Conditions: Type 2 Diabetes Mellitus Heart Failure
Keywords: Type 2 Diabetes Mellitus Heart Failure Saxagliptin Sitagliptin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 348
Healthy volunteers: no

Brief summary:
This is a 24 week, multicenter, randomized, double-blind, parallel group, placebo-controlled study to investigate the effects of saxagliptin and sitagliptin on cardiac dimensions and function in patients with type 2 diabetes (T2DM) mellitus and heart failure (HF).

Detailed description:

Arms:
arm 1: one tablet of saxagliptin 5 mg or 2.5 mg + one placebo capsule matching sitagliptin arm 2: one capsule of sitagliptin 100 mg or 50 mg + one placebo tablet matching saxagliptin arm 3: one placebo tablet matching saxagliptin + one placebo capsule matching sitagliptin

Interventions: intervention 1: Saxagliptin intervention 2: Sitagliptin intervention 3: Placebo to match saxagliptin intervention 4: Placebo to match sitagliptin
Intervention descriptions: intervention 1: 5 mg or 2.5 mg, plain, yellow, biconvex, round, film-coated tablet intervention 2: 50 mg or 100 mg, gray capsule intervention 3: 2.5 mg or 5 mg, plain, yellow, biconvex, round, film-coated tablet intervention 4: 50 mg or 100 mg, gray capsule

Protocol document:
Prot_002.pdf: 
• Protocol number: D1680C00016 
• Document title: A 24-Week, Multicenter, Randomized, Double-blind, 
Parallel Group, Placebo-controlled Study to Investigate the Effects of 
Saxagliptin and Sitagliptin in Patients with Type 2 Diabetes Mellitus   
and Heart Failure 
• NCT number: NCT02917031 
• Version number: 5.0 
• Date of the document: 14 February 2020 


This protocol version includes Addendum 1.0 dated 3 Aug 2017.
Clinical Study Protocol 
Drug Substance
saxagliptin
Study Code
D1680C00016
Version
5.0 
Date
14 February 2020
MEASURE-HF
MEchAniStic evalUation of glucose-loweRing strategiEs in patients with 
Heart Failure
A 24-Week, Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo-controlled Study to Investigate the Effects of Saxagliptin and 
Sitagliptin in Patients with Type 2 Diabetes Mellitus and Heart Failure
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden 


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
2 (85)
VERSION HISTORY
Version 5.0 14 February 2020
Minor typographical errors have been corrected in the protocol.
Protocol synopsis (Statistical methods) The actual non-inferiority margin for the study 
primary objective is clarified as 10% of the overall baseline mean LVEDV index across all 
treatment groups.  
Section 2. (Study objectives) Primary objective was not changed but added further 
clarification to the NI margin.
Section 8.1 Added that combination of stratification levels and/or variables or dropping of 
variables could be done for imputation models, (in addition to analysis models which was 
specified originally).
Section 8.2. (Sample size estimate) clarification that the 6.5 value used for the NI margin in 
this section is an estimate used for sample size calculation purposes and is not necessarily 
the NI margin that will be applied in the analysis (which will be 10% of the overall baseline 
mean).  
Section 8.5 (Method of statistical analysis)
To more closely follow past health authority recommendations, a change to the handling of 
missing data has been made.  Instead of complete case analysis, multiple imputation will be 
done.  Clarification on how the non-inferiority margin will be tested is also added.
Section 8.5.6 (Sensitivity analysis) Sensitivity analyses methodology for the primary 
endpoint described.
Version 4.0 13 June 2018
Study timelines, number of sites and countries updated.
Minor typographical errors and house style issues have been corrected throughout the 
protocol.
Protocol Synopsis updated according to the revised protocol.
List of abbreviations and definitions was updated to cover new abbreviations added in the 
revised CSP wording.


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
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Exploratory objective regarding PKs collection updated to reflect that the number of PKs 
collected may be higher than 150.
Section 1.3 (Study Design): NT-proBNP inclusion level lowered to >300 pg/mL, central 
laboratory HbA1c range deleted as no longer needed for inclusion criteria, pre-
screening/screening period extended to 28 days, wording on requirement to perform blood 
sampling before change in diuretics removed.
Figure 1 (Study flow chart): The flow chart updated to reflect the revised study design.
Section 3.1 (Inclusion criteria): Section updated to reflect revised study design: definition of 
documented, controlled T2DM revised; NT-proBNP lowered to >300 pg/mL; HF 
medications requirements updated; removal of normal sinus rhythm requirement on the 
qualifying ECG.  
Section 3.2 (Exclusion criteria): Criterion #2 on atrial fibrillation added with the adjustment 
in criteria numbering. Criterion #3 modified by adding claustrophobia or unwillingness to 
undergo the required MRI imaging that may preclude the ability to perform an MRI scan of 
acceptable quality; criteria 4 and 5 changed to reflect shortened (to 8 weeks) exclusion period 
after receipt of incretin therapy and/or therapy with TZD; criteria 10 and 11 updated with 
shortened exclusion period to 3 months before screening after MI/stroke/TIA and other 
procedures/surgeries; criterion 17 wording updated to reflect Addendum 1,0 dated 3 Aug 
2017; criterion 22 changed.
Section 3.3 (Patient pre-screening, enrollment and randomization): procedure requiring 
blood collection for HbA1c measurement removed from pre-screening/screening period; 
Section 3.8 (Restrictions): change in exclusion period for prohibited medications listed from 
3 months to 8 weeks before randomization reflected. 
Section 3.9. (Discontinuation of investigational product): Clarification on procedures 
regarding discontinuation of investigational product added. 
Section 3.10.2 (Withdrawal of the informed consent): Clarification on procedures in case of 
withdrawal of consent added. 
Table 2 (Study Plan): Table adjusted to reflect revised study design.
Section 4.1 (Pre-screening/Enrollment/screening period): (Pre) screening period changed 
from 21 to 28 days; procedure requiring blood collection for HbA1c measurement removed 
from pre-screening/screening period.
Section 4.1.1 (Pre-screening Informed Consent Form and Informed Consent Form): HbA1c 
laboratory test removed from the risks described in pre-screening ICF.
Section 4.1.7 (Clinical laboratory test): HbA1c removed from the pre-screening procedures.


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
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Section 4.1.8 (Electrocardiogram (ECG)): clarification on the wording regarding assessment 
of ECG. 
Section 4.1.9.1. (Urine pregnancy test): Week number added to visit number to be 
consistent with the visit descriptions throughout the CSP wording.
Section 4.2.1. (Scheduled telephone contacts): Week number added to visit number to be 
consistent with the visit description throughout the protocol.
Section 5.1.3.1. Clarification added that patients with HbA1c interference issue can be 
included in the study.
Table 4 (Blood sample volume): Blood volume updated due to removal of Hb1Ac testing at 
prescreening Visit, removal of biomarkers back-ups and recalculation of blood volume 
based on the lab manual.
Section 5.2.2.1 (Complete physical examination): Week number added to visit number to be 
consistent with the visit descriptions throughout the CSP wording.
Section 5.2.2.2. (Brief physical examination): Week number added to visit number to be 
consistent with the visit descriptions throughout the CSP wording
Section 5.3 (Pharmacokinetics) and section 5.3.1. (Collection of samples) – updated 
wording to reflect that the number of PKs collected may be higher than 150.
Section 5.6.4. (Withdrawal of Informed Consent for donated biological samples): 
Clarification added regarding procedures on withdrawal of consent for donated biological 
samples.
Section 7.7.1.1(Diuretics) removed.
Section 7.7.3 (Concomitant treatment): List of strong CYP 3A 4/5 inhibitors updated.
Section 8.3 (Definition of analysis set): Full analysis set definition updated with secondary 
efficacy analysis.
Section 8.3.1. (Efficacy analysis set): Definition of FAS ad PP updated. Clarification added 
that important protocol deviations will be defined in statistical analysis plan.
Section 8.3.2. (Safety analysis set): Definition of safety analysis set updated.
Section 8.3.3 (PK Analysis set): Updated wording to reflect that the number of PKs 
collected may be higher than 150.
Section 8.4.2 (Secondary efficacy variables). Definition of variables updated in more detail.


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
5 (85)
Section 8.5 (Methods for statistical analyses): Definition of statistical methods updated.
Section 8.5.1 (Analysis of the primary variable(s)): Methods for primary analysis updated.
Section 8.5.3. (Exploratory analyses): Wording added that subjects without central value of 
HbA1c will be removed from exploratory analysis.
Section 8.5.7: (Safety analysis) Definition of safety analysis updated.
Section 9.4. (Data management by AstraZeneca): AZ Drug Dictionary replaced with WHO 
Drug Dictionary.
Section 10.4.1(Pre-screening Informed Consent) updated to reflect removal of central 
testing of HbA1c at prescreening.
List of Appendixes updated: Added new Appendix C (Criteria for Diagnosis of Diabetes 
Mellitus); Appendix on NYHA reclassified as Appendix D.


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
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This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The clinical study protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


7 (85)
PROTOCOL SYNOPSIS
A 24-Week, Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo-controlled Study to Investigate the Effects of Saxagliptin and 
Sitagliptin in Patients with Type 2 Diabetes Mellitus and Heart Failure
International Co-ordinating Investigator 
 University of Michigan School of Medicine
Ann Arbor
MI   48104
United States
This protocol version includes Addendum 1.0 dated 3 Aug 2017.
Study site(s) and number of subjects planned
This study will be conducted at approximately 90 sites in 9 countries.
Approximately 330 patients will be randomized in equal proportions (110 patients per group) 
to treatment with saxagliptin, sitagliptin or placebo.
Study period
Phase of development
Estimated date of first subject enrolled
Q1 2017
Phase 4
Estimated date of last subject completed
Q3 2019
Study design
This is a 24 week, multicenter, randomized, double-blind, parallel group, placebo-controlled 
study to investigate the effects of saxagliptin and sitagliptin on cardiac dimensions and 
function in patients with type 2 diabetes (T2DM) mellitus and heart failure (HF).
PPD
PPD
PPD


Clinical Study Protocol Synopsis
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
8 (85)
Objectives
Primary Objective:
Outcome Measure:
To exclude an increase in left ventricular end 
diastolic volume (LVEDV) index of greater 
than 10% of the overall baseline value (non-
inferiority margin) in patients with T2DM and 
HF treated with saxagliptin for 24 weeks, 
compared to placebo

Change from baseline in LVEDV index 
measured by Magnetic Resonance Imaging
(MRI) at 24 weeks
Secondary Objectives:
Outcome Measure:
Evaluate the effects of saxagliptin compared to 
placebo on left ventricular end systolic volume 
(LVESV) index, left ventricular ejection 
fraction (LVEF), and left ventricular mass 
(LVM) after 24 weeks in patients with T2DM 
and HF

Change from baseline in LVESV index, 
LVEF, and LVM measured by MRI at 24 
weeks
Evaluate the effects of saxagliptin compared to 
placebo on N-terminal prohormone of brain 
natriuretic peptide (NT-proBNP) after 24 weeks 
of treatment

Change from baseline in NT-proBNP after 24 
weeks of treatment.
Safety Objective:
Outcome Measure:
To assess the safety and tolerability of 
saxagliptin and sitagliptin treatment in patients 
with T2DM and HF

Incidence of adverse events (AEs), serious 
adverse events (SAEs), AEs of special 
interest 

Collection of clinical chemistry/hematology 
parameters 

Vital signs 

Physical examination

Incidence of independently adjudicated 
Cardiovascular (CV) events [CV death, 
myocardial infarction (MI), stroke, and 
hospitalization for heart failure (hHF)]


Clinical Study Protocol Synopsis
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
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Exploratory Objectives:
Outcome Measure:
Evaluate the effects of sitagliptin compared to 
placebo on LVEDV index, LVESV index, 
LVEF, and LVM after 24 weeks of treatment in 
patients with T2DM and HF

Change from baseline in LVEDV index, 
LVESV index, LVEF, and LVM measured 
by MRI at 24 weeks
Evaluate the effects of saxagliptin at Weeks 6 
and 12 and sitagliptin at 6, 12, and 24 weeks, 
compared to placebo on NT-proBNP

Change from baseline in NT-proBNP after 6, 
12, and 24 weeks
Evaluate the effects of saxagliptin and 
sitagliptin on plasma volume at 6, 12, and 24 
weeks

Percent change from baseline in plasma 
volume using the Strauss formula after 6, 12, 
and 24 weeks
Evaluate the effects of saxagliptin and 
sitagliptin on changes from baseline body 
weight compared to placebo at 12 and 24 weeks

Change from baseline in body weight at 12 
and 24 weeks
Evaluate the effects of saxagliptin and 
sitagliptin 
on 
changes 
from 
baseline 
glycosylated hemoglobin (HbA1c) compared to 
placebo at 12 and 24 weeks

Change from baseline in HbA1c at 12 and 24 
weeks
Collect and analyze blood and urine samples for 
changes from baseline in 
 
at 6, 12, and 24 weeks.  
Samples will also be collected for additional 
biomarkers that may be analyzed at the 
Sponsor’s discretion.

Change from baseline of blood and urine 
biomarker values at 6, 12, and 24 weeks
Collect sparse pharmacokinetic (PK) samples 
for analysis of plasma concentrations of 
saxagliptin and its major metabolite, 5-hydroxy 
saxagliptin 
and 
sitagliptin 
for 
PK/pharmacodynamic (PD) modelling at 6, 12, 
and 24 weeks in a subset of at least 150 patients

Plasma concentration in PK samples
-
Saxagliptin and its major metabolite, 
5-hydroxy saxagliptin 
-
Sitagliptin
Target subject population
The target population includes male and female patients aged 18 years and older with 
documented type 2 diabetes mellitus and with a prior diagnosis of heart failure. Approximately 
330 patients with documented LVEF ≤45% and NT-proBNP >300 pg/mL will be randomized 
in equal proportions (110 patients per group) to treatment with saxagliptin, sitagliptin or 
placebo.  
Patients must have an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at 
screening to qualify for enrollment. The proportion of randomized patients with an eGFR of 
≥30 and <50 mL/min/1.73 m2 will be limited to 30% and randomization will be stratified to 
randomize a maximum of 99 patients (maximum 33 for each treatment group).  Patients whose 
CCI


Clinical Study Protocol Synopsis
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
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eGFR falls below 30 mL/min/1.73 m2 must be permanently discontinued from the study after 
an initial result is confirmed on repeat testing.
Patients must have a diagnosis of Type 2 DM based on current ADA guidelines.   
Duration of treatment
In this study, sites will perform a pre-screening assessment prior to the enrollment visit to 
determine if patients meet eGFR inclusion criteria.  All potentially eligible patients will be 
enrolled for screening, provide Informed Consent, and undergo screening for all applicable 
inclusion/exclusion criteria. Patients can enter screening as soon as laboratory results for eGFR 
are available, provided the patient meets the inclusion/exclusion criteria. The total duration of 
the pre-screening and screening periods should not exceed 28 days.
Patients with a recent (within 1 month) laboratory results for eGFR that meet the protocol 
mandated criteria can enter the screening period directly without pre-screening procedures 
needing to be performed.
Patients who do not qualify for the protocol based upon their pre-screening or screening results 
may have additional attempts to qualify. There may be no more than 3 attempts in total. If the 
patient failed to qualify during screening period (including, but not limited due to study supplies, 
equipment failure, unforeseen personal events that mandate missed screening visits, or out-of-
range laboratory/clinical tests), the patient may potentially be re-screened. These cases should 
be discussed with the AstraZeneca Monitor and documented in the Investigator Study File (ISF). 
The Investigator may use his/her judgment regarding the interval between screening periods. 
The Investigator must track all attempts in the form of a log at the site. Screening will be 
followed by a 24-week randomized treatment period. Patients who complete the treatment 
period will be asked to return for an end-of-study visit at Week 28.
Investigational product, dosage and mode of administration
For patients randomized to treatment with saxagliptin, saxagliptin 5mg tablets and sitaglipitin 
placebo capsules will be administered orally once daily for a 24-week treatment period for 
patients with an eGFR ≥50 mL/min/1.73 m2.  For patients with an eGFR <50 mL/min/1.73 m2, 
the dose of saxagliptin will be adjusted to 2.5 mg.
For patients randomized to treatment with sitagliptin, sitagliptin 100 mg capsules and 
saxagliptin placebo tablets will be administered orally once daily for a 24-week treatment period 
for patients with an eGFR ≥50 mL/min/1.73 m2.  For patients with an eGFR <50 mL/min/1.73 
m2, the dose of sitagliptin will be adjusted to 50 mg. 
Saxagliptin placebo tablets and sitagliptin placebo capsules will be administered orally once 
daily for a 24-week treatment period for patients randomized to receive placebo.
Statistical methods
To demonstrate non-inferiority of saxagliptin compared to placebo for the change from baseline 
to Week 24 in LVEDV index with an assumed non-inferiority margin of 6.5 mL/m2 , (This is 


Clinical Study Protocol Synopsis
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
11 (85)
an estimate of the NI margin from publication [Foster et al]) and assuming a standard deviation 
(SD) of 15 mL/m2, and at a 1-sided significance level of 0.025, approximately 88 patients will 
be needed in each treatment group to provide approximately 80% power (given a true difference 
of zero between saxagliptin and placebo). Assuming that 20% of patients have a missing
endpoint assessment, a total of approximately 330 patients (110 patients in each of the 3 
treatment groups) must be randomized in a 1:1:1 ratio to saxagliptin, sitagliptin, and placebo.  
Note, that the actual NI margin for the study will be calculated as 10% of the overall baseline 
mean LVEDV index across all treatment groups.  Non-inferiority will be demonstrated if the 
upper bound of the 95% confidence interval for the difference in treatments (saxagliptin minus 
placebo) is less than the NI margin.
Randomization will be stratified by eGFR status and SGLT-2 inhibitor use, based on potential 
impact on the primary endpoint. 
For purely administrative reasons, the randomization will also be stratified by regional drug 
distribution center to improve the efficiency of drug allocation.
LVEDV index and other continuous variables collected at only one visit during randomization 
treatment period (LVESV index, LVEF, and LVM by MRI, etc.) will be analyzed using analysis 
of covariance (ANCOVA) for the change from baseline at Week 24, with terms for treatment 
group, eGFR category (<50, ≥50 mL/min/1.73 m2), SGLT-2 inhibitor use, region, and baseline 
value as covariates 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.
NT-proBNP and other continuous variables collected at more than one visit during randomized 
treatment period (biomarkers, HbA1c, body weight, percent change of plasma volume by 
Strauss formula, blood pressure, etc.) will be analyzed using a mixed-model repeated-measures 
(MMRM) approach with terms for treatment group, eGFR category (<50, ≥50 mL/min/1.73 
m2), SGLT-2 inhibitor use, region, 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.  Biomarkers or data with extremely skewed distribution may be log transformed prior 
to ANCOVA or MMRM analysis.
Plasma concentrations of saxagliptin, 5-hydroxy saxagliptin and sitagliptin will be used to 
develop exploratory PK/PD models, which may be reported separately from the clinical study 
report.
The efficacy analyses will be performed based on the full analysis set (FAS). No multiplicity 
control will be applied for the statistical comparisons.
Safety analyses for the double-blind treatment period will be performed using the safety analysis 
set, including data after the addition of glycemic concomitant medication or change of heart 
failure concomitant medication.  Safety analyses will include, where appropriate, descriptive 


Clinical Study Protocol Synopsis
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
12 (85)
statistics, counts, and percentages for AEs and other safety measures.  No formal statistical tests 
will be performed for safety endpoints.


