dehydration or 
volume depletion that may affect the interpretation of efficacy or safety data. 
(d) 
Patient is currently abusing alcohol or other drugs or has done so within the last 6 
months. 
3. 
Acute vascular event: 
(a) 
Uncontrolled hypertension defined as systolic blood pressure (SBP) 160mmHg 
and/or diastolic blood pressure (DBP) 100mmHg. 
Note: Patients with SBP160mmHg and < 180mmHg or a DBP 100mmHg and < 
110mmHg will be able to enter the Enrolment (Visit 1), provided their hypertension 
treatment is adjusted as deemed appropriate by the investigator.  These patients cannot be 
randomised if their blood pressure remains SBP  160mmHg or DBP  100mmHg 
measured at randomisation (Visit 2). 
(b) 
Cardiovascular Disease within 3 months prior to Enrolment visit [ie myocardial 
infarction, cardiac surgery or revascularization (CABG/PCI), unstable angina, 
stroke or transient ischemic attack (TIA). 
(c) 
Congestive heart failure as New York Association (NYHA) class III-IV (see 
Appendix C), unstable or acute congestive heart failure. 
Note: eligible patients with congestive heart failure, especially those who are on diuretic 
therapy, should have careful monitoring of their volumes status throughout the study. 
4. 
Renal diseases: 
(a) 
Moderate or severe impairment of renal function [defined as eGFR 
<60mL/min/1.73m2 (estimated by MDRD) or serum creatinine 1.5mg/dL in males 
or 1.4mg/dL in females]. 
(b) 
Conditions of congenital renal glucosuria, history of unstable or rapidly progressing 
renal disease. 
5. 
Hepatic diseases: 


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(a) 
Significant hepatic disease, including, but not limited to, chronic active hepatitis 
and/or severe hepatic insufficiency and/or significant abnormal liver function, 
including patients with ALT and/or AST 3x ULN and/or Total Bilirubin 2.0x 
ULN. 
(b) 
History of severe hepatobiliary disease or hepatotoxicity with any medication. 
(c) 
Positive serologic evidence of current infectious liver disease, including patients 
who are known to be positive for Hepatitis viral antibody IgM, Hepatitis B surface 
antigen, and Hepatitis C virus antibody. 
6. 
Pancreatic disease: 
(a) 
History of pancreatitis. 
7. 
Hematological/Oncological disease/conditions: 
(a) 
History of haemoglobinopathy, with the exception of sickle cell trait (SA) or 
thalassemia; or chronic or recurrent hemolysis. 
(b) 
Malignancy within 5 years of the Enrolment (Visit 1) with the exception of treated 
basal cell or treated squamous cell carcinoma. 
(c) 
Known immunocompromised status, including but not limited to, individuals who 
have undergone organ transplantation or who are positive for the human 
immunodeficiency virus. 
(d) 
Donation of blood or blood products to a blood bank, blood transfusion, or 
participation in a clinical study requiring withdrawal of >400mL of blood during the 
6 months prior to the Enrolment (Visit 1). 
8. 
Prohibited treatment and therapies: 
(a) 
Administration of any antihyperglycaemic therapy, other than metformin, for more 
than 14 days (consecutive or not) during the 8 weeks prior to enrolment. 
(b) 
Any use of DPP-4 inhibitor or SGLT-2 inhibitor within 8 weeks prior to enrolment. 
(c) 
Current treatment with potent cytochrome P450 3A4/5 inhibitors (in countries 
where dose adjustment would be required by the saxagliptin label) 
(d) 
Prescription and over-the-counter weight loss medications within 3 months prior to 
Enrolment (Visit 1) 
(e) 
Current or frequent use of therapeutic doses of systemic glucocorticoids is an 
exclusion criterion.  Treatment with any stable replacement therapy at the time of 
enrolment is permitted (See Section 7.9). 


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Note: Topical or inhaled corticosteroids are allowed. 
(f) 
Administration of any other investigational drug or participation in any 
interventional clinical studies within 30 days prior to Enrolment (Visit 1). 
9. 
Physical and laboratory test findings: 
(a) 
Haemoglobin 11.0g/dL (110g/L) for men; haemoglobin 10.0g/dL (100g/L) for 
women 
(b) 
Male patients with a confirmed benign cause of microscopic hematuria can be 
randomised with a documented negative microscopic urinalysis. 
NOTE: Female patients with hematuria can be randomised, but should be investigated 
according to local standards and best clinical practices (See Appendix E). 
(c) 
Other central laboratory test findings: 
 
Abnormal free T4 values.  Abnormal thyroid stimulating hormone (TSH) value 
at Enrolment (Visit 1) will be further evaluated by free T4.  Patients with 
abnormal free T4 values will be excluded. 
10. 
 Allergies and adverse drug reaction: 
(a) 
Patients who have contraindications, including but not limited to a history of serious 
hypersensitivity reaction to saxagliptin, dapagliflozin as outlined in the saxagliptin 
and dapagliflozin Investigator Brochure, the local saxagliptin and dapagliflozin 
package insert, or the local metformin package insert.   
11. 
Sex and reproductive status: 
(a) 
Women who are pregnant or breast-feeding. 
12. 
Other exclusion criteria: 
(a) 
Prisoners or patients who are involuntarily incarcerated. 
(b) 
Patients who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness. 
(c) 
Patients on a commercial weight loss program with ongoing weight loss, or on an 
intensive exercise program. 
(d) 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site). 


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(e) 
Patient is a participating investigator, study coordinator, employee of an 
investigator or immediate family member of any of the aforementioned. 
(f) 
Previous enrolment or randomisation in the present study. 
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4. 
3.3 
Patient enrolment and randomisation 
Investigators will 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 (Visit 1) into the study, the Investigators will: 
1. 
Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed. 
2. 
Assign (using the Interactive Voice Response System (IVRS) or Interactive Web 
Response System (IWRS) potential patient a unique enrolment number, beginning 
with ‘E + 4-digit site number + 3 digit patient number starting with 001.  For 
example, the first patient at site 9999 would be assigned the patient number: 
E9999001.  This number will be used for identification throughout the study. 
3. 
Determine patient eligibility in accordance with inclusion/exclusion criteria. 
4. 
Assign an eligible patient unique randomisation code, by accessing IVRS or IWRS, 
see Section 3.5.  Patient is considered randomised in the study after this assignment. 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. 
3.4 
Procedures for handling incorrectly enrolled or randomised 
patients 
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 must not be 
randomised or initiated on treatment, and must be withdrawn from the study. 
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the following steps need to be taken: 
1. 
The Investigator or Study Monitor should inform the AstraZeneca study physician 
immediately, ensuring patient safety must always be the number one priority. 


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2. 
Study Treatment must be discontinued in all cases where continued treatment is 
deemed to pose a safety risk to the patient.  A discussion should occur between the 
AstraZeneca study physician and the investigator, a decision may be reached that 
whether to continue or discontinue the patient from study treatment.  The 
AstraZeneca study physician must ensure all decisions are appropriately 
documented. 
3. 
In those cases where continuation of study therapy is judged not to present a 
concern related to safety and disease management, the rationale for continuing 
study therapy must be clearly documented.  The patient should continue follow up 
in accordance with defined study procedures.  
3.5 
Methods for assigning treatment groups 
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.  The randomisation codes will be computer generated 
using the AZ Randomisation system (AZRand) and loaded into the IVRS/IWRS database.  
The patients will be randomised in a 1:1:1 ratio to the following treatment groups: 
1. 
Dapagliflozin 5mg + placebo for saxagliptin 
2. 
Dapagliflozin 5mg + saxagliptin 5mg 
3. 
Saxagliptin 5mg + placebo for dapagliflozin 
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 and the 
respective placebo tablets will be identical in size, colour, smell, and taste as described in 
Table 5.  The bottles with IPs will be labelled with unique identification numbers allocated 
from the IVRS/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 IVRS/IWRS and 
carrying out the packaging and labelling of IPs. 


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3.7 
Methods for unblinding  
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the Investigator(s) from the IVRS/IWRS. Routines for this will be 
described in the IVRS/IWRS user manual that will be provided to each center. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation.  The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient and 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 investigational product and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented. 
3.8 
Restrictions 
Once screened and qualified for entry, patients will be instructed as follows: 
1. 
Fast overnight for 8 to 12 hours prior to each study site visit, i.e., no food or 
beverage except water.  Allowed medications can be taken with water only. 
2. 
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. 
3. 
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. 
4. 
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. 
5. 
Do not donate blood for the duration of the study and for 3 months following the 
last study visit. 
6. 
Comply with prescribed dosing regimen to preserve study integrity and ensure 
patient safety. 
7. 
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. 
8. 
Make every attempt to adhere to the diet and exercise counseling and to the protocol 
visit schedule. 


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9. 
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. 
3.9 
Discontinuation of investigational product 
3.9.1 
General discontinuation criteria: 
Patients may be discontinued from investigational product (IP) in the following situations: 
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. 
3. 
The Investigator feels it is in the patient's best interest to discontinue study 
medication for reasons other than AE. 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 6.4). 
4. 
Severe non-compliance with the study protocol as judged by the Investigator and/or 
AstraZeneca 
5. 
Incorrectly enrolled patients (see Section 3.4) 
6. 
Lack of Therapeutic response 
3.9.2 
Study-specific discontinuation criteria: 
1. 
Initial and repeat laboratory tests meet any of the following criteria (see Appendix 
D): 
 
ALT and/or AST are >3x ULN and TB >2x ULN 
 
ALT and/or AST are >5x ULN for 14 consecutive days, at any time after 
initial confirmatory results 
 
ALT and/or AST are >8x ULN 
2. 
Pregnancy confirmed by a positive pregnancy test or otherwise verified 
3. 
Hypoglycaemia episodes as defined in Section 3.9.3 


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4. 
Use of (need for) any anti-hyperglycaemic medication other than IP or background 
metformin or rescue therapy allowed by protocol.  Insulin use is permitted in the 
following situations: 
 
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) 
 
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 
 
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 
 
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. 
5. 
eGFR <60mL/min/1.73m2 (by MDRD) confirmed by a repeated central lab 
measurement within 1 week. 
Note: Withhold the study medication until results for the retest of eGFR are 
available ONLY for randomisation visit (For all other visits, there is no need to 
interrupt the study medication) 
3.9.3 
Discontinuation guidelines for protocol-defined severe hypoglycaemia episodes 
or recurrent non-severe hypoglycaemia episodes 
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: 
(a) 
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 (e.g., sweating, shakiness, increased 
heart rate, confusion, dizziness, light-headedness, or hunger) in the absence of 
environmental factors known to contribute to hypoglycaemia (i.e., excess 
physical activity, concurrent illness, or missed or delayed meal) 


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and/or 
 
Documented finger stick glucose values <54mg/dL (<3.0mmol/L) 
(b) 
A patient may also be discontinued from the study because of severe 
hypoglycaemia, as determined by the Investigator. 
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. 
3.9.4 
Procedures for discontinuation of a patient from investigational product  
At any time, patients are free to discontinue IP or withdraw from the study (i.e., IP and 
assessments – see Section 3.10), without prejudice to further treatment.  A 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 5 (Week 24/End of Treatment) assessments immediately following 
discontinuation of study medication (see Section 4.5). 
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. 
All patients who discontinue study drug should remain in the study and follow the 
original visit schedule. Patients unable or unwilling to return for scheduled visits will have 
the opportunity to receive follow-up via telephone calls placed by the site mainly to review 
safety and concomitant medications. The only exception to this procedure is when a patient 
withdraws consent for all study procedures or loses the ability to consent freely (i.e., is 
imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical 
illness). 
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. 
Lost to Follow-Up: Patient fails to return for study visits and cannot be reached with 
reasonable, repeated attempts. 


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To prevent patients being lost to follow-up, their contact details, including next of kin contacts 
should be collected initially and updated regularly by the site staff or representative.  The 
Investigator should educate the patient on the importance of contact with the Investigator 
throughout the study.  Every effort will be made to ensure that the patient continues to return 
to the clinic for study visits and to avoid “lost to follow-up” during the conduct of the study.   
The study staff should make diligent attempts to contact patients who fail to return for study 
visits by using institutional databases, patient’s health professionals, and any other means that 
comply with country and local laws and regulations.  After the first missed visit, patients who 
are considered temporarily lost to follow-up will have 2 documented telephone contact 
attempts and 1 certified letter in an effort to contact patients.  
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. 
3.10.1 
Screen failures  
Screening failures are patients who do not fulfil 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’ (i.e., 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.  
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 (e.g., 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 patients 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: 
1. 
Meet individual stopping criteria or are otherwise considered significant. 


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2. 
Are assessed as causally related to IP. 
3. 
Are not considered to be consistent with continuation of the study. 
In addition to above, study may be stopped if: 
1. 
Study terminated by Sponsor: The Sponsor discontinues the study   protocol. 
2. 
Administrative reasons: The EU or other regulatory authority discontinues the study 
protocol or the clinical study site discontinues participation. 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation must be recorded in the eCRF. All reasons for discontinuation of study 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  


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Table 1 
Study Plan 
 
Evaluation 
 
Screeni
nga 
Non-
fasting 
Enrolm
ent 
Fasting 
Treatment 
Period 
Fasting 
End of 
Treatment / 
Early 
Termination/
Rescue 
Fasting 
Notes 
Visit 
0 
1c 
2d 
3 
4 
5 
Week 
-3 
-2 
0 
6 
12 
24 
Relative to Randomisation 
(days) e 
-21 
-14 
R 
42 
84 
168 
Visit window (days) 
 
+3 
±3 
±7 
±7 
±7 
Informed consent  
Xb 
X 
 
 
 
 
Section 10.4 
Assign E-code 
 
X 
 
 
 
 
Section 3.3 
Demography and medical 
history 
 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
X 
 
 
 
Section 3.1 
Section 3.2 
Randomisation  
 
 
X 
 
 
 
Section 3.5 
Section 4.3.1 
Complete physical 
examination 
 
X 
 
 
 
X 
Section 5.2.2 
Brief Physical examination f 
 
 
X 
X 
X 
 
Section 5.2.2 
Vital signs (Blood Pressure, 
Heart Rate) 
 
X 
X 
X 
X 
X 
Section 5.2.3 
Height 
 
X 
 
 
 
 
Section 5.1.4 
Weight 
 
X 
X 
X 
X 
X 
Section 5.1.3 
BMI 
 
X 
 
 
 
X 
 
Review Concomitant 
medicationsg 
X 
X 
X 
X 
X 
X 
 
Diet and Exercise 
Counseling 
 
X 
X 
X 
X 
X 
Section 5.3.2 
Safety Assessment 
 
 
Assess Adverse 
Events/Serious Adverse 
Events 
 
X 
X 
X 
X 
X 
Section 6 
Patient diary review for 
glucometer values and/or 
 
 
X 
X 
X 
X 
Section 5.3.1 


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Table 1 
Study Plan 
 
Evaluation 
 
Screeni
nga 
Non-
fasting 
Enrolm
ent 
Fasting 
Treatment 
Period 
Fasting 
End of 
Treatment / 
Early 
Termination/
Rescue 
Fasting 
Notes 
Visit 
0 
1c 
2d 
3 
4 
5 
Week 
-3 
-2 
0 
6 
12 
24 
Relative to Randomisation 
(days) e 
-21 
-14 
R 
42 
84 
168 
Visit window (days) 
 
+3 
±3 
±7 
±7 
±7 
hypoglycaemic events 
Central Laboratory 
 
 
eGFR (MDRD) 
 
X 
X 
X 
X 
X 
Section 5.2.1. 
eGFR will be 
calculated by 
central 
laboratory 
HbA1cj 
X 
 
