Clinical trial NCT03387683
Conditions: Diabetes Mellitus Type 2
Sponsor: AstraZeneca
Start date: 2018-02-28; Completion date: 2019-03-19
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomised, placebo-controlled, double-blind, parallel-group, international, multicentre, Phase IV study to investigate the effects of dapagliflozin on cardiac substrate uptake, myocardial efficiency and myocardial contractile work in T2D patients. Eligible subjects with T2D before randomisation and fulfilling all of the inclusion criteria and none of the exclusion criteria will be randomised in a 1:1 ratio to dapagliflozin 10 mg or placebo once daily and treated for six weeks. The study includes five visits.

Detailed description:
The following will be assessed at Baseline and at the end of the treatment period;

1. MRI scanning in order to assess cardiac function and morphology. The MRI scanning will be made after fasting for at least 6 hours in the same time of day at all visits. The cardiac MRI examination will be performed in accordance with a pre-defined MRI protocol, with the total scan time at each visit estimated to 45 minutes. Images from all sites will be analyzed centrally at the core-lab using a dedicated software package and certified analysts.
2. CT-PET scanning will be made to assess myocardial function and metabolism, as well as fatty acid metabolism in brain, liver and kidney cortex. The CT-PET scanning will be made after a fast as well as abstinence from nicotine, alcohol and caffeine for at least 6 hours at the same time of day at all visits.

   * A cardiac 11C-Acetate PET/CT examination is performed (IV 400 MBq 11C-Acetate).
   * A cardiac 18F-FTHA PET/CT examination is performed (IV 150 MBq 18F-FTHA). The subject is further examined by PET/CT over the liver, kidney cortex and brain (in this order) for uptake of 18F-FTHA. Arterialized venous samples are acquired throughout to assess P-NEFA and 18F-FTHA metabolism by metabolite analysis

Arms: arm 1: placebo tablets once daily arm 2: dapagliflozin 10mg tablets once daily
Interventions: intervention 1: dapagliflozin intervention 2: placebo
Intervention descriptions: intervention 1: dapagliflozin 10mg intervention 2: placebo to match dapagliflozin

Protocol documents:
Prot_001.pdf: 
Clinical Study Protocol - 2
AstraZeneca
dapagliflozin - D1690C00063
Clinical Study Protocol 
Drug Substance
dapagliflozin
Study Code
D1690C00063
Version
2
Date
5 February 2018
DAPACARD
A double-blind, randomized, parallel group, Phase IV study to investigate 
the effects of DAPAgliflozin on CARDiac substrate uptake, myocardial 
efficiency and myocardial contractile work in type 2 diabetes patients 
Sponsor: AstraZeneca AB, S-151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s): 2017-003820-58


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VERSION HISTORY
Version 1, 25 October 2017
Initial creation
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.
Version 2, 5 February 2018
Additional scanner type (integrated MRI/PET machine) for assessment of PET related 
endpoints.
Rational for change: To provide the possibility to use several machines to optimize PET 
assessment availability.
Sections affected: 1.1 (Schedule of Activities), 2.3 (Benefit/risk assessment), 5.2 (Exclusion 
criteria), 5.3 (Lifestyle restrictions), 7.1.2 (Procedures for discontinuation of study 
treatment), 8.1.2 (Cardiac Assessment via Computed Tomography and Positron Emission 
Tomography (CT-PET)).
---
Update regarding PET assessment with 18F-FTHA tracer. The 18F-FTHA examinations are 
exploratory and will not be performed in all the randomized patients. Instead, a minimum 40 
and maximum of 44 of the randomized patients will perform the examinations.
Rational for change: The change is due to ethical reasons and aims to limit unnecessary 
exposure to radioactivity.
Sections affected: 2.3 (Benefit/risk assessment), 3 (Objectives and endpoints), 8.1.2 (Cardiac 
Assessment via Computed Tomography and Positron Emission Tomography (CT-PET)), 
9.2 (Sample size determination), 10 (References).


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TABLE OF CONTENTS
TITLE PAGE............................................................................................. 1
VERSION HISTORY................................................................................ 2
TABLE OF CONTENTS........................................................................... 3
1.
PROTOCOL SUMMARY ......................................................................... 7
1.1
Schedule of Activities (SoA)...................................................................... 7
1.2
Synopsis .................................................................................................... 9
1.3
Schema .................................................................................................... 11
2.
INTRODUCTION ................................................................................... 12
2.1
Study rationale......................................................................................... 12
2.2
Background.............................................................................................. 12
2.2.1
Cardiovascular disease in type 2 diabetes mellitus.................................... 12
2.2.2
Cardiovascular outcomes with SGLT-2 inhibition.................................... 12
2.3
Benefit/risk assessment ............................................................................ 13
3.
OBJECTIVES AND ENDPOINTS.......................................................... 14
4.
STUDY DESIGN..................................................................................... 16
4.1
Overall design.......................................................................................... 16
4.2
Scientific rationale for study design ......................................................... 16
4.3
Justification for dose................................................................................ 18
4.4
End of study definition............................................................................. 18
5.
STUDY POPULATION .......................................................................... 18
5.1
Inclusion criteria ...................................................................................... 18
5.2
Exclusion criteria ..................................................................................... 19
5.3
Lifestyle restrictions................................................................................. 21
5.3.1
Meals and dietary restrictions................................................................... 21
5.3.2
Caffeine, alcohol, and tobacco.................................................................. 21
5.3.3
Activity.................................................................................................... 21
5.4
Screen failures ......................................................................................... 21
6.
STUDY TREATMENTS......................................................................... 21
6.1
Treatments administered .......................................................................... 22
6.1.1
Investigational products ........................................................................... 22
6.1.2
Non-Investigational Medicinal Products................................................... 22
6.2
Preparation/handling/storage/accountability............................................. 22
6.3
Measures to minimise bias: randomisation and blinding........................... 23
6.4
Treatment compliance.............................................................................. 24


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6.5
Concomitant therapy................................................................................ 24
6.5.1
Background medication............................................................................ 24
6.5.2
Other concomitant treatment .................................................................... 25
6.6
Dose modification (Not applicable).......................................................... 25
6.7
Treatment after the end of the study (Not applicable) ............................... 25
7.
DISCONTINUATION OF TREATMENT AND SUBJECT 
WITHDRAWAL ..................................................................................... 25
7.1
Discontinuation of study treatment........................................................... 25
7.1.1
Temporary discontinuation (Not applicable)............................................. 26
7.1.2
Procedures for discontinuation of study treatment .................................... 26
7.2
Lost to follow-up ..................................................................................... 26
7.3
Withdrawal from the study....................................................................... 27
8.
STUDY ASSESSMENTS AND PROCEDURES..................................... 27
8.1
Efficacy assessments................................................................................ 28
8.1.1
Cardiac Assessment via Magnetic Resonance Imaging (MRI).................. 28
8.1.2
Cardiac Assessment via Computed Tomography and Positron Emission 
Tomography (CT-PET) or via Magnetic Resonance Imaging and Positron 
Emission Tomography (MRI-PET) .......................................................... 29
8.2
Safety assessments................................................................................... 31
8.2.1
Clinical safety laboratory assessments...................................................... 31
8.2.2
Physical examinations.............................................................................. 32
8.2.3
Vital signs................................................................................................ 32
8.2.4
Electrocardiograms .................................................................................. 32
8.2.5
Echocardiograms ..................................................................................... 33
8.2.6
Other safety assessments.......................................................................... 33
8.2.6.1
Diabetic ketoacidosis ............................................................................... 33
8.3
Collection of adverse events..................................................................... 33
8.3.1
Method of detecting AEs and SAEs ......................................................... 34
8.3.2
Time period and frequency for collecting AE and SAE information ......... 34
8.3.3
Follow-up of AEs and SAEs .................................................................... 34
8.3.4
Adverse event data collection................................................................... 35
8.3.5
Causality collection.................................................................................. 35
8.3.6
Adverse events based on signs and symptoms.......................................... 36
8.3.7
Adverse events based on examinations and tests ...................................... 36
8.4
Safety reporting and medical management ............................................... 36
8.4.1
Reporting of serious adverse events ......................................................... 36
8.4.2
Pregnancy ................................................................................................ 37
8.4.2.1
Maternal exposure.................................................................................... 37
8.4.3
Overdose.................................................................................................. 38
8.4.4
Medication error ...................................................................................... 38
8.5
Pharmacokinetics ..................................................................................... 38


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8.5.1
Determination of drug concentration........................................................ 39
8.5.2
Storage and destruction of pharmacokinetic samples................................ 39
8.6
Pharmacodynamics .................................................................................. 39
8.7
Genetics................................................................................................... 39
8.8
Biomarkers .............................................................................................. 39
8.8.1
Storage, re-use and destruction of biomarker samples .............................. 41
8.9
Medical Resource Utilization and Health Economics ............................... 41
9.
STATISTICAL CONSIDERATIONS...................................................... 41
9.1
Statistical hypotheses ............................................................................... 41
9.2
Sample size determination........................................................................ 41
9.3
Populations for analyses........................................................................... 42
9.4
Statistical analyses ................................................................................... 43
9.4.1
Efficacy analyses ..................................................................................... 43
9.4.2
Safety analyses......................................................................................... 44
9.4.3
Other analyses.......................................................................................... 44
9.4.4
Methods for multiplicity control............................................................... 44
9.5
Interim analyses (Not applicable)............................................................. 44
9.5.1
Data monitoring committee (DMC) (Not applicable)................................ 44
10.
REFERENCES ........................................................................................ 44
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS............................................................................... 48
LIST OF TABLES
Table 1
Study of Assessments......................................................................... 7
Table 2
Study Objectives ............................................................................... 14
Table 3
Study Treatments .............................................................................. 22
Table 4
Restricted medications ...................................................................... 24
Table 5
Prohibited medications...................................................................... 24
Table 6
MRI variables.................................................................................... 29
Table 7
CT-PET or MRI-PET variables ......................................................... 31
Table 8
Laboratory safety variables................................................................ 32
Table 9
Biomarkers........................................................................................ 40


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LIST OF FIGURES
Figure 1
Study design...................................................................................... 11
LIST OF APPENDICES
Appendix A Regulatory, ethical and study oversight considerations ...................... 48
Appendix B
Adverse event definitions and additional safety information.............. 52
Appendix C Handling of Human Biological Samples............................................ 56
Appendix D Abbreviations.................................................................................... 58


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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA) 
Table 1
Study of Assessments
Screening
Randomization 
Baseline
Interim visit 
(Phone visit)
End of 
treatment
Safety Follow-up
(Phone visit)
Details in protocol section or 
Appendix
Visit
1
2
3
4
5
Visit 2 and 4 may be conducted 
over two days
Day 
-21 to 0
1
14
42
49
(visit window ± 4 days from Day 14 onwards)
Informed consent 
X
Section 5.1
Inclusion / exclusion criteria
X
X
Section 5.1 and 5.2
Routine clinical procedures
Demography
X
Section 5.1
Physical examination
X
Section 8.2.2
Medical history and comorbid conditions
X
Section 5.1
Vital signs
X
X
X
Section 8.2.3
Height
X
Section 8.2.2
Weight
X
X
X
Section 8.2.2
ECG 
X
Section 8.2.4
Echocardiogram
X
Section 8.2.5
Concomitant medication
X
X
X
X
Section 6.5
Routine safety measurements
SAE
X
X
X
X
X
Section 8.3
DAE
X
X
X
X
Section 8.3
Diabetic ketoacidosis events
X
X
X
X
Section 8.2.6.1
Pregnancy test (serum or urine)
X
X
X
Section 5.2, 8.1.2 and Table 8
Clinical chemistry and haematology
X
X
X
Section 8.2.1
Blood and Urine analyses (except Safety analyses)
HbA1c (screening)
X
Section 5.1
Biomarkers (fasting)
X
X
Section 8.5, 8.8 and Table 9


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Table 1
Study of Assessments
Screening
Randomization 
Baseline
Interim visit 
(Phone visit)
End of 
treatment
Safety Follow-up
(Phone visit)
Details in protocol section or 
Appendix
Visit
1
2
3
4
5
Visit 2 and 4 may be conducted 
over two days
Day 
-21 to 0
1
14
42
49
(visit window ± 4 days from Day 14 onwards)
Urine sample
X
X
Section 8.8
Pharmacokinetic measurements
Pre-dose blood sample
X
Section 8.5
Efficacy measurements
MRI (fasting)
X
X
Section 8.1.1 and 5.3
CT-PET/MRI-PET (fasting)
X
X
Section 8.1.2 and 5.3
Study Treatment Administration
Randomisation
X
Section 6.3
Study treatment dispensed (daily dosing)
X
Section 6
Study treatment return
X
Section 6.4


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1.2
Synopsis
National Coordinating Investigator, Sweden
 SWEDEN
National Coordinating Investigator, Finland
 