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
13 (85)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
VERSION HISTORY..........................................................................................................2
PROTOCOL SYNOPSIS.....................................................................................................7
TABLE OF CONTENTS................................................................................................... 13
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................................... 19
1
INTRODUCTION ............................................................................................. 21
1.1
Background and rationale for conducting this study ........................................... 21
1.1.1
Rationale for the study design, doses, treatment and control groups.................... 23
1.2
Benefit/risk and ethical assessment .................................................................... 24
1.3
Study Design...................................................................................................... 24
2
STUDY OBJECTIVES...................................................................................... 28
2.1
Primary objective............................................................................................... 28
2.2
Secondary objectives.......................................................................................... 28
2.3
Safety objectives................................................................................................ 28
2.4
Exploratory objectives ....................................................................................... 29
3
PATIENT SELECTION, PRE-SCREENING, ENROLLMENT, 
RANDOMIZATION, RESTRICTIONS, DISCONTINUATION AND 
WITHDRAWAL ............................................................................................... 29
3.1
Inclusion criteria ................................................................................................ 29
3.2
Exclusion criteria ............................................................................................... 31
3.3
Patient pre-screening, enrollment and randomization.......................................... 33
3.4
Procedures for handling incorrectly enrolled or randomized patients.................. 34
3.5
Methods for assigning treatment groups............................................................. 34
3.6
Methods for ensuring blinding ........................................................................... 35
3.7
Methods for unblinding...................................................................................... 35
3.8
Restrictions........................................................................................................ 36
3.9
Discontinuation of investigational product ......................................................... 37
3.9.1
Procedures for discontinuation of a patient from investigational product ............ 38
3.10
Criteria for withdrawal....................................................................................... 38
3.10.1
Screen failures ................................................................................................... 38


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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3.10.2
Withdrawal of the informed consent................................................................... 38
3.11
Discontinuation of the study............................................................................... 39
4
STUDY PLAN AND TIMING OF PROCEDURES........................................... 39
4.1
Pre-screening/Enrollment/screening period ........................................................ 47
4.1.1
Pre-screening Informed Consent Form & Informed Consent Form (ICF)............ 47
4.1.2
Demography ...................................................................................................... 47
4.1.3
Medical/surgical history..................................................................................... 47
4.1.4
Prior/concomitant treatments.............................................................................. 48
4.1.5
Inclusion/Exclusion criteria................................................................................ 48
4.1.6
Estimated glomerular filtration rate (eGFR) ....................................................... 48
4.1.7
Clinical laboratory test ....................................................................................... 49
4.1.8
Electrocardiogram (ECG)................................................................................... 49
4.1.9
Pregnancy test.................................................................................................... 49
4.1.9.1
Urine pregnancy tests......................................................................................... 49
4.1.9.2
Serum pregnancy test......................................................................................... 49
4.2
Treatment period................................................................................................ 49
4.2.1
Scheduled telephone contacts............................................................................. 50
4.2.2
Fasting plasma glucose (FPG)............................................................................ 50
4.3
End of Study Visit.............................................................................................. 50
5
STUDY ASSESSMENTS.................................................................................. 50
5.1
Efficacy assessments.......................................................................................... 50
5.1.1
Primary Efficacy Variable.................................................................................. 50
5.1.1.1
Magnetic Resonance Imaging (MRI).................................................................. 50
5.1.2
Secondary Efficacy Variable.............................................................................. 51
5.1.2.1
N-terminal prohormone of brain natriuretic peptide (NT-proBNP)..................... 51
5.1.3
Exploratory Efficacy Variable............................................................................ 51
5.1.3.1
HbA1c ............................................................................................................... 51
5.1.3.2
Body weight....................................................................................................... 52
5.1.3.3
......................................................... 52
5.2
Safety assessment............................................................................................... 52
5.2.1
Laboratory safety assessments............................................................................ 52
5.2.1.1
Volume of blood................................................................................................ 53
5.2.2
Physical examination ......................................................................................... 54
5.2.2.1
Complete physical examination.......................................................................... 54
5.2.2.2
Brief physical examination................................................................................. 54
5.2.3
Vital signs.......................................................................................................... 54
5.2.4
Other safety assessments.................................................................................... 54
5.2.4.1
CV Events Adjudication Committee................................................................... 54
5.3
Pharmacokinetics ............................................................................................... 55
5.3.1
Collection of samples......................................................................................... 55
5.3.2
Determination of drug concentration.................................................................. 55
5.3.3
Storage and destruction of pharmacokinetic samples.......................................... 55
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Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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5.4
Pharmacodynamics – Not applicable.................................................................. 56
5.5
Pharmacogenetics – Not applicable.................................................................... 56
5.6
Biomarker analysis............................................................................................. 56
5.6.1
Storage, re-use and destruction of biological samples......................................... 56
5.6.2
Labelling and shipment of biological samples .................................................... 56
5.6.3
Chain of custody of biological samples .............................................................. 56
5.6.4
Withdrawal of Informed Consent for donated biological samples....................... 57
6
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 57
6.1
Definition of adverse events............................................................................... 57
6.1.1
AEs of special interest........................................................................................ 58
6.2
Definitions of serious adverse event ................................................................... 58
6.3
Recording of adverse events............................................................................... 58
6.3.1
Time period for collection of adverse events ...................................................... 58
6.3.2
Follow-up of unresolved adverse events............................................................. 59
6.3.3
Variables............................................................................................................ 59
6.3.4
Causality collection............................................................................................ 60
6.3.5
Adverse events based on signs and symptoms .................................................... 60
6.3.6
Adverse events based on examinations and tests ................................................ 60
6.4
Reporting of serious adverse events ................................................................... 61
6.5
Overdose............................................................................................................ 61
6.6
Pregnancy .......................................................................................................... 62
6.6.1
Maternal exposure.............................................................................................. 62
6.6.2
Paternal exposure............................................................................................... 63
6.7
Management of IP related toxicities – Not applicable......................................... 63
6.8
Study governance and oversight......................................................................... 63
6.8.1
Executive Committee......................................................................................... 63
6.8.2
Safety Monitoring Committee (SMC) ................................................................ 63
7
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 64
7.1
Identity of investigational product(s).................................................................. 64
7.2
Dose and treatment regimens ............................................................................. 64
7.3
Labelling............................................................................................................ 65
7.4
Storage............................................................................................................... 65
7.5
Compliance........................................................................................................ 65
7.6
Accountability.................................................................................................... 66
7.7
Concomitant and other treatments ...................................................................... 66
7.7.1
Concomitant treatment....................................................................................... 66
7.7.2
Rescue medication ............................................................................................. 66


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
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7.7.2.1
Glycemic rescue medication............................................................................... 67
7.7.3
Prohibited medications....................................................................................... 67
8
STATISTICAL ANALYSES BY ASTRAZENECA.......................................... 68
8.1
Statistical considerations .................................................................................... 68
8.2
Sample size estimate .......................................................................................... 68
8.3
Definitions of analysis sets................................................................................. 69
8.3.1
Efficacy analysis sets ......................................................................................... 69
8.3.2
Safety analysis set.............................................................................................. 69
8.3.3
PK analysis set................................................................................................... 70
8.4
Outcome measures for analyses.......................................................................... 70
8.4.1
Primary efficacy variable ................................................................................... 70
8.4.2
Secondary efficacy variables.............................................................................. 70
8.4.3
Safety variables.................................................................................................. 70
8.4.4
Exploratory variables ......................................................................................... 70
8.5
Methods for statistical analyses.......................................................................... 71
8.5.1
Analysis of the primary variable (s).................................................................... 71
8.5.2
Analysis of the secondary variable(s) ................................................................. 72
8.5.3
Exploratory analyses.......................................................................................... 72
8.5.4
Subgroup analysis.............................................................................................. 72
8.5.5
Interim analysis – Not applicable ....................................................................... 73
8.5.6
Sensitivity analysis............................................................................................. 73
8.5.7
Safety analysis ................................................................................................... 73
9
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 74
9.1
Training of study site personnel ......................................................................... 74
9.2
Monitoring of the study...................................................................................... 74
9.2.1
Source data ........................................................................................................ 74
9.2.2
Study agreements............................................................................................... 75
9.2.3
Archiving of study documents............................................................................ 75
9.3
Study timetable and end of study........................................................................ 75
9.4
Data management by AstraZeneca ..................................................................... 75
10
ETHICAL AND REGULATORY REQUIREMENTS....................................... 76
10.1
Ethical conduct of the study ............................................................................... 76
10.2
Patient data protection........................................................................................ 76
10.3
Ethics and regulatory review .............................................................................. 76
10.4
Informed consent ............................................................................................... 77
10.4.1
Pre-screening Informed Consent ........................................................................ 77
10.5
Changes to the protocol and informed consent form........................................... 78
10.6
Audits and inspections ....................................................................................... 78


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Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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11
LIST OF REFERENCES ................................................................................... 78
LIST OF TABLES
Table 1
Recruitment information .......................................................................26
Table 2
Study plan.............................................................................................40
Table 3
Laboratory Safety Variables..................................................................53
Table 4
Blood sample volume............................................................................53
Table 5
Identity of investigational product.........................................................64
Table 6
Lack of Glycemic Control Criteria for Initiation of Open-Label 
Rescue Medication................................................................................67
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................27
LIST OF APPENDICES
Appendix A
Additional Safety Information...............................................................81
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document..............................................................................83
Appendix C
Criteria for Diagnosis of Diabetes Mellitus............................................84
Appendix D
New York Heart Association (NYHA) Classification............................85


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Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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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
ACE inhibitor
AE
Angiotensin converting enzyme inhibitor
Adverse event
ALT
AF
Alanine transaminase
Atrial fibrillation/flutter
ANCOVA
Analysis of covariance
ARB
Angiotensin receptor blocking
AST
Aspartate transaminase
eCRF
electronic Case Report Form
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Event
CV
Cardiovascular
CVD
Cardiovascular disease
DAE
Discontinuation of Investigational Product due to Adverse Event
DCCT
Diabetes Control and Complications Trial
DILI
Drug-induced liver injury 
DNA
Deoxyribonucleic acid 
DPP4
Dipeptidyl peptidase-4
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
eGFR
ETD
Estimated glomerular filtration rate
Early Treatment Discontinuation
FA
Full analysis
FDA
Food and Drug Administration
FPG
Fasting plasma glucose
GCP
Good Clinical Practice
GLP-1
Glucagon-like peptide-1
HF
Heart failure


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Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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Abbreviation or 
special term
Explanation
HFrEF
Heart Failure with reduced Ejection Fraction
hHF
hospitalization for heart failure
HbA1c
glycosylated hemoglobin
hs-CRP
high-sensitivity C-reactive protein
HR
Hazard Ratio
ICH
International Conference on Harmonisation
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally. 
IP
Investigational Product 
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LSLV
Last Subject Last Visit
LVEF
Left Ventricular Ejection Fraction
LVEDV
Left Ventricular End Diastolic Volume
LVESV
Left Ventricular End Systolic Volume
LVM
Left ventricular mass
MACE
Major adverse cardiovascular event
MRA
Mineralocorticoid receptor antagonist
MMRM
Mixed-model repeated-measures  
MRI
Magnetic Resonance Imaging
NGSP
National Glycohemoglobin Standardization Program
NT-proBNP
N-terminal prohormone of brain natriuretic peptide
NYHA
New York Heart Association
OAE
Other Significant Adverse Event
OGTT
Oral glucose tolerance test
PD
Pharmacodynamic
PI
Principal Investigator 
PK
Pharmacokinetic
PP
Per protocol
PV
Plasma volume
CCI


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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Abbreviation or 
special term
Explanation
RCV
Red blood cell volume
SAE
Serious adverse event 
Scr
Serum creatinine
SD
Standard deviation 
SGLT-2
Sodium-glucose cotransporter 2
SMC
Safety Monitoring Committee
SU
Sulfonylurea
TECOS
Trial Evaluating Cardiovascular Outcomes with Sitagliptin
T2DM
Type 2 diabetes mellitus
TZD
Thiazolidinedione
TB
Total Bilirubin
VIVIDD
Vildagliptin in Ventricular Dysfunction Diabetes
WBDC
Web Based Data Capture
WHO
World Health Organization
1
INTRODUCTION
1.1
Background and rationale for conducting this study
Type 2 Diabetes mellitus (T2DM) is a chronic progressive disease, characterized by
hyperglycemia and an increased risk of microvascular and macrovascular complications.  CV 
disease is by far the greatest cause of death in individuals with diabetes (Skyler et al 2009).  
Diabetes is also a significant and often underappreciated risk factor for the development of 
heart failure.  Diabetics are 2.5-fold more likely to develop HF than patients without diabetes, 
(Nichols et al 2004).  The pathogenesis of heart failure among patients with diabetes is 
multifactorial with coronary artery disease, hypertension, diabetic cardiomyopathy, and 
extracellular fluid expansion playing major contributory roles (Foster et al 1998, Gilbert and 
Krum 2015).  
Therapeutic options for treatment of T2DM in patients with heart failure are more limited, as 
there is uncertainty about the safety of many diabetes therapies in these patients.  There is a 
need for carefully performed studies to characterize the safety of newer therapies in patients 
with known HF.   
Saxagliptin
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Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
22 (85)
Saxagliptin is a highly potent, selective, reversible, and competitive dipeptidyl peptidase-4 
(DPP4) inhibitor.  DPP4 is the enzyme responsible for the inactivation of glucagon-like 
peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP).  By inhibiting the enzyme DPP4, 
saxagliptin potentiates active endogenous GLP-1 concentrations, augmenting the 
physiological mechanism of insulin secretion and decreasing glucagon release, thereby 
reducing postprandial and fasting glucose levels in patients with T2DM.  The clinical 
development program for saxagliptin supports its efficacy in a wide range of patients with 
T2DM, as monotherapy, as add-on therapy (to metformin, a sulfonylurea, a thiazolidinedione 
(TZD), or insulin), and as initial therapy in combination with metformin.  Saxagliptin has a 
well-established safety profile, with a low risk of hypoglycemia and weight neutrality 
(Hirshberg et al 2014). Details on the efficacy and safety of saxagliptin can be found in the 
ONGLYZA™ prescribing information and Investigator Brochure.  
Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes 
Mellitus (the SAVOR study) 
SAVOR was designed to investigate the cardiovascular safety of saxagliptin.  It was a 
multicenter, randomized, double-blind, placebo-controlled study in 16492 patients with type 2 
diabetes who had a history of, or were at risk for, cardiovascular events that followed patients 
for a median of 2.1 years. SAVOR enrolled 2105 patients (12.8%) with a prior history of 
heart failure; 2576 (15.6%) had impaired renal function (eGFR ≤50 mL/min). The SAVOR 
study met its primary safety objective by demonstrating saxagliptin was non-inferior to 
placebo for the primary composite MACE endpoint of CV death, non-fatal MI, or non-fatal 
ischemic stroke; hazard ratio (HR) 1.00 (95% CI 0.89, 1.12).  However, superiority of 
saxagliptin versus placebo on the composite MACE endpoint was not demonstrated 
(p=0.986).  For the secondary composite endpoint of non-fatal MI, non-fatal stroke, CV death, 
hospitalization for heart failure (hHF), hospitalization for unstable angina, or hospitalization 
for coronary revascularization, no statistically significant treatment differences were observed 
between saxagliptin and placebo (HR 1.02 [95% CI 0.94, 1.11]; nominal p=0.662 for a 
difference between the 2 treatment groups).  However, for the hHF component of the 
secondary composite endpoint, more events were observed with saxagliptin treatment 
compared with placebo (3.5% [289/8280 patients] versus 2.8% [228/8212 patients]; HR 1.27; 
95% CI 1.07, 1.51; nominal p=0.007).  There is no definitive mechanism to explain the hHF 
findings in SAVOR.  No signal for heart failure was observed in preclinical studies, other 
studies in the clinical development program, or in post-marketing surveillance.  
No heart failure signal was observed in TECOS (Trial to Evaluate Cardiovascular Outcomes 
after Treatment with Sitagliptin).  TECOS was a multicenter, randomized, double-blind, 
placebo-controlled study in 14671 patients with type with T2DM and established CV disease.  
Sitagliptin was non-inferior to placebo for the primary composite outcome of CV death, 
nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina (HR 
0.98 [95% CI 0.88 to 1.09]; p=0.99 for superiority; p<0.001 for non-inferiority).  Rates of 
hHF did not differ between the 2 groups (HR 1.00 [95% CI 0.83 to 1.20]; p=0.98, Green et al 
2015).  Reasons for the lack of a heart failure signal in TECOS, compared with SAVOR, may 
relate to differences in patient populations, the type of background care provided, the 


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Drug Substance saxagliptin
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Edition Number 5.0
Date 14 February 2020
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capturing and adjudication of hHF events, differences among DPP4 inhibitors, or play of 
chance.   
1.1.1
Rationale for the study design, doses, treatment and control groups
Because no mechanism for the increase in hHF observed in SAVOR has been identified, the 
current study is planned to investigate whether treatment with saxagliptin might affect cardiac 
dimensions, cardiac function, changes in plasma volume, and relevant blood and urine 
biomarkers.
This is a 24-week, randomized, double-blind, parallel-group, placebo-controlled, multicenter 
study.  Approximately 330 patients with T2DM and HF will be randomized in equal 
proportions (110 patients per group) to treatment with saxagliptin, sitagliptin, or placebo.  The 
study’s primary objective is to exclude a meaningful increase in left ventricular end diastolic 
(LVEDV) index of greater than 10% for saxagliptin compared with placebo using magnetic 
resonance imaging (MRI).  The rationale for choosing this endpoint is based on the findings of 
the Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) study.  VIVIDD was an 
echocardiographic study performed in patients with HF and LVEF <40%.  The study met its 
primary endpoint of non-inferiority between vildagliptin versus placebo for a change in LVEF 
over 52 weeks, but unexpectedly found that treatment with vildagliptin was associated with a 
significant increase in LVEDV and a trend towards an increase in left ventricular end systolic 
volume (LVESV, McMurray et al 2013).  For the present study, LVEDV index will be the 
primary endpoint and cardiac MRI, rather than echocardiography, has been chosen for the 
assessment of the primary endpoint because of its high accuracy and reproducibility (Grothues 
et al 2002). 
Events of hHF occurred at a consistent rate throughout the SAVOR study.  However, most of 
the difference in the rate of events between saxagliptin and placebo accrued in the first 6 to 
9 months of treatment, with little increase in this difference afterward.  The MRI primary 
endpoint analysis will be conducted at 24 weeks (by which time over three-fourths of the hHF 
events in SAVOR had occurred) to also investigate the potential for remodelling changes to 
occur.  
In addition to the saxagliptin and placebo arms, there is another active antidiabetic treatment 
arm sitagliptin.  Sitagliptin has been chosen as a reference DPP4 inhibitor that has not been 
associated with an increase in hHF in TECOS. 
Sitagliptin
Sitagliptin is an orally active DPP4 inhibitor that is marketed as JANUVIA™ (Merck & Co) 
for use as an adjunct to diet and exercise to improve glycemic control in adults with T2DM.  
Details on the efficacy and safety of sitagliptin can be found in the JANUVIA™ prescribing 
information.


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Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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1.2
Benefit/risk and ethical assessment
As stated in Section 1.1, an excess in heart failure hospitalizations was observed in the 
SAVOR trial.  However, a mechanism to explain these findings has yet to be identified and an 
increase in hospitalization for heart failure was not observed in the TECOS study with 
sitagliptin.  Saxagliptin and sitagliptin are effective anti-diabetic agents that have been 
extensively studied in clinical trials, are approved worldwide, and have substantial 
postmarketing experience with well-established safety profiles.  For information on 
saxagliptin, please consult the respective Investigator Brochure; for sitagliptin, please refer to 
its Product Label.
Benefits related to participation in this trial include close follow-up of a patient’s diabetes and 
treatment with anti-diabetes agents that are both efficacious and well tolerated.   While one of 
the three possible treatments is placebo, patients will continue to be treated with their current 
anti-glycemic regiments as background therapy.  Furthermore, appropriate rescue therapy for 
worsening glycemic control should be implemented if required, as recommended in Section 
7.7.2.1.  
Although the findings from SAVOR suggest that saxagliptin therapy could potentially result 
in an increased risk for hospitalization for heart failure, patients in this study will be closely 
monitored for signs and symptoms of worsening heart failure with frequent study visits.  In 
SAVOR, therapy with saxagliptin was not associated with an increase in CV death, 
myocardial infarction, or stroke, even among patients with baseline risk factors for hHF.  As 
previously discussed, sitagliptin has not been associated with an increase in hHF.
Further, study data on cardiac function, biomarkers, and plasma volume may result in 
improved patient management, on both an individual and population basis.
1.3
Study Design 
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled study to 
investigate the effects of saxagliptin on cardiac dimensions and function, in patients with 
T2DM and HF with abnormal systolic function from both ischemic and non-ischemic causes. 
Approximately 330 patients with documented LVEF ≤45% and NT-proBNP >300 pg/mL will 
be randomized in equal proportions (110 patients per group) to treatment with saxagliptin, 
sitagliptin, or placebo. The calculated sample size is expected to yield approximately 
88 patients per group with complete data (ie, patients with a nonmissing primary endpoint 
assessment). In this study, sites will perform a pre-study screening assessment prior to 
enrollment visit to screen for eGFR criteria. Patients must have an estimated glomerular 
filtration rate (eGFR) ≥30 mL/min/1.73 m2 at pre-screening to qualify for enrollment. 
Following Informed Consent, all potentially eligible patients will be enrolled and undergo 
screening for all applicable inclusion/exclusion criteria. The pre-screening value of eGFR can 
be used to qualify a patient for randomization. 


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Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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Patients can enter screening as soon as laboratory pre-screening results for eGFR are available 
provided the patient meets the inclusion/exclusion criteria.  The total duration of the pre-
screening and screening periods should not exceed 28 days. 
Patients with a recent (within 1 month) eGFR value will be allowed to enter the screening 
directly without pre-screening procedures performed.
Patients who do not qualify for the protocol based upon their pre-screening or screening 
results may have additional attempts to qualify. There may be no more than 3 attempts in 
total. If the patient failed to qualify during screening period (including, but not limited due to 
study supplies, equipment failure, unforeseen personal events that mandate missed screening 
visits, or out-of-range laboratory/clinical tests), the patient may potentially be re-screened. 
These cases should be discussed with the AstraZeneca Monitor and documented in the 
Investigator Study File (ISF). The investigator may use his/her judgment regarding the 
interval between screening periods. The Investigator must track all attempts in the form of a 
log at the site. Re-screened patients should re-sign informed consent on the re-screening 
visit. All procedures from screening period should be repeated.
The study will comprise a pre-screening period (optional – see section 3.3) and screening 
period that in total should not exceed 28 days, a 24-week randomized treatment period and a 
4-week follow up period.  After randomization, patients will visit the study site for study 
assessments at Weeks 2, 6, 12, 18, and 24.  Follow-up telephone calls will be conducted at 
Day 7, Week 3, and Week 9.  Patients who complete the treatment period will be asked to 
return for an end-of- study visit at Week 28.  The schedule of study assessments is shown in 
Table 2.
Study treatment will be administered once daily, according to randomized treatment 
allocation.  For patients with an eGFR ≥50 mL/min/1.73 m2, the doses of the active treatments 
are as follows: saxagliptin 5 mg and sitagliptin 100 mg.  For patients with an eGFR <50 
mL/min/1.73 m2, the doses of the active treatments will be adjusted as follows: saxagliptin 2.5 
mg and sitagliptin 50 mg.  
MRI to evaluate cardiac dimensions, and function will be performed at baseline (<= 7 days 
prior to randomization), and at Week 24 (<= 7 days prior to Week 24) for all study patients.  
The Week 24 MRI will provide the primary endpoint data.  The MRI evaluations will be 
performed according to a standard protocol and will be centrally read by a core laboratory.  
Changes in plasma volume will be measured using the Strauss formula, as has been utilized in 
the EPHESUS study (Kalra et al 2002; Strauss et al 1951; Rossignol PR et al 2011).
During the study, patients will continue to receive their usual, stable treatment regimens for 
diabetes and HF as prescribed by their physicians.  Medications for diabetes and HF, 
including diuretic dose, should continue unchanged, unless there is a change in the patient’s 
clinical status.  Changes in diabetes and HF medications, including dose, must be recorded in 
the electronic case report form (eCRF).  In cases where doses of medications, including 
diuretics, require adjustment, patients should be encouraged to remain in the trial and 


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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complete all regularly scheduled study assessments. If a patient discontinues early from the 
study, he or she should be asked, at the discretion of the treating physician, to return to the 
study site as soon as possible but no later than 7 days from the last IP dose. All endpoint 
(Week 24/ETD) assessments, including cardiac MRI, and blood and urine biomarker 
assessments, must be performed at this visit. The patient should also be asked to return 4 
weeks later for end of study (Week 28) assessments. If the patient is unable or unwilling to 
return, a phone follow-up should be conducted.
Table 1
Recruitment information
Category
Number of patients 
Expected number of screened patients
660
Expected number of randomized patients
330
Expected number of complete primary 
endpoint data
264
Expected screen failures including pre-
screened patients (%)
50
Expected non-evaluable rate of incomplete 
primary endpoint data (%)
20