X 
X 
X 
X 
Section 5.2.1 
FPG  
 
X 
X 
X 
X 
X 
Section 5.2.1 
Urinalysis 
 
X 
X 
X 
X 
X 
Section 5.2.1 
Pregnancy test (urine, 
WOCBP only)h 
 
X 
X 
 
 
 
Section 5.2.1 
Clinical Chemistry 
 
X 
X 
X 
X 
X 
Section 5.2.1 
Hematology 
 
X 
X 
 
X 
X 
Section 5.2.1 
Hematuria Dipstick 
Urinalysis  
 
X 
 
 
 
 
Positive dipstick 
result requires 
repeat test 
with 
microscopy 
(Refer to 
Appendix E)  
Hematuria Microscopic 
Urinalysis* 
 
X 
 
 
 
 
* Urinalysis 
with 
microscopy will 
be repeated 
until its 
negative (Refer 
CCI


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Table 1 
Study Plan 
 
Evaluation 
 
Screeni
nga 
Non-
fasting 
Enrolm
ent 
Fasting 
Treatment 
Period 
Fasting 
End of 
Treatment / 
Early 
Termination/
Rescue 
Fasting 
Notes 
Visit 
0 
1c 
2d 
3 
4 
5 
Week 
-3 
-2 
0 
6 
12 
24 
Relative to Randomisation 
(days) e 
-21 
-14 
R 
42 
84 
168 
Visit window (days) 
 
+3 
±3 
±7 
±7 
±7 
to Appendix E) 
Hepatitis Screening Panel, 
TSH 
 
X 
 
 
 
 
Section 5.2.1 
Other 
 
 
 
 
 
 
 
Dispense patient diary 
 
X 
X 
X 
X 
 
Section 5.3.1 
Dispense glucometer and/or 
supplies/instructions 
 
X 
X 
X 
X 
 
Section 5.3.1 
Dispense study medication 
 
 
X 
 
X 
 
Section 7 
Return study medicationk 
 
 
 
 
X 
X 
Section 4.5 
Study Medication 
Compliance Review 
 
 
 
X 
X 
X 
Section 7.6 
Dispense open label rescue 
medication (if necessary) 
 
 
 
X 
X 
 
Section 4.4 
Abbreviations: AE adverse event, BP blood pressure, BMI body mass index, E-code enrolment code, eGFR estimated 
glomerular filtration rate, FPG fasting plasma glucose, HbA1c haemoglobin A1c, R randomisation, SAE serious adverse 
event, WOCBP women of child-bearing potential, EOT end of treatment. 
a Screening visit (Visit 0) will occur 1 week prior to Enrolment (Visit 1) to screen for eligibility based on a non-fasting 
sample of HbA1c (assessed at central lab). See Section 4.1 for details. 
b An abbreviated informed consent form will be signed at Screening visit. 
c Enrolment visit will occur 7 days (+3 days) after patient provides signed abbreviated screening Informed Consent form. 
However patient can be enrolled as soon as laboratory screening results for HbA1c are available and it is determined that 
the value meets the inclusion/exclusion criteria.  
d Visit 2 (Randomisation/Baseline) should be performed 14 days (±3 days) after Enrolment visit, when laboratory results 
from Visit 1 are available. 
e Once a patient is randomised at Visit 2, all subsequent visits should be scheduled relative to Visit 2. 
f Brief physical examination could be performed at visit 2,3 and 4 at Investigators discretion  
g Review of concomitant medications includes over the counter drugs and herbal/nutritional therapies. 
h Urine HCG pregnancy test for WOCBP (performed at site by dipsticks provided by central laboratory) at Visit 1 and 2. In 
case of suspected pregnancy, home pregnancy testing should be performed after randomization 
. 
i 
 
j Re-testing of HbA1c at central laboratory is permitted once within one month of the initial screening visit if central 
laboratory result of HbA1c is >7.0% and <7.5% or >10% and <10.5%. 
k For rescued patients, rescue medication should also be returned at Visit 4 and 5. 
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4.1 
Screening Visit 
Procedures will be performed according to the Study Plan Table 1. 
Failure to meet the HbA1c inclusion criterion is the main reason for screening failure in 
diabetes treatment studies.  Therefore, in this study, sites need to mandatorily 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). 
In order to be considered for screening, patients must: 
1. 
Be 18 years old at time of informed consent. 
2. 
Have a documented diagnosis of T2DM. 
3. 
Currently treated with a stable MTD (1500mg/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: 
1. 
Abbreviated informed consent to the pre- study screening procedures will be 
obtained (see Section 10.4.1). 
2. 
A blood sample will be collected for measurement of HbA1c by a central 
laboratory.  Fasting is not required. 
3. 
Verification of current metformin therapy 
Patients with HbA1c result of 7.5% to 10.0% assessed based on central laboratory results 
from screening visit will be scheduled for an enrolment visit in approximately 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. 
Note: Re-testing of HbA1c is permitted once within one month of the initial screening 
visit if central laboratory result of HbA1c is >7.0% and <7.5% or >10% and <10.5%.  
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 site personnel. Patients with re-tested HbA1c at 
screening will have the same screening code. This code will identify screening laboratory 
results including retest results together with date of birth and gender. 


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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 this visit, patients are to 
have fasted overnight for 8 to 12 hours (no food, no beverage, except water).  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). 
4.2.1 
Enrolment visit (Visit 1, Week -2) 
Patients on a stable, MTD of metformin monotherapy 1500mg/day for the last 8 weeks prior 
to enrolment with an HbA1c 7.5% to 10.0% 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.  At Visit 1, 
informed consent for Protocol D1683C00005 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: 
1. 
Informed consent will be obtained. 
2. 
E-code will be assigned from IVRS/IWRS. 
3. 
The patient’s demography and complete medical history will be recorded. 
4. 
Inclusion and exclusion criteria will be verified. 
5. 
A complete physical examination will be conducted (see Section 5.2.2). 
6. 
Vital signs (sitting systolic and diastolic BP and Heart Rate) will be measured (see 
Section 5.2.3). 
7. 
Body weight and height will be measured (see Section 5.1.3 and 5.1.4). 
8. 
BMI will be calculated. 
9. 
All prior medications (prescription medications within 3 months) and concomitant 
medications (including over the counter and herbal/nutritional supplements) will be 
reviewed. 


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10. 
Blood samples will be collected for the following laboratory assessments: 
 
Clinical chemistry and Hematology (see Section 5.2.1) 
 
eGFR (MDRD) (see Section 5.2.1) 
 
FPG (samples for central laboratory testing, see Section 5.2.1) 
 
Hepatitis screening (hepatitis B surface antigen, antibody to hepatitis B core 
antigen IgM, and hepatitis C virus antibody) 
 
Thyroid Function (TSH) 
11. 
Urine will be collected for following (see Section 5.2.1) 
 
Urinalysis  
 
Urinary pregnancy test for beta human chorionic gonadotropin (ȕhCG) for 
female patients (WOCBP only) 
 
Hematuria Dipstick and/or Microscopic Urinalysis 
12. 
AEs/SAEs will be reviewed. 
13. 
Diet and Exercise counseling will be provided. 
14. 
Glucose meter and supplies and instructions will be provided. 
15. 
Patient diary and instructions will be provided. 
Individuals will be screen failed if results of any laboratory tests are abnormal and clinically 
significant as judged by the Investigator or medical monitor. 
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: 
1. 
Inclusion/exclusion and randomisation criteria will be verified. 


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2. 
Patients will be randomly assigned to 1 of 3 treatment groups (while continuing on 
metformin therapy) by IVRS/IWRS: 
 
Dapagliflozin 5mg + saxagliptin 5mg 
 
Dapagliflozin 5mg + placebo for saxagliptin  
 
Saxagliptin 5mg + placebo for dapagliflozin 
3. 
A brief physical examination may be conducted at Investigators discretion (see 
Section 5.2.2). 
4. 
Vital signs (sitting systolic and diastolic BP and Heart Rate) will be measured (see 
Section 5.2.3). 
5. 
Body weight will be measured Section 5.1.3. 
6. 
Concomitant medications (including over the counter and herbal/nutritional 
supplements) will be reviewed. 
7. 
Blood samples will be collected prior to administration of study medication for the 
following assessments: 
 
Clinical chemistry and Hematology (see Section 5.2.1) 
 
HbA1c 
 
eGFR (MDRD) 
 
FPG (samples for central laboratory testing, see Section 5.2.1) 
8. 
Urine will be collected for following (see Section 5.2.1) 
 
Urinalysis  
 
Urinary pregnancy test for beta human chorionic gonadotropin (ȕhCG) for 
female patients (WOCBP only) 
9. 
AEs and SAEs will be reviewed. 
10. 
Diet and Exercise counseling will be provided. 
11. 
Glucose meter and/or supplies and instructions will be provided. 
12. 
Patient diary and instructions will be provided. 
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Clinical Study Protocol 
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13. 
Patient diary will be reviewed for glucometer values and/or hypoglycaemic events 
history. 
14. 
Study medication will be dispensed.  Study site personnel will monitor 
administration of study medication and morning dose of metformin with food. 
4.3.2 
Treatment period visits (Visits 3 and 4; Weeks 6 and 12) 
Prior to these visits, patients are required to have fasted overnight (8 to12 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: 
1. 
A brief physical examination may be conducted at Investigators discretion (see 
Section 5.2.2). 
2. 
Vital signs (sitting systolic and diastolic BP and Heart Rate) will be measured (see 
Section 5.2.3). 
3. 
Body weight will be measured Section 5.1.3. 
4. 
Concomitant medications (including over the counter and herbal/nutritional 
supplements) will be reviewed. 
5. 
Blood samples will be collected prior to administration of study medication for the 
following assessments: 
 
Clinical chemistry (see Section 5.2.1) 
 
Hematology except Visit 3 (see Section 5.2.1) 
 
HbA1c 
 
eGFR (MDRD) 
 
FPG (samples for central laboratory testing, see Section 5.2.1 
6. 
Urine will be collected for urinalysis. 
7. 
AEs and SAEs will be reviewed. 
8. 
Patient diary will be reviewed for glucometer values and/or hypoglycaemic events 
history  


Clinical Study Protocol 
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9. 
Diet and Exercise counseling will be provided. 
10. 
Glucose meter and/or supplies and instructions will be provided. 
11. 
Patient diary and instructions will be provided. 
12. 
Study medication will be dispensed and returned (except Visit 3). Study site 
personnel will monitor administration of study medication and morning dose of 
metformin with food. 
13. 
Study medication compliance will be reviewed  
14. 
Rescue medication will be dispensed (as necessary, see Table 1) 
4.4 
Rescue therapy 
During the double-blind treatment period of the trial, patients may be eligible for treatment 
with open-label rescue medication (see Table 6) to replace their blinded treatment regimen in 
order to treat ongoing hyperglycaemia.  The sub-sections and table listed below define the 
lack of glycaemic control criteria for initiation of rescue medication. 
Pre-specified glycaemic criteria (see Table 2), based upon repeat confirmatory central 
laboratory FPG have been established during the double-blind treatment period, starting at 
Week 6, to determine eligibility for open-label rescue medication. 
Abbreviations: FPG Fasting plasma glucose 
Patients with a central laboratory FPG value meeting the lack of glycaemic control criterion at 
a pre-specified visit will be scheduled for a follow-up visit (within 3 to 5 days) to obtain a 
second central laboratory FPG value and review the patients glucose meter readings.  If the 
repeat central laboratory FPG value still meets the criterion, the patient must be rescued. 
Patients who meet rescue criteria in the double-blind treatment period must first 
complete the Rescue Visit procedures before receiving open-label rescue medication to 
ensure that important trial endpoint measurements are collected. 
Table 2 
Criteria for Initiation of Rescue Therapy During the Randomised 
Treatment Period 
Visit Period 
Central Laboratory glycaemic parameters 
At Week 6 
FPG >270mg/dL (15.0mmol/L) 
From Week 6 to Week 12 (Excluding Week 12) 
FPG > 240mg/dL (13.3mmol/L) 
Week 12 to Week 24 
FPG > 200mg/dL (11.1mmol/L) 


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Following completion of the Rescue Visit, rescued patients will be given open-label anti-
diabetic rescue medication (Saxagliptin 5mg and Dapagliflozin 10 mg as a first line or Insulin 
as a second line at Investigators discretion) and will discontinue study medication.  Rescued 
patients will then continue in the double-blind treatment period according to their original visit 
schedule. 
Note: Rescue medication (Saxagliptin 5mg and Dapagliflozin 10mg) will be provided by 
Sponsor in this study. Insulin will not be provided by Sponsor since it is part of patients 
standard of care. 
4.5 
End of treatment period visit/ Early Termination or Rescue (Visit 5, 
Week 24) 
Visit 5 (End of Treatment Visit) should occur 12 weeks after Visit 4 or if the patient 
discontinued early from IP or is rescued.  Prior to this visit, patients are required to have fasted 
overnight (8 to12 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. 
All patients who are rescued or who discontinue study drug should remain in the study 
and follow the visit schedule. 
The following procedures will be conducted:  
1. 
A complete physical examination may be conducted at Investigators discretion (see 
Section 5.2.2). 
2. 
Vital signs (sitting systolic and diastolic BP and Heart Rate) will be measured (see 
Section 5.2.3). 
3. 
Body weight will be measured Section 5.1.3. 
4. 
BMI will be calculated. 
5. 
Concomitant medications (including over the counter and herbal/nutritional 
supplements) will be reviewed. 
6. 
Blood samples will be collected prior to administration of study medication for the 
following assessments: 
 
Clinical chemistry (see Section 5.2.1) 
 
Hematology (see Section 5.2.1) 
 
HbA1c 


Clinical Study Protocol 
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Version 4.0 
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 
eGFR (MDRD) 
 
FPG (samples for central laboratory testing, see Section 5.2.1) 
7. 
Urine will be collected for urinalysis. 
8. 
AEs and SAEs will be reviewed. 
9. 
Patient diary will be reviewed for glucometer values and/or hypoglycaemic events 
history. 
10. 
Diet and Exercise counseling will be provided. 
11. 
Study medication compliance will be reviewed. 
12. 
Patient diary will be collected (not applicable for rescue visit, for end of treatment 
only). 
13. 
Study medication will be returned (not applicable for rescue visit). 
14. 
Glucose meter and/or supplies and instructions will be collected. 
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 
Efficacy 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. 
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Clinical Study Protocol 
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Study Code D1683C00005 
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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. 
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 (e.g., 95.3kg).  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. 
5.2 
Safety assessments 
The Investigator will evaluate all Screening, 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. 
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 
instructions for collection, processing, packaging, and shipping of the samples will be detailed 
in the laboratory manual. 


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Version 4.0 
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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 
center 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 
Volume of blood 
The total blood drawn from each patient over the course of the study will be approximately 
100ml. 
Table 3 
Volume of blood to be withdrawn from each patient 
 
Sample Volume (ml) 
Total 
Volume 
(ml) 
VISIT 
S 
V1 
V2 
V3 
V4 
V5 
Label 
Screen 
Enro
l 
Randomi
sation 
  
  
  
Week 
-3 
-2 
0 
6 
12 
24 
Haematology 
  
2 
2 
  
2 
2 
8 
(approx.) 
Chemistrya 
  
5 
2.5 
2.5 
2.5 
2.5 
15 
(approx.) 
FPG 
  
2 
2 
2 
2 
2 
10 
(approx.) 
HbA1c 
2 
  
 2 
2 
 2 
 2 
10 
(approx.) 
Hepatitis Panel 
 
3.5 
 
 
 
 
3.5 
(approx.) 
Total 
2 
22.5 
8.5 
6.5 
8.5 
18.5 67 to 100b 
a. 
Includes TSH and Free T4 
b. Includes a margin for additional visits such as rescue or unscheduled visits. 
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Protocol-Specific central laboratory assessments 
x HbA1c 
x FPG 
Chemistry and haematology assessments (see Table 4) will include the following 
 
 
Table 4 
Laboratory Safety Variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Red blood cell count 
Red Blood Count indices: 
BMean Cell Haemoglobin (MCH) 
_Mean Cell Volume (MCV) 
BMean Cell Haemoglobin Concentration (MCHC) 
BWhite blood cell Count and Differential 
BPlatelet count 
S/P-Creatinine.  Glomerular Filtration Rate will 
be calculated by the Central Laboratory using 
the re-expressed abbreviated (four-variable) 
Modification in Diet and Renal Disease 
(MDRD) formula and results will be reported to 
the sites and the Sponsor. 
 (Levey AS, Coresh J,Greene T, et al. Expressing the 
Modification of Diet in Renal Disease Study 
Equation for Estimating Glomerular Filtration Rate 
with Standardized Serum Creatinine Values. 
Clinical Chemistry 2007; 53:766-72). 
 