FINLAND
Co-coordinating Investigator, Sweden
 
 SWEDEN
Protocol Title: A double-blind, randomized, parallel group, Phase IV study to investigate the 
effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency and myocardial 
contractile work in type 2 diabetes patients
Short Title: DAPACARD
Rationale: 
The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin was associated with 
lower cardiovascular mortality and hospitalization for heart failure. The effect was apparent 
within months from treatment start, suggesting that mechanisms beyond improved glucose 
control may be involved. Additionally, the SGLT2 inhibitor canagliflozin reduced combined 
endpoint of cardiovascular death and disease, including hospitalization for heart failure further 
reinforcing that SGLT2 inhibitors protect the heart in type 2 diabetes. The aim of the current 
study is to investigate the effects of dapagliflozin (a SGLT2i) on myocardial function and 
metabolism.
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To compare the changes in global longitudinal strain of 
the left ventricle (GLSLV) achieved with dapagliflozin 
versus placebo after 6 weeks of double-blind treatment.
Change from baseline in GLSLV (%)
Secondary objective:
To compare the changes in myocardial efficiency (%) 
achieved with dapagliflozin versus placebo after 6 weeks 
of double-blind treatment.
Endpoint/variable:
Change from baseline in myocardial efficiency (%)
Safety objective:
Endpoint/variable:
PPD
PPD
PPD
PPD


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Objectives and Endpoints
To evaluate the safety and tolerability of dapagliflozin.
Adverse Events leading to Discontinuation of Study 
Medication (DAEs) / Serious Adverse Events (SAEs)
Collection of clinical chemistry/haematology 
parameters
Overall design:
A double-blind, randomized, parallel group placebo controlled Phase IV study in type 2 
diabetes patients.
Planned number of sites: 
approximately 3-4
Participating countries: 2, Sweden and Finland
Study Period:
Estimated date of first patient enrolled Q1 2018
Estimated date of last patient completed Q3 2019
Number of Subjects:
Planned number of subjects: 52 (26 per arm) randomized subjects, assuming a 15% non-
evaluable rate. The evaluable population is the Per Protocol population.
It is estimated that approximately 80-100 subjects need to be screened. Screen failures are 
defined as subjects who signed the informed consent form to participate in the clinical study 
but are not subsequently randomly assigned to Study treatment.
Treatments and treatment duration:
The study includes 5 visits; screening, randomization/baseline, interim, end-of-treatment and 
follow-up during a total period of maximum 74 days for each subject.
After a screening period of up to 21 days, subjects will be randomized in a 1:1 ratio to 
dapagliflozin 10 mg or placebo tablet, taken orally once daily. The treatment period is 6 weeks 
after which a follow-up contact is made approximately 7 days later.
Statistical methods
The analysis of efficacy will be based on the evaluable analysis set. Change from baseline 
values for the primary variable, global longitudinal strain of left-ventricle, will be analyzed 
using analysis of covariance. The model will include terms for baseline value and treatment.
Least square mean change from baseline estimates, as well as the corresponding 95 percent 
confidence limits, will be generated from the fitted model for each treatment group. The 
difference in least square mean between the dapagliflozin and placebo treatment groups, the 
corresponding 95 percent confidence interval and the p-value will also be presented. Statistical 
significance will be inferred at a (two-sided) 0.05 level.


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The analysis of safety will be based on the safety analysis data set. Safety data during the 
treatment period will be evaluated and variables will only be summarized descriptively. 
Discontinuation due to adverse events and serious adverse events will be summarized by 
system organ class and preferred term and listed for each patient. The number and percent of 
subjects that discontinue due to adverse events and, separately, that experience at least one 
serious adverse event will be summarized for each treatment group. Descriptive statistics of 
continuous measurements (e.g. safety laboratory assessments and vital signs) will be presented 
by treatment for both absolute values and changes from baseline. Safety laboratory, vital signs, 
physical examination and ECG findings will be listed by patient.
1.3
Schema
The general study design is summarised in Figure 1.
Figure 1
Study design


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2.
INTRODUCTION
2.1
Study rationale
The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin was associated with 
lower cardiovascular (CV) mortality and hospitalization for heart failure in the EMPA-REG 
study (Zinman et al 2015). The effect was apparent within months from treatment start, 
suggesting that mechanisms beyond improved glucose control may be involved. Additionally, 
the SGLT2 inhibitor canagliflozin reduced combined endpoint of CV death and disease, 
including hospitalization for heart failure in the recently presented CANVAS study (Neal et 
al 2017) further reinforcing that SGLT2 inhibitors protect the heart in Type 2 diabetes (T2D)
patients. 
The aim of the current study is to investigate the effects of dapagliflozin (a SGLT2i) on 
myocardial function and metabolism.
2.2
Background
2.2.1
Cardiovascular disease in type 2 diabetes mellitus
Worldwide, CV disease is the leading cause of death in patients with diabetes and make up 
approximately 50 % of deaths in patients with T2D (WHO 2016). Although improved 
glycaemic control in patients with diabetes reduces the risk of microvascular complications 
(Holman et al 2008, Lampa 2015, UKPDS-Group 1998), evidence that glucose lowering leads 
to reduced cardiovascular events and death is sparse (Holman et al 2014). The results of the 
10 year post-trial follow up of the UK Prospective Diabetes Study suggested a long-term 
modest effect on myocardial infarction or on all-cause mortality (Holman et al 2008). On the 
other hand, results from ACCORD, ADVANCE, and VADT did not show that intense 
glucose-lowering in T2D patients lowered the CV risk (Holman et al 2014).
2.2.2
Cardiovascular outcomes with SGLT-2 inhibition
There are a number of potential mechanisms that could help to explain the CV benefits 
reported in the EMPA-REG and CANVAS studies (Neal et al 2017, Zinman et al 2015). 
SGLT2 inhibition leads to increased urinary excretion of glucose and sodium and thus 
increased diuresis. As a consequence of SGLT2 inhibition, a decrease in Hemoglobin A1c 
(HbA1c), body weight, and blood pressure and an increase in hematocrit (Hct) is observed. 
However, none of these effects is believed to fully explain the reported CV benefits. 
Mechanistic studies are therefore warranted to elucidate potential SGLT2i beneficial effects 
on the cardiovascular system (Ferrannini 2017). A complementary hypothesis is based on the 
increased urinary glucose excretion by dapagliflozin, which will lead to enhanced night-time 
catabolism, followed by increased glycogenolysis, gluconeogenesis and production of ketone 
bodies. The increased gluconeogenesis during night-time would inhibit mammalian Target Of 
Rapamycin (mTOR), which would increase autophagy/mitophagy of damaged mitochondria 
and biogenesis as well as fusion of mitochondria maximizing bioenergetic efficiency
(Rambold et al 2015), hence supporting myocardial health. 


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A detailed description of the chemistry, pharmacology, efficacy, and safety of dapagliflozin is 
provided in the Investigator’s Brochure (IB).
2.3
Benefit/risk assessment
Dapagliflozin has global market approval and based on global cumulative sales figures up to 
March 2016, it is estimated that dapagliflozin has been administered during >1 000 000 patient 
years and approved in more than 85 countries. Details regarding potential risks associated with 
administration of dapagliflozin once a day are provided in the IB. 
Due to its mode of action resulting in increased urinary glucose excretion, an increased risk of 
urinary tract infections and genital infections has been seen. Based on the mechanism of action 
of dapagliflozin there may be a potential risk for this compound to cause hypovolaemia or 
electrolyte imbalance. As a precaution, patients who, in the judgment of the Investigator, may 
be at risk for dehydration or volume depletion due to co-existing conditions or concomitant 
medications, such as loop diuretics, will be carefully monitored for their volume status. Note 
that in this study use of loop diuretics is considered an exclusion criteria. In patients already 
receiving dapagliflozin who develop conditions that may cause hypovolaemia or electrolyte 
imbalance, decisions to interrupt or discontinue dapagliflozin therapy and management of 
patients will be based on clinical judgment.
After the introduction of dapagliflozin and other SGLT2 inhibitors, there have been post 
marketing reports of ketoacidosis, including diabetic ketoacidosis (DKA), in patients with 
Type 1 diabetes (T1D) and T2D, although a causal relationship has not been established. 
Patients presenting signs and symptoms consistent with ketoacidosis, including nausea, 
vomiting, abdominal pain, malaise, and shortness of breath, will be assessed for ketoacidosis, 
even if blood glucose levels are < 14 mmol/L (250 mg/dL). If ketoacidosis is suspected, 
discontinuation of Study treatment should be considered and the patient should be promptly 
evaluated.
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from 
pancreatic disorders (e.g., T1D, history of pancreatitis, or pancreatic surgery), insulin dose 
reduction, reduced caloric intake, or increased insulin requirements due to infections, illness or 
surgery and alcohol abuse.
The CT-PET and MRI-PET examinations involve ionizing radiation. Each PET scanning with 
[11C]-Acetate (400 MBq) and [18F]-6-thia-heptadecanoic acid ([18F]-FTHA) (150 MBq) 
causes a calculated radiation burden of 1.4 and 3.15 mSv, respectively, to each subject. 
The total PET radiation burden for subjects undergoing two scans with both [11C]-Acetate 
and [18F]-FTHA will be 9.1 mSv. The total PET radiation burden for subjects only 
undergoing two scans of [11C]-Acetate will be 2.8 mSv.
The attenuation localization CT examinations associated with the CT-PET examinations will 
give a summarized dose of 0.8 mSv. The attenuation MRI examination associated with the 
MRI-PET examinations is not associated with any radioactive dose. 


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The total absorbed dose from all CT-PET or MRI-PET examinations for individuals enrolled 
in this study will therefore be less than 10mSv, which is within the annual limits for medical 
radiation exposure (ICRP 2007).
Considering the non-clinical and clinical experience with dapagliflozin and the precautions 
included in the study protocol, participation in this study should present a minimal and thus 
acceptable risk to patients who meet the inclusion/exclusion criteria and consent to take part in 
the study.
3.
OBJECTIVES AND ENDPOINTS
Table 2
Study Objectives
Primary Objective:
Endpoint/Variable:
To compare the changes in global longitudinal strain 
of the left ventricle (GLSLV) achieved with 
dapagliflozin versus placebo after 6 weeks of double-
blind treatment.
Change from baseline in GLSLV (%)
Secondary Objective:
Endpoint/Variable:
To compare the changes in myocardial efficiency (%) 
achieved with dapagliflozin versus placebo after 6 
weeks of double-blind treatment.
Change from baseline in myocardial efficiency (%)
Safety Objective:
Endpoint/Variable:
To evaluate the safety and tolerability of dapagliflozin.
Adverse Events leading to Discontinuation of Study 
Medication (DAEs) / Serious Adverse Events (SAEs)
Collection of clinical chemistry/haematology 
parameters 
Exploratory Objective:
Endpoint/Variable:
To compare the changes in wash-out in the 
myocardium of [11C]-Acetate (Kmono, 1/min) 
achieved with dapagliflozin vs. placebo after 6 weeks of 
double-blind treatment.
Changes from baseline in wash-out in the 
myocardium of [11C]-Acetate (Kmono) 
To compare the changes in myocardial perfusion 
(ml/min/g) measured by [11C]-Acetate achieved with 
dapagliflozin vs. placebo after 6 weeks of double-blind 
treatment.
Changes from baseline in myocardial perfusion 
measured by [11C]-Acetate
To compare the changes in wash-out of [11C]-Acetate 
(Kmono, 1/min) in relation to myocardial perfusion 
(K1, ml/min/g) achieved with dapagliflozin vs. placebo 
after 6 weeks of double-blind treatment.
Change from baseline in wash-out of [11C]-Acetate 
(Kmono) in relation to myocardial perfusion (K1)
To compare the changes in myocardial fatty acid 
uptake (MFAU, μmol/min/g) by [18F]-FTHA) 
achieved with dapagliflozin versus placebo after 6
weeks of double-blind treatment.
Changes from baseline in myocardial fatty acid 
uptake by [18F]-FTHA
To compare the changes in fatty acid uptake in liver 
(μmol/min/g) by [18F]-FTHA achieved with 
dapagliflozin versus placebo after 6 weeks of double-
blind treatment.
Changes from baseline in fatty acid uptake in liver by 
[18F]-FTHA