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Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
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Figure 1
Study flow chart


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
28 (85)
2
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To exclude an increase in LVEDV index of 
greater than 10% of the overall baseline value 
(non-inferiority margin) in patients with 
T2DM and HF treated with saxagliptin for 24 
weeks, compared to placebo

Change from baseline in LVEDV index 
measured by MRI at 24 weeks
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :
Evaluate the effects of saxagliptin compared to 
placebo on LVESV index, LVEF, and LVM 
after 24 weeks in patients with T2DM and HF

Change from baseline in LVESV, index, 
LVEF, and LVM measured by MRI at 24 
weeks
Evaluate the effects of saxagliptin compared to 
placebo on NT-proBNP after 24 weeks of 
treatment

Change from baseline in NT-proBNP after 24 
weeks of treatment
2.3
Safety objectives
Safety Objective:
Outcome Measure:
To assess the safety and tolerability of 
saxagliptin and sitagliptin treatment in 
patients with T2DM and HF

Incidence of adverse events (AEs), serious 
adverse events (SAEs), AEs of special 
interest 

Collection of clinical chemistry/hematology 
parameters 

Vital signs 

Physical examination

Incidence of independently adjudicated 
Cardiovascular (CV) events [death, 
myocardial infarction (MI), stroke, and 
hospitalization for heart failure (hHF)]


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Edition Number 5.0
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2.4
Exploratory objectives  
Exploratory Objective:
Outcome Measure:
Evaluate the effects of sitagliptin compared to 
placebo on LVEDV index, LVESV index, 
LVEF, and LVM after 24 weeks of treatment 
in patients with T2DM and HF

Change from baseline in LVEDV index, 
LVESV index, LVEF, and LVM measured 
by MRI at 24 weeks
Evaluate the effects of saxagliptin at Weeks 6 
and 12 and sitagliptin at 6, 12, and 24 weeks, 
compared to placebo on NT-proBNP

Change from baseline in NT-proBNP after 6, 
12, and 24 weeks 
Evaluate the effects of saxagliptin and 
sitagliptin, on plasma volume at 6, 12, and 24 
weeks

Percent change from baseline in plasma 
volume using the Strauss formula after 6, 12, 
and 24 weeks
Evaluate the effects of saxagliptin and 
sitagliptin on changes from baseline body 
weight compared to placebo at 12 and 24 
weeks

Change from baseline in body weight at 12 
and 24 weeks
Evaluate the effects of saxagliptin and 
sitagliptin on changes from baseline HbA1c 
compared to placebo at 12 and 24 weeks

Change from baseline in HbA1c at 12 and 24 
weeks
Collect and analyze blood and urine samples 
for changes from baseline in 
 
 at 6, 12, 
and 24 weeks.  Samples will be collected for 
additional biomarkers that may be analyzed at 
the Sponsor’s discretion

Change from baseline of blood and urine 
biomarker values at 6, 12, and 24 weeks
Collect PK samples for analysis of plasma 
concentrations of saxagliptin and its major 
metabolite, 5-hydroxy saxagliptin; , and 
sitagliptin for PK/pharmacodynamic (PD) 
modelling at 6, 12, and 24 weeks in a subset of 
at least 150 patients 

Plasma concentration in PK samples
- Saxagliptin and its major metabolite, 5-
hydroxy saxagliptin 
- Sitagliptin
3
PATIENT SELECTION, PRE-SCREENING, ENROLLMENT, 
RANDOMIZATION, 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.
Provision of informed consent prior to any study specific procedure (Pre-screening 
ICF and Informed Consent collected at screening)
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Edition Number 5.0
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2.
Male or female, aged ≥18 years at the time of consent
3.
Documented, controlled T2DM, as defined by:

Diagnosis of Type 2 DM based on current ADA guidelines (Appendix C)  
Treatment with stable doses of antidiabetic medications that have not increased 
or decreased for ≥8 weeks before screening

For patients taking insulin, the investigator must query the patient at pre-
screening or screening regarding his/her usual total daily insulin dose (all types 
combined) during the previous 8 weeks. Insulin dosages during pre-screening 
and screening should not vary by more than ±20% on more than two occasions

Dosage reductions of insulin and sulfonylurea agents may be considered at 
randomization to minimize the possibility of hypoglycemia

Any reductions in the dosage of insulin and sulfonylurea agents will be at 
the discretion of the investigator

For patients treated with insulin, consider a reduction in dose of 20% at 
randomization

For patients receiving sulfonylurea agents, consider a reduction in dose of 
50% or discontinue if on a dosage that is considered low at randomization 
4.
HFrEF demonstrated by all 3 of the following criteria:

History of HF and LVEF ≤45% within the last 6 months (echocardiogram, 
MRI, left ventriculography, or other accepted methodology). Patients without a 
recent assessment of LV function will undergo a local echocardiogram at the 
time of screening to determine ejection fraction  

Elevated NT-proBNP (>300 pg/mL) during screening 

Patients should receive background standard of care for HFrEF and be treated 
according to locally recognized guidelines as appropriate. Guideline-
recommended medications should be used at recommended doses unless 
contraindicated or not tolerated. Therapy should have been individually 
optimized and stable for >or = 4 weeks (this does not apply to diuretics-see NB 
below) before screening visit and include (unless contraindicated or not 
tolerated):

an ACE inhibitor, or ARB, or sacubitril/valsartan

and


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
a beta-blocker

and 

if considered appropriate by the patient’s treating physician; a 
mineralocorticoid receptor antagonist (MRA)

NB: Most patients with heart failure require treatment with a diuretic to control 
sodium and water retention leading to volume overload. It is recognized that 
diuretic dosing may be titrated to symptoms, signs, weight, and other 
information and may thus vary. Each patient should, however, be treated with a 
diuretic regimen aimed at achieving optimal fluid/volume status for that 
individual
5.
Stable HF, with no evidence of volume overload (no rales, jugular venous 
distention, peripheral edema) at screening
6.
Women of childbearing potential (WOCBP):

Must be using appropriate birth control to avoid pregnancy throughout the 
study and for up to 4 weeks after the last dose of investigational product

Must have a negative serum or urine pregnancy test within 72 hours prior to the 
start of investigational product

Must not be breastfeeding
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
MRI contraindications: all implanted defibrillators; implanted pacemakers and other 
devices/implants that in the judgment of the investigator preclude an MRI 
evaluation
2.
Patients with atrial fibrillation/flutter, or any rhythm that would impact on MRI 
imaging quality would be excluded. Patients with a prior history of atrial fibrillation 
or paroxysmal atrial fibrillation may be eligible for entry into the study based on the 
investigator’s judgment related to the frequency of AF events and the patient’s 
overall condition
3.
Body mass index >45 kg/m2 or any condition, including, but not limited to known 
claustrophobia, that may preclude the ability to perform an MRI scan of acceptable 
quality, or unwillingness to undergo MRI imaging
4.
Receiving incretin therapy (DPP4 inhibitors, GLP-1 mimetics), or having received 
incretin therapy within the previous 8 weeks of randomization


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
32 (85)
5.
Receiving therapy with a TZD or having received TZD therapy within the previous 
8 weeks of randomization
6.
Type 1 diabetes mellitus
7.
History of unstable or rapidly progressing renal disease 
8.
A central lab eGFR value <30 mL/min/1.73 m2 on pre-screening or screening
9.
New York Heart Association (NYHA) Class IV HF
10.
Myocardial infarction, stroke, transient ischemic attack, or coronary 
revascularization (percutaneous coronary intervention [PCI] or coronary artery 
bypass graft [CABG]) within the past 3 months of screening
11.
Inoperable aortic or mitral valvular heart disease.  Recent (within 3 months) or 
planned valvular heart procedure
12.
Heart failure secondary to restrictive cardiomyopathy, active myocarditis, 
constrictive pericarditis, and hypertrophic obstructive cardiomyopathy
13.
Previous cardiac transplantation or transplantation indicated or expected within 
6 months of randomization
14.
Contraindications to saxagliptin therapy as outlined in the saxagliptin Investigator’s 
Brochure, or to sitagliptin therapy as outlined in the sitagliptin prescribing 
information
15.
Current treatment with strong cytochrome P450 (CYP) 3A4/5 inhibitors
16.
Involvement in the planning and/or conduct of the study (applies to both AZ staff 
and/or staff at the study site)
17.
Previous enrollment which disqualifies patient from re-enrollment based on the 
rules in Section 4.1 of the protocol, or previous randomization in the study
18.
Participation in another clinical study with an investigational product during the last 
30 days
19.
Patients either employed by or immediate relatives of the Sponsor
20.
Known human immunodeficiency virus (HIV) infection
21.
Severe hepatic disease, including chronic active hepatitis. Positive serologic 
evidence of current infectious liver disease, including patients who are known to be
positive for hepatitis B viral antibody IgM, hepatitis B surface antigen, or hepatitis 


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
33 (85)
C virus antibody; or aspartate transaminase (AST) or alanine transaminase (ALT) 
>3X the upper limit of normal; or total bilirubin (TB) >2 mg/dL
22.
Active malignancy requiring treatment at the time of Visit 1(with the exception of
successfully treated basal cell or treated squamous cell carcinoma).
23.
Pregnant, positive pregnancy test, planning to become pregnant during clinical trial 
or breast feeding
24.
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
25.
Unable or unwilling to provide written informed consent
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient pre-screening, enrollment and randomization
Investigators must keep a record of patients who entered pre-screening in the form of a log 
with assigned code associated with the Lab Kit used for pre-screening procedures. The pre-
screening visit will not be captured in the eCRF. The investigator shall also keep a log of all 
patients who entered screening. Patients with a recent (within 1 month) eGFR value (the Scr 
value used for the eGFR calculation should be accurate to two decimal places) will be allowed 
to enter the screening directly without pre-screening procedures performed and only the main 
informed consent form will be signed.  See section 4.1.1.
Patients who do not qualify for the protocol based upon their pre-screening or screening 
results may have additional attempts to qualify. There may be no more than 3 attempts in 
total. If the patient failed to qualify during screening period (including, but not limited due to 
study supplies, equipment failure, unforeseen personal events that mandate missed screening 
visits, or out-of-range laboratory/clinical tests), the patient may potentially be re-screened. 
These cases should be discussed with the AstraZeneca Monitor and documented in the 
Investigator Study File (ISF). The investigator may use his/her judgment regarding the 
interval between screening periods. The Investigator must track all attempts in the form of a 
log at the site. Re-screened patients should re-sign informed consent on the re-screening 
visit. All procedures from screening period should be repeated.
The Investigators will:
1.
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed.  Separate, specific ICFs will be collected before pre-
screening and screening procedures.
2.
Assign the patient a unique pre-screening code associated with Lab Kit used for 
pre-screening procedures.


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
34 (85)
After positive verification of pre-screening criteria, the investigator will assign 
potential patients a unique enrollment number via IVRS/IWRS beginning with 
‘E#’ during screening.
3.
Determine patient eligibility. See Sections 3.1 and 3.2
At the randomization visit, once the patient is confirmed to be eligible, the Principal 
Investigator or suitably trained delegate will:
4.
Assign the eligible patient a unique randomization number via IVRS/IWRS.
If a patient withdraws from participation in the study, then his/her enrollment/randomization 
code cannot be reused.
Randomization codes will be assigned strictly sequentially as patients become eligible for
randomization.
3.4
Procedures for handling incorrectly enrolled or randomized 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study 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 
randomized or initiated on treatment.
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the patient from 
treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups
Eligible patients will be randomized to receive either saxagliptin or sitagliptin orally once 
daily or matching placebo in a 1:1:1 (saxagliptin, sitagliptin, placebo) ratio using the 
IVRS/IWRS system.   
Randomization will be stratified by eGFR status and SGLT-2 inhibitor use, based on potential 
impact on the primary endpoint. 
For purely administrative reasons, the randomization will also be stratified by regional drug 
distribution centre to improve the efficiency of drug allocation.
The proportion of randomized patients with an eGFR of ≥30 and <50 mL/min/1.73 m2 will be 
limited to 30% or a maximum of 99 patients.  


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
35 (85)
For patients with an eGFR ≥50 mL/min/1.73 m2, the doses of the active treatments are as 
follows: saxagliptin 5 mg and sitagliptin 100 mg.  For patients with an eGFR <50 
mL/min/1.73 m2, the doses of the active treatments will be adjusted as follows: saxagliptin 2.5 
mg and sitagliptin 50 mg.
If a patient is discontinued from the study, his/her randomization or enrollment number will 
not be reused, and the patient will not be allowed to re-enter the study.  Randomized patients 
who discontinue early from the study will not be replaced.
3.6
Methods for ensuring blinding
Investigational product (IP, also referred to as ‘study drug’ in this protocol) will be labelled 
using a unique material kit ID, which is linked to the randomization code.  The IVRS/IWRS 
will assign the bottles of study material to be dispensed to each patient.  This is a double-blind 
study wherein each patient will receive either the active drug or matching placebo.  The active 
drug and placebo tablets and capsules will be identical and presented in identical packaging to 
ensure blinding of the medication.
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment allocation for each randomized patient, 
will be available to the investigator(s) or pharmacists from the IVRS/IWRS. Routines for this 
will be described in the IVRS/IWRS user manual that will be provided to each center.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomization.  The 
investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an 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.
The following personnel will be unblinded as to the exact content of investigational treatments
(ie, the randomization code):

Personnel carrying out the packaging and labelling of investigational treatment

Personnel generating the randomization list.                                                                                 

Personnel analyzing the pharmacokinetic samples.

Personnel overseeing the overall supply chain.


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
36 (85)
No other personnel involved in the conduct of the study may have access to this information, 
which will be maintained in a secure location until after clean file and database lock have been 
declared.  The sole exception will be in the event the PI determines knowledge of 
investigational treatment allocation to be essential for appropriate clinical management of a 
patient.
The randomization list will be kept in a secure location until the end of the study.
3.8
Restrictions
The following restrictions apply while the patient is receiving study drug and for the specified 
times before and after:
Once screened and qualified for entry, patients will be instructed as follows:

Fast for at least 8 hours prior to the randomization visit and each study site visit at 
which fasting plasma glucose is obtained (Weeks 6, 12, and 24, as well as Week 18 
if the patient was rescued at Week 12), ie, no food or beverage except water, until 
glycemic assessments scheduled for that day are performed.  Allowed medications 
can be taken with water only*. Delay administering the IPs (as applicable) on the 
day of the clinic visit and bring study medication to each study site visit*

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*

Do not donate blood for the duration of the study and for 3 months following the 
last study visit

Comply with prescribed dosing regimen to preserve study integrity and ensure 
patient safety 

Discuss any new prescriptions and over-the-counter or herbal/nutritional therapies 
with the investigator, as concomitant use could result in alterations to their glycemic 
control and may place them at risk for significant hypoglycemic episodes

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. 
Women of childbearing potential (including perimenopausal women who have had a 
menstrual period within 1 year) must practice, and be willing to continue to practice, 


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
37 (85)
appropriate birth control.  As applicable, all methods must be in effect before the patient takes 
the first dose of study medication.
All concomitant medications should be captured on the electronic case report form (eCRF). 
The following medications are prohibited from up to 8 weeks prior to study randomization 
and during randomized treatment:

Incretin therapy (DPP4 inhibitors, GLP-1 mimetics) 

Therapy with thiazolidinedione agents (TZDs)

Strong CYP3A4/5 inhibitors (see section 7.7.3)

Background therapy with stable dosages of SGLT-2 inhibitors is permitted in 
patients qualifying for the study and can continue during the randomized treatment 
period. SGLT-2 inhibitors cannot be initiated or their dosages modified during 
randomized treatment or used as rescue therapy
3.9
Discontinuation of investigational product
Patients may be discontinued from investigational product (IP) in the following situations:

Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.  Patients who choose to discontinue study treatment 
are expected to continue in the study until the end of the study as described in the 
Section 3.9.1 of the protocol.

Safety reasons as judged by the investigator or by AstraZeneca representative

Adverse Event

Severe non-compliance with the study protocol as judged by the investigator and/or 
AstraZeneca

Pregnancy (discontinue IP and notify AstraZeneca representative). See Section 6.6

eGFR < 30 mL/min/1.73m2  

if at any time the patient´s eGFR (calculated by MDRD) falls below 
30 mL/min/1.73m2 and is confirmed at a repeated calculation (the re-test should 
be scheduled within 7 days),  the patient should be discontinued from IP

ALT and/or AST >3 x ULN and TB >2 x ULN

ALT and/or AST >5 x ULN for ≥14 consecutive days, at any time after initial 
confirmatory results


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
38 (85)

ALT and /or AST >8 x ULN

Incorrectly enrolled patients (see Section 3.4)
Cases in which patients are incorrectly randomized (ie, the patient does not meet the required
inclusion/exclusion criteria for the study), should be discussed with AstraZeneca 
representative prior to any actions being taken (see Section 3.4). 
3.9.1
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue investigational product or withdraw from the study 
(ie, investigational product and assessments – see Section 3.10), without prejudice to further 
treatment. A patient who decides to discontinue investigational product will always be asked 
about the reason(s) and the presence of any adverse events. If possible, they will be seen and 
assessed by an investigator(s). 
All patients that are randomized will be followed until the end of the study. If a patient 
temporarily discontinues from study medication, it is the intention that the scheduled study 
visits, data collection and procedures continue according the study protocol until the study ends.
If a patient permanently discontinues from the study medication, he or she should be asked, at 
the discretion of the treating physician, to return to the study site as soon as possible, but not 
later than 7 days from last IP dose. All endpoint (Week 24/ETD) assessments, including 
cardiac MRI, and blood and urine biomarker assessments, must be performed at this visit. All 
study drugs should be returned by the patient. The patient should also be asked to return 4 
weeks later for end of study (Week 28) assessments. If the patient is unable or unwilling to 
return, a follow up by phone call should be conducted. Adverse events will be collected 
throughout the treatment period and SAEs will be collected up to 4 weeks after the end-of-
study visit or an Early Treatment Discontinuation Visit (see Section 6.3.1). 
Only if a patient has explicitly refused to attend any visit or to have any future contact, 
including telephone follow up, then the patient is considered to have withdrawn informed 
consent (see Section 3.10.2).
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomized.  These patients should have the reason for study 
withdrawal recorded as ‘Screen Failure’ (ie. patient does not meet the required 
inclusion/exclusion criteria).  This reason for study withdrawal is only valid for screen failures 
(not randomized patients).
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
39 (85)
A patient who desires to withdraws consent will always be asked about the reason(s) for 
withdrawal and the presence of any adverse events (AE). The investigator will follow up AEs 
outside of the clinical study.  If a patient expresses a desire to withdraw from the study, modified 
follow up options, including telephone follow up, should be offered as an alternative. The 
patient will also be asked if they agree to the use of previously donated, stored biological 
samples for the purposes of research (see Section 5.6.4). Once withdrawal of consent is 
confirmed, no further patients visits or contact can occur.
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of Executive Committee and AstraZeneca, trial 
patients are placed at undue risk because of clinically significant findings that:

Meet individual stopping criteria or are otherwise considered significant 

Are assessed as causally related to study drug

Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF.  All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.
4
STUDY PLAN AND TIMING OF PROCEDURES 


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
40 (85)
Table 2
Study plan
Study procedure
Pre-
screeninga
Scree
ninga
Randomi-
zation
Randomized treatment period
End-
of-
study 
visit
For 
details
See 
Protocol
Section
Study week (W) or 
day (D)
D --28 to -1
D -7l
D1
D7
W2
W3
W6
W9
W12
W18
D-7l
Before 
visit 10
W24 /
Early
Treatment
Discontinu-
ation(ETD)
b
W28
Visit window
±0 days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5 days
±5
days
Visit number
0
1
2
3
4
5
6
7
8
9
10
11
Site visit
X
X
Xl
X
X
X
X
X
Xl
X
X
Telephone follow-
up
X
X
X
Informed consent
X
X
4.1.1, 10.4
Demography
X
4.1.2
Medical/surgical 
history
X
4.1.3
Prior/concomitant 
treatments
X
X
X
X
X
X
X
X
X
X
X
4.1.4, 7.7.1
Inclusion/exclusion 
criteria
X
X
3.1, 3.2
Echocardiogram for 
assessment of left 
ventricular 
functionc
X


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
41 (85)
Table 2
Study plan
Study procedure
Pre-
screeninga
Scree
ninga
Randomi-
zation
Randomized treatment period
End-
of-
study 
visit
For 
details
See 
Protocol
Section
Study week (W) or 
day (D)
D --28 to -1
D -7l
D1
D7
W2
W3
W6
W9
W12
W18
D-7l
Before 
visit 10
W24 /
Early
Treatment
Discontinu-
ation(ETD)
b
W28
Visit window
±0 days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5 days
±5
days
Visit number
0
1
2
3
4
5
6
7
8
9
10
11
Site visit
X
X
Xl
X
X
X
X
X
Xl
X
X
Telephone follow-
up
X
X
X
Magnetic resonance 
imaging (MRI)
Xd
(max 7 days before 
visit 2)
Xd
(max. 7 days before 
visit 10)
5.1.1.1
Complete physical 
examination (with 
focus on signs and 
symptoms of heart 
failure)
X
X
X
X
5.2.2.1
Brief physical 
examination (with 
focus on signs and 
symptoms of heart 
failure)
X
X
X
X
5.2.2.2
Height
X
5.2.3


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
42 (85)
Table 2
Study plan
Study procedure
Pre-
screeninga
Scree
ninga
Randomi-
zation
Randomized treatment period
End-
of-
study 
visit
For 
details
See 
Protocol
Section
Study week (W) or 
day (D)
D --28 to -1
D -7l
D1
D7
W2
W3
W6
W9
W12
W18
D-7l
Before 
visit 10
W24 /
Early
Treatment
Discontinu-
ation(ETD)
b
W28
Visit window
±0 days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5 days
±5
days
Visit number
0
1
2
3
4
5
6
7
8
9
10
11
Site visit
X
X
Xl
X
X
X
X
X
Xl
X
X
Telephone follow-
up
X
X
X
Vital signs and body 
weight
X
X
X
X
X
X
X
X
5.1.3.2, 
5.2.3
Clinical laboratory 
tests (standard 
hematology and 
clinical chemistry)
X
X
X
X
X
4.1.7, 5.2.1
Calculation of 
eGFRf
X
Xk
X
X
X
X
4.1.6, 4.1.7
Glycosylated 
hemoglobin 
(HbA1c)
X
X
X
4.1.7, 
5.1.3.1
FPG
X
X
Xe
X
4.2.2
NT-proBNP
X
X
X
X
X
5.1.2.1