S/P-Bilirubin, total (TB) 
B-Haemoglobin (Hb) 
S/P-Alkaline phosphatase (ALP) 
B-Haematocrit 
S/P-Aspartate transaminase (AST) 
 
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 
S/P- Total Protein 
S/P Creatine Kinase (CK).  Reflex Testing: 
Troponin I will be ordered if CK >400IU/L). 
Abbreviations:  AST aspartate transaminase, ALP alkaline phosphatase, ALT alanine transaminase, B blood, Hb 
haemoglobin, P plasma, S serum, TB total bilirubin. 


Clinical Study Protocol 
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NB. In case a patient shows an AST or ALT >3xULN or total Bilirubin > 2xULN please refer 
to Appendix D ‘Algorithm on Management of Sustained Elevated Liver Safety 
Abnormalities’, for further instructions. 
Urinalysis 
Urinalysis assessments will be performed according to Study Plan (Table 1) and will include 
the following: blood, protein, albumin, glucose, urine ketones, creatinine and calculated 
urinary albumin:creatine ratio. 
In addition to the above assessments, if dipstick urinalysis at Visit 1 is positive, urinalysis with 
microscopy will be repeated until its negative. 
1. 
Hematuria 
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 (dipsticks provide by central laboratory and analysed at 
local lab) 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. 
Enrolment specific safety panel 
1. 
Thyroid Stimulating Hormone (TSH) 
 
Reflex Testing: Abnormal TSH value at enrolment will be further evaluated by 
free T4. 
2. 
Hepatitis Panel: 
 
Hepatitis C virus antibody 
 Reflex Testing: HCV Ab Low Positive results require confirmation. 
 
Hepatitis B surface antigen 
 
Antibody to Hepatitis B core antigen IgM 
5.2.2 
Physical examination 
A complete physical examination will be performed according to the schedule presented in the 
Study Plan (Table 1).  A complete physical examination includes an assessment of the 
following: general appearance including skin inspection (including injection site), head, eyes, 
ears, nose, throat, neck,cardiovascular, lymph nodes, thyroid, musculoskeletal/extremities, 
lungs, abdomen, neurological and reflexes.  Baseline physical examination data are collected 


Clinical Study Protocol 
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Study Code D1683C00005 
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at Visit 1 and new findings at the following physical examinations are recorded as change 
from baseline. 
A brief physical examination should include cardiovascular, lungs, abdomen and extremities; 
and any organ systems pertinent to the patient's signs, symptoms or adverse events.  
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 6.4 for reporting AEs. 
5.2.3 
Vital signs 
Vital sign measurements in this study will include sitting systolic and diastolic BP and heart 
rate (HR).  Vital signs should be measured from Visit 1 after the patient rests for 
approximately 5 minutes and with the patient in a sitting position. 
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. 
5.2.4 
Other safety assessments 
5.2.4.1 
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. 
Adjudication for heart failure will be performed according to the respective charter. 
5.2.4.2 
Liver function test abnormalities 
Please see Appendix D, ‘Algorithm on Management of Sustained Elevated Liver Safety 
Abnormalities’’, for further guidance. 


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5.3 
Other assessments 
5.3.1 
Self-monitored blood glucose and hypoglycaemic events 
Patients will receive a hypoglycaemia/blood glucose diary.  Glucose meter will be supplied to 
each study site.  Patients will receive a glucose meter, supplies and instructions on their use. 
The Sponsor recommends instructing the patients to self-monitor their blood glucose at least 
one time per day and document results in their patient diary.  Patients should bring their 
glucose meter with them to each study visit to ensure that it is functioning properly.  Patients 
will be asked to also check their blood glucose when: 
1. 
The patient experiences signs or symptoms of hypoglycaemia. 
2. 
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. 
3. 
Patients will be instructed to contact the Investigator any time they experience a 
frequent or severe 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 patient experiences 
either of the following: 
4. 
Signs and symptoms of hypoglycaemia (regardless of blood glucose value by finger 
stick). 
5. 
Blood glucose value by finger stick 70mg/dL (3.9mmol/L) (regardless of 
symptoms). 
For these hypoglycaemic events, patients must record the following information in the diary: 
1. 
Date and time of hypoglycaemic event. 
2. 
Whether symptoms, were present and list of symptoms. 
3. 
Blood glucose value by finger stick and time of finger stick. 
4. 
Whether the patient experienced incoherence, unconsciousness, or required 
assistance of another person to recover. 
5. 
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 patient and reviewed by site personnel 
at every subsequent visit.  Completed diary pages will be added to the patient’s source record, 
and data from the diary will be entered in the appropriate eCRF page for hypoglycaemic 
episodes. 


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Hypoglycaemia eCRF pages will be used to document all reported episodes of 
hypoglycaemia. The Investigator or designee is responsible for questioning the patient 
about all symptoms reported on the hypoglycaemia log and for determining if they meet 
the clinical definition of hypoglycaemia.  Signs and symptoms of hypoglycaemia, 
hypoglycaemia episode or discontinuation due to hypoglycaemia should not be reported on 
AE eCRF page, unless the event fulfills protocol criteria for a Serious Adverse Event (see 
section 6.2), in which case an SAE form must be completed in addition to hypoglycaemia 
eCRF page for hypoglycaemia.  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 6.3.7. 
5.3.2 
Diet and exercise counseling 
Starting at the Enrolment Visit (Visit 1), patients will be instructed on a diet and exercise 
program in accordance with the ADA or similar local guidelines to be followed for the study 
duration. 
A Registered Dietitian, Registered Nurse, Physician, Certified Diabetes Educator, Nutritionist, 
or other qualified member of the study team who has appropriate documented training will 
provide this counseling. 
In addition, as part of the diet and exercise program, the Investigator or designee should 
ensure that each patient receives an adequate daily intake of minerals and vitamins, in 
accordance with the National Academy of Sciences or similar local guidelines. 
5.4 
Pharmacokinetics (Not Applicable) 
5.5 
Pharmacodynamics (Not Applicable) 
5.6 
Pharmacogenetics (Not Applicable) 
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6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
6.1 
Definition of adverse events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
6.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., enrolment and), that 
fulfils one or more of the following criteria: 
1. 
Results in death 
2. 
Is immediately life-threatening 
3. 
Requires in-patient hospitalisation or prolongation of existing hospitalisation  
4. 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
5. 
Is a congenital abnormality or birth defect 
6. 
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix A, ‘Additional Safety 
Information’ to the Clinical Study Protocol. 
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6.3 
Recording of adverse events 
6.3.1 
Time period for collection of adverse events 
AEs will be collected from time of signature of informed consent, during the Enrolment, 
Randomisation, and throughout the treatment period and until End of treatment (Visit 5)/early 
termination.  
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; 
1. 
AE (verbatim) 
2. 
The date when the AE started and stopped 
3. 
Maximum intensity  
4. 
Whether the AE is serious or not 
5. 
Investigator causality rating against the IP (yes or no) 
6. 
Action taken with regard to IP 
7. 
AE caused patient's withdrawal from study (yes or no) 
8. 
Outcome 
In addition, the following variables will be collected for SAEs: 
1. 
Date AE met criteria for SAE 
2. 
Date Investigator became aware of SAE 
3. 
AE is serious due to 
4. 
Date of hospitalisation 


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5. 
Date of discharge 
6. 
Probable cause of death 
7. 
Date of death 
8. 
Autopsy performed 
9. 
Causality assessment in relation to Study procedure(s) 
10. 
Description of AE 
11. 
Whether treatment of AE was required 
6.3.3.1 
Intensity rating scale 
The maximum intensity of an AE will be rated according to the following definition: 
1. 
Mild (awareness of sign or symptom, but easily tolerated) 
2. 
Moderate (discomfort sufficient to cause interference with normal activities) 
3. 
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?’ 
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure, the causal relationship 
is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A to the 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 


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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 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 (e.g., anaemia versus low 
haemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as 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. 
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. 
6.3.7 
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. 
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. 
Hypoglycemia episodes will be classified in the Clinical Study Report according to the ADA 
Criteria. The ADA Workgroup on Hypoglycemia classifies hypoglycemia as follows 
(Elizabeth R. Seaquist et al 2013) 
Severe hypoglycaemia: An event requiring assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions.  These episodes may be 
associated with sufficient neuroglycopenia to induce seizure or coma.  Plasma glucose 
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence 
that the event was induced by a low plasma glucose concentration. 


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Documented symptomatic hypoglycaemia: An event during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration less than or 
equal to 70mg/dL (3.9mmol/L). 
Asymptomatic hypoglycaemia: An event not accompanied by typical symptoms of 
hypoglycaemia but with a measured plasma glucose concentration less than or equal to 
70mg/dL (3.9mmol/L).  Since the glycaemic threshold for activation of glucagon and 
epinephrine secretion as glucose levels decline is normally 65 to 70mg/dL (3.6 to 3.9mmol/L) 
and since antecedent plasma glucose concentrations of less than or equal to 70mg/dL 
(3.9mmol/L) reduce sympathoadrenal responses to subsequent hypoglycaemia, this criterion 
sets the lower limit for the variation in plasma glucose in nondiabetic, nonpregnant individuals 
as the conservative lower limit for individuals with diabetes. 
Probable symptomatic hypoglycaemia: An event during which symptoms of hypoglycaemia 
are not accompanied by a plasma glucose determination, but was presumably caused by a 
plasma glucose concentration less than or equal to 70 mg/dL (3.9 mmol/L). Since many 
people with diabetes choose to treat symptoms with oral carbohydrate without a test of plasma 
glucose, it is important to recognize these events as probable hypoglycaemia. Such self-
reported episodes that are not confirmed by a contemporaneous low plasma glucose 
determination may not be suitable outcome measures for clinical studies that are aimed at 
evaluating therapy, but they may be reported. 
Relative hypoglycaemia: An event during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia, and interprets the symptoms as indicative of 
hypoglycaemia, but with a measured plasma glucose concentration greater than 70mg/dL 
(3.9mmol/L).  This classification reflects the fact that patients with chronically poor 
glycaemic control can experience symptoms of hypoglycaemia at plasma glucose levels 
greater than 70mg/dL (3.9mmol/L) as plasma glucose concentrations decline toward that 
level.  Though causing distress and interfering with the patient’s sense of well-being, and 
potentially limiting the achievement of optimal glycaemic control, such episodes probably 
pose no direct harm and, therefore, may not be a suitable outcome measure for clinical studies 
that are aimed at evaluating therapy, but they may be reported. 
At a minimum, hypoglycaemic events should be reported in each of the first three 
classifications: severe hypoglycaemia, documented symptomatic hypoglycaemia, and 
asymptomatic hypoglycaemia  
6.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the CRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours  of when he or she becomes aware of it. 


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The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the Investigator or other study site personnel 
reports 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, cardiac failure (including 
confirmed adjudicated cardiac failure events), renal impairment/renal failure, volume 
depletion (hypotension, dehydration, and hypovolemia), and liver injury(including confirmed 
adjudicated hepatic events). 
6.5 
Overdose 
For the purpose of this study, an overdose is defined as a dose of study medication in excess 
of that specified in the CSP (i.e., more than 1 tablet per day of either study drug) as reported 
by patient. 
If an overdose is suspected, monitoring of vital functions as well as treatment as appropriate 
should be performed: 
1. 
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.   
2. 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 


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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.  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 i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the 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. 
6.7 
Management of IP related toxicities 
Dose reductions are not permitted in this study. 


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6.8 
Study governance and oversight 
6.8.1 
Hepatic Adjudication Committee 
An independent 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. 
Criteria for adjudication of hepatic events are defined as follows: 
1. 
AST and/or ALT >3x ULN and TB >2x ULN  (within 14 days of the AST and/or 
ALT elevation); see Appendix D 
2. 
AST and/or ALT >10x ULN 
3. 
Hepatic events timely related to death (within 30 days before death) 
A separate HAC adjudication charter further defines and describes the procedure for the 
handling, reporting and classification of these events. 
6.8.2 
Cardiovascular Adjudication Committee 
Adjudication for heart failure will be performed 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. 


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7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
Table 5 
Investigational Products for Study D1683C00005 
Investigational product 
Dosage, route, form and 
strength 
Manufacturer 
Dapagliflozin 
5mg, orally, Green, plain, 
diamond-shaped, film-coated 
tablet 
Placebo for dapagliflozin 
Does not contain active 
ingredient, orally, Green, plain,
diamond-shaped, film-coated 
tablet 
Saxagliptin 
5mg, orally, plain, Yellow, 
biconvex, round, film-coated 
tablet 
Placebo for saxagliptin 
Does not contain active 
ingredient, orally, plain, 
Yellow, biconvex, round, film-
coated tablet 
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 is described in Table 5. 
The formulation number and batch number will be recorded in the electronic Trial Master File 
and identified in the CSR. 
Dapagliflozin, saxagliptin, 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 (Saxagliptin 5mg and dapagliflozin 10mg) will be 
provided by the sponsor.  However, insulin and metformin will not be provided by the 
Sponsor, since it is part of patient’s standard of care. 
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7.2 
Dose and treatment regimens 
The study consists of an Enrolment visit (Visit 1), a Randomisation visit (Visit 2), followed by 
a 24-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 center should notify the Investigator immediately in order 
to receive a replacement kit via the IVRS/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 5mg tablets, saxagliptin 5mg 
tablets, and matching placebo tablets.  Study medication will be dispensed according to the 
schedule presented in Table 1. 
During the treatment period, patients will take 2 tablets everyday: 1 from the 
dapagliflozin/placebo bottle, 1 from the saxagliptin/placebo bottle. 
The first doses of study medication will be taken at the study site.  Patients will subsequently 
self-administer saxagliptin, dapagliflozin, and matching placebos QD orally for the 24-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. 
7.3 
Identity of Open Label Rescue Medications 
 
Table 6 
Open label Rescue Medication for Study D1683C00005 
Rescue Medication 
Dosage, route, form and 
strength 
Manufacturer 
Dapagliflozin 
10mg, orally, Green, plain, 
diamond-shaped, film-coated 
tablet 
Saxagliptin 
5mg, orally, plain, Yellow, 
biconvex, round, film-coated 
tablet 
 
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7.4 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.  
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 and sight of children” 
11. 
The name of the Investigator, where applicable (to be added on the label when IP is 
dispensed) 
12. 
Visit number (to be added on the label when IP is dispensed) 
7.5 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the bottle specifies the appropriate storage. 
7.6 
Compliance 
The patient will be asked about compliance at each study visit starting from visit 2 onwards. 
When study medication is returned, compliance will be assessed based upon patients interview 
and a count of the tablets returned. Compliance should be between 80% and 120% of that 
prescribed. If the patient is not 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 
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medication dispensed and returned at each visit as described in Table 1, 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.  
The administration of all study medications (including IPs) should be recorded in the 
appropriate sections of the eCRF. 
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF. 
7.7 
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 
 
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: 
1. 
On-site disposal practices must not expose humans to risks from the drug. 
2. 
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous 
substances. 
3. 
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. 
4. 
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. 
5. 
Accountability and disposal records are complete, up-to-date, and available for the 
Study Monitor to review throughout the clinical trial period. 
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6. 
If conditions for destruction cannot be met, the responsible Study Monitor will 
make arrangements for return of study drug. 
7. 
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. 
7.8 
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. 
7.9 
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 then 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 4.4) 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. 