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Table 2
Study Objectives
To compare the changes in fatty acid uptake in kidney 
cortex (μmol/min/g) by [18F]-FTHA achieved with 
dapagliflozin versus placebo after 6 weeks of double-
blind treatment
Changes from baseline in fatty acid uptake in kidney 
cortex by [18F]-FTHA
To compare the changes in fatty acid uptake in brain 
(μmol/min/g) by [18F]-FTHA achieved with 
dapagliflozin versus placebo after 6 weeks of double-
blind treatment.
Changes from baseline in fatty acid uptake in brain 
by [18F]-FTHA
To compare the changes in Left Ventricular (LV) 
global radial strain and LV global circumferential 
strain achieved with dapagliflozin versus placebo after 
6 weeks of double-blind treatment.
Changes from baseline in LV global radial strain (%) 
and LV global circumferential strain (%)
To compare the changes in LV global systolic 
longitudinal strain rate, LV global diastolic 
longitudinal strain rate, LV global diastolic radial 
strain rate, LV global systolic radial strain rate, LV 
global diastolic circumferential strain rate and LV 
global systolic circumferential strain rate, achieved 
with dapagliflozin versus placebo after 6 weeks of 
double-blind treatment.
Changes from baseline in LV global systolic 
longitudinal strain rate (%s-1 ), LV global diastolic 
longitudinal strain rate(%s-1 ), LV global diastolic 
radial strain rate (%s-1 ), LV global systolic radial 
strain rate (%s-1 ), LV global diastolic 
circumferential strain rate (%s-1) and LV global 
systolic circumferential strain rate (%s-1 )
To compare the changes in LV end-diastolic volume 
(mL), LV end-systolic volume (mL), and LV stroke 
volume (mL) achieved with dapagliflozin versus 
placebo after 6 weeks of double-blind treatment.
Changes from baseline in LV end-diastolic volume 
(mL), LV end-systolic volume (mL), and LV stroke 
volume (mL)
To compare the changes in LV mass (g), LV mass/end-
diastolic volume (g/mL) and LV ejection fraction (%) 
achieved with dapagliflozin versus placebo after 6 
weeks of double-blind treatment.
Changes from baseline in LV mass (g), LV mass/end-
diastolic volume (g/mL) and LV ejection fraction (%)
To compare the changes in Left atrial volume (min, 
max) (mL), Left atrial ejection fraction (%) and 
transmitral flow velocity indicies (E/A (1), E (cm/s), 
A (cm/s) and DT (ms)), achieved with dapagliflozin 
versus placebo after 6 weeks of double-blind treatment.
Changes from baseline in Left atrial min volume
(mL), Left atrial max volume (mL), Left atrial 
ejection fraction (%) and transmitral flow velocity
indicies (E/A (1), E (cm/s), A (cm/s) and DT (ms))
To compare the changes in blood biomarkers (e.g. 
HbA1c, Hematocrit, Hb, FGF-21, NT-proBNP)
achieved with dapagliflozin vs. placebo after 6 weeks of 
double-blind treatment.
Changes from baseline in blood biomarkers (e.g. 
HbA1c, Hematocrit, Hb, FGF-21, NT-proBNP)
To compare the changes from baseline in body weight, 
and blood pressure achieved with dapagliflozin versus 
placebo after 6 weeks of double-blind treatment.
Changes from baseline in body weight, as well as 
systolic and diastolic blood pressure
To explore associations between change in GLSLV 
and change in myocardial efficiency as well as 
associations to changes in other exploratory end-
points with potential importance.
Change from baseline in GLSLV and change from 
baseline in myocardial efficiency, as well as changes in 
other endpoints as defined above


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Table 2
Study Objectives
To evaluate the pharmacokinetics of dapagliflozin by a 
single pre-dose sample at end of study.
Plasma concentrations of dapagliflozin in a sample at 
end of study (pre-dose)
4.
STUDY DESIGN
4.1
Overall design
This is a randomised, placebo-controlled, double-blind, parallel-group, international,
multicentre, Phase IV study to investigate the effects of dapagliflozin on cardiac substrate 
uptake, myocardial efficiency and myocardial contractile work in T2D patients. Eligible 
subjects with T2D before randomisation and fulfilling all of the inclusion criteria and none of 
the exclusion criteria will be randomised in a 1:1 ratio to dapagliflozin 10 mg or placebo once 
daily and treated for six weeks. The study includes five visits.
For an overview of the study design, see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 6.1 Treatments Administered.
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives 
and Endpoints.
4.2
Scientific rationale for study design
The study is investigating early changes in the heart metabolism and function. The reason for 
this is the rapid effects on CV risk and especially risk for heart failure hospitalization reported 
in the EMPA-REG and CANVAS studies (Ferrannini 2017, Ferrannini et al 2016, Neal et 
al 2017, Zinman et al 2015). The study is therefore designed to mainly assess changes in the 
heart that could be ascribed to changed metabolism and fluid balance, and not effects 
secondary to structural changes/re-modelling of the heart.
In this study, we will investigate the effects of dapagliflozin (a SGLT2i) on myocardial 
metabolism and function. Energy metabolism in the heart includes several components such as 
micro- and macrovascular circulation, substrate utilization, oxidative phosphorylation and 
production of Adenosine triphosphate (ATP) taking place in the mitochondria
(Neubauer 2007). We will also investigate myocardial perfusion, substrate utilization and 
measures of energy status of the heart including myocardial energy efficiency and strain as a 
surrogate for myofibril contractile work. 
The primary end-point is GLSLV (Global Longitudinal Left Ventricular Strain) measured with 
Magnetic Resonance Imaging (MRI). GLSLV is a marker of myofibril contractile work, which 
is dependent on ATP production. Changed ATP production can occur as a result of changed 
perfusion or altered mitochondrial function in the heart. Moreover, GLSLV has been 
associated with relevant clinical endpoints. GLSLV was the best predictor of future CV events 
in a Heart Failure with preserved Ejection Fraction (HFpEF) population (Shah et al 2015). 
Moreover, optimisation of glucose control, blood pressure, and lipids of T2D patients with 
poor glycemic control for 12 months has been shown to improve GLSLV (Leung et al 2016). 


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Preliminary findings from an in-house study investigating the effects of dapagliflozin on 
monkeys with metabolic syndrome and no diabetes indicated improvements of different 
measures of longitudinal strain of the heart after 5 weeks of treatment. 
The secondary endpoint is myocardial efficiency (%). The myocardial efficiency calculation is 
based on an estimate of energy used for producing LV contractile work (mean arterial pressure 
(MAP) x stroke volume (SV) x heart rate (HR) / myocardial mass) compared to the total 
cardiac work which is calculated based on the total myocardial oxygen consumption per 
myocardial mass (Tuunanen et al 2006). The myocardial oxygen consumption is directly 
proportional to the clearance of [11C]-Acetate. [11C]-Acetate is immediately converted into 
[11C]-Acetyl CoA in the cell and after entering the citric acid cycle the label 11C is released 
as 11C-CO2. Therefore it is assumed that the myocardial monoexponential washout of [11C]-
Acetate is a marker of the citric cycle activity and hence mitochondrial function. This tracer 
has been used in multiple studies of oxidative metabolism (Lindner et al 2016, Nesterov et 
al 2015, Tuunanen et al 2006, Tuunanen et al 2007). Moreover, initial uptake of [11C]-Acetate 
in the heart will be used to estimate myocardial perfusion (van den Hoff et al 2001).
Myocardial perfusion will be investigated as an exploratory end-point. 
Patients with T2D seems to have impaired myocardial metabolism both in the fasting state and 
during insulin infusion. Interestingly, insulin infusion resulted in increased heart work and 
reduced myocardial efficiency (Mather et al 2016). Moreover, T2D patients with no evidence 
of coronary artery disease or impaired cardiac function have reduced cardiac energy 
metabolism as indicated by lower PCr/ATP ratio as compared to healthy volunteers 
(Scheuermann-Freestone et al 2003). The PCr/ATP ratio was negatively correlated with 
fasting plasma free fatty acid (FFA) levels, suggesting a negative effect of higher FFA levels 
on cardiac energy metabolism. Thus, insulin, which lowers plasma free fatty acids increase 
cardiac work and reduce myocardial efficiency, but higher levels of FFA is associated with 
reduced myocardial energy reserve (PCr/ATP) indicating a complex relationship between 
myocardial energy state and substrate uptake in T2D that is not fully understood. 
A key exploratory endpoint in the study is the difference in uptake of FFA in the myocardium 
by dapagliflozin versus placebo measured by a fatty acid PET-ligand, [18F]-FTHA. This tracer 
has been used in several intervention and non-intervention studies of myocardial metabolism 
previously (Labbé et al 2012, Labbé et al 2014, Tuunanen et al 2007). It is hypothesized that 
FFA uptake will increase more with dapagliflozin than with placebo treatment in the planned 
experimental situation (≥6 hour fast). Since there are reasons to believe that dapagliflozin 
treatment also results in different exposure to FFA in other tissues, the brain, liver and kidney 
will be investigated with respect to FFA uptake.
Plasma/serum samples obtained in the study will either be assessed directly such as FGF-21 
and NT-proBNP or stored in a biobank for potential future analysis of blood biomarkers to 
further explore the mechanisms behind the effects of SGLT2i on myocardial metabolism.
In summary, the primary aim of the DAPACARD study is to investigate the effects of 
dapagliflozin on GLSLV and the secondary aim is to investigate the effects of dapagliflozin on 
myocardial efficiency. These effects will be associated with other potential effects of 
dapagliflozin which could impact heart metabolism and function such as FFA uptake, changes 


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in plasma substrates (glucose, free fatty acids and beta-hydroxybutyrate), hemoglobin 
(Hb)/hematocrit, and heart perfusion. 
4.3
Justification for dose
Dapagliflozin (Forxiga®) will be given at the dose of 10 mg per day. That is the dose of 
Forxiga® that is approved in Sweden and Finland for treatment of T2D. The treatment duration 
is 6 weeks and chosen to be able to detect changes in myocardial metabolism that would 
influence heart function. The comparator is placebo since the study duration is relatively short 
and use of placebo allow specific conclusions regarding the effects of dapagliflozin. 
4.4
End of study definition
The end of study is defined as the last expected visit/contact of the last subject undergoing the 
study.
A subject is considered to have completed the study when he/she has completed his/her last 
scheduled visit or last scheduled procedure shown in the Schedule of Activities (SoA).
See Appendix A 6 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, are not permitted.
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomised to a study intervention. Under no circumstances can 
there be exceptions to this rule. Subjects who do not meet the entry requirements are screen 
failures, refer to Section 5.4.
In this protocol, “enrolled” subjects are defined as those who sign informed consent.
“Randomized” subjects are defined as those who undergo randomization and receive a 
randomization number.
For procedures for withdrawal of incorrectly enrolled subjects see Section 7.3.
5.1
Inclusion criteria
Subjects are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply:
1.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.


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2.
Provision of signed and dated, written informed consent form prior to any 
mandatory study specific procedures, sampling, and analyses. The ICF process is 
described in Appendix A 3.
3.
Females or males ≥40 years up to 75 years of age.
4.
Individuals with type 2 diabetes diagnosed for at least 6 months based on the 
American Diabetes Association standards (ADA 2017) and on stable dose of 
metformin for at least 6 weeks prior to screening and HbA1c at screening visit of 
≥42 mmol/mol (6.0%) and ≤75 mmol/mol (9.0%) measured at local hospital 
laboratory.
5.
No significant signs or symptoms of coronary artery disease or, if known coronary 
artery disease, currently free of symptoms and a) all major epicardial vessels with 
<50% stenosis within 12 months prior to screening, or b) if revascularized with all 
major epicardial vessels with <50% remaining stenosis after stenting or bypass 
surgery procedure determined between 3 and 12 months prior to screening.
6.
Normal left ventricular ejection fraction (≥50%) assessed within 1 year prior to 
informed consent, and if applicable, after most recent acute episode of coronary 
artery syndrome, or at screening visit. 
7.
Body mass index (BMI) ≥ 25 kg/m2.
5.2
Exclusion criteria
Medical conditions
1.
Blood pressure at screening that would require a change in blood pressure treatment 
over the study period or any of the following: systolic blood pressure >160 mmHg 
or diastolic blood pressure >100 mmHg. 
2.
History of stroke or other clinically significant cerebrovascular disease.
3.
Any of the following cardiovascular diseases known within 3 months prior to 
signing the consent at enrolment: 
a.
Atrial fibrillation, or other unstable or severe arrhythmia affecting heart 
function
b.
Unstable heart failure or any heart failure with NYHA class III and IV 
c.
Significant valvular disease
d.
Significant peripheral artery disease 
4.
Planned cardiac surgery or angioplasty within 3 months from enrolment. 
5.
Clinical diagnosis of type 1 diabetes, maturity onset diabetes of the young (MODY), 
secondary diabetes or diabetes insipidus.
6.
Verified body weight variability of >3 kg during the 3 proceeding months before 
screening.
7.
Active malignancy requiring treatment at the time of visit 1 (with the exception of 
successfully treated basal cell or treated squamous cell carcinoma).


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8.
Patients with severe hepatic impairment (Child-Pugh class C).
9.
Unstable or rapidly progressing renal disease.
10.
Clinically significant disease or disorder which, in the opinion of the investigator, 
may either put the subject at risk because of participation in the study, or influence 
the results or the subject’s ability to participate in the study.
Prior/concomitant therapy
11.
Ongoing treatment with other antidiabetic drugs than metformin.
12.
Ongoing treatment with loop diuretics. 
13.
Ongoing weight-loss diet (hypocaloric diet) or use of weight loss agents.
14.
Contraindications to dapagliflozin therapy. 
15.
Ongoing treatment with systemic steroids at time of informed consent or change in 
dosage of thyroid hormones within 6 weeks prior to informed consent or any other 
uncontrolled endocrine disorder except for T2D.
Prior/concurrent clinical study experience
16.
Previous enrolment in the present study or participation in another clinical study 
with an investigational product during the last 1 month prior to screening.
Diagnostic assessments
17.
Estimated Glomerular Filtration Rate (eGFR) <45 mL/min/1.73 m2, based on the 
MDRD study equation (www.kidney.org/content/mdrd-study-equation) (eGFR 
=175 x (SCr)-1.154 x (age)-0.203 x 0.742 [if female] x 1.212 [if Black]). 
18.
Alcohol or drug abuse within the 3 months prior to informed consent that would 
interfere with trial participation or any ongoing condition leading to a decreased 
compliance to study procedures or study treatment intake.
19.
Any condition when MRI and CT-PET or MRI-PET is contraindicated such as, but 
not limited to, having a metallic implant (such as pacemaker or cochlear implant), 
permanent make up, claustrophobia or BMI ≥40 kg/m2).
Other exclusions
20.
Involvement in the planning and/or conduct of the study (applies to AstraZeneca, 
UCR and/or Antaros staff and/or staff at the study site).
21.
Plasma donation within one month of screening or any blood donation/blood loss 
>450 mL during the 3 months prior to screening.
22.
Women who has a positive pregnancy test at enrolment or randomization, or are 
breastfeeding.