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
43 (85)
Table 2
Study plan
Study procedure
Pre-
screeninga
Scree
ninga
Randomi-
zation
Randomized treatment period
End-
of-
study 
visit
For 
details
See 
Protocol
Section
Study week (W) or 
day (D)
D --28 to -1
D -7l
D1
D7
W2
W3
W6
W9
W12
W18
D-7l
Before 
visit 10
W24 /
Early
Treatment
Discontinu-
ation(ETD)
b
W28
Visit window
±0 days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5 days
±5
days
Visit number
0
1
2
3
4
5
6
7
8
9
10
11
Site visit
X
X
Xl
X
X
X
X
X
Xl
X
X
Telephone follow-
up
X
X
X
X
X
X
X
Blood biomarkers
(plasma or serum)g, 
X
X
X
X
5.6
 
g,
X
X
X
X
5.1.3.3, 5.6
Pharmacokinetic 
samplingh
X
X
X
5.3
Plasma volume 
measurement 
(Strauss formula)
X
X
X
X
8.4.4
Urinalysis
X
5.2.1
CCI
CCI


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
44 (85)
Table 2
Study plan
Study procedure
Pre-
screeninga
Scree
ninga
Randomi-
zation
Randomized treatment period
End-
of-
study 
visit
For 
details
See 
Protocol
Section
Study week (W) or 
day (D)
D --28 to -1
D -7l
D1
D7
W2
W3
W6
W9
W12
W18
D-7l
Before 
visit 10
W24 /
Early
Treatment
Discontinu-
ation(ETD)
b
W28
Visit window
±0 days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5 days
±5
days
Visit number
0
1
2
3
4
5
6
7
8
9
10
11
Site visit
X
X
Xl
X
X
X
X
X
Xl
X
X
Telephone follow-
up
X
X
X
Serum pregnancy 
test (women of 
childbearing 
potential)i
X
4.1.9.2
Urine pregnancy 
test (women of 
childbearing 
potential)i
X
X
X
X
X
X
4.1.9.1
Hepatitis B and C 
test
X
3.2
New York Heart 
Association 
(NYHA) Functional 
Classification
X
3.2


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
Date 14 February 2020
45 (85)
Table 2
Study plan
Study procedure
Pre-
screeninga
Scree
ninga
Randomi-
zation
Randomized treatment period
End-
of-
study 
visit
For 
details
See 
Protocol
Section
Study week (W) or 
day (D)
D --28 to -1
D -7l
D1
D7
W2
W3
W6
W9
W12
W18
D-7l
Before 
visit 10
W24 /
Early
Treatment
Discontinu-
ation(ETD)
b
W28
Visit window
±0 days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5
days
±5 days
±5
days
Visit number
0
1
2
3
4
5
6
7
8
9
10
11
Site visit
X
X
Xl
X
X
X
X
X
Xl
X
X
Telephone follow-
up
X
X
X
12-lead 
electrocardiogram
X
4.1.8
Drug dispensing
X
X
X
X
Collection of 
unused study drug
X
X
X
X
Compliance 
assessment
X
X
X
X
X
7.5
Adverse event (AE) 
review (AEs, 
AEoSI, and serious 
AEs)
Xj
X
X
X
X
X
X
X
X
X
Xj
6
a
Patient can be enrolled to screening as soon as laboratory pre-screening result for eGFR is available and it is determined that the value meet the inclusion/exclusion 
criteria.  Total duration of pre-screening and screening periods should not exceed 28 days. Up to 3 (in total) pre-screening/screening attempts are permitted.


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Edition Number 5.0
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b
If a patient permanently discontinues from the study medication, he or she should be asked, at the discretion of the treating physician, to return to the study site as soon as 
possible but no later than 7 days from the last IP dose.  All endpoint (Week 24/ETD) assessments, including an MRI and blood and urine biomarker assessments, must be 
performed at this visit. All study drugs should be returned by the patient. 
c
If no LV assessment has been performed within the 6 months prior to screening.  If required, the test can be performed locally.
d
RANDOMIZATION: The MRI must be performed before randomization and drug dispensing but no more than 7 days prior to Day 1. The MRI scan of acceptable 
quality must be confirmed before the patient is randomized and takes study medication. If a repeat MRI is required, it may be performed within 7 days of the prior scan 
and the randomization visit should be rescheduled if necessary to allow confirmation of quality before randomization and dosing.
WEEK 24: An MRI scan of acceptable quality must be confirmed before the visit occurs. Therefore, the MRI can be performed in advance of the planned visit but no 
more than 7 days. If a repeat MRI is required, it may be performed within 7 days of the prior scan. If necessary, the Week 24 visit should be re-scheduled until after the 
MRI has been qualified as acceptable and the patient should continue study medication.
cMRI assessment must be performed and approved according to Investigator Site Operations Manual and Image Acquisition Guideline.
A urine pregnancy test must be performed in women of child bearing potential before each MRI.
e
A fasting plasma glucose at week 18 will only be required for individuals who require ‘rescue’ therapy at Week 12
f        eGFR will be calculated by the central laboratory.
g
Ideally to be obtained at the same time of day throughout the study, but max. ±6 hours’ time window is acceptable.  Biological samples (urine and blood) will be
collected and will be analyzed for exploratory biomarkers to assess correlations with study endpoints and effects of study drug. The biomarkers assessed in the study 
include NT-proBNP, 
.  Additional blood and urine samples may be assayed either during the study or stored for 
potential future analyses of other renal, cardiac, inflammatory, and metabolic disease-specific biomarkers. Those measurements, as well as other potential relevant 
biomarkers, will be performed at Sponsor`s discretion.  
h
Blood samples will be obtained at each visit indicated for analysis of trough plasma drug concentrations.  Therefore, on these days, patients must take their study 
medication at the study site, after a pre-dose blood sample is collected.  At Week 6 and 24 blood samples for PK analysis will be collected pre-dose only, while at Week 
12 the blood samples will be collected pre-dose and at 30, 60, 120, and 180 minutes post dose for determination of plasma concentration – time profiles.  In all cases, the 
time of day and date of the dose given prior to the trough sample being drawn and on the visit day at Week 12 must be recorded.
i
A serum pregnancy test must be performed at screening.  Urine pregnancy tests must be performed before the MRI and at Week 24 (or the final visit, if the patient 
discontinues early), and at all other on-site visits during the randomized treatment period.
j           SAEs only - SAEs are collected from screening until follow-up at Week 28.
k       eGFR must be obtained at screening visit, if no central laboratory value was obtained during pre-screening due to presence of recent local laboratory values (within 1 
month) in patient medical history.
l        Procedure that needs to be performed before the visit at the site – see Section 5.1.1.1
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4.1
Pre-screening/Enrollment/screening period
The study will comprise a pre-screening and screening periods of up to 28 days.  Study 
procedures and timing required during enrollment/screening period are indicated in the Study 
Plan, Table 2.      
At pre-screening and screening, consenting patients are assessed to ensure that they meet 
eligibility criteria.  Patients who do not meet these criteria must not be enrolled in the study.
All patients will be required to provide consent to supply biological samples for entry into this 
study.  This consent is included in the main patient informed consent form. 
Patients who do not qualify for the protocol based upon their pre-screening or screening 
results may have additional attempts to qualify. There may be no more than 3 attempts in 
total. If the patient failed to qualify during screening period (including, but not limited due to 
study supplies, equipment failure, unforeseen personal events that mandate missed screening 
visits, or out-of-range laboratory/clinical tests), the patient may potentially be re-screened. 
These cases should be discussed with the AstraZeneca Monitor and documented in the 
Investigator Study File (ISF). The investigator may use his/her judgment regarding the 
interval between screening periods. The Investigator must track all attempts in the form of a 
log at the site. Re-screened patients should re-sign informed consent on the re-screening 
visit. All procedures from screening period should be repeated
4.1.1
Pre-screening Informed Consent Form & Informed Consent Form (ICF)
The Pre-screening informed consent for Protocol D1680C00016 is an abbreviated document 
that explains the risks associated with the screening laboratory tests for eGFR performed to 
assess qualification to the study. This document will provide only general information about 
the study, without the need to provide any specific details about the study procedures, and 
risks or benefits from study participation.  The Pre-screening ICF will also document the 
patient’s consent to return to the enrollment visit (Visit 1) in case they are considered eligible 
for the study. 
For any patient that undergoes the pre-screening procedure and is considered eligible to 
participate in the study, the full Informed Consent for Protocol D1680C00016 will be 
provided at the enrollment (Visit 1) See section 10.4.
4.1.2
Demography
Demographic characteristics such as age, gender, race, and ethnicity will be collected.  Date of
birth will be collected if allowed by local regulations.
4.1.3
Medical/surgical history
A complete medical/surgical history will be performed at screening and will include current
medical conditions, past or present, and any diseases or disorders. Surgical procedures within 
the previous 5 years will be collected at screening.


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4.1.4
Prior/concomitant treatments
At screening, all concomitant medications will be recorded.  All new concomitant medication 
started during the treatment period must be reported.  See Section 7.7 for more information on 
concomitant medications.
4.1.5
Inclusion/Exclusion criteria
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.
4.1.6
Estimated glomerular filtration rate (eGFR)
Estimated GFR will be calculated from serum creatinine (Scr) according to the Modification of 
Diet in Renal Disease (MDRD) formula and the eGFR value will be provided with accuracy to 
two decimal places.
Estimated GFR will be calculated using the MDRD formula (Levy et al 2006):
eGFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x 1.212 (if African American) x (0.742 if female) 
For the purpose of eGFR calculation the creatinine value will be provided with accuracy to 
two decimal places. 
The eGFR will be used for verification of patient eligibility criteria during pre-screening, and 
will also be calculated at randomization and visit 6 (week 6), visit 8 (week 12) and visit 10 
(week 24).  It will also be used to determine the dosage of saxagliptin and sitagliptin at 
randomization and the need for dose adjustment during the treatment period.  Please refer to 
Section 7.2.
Patients who, during the course of the study, develop eGFR <50mL/min/1.73m2 based on the 
central laboratory serum creatinine value, will be scheduled for a follow-up visit (within 7 
days) to obtain a second central laboratory serum creatinine value and to repeat the calculation 
of eGFR. If the repeat eGFR is still <50mL/min/1.73m2, the patient’s dose of IP will be 
adjusted. The patient must be invited for an additional visit to receive the down-titrated IP 
within 3 days after results arrival at the site.
The dose adjustments will be to 2.5 mg saxagliptin, 50 mg sitagliptin, or matching placebo. 
Once reduced to 2.5 mg saxagliptin, 50 mg sitagliptin or placebo, there will be no further 
dose-adjustment even if the eGFR subsequently increased sufficiently to meet initial 
requirements for the 5 mg saxagliptin and 100 mg sitagliptin dosing regimen.  The 
IVRS/IWRS will be used to allocate the adjusted IP.
If at any time the patient´s eGFR falls below 30 mL/min/1.73m2 and confirmed at a repeated 
calculation (the re-test should be scheduled within 7 days), the patient should be discontinued 
from IP, see Section 3.9.1.


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4.1.7
Clinical laboratory test
At the pre-screening visit only the creatinine (for eGFR calculation) will be measured. 
At screening a laboratory panel (standard hematology and clinical chemistry) will be obtained. 
Pre-screening/screening values will be used at the randomization visit.  Please refer to section 
5.2.1, and Study Plan, Table 2.
All samples will be processed by a central laboratory and results will be reported back to the 
clinic.
4.1.8
Electrocardiogram (ECG)
A 12-lead ECG will be taken locally to assess the cardiac rhythm (supine position, standard 
ECG with a paper speed of 25 mm/second covering at least 6 sequential beats) after the 
patient has been lying down resting for at least 5 minutes, at the screening Visit 1 only. 
4.1.9
Pregnancy test
4.1.9.1
Urine pregnancy tests 
Urine pregnancy test must be performed in women of child bearing potential at Visits 2 (Day 
1), 4 (Week 2), 6 (Week 6), 8 (Week 12), 9 (Week 18), and 10 (Week 24).  At Visits 2 (Day 
1), and 10 (Week 24), or the final visit, if patient discontinues early), the pregnancy test must 
be performed before the MRI.  Women of child bearing potential must have a negative 
pregnancy test within 72 hours prior to the start of the investigational product.  A positive 
urine pregnancy test should be confirmed by a serum pregnancy test.
4.1.9.2
Serum pregnancy test
At the Screening Visit, a serum pregnancy test will be collected from all women of child-
bearing potential only.
4.2
Treatment period
The study will comprise a 24-week randomized treatment period.  The last dose of study 
medication is to be taken at the Week 24 (Visit 10) after the required pre-dose blood samples 
are obtained. Patients who complete the study medication will be asked to return for an end-
of-study visit at Week 28 (Visit 11). Patients discontinued from the treatment prematurely will 
be asked to return to the study site as soon as possible but not later than 7 days from the last IP 
dose (See section 3.9.1).
Patients will be randomized at Visit 2 (Day1) and receive either saxagliptin, sitagliptin, or 
matching placebo.
The assessments required during the treatment period are detailed in the Study Plan, (Table 2).


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4.2.1
Scheduled telephone contacts
Visits 3 (Day 7), 5 (Week 3), and 7 (Week 9) will be conducted by phone.  The responses 
regarding concomitant medications, AEs and SAEs will be transferred into the eCRF. Patients 
will be asked about signs and symptoms of heart failure.
4.2.2
Fasting plasma glucose (FPG)
FPG will be analyzed by a central laboratory according to the procedures described in the 
Laboratory Manual which will be distributed to each study site during site initiation. 
If the FPG (value from central laboratory) meets rescue limits (See section 7.7.2), the patient 
should be brought back within 3-5 days for an unscheduled confirmatory visit to confirm the 
high FPG and assess eligibility for rescue during the double-blind treatment period.
4.3
End of Study Visit
Study procedures and timing required during End of Study (Visit 11) are indicated in the
Study Plan, Table 2.
If a patient discontinues early from the study, he or she should be asked to return to the study 
site as soon as possible (see Section 3.9.1). All endpoint (Week 24, Visit 10/ETD) 
assessments, including a cardiac MRI, and blood and urine biomarker assessments, must be 
performed at this visit. The patient should also be asked to return 4 weeks later for end of 
study (Week 28) assessments. If the patient is unable or unwilling to return, a phone follow up
should be conducted.
5
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The investigator will ensure that data are recorded on the electronic Case 
Report Forms as specified in the study protocol and in accordance with the instructions 
provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement.  The 
investigator will sign the completed electronic Case Report Forms.  A copy of the completed 
electronic Case Report Forms will be archived at the study site.
5.1
Efficacy assessments
5.1.1
Primary Efficacy Variable
5.1.1.1
Magnetic Resonance Imaging (MRI)
MRI is the primary assessment to evaluate cardiac dimensions and function.  MRI will be 
performed at baseline and Visit 10 (Week 24) for all study patients.  The Week 24 MRI will 


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provide the primary endpoint data.  The MRI evaluations will be performed according to a 
standard protocol and will be centrally read by a core laboratory.
Baseline MRI must be performed before randomization and drug dispensing but no more than 
7 days prior to Day 1.  The MRI scan of acceptable quality must be confirmed before the 
patient is randomized and takes study medication. If a repeat MRI is required, it may be 
performed within 7 days of the poor-quality scan query received, and the randomization visit 
should be rescheduled if necessary to allow confirmation of quality before randomization and 
dosing.
At Week 24 an MRI scan of acceptable quality must be confirmed before the visit occurs. 
Therefore, the MRI can be performed in advance of the planned visit but no more than 7 days. 
If a repeat MRI is required, it may be performed within 7 days of the poor-quality scan query 
received. If necessary, the Week 24 visit should be re-scheduled until after the MRI has been 
qualified as acceptable and the patient should continue study medication.
The cMRI assessment must be performed and approved according to Investigator Site 
Operations Manual and Image Acquisition Guideline.
A urine pregnancy test must be performed before each MRI in women of child bearing 
potential.
The cardiac MRI will be reviewed locally by a qualified physician for incidental 
findings. Any incidental findings of potential clinical significance should be communicated 
directly to the investigator and then evaluated and handled by the investigator as per standard 
medical practice. Investigations and treatments required as follow up to MRI incidental 
findings are not covered by this study protocol and the costs will not be paid by AstraZeneca.
5.1.2
Secondary Efficacy Variable
5.1.2.1
N-terminal prohormone of brain natriuretic peptide (NT-proBNP)
NT-proBNP is primarily used to help detect, diagnose, and evaluate the severity of heart 
failure, as well as the response to therapy, and will be analyzed by a central laboratory 
according to the procedures described in the Laboratory Manual which will be distributed to 
each study site during site initiation.
5.1.3
Exploratory Efficacy Variable
5.1.3.1
HbA1c
HbA1c is the assessment for the determination of glycemic efficacy and will be analyzed by a 
central laboratory according to the procedures described in the Laboratory Manual which will 
be distributed to each study site during site initiation. In cases where the central measurement 
of HbA1C in not possible due to hemoglobin variants not compatible with the central assay, 
no value will be centrally collected.


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5.1.3.2
Body weight
The patient’s body weight will be recorded in kilograms (kg) to one decimal place, with light 
clothing and no shoes.  All readings should be recorded as accurately as possible and the same 
scale should be used for all assessments for a given patient.  The same scale should be used 
throughout the study, and calibrated on a regular basis as recommended by the manufacturer. 
5.1.3.3
 
 
 
5.2
Safety assessment
The investigator will evaluate all enrollment 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 2).
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, hematology, and urinalysis
will be taken at the times indicated in the Study Plan (Table 2).
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator.  The detailed methods for specimen collection, handling, processing, shipping 
and storage will be supplied in the Investigator’s Laboratory Manual provided by the Central
Laboratory.  The date, time of collection and sample ID will be recorded on the appropriate 
eCRF.
The clinical chemistry, hematology and urinalysis will be performed at a central laboratory.  
The samples will be processed by a central laboratory and results will be reported back to the 
clinic. 
All samples should be taken by adequately trained study personnel and handled in accordance 
with instructions in the Laboratory Manual.
The following laboratory variables will be measured:
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Study Code D1680C00016
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Date 14 February 2020
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Table 3
Laboratory Safety Variables
Hematology/Hemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Hemoglobin (Hb)
B-Hematocrit (Hct)
S/P Glucose
S/P HbA1c
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count
S/P-Alkaline phosphatase (ALP)
B-Platelet count
S/P-Aspartate transaminase (AST)
S/P-Alanine transaminase (ALT)
Urinalysis
S/P-Albumin
U-Hb/Erythrocytes/Blood 
S/P-Potassium
U-Protein/Albumin 
S/P-Sodium
U-Glucose 
U-Ketones
S/P-Creatine kinase (CK)
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 6.3.6
5.2.1.1
Volume of blood
Total mandatory blood volume in the study is approximately 260.5 mL.
Table 4
Blood sample volume
Visit
Safety 
(mL)
FPG
PK analysis 
(mL)
Blood 
biomarkers 
(mL)
Pre-Screening
2.5
Screening
15*
Day 1
5.5
43
Week 6
5.5
2 (1 x 2 mL)
3 (1 x 3 mL)
43
Week 12
5.5
2 (1 x 2 mL)
15 (5 x 3 
mL)
43
Week 18*
2 (1 x 2 mL)
Week 24
5.5
2 (1 x 2 mL)
3 (1 x 3 mL)
43


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Study Code D1680C00016
Version 5.0
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Visit
Safety 
(mL)
FPG
PK analysis 
(mL)
Blood 
biomarkers 
(mL)
SUBTOTAL 
(mandatory)
39.5
8
21
172
PK = pharmacokinetics, FPG = fasting plasma glucose, * will only be required for individuals who require ‘rescue’ 
therapy at Week 12
*Including blood biomarker (NT-proBNP)
5.2.2
Physical examination
5.2.2.1
Complete physical examination
A complete physical examination will be performed at screening and include an assessment of 
the following: general appearance, skin inspection, lymph nodes, thyroid, abdomen, 
musculoskeletal/extremities, CV system, lungs, and reflexes.  The results of the complete 
physical examination will be recorded for the screening visit, randomization visit (Day 1), 
visit 8 (Week 12), and visit 10 (Week 24).  The baseline physical examination is performed at 
the screening visit (Visit 1).  
5.2.2.2
Brief physical examination
The brief physical examination will focus on signs and symptoms of heart failure at Visit 4 
(Week 2), 6 (Week 6), 9 (Week 18), and End-of-Study Visit (Week 28).  
5.2.3
Vital signs 
Vital signs will be assessed following the study plan (see Table 2). Weight will be measured 
as part of vital signs.  The patient’s weight will be recorded in kilograms, to 1 decimal place, 
with light clothing and no shoes.  The patient’s height will be recorded in centimeters, with no 
shoes.  Height will be measured as part of vital signs at Visit 1 only.
Pulse and seated BP will be measured twice (5 minutes apart) before any blood sampling is 
done using a standardized cuff adapted to the size of the patient’s arm after the patient has 
been sitting and resting for least 5 minutes.  For timings of assessments see Table 2.
5.2.4
Other safety assessments
5.2.4.1
CV Events Adjudication Committee
An independent Events Adjudication Committee will be appointed and will adjudicate all CV 
events (including hHF).  The committee members will not have access to individual treatment 
codes for any patient or clinical efficacy and safety event.  The precise responsibilities and 
procedures applicable for the Committee will be detailed in a separate Adjudication Manual.
For all CV events identified for adjudication, the investigator will complete the appropriate 
modules of the eCRF and provide source documentation.  Guidance for reporting CV events is 
provided in the Event Reporting Manual.