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-For up to 14 days in total and up to 7 consecutive 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 10mg 
(betamethasone 1.2mg, dexamethasone 
1.5mg, hydrocortisone 40mg) per day 
Treatment with any stable replacement corticosteroid 
therapy at the time of screening is permitted. Newly 
initiation of treatment with any systemic corticosteroid 
therapy that will involve 5 days of therapy (inhaled and 
topical are allowed). The Medical Monitor (AZ study 
physician) 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 
 
7.9.1 
Metformin 
Patients will remain on their pre-study stable, maximum tolerated metformin doses 
1500mg/day, during the 24-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 by the Sponsor as it is the usual care prior to study 
participation. 
7.9.2 
Open label Rescue Medications 
Patients may be eligible for rescue therapy (see Section 4.4) with open-label rescue 
medication (Saxagliptin 5mg and Dapagliflozin 10mg as a first line therapy) in order to treat 
ongoing hyperglycaemia.  Patients should stop receiving blinded study medication while 
receiving rescue therapy.  If rescue therapy fails, sufficient therapy will be given at the 
discretion of the Investigator. 
Rescue medication (Saxagliptin 5mg and dapagliflozin 10mg) will be provided by the 
sponsor.  However, insulin will not be provided by the Sponsor, since it is part of patient’s 
standard of care. 


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7.9.3 
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. 
7.10 
Post Study Access to Study Treatment (Not Applicable) 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1 
Statistical considerations 
1. 
All personnel involved with the analysis of the study will remain blinded until 
database lock and protocol violators identified. 
2. 
Analyses will be performed by AstraZeneca or its representatives.     
3. 
Refer to Statistical Analysis Plan (SAP) for details. 
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violators identified. 
Analyses will be performed by AstraZeneca or its representatives.  
A comprehensive SAP will be initiated prior to first patient randomised and any subsequent 
amendments will be documented, with final amendments completed prior to unblinding of the 
data. 
8.2 
Sample size estimate 
The mean change from baseline in HbA1c at Week 24 will be assessed comparing the 
saxagliptin plus dapagliflozin treatment group versus the saxagliptin treatment group and 
versus the dapagliflozin treatment group. 
Power calculations for longitudinal repeated measures analyses depend on many factors, 
including the pattern of drop out over time and correlations among the various time points 
included in the model.  The choice of these parameters will affect any estimates of power and 
their true values may not be known.  Based on comparisons of results of longitudinal repeated 
measures analyses and analysis of covariance using last observation carried forward 
(ANCOVA with LOCF) from previous diabetes trials, the estimated standard errors of the 
treatment differences were similar between analyses.  Therefore, power calculations are based 
on ANCOVA with LOCF, with the expectation that this will provide a good estimate of the 
power for the primary analysis using a longitudinal repeated measures model. 
A sample size of 300 patients per group will provide at least 90% power to simultaneously 
detect a difference in mean change from baseline to week 24 in HbA1c of -0.30 (%) for both 
primary endpoint comparisons of saxagliptin / dapagliflozin vs its components at the 2-sided 


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alpha = 0.05 level.  This assumes a common standard deviation of 1.0% and a 3% non-
evaluability rate. 
8.3 
Definitions of analysis sets 
The Enrolled patients Data Set will consist of all patients who sign informed consent.  This 
data set will be used to summarize the patient disposition data. 
8.3.1 
Efficacy analysis set 
Full analysis set 
The full analysis (FA) set will be defined as all randomised patients who take at least one dose 
of the study medication and have a baseline value for HbA1c. 
Per protocol 
The per protocol (PP) population 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. 
8.3.2 
Safety analysis set 
The safety analysis set will be defined as all randomised patients who received at least one 
dose of study medication.  This data set will be used to summarize safety data (AE, Vital signs 
and Laboratory parameters), and patient demography and their baseline data as well. 
Data in this data set will be analysed based on randomised treatment, except in cases where a 
patient received a different treatment for the entire course of his/her participation in the 
double-blind treatment period.  In this case, safety data for such a patient will be analysed 
based on the first treatment the patient actually received. 
8.3.3 
PK analysis set (Not Applicable) 
8.3.4 
PRO analysis set (Not Applicable) 
8.4 
Outcome measures for analyses 
Primary endpoint 
1. 
Mean change from baseline in HbA1c at Week 24 
Secondary endpoints 
1. 
Percent of patients achieving a therapeutic glycaemic response, defined as a HbA1c 
<7.0% at Week 24 
2. 
Mean change in Fasting plasma glucose (FPG) at 24 weeks 
3. 
Mean change in total body weight at 24 weeks 


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Exploratory endpoint(s) 
1. 
Mean change from baseline in HbA1c at Week 12 
2. 
Proportion of patients achieving therapeutic glycaemic response, defined as HbA1c 
<7.0%, after 12 weeks 
3. 
Percent of patients who require glycaemic rescue or discontinue study treatment for 
lack of efficacy (12 and 24 weeks) 
4. 
Mean change in Fasting plasma glucose (FPG) at 12 weeks 
5. 
Mean change in total body weight at 12 weeks 
6. 
Mean change from baseline in systolic blood pressure (12 and 24 weeks) 
7. 
Mean change from baseline HbA1c after 12 weeks in patients whose baseline 
HbA1c was >8% 
8. 
Mean change from baseline HbA1c after 12 weeks in patients whose baseline 
HbA1c was 8% 
9. 
Mean change in HbA1c from baseline in patients with baseline >8% at 24 weeks 
10. 
Mean change in HbA1c from baseline in patients with baseline 8% at 24 weeks 
11. 
Proportion of patients achieving HbA1c <7.0% and a weight loss of 2 kg after 24 
weeks 
8.5 
Methods for statistical analyses 
Efficacy analyses will be run for the FA population and for the PP population if more than 
10% of patients from the FA population are excluded from the PP population for important 
protocol deviations. 
All analyses related glycaemic variables (for example, HbA1c) will be done using values 
regardless of rescue/intensification of treatment or discontinuation of the study treatment.  
Sensitivity analyses will be conducted for the primary endpoint excluding the data after rescue 
or more than 8 days after discontinuation of the study treatment. 
The primary endpoint will be tested for saxagliptin plus dapagliflozin versus saxagliptin and 
dapagliflozin arms simultaneously at the alpha = 0.05 level (two sided).  The secondary 
endpoints then will be tested sequentially as follows: 
1. 
saxagliptin plus dapagliflozin versus saxagliptin on percent of patients achieving a 
therapeutic glycaemic response, defined as a HbA1< 7.0% at Week 24 
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2. 
saxagliptin plus dapagliflozin versus dapagliflozin on percent of patients achieving 
a therapeutic glycaemic response, defined as a HbA1< 7.0% at Week 24 
3. 
saxagliptin plus dapagliflozin versus saxagliptin on mean change from baseline in 
fasting plasma glucose at Week 24 
4. 
saxagliptin plus dapagliflozin versus dapagliflozin on mean change from baseline in 
fasting plasma glucose at Week 24 
5. 
saxagliptin plus dapagliflozin versus saxagliptin on  mean change from baseline in 
total body weight at Week 24 
Each comparison will be tested at the alpha = 0.05 (two-sided) level.  
8.5.1 
Analysis of the primary variable (s) 
The primary efficacy analysis will be performed using a longitudinal repeated measures 
analysis (using a MIXED model) for the change from baseline at Week 24, with terms for 
treatment group, baseline value, time (each relevant visit), the interaction of treatment and 
time, and the interaction of baseline value and time in the model. This model assumes that 
data are missing at random (MAR). Point estimates and 95% confidence intervals will be 
calculated for the adjusted mean changes within each treatment group as well as for the 
differences in adjusted mean changes between treatment groups. 
8.5.2 
Analysis of the secondary variable(s) 
The analysis of the change from baseline for FPG and total body weight at week 24 will be 
performed using the same longitudinal repeated measures model as for the primary efficacy 
endpoint. 
The proportion of patients achieving a therapeutic glycaemic response (defined as HbA1c 
<7.0%) at Week 24 will be summarized by treatment group and compared between treatment 
groups.  A 95% confidence interval for the difference in response rate or odd ratio between 
treatment groups will be calculated with adjustment for baseline HbA1c by a logistic 
regression. 
8.5.3 
Subgroup analysis (if applicable) 
The subgroup analysis will be performed on the primary efficacy endpoint (mean change from 
baseline in HbA1C) in subgroups defined by the following variables: 
1. 
Baseline HbA1c 
2. 
Gender 
3. 
Age 
4. 
Region 


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Subgroup analyses will be analysed as was done for the primary analysis model with subgroup 
by treatment interaction term.  Within each subgroup, point estimates and 95% confidence 
intervals will be calculated for the adjusted mean changes within each treatment group as well 
as for the differences in adjusted mean changes between treatment groups.  A nominal 
interaction p-value will be provided for the purpose of the completeness of the data analysis. 
8.5.4 
Interim analysis (Not Applicable) 
8.5.5 
Sensitivity analysis (if applicable) 
Sensitivity analyses for HbA1c will be performed using analyses that do not assume the data 
are missing at random and incorporate patients randomised and treated but with only baseline 
data for HbA1c. Details will be stated in the SAP. In addition, the repeated measures analyses 
will be performed by excluding values after rescue, and more than 8 days after study treatment 
discontinuation and based upon all patients completing the double-blind treatment period.   
8.5.6 
Exploratory analysis (if applicable)  
Analyses for exploratory efficacy endpoints will use the same methodology for binary and 
continuous endpoints as described above. 
Safety analyses will be performed using the Safety analysis set, including data after rescue.  
The number and percent of patients with at least one adverse event will be summarized for 
each treatment group, including summaries of AEs, SAEs, AEs leading to discontinuation, 
and AEs of special interest.  Summaries will include the number of patients with events by 
specified system organ classes and preferred terms.  The summary of AEs will be performed 
both overall and by subgroup.  Additionally, the incidence of adverse events and frequency of 
recurring adverse events will be summarized for each treatment group for both frequent events 
(occurring in at least 5% of patients) and for selected adverse events of special interest. 
Values and changes from baseline at each scheduled time point for clinical laboratory 
parameters and vital signs, including blood pressure and heart rate, will be summarized by 
treatment group using descriptive statistics.  The number and percent of patients with 
laboratory values meeting marked abnormality criteria will be summarized for each treatment 
group and by shift tables.  Other safety assessments including serum creatinine, and eGFR by 
MDRD will be summarized by treatment group using descriptive statistics of values and 
changes from baseline at each scheduled time point. 
Additional analyses for adverse events and laboratory marked abnormalities will be performed 
excluding data after rescue in the double-blind treatment period. The primary analysis of 
events of hypoglycaemia will be performed excluding data after rescue, and more than 4 days 
after study treatment discontinuation. 


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9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1 
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the CSP and related documents with the investigational staff and 
also train them in any study specific procedures and the WBDC system utilised. 
The 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 study site, 
including visits to: 
1. 
Provide information and support to the Investigator(s) 
2. 
Confirm that facilities remain acceptable 
3. 
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 
4. 
Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. This 
will require direct access to all original records for each patient (e.g., clinic charts) 
5. 
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. 
6. 
Ensure site is compliant with study procedures to avoid “lost to follow-up” as listed 
in Section 3.10. 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the center needs information and advice about the study conduct. 
9.2.1 
Source data 
Refer to the Clinical Study Agreement (CSA) for location of source data. 


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9.2.2 
Patients study agreements 
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study. In the event of any inconsistency 
between this CSP and the CSA, the terms of CSP shall prevail with respect to the conduct of 
the study and the treatment of patients and in all other respects, not relating to study conduct 
or treatment of patients, the terms of the CSA shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are screened. 
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 1st Quarter of 2016.  The study is expected to 
complete 3rd Quarter 2017. 
The study may be terminated at individual centers 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 
Data Management Center staff, according 
to the Data Management Plan. 
Data entered in the WBDC system or data captured electronically will be immediately saved 
to the applicable database and changes tracked to provide an audit trail. 
The data collected through third party sources will be obtained and reconciled against study 
data. 
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process. 
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail. 
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Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the AstraZeneca Drug Dictionary.  All coding will be 
performed by the Medical Coding Team at 
 Data Management Center. 
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked. 
Serious Adverse Event (SAE) Reconciliation 
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data associated with human biological samples 
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples. 
10.2 
Subject data protection 
The Informed Consent Form 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 or Institutional Review Board (EC/IRB) should approve the final study 
protocol, including the final version of the ICF and any other written information and/or 
materials to be provided to the patients.  The Investigator will ensure the distribution of these 
documents to the applicable EC/IRB, and to the study site staff. 
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrolment of any patient into the study. 
The EC/IRB should approve all advertising used to recruit patients for the study. 
AstraZeneca or designee should approve any modifications to the ICF that are needed to meet 
local requirements. 
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If required by local regulations, the CSP should be re-approved by the EC/IRB 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/IRBs and Investigators 
with safety updates/reports according to local requirements. 
Each Principal Investigator is responsible for providing the EC/ 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 Principal Investigator(s) at each center will: 
1. 
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 
2. 
Ensure each patient is notified that they are free to discontinue from the study at any 
time 
3. 
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided 
4. 
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 
5. 
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
6. 
Ensure a copy of the signed Informed Consent Form is given to the patient. 
7. 
Ensure that any incentives for patient who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an EC/IRB. 
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. 


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Study Code D1683C00005 
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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/IRB and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the CSP to each 
Investigator(s).  For distribution to EC/IRB see Section 10.3. 
If a protocol amendment requires a change to a centers ICF, AstraZeneca and the centers 
EC/IRB are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each EC/IRB. 
10.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the center, 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, Good 
Clinical. 


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11. 
LIST OF REFERENCES 
A. R. Chacra et al 2009 
A. R. Chacra,1 G. H. Tan, A. Apanovitch, S. Ravichandran, J. List, R. Chen for the CV181-
040 Investigators. Saxagliptin added to a submaximal dose of sulphonylurea improves 
glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: 
a randomised controlled trial. The international Journal of Clinical Practice. 2009; 63(9): 
1395-1406 
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 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. 
Elizabeth R. Seaquist et al 2013 
Elizabeth R. Seaquist, John Anderson, Belinda Childs, Philip Cryer, et al. Hypoglycemia and 
Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine 
Society. Diabetes Care. 2013; 36:1384-1395 
Hoerger et al 2008 
Hoerger, TJ, et al., Is Glycemic Control Improving in U.S. Adults Diabetes Care 31(1):81-86, 
2008 
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. 
Jaime A. Davidson 2014 
Jaime A. Davidson. Tolerability of Saxagliptin in Patients with Inadequately Controlled Type 
2 Diabetes: Results from 6 Phase III Studies. Journal of Managed Care Pharmacy. 2014; 
20(2): 120-129 
Levey et al 2007 
Levey AS, Coresh J,Greene T, et al. Expressing the Modification of Diet in Renal Disease 
Study Equation for Estimating Glomerular Filtration Rate with Standardized Serum Creatinine 
Values. Clinical Chemistry 2007; 53:766-72 


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Drug Substance Saxagliptin/Dapagliflozin  
Study Code D1683C00005 
Version 4.0 
Date 4 August 2016 
86 (100) 
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. 
Priscilla L Hollander et al 2011 
Priscilla L Hollander, Jia Li, Robert Frederich, Elsie Allen and Roland Chen for the 
CV181013 Investigators. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 
weeks in patients with type 2 diabetes mellitus. Diabetes & Vascular Disease Research. 2011; 
8(2): 125-35 
Ralph A. Defronzo et al 2009 
Ralph A. Defronzo, Miguel N. Hissa, Alan J. Garber, Jorge L. Gross, Raina Y. Duan, et al. 
The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With 
Inadequately Controlled Type 2 Diabetes With Metformin Alone. Diabetes Care. 2009; 
32(9):1649-55 
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 randomised double-blind 
trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or 
dapagliflozin to metformin. Diabetes Care. 2015; 38(3): 376-83. 
Scirica et al 2013 
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al (SAVOR-TIMI 
53 Steering Committee and Investigators). Saxagliptin and cardiovascular outcomes in 
patients with type 2 diabetes mellitus. N Engl J Med. 2013; 369:1317-1326. 