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5.3
Lifestyle restrictions
5.3.1
Meals and dietary restrictions
Biomarker samples will be obtained after an overnight fast of 9 hours ±1 hour in the morning, 
as according to Schedule of Activities (SoA). The information will be captured in the Case 
Report Form (CRF).
MRI and CT-PET or MRI-PET to be conducted after an overnight fast in the morning or 
≥6 hours fasting period, at the same time for each individual at the visits as according to SoA. 
The information will be captured in the CRF.
5.3.2
Caffeine, alcohol, and tobacco
Subjects are instructed to abstain from products containing nicotine, alcohol and caffeine for 
≥6 hours prior to MRI and CT-PET or MRI-PET examinations. Information and deviations are 
captured in the CRF.
5.3.3
Activity
Subjects should be encouraged not to change their lifestyle during study participation 
including exercise, eating and drinking habits.
5.4
Screen failures
Screen failures are defined as subjects who signed the informed consent form to participate in 
the clinical study but are not subsequently randomly assigned to Study treatment. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
subjects to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened.
In case of HbA1c, creatinine or other safety values (Table 8) are out of range and considered 
not clinically significant, retesting will be allowed within the screening visit period, at the 
Investigators discretion.
6.
STUDY TREATMENTS
Study treatment in this study refers to dapagliflozin or placebo.


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6.1
Treatments administered
6.1.1
Investigational products
Table 3
Study Treatments
Treatment 1
Treatment 2
Study treatment name:
Dapagliflozin
Placebo
Dosage formulation:
Plain, green, diamond-shaped, film-
coated tablet; 10 mg
Plain, green, diamond-shaped, film-
coated tablet
Route of administration 
Oral
Oral
Dosing instructions:
One tablet to be taken, once daily, in 
the morning (except of onsite visits 
days with fasting blood samples 
collection, when tablet needs to be 
taken afterwards)
One tablet to be taken, once daily, in 
the morning (except of onsite visits 
days with fasting blood samples 
collection, when tablet needs to be 
taken afterwards)
Packaging and labelling
Study treatment will be provided in 
bottles. Each bottle will be labelled 
in accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country 
regulatory requirement.
Study treatment will be provided in 
bottles. Each bottle will be labelled in 
accordance with GMP Annex 13 and 
per country regulatory requirement.
6.1.2
Non-Investigational Medicinal Products 
During the study the Non Investigational Medicinal Products (NIMP) will be sourced from a 
third part vendor at each PET facility and used during the study related procedures to assess 
end-points. All NIMPs will be stored, prepared, administered and handled by the site 
according to standard practice. See the Imaging charter and Core-lab manual for further 
information.
NIMPs in this study are [11C]-Acetate and [18F]-FTHA. GMP grade unlabelled precursors 
and reference standards for the NIMPs will be sourced by each imaging site from a third-party 
vendor. The precursors for [11C]-Acetate and [18F]-FTHA are radiolabelled locally with 
Carbon-11 and Fluorine-18, respectively, at each imaging site according to documented GMP 
procedures just prior the PET examinations.
6.2
Preparation/handling/storage/accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only subjects enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff.


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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study treatment are 
provided in the site agreement.
6.3
Measures to minimise bias: randomisation and blinding
All subjects will be centrally assigned to randomised study treatment using a telephone service 
(Call Centre). Before the study is initiated, the telephone number and call-in directions for the 
Call Centre, as well as log-in information and a User Manual for the Call Centre will be 
provided to each site. 
If a subject withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. Withdrawn subjects will not be replaced. 
Blinded study using 
Call Centre
The Call Centre will provide to the Investigator(s) or pharmacists the kit 
identification number to be allocated to the patient at the dispensing visit.
Routines for this will be described in the Call Centre user manual that will be 
provided to each centre.
The randomisation code should not be broken except in medical emergencies 
when the appropriate management of the subject requires knowledge of the 
treatment randomisation. The Investigator documents and reports the action to 
AstraZeneca, without revealing the treatment given to subject to the 
AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected 
and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities.
Randomisation codes will not be broken for the planned analyses of data until 
all decisions on the evaluability of the data from each individual subject have 
been made and documented.
Blind Break (via 
Call Centre)
The Call Centre will be provided with blind-breaking instructions. The blind 
may be broken if, in the opinion of the investigator, it is in the subject’s best 
interest for the investigator to know the study treatment assignment. The 
sponsor must be notified before the blind is broken unless identification of the 
study treatment is required for a medical emergency in which the knowledge 
of the specific blinded study treatment will affect the immediate management 
of the subject’s condition (e.g. antidote available). In this case, the sponsor 
must be notified within 24 hours after breaking the blind. The date and reason 
that the blind was broken must be recorded in the source documentation and 
CRF (electronic or paper), as applicable. Study unblinding should not occur 
until database lock and all decisions on the evaluability of the data from each 
individual subject have been made and documented.


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Personnel performing the pharmacokinetic (PK) analysis of dapagliflozin concentration will 
be provided the randomization code to identify patients on active drug and will therefore be 
unblinded. See Section 8.5.
6.4
Treatment compliance
Any change from the dosing schedule as well as dose discontinuations should be recorded in 
the CRF.
Subjects should return all unused study treatment, as well as empty bottles, as according to the 
SoA. If a subject discontinues study treatment prematurely all study medication should be 
returned at the earliest opportunity.
The Investigator or delegate is responsible for managing the study treatment from receipt by 
the study site until the destruction or return of all unused study treatment from the subjects. 
6.5
Concomitant therapy
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the subject is receiving at the time of enrolment or receives 
during the study must be recorded along with:
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
Table 4
Restricted medications
In general, all concomitant medications should be kept stable throughout the study. Most
important medication to keep at stable dose from 6 weeks before screen and during the study 
are metformin, thyroid hormones, thiazides, beta-blockers, mineralcorticoid antagonists,
ARBs and ACE inhibitors (affecting glucose, plasma volume and heart function). 
Table 5
Prohibited medications
Prohibited medication/class of drug:
Indication:
Other anti-diabetic treatments than metformin including: 
other SGLT2i, insulin, glitazones, pramlinitide, DPP-IV 
inhibitors, GLP-1 analogues and sulfonylurea
For treatment of T2D
Loop-diuretics such as furosemide
For treatment of fluid retention
6.5.1
Background medication
Subjects must be on a stable dose of metformin for at least 6 weeks prior to screening and 
throughout the study.


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6.5.2
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
subject’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the CRF.
6.6
Dose modification (Not applicable)
6.7
Treatment after the end of the study (Not applicable)
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL
7.1
Discontinuation of study treatment
Subjects may be discontinued from study treatment in the following situations. Note that 
discontinuation from study treatment is NOT the same thing as a complete withdrawal from 
the study
!
Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment.
!
SAE that, in the opinion of the Investigator contraindicated further dosing of study 
treatment.
!
Severe non-compliance with the Clinical Study Protocol. 
!
Safety reasons as judged by the Investigator or by the sponsor.
!
Positive pregnancy test (discontinue study treatment and notify AZ representative).
!
Subjects should be discontinued from study medication if they experience severe 
hypoglycaemia as defined by the American Diabetes Association (ADA):
!
Requires assistance of another person to actively administer carbohydrates, 
glucagon, or take other corrective actions.
Plasma glucose concentrations may not be available during an event, but 
neurological recovery following the return of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma glucose 
level.
!
Acute renal insufficiency or worsened chronic renal insufficiency based on repeat 
eGFR values (eGFR<45 mL/minute/1.73m2). The re-test should be scheduled 
within 4 days, whenever possible.
!
A decrease in renal function that would preclude continued treatment with 
metformin according to local guidance.
!
If ketoacidosis is suspected, discontinuation of study medication should be 
considered and the patient should be promptly evaluated.


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!
Patients should be discontinued from study treatment if the initial and repeat 
laboratory tests meet any of the following criteria:
!
ALT and/or AST are >3 x ULN and total bilirubin >2 x ULN
!
ALT and/or AST are >5 x ULN for ≥ 14 consecutive days, at any time after 
initial confirmatory results
!
ALT and /or AST are > 8 x ULN
Reason for discontinuation of study medication, safety assessments and potential DAE/SAEs 
should be collected if possible. Collection of efficacy data could be decided in collaboration 
between the Investigator and the Sponsor, depending duration of study treatment.
7.1.1
Temporary discontinuation (Not applicable)
7.1.2
Procedures for discontinuation of study treatment
The investigator should instruct the subject to contact the site before or at the time if Study 
treatment is stopped. A subject that decides to discontinue Study treatment will always be 
asked about the reason(s) and the presence of any SAEs/DAEs. The date of last intake of 
Study treatment should be documented in the CRF. All Study treatment should be returned by 
the subject at their next on-site study visit or unscheduled visit. Subjects permanently 
discontinuing Study treatment should be given locally available standard of care therapy, at 
the discretion of the Investigator.
Discontinuation of Study treatment, for any reason, does not impact on the subject´s 
participation in the study. The subject should continue attending subsequent study visits and 
data collection should continue according to the study protocol. If the subject does not agree to 
continue in-person study visits, a modified follow-up should be arranged if possible to collect 
safety information and endpoints. This could be a telephone contact with the subject, a contact 
with a relative or treating physician, or information from medical records. The approach taken 
should be recorded in the medical records. A subject that agrees to modified follow-up is not 
considered to have withdrawn consent or to have withdrawn from the study.
Collection of endpoints (primarily MRI and CT-PET or MRI-PET) should be decided in
collaboration between the Investigator and the Sponsor.
7.2
Lost to follow-up
A subject will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:
!
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule.


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!
Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject or next of kin by e.g. repeat telephone 
calls, certified letter to the subject´s last known mailing address or local equivalent 
methods. These contact attempts should be documented in the subject’s medical 
record. 
!
Efforts to reach the subject should continue until the end of the study. Should the 
subject be unreachable at the end of the study the subject should be considered to be 
lost to follow up with unknown vital status at end of study and censored at latest 
follow up contact.
7.3
Withdrawal from the study
A subject may withdraw from the study (e.g. withdraw consent), at any time (investigational 
product and assessments) at his/her own request, without prejudice to further treatment.
A subject who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (e.g. telephone contact, a contact with a relative or treating 
physician, or information from medical records).
If the subject withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a subject withdraws from the study, he/she may request destruction of any samples taken, 
and the investigator must document this in the site study records.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any SAEs/DAEs. The Investigator will follow up subjects as medically indicated. 
It should be decided in collaboration between the Investigator and the Sponsor what follow-up 
need to be completed for each discontinued subject. All Study treatment should be returned by 
the subject.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the Schedule of Activities (SoA).
The investigator will ensure that data are recorded on the electronic Case Report Forms 
(CRF). The Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.
The investigator ensures the accuracy, completeness, legibility 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 CRFs. A copy of the 
completed electronic CRFs will be archived at the study site.


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Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue Study treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
Procedures conducted as part of the subject’s routine clinical management (e.g. 
echocardiography) and obtained before signing of the ICF and recorded in the medical records
may be utilised for screening or baseline purposes provided the procedures meet the protocol-
specified criteria and were performed within the time frame defined in the SoA.
The maximum amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed 220 mL. However, 
repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
8.1
Efficacy assessments 
8.1.1
Cardiac Assessment via Magnetic Resonance Imaging (MRI)
Planned time points for Magnetic Resonance Imaging (MRI) assessments are provided in the 
SoA.
The patient will undergo MRI scanning in order to assess cardiac function and morphology, 
refer to Table 6 for variables. The MRI scanning will be made after fasting for at least 6 hours
and at the same time of day at both visits. Time of examination and fasting period should be 
captured in the CRF to ensure that the time of examinations will be same at following visit. 
The cardiac MRI examination will be performed in accordance with a pre-defined MRI 
protocol, with the total scan time at each visit estimated to 45 minutes. Images from all sites 
will be analyzed in a blinded fashion at the Antaros Medical core-lab in Uppsala using a 
dedicated software package and certified analysts.
A clinical radiologic assessment of all acquired MRI images will be performed by a local 
radiologist. The assessment will be reported to the Investigator at the referring site, who will 
review and file the assessment in the subject´s source documents. If clinically significant 
findings are noted the Investigator should evaluate and handle the finding as per standard 
medical/clinical judgement.
Prior to study start, MRI scan protocols will be setup at the respective imaging sites in 
accordance to an imaging manual. 