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5.3
Pharmacokinetics
5.3.1
Collection of samples
In a subset of at least 150 patients, blood samples for determination of saxagliptin, 5-hydroxy 
saxagliptin, and sitagliptin in plasma will be taken at the times presented in the study plan 
(Table 2).
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
Patients should be instructed to provide the exact time of the dose taken the previous day.  
This information and the time of the sample draw will be entered into CRF. 
5.3.2
Determination of drug concentration
Samples for determination of drug concentration in plasma will be analyzed by Covance on 
behalf of AstraZeneca, using an appropriate bioanalytical method.  
The randomization code will be provided to ensure that only samples from patients who were 
on active study treatment are analyzed.  Samples from patients not dosed with the relevant 
active study treatment will only be analyzed on a ‘for cause’ basis, for example, if there is 
suspicion that a patient has been dosed incorrectly.
The treatment allocation information will be kept in a secure location until the end of the 
study.
Full details of the analytical method used will be described in separate bioanalytical reports.
5.3.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report finalization 
or 6 months after issuance of the draft bioanalytical report (whichever is earlier), unless 
requested for future analyses.
Pharmacokinetic samples may be disposed of or destroyed and anonymized by pooling. 
Additional analyses may be conducted on the anonymized, pooled pharmacokinetic samples 
to further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical Report.
Any residual sample remaining after PK analysis has been performed may be used for 
exploratory biomarker research and characterization of metabolites.


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5.4
Pharmacodynamics – Not applicable
5.5
Pharmacogenetics – Not applicable
5.6
Biomarker analysis 
The patients’ consent to the use of biological samples is mandatory.  Biological samples (urine 
and blood) will be collected and will be analyzed for exploratory biomarkers to assess 
correlations with study endpoints and effects of study drug.  The biomarkers assessed in the 
study include NT-proBNP, 
, given their 
association to CV risk.  Additional blood and urine samples may be assayed either during the 
study or stored for potential future analyses of other renal, cardiac, inflammatory, and 
metabolic disease-specific biomarkers.  Those measurements, as well as other potential 
relevant biomarkers, will be performed at Sponsor`s discretion and for the purpose of this 
protocol only.
5.6.1
Storage, re-use and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of the last subject’s last visit, 
after which they will be destroyed.  The results of this biomarker research will be reported 
either in the Clinical Study Report itself or as an addendum, or separately in a scientific report 
or publication.  The results of this biomarker research may be pooled with biomarker data 
from other studies with the study drug to generate hypotheses to be tested in future research.
5.6.2
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix B ‘IATA 6.2 Guidance Document’.
5.6.3
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the center until shipment or disposal (where 
appropriate).  The sample receiver keeps full traceability of the samples while in storage and 
during use until used or disposed of or until further shipment and keeps documentation of 
receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered by the AstraZeneca Biobank team during the 
entire life cycle.
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5.6.4
Withdrawal of Informed Consent for donated biological samples 
If a patient insists on withdrawing consent from the study, the local investigator will confirm 
with the patient whether previously donated biological samples can still be used for the purposes 
of research. In the absence of expressed consent for their use, the biological samples will be 
disposed of/destroyed, and the action documented.  If samples are already analyzed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an integral part of the study, then the patient is 
withdrawn from further study participation.
The Principal Investigator:

Ensures patients’ withdrawal of informed consent to the use of donated samples is 
properly documented and is notified immediately to AstraZeneca. 

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site

Ensures that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
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 (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, 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.


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6.1.1
AEs of special interest
The following are considered to be AEOSI: 

Hypersensitivity reactions

Severe cutaneous adverse reactions (SCAR)

Decreased lymphocyte count

Pancreatitis

Cardiac failure (including confirmed adjudicated cardiac failure events)

Renal impairment/renal failure
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed previously.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse events will be collected from time of first administration of investigational product 
throughout the double-blind treatment period (Visit 10, Week 24).
Serious Adverse Events will be collected from signature of screening informed consent, 
throughout the double-blind treatment period and until the end-of-study visit (Visit 11, Week 
28).


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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 CRF. 
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collect for each AE:

AE (verbatim)

The date and time when the AE started and stopped

Maximum intensity

Whether the AE is serious or not

Investigator causality rating against the Investigational Product (yes or no)

Action taken with regard to investigational product

AE caused patient’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of serious AE

AE is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)


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
Description of AE
The maximum intensity of an AE will be rated according to the following definition:

Mild (awareness of sign of symptom but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Section 6.2.   An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The investigator will assess causal relationship between investigational product and each 
adverse event, 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 
and additional study drug.  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 were 
last asked, or revealed by observation will be collected and recorded in the CRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values/vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product.


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If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
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 ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 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 ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site personnel how to 
proceed. 
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug and the EU Summary of Product Characteristics (SPC) for the active comparator product 
(including any AstraZeneca comparator). 
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 (ie, more than 1 tablet per day of either study drug).


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
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
In the event of an overdose, appropriate supportive treatment should be initiated as dictated by
the patient’s clinical status. Saxagliptin and its active metabolite are removed by
hemodialysis (23% of dose over 4 hours). The Product Label for sitagliptin states the drug is 
modestly dialyzable.
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 investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product 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 a day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.


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The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
6.6.2
Paternal exposure 
There is no restriction on fathering children or donating sperm during the study
6.7
Management of IP related toxicities – Not applicable
6.8
Study governance and oversight
6.8.1
Executive Committee
The Executive Committee will be responsible for the overall study design, including the 
development of the protocol and any protocol amendments, supervision, interpretation, and 
reporting (presentations at international congresses and publications in peer reviewed 
journals) of the study.  The Executive Committee will make recommendations to AstraZeneca 
regarding recruitment and conduct of the study. The Executive Committee will be comprised 
of the International Co-ordinating Investigator (ICI) and designated academic leaders with 
expertise in the fields of heart failure and Type 2 DM.  The precise responsibilities and 
procedures applicable for the Committee will be detailed in a separate committee charter.
6.8.2
Safety Monitoring Committee (SMC)
An independent SMC will be appointed and will make recommendations to the Executive 
Committee and to AstraZeneca. 
The SMC will be responsible for safeguarding the interests of the patients in the study by 
assessing the safety of the intervention during the study, and for reviewing the overall conduct 
of the clinical study.  The SMC will make recommendations to AstraZeneca with regard to 
early stopping or modifications of the study.
The SMC will have access to the individual treatment codes and will be able to merge these 
with the collected study data while the study is ongoing. 
The Executive Committee and AstraZeneca will not be made aware of the treatment codes 
until after clean file and database lock are declared.  Similarly, all summary output reviewed 
at each SMC meeting will be held in confidence by the SMC members until the end of the 
study when clean file and database lock are declared.  The precise responsibilities and 
procedures applicable for the Committee will be detailed in a separate committee charter.


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7
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Table 5
Identity of investigational product
Investigational 
product
Dosage form and strength
Manufacturer
Saxagliptin
Plain, yellow, biconvex, round, 
film-coated tablet; 5 mg
AstraZeneca
Saxagliptin
Plain, yellow, biconvex, round, 
film-coated tablet; 2.5 mg
AstraZeneca
Sitagliptin
Gray capsule 100 mg (containing 
two 50 mg commercial Januvia® 
tablets)
AstraZeneca
Sitagliptin
Gray capsule 50 mg (containing 
one 50 mg commercial Januvia® 
tablet)
AstraZeneca
Placebo to match 
saxagliptin 2.5mg/5mg
Plain, yellow, biconvex, round, 
film-coated tablet
AstraZeneca
Placebo to match 
sitagliptin
Gray capsule
AstraZeneca
The IPs will be supplied by AstraZeneca. Primary packaging of the IP will be carried out by 
AstraZeneca or their designee in accordance with Good Manufacturing Practice (GMP).
The tablets may contain lactose, which may cause discomfort in lactose-intolerant individuals. 
7.2
Dose and treatment regimens
Study treatment will be administered once daily, according to randomized treatment 
allocation.  For patients with an eGFR ≥50 mL/min/1.73 m2, the doses of the active treatments 
are as follows: saxagliptin 5 mg and sitagliptin 100 mg.  For patients whose eGFR decreases 
to <50 mL/min/1.73 m2, the doses of the active treatments will be adjusted as follows: 
saxagliptin 2.5 mg and sitagliptin 50 mg.  
Patients whose eGFR falls below 30 mL/min/1.73 m2 must be discontinued from the study 
following confirmation of the initial result.
Patients will receive:

One saxagliptin 5 mg tablet and one sitaglipitin placebo capsule administered orally 
once daily for a 24 week treatment period for patients with an eGFR ≥50 
mL/min/1.73m2.  For patients with an eGFR ≥30 to <50 mL/min/1.73m2, the dose 
of saxagliptin will be adjusted to one 2.5 mg tablet


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or

One sitagliptin 100 mg capsule and one saxagliptin placebo tablet administered 
orally once daily for a 24-week treatment period for patients with an eGFR ≥50 
mL/min/1.73m2.  For patients with an eGFR ≥30 to <50 mL/min/1.73m2, the dose 
of sitagliptin will be adjusted to one 50 mg capsule
or

One saxagliptin placebo tablet and one sitagliptin placebo capsule administered 
orally once daily for a 24-week treatment period as a control.
Patients who, during the course of the study, develop renal impairment (eGFR 
<50 mL/min/1.73m2 on 2 consecutive tests at least 1 week apart) will have their dose adjusted 
to 2.5 mg saxagliptin, 50 mg sitagliptin, or matching placebo.  Once reduced to 2.5 mg 
saxagliptin, 50 mg sitagliptin or placebo, there will be no further dose-adjustment even if the 
estimated GFR subsequently increased sufficiently to meet initial requirements for the 5 mg 
saxagliptin, 100 mg sitagliptin or placebo dosing regimen.  The IVRS/IWRS will be used to 
allocate the adjusted IP.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.
The label will include the following information:  Name of the Sponsor, Study Code, For 
Clinical Trial use only, and/or any other market specific requirements.  The label will also 
state keep out of the reach of children.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the bottles specifies the appropriate storage.
7.5
Compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the Case Report Form.  This information plus drug 
accountability for all study drugs will be used to assess compliance with the treatment.
Each time study drug is dispensed, compliance will be reinforced.  When study drug is 
returned, compliance will be assessed based on returned tablet counts.  Compliance should be 
between ≥80% and ≤120%.  The investigator (or designee) will record the amounts of study 
medication dispensed and returned at each site, as well as document reasons for 
noncompliance, in the source document.  The dates of all study medication dosing, including 
interruptions, missed doses or overdose, must be recorded on the eCRF.  If the patient is not 
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noted as a protocol deviation and the Sponsor should be notified.  The patient may continue in 
the study, but should be counselled on the importance of taking their study medication and 
applicable ancillary medications as prescribed.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to and returned from the 
patient.
Study site personnel, if applicable, or the AZ monitor will account for all study drugs received 
at the site, unused study drugs, and for destruction according to local procedure.  Certificates 
of delivery, destruction should be signed.
7.7
Concomitant and other treatments 
Background, rescue medication, and post-study treatment will not be provided by the Sponsor.
7.7.1
Concomitant treatment
Therapy with the patient’s stable series of medications for T2DM and heart failure will 
continue during the duration of the trial.
For patients taking insulin, the investigator must query the patient at pre-screening or 
screening regarding his/her usual total daily insulin dose (all types combined).  Dosage 
reductions of insulin and sulfonylurea agents may be considered at randomization to minimize 
the possibility of hypoglycaemia. For patients treated with insulin, consider a reduction in 
dose of 20% at randomization.
For patients receiving sulfonylurea agents, consider a reduction in dose of 50% or discontinue 
if on a dosage that is considered low at randomization. 
Any reductions in the dosage of insulin and sulfonylurea agents will be at the discretion of the 
investigator.
Other medication 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 Case Report Form.
Concomitant herbal or nutritional therapies must also be entered into the eCRF.
7.7.2
Rescue medication
The Sponsor will not supply rescue medication during the study.  Patients should continue 
receiving study medication while receiving rescue therapy.  If rescue therapy fails, further 
therapy will be given at the discretion of the investigator.


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7.7.2.1
Glycemic rescue medication
During the double-blind treatment period of the trial, patients may be eligible for the addition 
of open-label rescue medication to their blinded treatment regimen in order to treat ongoing 
hyperglycemia, based upon central laboratory FPG values and repeat, confirmatory FPG 
criteria (Table 6). 
For participants with sustained hyperglycemia as outlined in Table 6, increased doses of 
background medication or additional agents, not listed in the exclusions, may be used 
according to local guidelines.
Patients with a central laboratory FPG value meeting the lack of glycemic control criterion at 
a pre-specified visit will be scheduled for a follow-up visit (within 3-5 days) to obtain a 
second central laboratory FPG value.  If the repeat central laboratory FPG value still meets the 
criterion, the patient will receive rescue medication.
If a patient has a local, or unplanned FPG value meeting the lack of glycemic control criterion, 
then a central laboratory FPG value should be obtained as soon as possible. If the central 
laboratory FPG value meets the criterion, the patient will receive rescue medication.
Table 6
Lack of Glycemic Control Criteria for Initiation of Open-Label Rescue 
Medication
Visit label
Central Laboratory FPG
Up to and including Week 6
FPG >270 mg/dL (15.0 mmol/L)
After Week 6 up to Week 12 
FPG >240 mg/dL (13.3 mmol/L)
At Weeks 12 to Week 24
FPG >200 mg/dL (11.1 mmol/L)
7.7.3
Prohibited medications
Other than study medication, and rescue medication as described in Section 7.7.2, the use of 
the following medications during randomized treatment is prohibited:

Incretin therapy (DPP4 inhibitors, GLP-1 mimetics) 

While background therapy with stable dosages of SGLT-2 inhibitors is permitted in 
patients qualifying for the study and can continue during the randomized treatment 
period, SGLT-2 inhibitors cannot be initiated or their dosages modified during 
randomized treatment or used as rescue therapy

Therapy with thiazolidinedione agents (TZDs)

Strong CYP3A4/5 inhibitors. 


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The list of strong CYP 3 A4/5 inhibitors includes, but not limited to: boceprevir, 
clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, diltiazem, 
elvitegravir/ritonavir, grapefruit juice*, idelalisib, indinavir/ritonavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, paritaprevir/ritonavir, 
ombitasvir, dasabuvir, posaconazole, ritonavir, saquinavir/ritonavir, telaprevir,
tipranavir/ritonavir, troleandomycin, voriconazole.
*The effect of grapefruit juice varies widely among brands and is concentration-, dose- and 
preparation dependent.  Studies have shown that it can be classified as a “strong CYP3A 
inhibitor” when a certain preparation was used (eg, high dose, double strength) or as a 
“moderate CYP3A inhibitor” when another preparation was used (eg, low dose, single 
strength).
Patients should continue their usual diabetes medication (other than prohibited medications 
listed above) and their usual HF medications (including diuretics, ACE inhibitors, or ARB 
agents, beta blockers, and aldosterone antagonists). The diabetes and HF treatment regimens 
should remain stable during the study unless a change is required due to a change in the 
patient’s clinical status. Any changes (dose adjustments, additions, deletions) must be 
recorded.
8
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violators identified.
Analyses will be performed by AstraZeneca or its representatives.    
The SAP will be signed off before review of any potential treatment revealing data is 
undertaken and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data. If one or more stratification cells has sparse or no 
data, then, for purposes of the imputation and analysis models, stratification levels and/or 
variables may be combined or variables may be dropped from the models.
8.2
Sample size estimate
The comparison of saxagliptin versus placebo in LVEDV index is used to estimate sample 
size.  The mean change from baseline in LVEDV index at Week 24 will be assessed 
comparing saxagliptin versus the placebo treatment group.  The efficacy assessment will claim 
non-inferiority if the upper bound of the 95% confidence interval (CI) for the adjusted mean 
treatment difference between saxagliptin and placebo is less than the non-inferiority margin, 
which will be taken as 10% of the overall (all treatments combined) baseline mean value. For 
purposes of the sample size calculation, this number will be assumed to be 6.5 mL/m2. (See 
below)  


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A total of 330 (110 each arm) eligible patients will be randomized in a 1:1:1 ratio to: 

Arm 1: Saxagliptin  

Arm 2: Sitagliptin

Arm 3: Placebo 
To demonstrate non-inferiority of saxagliptin compared to placebo for the change from 
baseline to Week 24 in LVEDV index within a non-inferiority margin of 6.5 mL/m2, assuming 
a standard deviation (SD) of 15 mL/m2, and at a 1-sided significance level of 0.025, 
approximately 88 patients will be needed in each treatment group to provide approximately 
80% power (given a true difference of zero between saxagliptin and placebo).  Assuming that 
20% of patients will be missing an endpoint assessment, a total of approximately 330 patients 
(110 patients in each of the 3 treatment groups) must be randomized.
The non-inferiority margin estimate for the sample size calculation for LVEDV index is based 
on data from Foster et al 1998, where the baseline LVEDV index is 65 ±13 (mean ±SD) 
mL/m2.  To exclude an increase in LVEDV index (relative to placebo) of greater than 10% of 
the baseline, the change seen with vildagliptin in LVEDV in the VIVIDD study, the non-
inferiority margin for these calculations is equivalent to 6.5 (65 × 0.10) mL/m2.  
8.3
Definitions of analysis sets
The primary and secondary efficacy analyses will be performed based on the full analysis set. 
The Safety analysis will be performed based on the safety analysis set.
8.3.1
Efficacy analysis sets
The full analysis set (FAS) will include all randomized patients who take at least one dose of 
the study medication. Patients will be analyzed according to the treatment groups to which 
they are randomized. 
The per-protocol (PP) analysis set is a subset of the FAS set that includes patients without 
important protocol deviations that might affect the primary analyses. Patients will be analyzed 
according to the treatment randomized. The criteria for important protocol deviations will be 
defined in the statistical analysis plan. The criteria for important protocol deviations will be 
established after protocol deviation reviews, before the data have been unblinded.
8.3.2
Safety analysis set
The safety analysis set will include all randomized patients who have received at least 1 dose 
of study treatment. Patients will be analyzed according to the treatment actually received. 


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8.3.3
PK analysis set
The PK analysis set will include a subset of at least 150 patients (approx. 50 per treatment 
group) for whom evaluable pharmacokinetic data are calculated (with no major protocol 
deviations or violations thought to significantly affect the pharmacokinetics of the drug). 
PK data will be reported separately from the clinical study report.
8.4
Outcome measures for analyses
8.4.1
Primary efficacy variable
Change from baseline in LVEDV index measured by MRI at 24 weeks, saxagliptin compared 
to placebo.
8.4.2
Secondary efficacy variables

Change from baseline in LVESV index, LVEF, and LVM measured by MRI after 
24 weeks, saxagliptin compared to placebo

Change from baseline in NT-proBNP after 24 weeks, saxagliptin compared to 
placebo.
8.4.3
Safety variables

Incidence of AEs/SAEs/ AEs of special interest 

Collection of clinical chemistry/hematology parameters 

Vital signs 

Physical examination

Incidence of independently adjudicated events (death, myocardial infarction, stroke, 
and hHF).
8.4.4
Exploratory variables

Change from baseline in LVEDV index, LVESV index, LVEF, and LVM-measured 
by MRI at 24 weeks, sitagliptin compared to placebo

Change from baseline in NT-proBNP after 6, 12, and 24 weeks  

Percent change from baseline in plasma volume using Strauss formula after 6, 12, 
and 24 weeks


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
Change from baseline in body weight at 12 and 24 weeks 

Change from baseline in HbA1c at 12 and 24 weeks

Change from baseline of blood and urine biomarker values at Weeks 6, 12, and 24

Plasma concentration in PK samples

Saxagliptin and its major metabolite, 5-hydroxy saxagliptin 

Sitagliptin  
8.5
Methods for statistical analyses
The full analysis set (FAS) will be used for the primary and secondary efficacy analyses. 
Efficacy analyses will also be conducted using the PP analysis set.  All primary and secondary 
analyses will be performed using values regardless of rescue or discontinuation of the study 
treatment. When patients have their final MRI measurements done at an ETD visit rather than 
at Week 24, these measurements will be used as the endpoint.  Sensitivity analyses for the 
primary and secondary variables will be performed using analyses that do not assume the data 
are missing at random and incorporate patients randomized and treated but with only baseline 
data.
All statistical comparisons will be tested at the alpha level of 0.05 (two-sided) level.  No 
multiplicity control will be applied for the statistical comparisons.
8.5.1
Analysis of the primary variable (s)
The primary analysis for LVEDV index, mean change from baseline at Week 24, will be 
performed using analysis of covariance (ANCOVA), with terms for treatment group, eGFR 
category (<50, ≥50 mL/min/1.73 m2), SGLT-2 inhibitor use, region, and baseline value as 
covariates in the model.  A multiple imputation approach will be used to impute the missing 
values of LVEDV at Week 24 for all FAS subjects with a nonmissing baseline value. Point 
estimates and 95% confidence intervals will be calculated for the adjusted mean changes 
within each treatment group, as well as for the differences in adjusted mean changes between 
treatment groups.  The NI margin for the study will be calculated as 10% of the overall 
baseline mean LVEDV index across all treatment groups.  Non-inferiority will be 
demonstrated if the upper bound of the 95% confidence interval for the difference in 
treatments (saxagliptin minus placebo) is less than the NI margin.