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SAP_001.pdf: 
Statistical Analysis Plan Amendment
Study Code D1683C00005
Edition Number 4.0
Date 09th Aug 2017
Statistical Analysis Plan
Study Code
D1683C00005
Edition Number
4.0
Date
09th Aug 2017
A Multi-Center, Randomised, Double-Blind, Active-Controlled, Parallel 
Group, Phase III Trial to Evaluate the Safety and Efficacy of 
Saxagliptin 5mg Co-administered with Dapagliflozin 5mg compared to 
Saxagliptin 5mg or Dapagliflozin 5mg all given as Add-on therapy to 
Metformin in Patients with Type 2 Diabetes who have Inadequate 
Glycaemic Control on Metformin Alone


PPD


PPD


Statistical Analysis Plan Amendment
Study Code D1683C00005
Edition Number 4.0
Date 09th Aug 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....................................................................7
AMENDMENT HISTORY.......................................................................9
1.
STUDY DETAILS..................................................................................12
1.1
Study objectives......................................................................................12
1.1.1
Primary objective ....................................................................................12
1.1.2
Secondary objectives...............................................................................12
1.1.3
Safety objectives .....................................................................................12
1.1.4
Exploratory objectives.............................................................................13
1.2
Study design............................................................................................14
1.3
Number of patients..................................................................................16
2.
ANALYSIS SETS...................................................................................16
2.1
Definition of analysis sets .......................................................................16
2.1.1
Enrolled patients set ................................................................................16
2.1.2
Full analysis set.......................................................................................16
2.1.3
Per protocol set .......................................................................................16
2.1.4
Safety analysis set ...................................................................................17
2.2
Violations and deviations ........................................................................17
3.
PRIMARY AND SECONDARY VARIABLES......................................19
3.1
General principles taken for analysis variables ........................................19
3.1.1
Study Day Definition ..............................................................................19
3.1.2
Duration of Type 2 Diabetes....................................................................19
3.1.4
Change from Baseline .............................................................................20
3.1.5
Visit Windows ........................................................................................20
3.1.6
Handling missing data.............................................................................21
3.1.6.1
Imputation of partial dates.......................................................................23
3.2
Primary efficacy variable ........................................................................25
3.3
Secondary efficacy variable.....................................................................25
3.4
Exploratory efficacy variable ..................................................................25


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3.5
Safety variables.......................................................................................26
3.5.1
Adverse Events .......................................................................................26
3.5.2
Vital sign ................................................................................................26
3.5.3
Laboratory Safety Variables....................................................................26
4.
ANALYSIS METHODS.........................................................................28
4.1
General principles ...................................................................................28
4.2
Analysis methods....................................................................................28
4.2.1
Patient disposition...................................................................................28
4.2.2
Demographics and other baseline characteristics .....................................29
4.2.2.1
Demography data....................................................................................29
4.2.2.2
Other baseline characteristics ..................................................................29
4.2.2.3
Medical History ......................................................................................30
4.2.2.4
Prior Medications....................................................................................30
4.2.3.1
Extent of Exposure – Study and Rescue Medications...............................30
4.2.3.2
Extent of Exposure – Concomitant Medications ......................................31
4.2.3.3
Measurement of Treatment Compliance ..................................................31
4.2.4
Efficacy analyses.....................................................................................32
4.2.4.1
Primary efficacy outcome variable ..........................................................32
4.2.4.2
Secondary efficacy variable.....................................................................33
4.2.4.3
Exploratory efficacy variables.................................................................34
4.2.5
Safety analyses........................................................................................35
4.2.5.1
Adverse Events .......................................................................................35
4.2.5.2
Deaths.....................................................................................................38
4.2.5.3
Clinical laboratory variables....................................................................38
4.2.6
Subgroup analyses...................................................................................38
5.
INTERIM ANALYSES (NOT APPLICABLE).......................................39
6.
CHANGES OF ANALYSIS FROM PROTOCOL ..................................39
7.
REFERENCES .......................................................................................39
8.
APPENDIX 1 – MARKED ABNORMALITY CRITERIA.....................41
LIST OF TABLES
Table 1 – List of Important Protocol Deviations ......................................................18
Table 2 - Visit Windows .........................................................................................21
Table 3 - Chemistry and haematology assessments..................................................27


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LIST OF FIGURES
Figure 1 - Study Design...........................................................................................15


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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ADA
American Diabetes Association 
AE
Adverse event
AESI
Adverse events of special interest 
ANCOVA
Analysis of covariance
B&I
Biometrics & Information Sciences
BMI
Body mass index 
BP
Blood pressure
cm
centimetre
CRF
Case report form 
eGFR
estimated Glomerular Filtration Rate
EPS
Enrolled Patients Set
FAS
Full Analysis Set
FDA
Food and Drug Administration
FPG
Fasting plasma glucose
HbA1c 
Haemoglobin A1c
HR
Heart rate
kg
kilogram
MCMC
Markov Chain Monte Carlo methodology
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation 
MTD 
Maximum Tolerated Dose
NMAR
Not missing at random
PDs
Protocol deviations
PMM
Pattern mixture model 
PPG
Post-prandial glucose
PPS
Per Protocol Set 
PT
Preferred Term 
SAE
Serious adverse event
SAF
Safety Analysis Set 


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Abbreviation or 
special term
Explanation
SAS
Statistical Analysis Software
SD
Standard deviation 
SE
Standard error
SOC
System Organ Class 
T2DM 
Type 2 diabetes mellitus


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AMENDMENT HISTORY
Date
Brief description of change
02 August 2017
The following updates were made:
-
Marked abnormality criteria has been updated with the gender 
specific abnormality range removed in Appendix 1
30 July 2017
The following updates were made:
-
The SAP was updated to incorporate a contingency analysis plan of 
excluding one site having serious potential GCP violations.  
Additionally, inserted definition of on-treatment for safety labs.
14 July 2017
The following updates were made:
-
Per protocol population definition updated using relevant protocol 
deviations detailed in section 2.2 Violations and deviations
4 July 2017
The following updates were made:
-
protocol deviations have been updated
-
additional efficacy sensitivity analysis has been added as per request 
from FDA
-
tipping point analysis updated to remove pre-defined points
-
imputation rules of partial dates for concomitant medications and AEs 
were updated to be more explicit
-
US and Non-US subgroup categories have been updated to be North 
American and Other Regions as per request at BDR1
-
New table defined for the presentation of metformin exposure which 
will present number and percentage of subjects that ever took 
metformin therapy at a dose of <1500mg per day during the treatment 
period
-
lab tables will present both SI and Conventional units for the 
following parameters, as requested at time of BDR1, by Safety 
Physician
-
wording for the presentation of abnormal laboratory values
-
AE overview will present updated categories to be in line with 
previous Saxa-Dapa studies.


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Date
Brief description of change
10 January 2017
The following updates were made:
-
removal of <9/J 9% baseline HbA1c, as this is not required per 
protocol, update of categories from to :<8%,> 8  to M8%,> 8, as per 
protocol.
-
update to Markedly Abnormal values (Appendix 2)
-
Rewording of text surrounding the specific delta values used
-
Include the following criteria for excluding patient from per protocol 
population ‘Patient was given rescue medication in error.’
-
Study day definition updated to be based on first treatment date for 
both safety and efficacy outputs.
-
Visit Window table updated.
-
Included following text for Urinalysis: In addition to the above 
assessments, hematuria to be defined basing on dipstick urinalysis 
results (for algorithm please refer to appendix E of protocol) and 
summarized separately in yes/no table. 
-
Removal of following text in how to identify  ‘Documented 
symptomatic hypoglycaemia:’, as this is not needed ‘This is identified 
by ticking ‘Yes’ in the CRF for ‘Any symptoms?’ but having a 
measure BPG of <=70mg/dL’ 
6 October 2016
The following updates were made:
-
include 6 weeks in the exploratory analysis of change from baseline in 
HbA1c
-
include 6 weeks in the exploratory analysis of change from baseline in 
FPG
-
include 6 weeks in the exploratory analysis of change from baseline in 
Body Weight
-
include 6 weeks in the exploratory analysis of change from baseline in 
systolic BP
-
include change from baseline in diastolic BP at 6, 12 and 24 weeks in 
the exploratory analysis
-
update to the method used to analyse secondary endpoint proportion 
of subjects achieving a therapeutic glycemic response at Week 24
-
update to Body mass index (kg/m2) categories to be presented as per 
AZ standard: now grouped as Normal ( <25 kg/m2), Overweight (J25 
kg/m2-   - M30 kg/m2), Obese (>30 kg/m2))
-
Extent of Exposure updated wording to include ‘each’ as will be 
presenting the exposure of each treatment separately.
-
Removed ‘excluding interruptions’ from exposure analysis as these 
will no longer be presented.
-
Compliance updated to include ‘Overall Compliance’ and its 
derivation
-
Updated subgroup ‘M 65 years, >65 years’ to be ‘<65 years, J65 years’ 
in order to be consistent with demography tables. 


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Date
Brief description of change
27 June 2016
-
N/A


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1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
Primary Objective:
Outcome Measure:
To demonstrate the superiority of the change 
from baseline Haemoglobin A1c (HbA1c)
achieved with the co-administered saxagliptin 
5mg and dapagliflozin 5mg to either agent 
individually after 24 weeks
Change from baseline HbA1c to week 24
1.1.2
Secondary objectives
Secondary Objective: 
Outcome Measure:
To demonstrate the effect of the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to either agent individually 
on proportion of patients achieving 
therapeutic glycaemic response with after 24 
weeks
Proportion of patients achieving HbA1c 
<7.0% at 24 weeks
To demonstrate the effect of the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to either agent individually 
on fasting plasma glucose (FPG) after 24 
weeks
Change in fasting plasma glucose (FPG) at 
24 weeks
To demonstrate the effect of the co-
administered saxagliptin 5mg and 
dapagliflozin 5mg to saxagliptin 5mg on total 
body weight after 24 weeks
Change in total body weight at 24 weeks
1.1.3
Safety objectives
Primary Objective: 
Outcome Measure:
To evaluate the safety and tolerability of the 
co-administered saxagliptin 5mg and 
Adverse Events (AEs)/Serious Adverse 
Events (SAEs)
Vital signs


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dapagliflozin 5mg to either agent individually 
after 24 weeks
Collection of clinical 
chemistry/hematology parameters
1.1.4
Exploratory objectives
Exploratory Objective: 
Outcome Measure:
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
either agent individually on the change from 
baseline HbA1c after 6 and 12 weeks
Change from baseline HbA1c to week 6 
and 12
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
either agent individually on proportion of 
patients achieving therapeutic glycaemic 
response with after 12 weeks
Proportion of patients achieving HbA1c 
<7.0%, after 12 weeks
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 
5mg to either agent individually on 
percent of patients who require 
glycaemic rescue or discontinue study 
treatment for lack of efficacy after 12 
and 24 weeks
Percent of patients who require glycaemic 
rescue or discontinue study treatment for 
lack of efficacy at 12 and 24 weeks
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
either agent individually on FPG after 6 and 
12 weeks
Change in FPG at 6 and 12 weeks
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
saxagliptin 5mg on total body weight after 6 
and 12 weeks
Change in total body weight at 6 and 12 
weeks
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
either agent individually on systolic blood 
pressure (BP) after 6, 12 and 24 weeks
Change from baseline in systolic BP (6, 12
and 24 weeks)
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
Change from baseline in diastolic BP (6, 
12 and 24 weeks)


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either agent individually on diastolic blood 
pressure (BP) after 6, 12 and 24 weeks
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
either agent individually on change of HbA1c 
after 12 weeks in patients whose baseline 
HbA1c was >8%
Change from baseline HbA1c after 12 
weeks in patients whose baseline HbA1c 
was >8%
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
either agent individually on change of HbA1c 
after 12 weeks in patients whose baseline 
HbA1c was M8%
Change from baseline HbA1c after 12 
weeks in patients whose baseline HbA1c 
was M8%
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
either agent individually on change of HbA1c 
after 24 weeks in patients whose baseline 
HbA1c was >8%
Change in HbA1c from baseline in patients 
with baseline >8% at 24 weeks
To explore the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
either agent individually on change of HbA1c 
after 24 weeks in patients whose baseline 
HbA1c was M8%
Change in HbA1c from baseline in patients 
with baseline M8% at 24 weeks
To compare the effect of the co-administered 
saxagliptin 5mg and dapagliflozin 5mg to 
either agent individually on proportion of 
patients achieving therapeutic glycaemic 
response and a weight loss after 24 weeks
Proportion of patients achieving 
HbA1c <7.0% and a weight loss of 2 kg 
after 24 week
Collect and analyse blood samples for 
changes from baseline after 24 weeks for 
exploratory research into biomarkers, such as, 
but not limited, to ketones.
Change from baseline of blood biomarker 
values at 24 weeks
1.2
Study design
Figure 1 below presents the overall design of the study.
Study D1683C00005 is a 24-week, multi-center, randomised, parallel-group, double-blind, 
active-controlled Phase III study to evaluate safety and efficacy of therapy with saxagliptin 
5mg co-administered with dapagliflozin 5mg added to metformin, compared to therapy with 


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saxagliptin 5mg or dapagliflozin 5mg added to metformin in adult patients with Type 2 
Diabetes Mellitus (T2DM) who have inadequate glycaemic control (HbA1c J7.5% to 
M10.0%) on maximum tolerated dose (MTD) of J1500mg/day of metformin monotherapy. 
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, MTD of metformin monotherapy (J1500mg/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:
1. Dapagliflozin 5mg + saxagliptin 5mg + metformin
2. Dapagliflozin 5mg + saxagliptin placebo + metformin
3. Saxagliptin 5mg + dapagliflozin placebo + metformin
Study duration will be at least 27 weeks, including a 1-week pre-study Screening period, a 
2-week enrolment period, and a 24-week double-blind treatment period.
Figure 1 - Study Design


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1.3
Number of patients
Approximately 900 patients with T2DM with inadequate glycaemic control receiving 
metformin at a MTD of J1500mg/day for at least 8 weeks prior to enrolment will be 
randomised to 1 of 3 treatment groups.
A sample size of 300 patients per group will provide at least 90% power to simultaneously 
detect a difference in mean change from baseline to week 24 in HbA1c of -0.30 (%) for both 
primary endpoint comparisons of saxagliptin plus dapagliflozin vs its components at the 
2-sided -alpha = 0.05 level. This assumes a common standard deviation of 1.0% and a 3% 
non-evaluability rate.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
There are four analysis (population) sets defined below for this study.  Analysis sets will be 
finalized prior to unblinding of the study.
2.1.1
Enrolled patients set 
The enrolled patients set (EPS) will consist of all patients who sign informed consent. This 
data set will be used to summarize the patient disposition data.
2.1.2
Full analysis set
The full analysis set (FAS) is defined as all randomised patients who take at least one dose of 
the study medication and have a baseline value for HbA1c.  Analysis of the FAS will be based 
on the randomised treatment.  
Note, that subjects from one site with potential serious GCP violations will be excluded from 
all tables and figures. A selection of key tables and figures will be rerun with the site data 
included to assess the impact of the exclusion.  See section 2.2.
FAS will be used to summarize important PDs, patient demography and baseline data; and 
conduct efficacy analyses.
2.1.3
Per protocol set
The per protocol set (PPS) will be defined as all FAS patients without a relevant protocol 
deviation (PD) that might affect the primary analyses. The criteria for relevant protocol 
deviations are detailed in Section 2.2 below. 
PPS will be used mainly to assess the sensitivity of the primary and secondary efficacy 
analyses conducted on FAS by excluding relevant PDs. Specifically, PPS will be used to 
summarize change of primary and secondary efficacy endpoints from baseline to week24, and 
repeat primary and secondary efficacy analyses done on FAS. 