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Table 6
MRI variables
Variables:
Unit:
GLSLV
%
LV global radial strain
%
LV global circumferential strain
%
LV global diastolic longitudinal strain rate
s-1
LV global systolic longitudinal strain rate
s-1
LV global diastolic radial strain rate
s-1
LV global systolic radial strain rate
s-1
LV global diastolic circumferential strain rate
s-1
LV global systolic circumferential strain rate
s-1
LV end-diastolic volume
mL
LV end-systolic volume
mL
LV stroke volume
mL
LV mass
g
LV mass/end-diastolic volume
g/mL
LVEF
%
Left atrial min volume
mL
Left atrial max volume
mL
Left atrial ejection fraction
%
E/A
1
E
cm/s
A
cm/s
DT
ms
8.1.2
Cardiac Assessment via Computed Tomography and Positron Emission 
Tomography (CT-PET) or via Magnetic Resonance Imaging and Positron 
Emission Tomography (MRI-PET)
Planned time points for Computed Tomography and Positron Emission Tomography (CT-
PET) or Magnetic Resonance Imaging and Positron Emission Tomography (MRI-PET)
assessments are provided in the SoA. The CT-PET or MRI-PET assessments can be performed 
on the same day as the MRI assessment if logistically possible, or on separate days.
The subject will undergo CT-PET or MRI-PET scanning to assess myocardial metabolism,
and, for subjects also undergoing 18F-FTHA CT-PET or MRI-PET scanning, fatty acid 
metabolism in myocardium, brain, liver and kidney cortex will be assessed as well (see
Table 7 for variables). Importantly, subjects will do either MRI-PET or CT-PET, and will do 
the same kind of methodology both at baseline and end-of study. The CT-PET or MRI-PET 
scanning will be made after a fast as well as abstinence from nicotine, alcohol and caffeine for 
at least 6 hours and at the same time of day at both visits. A pregnancy test is performed 


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before any PET radioligand administration (applicable if it is unclear to any extent if the 
woman is post-menopausal or not). Time of examination, result of pregnancy test, fasting 
period and any deviations from nicotine, alcohol and caffeine abstinence should be captured in 
the CRF to ensure that the time of examinations will be same at following visit. Heart rate and 
blood pressure is measured and recorded for input to the 11C-Acetate measurement but will 
not be entered into the CRF.
A cardiac 11C-Acetate CT-PET or MRI-PET examination is performed (IV 400 MBq 11C-
Acetate) on all randomised subjects. For this examination no blood sampling is performed. If 
the 18F-FTHA examination is performed on the same visit, the subject will rest for at least 
60 minutes while the 11C radioactivity decays before the 18F-FTHA examination. 
A cardiac 18F-FTHA CT-PET or MRI-PET examination is performed (IV 150 MBq 18F-
FTHA) on minimum 40 and maximum 44 randomised subjects. This is due to ethical reasons 
and aims to limit unnecessary exposure to radioactivity. A power calculation was performed 
using the variability of fatty acid measurements in a healthy population (Viljanen et al 2009)
and what is regarded as a clinically meaningful effect, indicating that about 40 patients is 
sufficient to reach approximately 80-90% power. The subject is further examined by CT-PET
or MRI-PET over the liver, kidney cortex and brain (in this order) for uptake of 18F-FTHA. 
Arterialized venous samples are acquired throughout to assess P-NEFA and 18F-FTHA 
metabolism by metabolite analysis (total blood volume taken <25mL per examination). In case 
18F-FTHA metabolite analysis data is incomplete (too few points to estimate a mono-
exponential curve) or missing due to technical issues, a population mean estimate from the 
study population (baseline or follow up subpopulation) will be used instead.
The 11C-acetate and 18F-FTHA CT-PET or MRI-PET examination may be performed on the 
same day or on separate visits. The duration of the 11C-Acetate visit at the PET facility is 
estimated to 1h (of which 0.5 h in the CT-PET or MRI-PET scanner). The duration of the 18F-
FTHA visit at the CT-PET or MRI-PET facility is estimated to 1.5 h (of which 1h in the CT-
PET or MRI-PET scanner).
A clinical radiologic assessment of acquired 11C-Acetate CT-PET or MRI-PET images will 
be performed by a local radiologist. The assessment will be reported to the Investigator at the 
referring site, who will review and file the assessment in the subject´s source documents. If 
clinically significant findings are noted the Investigator should evaluate and handle the finding 
as per standard medical/clinical judgement.
Images from all sites will be analyzed in a blinded fashion at the Antaros Medical core-lab in 
Uppsala using a dedicated software package and certified analysts.
A test CT-PET or MRI-PET examination with a cylindrical test phantom filled with Flourine-
18 will be performed at each site as part of the site initiation routine to ascertain that the 
correct scan protocols are in place.


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Table 7
CT-PET or MRI-PET variables
Variables:
Unit:
11C-Acetate 
18F-FTHA
Myocardial Efficiency
%
X
Myocardial Kmono 
1/min
X
Myocardial Kmono / Myocardial perfusion
-
X
Myocardial perfusion
mL/min/g
X
Myocardial Fatty Acid Uptake*
μmol/g/min
X
Liver Fatty Acid Uptake*
μmol/g/min
X
Kidney cortex Fatty Acid Uptake *
μmol/g/min
X
Brain Fatty Acid Uptake *
μmol/g/min
X
*
Not applicable for subjects only performing 11C-Acetate.
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Clinical safety laboratory assessments
See Table 8 for the list of clinical safety laboratory tests to be performed and to the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in the 
table, must be conducted in accordance with the laboratory manual and the SoA.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values and units) will be recorded on the 
appropriate CRF.
The clinical chemistry and haematology will be performed at a local laboratory. Urine dipstick 
will be analysed at the study centre.


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Table 8
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb*
S-Creatinine
B-Hematocrit*
S-Bilirubin, total
S-Alkaline phosphatase (ALP)
S-Aspartate transaminase (AST)
S-Alanine transaminase (ALT)
P-Glucose
Urinalysis (dipstick)
Pregnancy test (Urine HCG pregnancy test for WOCBP 
(HCG minimum sensitivity of 25 IU/L), dipstick analysed 
at the study centre)**
S/P-βHCG (if urine pregnancy dipstick result 
is positive)
*
B-Hb and B-Haematocrit also serves as efficacy variables
**
Applicable to women if it is unclear to any extent if the woman is post-menopausal or not
8.2.2
Physical examinations
A physical examination will be performed and include an assessment of the following: general 
appearance, respiratory, cardiovascular, abdomen and volume status.
Physical examination will be performed at timelines as specified in the SoA, Investigators 
should pay special attention to clinical signs related to previous serious illnesses, new or 
worsening abnormalities may qualify as adverse events, see Section 8.3.7 for details.
Body weight will be assessed as specified in the SoA; in the morning, after a visit to the 
lavatory, in underwear/light clothing. With exception for the screening visit, body weight 
should be assessed after an overnight fast. For a single individual, all weight assessments 
should be made using the same calibrated scale.
Height will be assessed only at screening.
8.2.3
Vital signs
Pulse rate and blood pressure will be assessed at timelines as specified in the SoA. Two 
measurements will be taken with at least 5 minutes of rest prior to and between measurements, 
in a quiet setting without distractions, in a sitting position and before any blood collection. The 
same arm for blood pressure assessment will be used throughout the study. Information 
regarding the measurement will be recorded in the CRF.
8.2.4
Electrocardiograms
Single resting 12-lead ECG will be obtained for screening purpose using an ECG machine. 
The ECG reading should be evaluated by the Investigator and recorded in the CRF as normal, 
abnormal, not clinically significant or clinically significant. 


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8.2.5
Echocardiograms
Echocardiogram will be obtained only at screening and assessed for normal left ventricular 
ejection fraction (≥50%) only if not available within 1 year prior to informed consent and, if 
applicable, after most recent acute episode of coronary artery syndrome. Information 
regarding the measurement will be recorded in the CRF.
Normal left ventricular ejection fraction is part of eligibility criteria.
8.2.6
Other safety assessments
8.2.6.1
Diabetic ketoacidosis
Subjects on Study treatment who present signs and symptoms consistent with Ketoacidosis 
(DKA), including nausea, vomiting, abdominal pain, malaise, and shortness of breath, should 
be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L (250 mg/dL). 
If ketoacidosis is suspected, discontinuation of Study Treatment should be considered and the 
subject should be promptly evaluated.
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from 
pancreatic disorders (e.g., type 1 diabetes, history of pancreatitis, or pancreatic surgery), 
insulin dose reduction, reduced caloric intake, or increased insulin requirements due to 
infections, illness or surgery and alcohol abuse. As dapagliflozin should be used with caution 
in these subjects it has been taken in consideration in the eligibility criteria.
Potential events of Diabetic Ketoacidosis
All potential events of DKA will be recorded in the CRF and submitted to an independent
DKA Adjudication Committee. The DKA Committee T2D will assess available information 
on each potential DKA event and will classify the event in accordance with the definitions in 
the DKA Adjudication Charter T2D.
The DKA Adjudication Committee will be kept blinded to the study treatment received by 
each subject with a potential DKA event in the clinical study. A separate DKA Adjudication 
Manual will define and describe the procedures for the collection of DKA information, 
handling, adjudication criteria and reporting of these events/cases.
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of AE/SAE can be found in Appendix B. In this study, collection of AE data 
is limited to collection of Serious Adverse Events (SAE) and Adverse Events leading to 
Discontinuation of Study Medication (DAE). In addition, all possible events (non-serious, 
SAE, DAE) of diabetic ketoacidosis are to be collected.
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).


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The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs see 
Section 8.3.3.
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.
8.3.2
Time period and frequency for collecting AE and SAE information 
SAE data will be collected from time of signature of informed consent (screening) throughout 
the treatment period including the follow-up period. 
DAE data will be collected from the first intake of study treatment, throughout the treatment 
period.
Diabetic ketoacidosis events will be collected from the first intake of study treatment
throughout the treatment period and including the follow-up period.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject’s last visit 
and he/she considers the event to be reasonably related to the Study treatment or study 
participation, the investigator may notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts. All SAE/DAE/Diabetic ketoacidosis events, will be followed 
until resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-
up. 
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated, 
but without further recording in the CRF. AstraZeneca retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.


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8.3.4
Adverse event data collection
The following variables will be collect for each SAE/DAE event;
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity
!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product(s) (yes or no)
!
Action taken with regard to Investigational Product(s)
!
AE caused subject’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 hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Causality assessment to other medication'
8.3.5
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.
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.


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8.3.6
Adverse events based on signs and symptoms
In this study, collection of AE data is limited to collection of SAE and DAE. In addition, all 
possible events (non-serious, SAE, DAE) of diabetic ketoacidosis are to be collected.
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘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.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR. Deterioration as compared to baseline in protocol-mandated 
laboratory values or 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 (DAE).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms,
the sign or symptom will be reported as a DAE or an SAE and the associated laboratory 
result/vital sign will be considered as additional information. Wherever possible the reporting 
Investigator uses the clinical, rather than the laboratory term (e.g. anaemia versus low 
haemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as DAE(s) or SAE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment that fulfil criteria for SAE/DAE will be reported.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product/study treatment, or to the study procedure(s). All SAEs will be reported via a specific 
SAE form and also recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
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.


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For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Investigators or other site personnel send the SAE form by fax to the designated AstraZeneca 
representative.
For further guidance on the definition of a SAE, see Appendix B.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca, via a specific 
pregnancy form, except for:
!
If the pregnancy is discovered before the study subject has received any study 
treatment
!
Pregnancies in the partner of male subjects
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a subject 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 subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.


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8.4.3
Overdose
Dapagliflozin has been well tolerated at doses of up to 500 mg/day in single dose testing in 
healthy volunteers and up to 100 mg/day in repeat dose testing for 14 days in healthy 
volunteers and patients with T2D. Suspected single intake of more than 50 tablets of 10 mg 
dapagliflozin tablets or repeated intake of more than 10 tablets of 10 mg dapagliflozin tablets 
should be reported on the CRF overdose module. If an overdose is suspected, monitoring of 
vital functions as well as treatment should be performed as appropriate.
!
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 treatment 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 8.3.2. For other overdoses, reporting must occur within 30 days.
8.4.4
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B.
8.5
Pharmacokinetics
Blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of Study treatment as specified in the SoA. Instructions for the collection and 
handling of biological samples will be provided by the sponsor or analytical test site. The 
actual date and time (24-hour clock time) of the sample will be recorded.
Samples will be used to evaluate the PK of Study treatment. The sample will be divided into 
2 aliquots (1 each for PK and a back-up).


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Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
8.5.1
Determination of drug concentration
Samples for determination of drug concentration will be analysed by analytical test sites on 
behalf of AstraZeneca, using an appropriate bioanalytical method. Full details of the analytical 
method used will be described in a separate bioanalytical report.
8.5.2
Storage and destruction of pharmacokinetic samples
Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report finalization 
or six 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 anonymised by pooling.
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the Clinical Study Report (CSR).
8.6
Pharmacodynamics
Pharmacodynamic parameters are an integrated part of the efficacy assessments of the study 
and are described in Section 8.1.1 and 8.1.2.
8.7
Genetics
Genetic testing is not evaluated in this study.
8.8
Biomarkers
Mandatory collection of samples for biomarker research is also part of this study. The 
following fasting blood and spot urine samples for biomarker research are required and will be 
collected from all subjects in this study as specified in the SoA:


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Table 9
Biomarkers
Source:
Analyte:
Comment:
Fasting blood
Glucose
HbA1c
NEFA
Serum sample taken for biomarker research. Samples 
also taken in association with PET (local lab)
Beta-hydroxybutyrate
Lactate
Uric acid
Insulin
Two samples taken 15 minutes apart
Glucagon
NT-proBNP
FGF-21
hsCRP
hsTroponin-I
Total cholesterol
Baseline (Visit 2) only
Triglycerides
Baseline (Visit 2) only
HDL-C
Baseline (Visit 2) only
Plasma and serum sample for 
biobank
Possible analyses after study end
Urine
Glucose
To assess after database lock
Creatinine
Urine sample for biobank
Possible analyses after study end
All protocol-required laboratory assessments, as defined in Table 9, must be conducted in 
accordance with the laboratory manual and the SoA.
Self-assessment of glucose is allowed, but not asked for nor captured in CRF.
Biomarkers, as specified in Table 9, will be tested in Plasma, Serum and Urine for exploratory 
objectives to evaluate changes achieved with dapagliflozin compared to placebo after 6 weeks 
of treatment.
In addition, Plasma, Serum and Urine samples will be collected and analysis may be 
performed on biomarkers thought to play a role for dapagliflozin mechanism of action 
especially heart metabolism and function including, but not limited to, metabolic, 
cardiovascular and renal biomarkers to evaluate their association with observed clinical 
responses to dapagliflozin treatment.