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8.5.2
Analysis of the secondary variable(s)
Continuous variables collected at only one visit during randomization treatment period 
(cardiac dimension and function LVEDV index, LVESV index, LVEF, and LVM by MRI, 
etc), will be analyzed using the same analysis of covariance (ANCOVA) approach used for 
the primary variable.
Continuous variables collected at more than one visit during randomization treatment period, 
(NT-proBNP, etc), will be analyzed using a mixed-model repeated-measures (MMRM) 
approach with terms for treatment group, eGFR category (<50, ≥50 mL/min/1.73 m2), SGLT-
2 inhibitor use, region, baseline value, time (each relevant visit), the interaction of treatment 
and time, and the interaction of baseline value and time in the model.  Biomarkers or data with 
extremely skewed distributions may be log transformed prior to ANCOVA or MMRM 
analysis. 
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.  No multiplicity control will be applied for the statistical comparisons.
8.5.3
Exploratory analyses
For continuous variables (percent change of plasma volume by Strauss formula, blood 
pressure, HbA1c (using values prior to rescue), body weight, and biomarkers, etc) collected at 
multiple visits post-baseline, the same MMRM approach will be used.  For continuous 
variables (LVEDV index, LVESV index, LVEF, and LVM, etc.) collected at one visit post-
baseline, the same ANCOVA model described for the primary variable will be used although 
multiple imputation of missing data may not be used.
Plasma concentrations of saxagliptin, 5-hydroxy saxagliptin, and sitagliptin will be used to 
develop exploratory PK/PD models, which may be reported separately from the clinical study 
report.
In cases where the central measurement of HbA1C is not possible due to hemoglobin variants 
not compatible with the central assay, no value will be centrally collected and these subjects 
will be excluded from the HbA1c analysis.
8.5.4
Subgroup analysis 
Details of the subgroup analysis will be specified in Statistical Analysis Plan. The treatment 
effect on the adjusted mean change from baseline in LVEDV index measured by MRI at 24 
weeks will be examined in the following subgroups: 

Baseline HbA1c (<7.0%, 7.0% to 9.0%, and >9.0%)

Gender (male, female)

Age (<65, ≥65 years)


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
Duration of T2DM

eGFR (<50, ≥50 mL/min/1.73 m2)

SGLT-2 inhibitor use

Region 

Baseline NYHA classification (I, II, III).
8.5.5
Interim analysis – Not applicable
8.5.6
Sensitivity analysis 
Multiple sensitivity analyses for the primary endpoint will be performed including analyses 
that do not assume the data are missing at random and incorporate patients randomized and 
treated but with only baseline data. Details will be stated in the SAP. 
8.5.7
Safety analysis 
Safety analyses for the double-blind treatment period will be performed using the Safety 
analysis set, including data after the addition of glycemic rescue concomitant medication or 
change of heart failure concomitant medication. Safety analyses will include, where 
appropriate, descriptive statistics, counts, and percentages for AEs and other safety measures.  
No formal statistical tests will be performed.
Descriptive statistics will be calculated for demographic and other baseline characteristics.  
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, 
AEs of special interest, and adjudicated CV events, including hHF.  Summaries will include 
the number of patients with events by specified system organ classes and preferred terms.  
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 seated 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.  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 may be 
performed excluding data after the addition of glycemic rescue concomitant medication.


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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 Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the EDC systems 
utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed

Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients.  This 
will require direct access to all original records for each patient (eg, clinic charts).  
The monitor should ensure that all CV endpoints are captured and that adjudication 
packages are complete.

Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient.
The AstraZeneca representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.


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9.2.2
Study agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol 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 Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study is expected to start in Quarter 1 2017 and to end by Quarter 3 2019.
The study may be terminated at individual centres if the study procedures are not being 
performed according to 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.
9.4
Data management by AstraZeneca
Data management will be performed by AstraZeneca Data Management Center staff 
according to the Data Management Plan.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).  
Medications will be classified according to the WHO Drug Dictionary. Classification coding 
will be performed by the Medical Coding Team at the AstraZeneca Data Management Centre.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, implausible, or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.


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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 laboratories 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
Patient 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 (EC)/IRB should approve the final study protocol, including the final 
version of the Informed Consent Form 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 enrollment of any patient into the study. 
The EC/IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.


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AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, EC/IRB, and Principal 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 
investigational product.  AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each centre will:

Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study

Ensure each patient is notified that they are free to discontinue from the study at any 
time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study

Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File

Ensure a copy of the signed Informed Consent Form is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an Ethics Committee.
10.4.1
Pre-screening Informed Consent
The pre-screening informed consent is an abbreviated document that explains the risks 
associated with the pre-screening laboratory test (eGFR) performed to assess qualification to 
the study.
This document will provide only general information about the study, without the need to 
provide any specific details about the study procedures, and risks or benefits from study 
participation. 


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Version 5.0
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For any patient that undergoes the pre-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 Executive 
Committee and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s).  For distribution to Ethics Committee see Section 10.3.
If a protocol amendment requires a change to a center’s Informed Consent Form, AstraZeneca 
and the center’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6
Audits and inspections
Authorized 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, analyzed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), 
and any applicable regulatory requirements.  The investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the center.
11
LIST OF REFERENCES
Foster et al 1998
Foster RE, Johnson DB, Barilla F, Blackwell GG, Orr R, Roney M, et al.  Changes in left 
ventricular mass and volumes in patients receiving angiotensin-converting enzyme inhibitor 
therapy for left ventricular dysfunction after Q-wave myocardial infarction.  Am Heart J 
1998;136: 269-75.


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
79 (85)
Gilbert and Krum 2015
Gilbert, R and Krum, H.  Heart failure in diabetes: effects of anti-hyperglycaemic drug 
therapy.  Lancet 2015; 385: 2107–17.
Green et al 2015
Green J, Bethel A, Armstrong P, Buse J, Engel SS, Garg J, et al for the TECOS Study Group.  
Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 
2015;373:232-242.
Grothues et al 2002
Grothues F, Smith GC, Moon JC, Bellenger NG, Collins P, Klein HU, et al.  Comparison of 
interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional 
echocardiography in normal patients and in patients with heart failure or left ventricular 
hypertrophy.  Am J Cardiol 2002 Jul-1;90(1):29-34.
Hirshberg et al 2014
Hirshberg B1, Parker A, Edelberg H, Donovan M, Iqbal N. Safety of saxagliptin: events of 
special interest in 9156 patients with type 2 diabetes mellitus.  Diabetes Metab Res Rev 
2014;30:556-69.
Kalra et al 2002
Kalra PR, Anagnostopoulos C, Bolger AP, Coats AJ, Anker SD. The regulation and 
measurement of plasma volume in heart failure. J Am Coll Cardiol 2002;39:1901– 8.
Levy et al 2006
Levy AS, et al. Chronic Kidney Disease Epidemiology Collaboration. Using standardized 
serum creatinine values in the modification of diet in renal disease study equation for 
estimating glomerular filtration rate.  Ann Intern Med 2006;145(4):247-54.
McMurray et al 2013
McMurray JJV, Ponikowski P, Bolli GB, Kozlovski P, Jhund P, Lewsey JD, et al.  Reported at the 
European Society of Cardiology Heart Failure Congress; Lisbon, Portugal; May 2013.
Nichols et al 2004
Nichols GA et al. The Incidence of Congestive Heart Failure in Type 2 Diabetes.  Diabetes 
Care 2004;27:1879-1884.
Rossignol PR et al 2011 
Eplerenone Survival Benefits in Heart Failure Patients Post-Myocardial Infarction Are 
Independent From its Diuretic and Potassium-Sparing Effects: Insights From an EPHESUS 
Substudy.  JACC 2011; 58:1958-1966.
Sitagliptin Prescribing Information
http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf


Clinical Study Protocol
Drug Substance saxagliptin
Study Code D1680C00016
Version 5.0
Date 14 February 2020
80 (85)
Skyler et al 2009
Skyler, JS, et al.  Intensive Glycemic Control and the Prevention of Cardiovascular Events: 
Implications of the ACCORD, ADVANCE, and VA Diabetes Trials.  A Position Statement of 
the American Diabetes Association and a Scientific Statement of the American College of 
Cardiology Foundation and the American Heart Association.  J Am Coll Cardiol 2009;53(3): 
298-304.
Spertus et al 2005
Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM, MD, MS, Jones P, 
McCullough PA, Pina I, Tooley J, Weintraub WS, Rumsfeld JS. Monitoring clinical changes 
in patients with heart failure: A comparison of methods. Am Heart J 2005; 150 (4): 707-715.
Strauss et al 1951
Strauss MB, Davis RK, Rosenbaum JD, Rossmeisl EC. Water dieresis produced during 
recumbency by the intravenous infusion of isotonic saline solution. J Clin Invest 
1951;30:862– 8.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d1680c00016-csp-v5
Document Title:
D1680C00016 Clinical Study Protocol version 5
Document ID:
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
18-Feb-2020 20:54 UTC
Content Approval
17-Feb-2020 13:23 UTC
Content Approval
17-Feb-2020 13:42 UTC
Content Approval
17-Feb-2020 11:35 UTC
Qualified Person Approval
17-Feb-2020 12:49 UTC
Qualified Person Approval
17-Feb-2020 23:24 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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CCI

SAP_001.pdf: 
• Protocol number: D1680C00016 
• Document title: A 24-Week, Multicenter, Randomized, Double-blind, 
Parallel Group, Placebo-controlled Study to Investigate the Effects of 
Saxagliptin and Sitagliptin in Patients with Type 2 Diabetes Mellitus   
and Heart Failure 
• NCT number: NCT02917031 
• Version number: 1.0 
• Date of the document: 14 October 2020 


Statistical Analysis Plan 
Study Code
D1680C00016
Edition Number
1.0
Date
13 October 2020
MEASURE-HF
MEchAniStic evalUation of glucose-loweRing strategiEs in patients with 
Heart Failure
A 24-Week, Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo-controlled Study to Investigate the Effects of Saxagliptin and
Sitagliptin in Patients with Type 2 Diabetes Mellitus and Heart Failure


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
2
MEASURE-HF
MEchAniStic evalUation of glucose-loweRing strategiEs in patients with 
Heart Failure
A 24-Week, Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo-controlled Study to Investigate the Effects of Saxagliptin and
Sitagliptin in Patients with Type 2 Diabetes Mellitus and Heart Failure
Study Statistician
Date
PPD


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
3
MEASURE-HF
MEchAniStic evalUation of glucose-loweRing strategiEs in patients with 
Heart Failure
A 24-Week, Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo-controlled Study to Investigate the Effects of Saxagliptin and
Sitagliptin in Patients with Type 2 Diabetes Mellitus and Heart Failure
AZ Study Statistician
Date
AZ Global Project Statistician
Date
PPD
PPD


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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
INTRODUCTION .............................................................................................10
1.
STUDY DETAILS.............................................................................................11
1.1
Study objectives.................................................................................................11
1.1.1
Primary objective ...............................................................................................11
1.1.2
Secondary objectives..........................................................................................11
1.1.3
Safety objectives ................................................................................................12
1.1.4
Exploratory objectives........................................................................................12
1.2
Study design.......................................................................................................13
1.3
Number of patients.............................................................................................14
2.
ANALYSIS SETS..............................................................................................15
2.1
Definition of analysis sets ..................................................................................15
2.1.1
Enrolled patients set ...........................................................................................15
2.1.2
Full analysis set..................................................................................................15
2.1.3
Per protocol set ..................................................................................................15
2.1.4
Biomarkers per protocol set................................................................................16
2.1.5
Safety analysis set ..............................................................................................16
2.1.6
PK analysis set...................................................................................................16
2.2
Violations and deviations ...................................................................................16
3.
PRIMARY AND SECONDARY VARIABLES.................................................17
3.1
General principles taken for analysis variables ...................................................17
3.1.1
Study Day Definition .........................................................................................17
3.1.2
Duration of Type 2 Diabetes...............................................................................18
3.1.3
Definition of Baseline Measurements.................................................................19
3.1.4
Change from Baseline ........................................................................................19
3.1.5
Visit Assignment Windows................................................................................19
3.1.6
Handling missing data........................................................................................21


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
5
3.1.6.1
Imputation of partial dates..................................................................................22
3.1.7
Study periods .....................................................................................................23
3.2
Primary endpoint................................................................................................23
3.3
Secondary endpoints ..........................................................................................24
3.4
Exploratory endpoints ........................................................................................24
3.5
Safety variables..................................................................................................24
3.5.1
Adverse Events ..................................................................................................24
3.5.2
Vital sign ...........................................................................................................25
3.5.3
Physical examination..........................................................................................25
3.5.4
Laboratory Safety Variables...............................................................................25
4.
ANALYSIS METHODS....................................................................................26
4.1
General principles ..............................................................................................26
4.2
Analysis methods...............................................................................................27
4.2.1
Patient disposition..............................................................................................27
4.2.2
Demographics and other baseline characteristics ................................................27
4.2.2.1
Demography data...............................................................................................28
4.2.2.2
Other baseline characteristics .............................................................................29
4.2.2.3
Medical History .................................................................................................29
4.2.2.4
Prior Medications...............................................................................................30
4.2.2.5
Elapsed time between randomization and final MRI measurements....................30
4.2.3
Extent of Exposure and Treatment Compliance..................................................30
4.2.3.1
Extent of Exposure – Study and Glycemic Rescue Medications..........................30
4.2.3.2
Extent of Exposure – Concomitant Medications .................................................30
4.2.3.3
Measurement of Treatment Compliance .............................................................31
4.2.3.4
Heart failure related medication at start of study treatment .................................32
4.2.4
Analyses of study objectives ..............................................................................32
4.2.4.1
Primary outcome variable...................................................................................34
4.2.4.2
Secondary variables ...........................................................................................35
4.2.4.3
Sensitivity analysis.............................................................................................36
4.2.4.4
Exploratory variables .........................................................................................37
4.2.4.5
Percent Change from Baseline in NT-proBNP and Biomarkers ..........................38
4.2.5
Safety analyses...................................................................................................38
4.2.5.1
Adverse Events ..................................................................................................39
4.2.5.2
Serious Adverse Events......................................................................................40
4.2.5.3
Adverse Events adjudicated as CV Deaths, heart failure, MIs, strokes................40
4.2.5.4
Hospitalization with heart failure........................................................................40
4.2.5.5
Deaths................................................................................................................40
4.2.5.6
Clinical laboratory variables...............................................................................41
4.2.5.7
Vital signs..........................................................................................................42
4.2.6
Subgroup analyses..............................................................................................42
4.2.7
PK analysis ........................................................................................................43


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
6
5.
INTERIM ANALYSES (NOT APPLICABLE)..................................................44
6.
CHANGES OF ANALYSIS FROM PROTOCOL .............................................44
7.
REFERENCES ..................................................................................................44
APPENDIX 1
CONVENTIONAL UNITS FOR PRESENTATION OF CLINICAL 
LABORATORY PARAMETERS......................................................................45
APPENDIX 2
MARKED ABNORMALITY CRITERIA ................................................46
APPENDIX 3
CRITERIA FOR ASSESSING IMPORTANT PROTOCOL 
DEVIATIONS ...................................................................................................49


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
7
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event
AEoSI
Adverse events of special interest
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
AST
Aspartate transaminase
BMI
Body mass index 
BP
Blood pressure
BPPS
Biomarkers per protocol set
BSA
Body surface area
cm
centimetre
CRF
Case report form
CV
Cardiovascular
CVD
Cardiovascular disease
ECG
Electrocardiogram
EPS
Enrolled Patients Set
ETD
Early treatment discontinuation
FAS
Full Analysis Set
FPG
Fasting plasma glucose
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
Hct
Hematocrit
hHF
Hospitalization for Heart failure
HF
Heart failure
HR
Heart rate
IP
Investigational Product
IWRS
Interactive Web Response System
LOCF
Last-Observation-Carried-Forward
LVEDV
Left Ventricular End Diastolic Volume
LVEF
Left Ventricular Ejection Fraction
LVESV
Left Ventricular End Systolic Volume
LVM
Left ventricular mass
MAR
Missing at random
MNAR
Missing not at random
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MRI
Magnetic Resonance Imaging
NT-proBNP
N-terminal prohormone of brain natriuretic peptide
NYHA
New York Heart Association
PDs
Protocol deviations  
PK
Pharmacokinetic
PPS
Per Protocol Set


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
8
Abbreviation or 
special term
Explanation
PT
Preferred Term
PV
Plasma Volume
IPDs
Important Protocol deviations  
SAE
Serious adverse event
SAF
Safety Analysis Set
SAS
Statistical Analysis Software
SCAR
Severe cutaneous adverse reaction
SD
Standard deviation
SE
Standard error
SGLT-2
Sodium-glucose cotransporter 2
SI
International System of Units
SOC
System Organ Class
SU
Sulfonylurea
T2DM
Type 2 Diabetes mellitus
VIVIDD
Vildagliptin in Ventricular Dysfunction Diabetes


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
9
AMENDMENT HISTORY
Date
Brief description of change
Date of signature
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Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
10
INTRODUCTION 
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled study to 
investigate the effects of saxagliptin on cardiac dimensions and function, in patients with 
T2DM and HF with reduced systolic function from both ischemic and non-ischemic causes.
Approximately 330 patients with documented LVEF ≤45% and NT-proBNP >300 pg/mL will 
be randomized in equal proportions (110 patients per group) to treatment with saxagliptin, 
sitagliptin, or placebo. 
MRI to evaluate cardiac dimensions, and function will be performed at baseline (≤ 7 days 
prior to randomization), and Week 24 (≤7 days Prior to Week 24) for all study patients. The 
Week 24 MRI will provide the primary endpoint data. The MRI evaluations will be performed 
according to a standard protocol and will be centrally read by a core laboratory.
An independent Events Adjudication Committee will be appointed and will adjudicate all CV 
events (including hHF). 
Analysis of PK data is not part of this statistical analysis plan and will be reported separately 
from the clinical study report. 
This Statistical Analysis Plan is based upon the 
Clinical Study Protocol, Version 5.0 (10 February 2020)


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
11
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
Primary Objective:
Outcome Measure:
To exclude an increase in left ventricular end 
diastolic volume (LVEDV) index of greater 
than 10% of the overall baseline value (non-
inferiority margin) in patients with T2DM and 
HF treated with saxagliptin for 24 weeks, 
compared to placebo
Change from baseline in LVEDV index 
measured by MRI at 24 weeks
1.1.2
Secondary objectives
Secondary Objective:
Outcome Measure:
Evaluate the effects of saxagliptin compared to 
placebo on LVESV index, LVEF, and LVM 
after 24 weeks in patients with T2DM and HF
Change from baseline in LVESV index, 
LVEF, and LVM measured by MRI at 24 
weeks
Evaluate the effects of saxagliptin compared to 
placebo on NT-proBNP after 24 weeks of 
treatment
Change from baseline in NT-proBNP after 
24 weeks of treatment


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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1.1.3
Safety objectives
Safety Objective: 
Outcome Measure:
To assess the safety and tolerability of 
saxagliptin and sitagliptin treatment in patients 
with T2DM and HF
• Incidence of adverse events (AEs), serious 
adverse events (SAEs), AEs of special 
interest
• Collection of clinical 
chemistry/hematology parameters
• Vital signs
• Physical examination
• Incidence of independently adjudicated 
Cardiovascular (CV) events [death, 
myocardial infarction (MI), stroke, and 
hospitalization for heart failure (hHF)]
1.1.4
Exploratory objectives
Exploratory Objective: 
Outcome Measure:
Evaluate the effects of sitagliptin compared to 
placebo on LVEDV index, LVESV index, 
LVEF, and LVM after 24 weeks of treatment 
in patients with T2DM and HF
Change from baseline in LVEDV index, 
LVESV index, LVEF, and LVM measured by 
MRI at 24 weeks
Evaluate the effects of saxagliptin at Weeks 6 
and 12 and sitagliptin at 6, 12, and 24 weeks, 
compared to placebo on NT-proBNP
Change from baseline in NT-proBNP after 6, 
12, and 24 weeks
Evaluate the effects of saxagliptin and 
sitagliptin, on plasma volume at 6, 12, and 24 
weeks
Percent change from baseline in plasma 
volume using the Strauss formula after 6, 12, 
and 24 weeks
Evaluate the effects of saxagliptin and 
sitagliptin on changes from baseline body 
weight compared to placebo at 12 and 24 
weeks
Change from baseline in body weight at 12 
and 24 weeks
Evaluate the effects of saxagliptin and 
sitagliptin on changes from baseline HbA1c 
compared to placebo at 12 and 24 weeks
Change from baseline in HbA1c at 12 and 24 
weeks


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
13
Collect and analyze blood and urine samples 
for changes from baseline in 
 
 
at 6, 12, and 24 weeks. 
Samples will be collected for additional 
biomarkers that may be analyzed at the 
Sponsor’s discretion
Change from baseline of blood and urine 
biomarker values at 6, 12, and 24 weeks
Collect PK samples for analysis of plasma 
concentrations of saxagliptin and its major 
metabolite, 5-hydroxy saxagliptin; , and 
sitagliptin for PK/pharmacodynamic (PD) 
modelling at 6, 12, and 24 weeks in a subset 
of at least 150 patients
Plasma concentration in PK samples

Saxagliptin and its major metabolite,
5-hydroxy saxagliptin

Sitagliptin
1.2
Study design
Study D1680C00016 is a 24-week, multicenter, randomized, double-blind, parallel group, 
placebo-controlled study to evaluate study objectives and safety of therapy with saxagliptin, 
and sitagliptin, compared to placebo in adult patients with T2DM and HF with abnormal 
systolic function from both ischemic and non-ischemic causes, who have a diagnosis of 
Type 2 DM based on current ADA guidelines and documented LVEF ≤45% and NT-proBNP 
>300 pg/mL. 
Approximately 330 patients will be randomized in equal proportions (110 patients per group) 
to treatment with saxagliptin, sitagliptin, or placebo.  For patients with an eGFR ≥50 
mL/min/1.73 m2, the doses of the active treatments are as follows: saxagliptin 5 mg and 
sitagliptin 100 mg.  For patients with an eGFR <50 mL/min/1.73 m2, the doses of the active 
treatments will be adjusted as follows: saxagliptin 2.5 mg and sitagliptin 50 mg.
The study will comprise pre-screening and screening periods, a 24-week randomized 
treatment period and a 4-week follow up period. After randomization, patients will visit the 
study site for study assessments at Weeks 2, 6, 12, 18, and 24. Follow-up telephone calls will 
be conducted at Day 7, Week 3, and Week 9. Patients who complete the study will be asked to 
return for an end-of-study visit at Week 28. The schedule of study assessments is shown in 
Study flow chart (Figure 1) in the clinical study protocol.
CCI


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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Figure 1 - Study Design
1.3
Number of patients
Approximately 330 patients with T2DM and HF with abnormal systolic function from both 
ischemic and non-ischemic causes, who have a diagnosis of Type 2 DM based on current 
ADA guidelines will be randomized in a 1:1:1 ratio to 1 of 3 treatment groups (110 patients 
each arm):
Arm 1: Saxagliptin
Arm 2: Sitagliptin
Arm 3: Placebo
Sample size estimate
The comparison of saxagliptin versus placebo in LVEDV index is used to estimate sample 
size.  The mean change from baseline in LVEDV index at Week 24 will be assessed 
comparing saxagliptin versus the placebo treatment group.  The MRI analysis will claim non-
inferiority for the LVEDV index if the upper bound of the 95% confidence interval (CI) for 
the adjusted mean treatment difference between saxagliptin and placebo is less than the non-
inferiority margin, which will be taken as 10% of the overall (all treatments combined) 
baseline mean value. For purposes of the sample size calculation, this number will be assumed 
to be 6.5 mL/m2.  