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2.1.4
Safety analysis set
The safety analysis set (SAF) will be defined as all randomised patients who received at least 
one dose of study medication. This data set will be used to summarize safety data (AE, vital 
signs and laboratory parameters), and patient demography and their baseline data as well. 
Note, that subjects from one site with potential serious GCP violations will be excluded from 
all tables and figures. A selection of key tables and figures will be rerun with the site data 
included to assess the impact of the exclusion.  See section 2.2.If there is a difference between 
the SAF and FAS, baseline and demography data will also be presented for the FAS.
Data in this data set will be analysed based on randomised treatment, except in cases where a 
patient received a different treatment for the entire course of his/her participation in the 
double-blind treatment period. In this case, safety data for such a patient will be analysed 
based on the first treatment the patient actually received.
2.2
Violations and deviations
Important PDs are defined as those deviations from the protocol likely to have an impact on 
the efficacy and/or safety of study treatments. Protocol deviations that the study team 
considers to be important will be tabulated or listed in CSR.  Relevant PDs are defined as 
those deviations likely to have an impact on the primary efficacy analysis and are the basis for 
exclusion of data for the per protocol analysis of the primary endpoint.  The criteria for 
relevant protocol deviations and any action to be taken regarding the exclusion of patients or 
affected data from the per protocol primary efficacy analysis are defined in
Table 1 – List of Important Protocol Deviations below.
Important and Relevant PDs will be identified from two sources:
1. IMPACT monitoring – deviations will be reported as a protocol deviation in the 
IMPACT system by the Site Monitor. A report will be generated in IMPACT and 
will be sent from a study team representative to Biometrics & Information 
Sciences (B&I).
2. Statistical programming - deviations will be identified by execution of programs 
run on the clinical database.
The reports or information collected from the IMPACT monitoring report will be reviewed 
and assessed periodically during study conduct by AZ/vendor study team and documented in 
an EXCEL spreadsheet (or other appropriate format).
The final derivation of the per protocol criteria will be done using both approaches above.  A 
meeting of the study team will be held prior to unblinding to make the final determination (or 
rules for the final determination in the case of criteria which require unblinding) of all subject 
and data exclusions for the per protocol analysis based on consideration of the results of the 2 
approaches above and resolving any inconsistencies between the two approaches. In the case 
of a discrepancy (e.g. statistical programming shows patient is 100% compliant with study 
drug but IMPACT monitoring report shows patient is non-compliant), the statistical 


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programming from the clinical database will generally be considered as the more definitive 
source, but decisions will be made by the study team. 
Note that the content of Table 1 is not an exhaustive list of important PDs but rather applies 
only to relevant PDs for the per protocol analysis. A complete list of protocol deviations 
(including important protocol deviations) will be compiled separately and finalised prior to
DBL.
Table 1 – List of Important Protocol Deviations
No.
Deviation
Action
1
Randomized subjects without Type II diabetes or with 
central laboratory HbA1c at screening outside of 
specified limits (i.e. violation of inclusion criterion # 2a 
or screening HbA1c value out of range specified in 2a)
Completely Exclude from PPS
2
Randomized subjects who did not receive stable doses of 
metformin for at least 8 weeks prior to enrolment (visit 
1) (i.e. violation of inclusion criterion 2c)
Completely Exclude from PPS
3
Randomized subjects with abnormal free T4 values at 
enrolment (i.e. violation of exclusion criterion #9c)
Completely Exclude from PPS
4
Randomized subjects with a history of 
haemoglobinopathy with the exception of sickle cell trait 
(SA) or thalassemia; or chronic recurrent hemolysis. (i.e. 
violation of exclusion criterion #7a)
Completely Exclude from PPS
5
Randomized subjects with current or frequent use of 
therapeutic doses of systemic glucocorticoids (i.e. 
violation of exclusion criterion #8e) at enrolment
Completely Exclude from PPS
6
Patient’s overall compliance is < 80% or > 120%.
Completely Exclude from PPS
7
Patient incorrectly received rescue medication
Exclusion from the day the rescue 
medication was given onwards.
8
Randomized subjects newly initiating or changing 
treatment with systemic glucocorticoids for >= 5 days 
after enrolment 
Exclude data from PPS from the 5th
day onwards.  If this day is prior to 
randomization then this becomes a 
complete exclusion.
9
Randomized subjects who used anti-hyperglycaemic 
medication other than IP, metformin or rescue therapy 
for more than 14 days during the 8 weeks prior to 
enrolment (i.e. violation of exclusion criterion #8a)  or 
afterwards (i.e. use of prohibited concomitant diabetes 
medication).
Exclude data from PPS from the 
15th day onwards.  If this day is 
prior to randomization then this 
becomes a complete exclusion.
10
Randomized subjects who took no metformin or < 1500 
mg metformin per day for more than 2 consecutive 
weeks after enrolment.
Exclude data from PPS from the 
15th day onwards.  If this day is 
prior to randomization then this 
becomes a complete exclusion.
11
Randomized subjects who did not take the required study 
medication (either saxagliptin, dapagliflozin or both) for 
more than 2 consecutive weeks after randomization.
Exclude data from PPS from the 
15th day onwards.  


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The Per protocol analysis will not be conducted if <10% of patients have relevant protocol 
deviations.  
Note, during the conduct of the study, serious potential GCP violations were found in one site.  
These issues cast doubt on the validity of the data from this site.  Consequently, all key tables 
and figures will include a version which excludes data from this site.  Specifically, a selected
set of key tables (which will include the primary and key secondary endpoints and key safety 
tables) will be run twice (both with and without the site) to assess the impact of this exclusion.  
Listings will include all sites.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
General principles taken for analysis variables 
3.1.1
Study Day Definition
For the purposes of the data summaries, Study Day 1 is defined as the first date of study 
treatment.  For visits (or events) that occur on or after first date of study treatment, study day 
is defined as:
(date of visit [event] - first date of study treatment + 1).
For visits (or events) that occur prior to first date of study treatment, study day is defined as:
(date of visit [event] - first date of study treatment). 
There is no Study Day 0.
For listings (such as for AEs/SAEs that include the derivation of “days since last dose”, this is 
defined as:
(event date - date of last dose). 
Events that occur on the same day as the last dose of study treatment will therefore be 
described as occurring zero days from the last dose of study treatment.
3.1.2
Duration of Type 2 Diabetes
Duration of T2DM is calculated as the number of years from T2DM diagnosis date to 
informed consent date:
(consent date - diagnosis date +1) / 365.25.
The duration of diabetes will be included in the baseline diabetes characteristics listing.
12
Randomized subjects given incorrect study treatment for 
more than 2 consecutive weeks after randomization.
Exclude data from PPS from the 
15th day onwards.  


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If the date T2DM 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 T2DM.
!
Missing day, month and year: No imputations will occur, and the patient will be 
excluded from all summaries related to duration of T2DM.
!
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.
3.1.3
Definition of Baseline Measurements 
Unless otherwise stated, for each patient, baseline value of a parameter (e.g., efficacy
laboratory parameter, safety laboratory test) is defined as the last assessment on or prior to the 
date of the first dose of the study medication.
3.1.4
Change from Baseline
Change from baseline to any Week t is defined as follows:
CWeek t = MWeek t - Mbaseline,
where:
-
CWeek t is the change from baseline at Week t,
-
MWeek t is the measurement at Week t,
-
Mbaseline is the measurement at baseline.#
The “Week t” to which a measurement belongs is determined using the conventions described 
in Table 2 below.
3.1.5
Visit Windows
For summaries of vital signs and laboratory data, assessments will be assigned to calculated 
visit windows (using study day) as described in Table 2 below. 
Inclusion within the visit window should be based on the actual date and not the intended date 
of the visit.  The window for the visits following baseline (including unscheduled visits) will 
be constructed in such a way that the upper limit of the interval falls half way between the two 
visits.
For laboratory and non-laboratory parameters, unless otherwise specified, if a patient has 
more than one measurement included within a window, the assessment closest to the target 


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day will be used. In case of ties between observations located on different sides of the target 
day, the earlier assessment will be used. In case of ties located on the same side of the target 
day (i.e. more than one value for the same day but different time), the value with the earlier 
entry date/time will be used.
Table 2 - Visit Windows
Assessment 
Visit
Week
Target Day
Day Range
Screening/Baseline
0
Post Baseline
1.5
2-22* 
(1-22)
Week 6
2
6
43
23-64
Week 12
3
12
85
65-126
Week 24/ End of 
Treatment 
4
24
169
127-190
Post Treatment
999
PT
>190
* 
for vital signs and laboratory assessments only.  These will only be displayed in the 
listings.
3.1.6
Handling missing data 
In general, other than for partial dates, missing data will not be imputed and will be treated as 
missing, with some exceptions specified for certain efficacy variables.
The main analysis for change from baseline specified for primary and secondary endpoints in 
following sections will use the repeated measures model. There will be no imputations used 
for missing values for the primary analysis data. There will be four sensitivity analyses, as 
described below, which will look at the effect of missingness.
1) For patients who started rescue medication or terminated the study medication, a 
sensitivity analysis will be performed using the same MMRM model as the primary 
analysis where only measurements taken prior to the date of the first dose of rescue 
medication or up to 8 days post the last dose date of the study medication will be used. 
This model assumes that the time course of the endpoint values for patients who 
discontinue treatment or are rescued at a specified time point is consistent with the 
time course for patients who are ongoing at that time point. 
2) A tipping point sensitivity analysis using ANCOVA for the primary endpoint at week 
24 that will use the delta-adjustment method to impute missing data via the multiple 
imputation method within the pattern-mixture model [1].


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A sensitivity analysis will be done which utilizes ANCOVA for the primary endpoint at week 
24 with a multiple imputation that makes a not missing at random (NMAR) assumption for 
missing data from subjects who discontinued treatment.  Multiple imputation models will be 
built separately for each arm which utilize only the data from subjects who discontinued 
treatment but still obtained the week 24 endpoint assessment (called MI-RD). The delta 
adjustment method uses the assumption that patients from the main treatment arm of interest 
(saxagliptin 5mg co-administered with dapagliflozin 5mg added to metformin) who 
discontinue treatment would have, on average, their unobserved HbA1c at week 24 worse by 
some amount compared with the observed HbA1c at week 24 of similar patients that continue
treatment. Patients who discontinue from the control arms (saxagliptin 5mg or dapagliflozin 
5mg added to metformin) would exhibit the same evolution of the disease as similar control 
patients that stay on study.
Using these assumptions we can define 4 groups of patients with regards to observed data and 
patterns of missingness. The control patients refer to saxagliptin 5mg or dapagliflozin 5mg 
added to metformin patients, and the experimental arm patients refer to saxagliptin 5mg + 
dapagliflozin 5mg + metformin patients.
At each time-point t, consider four groups of patients:
-
(P1) 
control patients with assessment observed at time-point t
-
(P2) 
pattern of control patients with missing assessment at time-point t
-
(P3) 
experimental arm patients with assessment observed at time-point t
-
(P4)
pattern of experimental arm patients with missing assessment at time-point t
Observed data (P1) serves as a model for the pattern (P2) such that the imputation model 
estimated within (P1) is used without any changes to draw imputations for patients in pattern 
(P2).  Observed data (P3) would serve as a basis for a model for the pattern (P4). However, 
predictions from the model estimated within (P3) would be altered before being imputed for 
patients in (P4). Specifically, the predicted values would be worsened by a pre-fixed value, [, 
([ adjustment strategy) using a regression based multiple imputation method, at week 24. 
This would reflect an assumption that patients who drop out from the experimental arm 
would do worse after dropout than otherwise predicted by their observed outcomes and 
covariates.
The tipping point analysis will be performed as follows if the primary analysis is statistically 
significant:
1. The missing data should first be imputed assuming MAR with the delta being added the 
week 24 endpoint.  
2. Run the delta-adjustment method using a binary search (or other appropriate algorithm) to 
select the value of delta which yields a p-value exactly equal to 0.05.
3. Also report the analysis results for delta values with p-values equal to 0.01 and 0.025.  
The multiple imputation sensitivity analysis will build three separate multiple imputation 
models using the regression method for monotone missing data.  Nonmonotone missing data 


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should be imputed using the Markov Chain Monte Carlo (MCMC) method prior to using the 
regression method.  The data used in the imputation model will be restricted to only those 
subjects who have discontinued treatment but have the primary endpoint available at week 
24.  
The secondary efficacy variable of proportion of patients achieving a therapeutic glycaemic 
response is defined as having HbA1c <7.0% at Week 24.   Patients who did not have A1c 
measurement at week 24 will be treated as those who did not to achieve a therapeutic 
glycaemic response. 
3.1.6.1
Imputation of partial dates
Concomitant Medication Dates
Imputation of start dates allows medications for subjects to be classified into the categories of 
prior, concomitant (or both) for tables.  An assessment should be made as to the possibility 
that the subject’s medication could fall into each category given the information available for 
the dates.  If it is possible given the date information that a subject’s medication could fall into 
a given category, then the subjects’ medication should be included for tables for that category.  
If a particular category can be ruled out based on partial or full dates available, then the 
subject’s medication should be excluded from that category.  The following date imputation 
should accomplish this:
Start Dates
!
If year is missing (or the date is completely missing), set start date equal to the consent 
date.
!
If (year is present and month and/or day are missing then impute start date as the 
earliest possible date given the partially entered date, i.e. first day of month, or first 
day of first month.  
!
If the resulting imputed start date is after a non-missing (i.e. not imputed) end date 
then set the start date equal to the end date.
End Dates
!
If year is missing (or the date is completely missing) set end date equal to the latest 
database extraction date.  
!
If the year is known but month and/or day is missing, then set end date equal to the 
latest known date for this patient unless it is after the concomitant med start date
(actual or imputed).  If it is before the concomitant med start date then set it equal to 
the concomitant med start date.
Adverse Events Dates
In case of missing dates, prior to assigning the treatment that the subject received at the onset
of an AE or at the time of a laboratory assessment, imputation rules will be applied as follows:


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If the onset date for an AE is missing or incomplete, an imputed date will be derived. 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 completely missing (or the year is missing), the derived onset date will be 
calculated as the first non-missing valid (actual) date from the following list (in order of 
precedence):
-
First active study medication date
-
Consent date
-
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:
Calculate a surrogate date as the first non-missing valid date from the following list (in 
order of precedence):
-
First active study medication date
-
Consent date
-
If a valid non-missing date is not available for any of these dates, the surrogate 
date will be set to missing.
Based on the information provided, set the initial derived date to the earliest possible date. If 
only a year is provided, set the derived date to January first of that year. If a year and month is 
provided, set the derived date to the first day of that month.
If the surrogate date is non-missing then:
!
If the derived date is on or after the surrogate date use the derived date as calculated
!
If the derived date is prior to 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 prior to 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.
If all 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.
End Dates