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8.8.1
Storage, re-use and destruction of biomarker 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 (CSR) 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 treatment to generate hypotheses to be tested 
in future research.
8.9
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9.
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
The primary null statistical hypothesis: The adjusted mean change in the GLSLV from 
baseline to the end of treatment for patients on dapagliflozin is equal to the corresponding 
change for patients on placebo.
The primary alternative statistical hypothesis: The adjusted mean change in GLSLV from 
baseline to the end of treatment for patients on dapagliflozin is not equal to the corresponding 
change for patients on placebo. 
9.2
Sample size determination
Change in GLSLV from baseline to the end of treatment has been selected as the primary 
endpoint in the DAPACARD study. 
In patients with pre-existing cardiac abnormality (i.e. aortic stenosis or atherosclerosis) but 
without T2D, the average GLSLV at baseline is approximately -16.0% (Gjesdal et al 2016,  
Singh et al 2015). The common standard deviation in estimated change from baseline GLSLV 
is assumed to be 2.0%, which is a conservative approximation of the results found in the 
literature (1.73% in (Singh et al 2015), 1.3% in (Gjesdal et al 2016). Average GLSLV in T2D 
subjects with prior MI at baseline is anticipated to be -11%. The estimated between-group 
difference in average improvement in GLSLV is anticipated to be -2%. It is estimated that 
17 evaluable patients/arm provides 80% power at a two-sided alpha level of 0.05 to detect a 
treatment difference of 2% in the change from baseline in GLSLV between dapagliflozin and 
placebo, assuming a common standard deviation in estimated change from baseline in GLSLV 
of 2.0%. To accommodate the statistical testing of secondary endpoint, the number of 
evaluable patients/arm is increased to 22 (total of 44). 
Change in myocardial efficiency from baseline to the end of treatment (%, measured as 
external LV work per gram (defined as MAP x SV x HR/ LV mass) divided by total LV work 


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per gram(linearly proportional to MVO2 in turn linearly proportional from [11C]-Acetate 
clearance / LV mass) is the secondary endpoint in the DAPACARD study.
Tuunanen et al reported the healthy subjects baseline myocardial efficiency in two different 
studies to be 54.3 (N=36) and 49.3 (N=8) (pooled mean of 50.21) mmHg · L · g-1, with a 
standard deviation (SD) of 8.9 and 14.2 mmHg · L · g-1, respectively (Tuunanen et al 2006, 
Tuunanen et al 2007). A 25% increase translates into 12.55 with a SD of 14.2 mmHg · L · g-1 
between dapagliflozin and placebo treatment group. Twenty two (22) evaluable subjects per 
group (total of 44) are needed to detect a treatment difference of 12.55, at a 2-sided 
significance level of 0.05 and 80% power. Assuming a 15% non-evaluable rate, total of 52 
(26 per group) subjects will be randomized.
The 18F-FTHA examinations are exploratory and will not be performed in all the randomized 
patients. Instead, a minimum 40 and a maximum of 44 of the randomized patients will be 
scheduled for examination for 18F-FTHA uptake in heart, liver, kidney and the brain. This is 
due to ethical reasons and aims to limit unnecessary exposure to radioactivity. The authors in 
Viljanen et al (Viljanen et al 2009), report SD of myocardial fatty acid uptake to be 0.4 (before 
diet) and 0.2 (after diet) in a healthy population, leading to a pooled SD of 0.32. No 
information is available regarding the magnitude of the treatment effect in the planned study, 
but an effect of approximately 0.3-0.4 (approximately 10% relative change) is judged to be 
clinically relevant. Using this assumption, and the pooled estimate of the SD as a conservative 
approximation of the variability of measurement differences between baseline and end of 
treatment, leads to approximately 80-90% power with 40 randomized patients (at a two-sided 
alpha level 0.05 and assuming 15% non-evaluable rate).
9.3
Populations for analyses
For purposes of analysis, the following populations are defined: 
Population
Description
Enrolled Analysis Set
The Enrolled Analysis Set will consist of all subjects who signed 
informed consent.
Randomized Analysis Set
The Randomized Analysis Set will consist of all randomized subjects 
who received at least one dose of study medication during the treatment 
period. In analyses of the Randomized Subjects Dataset, subjects will 
be summarized by the treatment group to which they were randomized 
(even if the treatment they received is different).
Evaluable Analysis Set
The Evaluable Analysis Set will be the primary analysis dataset, and is 
a subset of the Randomized Analysis Set. This is also known as the Per-
Protocol population. All data points after an important protocol 
deviation will be excluded from this analysis. Important protocol 
deviations are defined as deviations which could potentially affect the 
interpretability of the study results. The criteria for important protocol 
deviations will be defined in the statistical analysis plan. Subjects will 
be represented using the treatment group to which they were received. 


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Population
Description
Safety Analysis Set 
The Safety Analysis Set will consist of all subjects who received at least 
one dose of study medication during the treatment period. Subjects will 
be presented by randomized treatment group, except if information 
indicates that a subject received a different treatment for the entire 
course of their participation in the treatment period. In this case, the 
safety data for such a subject will be presented by the treatment which 
they actually received.
PK Analysis Set
The PK analysis set will include subjects for whom PK data are 
evaluable (with no important protocol deviations thought to 
significantly affect the pharmacokinetics of the drug). PK data may be 
reported separately from the clinical study report.
9.4
Statistical analyses
All personnel involved with the analysis of the study will remain blinded until database lock 
and Clinical Study Protocol deviations identified.
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan (SAP) will be developed and finalised before database lock and will describe in 
more detail the subject populations to be included in the analyses, as well as procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary, secondary and exploratory endpoints. Any deviations from
this plan will be reported in the clinical study report.
9.4.1
Efficacy analyses
The analysis of efficacy will be based on the evaluable analysis set. Change from baseline 
values for the primary variable (GLSLV) will be analyzed using Analysis of Covariance 
(ANCOVA). The model will include terms for baseline value and treatment. 
Least Square Mean (LSM) change from baseline estimates, as well as the corresponding
95 percent confidence limits, will be generated from the fitted model for each treatment group. 
The difference in LSM between the dapagliflozin and placebo treatment groups, the 
corresponding 95 percent confidence interval and the p-value will also be presented. Statistical 
significance will be inferred at a (two-sided) 0.05 level.
Analysis of secondary variable will be performed using the evaluable analysis set. ANCOVA, 
as described above for the primary analysis, will be used. Statistical significance will be 
inferred at a (two-sided) 0.05 level. 
Analysis of exploratory variables will be performed using the evaluable analysis set. Analysis 
of the change from baseline endpoints will be performed using ANCOVA, as for the primary 
endpoint. Details of the statistical analysis of the other exploratory objectives, as well as 
procedures for handling of missing values, will be provided in the SAP.


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9.4.2
Safety analyses
The analysis of safety will be based on the safety analysis set. All SAEs occurring from the 
time of signature of informed consent up to the follow-up period will be summarized by 
system organ class (SOC) and preferred term (PT). The number and percent of subjects that 
discontinue due to adverse events (DAE) and serious adverse event (SAE) will be summarized 
for each treatment group. Descriptive statistics of continuous measurements (e.g. safety 
laboratory assessments and vital signs) will be presented by treatment for both absolute values 
and changes from baseline. Safety laboratory, vital signs, physical examination and ECG 
findings will be listed by patient. Further details on planned safety analyses will be provided in 
SAP.
9.4.3
Other analyses 
PK and biomarker exploratory analyses will be described in the statistical analysis plan. The 
population PK analysis will be described and presented separately from the main clinical study 
report (CSR). 
9.4.4
Methods for multiplicity control
As the nature of the study is exploratory (based on hypotheses presented in Section 4.2, 
Scientific rationale of the study), with no confirmatory component, no control of family-wise 
error rate will be performed. However, due to the large number of considered endpoints, it is 
likely that several of them will be found to be “significant” as a consequence of the Type I 
error rate allowable by the hypothesis testing procedure, even if no effect is truly present. 
Thus, the interpretation of the findings will be done with care, keeping in mind both whether 
the detected patterns are clinically meaningful and the expected number of false discoveries 
that might occur due to chance.
9.5
Interim analyses (Not applicable)
9.5.1
Data monitoring committee (DMC) (Not applicable)
10.
REFERENCES
ADA 2017
American Diabetes Association (ADA) Standards of medical care in diabetes 2017;40, 
suppl 1. [Online] Available from http://care.diabetesjournals.org/content/40/Supplement_1. 
[Accessed].
Ferrannini et al 2016
Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A 
"Thrifty Substrate" Hypothesis. Diabetes Care 2016;39(7):1108-14.
Ferrannini 2017
Ferrannini E. Sodium-Glucose Co-transporters and Their Inhibition: Clinical Physiology. 
Cell Metab 2017;26(1):27-38.


Clinical Study Protocol - 2
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Gjesdal et al 2016
Gjesdal O, Yoneyama K, Mewton N, Wu C, Gomes AS, Hundley G et al. Reduced long axis 
strain is associated with heart failure and cardiovascular events in the multi-ethnic study of 
Atherosclerosis. J Magn Reson Imaging 2016;44(1):178-85.
Holman et al 2008
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive 
glucose control in type 2 diabetes. N Engl J Med 2008;359(15):1577-89.
Holman et al 2014
Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucose-lowering drugs or 
strategies in type 2 diabetes. Lancet 2014;383(9933):2008-17.
ICRP 2007
ICRP, 2007. The 2007 Recommendations of the International Commission on Radiological 
Protection. ICRP Publication 103. Ann. ICRP 37 (2-4). [Online] Available from 
http://www.icrp.org/publication.asp?id=ICRP%20Publication%20103. [Accessed: 2017].
Labbé et al 2012
Labbé SM, Grenier-Larouche T, Noll C, Phoenix S, Guerin B, Turcotte EE et al. Increased 
myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant 
humans. Diabetes 2012;61(11):2701-10.
Labbé et al 2014
Labbé SM, Noll C, Grenier-Larouche T, Kunach M, Bouffard L, Phoenix S et al. Improved 
cardiac function and dietary fatty acid metabolism after modest weight loss in subjects with 
impaired glucose tolerance. Am J Physiol Endocrinol Metab 2014;306(12):E1388-96.
Lampa 2015
Lampa E. Mixture Effects of Environmental Contaminants. Acta Universitatis Upsaliensis: 
Summaries of Uppsala Dissertations from the Faculty of Medicine 1059. 85 pp.
Leung et al 2016
Leung M, Wong VW, Hudson M, Leung DY. Impact of Improved Glycemic Control on 
Cardiac Function in Type 2 Diabetes Mellitus. Circ Cardiovas Imaging 2016;9(3):e003643.
Lindner et al 2016
Lindner O, Sorensen J, Vogt J, Fricke E, Baller D, Horstkotte D et al. Cardiac efficiency and 
oxygen consumption measured with 11C-acetate PET after long-term cardiac 
resynchronization therapy. J Nucl Med 2006;47(3):378-83.
Mather et al 2016
Mather KJ, Hutchins GD, Perry K, Territo W, Chisholm R, Acton A et al. Assessment of 
myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-
[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer. 
Am J Physiol Endocrinol Metab 2016;310(6):E452-60.


Clinical Study Protocol - 2
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Neal et al 2017
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N et al. Canagliflozin 
and Cardiovascular and Renal Events in Type 2 Diabetes. New Engl J Med 2017;377:644-57.
Nesterov et al 2015
Nesterov SV, Turta O, Han C, Maki M, Lisinen I, Tuunanen H et al. C-11 acetate has 
excellent reproducibility for quantification of myocardial oxidative metabolism. 
Eur Heart J Cardiovasc Imaging 2015;16(5):500-6.
Neubauer 2007
Neubauer S. The Failing Heart - An Engine Out of Fuel. N Engl J Med 2007;356(11):1140-51.
Rambold et al 2015
Rambold AS, Cohen S, Lippincott-Schwartz J. Fatty acid trafficking in starved cells: 
regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. 
Dev Cell 2015;32(6):678-92.
Scheuermann-Freestone et al 2003
Scheuermann-Freestone M, Madsen PL, Manners D, Blamire AM, Buckingham RE, Styles P 
et al. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 
diabetes. Circulation 2003;107(24):3040-6.
Shah et al 2015
Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, Liu L et al. Prognostic Importance of 
Impaired Systolic Function in Heart Failure With Preserved Ejection Fraction and the Impact 
of Spironolactone. Circulation 2015;132(5):402-14.
Singh et al 2015
Singh A, Steadman CD, Khan JN, Horsfield MA, Bekele S, Nazir SA et al. Intertechnique 
agreement and interstudy reproducibility of strain and diastolic strain rate at 1.5 and 3 Tesla: a 
comparison of feature-tracking and tagging in patients with aortic stenosis. 
J Magn Reson Imaging 2015;41(4):1129-37.
Tuunanen et al 2006
Tuunanen H, Engblom E, Naum A, Nagren K, Hesse B, Airaksinen KE et al. Free fatty acid 
depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. 
Circulation 2006;114(20):2130-7.
Tuunanen et al 2007
Tuunanen H, Kuusisto J, Toikka J, Jaaskelainen P, Marjamaki P, Peuhkurinen K et al. 
Myocardial perfusion, oxidative metabolism, and free fatty acid uptake in patients with 
hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the alpha-
tropomyosin gene: a positron emission tomography study. 
J Nucl Cardiol 2007;14(3):354-65.