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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To demonstrate non-inferiority of saxagliptin compared to placebo for the change from 
baseline to Week 24 in LVEDV index within a non-inferiority margin of 6.5 mL/m2, assuming 
a standard deviation (SD) of 15 mL/m2, and at a 1-sided significance level of 0.025, 
approximately 88 patients will be needed in each treatment group to provide approximately 
80% power (given a true difference of zero between saxagliptin and placebo).  Assuming that 
20% of patients will be missing an endpoint assessment, a total of approximately 330 patients 
(110 patients in each of the 3 treatment groups) must be randomized.
The non-inferiority margin estimate for the sample size calculation for LVEDV index is based 
on data from Foster et al 1998 [1], where the baseline LVEDV index is 65 ±13 (mean ±SD) 
mL/m2.  To exclude an increase in LVEDV index (relative to placebo) of greater than 10% of 
the baseline, the change seen with vildagliptin in LVEDV in the VIVIDD study, the non-
inferiority margin for these calculations is equivalent to 6.5 (65 × 0.10) mL/m2.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
There are six 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) will be defined as all randomized patients who take at least one 
dose of the study medication. Analysis of the FAS will be based on the randomized treatment.
2.1.3
Per protocol set
The per protocol set (PPS) will be defined as all FAS patients without any important protocol 
deviation (IPD) that might affect the analyses for the primary and secondary MRI endpoints
for the whole patient profile including baseline.  Patients with any IPD affecting post-baseline 
MRI values will partially be excluded from the per protocol MRI analyses for their post-
baseline measurements.
Treatment exposure less than 20 weeks
The clinical study protocol defines the analysis parameters for patients after a study treatment 
of 24 weeks. Patients who discontinued the study treatment earlier than 20 weeks after their 
individual first dose will be considered having a major impact on the primary endpoint, and 
will therefore also be partially excluded from the per protocol MRI analyses for their post-
baseline measurements.


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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The criteria for important protocol deviations are detailed in Appendix 3. 
2.1.4
Biomarkers per protocol set
The Biomarkers per protocol set (BPPS) will be defined as all FAS patients without any
important protocol deviation (PD) that might affect the analyses for the secondary endpoint 
for N- Terminal Pro-Brain Natriuretic Peptide for the whole patient profile including baseline. 
Patients with any IPD affecting post-baseline NT-proBNP values will partially be excluded 
from the per protocol analyses for their post-baseline measurements.
The criteria for important protocol deviations are detailed in Appendix 3. 
2.1.5
Safety analysis set
The safety analysis set (SAF) will be defined as all randomized patients who received at least 
one dose of study medication. This data set will be used to summarize safety data (AE, SAE, 
AEoSIs, adjudicated events, vital signs and laboratory parameters), and patient demography 
and their baseline data as well. 
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 
treatment period. In this case, safety data for such a patient will be analysed based on the first 
treatment the patient actually received.
2.1.6
PK analysis set
The PK analysis set will include all randomized patients for whom any plasma concentrations 
data were recorded.
2.2
Violations and deviations
IPDs are defined as those important deviations from the protocol likely to have an impact on 
the study objectives and/or safety of study treatments.
Protocol deviation monitoring
During study conduct, protocol deviations will be closely monitored and identified from two 
sources:

IMPACT monitoring – These are manually entered protocol deviations identified by the 
monitor during study conduct.

Programmed protocol deviations – These are deviations generated by execution of  
programs written using the predefined deviator descriptions in the SAP, see Appendix 3


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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The reports or information collected from IMPACT monitoring report will be reviewed and
assessed periodically during study conduct by AZ study team and documented in EXCEL 
spreadsheet.
Protocol deviation reporting
Protocol deviations will be reviewed in a blinded fashion by the study team prior to database 
lock. All decisions to exclude patients and/or data from the Full Analysis Set (to form the Per-
Protocol Analysis Set) will be made prior to the unblinding of the study and agreed by the 
study team. Protocol deviations that are determined to affect the primary analysis results are 
deemed IPDs. 
Appendix 3 specifies the criteria for IPDs for patients to be excluded from the per protocol 
analysis. Patients having IPDs will be summarized and listed by treatment group and overall. 
The list of protocol deviations (including IPDs) will be compiled separately and finalised prior 
to DBL. 
Potential Unblinding of treatment code to AstraZeneca Monitors
Mid March 2018 The Global Study Team made an incidental finding: Unblinding data was 
shown in the IWRS system where the Study Drug Accountability is recorded. It was possible 
to see the actual treatment allocation in the returned/accounted bottle after drilling down two 
levels in the module. This module was only accessible to AZ Monitors and the Global 
Operational Study Team. No AZ Monitors have reported that the unblinded information has 
been visible. This module was reportedly used only rarely during study conduct. Paper logs 
were used instead. Access to the module was removed immediately upon discovery of the 
flaw in the module. In response to queries no investigator or staff has claimed to have seen 
unblinded codes. The Quality issue has been investigated and managed according to AZ SOPs 
on how to handle a Quality Issue. A CAPA has been established.
The integrity of the study is not at risk because the primary and secondary endpoint data were 
not biased as the adjudicators do not get clinical data and so are still blinded to treatment. 
However, a subgroup analysis will be performed by the status of the patients being potentially 
unblinded or not, see section 4.2.6. Patients, who were randomized before the date of the 
corrective action on 15 March 2018 are stated as being potentially unblinded. The remaining 
patients were not unblinded. 
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 patients who were randomized but no actual treatment data is available, the 


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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Day 1 will be the date of randomization. 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. 
If the date T2DM was diagnosed is missing or 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 30th  
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. 


Statistical Analysis Plan 
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Edition Number 1.0
Date 13 October 2020
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3.1.3
Definition of Baseline Measurements 
Unless otherwise stated, for each patient, baseline value of a parameter is defined as the last 
available assessment on or prior to the date of the first dose of the study medication. 
Composed parameters will be derived from corresponding assessments as recorded at the 
same timepoint.
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.
3.1.5
Visit Assignment Windows
For all assessments recorded by visit and considered as obtained during the treatment period, 
the data records will be assigned to calculated visit windows (using study day) as described in 
Table 1 below. A data record refers to a unique set of assessments as specified with the Table 
2 in the CSP, as recorded on a visit. Single missing assessments in a data record will not be 
substituted by non-missing assessments from other data records.
Inclusion of a data record within the visit window will 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, see Table 1 - Visit Assignment Windows.
If a patient has more than one data record included within a window, the assessment closest to 
the target 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.
In case of two or more measurements for laboratory data with identical dates and times 
(including possibly missing times), the average value will be derived and in case that the 
record is assigned for the respective analysis visit the average value will be used for analysis. 
This will be done both for cases with multiple baseline values or with multiple post-baseline 
values with the same date and time.
Early termination visits will be assigned to their respective visit assignment window. 
The visits not considered as obtained during the treatment period will be reported as recorded, 
without re-assignment, e.g. end-of-study visit at Week 28. 


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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Table 1 - Visit Assignment Windows
Assessment 
Visit
Week
Target 
Day
Day Range
Vital signs, Body weight, Pregnancy testing
Day 1/Baseline
2
1
1 [a]
Week 2
4
2
15
2 to 29
Week 6
6
6
43
30 to 64
Week 12
8
12
85
65 to 106
Week 18
9
18
127
107 to 148
Week 24
10
24
169
from 149 onwards [b]
Safety laboratory, eGFR, Plasma volume, PK sampling, NT-proBNP, Biomarkers
Day 1/Baseline
2
1
1 [a]
Week 6
6
6
43
2 to 64
Week 12
8
12
85
65 to 127
Week 24
10
24
169
from 128 onwards [b] [c]
FPG
Week 6
6
6
43
2 to 64
Week 12
8
12
85
65 to 106
Week 18
9
18
127
107 to 148
Week 24
10
24
169
from 149 onwards [b]
HbA1c
Day 1/Baseline
2
1
1 [a]
Week 12
8
12
85
2 to 127
Week 24
10
24
169
from 128 onwards [b]
MRI
Day 1/Baseline
2
1
1 [a]
Week 24
10
24
169
any post-baseline assessment [d]
[a]
Study Day 1 is defined as date of study treatment.


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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[b] 
Safety laboratory data as defined in Table 2 - Chemistry and hematology 
assessmentsTable 2, and vital signs obtained up to and including 4 days (30 days for 
liver function laboratory tests) after the last dosing date will be used for assignment to 
the analysis visit windows.  Data obtained outside of this range will not be assigned to 
an analysis visit.
[c] 
For the biomarkers (NT-proBNP, 
 
) any post-baseline value is supposed to be 
mapped to the visit windows. For multiple values within the Week 24 window, the one 
will be selected, which was recorded:
1.
On treatment;
2.
In case of more than one value is on treatment, then the one closest to the target 
date (on day 128);
3.
In case of no on-treatment value in Week 24 window, the one closest to the end 
of treatment date will be chosen.
All Laboratory data for the biomarker endpoints will be used for assignment to the 
analysis windows with no exclusions because of rescue or treatment discontinuation.
[d]
Any post-baseline MRI recording is supposed to be selected for analysis. In case of 
multiple post-baseline MRIs, the one will be selected, which was recorded:
1.
On treatment;
2.
In case of more than one MRIs on treatment, then the one closest to the target 
date (on day 169);
3.
In case of no on-treatment MRI, the one closest to the end of treatment date 
will be chosen.
If ties still exist after these rules are applied, then the above rules for picking values 
closest to target will be used for the remaining values under consideration.
3.1.6
Handling missing data 
Missing data for the primary and secondary MRI analyses will be imputed using multiple 
imputation.  Partial dates will also be imputed.  For other values, missing data will not be 
imputed and will be treated as missing.
The primary, secondary, and exploratory analyses will be performed based on full analysis set 
(FAS) on observed data, regardless of rescue or discontinuation of the study treatment. When 
patients have their final MRI measurements done at ETD visit rather than at Week 24, these 
measurements will be used as the endpoint (effectively, a last observation carried forward 
(LOCF) analysis).
Multiple imputation will generally be performed for the analyses of the MRI parameters based 
on the MAR assumption, and on MNAR assumption for the primary endpoint as sensitivity 
analysis.
CCI


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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3.1.6.1
Imputation of partial dates
Concomitant Medication Dates
Start and stop date of all concomitant medications are collected on the CRF. In order to 
classify medication as prior, current or concomitant, partial, missing or invalid start and stop 
dates will be imputed where possible as follows:

If the reported start date is missing or invalid and the informed consent date is not 
missing or invalid, then the imputed start date is set equal to the informed consent date. 
If the consent date is missing or invalid and the birth date is not missing or invalid, 
then the imputed start date is set equal to the birth date. If the start date, the consent 
date and the birth date are all invalid or missing, then the imputed start date is set equal 
to missing.

If the reported start date is partially entered, then the imputed start date is set equal to 
the earliest possible reported start date based on the partial entered reported start date.

If the reported end date is missing, continuing, unknown or invalid, then the imputed 
end date is set equal to the most recent database extraction date or date of database 
lock.

If the reported end date of the medication is partial, then the imputed end date is set 
equal to the last possible reported end date based on the partial entered reported end 
date.
Imputed dates will not appear on the listings of non-study medication.
Adverse Events Onset Date
In the case an AE onset date is missing or partially missing, an imputation needs to be done to 
determine if the event is to be classified as occurring during the treatment period according to 
the rules in section 4.2.5.1.
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


Statistical Analysis Plan 
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-
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. 
A missing or incomplete end date of an AE will not be imputed.
3.1.7
Study periods
Screening Period: the Screening Period includes all data recorded on a date before the date of 
Day 1. 
Treatment Period: the start of the Treatment Period is the date of Day 1. The end of the 
Treatment Period is the date of Visit 10 (Week 24) or the date of last dose for subjects who 
prematurely and permanently discontinued.
For subjects who were lost to follow up during the Treatment Period without a recorded date 
of last dose, the end of the Treatment Period is the date of last known visit date (including 
contact visits), or the date of discontinuation, whichever is the latest.
3.2
Primary endpoint
The primary endpoint is the change from baseline in LVEDV index at 24 weeks of treatment 
measured by MRI to evaluate the effects of saxagliptin compared to placebo. 


Statistical Analysis Plan 
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Edition Number 1.0
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3.3
Secondary endpoints 
The following secondary variables will be analyzed to evaluate the effects of saxagliptin 
compared to placebo:

Change from baseline in LVESV index, LVEF, and LVM at 24 weeks of treatment 
measured by MRI; 

Change from baseline in NT-proBNP after 24 weeks of treatment.
3.4
Exploratory endpoints
The following exploratory endpoints will be analyzed:

Change from baseline in LVEDV index, LVESV index, LVEF, and LVM measured by 
MRI at 24 weeks to evaluate the effects of sitagliptin compared to placebo;

Change from baseline in NT-proBNP after 6, and 12 weeks to evaluate the effects of 
saxagliptin compared to placebo;

Change from baseline in NT-proBNP after 6, 12, and 24 weeks to evaluate the effects 
of sitagliptin compared to placebo;

Percent change from baseline in plasma volume using the Strauss formula after 6, 12, 
and 24 weeks;

Change from baseline in body weight at 12 and 24 weeks;

Change from baseline in HbA1c at 12 and 24 weeks;

Change from baseline of blood and urine biomarker values at 6, 12, and 24 weeks;

Plasma concentration in PK samples for:
o
Saxagliptin and its major metabolite, 5-hydroxy saxagliptin; and
o
Sitagliptin.
For analysis of PK data see section 4.2.7 PK analysis
3.5
Safety variables
The safety data, which will be collected for this study comprises: AEs/SAEs, AEoSIs, 
CV events, physical examination, 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 as start and stop 
date of AE, action taken and outcome will be recorded. 


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The incidences of CV events will independently be adjudicated according to the categories of:

CV Death, 

Myocardial infarction (MI), 

Stroke, and 

Heart failure.
For heart failure events the status about hospitalization (hHF), and/or urgent outpatient visits 
will be recorded.
The following AEs will be recorded and considered as adverse events of special interest 
(AEoSI):

Hypersensitivity reactions,

Severe cutaneous adverse reactions (SCAR),

Decreased lymphocyte count,

Pancreatitis,

Cardiac failure (including confirmed adjudicated cardiac failure events),

Renal impairment/renal failure.
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 at the Visits 2, 4, 6, 8, 10 for the Weeks 2, 6, 12, 18, and 
24 after randomization. The Pulse and seated BP will be measured twice (5 minutes apart).
3.5.3
Physical examination 
Physical examination findings from general appearance, skin inspection, lymph nodes, 
thyroid, abdomen, musculoskeletal/extremities, CV system, lungs, and reflexes observed at 
screening will be recorded with the medical history, whereas the findings which are new or 
aggravated compared to baseline will be recorded with the adverse events data. Therefore, no 
specific analysis for findings by body system from the physical examination will be 
performed. 
3.5.4
Laboratory Safety Variables
The following laboratory variables will be recorded during this study and summarized using 
descriptive statistics:


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Table 2 - Chemistry and hematology assessments
Hematology/Hemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Hemoglobin (Hb)
S/P Glucose
B-Hematocrit (Hct)
S/P HbA1c
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count
S/P-Alkaline phosphatase (ALP)
B-Platelet count
S/P-Aspartate transaminase (AST)
S/P-Alanine transaminase (ALT)
Urinalysis
S/P-Albumin
U-Hb/Erythrocytes/Blood
S/P-Potassium
U-Protein/Albumin
S/P-Sodium
U-Glucose
S/P-Creatine kinase (CK) 
U-Ketones
Hematology and Clinical Chemistry assessments will be performed according to the 
Study Plan (Table 2) in the clinical study protocol, whereas Urinalysis is performed during the 
screening period only.
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 primary, secondary, and 
exploratory 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 


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observed during the treatment period. Treatment group differences will not be assessed in 
summaries of shifts.
To demonstrate non-inferiority of saxagliptin compared to placebo the change from baseline 
in LVEDV index at Week 24 will be assessed and claimed non-inferiority if the upper bound 
of 95% confidence interval (CI) for the adjusted mean treatment difference between 
saxagliptin and placebo is less than 10% of the overall baseline value. 
The non-inferiority margin estimate for the sample size calculation for LVEDV index is based 
on data from Foster et al 1998 [1], where the baseline LVEDV index is 65 ±13 (mean ±SD) 
mL/m2.  To exclude an increase in LVEDV index (relative to placebo) of greater than 10% of 
the baseline, the change seen with vildagliptin in LVEDV in the VIVIDD study, the non-
inferiority margin for these calculations is equivalent to 6.5 (65 × 0.10) mL/m2.
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) using FAS.  The following patient disposition summaries 
will be provided: 

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 
patient's disposition page on the CRF) (Analysis Population: FAS).

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).

Number and percentage of screen failure-patients (i.e., patients enrolled but not 
randomized), further classified by reasons for screen failure (Analysis Population: 
EPS).
4.2.2
Demographics and other baseline characteristics
Demographic and baseline patient characteristics will be listed and summarized for the SAF.  
If the FAS differs 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).


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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;

Baseline BSA.
The baseline BSA will be calculated using the formula as defined by Mosteller [3]:
BSA (m²) = Height (cm) × Weight (kg)
3600
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 years, ≥65 years, ≥75 years);

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 (≥25 kg/m2 - ≤30 kg/m2), Obese (>30 kg/m2));

Geographic Region, as defined in Table 3:
Table 3 - Geographic regions
Geographic Region
Countries
North America
USA
South America
Chile
Asia Pacific
South Korea/ Republic of Korea, Thailand
Central Europe
Hungary, Romania, Bulgaria 
Eastern Europe
Russia, Ukraine


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4.2.2.2
Other baseline characteristics
As applicable, standard descriptive statistics, and total frequency counts and percentages of 
patients will be presented, as follows:
Baseline disease characteristics

Duration of type 2 Diabetes (years)

Duration of type 2 Diabetes (grouped as < 3years, ≥ 3 and ≤ 10 years, > 10 years);

Baseline HbA1c (%)

Baseline HbA1c (grouped as <7.0%, 7.0% to 9.0%, and >9.0%);

eGFR (mL/min/1.73 m2)

eGFR (grouped as <50 and >=50 mL/min/1.73 m2);

SGLT-2 inhibitor use (grouped as Yes/ No);

Baseline NYHA classification (grouped as I, II, III, IV);

;

  
 
  
 
  

LVEF (%)

LVEF (grouped as <= 45%, > 45%)

LVEF (grouped as <= 65%, > 65%)

LVEF (grouped as <40, >=40 - <50, >=50 - <60, >=60%)

Sinus rhythm (grouped as Yes, No)

Main etiology (grouped as Non-Ischemic, Ischemic, Valvular, Arrythmia, Unknown, 
Other);

NT-proBNP (pg/mL).

Serum Potassium (mmol/L);

Sodium (mmol/L);

Haemoglobin (g/L);
The baseline disease characteristics will also be presented by subgroups of LVEF at baseline 
at <=45%, > 45%, and <=65%, > 65%.
Baseline LVEDV index 
For determination of the non-inferiority margin for the primary endpoint the baseline LVEDV 
index will be summarized by treatment group and overall. 
4.2.2.3
Medical History
Diabetes-related medical history, surgical, and general medical history will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of 
patients will be summarized for the FAS by system organ class (SOC) and preferred term 
(PT). 
CCI
CCI


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The number and percentages of patients with diabetes complications (grouped as Any, 
Retinopathy, Neuropathy Autonomic, Neuropathy Peripheral, Nephropathy, Angiopathy, 
Other) will be presented. 
All medical history will be listed.
4.2.2.4
Prior Medications 
Previous medications, including any medication (other than study medication) taken prior and 
discontinued before the date of the first dose of study treatment (Day 1) 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 actual WHO Drug Dictionary version from the date of database 
lock will be used to code the non-study medication.
4.2.2.5
Elapsed time between randomization and final MRI measurements  
The elapsed time between baseline MRI measurements and final MRI measurements will be 
summarized as patient-24-weeks of follow up time, see also section 4.2.4.3.
4.2.3
Extent of Exposure and Treatment Compliance
4.2.3.1
Extent of Exposure – Study and Glycemic 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 each study medication will be summarized using the SAF for the 
treatment period, 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 
each study medication will also be presented.  Summaries will be presented for both methods 
including and excluding periods of treatment interruptions (defined by record of 0 tablets of 
study medications on the CRF). 
All glycemic rescue medication use during the treatment period will be summarized and listed 
by treatment group. 
A listing of patients by packaging/batch number of study medication will also be generated.
4.2.3.2
Extent of Exposure – Concomitant Medications
Concomitant medications include any medication taken at any time point during the treatment 
period regardless if the medication started during or prior to, but continued into the treatment
period.


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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 anti-diabetic medication

all concomitant heart failure related medication
The type of medication in terms of common concomitant, anti-diabetic, and heart failure 
related medication will be derived from the CRF module assigned to the respective type of 
medication.  Missing and partial date handling of start and stop dates of concomitant 
medications is described in section 3.1.6.1 above. 
For grouping of subjects taking, and not taking insulin and/or SUs (sulfonylurea agents) these 
medications will be identified from the anti-diabetic drugs by the ATC-codes: A10A for 
Insulin and A10BB for use of SUs.
4.2.3.3
Measurement of Treatment Compliance
Percent treatment compliance is calculated during treatment period for each study medication 
and overall. For each study treatment and overall, percent compliance is defined as follows: 
Number of doses actually administered
Number of doses planned
∗100
Where the number of doses planned is calculated as the number of days of the duration of the 
treatment period based on 1 tablet/day or 1 capsule/day during this period for saxagliptin and 
sitagliptin respectively: 
end date – start date + 1
The overall compliance rate refers to both 1 tablet/day and 1 capsule/day for the number of 
days during the treatment period: 
(end date – start date + 1) ∗2
The number of doses actually administered is calculated as: Total number of tablets or 
capsules dispensed - total number of tablets or capsules returned based on the CRF 
accountability pages.
A patient is considered compliant if percent overall compliance is ≥ 80% and ≤ 120%.  The 
number and percent of patients being compliant during the treatment period and a summary 
for the percent study treatment compliance rates will be displayed for the SAF per study 
treatment.