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A missing or incomplete end date of an AE will be imputed according to the following
conventions:
!
If an end date is missing, the derived end date will be set to missing
!
If an end date is incomplete, set the derived end 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.
3.2
Primary efficacy variable
The primary efficacy variable is the mean change from baseline in HbA1c at Week 24. 
3.3
Secondary efficacy variable  
The following secondary efficacy variables will be analysed:
!
Percent of patients achieving a therapeutic glycaemic response, defined as a HbA1c 
<7.0% at Week 24
!
Mean change in Fasting plasma glucose (FPG) at 24 weeks
!
Mean change in total body weight at 24 weeks
3.4
Exploratory efficacy variable
The following exploratory endpoints will be analysed:
!
Mean change from baseline in HbA1c at week 6 and 12
!
Proportion of patients achieving therapeutic glycaemic response, defined as HbA1c
<7.0%, after 12 weeks
!
Percent of patients who require glycaemic rescue or discontinue study treatment for
lack of efficacy (12 and 24 weeks)
!
Mean change in FPG at 6 and 12 weeks
!
Mean change in total body weight at 6 and 12 weeks
!
Mean change from baseline in systolic BP (6, 12 and 24 weeks)
!
Mean change from baseline in diastolic BP (6, 12 and 24 weeks)
!
Mean change from baseline HbA1c after 12 weeks in patients whose baseline HbA1c 
was >8%
!
Mean change from baseline HbA1c after 12 weeks in patients whose baseline HbA1c 
was M8%
!
Mean change in HbA1c from baseline in patients with baseline >8% at 24 weeks
!
Mean change in HbA1c from baseline in patients with baseline M8% at 24 weeks
!
Proportion of patients achieving HbA1c <7.0% and a weight loss of 2 kg after 24 
weeks
!
Mean change from baseline of blood biomarker values at 24 weeks


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3.5
Safety variables
The following safety data will be collected and analysed: AEs/SAEs, clinical 
chemistry/hematology parameters and vital sign measurements. 
3.5.1
Adverse Events
All AEs and SAEs occurring during the study will be recorded. Details such a start and stop 
date of AE, action take and outcome will be recorded.
3.5.2
Vital sign 
Vital sign measurements in this study will include sitting systolic and diastolic BP and heart
rate (HR). Vital signs should be measured from Visit 1 after the patient rests for
approximately 5 minutes and with the patient in a sitting position, and again as per the 
schedule of event defined in protocol.
3.5.3
Laboratory Safety Variables
Safety laboratory variables will be analysed including values regardless of rescue but on 
treatment.  On treatment is defined as first dose to last dose + 4 days for all variables except 
liver function tests (alanine aminotransferase, aspartate aminotransferase, bilirubin and 
alkaline phosphatase) which will use first dose to last dose + 30 days.  
The following laboratory variables will be summarised:


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Table 3 - Chemistry and haematology assessments
Urinalysis
Urinalysis assessments will be performed according to Study Plan (Table 1) of protocol and 
will include the following: blood, protein, albumin, glucose, urine ketones, creatinine and 
calculated urinary albumin: creatinine ratio.
In addition to the above assessments, hematuria to be defined basing on dipstick urinalysis 
results (for algorithm please refer to appendix E of protocol) and summarized separately in 
yes/no table. 


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4.
ANALYSIS METHODS
4.1
General principles
Continuous data will be summarized in terms of the number of observations, mean, standard 
deviation (SD), standard error (SE), upper quartile, median, lower quartile, minimum and 
maximum unless otherwise stated. In addition, 95% confidence interval for the mean 
(percent) change from baseline will be calculated for continuous efficacy variables. They will 
be presented by treatment group and time point where applicable.  The minimum and 
maximum will be reported to the same number of decimal places as the raw data recorded in 
the database. The mean, median, lower quartile and upper quartile will be reported to one 
more decimal place than the raw data recorded in the database. The SD will be reported to two 
more decimal places than the raw data recorded in the database and the SE will be reported to 
three more decimal places than the raw data recorded in the database . In general, the 
maximum number of decimal places reported shall be four for any summary statistic.
Descriptive summaries of categorical variables will consist of frequencies and percentages for 
each treatment group and overall, where applicable.
Descriptive summaries of change from baseline in categorical variables will be provided using 
shift tables. Frequencies and percentages of patients within each treatment group will be 
generated for levels of cross-classifications of baseline and the on-treatment value of the 
parameter. The on-treatment value can either be the value at a certain time point, or e.g. for 
laboratory tests, the minimum/maximum value in the direction of toxicity, which has been 
observed during the treatment period. Treatment group differences will not be assessed in 
summaries of shifts.
Note, that subjects from one site with potential serious GCP violations will be excluded from 
all tables and figures. A selection of key tables and figures will be rerun with the site data 
included to assess the impact of the exclusion.  See section 2.2.
4.2
Analysis methods
4.2.1
Patient disposition 
A clear accounting of the disposition of all patients who enter the study will be provided, from 
screening to study completion.  Summaries of patient disposition will be presented by 
treatment and overall (column), while summaries in the EPS (when applicable) will be 
presented only by overall (column).  The following patient disposition summaries will be 
provided: 
!
Number and percentage of patients in the EPS, FAS, PP and SAF populations will be 
presented on their own as well as by country, study centre and overall (row) (Analysis 
Population: EPS).


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!
Number and percentage of screen-failure patients (i.e., patients enrolled but not 
randomized), further classified by reasons for screen failure (Analysis Population: 
EPS).
!
Number and percentage of patients who complete the study and who withdraw from 
the study, further classified by reasons for withdrawal from the study (as recorded on 
Disposition (DS) page of Case Report Form [CRF]).(Analysis Population: FAS)
4.2.2
Demographics and other baseline characteristics
Demographic and baseline patient characteristics will be listed and summarised for the SAF. 
If the FAS differs significantly from the SAF, the analysis will be repeated for the FAS.  All 
summaries of continuous characteristics will be based on non-missing observations. For 
categorical characteristics, percentages will be calculated out of the total number of patients in 
the data set, overall and by treatment group, where applicable (i.e., each denominator includes 
the number of patients with missing/unknown values for the characteristic).
4.2.2.1
Demography data 
Standard descriptive statistics will be presented for the continuous variables of:
!
Age (years).
!
Weight (kg).
!
Height (cm).
!
Body mass index (BMI) (kg/m2), calculated as: weight/(height)2
The total frequency counts and percentages of patients will be presented for the categorical 
variables of:
!
Sex (grouped as male, female)
!
Age group (years) (grouped as <65, J65 and J75)
!
Race (grouped as White, Black or African American, Asian, Native Hawaiian or Other 
Pacific Islander, American Indian or Alaska Native, or Other)
!
Ethnic group (grouped as Hispanic/Latino, Non Hispanic/Latino)
!
Body mass index (kg/m2) (grouped as Normal ( <25 kg/m2), Overweight (J25 kg/m2-
- M30 kg/m2), Obese (>30 kg/m2))
!
Geographic Region (grouped as North American/ Other Regions)
4.2.2.2
Other baseline characteristics 
Standard descriptive statistics will be presented for the continuous variables of:
!
Duration of Type 2 Diabetes (years).
!
HbA1c
!
FPG
!
Post-prandial glucose (PPG)


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The total frequency counts and percentages of patients will be presented for the categorical 
variables of:
!
Duration of Type 2 Diabetes (years) (grouped as < 3, J 3 and M 10 yrs, > 10 yrs)
!
Diabetes Complications (grouped as Any, Retinopathy, Neuropathy Autonomic,
Neuropathy Peripheral, Nephropathy Angiopathy, Other)
!
HbA1c (grouped as: M8%,> 8)
4.2.2.3
Medical History
Diabetes related medical history and general medical history will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA). All disease related medical history will be 
listed and the number and percentage of patients with any disease related medical history will 
be summarised for the FAS by system organ class (SOC) and preferred term (PT).
All general medical history will be listed and summarised similarly.
4.2.2.4
Prior Medications 
Previous medications, including any medication (other than study medications) with a start 
date prior to Day 1 of treatment period, will be summarized.
Missing and partial date handling of start and stop dates of previous medications is described 
in Section 3.1.6.1 above. The AZ Drug Dictionary v16.1is used to code the non-study 
medication.
4.2.3
Extent of Exposure and Treatment Compliance
4.2.3.1
Extent of Exposure – Study and Rescue Medications
The extent of exposure to each study medication during the treatment period is defined as: 
treatment end date – treatment start date +1 
The extent of exposure to study medication will be summarized using the SAF for the 
treatment period and the treatment period prior to rescue, where the number and percent of 
patients with an extent of exposure within specified day ranges (1-7, 8-30, 31-60, 61-90, 91-
120, 121-180, > 180 days) will be presented by treatment group.
The mean, standard deviation (SD), median and range of the number of days of exposure to 
study medication will also be presented. Summaries will be presented including periods of 
interruptions (defined by record of 0 tablets of study medications on the CRF). 
All rescue medication use during the treatment period will be summarized and listed by 
treatment group. 
A listing of patients by batch number of study medication will also be generated.


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4.2.3.2
Extent of Exposure – Concomitant Medications
Concomitant medications include any medication taken from start of the treatment period up 
to the end of the treatment period.
Concomitant medications will be summarized using the SAF dataset by drug class and 
(generic) drug name. A summary table by drug class and generic drug name will be generated 
for each of the following:
!
all concomitant medication
!
all concomitant diuretic medication
!
all concomitant anti-hypertensive medication
To identify each type of diuretic medication and anti-hypertensive medication a list of terms 
will be selected before database lock and unblinding of the database.  Missing and partial date 
handling of start and stop dates of concomitant medications is described in Section 3.1.6.1
above. 
4.2.3.3
Measurement of Treatment Compliance
Percent treatment compliance is calculated during treatment period for study medication (i.e. 
saxagliptin or matching placebo and dapagliflozin or matching placebo) and overall. 
(Number of tablets taken / Planned number of tablets)*100%
Where the planned number of tablets is calculated as:
(End date – Start date +1) * prescribed daily number of tablets
The number of tablets taken is calculated as:
total number of tablets dispensed - total number of tablets returned
based on the CRF accountability pages.
Overall compliance is defined as : 
             (Total number of tablets taken / Total planned number of tablets)*100; where 
the planned number of tablets is calculated as: 
             (latest end date – earliest start date +1) * prescribed daily number of tablets
and the number of tablets taken is calculated as: 
              total number of tablets dispensed - total number of tablets returned.


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A patient is considered compliant if percent compliance is J 80% and M 120%.  For each type 
of medication and overall, the number and percent of patients compliant during the treatment 
period will be displayed for the SAF.
For metformin, a summary for the SAF, including number and percentage of subjects that ever 
took metformin therapy at a dose of <1500mg per day during the treatment period, will be 
provided separately in addition to the compliance summary of the study medications. 
4.2.4
Efficacy analyses
This section addresses separately the analyses to be conducted on the primary efficacy 
endpoint, on the secondary and other efficacy endpoints. 
Summary statistics will be presented for each primary, secondary and exploratory variable as 
described in Section 4.1, as well as the statistical analyses as described below.
This study is designed to demonstrate the superiority of the co-administered saxagliptin 5mg 
and dapagliflozin 5mg vs its components in mean change from baseline to week 24 in HbA1c 
at the 2-sided alpha = 0.05 level.
4.2.4.1
Primary efficacy outcome variable
A longitudinal repeated measures analysis using ‘direct likelihood’ will be performed. 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.
The following model will be used:
Cijk = intercept + ß1 [Mbaseline,ij] + ]i + ^ k+ (^ ])ik + (^ Mbaseline)ijk + error ijk
where
-
Cijk is the change from baseline for patient j in treatment group i at time k,
-
ß1 is the slope coefficient for the baseline measurement,
-
Mbaseline,ij is the baseline measurement of patient j in treatment group i,
-
]i is the mean effect of treatment group i,
-
^ k is the mean effect at time k
-
(^ ])ik is the interaction term between treatment group i and time k.
-
(^ Mbaseline)ijk is baseline measurement-by-week interaction term for patient j in treatment 
group i at time k, and
-
error ijk is the error term for patient j in treatment group i at time k.
An unstructured matrix for the within-patient error variance-covariance will be used. The 
denominator degrees of freedom will be calculated according to the Kenward-Roger method. 


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In case of non-convergence of the preferred model or memory space issues, the following 
back-up models are defined:
-
The first backup model is the same as the preferred model but the Kenward-Roger method 
will be replaced by Satterthwaite approximation.
-
The second backup model is the same as the preferred model but without the term for 
baseline measurement-by-week interaction.
The second back-up model will only be provided if the first back-up model does not converge 
or has memory issues.
The model will provide least-squares mean estimates, SE and 2-sided 95% confidence 
intervals for mean change at all time points within and between treatments.
Sensitivity analysis
A sensitivity analysis will be conducted for the primary efficacy using data up to date of 
rescue medication or prior to the study medication termination + 8 days and will be completed 
using the same model as described above.
Additional sensitivity analyses of HbA1c changes from baseline at Week 24 (having used 
SAS procedures PROC MI and MIANALYZE to impute any missing data and analyze the 
data after imputation, see Section 3.1.6) will be performed using an ANCOVA model at week 
24. If the missing data pattern is non-monotone, then the Markov Chain Monte Carlo 
methodology (MCMC) is first employed to generate a monotone missing pattern (the number 
of simulation is 1000 and a simulation seed is 725). When the missing data pattern is 
monotone, then a linear regression will be used to impute the missing HbA1c, i.e. missing 
values of HbA1c are predicted in turn, given the observed values of HbA1c (a simulation seed 
is 229).
The per protocol analysis of the primary endpoint, if it is done, will exclude data after rescue 
or more than 8 days after treatment discontinuation.
For each sensitivity analysis least squares mean estimates and 2-sided 95% confidence 
intervals for mean changes from baseline within and (when warranted) differences in mean 
change from baseline between treatments will be provided.
A value of the delta in the tipping point analysis will be reported if it exists.
4.2.4.2
Secondary efficacy variable
The primary endpoint will be tested for saxagliptin plus dapagliflozin versus saxagliptin and 
dapagliflozin arms simultaneously at the alpha = 0.05 level (two sided). In order to protect the 
overall type I error rate, the interpretation of the statistical significance of treatment 
comparisons for each secondary efficacy endpoint will be done using a stepwise procedure.  
The secondary endpoints then will be tested sequentially as follows:


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1- saxagliptin plus dapagliflozin versus saxagliptin on percent of patients achieving a 
therapeutic glycaemic response, defined as a HbA1< 7.0% at Week 24
2- saxagliptin plus dapagliflozin versus dapagliflozin on percent of patients achieving a 
therapeutic glycaemic response, defined as a HbA1< 7.0% at Week 24
3- saxagliptin plus dapagliflozin versus saxagliptin on mean change from baseline in FPG
at Week 24
4- saxagliptin plus dapagliflozin versus dapagliflozin on mean change from baseline in 
FPG at Week 24
5- saxagliptin plus dapagliflozin versus saxagliptin on mean change from baseline in total 
body weight at Week 24
Each comparison will be tested at the alpha = 0.05 (two-sided) level.
The analysis of the change from baseline for FPG and total body weight at week 24 will be 
performed using the same longitudinal repeated measures model as for the primary efficacy 
endpoint.
The proportion of subjects achieving a therapeutic glycemic response (defined as HbA1c 
<7.0%) at Week 24 will be summarized by treatment group and compared between treatment 
groups using the methodology of Zhang, Tsiatis, and Davidian [3], and Tsiatis, Davidian, 
Zhang, and Lu [4]. 95% confidence intervals for the response rate within each treatment 
group as well as for the difference in response rates between treatment groups will be 
calculated with adjustment for baseline HbA1c.  As defined in Section 3.1.6 patients who did 
not have A1c measurement at week 24 will be treated as those who did not achieve a 
therapeutic glycaemic response.
4.2.4.3
Exploratory efficacy variables 
The following exploratory endpoints will be analysed using a repeated measure mixed model 
as was used for the primary efficacy variable: 
!
The mean change from baseline in HbA1c at week 6 and week 12
!
Mean change in FPG at 6 and 12 weeks
!
Mean change in total body weight at 6 and 12 weeks
!
Mean change from baseline in systolic BP (6, 12 and 24 weeks)
!
Mean change from baseline in diastolic BP (6, 12 and 24 weeks)
!
Mean change from baseline HbA1c after 12 weeks in patients whose baseline HbA1c 
was >8%
!
Mean change from baseline HbA1c after 12 weeks in patients whose baseline HbA1c 
was M8%
!
Mean change in HbA1c from baseline in patients with baseline >8% at 24 weeks
!
Mean change in HbA1c from baseline in patients with baseline M8% at 24 weeks
!
Mean change from baseline of blood biomarker values at 24 weeks