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UKPDS-Group 1998
UKPDS-Group (1998). Intensive blood-glucose control with sulphonylureas or insulin 
compared with conventional treatment and risk of complications in patients with type 2 
diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. 
Lancet 1998;352(9131):837-53.
van den Hoff et al 2001
van den Hoff J, Burchert W, Borner AR, Fricke H, Kuhnel G, Meyer GJ et al. [1-
(11)C]Acetate as a quantitative perfusion tracer in myocardial PET. 
J Nucl Med 2001;42(8):1174-82.
Viljanen et al 2009
Viljanen AP, Karmi A, Borra R, Parkka JP, Lepomaki V, Parkkola R, et al. (2009). Effect of 
caloric restriction on myocardial fatty acid uptake, left ventricular mass, and cardiac work in 
obese adults. Am J Cardiol 103: 1721-1726.
WHO 2016
World Health Organization (WHO) Diabetes: fact sheet no. 312. [Online] Available from 
http://www.who.int/mediacentre/factsheets/fs312/en/#. [Accessed].
National Kidney Foundation
National Kidney Foundation MDRD Study Equation, https://www.kidney.org/content/mdrd-
study-equation. [Online] Available from https://www.kidney.org/content/mdrd-study-
equation. [Accessed].
Zinman et al 2015
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S et al. Empagliflozin, 
Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. 
N Engl J Med 2015;373(22):2117-28.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
Appendix A
Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:
!
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
!
Applicable ICH Good Clinical Practice (GCP) Guidelines
!
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g. advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.
The investigator will be responsible for the following:
!
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
!
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
!
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
A 2
Financial disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study.


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A 3
Informed consent process
The investigator or his/her representative will explain the nature of the study to the subject and 
answer all questions regarding the study.
Subjects must be informed that their participation is voluntary. Subjects will be required to 
sign a statement of informed consent that meets the requirements of local regulations, ICH 
guidelines and the IRB/IEC or study centre.
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF.
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.
The ICF will contain a separate section that addresses the use of samples for exploratory 
research. The investigator or authorised designee will explain to each subject the objectives of 
the exploratory research. Subjects will be told that they are free to refuse to participate and 
may withdraw their consent at any time and for any reason during the storage period. If a 
subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples already have been analysed at 
the time of the request, AstraZeneca will not be obliged to destroy the results of this research.
A 4
Data protection
Each subject will be assigned a unique identifier by the sponsor. Any subject records or data 
sets transferred to the sponsor will contain only the identifier; subject names or any 
information which would make the subject identifiable will not be transferred.
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject.
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to Investigators.


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A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical trial and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the study is conducted.
A 7
Data quality assurance
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
Definitions of what constitutes source data can be found in the Source Data Agreement for 
each site.


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A 9
Publication policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments.
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.


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Appendix B
Adverse event definitions and additional safety information
In this study, collection of AE data is limited to collection of Serious Adverse Events (SAE) 
and Adverse Events leading to Discontinuation of Study Medication (DAE). In addition, all 
possible events (non-serious, SAE, DAE) of diabetic ketoacidosis are to be collected.
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (e.g. an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-subject hospitalisation or prolongation of existing hospitalisation 
!
Results in persistent or significant disability or incapacity.
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the subject or may require 
medical treatment to prevent one of the outcomes listed above.
B 3
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.


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B 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
B 6
Intensity rating scale:
1.
mild (awareness of sign or symptom, but easily tolerated)
2.
moderate (discomfort sufficient to cause interference with normal activities)
3.
severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 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 Appendix B 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 Appendix B 2.
B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course. Exposure to suspect drug. Has the subject actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 


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pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a re-challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study treatment that either causes harm to the 
participant or has the potential to cause harm to the participant.
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error
!
occurred
!
was identified and intercepted before the participant received the drug
!
did not occur, but circumstances were recognize that could have led to an error


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CONFIDENTIAL AND PROPRIETARY
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Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error e.g. medication prepared incorrectly, even if it was not actually 
given to the participant
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
!
Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as 
a solid tablet 
!
Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature 
!
Wrong participant received the medication (excluding Call centre errors)
!
Wrong drug administered to participant (excluding Call centre errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from Call centre - including those which lead to one of 
the above listed events that would otherwise have been a medication error 
!
Participant accidentally missed drug dose(s) e.g. forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Participant failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or standard of care medication 
in open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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CONFIDENTIAL AND PROPRIETARY
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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
subjects while in storage at the centre 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 will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the subject is 
withdrawn from further study participation.
The Investigator:
!
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca
!
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
!
Ensures the organization(s) 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 subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations 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.


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


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Appendix D
Abbreviations 
Abbreviation or special 
term
Explanation
ACE
angiotensin converting enzyme
ADA
American diabetes association
AE
adverse event
ANCOVA
analysis of covariance
ARB
angiotensin receptor blocker
ATP
adenosine triphosphate
BMI
body mass index
BP
blood pressure
CRF
case report form (electronic/paper)
CSA
clinical study agreement
CSR
clinical study report
CT
computed tomography
CV
cardiovascular
DAE
discontinuation of investigational product due to adverse event
DKA
diabetic ketoacidosis
EC
ethics committee, synonymous to institutional review board (IRB) and 
independent ethics committee (IEC)
ECG
electrocardiogram
EF
ejection fraction
eGFR
estimated glomerular filtration rate
FFA
free fatty acid
FTHA
[18F]-6-thia-heptadecanoic acid
GCP
Good Clinical Practice
GLSLV
global longitudinal strain of the left ventricle
GMP
Good Manufacturing Practice
HbA1c
hemoglobin A1c
HCG
Human chorionic gonadotropin
Hct
hematocrit
HFpEF
heart failure with preserved ejection fraction
HR
heart rate
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation


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Abbreviation or special 
term
Explanation
International Coordinating 
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.
LSLV
last subject last visit
LSM
least square mean
LV
left ventricular
MAP
mean arterial pressure
MDRD study equation
modification for diet in renal disease study equation, for estimating eGFR 
with standardized serum creatinine values
MFAU
myocardial fatty acid uptake
MI
myocardial infarction
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
NEFA
Non-esterified (“free”) Fatty Acid
NIMP
non-investigational medicinal product
OAE
other significant adverse event
PET
positron emission tomography
PI
principal investigator 
PK
pharmacokinetic
SAE
serious adverse event 
SAP
statistical analysis plan
SD
standard deviation
SGLT2i
sodium-glucose cotransporter 2 inhibitor
SoA
Schedule of Activities
SOC
system organ class
SUV
standardised uptake value
SV
stroke volume
TIA
transient ischemic attack
T1D
type 1 diabetes
T2D
type 2 diabetes
UCR
Uppsala Clinical Research center
WBDC
web based data capture

SAP_000.pdf: 
Statistical Analysis Plan
Study Code
D1690C00063
Edition Number
2.0   
Date
11/04/2019
DAPACARD
A double-blind, randomized, parallel group, Phase IV study to investigate 
the effects of DAPAgliflozin on CARDiac substrate uptake, myocardial 
efficiency and myocardial contractile work in type 2 diabetes patients


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
2
DAPACARD
A double-blind, randomized, parallel group, Phase IV study to investigate 
the effects of DAPAgliflozin on CARDiac substrate uptake, myocardial 
efficiency and myocardial contractile work in type 2 diabetes patients
Study Statistician
Date
PPD


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
3
DAPACARD
A double-blind, randomized, parallel group, Phase IV study to investigate 
the effects of DAPAgliflozin on CARDiac substrate uptake, myocardial 
efficiency and myocardial contractile work in type 2 diabetes patients
Global Product Statistician
Date
PPD


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
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 ..............................................................................................6
AMENDMENT HISTORY..................................................................................................8
1.
STUDY DETAILS............................................................................................. 12
1.1
Study objectives.................................................................................................12
1.2
Study design ...................................................................................................... 14
1.3
Number of subjects ............................................................................................ 15
2.
ANALYSIS SETS ............................................................................................. 16
2.1
Definition of analysis sets .................................................................................. 16
2.2
Violations and deviations ................................................................................... 17
2.2.1
General protocol deviations................................................................................ 17
2.2.2
Procedure-specific protocol deviations............................................................... 18
3.
PRIMARY AND SECONDARY VARIABLES................................................. 19
3.1
Study endpoints .................................................................................................19
3.1.1
Adjudication of clinical endpoints...................................................................... 19
3.1.2
Baseline demographics and patient characteristics.............................................. 19
3.1.3
Disease history................................................................................................... 21
3.1.4
Prior and/or concomitant medications ................................................................ 22
3.1.5
Efficacy ............................................................................................................. 22
3.1.6
Safety................................................................................................................. 24
3.1.7
Duration of exposure and treatment compliance................................................. 27
3.2
Management of missing data.............................................................................. 27
4.
ANALYSIS METHODS.................................................................................... 27
4.1
General principles.............................................................................................. 27
4.1.1
Baseline characteristics ...................................................................................... 28
4.1.2
Efficacy ............................................................................................................. 28
4.1.3
Safety................................................................................................................. 30
4.2
Analysis methods............................................................................................... 31
4.2.1
Analysis of the effect of treatment...................................................................... 31


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
5
4.2.2
Evaluation of plausibility of model assumptions................................................. 31
4.2.3
Analysis of co-dependence................................................................................. 32
5.
INTERIM ANALYSES (NOT APPLICABLE).................................................. 33
6.
CHANGES OF ANALYSIS FROM PROTOCOL (NOT APPLICABLE).......... 33
7.
REFERENCES .................................................................................................. 34
8.
APPENDIX ....................................................................................................... 35
8.1
Overview of the study assessments..................................................................... 35
8.2
Medical history of special interest ...................................................................... 36
8.3
Imputation of missing dates................................................................................ 36
8.4
Reference limits for ALT, AST, ALP and total bilirubin .................................... 38
8.5
Protocol Deviation Process................................................................................. 39


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
6
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
A
Peak velocity flow in late diastole caused by atrial contraction (the A
wave)
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase 
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase 
ATC
Anatomic therapeutic chemical
BMI
Body mass index
CRF
Case report form
CSP
Clinical study protocol
CI
Confidence interval
CT
Computed tomography
DAE
Adverse events leading to discontinuation of study medication
DKA
Diabetic ketoacidosis
E
Mitral peak velocity of Early filling 
E/A
Peak velocity flow in early diastole (the E wave) to peak velocity 
flow in late diastole caused by atrial contraction (the A wave)
ECG
Electrocardiography
FGF-21
Fibroblast growth factor 21
GLSLV
Global longitudinal strain of the left ventricle
Hb
Haemoglobin
HbA1c
Glycosylated haemoglobin
HDL-C
High density lipoprotein cholesterol
IP
Investigational Product
K1
A rate constant
Kmono
A rate constant
LV
Left ventricular
LSM
Least squares mean
MFAU
Myocardial fatty acid uptake
MRI
Magnetic resonance imaging 


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
7
Abbreviation or 
special term
Explanation
n
Number of subjects with non-missing values
NEFA 
Non-esterified fatty acids
NT-proBNP
N-terminal prohormone of brain natriuretic peptide 
PD
Protocol deviation
PET
Positron emission tomography
PK
Pharmacokinetic
PT
Preferred term
Q1
25th percentile
Q3
25th percentile
SAE
Serious adverse event
SOC
System organ class
SD
Standard deviation
T2D
Type 2 diabetes


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
8
AMENDMENT HISTORY
Date
Brief description of change
11 April 2019
In general:
Minor updates concerning typographical errors, grammar etc. 
Section 2.1: 
Added the PD specification as an appendix to the SAP: “The overall criteria 
for important protocol deviations is defined in section 2.2 and details further 
specified in the protocol deviations process document (Appendix 8.5).”
Rephrased two sentences regarding subject representation in datasets.
Section 2.2.1: 
Changed protocol deviation criteria from
-
“Eligibility criteria not fulfilled (e.g. patients who were randomized in 
error or who developed discontinuation criteria after randomization and 
were not discontinued)
-
Study drug compliance <90% or >120%
-
Administration of wrong type of study drug (i.e. the one not randomized 
to) for the whole study period
-
Onset of serious disease that will influence the effects of any of the 
study drugs
-
Use of disallowed concomitant medications”
to 
-
“Randomized but did not meet the eligibility criteria
-
Developed criteria for discontinuation of treatment but were not 
discontinued
-
Received wrong study drug
-
Received disallowed concomitant medication(s)
-
Suspected study drug compliance less than 90% or more than 
120%
-
Severe non-compliance to the protocol
-
Other”
Section 2.2.1
Added “Protocol deviations will be further defined in a separate protocol 
deviations process document, see appendix 8.5.”
Section 3.1.3:
Added LV global longitudinal strain (GLSLV), Myocardial efficiency, P-
Glucose, P-Insulin, P-Glucagon, P-Glucagon/Insulin to the list of 
measurements