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Edition Number 1.0
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4.2.3.4
Heart failure related medication at start of study treatment
This analysis includes heart failure related medications taken prior to and continued at date of 
first dose of investigational product (Day 1). The medications will be summarized using the 
SAF dataset by drug class.
The type of medication in terms of heart failure related medication will be derived from the 
CRF module assigned to the respective type of medication.  Missing and partial date handling
of start and stop dates of concomitant medications is described in section 3.1.6.1 above. 
4.2.4
Analyses of study objectives
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 non-inferiority of saxagliptin compared to placebo for 
LVEDV index in the change from baseline to Week 24 within a non-inferiority margin of 10% 
of the overall baseline mean value in LVEDV index from FAS.
For a given MRI, values for the set of 4 left ventricular heart function parameters will be 
obtained from three different readers.  For each parameter, the average of all values provided 
by the readers will be used for analysis. 
The patient's LVEDV index (mL/m²) value will be derived from LVEDV (mL) as measured at 
baseline and week 24/ETD visit divided by the baseline BSA (m²), as 
LVEDV index (mL/m²) = LVEDV (mL)
BSA (m2)
LVESV index (mL/m²) value will similarly be derived, as
LVESV index (mL/m²) = LVESV (mL)
BSA (m2)
For the derivation of the baseline BSA (m²) see section 4.2.2.2 Other baseline characteristics.
The analyses for the MRI parameters on the full analysis set (FAS) will be performed based 
including all patients in the FAS having a non-missing baseline value. For the selection of 
MRI image readings for analysis see section 3.1.5.


Statistical Analysis Plan 
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Multiple imputation
Multiple imputation for Week 24 will be applied for all MRI analyses for FAS and PPS under 
the MAR assumption using the linear regression model: 
Y = intercept + ß1τ + ß2κ1 + ß3κ2 + ß4κ3 + ß5Mbaseline 
where
-
Y is the observed change from baseline,
-
κ1 is eGFR category (<50, ≥50 mL/min/1.73 m2), 
-
κ2 is SGLT-2 inhibitor use (yes, no), 
-
κ3 is the region,
-
τi is treatment group,
-
Mbaseline is the baseline measurement,
This will be implemented by use of the MONOTONE REG option in PROC MI including 
baseline as independent variable, and with:
-
NIMPUTE=200 steps; 
-
SEED=512. 
The results from the analyses will be combined for statistical inference using Rubin's rules 
from the SAS procedure MIANALYZE.
The remaining non-MRI endpoints will be analyzed based on observed data. No imputation 
will be applied on missing data.
Per protocol analysis
For the analyses of the MRI parameters for the per protocol set (PPS) the post-baseline 
measurements are required to be within 14 days after the last study treatment.  MRI 
measurements more than 14 days after the last study medication will be set to missing and not 
considered in the windows.  Missing final MRI values generated as a result of this will be 
imputed by use of the multiple imputation method as described above. Additionally, any other 
patients with missing final MRI data (but not missing baseline MRI data) generated by 
application of the per protocol criteria, (see Appendix 3) will be imputed using the same 
methodology.  Missing baseline MRI values will not be imputed.  All subjects in the per 
protocol population with a non-missing baseline value (after exclusions of data from 
application of the PP criteria) will be included in the primary per protocol analyses.
Maintain model convergence
The models will include stratification variables as fixed categorical effects. If the model does 
not converge or effects are not estimable then stratification levels will be combined or 
stratification variables will be dropped according to the following sequence:


Statistical Analysis Plan 
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1. Region will be combined as: Europe (Central Europe + Eastern Europe) vs others;
2. If the model still does not converge or if any effects are not estimable, the region 
variable will be dropped from the model;
3. If the model still does not converge or if any effects are not estimable, the variable for 
SGLT-2 use will be dropped from the model and instead the model will include the 
combined regions Europe/Others and eGFR status;
4. If the model still does not converge or if any effects are not estimable, then region 
variable will be dropped from the model and the model will include only the eGFR 
status variable;
5. If the model still does not converge or if any effects are not estimable, then eGFR 
status variable will be dropped from the model and no adjustments will be made for 
stratification variables.
4.2.4.1
Primary outcome variable
For the evaluation of the effects of saxagliptin compared to placebo in the change from 
baseline in LVEDV index at 24 weeks of treatment measured by MRI an analysis of 
covariance (ANCOVA) will be performed.  The SAS procedure PROC MIXED will be used.  
The preferred model will include the fixed categorical effects of treatment, eGFR category 
(<50, ≥50 mL/min/1.73 m2), SGLT-2 inhibitor use, region, and the continuous fixed 
covariates of baseline measurement. 
The following model will be used:
Cij = intercept + ß1 [Mbaseline,ij] + τi + κ1,m + κ2,q + κ3,r + error ij
where
-
Cij is the change from baseline for patient j in treatment group i,
-
ß1 is the slope coefficient for the baseline measurement,
-
κ1,m is the mean effect of eGFR category (<50, ≥50 mL/min/1.73 m2), 
-
κ2,q is the mean effect of SGLT-2 inhibitor use (yes, no), 
-
κ3,r is the mean effect of the region,
-
Mbaseline,ij is the baseline measurement of patient j in treatment group i,
-
τi is the mean effect of treatment group i,
-
error ij  is the error term for patient j in treatment group i.
The model will be calculated including all three treatment groups, and will provide 
least-squares mean estimates, SE and 2-sided 95% confidence intervals for the change from 
baseline per treatment group and for the differences between the treatment groups.  For the 
primary endpoint the results per treatment groups saxagliptin and placebo and for their
difference will be presented.  For the treatment difference the corresponding nominal p-value 
will also be presented on a descriptive level.


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Edition Number 1.0
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4.2.4.2
Secondary variables
The secondary endpoints to evaluate the effects of saxagliptin compared to placebo in the 
changes from baseline in LVESV index, LVEF, and LVM at 24 weeks of treatment measured 
by MRI the same model as described above for the primary endpoint will be applied. 
For the change from baseline in NT-proBNP after 24 weeks of treatment 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, eGFR category (<50, ≥50 mL/min/1.73 m2), SGLT-2 inhibitor use, region, 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 for analysis:
Cijk = intercept + ß1 [Mbaseline,ij] + τi + κ1,m + κ2,q + κ3,r + α k+ (α τ)ik + (α 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,
-
κ1,m is the mean effect of eGFR category (<50, ≥50 mL/min/1.73 m2), 
-
κ2,q is the mean effect of SGLT-2 inhibitor use (yes, no), 
-
κ3,r is the mean effect of the region,
-
Mbaseline,ij is the baseline measurement of patient j in treatment group i,
-
τi is the mean effect of treatment group i,
-
α k is the mean effect at time k
-
(α τ)ik is the interaction term between treatment group i and time k.
-
(α 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. 
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.


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For the selection of NT-proBNP measurements for analysis see section 3.1.5.
The models will be calculated including all three treatment groups, and will provide 
least-squares mean estimates, SE and 2-sided 95% confidence intervals for the change from 
baseline at all time points within and between treatments.  For the secondary endpoints the 
results per treatment groups saxagliptin and placebo and for their difference will be presented.  
For the treatment difference the corresponding nominal p-value will also be presented on a 
descriptive level.
For the analysis of the NT-proBNP for the biomarkers per protocol set (BPPS) the post-
baseline measurements are required to be within 14 days after the last study treatment.  
Measurements more than 14 days after the last study medication will not be included into the 
analysis.
4.2.4.3
Sensitivity analysis
Sensitivity analyses will be conducted for the primary endpoint for FAS using the same model 
and multiple imputation as described above. The multiple imputation will be done for the 
MNAR assumption by adding to each of the imputed values for the saxagliptin group, the 
non-inferiority margin of 10% of the overall baseline value.
Additional sensitivity analyses will be conducted on the primary and secondary MRI 
endpoints using post-baseline MRI values of at least 20 weeks (140 days) but no more than 28 
weeks (196 days) of follow up before the MRI measurements. The analysis will use the same 
ANCOVA approach, including multiple imputation, as the primary analysis.  Post-baseline 
MRI values outside this range will be set to missing and imputed using MAR multiple 
imputation.


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Another set of sensitivity analyses will be conducted on the primary and secondary MRI 
endpoints adjusting the change in the MRI endpoints for follow-up time between the initial 
and final MRI. A rate of change in the MRI endpoints will be expressed per patient-24-weeks
of follow up time, as: 
Adjusted MRI endpoint =
789 :;<=>?;@
AB@?:;@-24-E::FG >H H>II>E J= @?K:
Whereas: 
Patient-24-weeks of follow up time
= NB@: >H =>G@-OBG:I?;: 789 −NB@: >H OBG:I?;: 789
168
The analysis will use the same multiple imputation and ANCOVA approach as the primary 
analysis. Scatter plots will be provided, presenting the changes in the MRI values from 
baseline to Week 24 versus the patient-24-weeks of follow up time.
Furthermore, the primary endpoint for the full analysis set will be analyzed for sensitivity 
based on the actual strata eGFR category (<50, ≥50 mL/min/1.73 m2), and SGLT-2 inhibitor 
use, as derived from the clinical data. 
For the sensitivity analyses, least squares mean estimates and 2-sided 95% confidence 
intervals for changes from baseline within and differences in change from baseline between 
treatments will be provided.  For the treatment differences the corresponding nominal p-values 
will also be presented on a descriptive level.
4.2.4.4
Exploratory variables 
The following exploratory endpoints will be analyzed using the same models as described 
above for the primary and secondary variables, as applicable (using MMRM for variables with 
multiple post-baseline measurements and ANCOVA for those with a single scheduled post-
baseline measurement).:

Change from baseline in LVEDV index, LVESV index, LVEF, and LVM measured by 
MRI at 24 weeks to evaluate the effects of sitagliptin compared to placebo;

Change from baseline in NT-proBNP after 6, and 12 weeks to evaluate the effects of 
saxagliptin compared to placebo;

Change from baseline in NT-proBNP after 6, 12, and 24 weeks to evaluate the effects 
of sitagliptin compared to placebo;

Percent change from baseline in plasma volume after 6, 12, and 24 weeks based on the 
Strauss formula as defined in Strauss et al 1951 [2]:
% Change in PV = 100 ∗
TOUVWXYZ[X
TO\]W^_UVWXYZ[X
∗1 −T`@\]W^_UVWXYZ[X
1 −T`@UVWXYZ[X
−100


Statistical Analysis Plan 
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A baseline covariate for the model will be derived according to Hakim RM [5]:
Baseline PV = 1 −T`@UVWXYZ[X(aB@?>) ∗a + b ∗b:?cℎ@UVWXYZ[X(kg)
Whereas:
a = e
1530, KBI:
864,H:KBI:
O = e
41, KBI:
47.9, H:KBI:
The modelling will be performed twice, one without, and one with applying of the 
Baseline PV covariate. 

Change from baseline in body weight at 12 and 24 weeks;

Change from baseline in HbA1c at 12 and 24 weeks; 
(In case where the central measurement of HbA1C was not possible due to hemoglobin 
variants not compatible with the central assay, no value will be centrally collected and 
these subjects will be excluded from the HbA1c analysis);

Change from baseline of blood and urine biomarker values at 6, 12, and 24 weeks;
For the exploratory analyses, least squares mean estimates and 2-sided 95% confidence 
intervals for changes from baseline within and differences in change from baseline between 
treatments will be provided.  For the treatment differences the corresponding nominal p-values 
will also be presented on a descriptive level.
4.2.4.5
Percent Change from Baseline in NT-proBNP and Biomarkers
In case of skewed distribution for NT-proBNP and the Biomarkers (
 
) the MMRM models 
will be applied as described above for the logarithms (ln) of the post- to pre-treatment ratios, 
and the logarithms of the baseline measurements. The results from PROC MIXED (adjusted 
means and the confidence intervals) will be back-transformed to the percentage scale using the 
formula: 
A:a`:;@Bc: = 100 ∗(:kXWlY^ −1).
The estimate of the difference versus PLAC and the confidence interval will be transformed to 
the ratio by: rB@?> = :XW^ZmV^X.
4.2.5
Safety analyses
Safety analyses will be performed using the Safety analysis set, including data after the 
addition of glycemic rescue concomitant medication or change of heart failure concomitant 
medication.
CCI


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4.2.5.1
Adverse Events
Adverse Events (AEs) will be classified by Primary SOC and PT according to MedDRA.
In summaries by SOC and PT, AEs will be sorted by overall decreasing frequency within each 
SOC and PT within the saxagliptin group.  In summaries by PT, AEs will be sorted by 
decreasing frequency of each PT within the saxagliptin group.
For summaries presenting the incidence rates per 100 patient years, this will be calculated by 
number of patients with AEs divided by the total number of days under study treatment across 
all patients per treatment group, multiplied by 365.25 multiplied by 100.
All Adverse Events
An overall summary of adverse events occurred during the study and during the treatment 
period at patient level, including AEs, SAEs, death, severe events, treatment-related events, 
events leading to the discontinuation of study medication, events leading to death will be 
presented.  All AEs (serious and non-serious) occurred during the study and during the 
treatment period will be summarized by SOC and PT.  In addition, a patient listing of all 
reported AEs will be produced.  This will include displaying events that occurred prior to the 
start date of treatment period, if any. All AEs (serious and non-serious) will also be 
summarized by treatment group, where applicable.
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 
treatment emergent. Adverse events leading to discontinuation with onset on or after Day 1 
will generally be considered as treatment emergent.
In addition, the following summaries will be provided for the treatment period:

Most common adverse events and incidence rates per 100 patient years by preferred 
term and treatment group (i.e., reported by ≥ 5 % 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 ≥ 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
Number of adverse events of special interest and their incidence rates per 100 patient years 
will be tabulated. The event categories of AEoSI for this study may include, but are not 
limited to:  


Statistical Analysis Plan 
Study Code D1680C00016
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-
Hypersensitivity reaction;  
-
Severe cutaneous adverse reaction (SCAR) (explicitly including bullous pemphigoid);
-
Decreased lymphocyte count (lymphocytopenia);
-
Pancreatitis;
-
Cardiac failure (including confirmed adjudicated cardiac failure events);
-
Renal impairment/renal failure.
For identification of the AEoSI the Sponsor provides a set of the specific Standard and 
Customized MedDRA queries. 
Separate summaries similar to those produced for AEs/SAEs will be provided for AEoSI.
4.2.5.2
Serious Adverse Events
All adverse events, which are indicated as serious in the CRF, will be summarized for the 
number of patients with at least one serious adverse event by treatment group.
4.2.5.3
Adverse Events adjudicated as CV Deaths, heart failure, MIs, strokes
An overall summary will be presented showing death cases, and adverse events related to: 
heart failure, MIs, and strokes as recorded in the CRF and adjudicated as:
-
CV Death; 
-
Heart Failure;
-
Cardiac Ischemic Event (MIs);
-
Cerebrovascular Event (strokes).
In case of adjudication of an event in more than one category (e.g. a heart failure event with 
fatal outcome adjudicated as both a heart failure event and cardiovascular death event) the 
event will be counted once within each category.   
4.2.5.4
Hospitalization with heart failure
A summary will be presented showing number of patients who experienced a hospitalization 
with heart failure by the primary reason for the hospitalization, as:
-
Heart failure
-
Acute coronary syndrome
-
Pneumonia
-
Other infection
-
Other cause.
4.2.5.5
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 captured and 
included 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.


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
41
4.2.5.6
Clinical laboratory variables  
The clinical laboratory values and changes from baseline at each scheduled time point will be 
summarized by treatment group using descriptive statistics, for laboratory tests as described in 
in the CSP, see
Table 4 below. All other tests will be included in patient listings, only. 
The summaries will be presented using SI units in general and for the conventional units, as 
listed in Appendix 1.
Laboratory data obtained after the start of study medication dosing up to and including 4 days 
(30 days for liver function laboratory tests) after the last dosing date will be considered as 
obtained during the treatment period.
Table 4 - Laboratory Safety Variables
Hematology/Hemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Hemoglobin (Hb)
S/P Glucose
B-Hematocrit (Hct)
S/P HbA1c
B-Leukocyte count
S/P-Creatinine
B-Leukocyte differential count
S/P-Bilirubin, total
B-Platelet count
S/P-Alkaline phosphatase (ALP)
S/P-Aspartate transaminase (AST)
S/P-Alanine transaminase (ALT)
Urinalysis
S/P-Albumin
U-Hb/Erythrocytes/Blood
S/P-Potassium
U-Protein/Albumin
S/P-Sodium
U-Glucose
S/P-Creatine kinase (CK) 
U-Ketones
The number and percentage of patients with laboratory values outside normal range will be 
summarized by shift tables from baseline to the post-baseline maximum and minimum value 
during the treatment period for each treatment group. 
Laboratory values meeting marked abnormality criteria, as defined in Appendix 2, will be 
summarized for each treatment group. The marked abnormalities will be analyzed overall for 
any post-baseline data, regardless the baseline values are available for the parameters.
To apply for a worst-case scenario for missing data, for patients having missing pre-treatment 
values the respective portion of the marked abnormality criterion will be assumed as fulfilled.


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
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For liver safety, a summary of proportion of subjects with elevated liver test including 
elevated AT (ALT and/or AST) and total bilirubin (see Appendix 2 for definition) will be 
provided. No comparison vs. baseline is required to include these elevations in the summary.
For laboratory test values that have been received with an operator sign as a part of the result 
(>, ≥, <, or ≤), the operator sign will be stripped and the resulting numeric value will be used 
for data analysis. The raw value with operator will remain in the database as such in the 
electronic record and will be displayed in listings.
Baseline urinalysis results will be presented by means of frequency and percentage.
4.2.5.7
Vital signs 
Vital signs measurements in terms of systolic blood pressure, diastolic blood pressure, and 
heart rate will be recorded according to the Study Plan (Table 2) in the clinical study protocol 
by two readings and average reading.
The average values and changes from baseline of the average values will be summarized for 
each scheduled time point by treatment group using descriptive statistics.
Vital signs measurements obtained after the start of study medication dosing up to and 
including 4 days after the last dosing date will be considered as obtained during the treatment 
period.
4.2.6
Subgroup analyses
Primary and secondary variables
The subgroup analyses of the primary variable (change from baseline in LVEDV index) will 
be performed on the primary analysis model for the comparison of SAXA vs. PLAC for the 
full analysis set on the subgroups as defined by the following variables:

Baseline HbA1c (<7.0%, 7.0% to 9.0%, and >9.0%);

Gender (male, female);

Age (<65, ≥65 years);

Duration of T2DM (< 3 years, ≥ 3 and ≤ 10 years, > 10 years);

eGFR (<50, ≥50 mL/min/1.73 m2);

SGLT-2 inhibitor use (Yes/ No);

Geographic Region (North America, South America, Asia Pacific, Central Europe, 
Eastern Europe);


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
43

Baseline NYHA classification (I, II, III, IV);

Patient status of potentially unblinded, see section 2.2 for the paragraph Potential 
Unblinding of treatment code to AstraZeneca Monitors.
In addition subgroup analyses of the primary and secondary variables (change from baseline 
in LVEDV index, LVESV index, LVEF, LVM, NT-proBNP after 24 weeks) will be 
performed on the subgroups of LVEF at baseline (<=45%, > 45%) for the treatment 
comparison of SAXA vs. PLAC for both, full analysis set and per protocol set, and for SITA 
vs. PLAC for the full analysis set using the same models as defined for the primary and 
secondary analyses in section 4.2.4 and 4.2.4.2, as applicable.
Similarly, analysis for LVEDV index will be performed on the subgroups of LVEF at baseline 
(<=65%, > 65%) for the treatment comparison of SAXA vs. PLAC for the full analysis set. 
Point estimates and 95% confidence intervals will be calculated for the adjusted changes 
within each treatment group as well as for the differences in adjusted changes between 
treatment groups.  For the treatment differences the corresponding nominal p-values will also 
be presented on a descriptive level.  For each subgroup analysis, the median p-values for the 
interaction tests will be reported along with the results obtained from Rubin’s rules.  In case 
that the subgroup classification was derived from a continuous variable, the continuous 
variable will be submitted with the treatment interaction term to a separate model to obtain the 
interaction p-value.  
If problems with convergence or estimability occur for the subgroup analyses, the effects in 
the model will be modified or dropped according to the modification rules as defined in 
section 4.2.4.
Adverse events
The overall summary for adverse events adjudicated as CV Deaths, heart failure, MIs, strokes, 
as defined in section 4.2.5.3, and the summary of the number of patients who experienced a 
hospitalization with heart failure by the primary reason, as described in section 4.2.5.4 will 
separately be presented per LVEF subgroup at baseline (<=45%, > 45%).
4.2.7
PK analysis
Analysis of PK data is not part of this statistical analysis plan and will be reported separately 
from the clinical study report. The plasma concentrations will be listed. Not any transition of 
the concentration data to numeric analysis variables will be performed.


Statistical Analysis Plan 
Study Code D1680C00016
Edition Number 1.0
Date 13 October 2020
44
5.
INTERIM ANALYSES (NOT APPLICABLE)
6.
CHANGES OF ANALYSIS FROM PROTOCOL 
No updates were made from the clinical study protocol. 
7.
REFERENCES 
1
Foster RE, Johnson DB, Barilla F, Blackwell GG, Orr R, Roney M, et al. Changes in 
left ventricular mass and volumes in patients receiving angiotensin-converting enzyme 
inhibitor therapy for left ventricular dysfunction after Q-wave myocardial infarction. 
Am Heart J 1998;136: 269-75.
2
Strauss et al 1951
Strauss MB, Davis RK, Rosenbaum JD, Rossmeisl EC. Water dieresis produced 
during recumbency by the intravenous infusion of isotonic saline solution. 
J Clin Invest 1951;30:862– 8.
3
Mosteller RD 1987 
Simplified calculation of body-surface area. 
N Engl J Med. Oct 22; 317(17):1098
4
Maceira et al. 2010
Reference left atrial dimensions and volumes by steady state free precession 
cardiovascular magnetic resonance. 
Journal of Cardiovascular Magnetic Resonance 2010 12:65.
5
Hakim RM
Daugirdas JT, Blake PG, Ing TS, eds. Handbook of  dialysis, 3rd ed. 
Philadelphia: Lippincott, Williams and Wilkins; 2001. p 236.
6
SAS
SAS/STATS® User Guide, Version 9.4, Cary, North Carolina, SAS Institute 
Inc.


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Document Name: d1680c00016-sap-ed-1
Document Title:
Statistical Analysis Plan Edition 1.0
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Version Label:
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22-Oct-2020 15:31 UTC
Content Approval
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Content Approval
22-Oct-2020 15:24 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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