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Whilst the following exploratory efficacy endpoints will be summarized by treatment group 
and compared between treatment groups using the methodology described for analysis of 
proportion of patients achieving a therapeutic response at week 24, above.  95% confidence 
intervals for the response rate within each treatment group as well as for the difference in 
response rates between treatment groups will be calculated with adjustment for baseline 
HbA1c.
!
Proportion of patients achieving therapeutic glycaemic response, defined as HbA1c 
<7.0%, after 12 weeks
!
Percent of patients who require glycaemic rescue or discontinue study treatment for 
lack of efficacy (12 and 24 weeks)
o
if > 10% require glycaemic rescue or discontinue study treatment for lack of 
efficacy (12 and 24 weeks) a KM curve will present time to this event.
!
Proportion of patients achieving HbA1c <7.0% and a weight loss of 2 kg after 24 
weeks
4.2.5
Safety analyses
4.2.5.1
Adverse Events
Adverse Events (AEs) will be classified by Primary SOC and PT according to the MedDRA.
In summaries by SOC and PT, AEs will be sorted by overall decreasing frequency within each 
SOC and PT. In summaries by PT, AEs will be sorted by decreasing frequency within PT
according to the highest of either of the combinational dose group across the study.
Separate pages to capture events of hypoglycemia are contained within the CRF.
Hypoglycemia or discontinuation due to hypoglycemia would not be reported on an AE CRF 
page unless the event fulfilled criteria for an SAE in which case an SAE form would be 
completed. Hypoglycemia events that are reported as SAEs will be included in all summaries 
of AEs or SAEs. Separate summaries will be provided including hypoglycemia events 
reported on the special CRF pages.
All Adverse Events
An overall summary of adverse events at patient level, including patients who experienced at 
least one: AE, hypoglycaemic event, treatment-related AE, death, SAE, treatment-related 
SAE, SAE leading to the discontinuation of study medication, hypoglycaemic event leading to 
the discontinuation of study medication, and AESI. All AEs (serious and non-serious, 
excluding hypoglycemic events that are not reported as SAEs) will be summarized by SOC
and PT. In addition, a patient listing of all reported AEs will be produced, displaying all 
events that occurred prior to the start date of treatment period, if any. All AEs (serious and 
non-serious) including all hypoglycemic events will also be summarized by treatment group, 
where applicable.


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Adverse events and SAEs with an onset from Day 1 of treatment up to and including 4 days 
and 30 days respectively, after the last dose date in the treatment period will be considered as 
occurring during the treatment period.
In addition, the following summaries will be provided for the treatment period (excluding 
hypoglycemic events that are not reported as SAEs):
!
Most common adverse events by preferred term and treatment group (i.e., reported by 
J 2 % of patients in any treatment group),
!
Adverse events by system organ class, preferred term, intensity and treatment group,
!
Adverse events related to study medication by system organ class, preferred term and 
treatment group.
!
Proportion of patients with adverse events by SOC and PT in subgroups of patients 
defined by age category (< 65 and J 65 years), gender and race.
No formal comparisons will be made between treatments. No formal statistical testing will be 
performed, only summary statistics will be provided.
Adverse Events of Special Interest
Event categories of adverse events special interest (AESI) 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, cardiac failure 
(including confirmed adjudicated cardiac failure events), renal impairment/renal failure, 
volume depletion (hypotension, dehydration, and hypovolemia), and liver injury(including 
confirmed adjudicated hepatic events).
To identify each type of adverse event of special interest, a list of PTs will be selected before 
database lock and unblinding of the database.  AEs and SAEs of special interest with an onset 
from Day 1 of treatment up to and including 4 days and 30 days respectively, after the last 
dose date will be considered as occurring during the treatment period. 
Separate summaries similar to those produced for AEs/SAEs will be provided for AESI.
Hypoglycemic Events
Separate pages to capture events of hypoglycemia are contained within the CRF.
Hypoglycemic events with an onset from Day 1 of treatment to and including 4 days after the 
last dose date of treatment will be considered as occurring during the treatment period, or up 
to rescue. The proportion of patients with hypoglycemic events will be tabulated by treatment 
group. 
Hypoglycemia episodes will be categorised according to the American Association of 
Diabetes (ADA) Criteria [5] which classifies hypoglycemia as follows:
Severe hypoglycaemia:  
An event requiring assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions.


Statistical Analysis Plan Amendment
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A severe hypoglycemic event is identified by those ticking ‘Yes’ 
on the CRF for ‘Was third party intervention required for this 
episode of hypoglycaemia?’
Documented 
symptomatic 
hypoglycaemia:
An event during which typical symptoms of hypoglycaemia are 
accompanied by a measured plasma glucose concentration less 
than or equal to 70mg/dL (3.9mmol/L).
Asymptomatic 
hypoglycaemia: 
An event not accompanied by typical symptoms of 
hypoglycaemia but with a measured plasma glucose 
concentration less than or equal to 70mg/dL (3.9mmol/L).
Probable symptomatic 
hypoglycaemia: 
An event during which symptoms of hypoglycaemia are not 
accompanied by a plasma glucose determination, but was 
presumably caused by a plasma glucose concentration less than 
or equal to 70 mg/dL (3.9 mmol/L).
Relative hypoglycaemia
An event during which the person with diabetes reports any of 
the typical symptoms of hypoglycaemia, and interprets the 
symptoms as indicative of hypoglycaemia, but with a measured 
plasma glucose concentration greater than 70mg/dL 
(3.9mmol/L).
Number and percentage of patients who had any hypoglycaemic event and total number of 
events by treatment group will be presented for the SAF.
A summary of proportion of patients having severe hypoglycemia, documented symptomatic 
hypoglycemia or asymptomatic hypoglycemia as categorised by the ADA criteria above will 
also be presented for the SAF. All incidences of hypoglycaemic events and their ADA 
categorisation will be listed.
Hypoglycemic events will be categorized using the following classes in addition to overall 
reported hypoglycemic events:
•
Major episodes of hypoglycemia - defined as symptomatic episodes requiring 
external (3rd party) assistance due to severe impairment in consciousness or 
behaviour with a capillary or plasma glucose value < 3 mmol/L (< 54 mg/dL) and 
prompt recovery after glucose or glucagon administration,
•
Minor episodes of hypoglycemia - defined as either a symptomatic episode with a 
capillary or plasma glucose measurement below 3.5 mmol/L (63 mg/dL) regardless 
of need for third-party assistance or an asymptomatic capillary or plasma glucose 
measurement below 3.5 mmol/L (63 mg/dL), that does not qualify as a major 
episode,


Statistical Analysis Plan Amendment
Study Code D1683C00005
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•
Other episodes of hypoglycemia - defined as episodes reported by the investigator 
that are suggestive of hypoglycemia but do not meet the above criteria.
A summary of proportion of patients having major, minor and other episodes of hypoglycemia 
will be presented for the SAF.  
4.2.5.2
Deaths
All deaths recorded on the disposition page, the AE page, or SAE page (with a death date, 
cause of death, outcome or SAE categorization present) of the CRF will be considered a death 
in the analyses. Any deaths that occur during the study will be described in depth as narrative 
in the CSR. A listing of all deaths that occur during the study will be produced.
4.2.5.3
Clinical laboratory variables
Summary statistics for observed values and change from baseline at each visit will be 
presented for each laboratory parameters in SI units. The following parameters will also be 
presented for conventional units: alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, bicarbonate, bilirubin, calcium, chloride, creatine kinase, creatinine, 
glucose, magnesium, phosphate, potassium, total protein, sodium, urate, hemoglobin, urinary 
albumin to creatinine ratio.  Shift tables will present the change from baseline value 
categorised as low/normal/high based on the laboratory reference range, to post baseline value 
category.
The number and percent of patients with laboratory values meeting marked abnormality 
criteria, as per criteria defined in Appendix 1 – MARKED ABNORMALITY CRITERIA, will 
be summarized for each treatment group.  Shift tables will present the change from baseline 
value (categorized as low/normal/high based on the laboratory reference range), to post 
baseline value category. 
Other safety assessments including serum creatinine, and eGFR by Modification of Diet in 
Renal Disease (MDRD) will be summarized by treatment group using descriptive statistics of 
values and changes from baseline at each scheduled time point.
Additional analyses for laboratory marked abnormalities will be performed excluding data 
after rescue in the double-blind treatment period. 
4.2.5.4
Vital signs
Values and changes from baseline at each scheduled time point for vital signs, including 
weight, blood pressure and heart rate, will be summarized by treatment group using 
descriptive statistics.
4.2.6
Subgroup analyses
The subgroup analysis will be performed on the primary efficacy endpoint (mean change from 
baseline in HbA1C) in subgroups defined by the following variables:


Statistical Analysis Plan Amendment
Study Code D1683C00005
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-
Baseline HbA1c (M8%, >8%)
-
Gender (male, female)
-
Age (<65 years, J65 years)
-
Region (North American, Other Regions)
Subgroup analyses will be carried out as for the primary analysis model with subgroup by 
treatment interaction term. Within each subgroup, point estimates and 95% confidence 
intervals will be calculated for the adjusted mean changes within each treatment group as well 
as for the differences in adjusted mean changes between treatment groups. A nominal 
interaction p-value will be provided for the purpose of the completeness of the data analysis.
Additionally, the following data will be presented for the North American Region subgroup, 
as requested by the FDA
-
patient disposition
-
demographics and baseline characteristics
-
medical history
-
adverse events/ serious adverse events
5.
INTERIM ANALYSES (NOT APPLICABLE)
6.
CHANGES OF ANALYSIS FROM PROTOCOL
The following updates were made 6th Oct 2016:
-
include 6 weeks in the exploratory analysis of change from baseline in HbA1c
-
include 6 weeks in the exploratory analysis of change from baseline in FPG
-
include 6 weeks in the exploratory analysis of change from baseline in Body Weight
-
include 6 weeks in the exploratory analysis of change from baseline in systolic BP
-
include change from baseline in diastolic BP at 6, 12 and 24 weeks in the exploratory analysis
The following updates were made 30th of July 2017:
-
Subjects from one site with potential serious GCP violations will be excluded from all tables 
and figures. A selection of key tables and figures will be rerun with the site data included to 
assess the impact of the exclusion.  
         


Statistical Analysis Plan Amendment
Study Code D1683C00005
Edition Number 4.0
Date 09th Aug 2017
40
7.
REFERENCES
1
Pharmaceutical Statistics, 2013: Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models† Bohdana 
Ratitch,a*Michael O’Kelly,b and Robert Tosielloc
2
CV181169: A Multicenter, Randomized, Double-Blind, Active Controlled, Parallel 
Group, Phase 3 Trial to Evaluate the Safety and Efficacy of add-on therapy with 
Saxagliptin and Dapagliflozin added to Metformin compared to add-on therapy with 
Saxagliptin in combination with Metformin or Dapagliflozin in Combination with 
Metformin in subjects with Type 2 Diabetes who have inadequate glycemic control on 
Metformin alone
3
Zhang M., Tsiatis A., Davidian M. Improving efficiency of inference in randomized 
clinical trials using auxiliary covariates. Biometrics. 2008; DOI: 10.1111/j.1541-
0420.2007.00976.x.
4
Tsiatis A., Davidian M., Zhang M., Lu X. Covariate adjustment for two-sample 
treatment comparisons in randomized clinical trials: a principled yet flexible approach. 
Statistics in Medicine. 2007; DOI: 10.1002/sim.3113.
5
Diabetes Care, 2005, 28: 1245 American Diabetes Association Workgroup on 
Hypoglycemia; Defining and reporting hypoglycemia in diabetes: a report from the 
American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 
2005;28:1245–1249.


Statistical Analysis Plan Amendment
Study Code D1683C00005
Edition Number 4.0
Date 09th Aug 2017
8.
APPENDIX 1 – MARKED ABNORMALITY CRITERIA
The criteria for marked abnormality for each variable are listed in the following table. Note 
   Clinical Laboratory variables 
Units 
Marked Abnormality Criteria
Low
High
HAEMATOLOGY
HCT (haemoatocrit)
%
< 20%
> 55%
HCT 
%
> 60%
Haemoglobin 
g/dL
< 6 g/dL
> 18 g/dL
Haemoglobin 
g/dL
> 20 g/dL
BLOOD CHEMISTRY
Albumin
g/dL
M 2 g/dL
> 6 g/dL
Total protein
g/dL
> 10 g/dL
ALP
U/L
> 3X ULN
ALT
U/L
> 3X ULN
AST
U/L
> 3X ULN
ALT
U/L
> 5X ULN
AST
U/L
> 5X ULN
ALT
U/L
> 10X ULN
AST
U/L
> 10X ULN
ALT
U/L
> 20X ULN
AST
U/L
> 20X ULN
Total Bilirubin
mg/dL
> 2X ULN if PreRx M ULN;
> 3X ULN if PreRx > ULN
Glucose, Plasma Unspecified
mg/dL
< 54 mg/dL
> 350  mg/dL
Na (Sodium)
mEq/L
< 130 mEq/L
> 150 mEq/L
Na (Sodium)
mEq/L
< 120 mEq/L
K (Potassium)
mEq/L
M 2.5 mEq/L
J 6.0 mEq/L
HCO3 (Bicarbonate)
mEq/L
M 13 mEq/L


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Edition Number 4.0
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1Forcreatine kinase, ULN: Males (<65 years=250 U/L; J65 years=203 U/L), Females (<65 years=170 U/L; J65 
years=160 U/L)
Elevated AT (ALT and/or AST) and Total Bilirubin
The following three criteria will be summarized in examination of elevated AT (ALT and/or 
AST) and total bilirubin:
!
(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)}
Clinical Laboratory variables 
Units 
Marked Abnormality Criteria
Low
High
Creatinine
mg/dL
J 1.5X PreRx CREAT
Creatinine
mg/dL
J 2.5 mg/dL
CK (Creatine Kinase)1
U/L
> 5X ULN
CK (Creatine Kinase)1
U/L
> 10X ULN
Total Calcium
mg/dL
< 7.5 mg/dL
 1 mg/dL from ULN and  0.5 
mg/dL from PreRx CA
Phosphorus, inorganic
mg/dL
M 1.8 mg/dL if age 17-65 or 
M 2.1 mg/dL if age  66 
 5.6 mg/dL if age 17-65 or 
 5.1 mg/dL if age  66                  
Magnesium, serum  
mEq/L
<1 MEQ/L
>4 mEq/L 
QUANT. URINE CHEMISTRY (TIMED SPECIMEN)
Albumin/Creatinine Ratio 
mg/g
>1800 mg/g