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
9
Date
Brief description of change
Section 3.1.4: 
Changed from “In addition, the usage of metformin will be tabulated as part of 
the disease characteristics. The tabulation will be done for each treatment 
group and in total and include the daily metformin dosage at the time of 
screening visit and duration of metformin treatment.” to “In addition, the 
concomitant usage of metformin will be tabulated as part of the disease 
characteristics. The tabulation will be done for each treatment group and in 
total and include the total daily metformin dosage at the time of screening 
visit and duration of metformin treatment.”
Section 3.1.7:
Reformulated text regarding duration and compliance.
Table 3.3:
Removed: “Currently taking antidiabetic medication”
Added: “Metformin dose”
Table 3.4:
Minor changes, related to units and footnotes. 
P-Glucagon/Insulin, (Ratio) (b) moved from the category “Fatty acid blood 
biomarkers” to the category “Glucose control biomarkers”.
Section 4.1:
Added “Minimum and maximum values will be reported to the same 
degree of precision as the raw data up to a maximum of 3 decimal places. 
Mean, first quartile, median, third quartile, and SD will be reported to 
one further degree of precision. Percentages will be rounded to 1 decimal 
place. In general, baseline will be defined as the last value prior to the 
date of the first dose.
For insulin and vital status two measurements are taken with a few 
minutes apart. The average of those measurements will be used in the
calculations.
In general, the laboratory results from the blood biomarkers will be used 
for the efficacy endpoints and the clinical safety laboratory assessments
will be used for the safety endpoints.”
Section 4.1.1:
Sentences about purpose and imbalance were removed.
Changed which compliance intervals to present.
Removed the text: “The distribution of baseline characteristics in the two 
treatment groups and in all patients combined will be examined. To this end”


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
10
Date
Brief description of change
Section 4.1.2.2:
The method linear regression exchanged to correlation.
Section 4.1.2.3:
Changed from “The population PK analysis will be described and presented 
separately from the main clinical study report.” to “The pharmacokinetic 
concentration data from the pre-dose blood sample at visit 4 will be listed 
for all patients in the PK analysis set. Further analysis may be presented 
separately from the main clinical study report.” 
Section 4.1.3.1:
Added “For clinical chemistry and haematology, only fasting values will 
be analysed.” 
Section 4.1.3.2:
Changed “All collected AEs (which, for this study, consist of DAEs and 
SAEs) with start date greater or equal to the date of the randomization will be 
summarized using descriptive statistics (number of patients, percentage of 
patients).” to “All collected AEs (which, for this study, consist of DAEs and 
SAEs) with onset date during the treatment period will be summarized 
using descriptive statistics (number of patients, percentage of patients).”. 
Section 4.1.3.2:
Added “All SAEs occurring from the time of signature of informed 
consent up to and including the follow-up period will be summarized by 
system organ class (SOC) and preferred term (PT).”. 
Section 4.2:
The wording in the section 4.2 Analysis Methods has been simplified, and 
presentation of results has been clarified. 
Added: “Any marked violations of model assumptions will be discussed in 
the CSR and the supporting results will be presented in appendices.” 
Section 4.2 in general:
Minor updates and restructuring within the section.


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
11
Date
Brief description of change
Section 4.2.2:
Changed from: 
“The relationship of the response to the nuisance variable is linear within each 
treatment group”
to:
“The relationship of the response to the baseline variable is linear within each 
treatment group”
Added: “Any impact of the potential outliers and subgroups will also be 
investigated. Outlier as an observation with a residual that is more than 
three times the interquartile range above the 75th percentile or below the 
25th percentile. Outliers will be identified using standardized residuals 
from the original ANCOVA model. If outliers are present, then additional 
sensitivity analyses will be performed with the outliers excluded.”
Added:
“If the relationship of the response to the baseline variable is non-linear, 
then a suitable transformation of the response and the baseline variable 
(e.g., natural logarithm, square root, inverse, quadratic, etc.) may be used 
for analysis.”
Section 4.2.3:
The method linear regression is changed to correlation.
Section 4.2.3:
Following has been removed in the section of Analysis of co-dependence:
!
The Spearman correlation analysis. 
!
The quadratic term from the linear regression model. 
!
The multivariate model.


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
12
1.
STUDY DETAILS
1.1
Study objectives
The aim of the DAPACARD study is to explore the effect of dapagliflozin on cardiac substrate 
uptake, myocardial efficiency and myocardial contractile work in type 2 diabetes patients. 
Explicitly, the objectives of the study are as follows:
Primary objective:
To compare the changes in global longitudinal strain of the left ventricle (GLSLV) achieved 
with dapagliflozin versus placebo after 6 weeks of double-blind treatment.
Secondary Objective: 
To compare the changes in myocardial efficiency (%) achieved with dapagliflozin versus 
placebo after 6 weeks of double-blind treatment.
Safety Objective: 
To evaluate the safety and tolerability of dapagliflozin.
Exploratory Objectives:
1) To compare the changes in wash-out in the myocardium of [11C]-Acetate (Kmono,
1/min) achieved with dapagliflozin vs. placebo after 6 weeks of double-blind treatment.
2) To compare the changes in myocardial perfusion (ml/min/g) measured by [11C]-
Acetate achieved with dapagliflozin vs. placebo after 6 weeks of double-blind
treatment.
3) To compare the changes in wash-out of [11C]-Acetate (Kmono, 1/min) in relation to 
myocardial perfusion (K1, ml/min/g) achieved with dapagliflozin vs. placebo after 6 
weeks of double-blind treatment.
4) To compare the changes in myocardial fatty acid uptake (MFAU, μmol/min/g) by 
[18F]-FTHA achieved with dapagliflozin versus placebo after 6 weeks of double-blind
treatment.
5) To compare the changes in fatty acid uptake in liver (μmol/min/g) by [18F]-FTHA 
achieved with dapagliflozin versus placebo after 6 weeks of double-blind treatment.


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
13
6) To compare the changes in fatty acid uptake in kidney cortex (μmol/min/g) by [18F]-
FTHA achieved with dapagliflozin versus placebo after 6 weeks of double-blind
treatment
7) To compare the changes in fatty acid uptake in brain (μmol/min/g) by [18F]-FTHA 
achieved with dapagliflozin versus placebo after 6 weeks of double-blind treatment.
8) To compare the changes in Left Ventricular (LV) global radial strain and LV global 
circumferential strain achieved with dapagliflozin versus placebo after 6 weeks of
double-blind treatment.
9) To compare the changes in LV global systolic longitudinal strain rate, LV global 
diastolic longitudinal strain rate, LV global diastolic radial strain rate, LV global 
systolic radial strain rate, LV global diastolic circumferential strain rate and LV 
global systolic circumferential strain rate, achieved with dapagliflozin versus placebo
after 6 weeks of double-blind treatment.
10) To compare the changes in LV end-diastolic volume (mL), LV end-systolic volume 
(mL), and LV stroke volume (mL) achieved with dapagliflozin versus placebo after 6 
weeks of double-blind treatment.
11) To compare the changes in LV mass (g), LV mass/end-diastolic volume (g/mL) and 
LV ejection fraction (%) achieved with dapagliflozin versus placebo after 6 weeks of
double-blind treatment.
12) To compare the changes in Left atrial volume (min, max) (mL), Left atrial ejection 
fraction (%) and transmitral flow velocity indices (E/A (1), E (cm/s), A (cm/s) and
DT (ms)), achieved with dapagliflozin versus placebo after 6 weeks of double-blind
treatment.
13) To compare the changes in blood biomarkers (e.g. HbA1c, Hematocrit, Hb, FGF-21, 
NT-proBNP) achieved with dapagliflozin vs. placebo after 6 weeks of double-blind 
treatment.
14) To compare the changes from baseline in body weight, and blood pressure achieved 
with dapagliflozin versus placebo after 6 weeks of double-blind treatment.
15) To explore associations between change in GLSLV and change in myocardial 
efficiency as well as associations to changes in other exploratory end-points with
potential importance.
Pharmacokinetics objectives:
1) To evaluate the pharmacokinetics of dapagliflozin by a single pre-dose sample at end 
of study.


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
14
1.2
Study design
DAPACARD is a randomized, placebo-controlled, double-blind, parallel-group, international, 
multicentre, Phase IV mechanistic study. Eligible subjects with Type 2 diabetes (T2D) before 
randomization and fulfilling all of the inclusion criteria and none of the exclusion criteria (see
clinical study protocol, CSP, Section 5, for a complete list of the inclusion and the exclusion 
criteria) will be randomised in a 1:1 ratio to dapagliflozin 10 mg or placebo once daily and 
treated for approximately six weeks. 
The study includes five visits. The information collected at these visits can be briefly outlined 
as follows. For a complete overview of the assessments done at each visit, see Appendix 8.1 or 
CSP v2 Table 1.
Visit 1: Screening (day -21-0)
Demography, including birth date, sex and race / ethnicity. Vital signs, including pulse rate and 
blood pressure. Height and weight. Medical history, with a special attention paid to history of 
diabetes. Information about concomitant medications. Electrocardiogram (ECG) and 
echocardiogram (ECHOC) will be performed and safety information (SAE, laboratory tests) 
will be collected.
Visit 2: Randomization / baseline (day 1)
All the efficacy measures as listed in Section 3 will be collected. Vital signs, safety information 
(SAE, laboratory tests) and changes in concomitant medications will also be registered. 
Inclusion and exclusion criteria will again be checked.
Visit 3: Interim visit, phone (day 14 ± 4)
This is a check-up visit with a primary purpose to collect changes in concomitant medications 
or life style, treatment regimen compliance and safety information (SAE, DAE and symptoms 
of diabetic ketoacidosis [DKA]).
Visit 4: End of treatment (day 42 ± 4)
The efficacy measures will again be collected here. The safety information (SAE, DAE, DKA 
symptoms, laboratory values), and the possible changes in concomitant medication and life style 
will be captured.
Visit 5: Safety follow-up, phone (day 49 ± 4)
This is a phone visit with the purpose of capturing safety information (SAE, DAE and DKA 
symptoms).


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
15
1.3
Number of subjects
The sample size calculations were based on both the primary (change in GLSLV from baseline 
to the end of treatment) and the secondary (change in myocardial efficiency from baseline to 
the end of treatment) endpoints. 
For the primary endpoint, the assumptions used in the sample size calculation are as follows: 
The between-group difference in average improvement in GLSLV is anticipated to be -2% and 
the standard deviation (SD) of change in GLSLV for the population under study to be 2%. The 
choice of these values is motivated by the literature, namely Gjesdal et al., 2016 (Gjesdal et al., 
2016) and Singh et al., 2015 (Singh et al., 2015). There, the average GLSLV in patients with 
pre-existing cardiac abnormality (i.e. aortic stenosis or atherosclerosis), but without T2D, was 
estimated to be approximately -16.0%. The corresponding SD was 1.3% (Gjesdal et al., 2016, 
population SD) and 1.73% (Singh et al., 2015, SD of difference from baseline), of which 2% is 
a conservative approximation. Average GLSLV in T2D subjects with prior myocardial 
infarction at baseline is anticipated to be -11%, leading to a conservative approximation of 
expected difference of -2%.
For the secondary endpoint, the assumptions are as follows:
The between-group difference in average improvement in myocardial efficiency is anticipated 
to be 12.55 mmHg · L · g-1 with a corresponding SD of 14.2 mmHg · L · g-1. This is motivated 
by the literature, namely Tuunanen et al., 2006 and 2007 (Tuunanen et al., 2006; Tuunanen et 
al., 2007), who reported the healthy subjects baseline myocardial efficiency in two different 
studies to be 54.3 (N=36) and 49.3 (N=8) (pooled mean of 50.21) mmHg · L · g-1, with a 
corresponding standard deviation (SD) of 8.9 and 14.2 mmHg · L · g-1, respectively. A 
hypothesized 25% increase in myocardial efficiency translates into 12.55 mmHg · L · g-1.
Assuming 80% statistical power, a two-sided type I error rate alpha of 0.05 and a two-sample t-
test as the testing procedure, leads to approximately 17 patients per group for the primary 
endpoint and approximately 22 patients per group for the secondary endpoint.  Thus, a total of 
44 evaluable subjects should be available at the end of the study. Assuming a 15% non-
evaluable rate, total of 52 (26 per group) subjects will be randomized.
The 18F-FTHA examinations are exploratory and will not be performed in all the randomized 
patients. Instead, a minimum 40 and a maximum of 44 of the randomized patients will be 
scheduled for examination for 18F-FTHA uptake in heart, liver, kidney and the brain. This is 
due to ethical reasons and aims to limit unnecessary exposure to radioactivity. The authors in 
Viljanen et al. (Viljanen et al., 2009), report SD of myocardial fatty acid uptake to be 0.4 (before 
diet) and 0.2 (after diet) in a healthy population, leading to a pooled SD of 0.32. No information 
is available regarding the magnitude of the treatment effect in the planned study, but an effect 
of approximately 0.3-0.4 (approximately 10% relative change) is judged to be clinically 
relevant. Using this assumption, and the pooled estimate of the SD as a conservative 
approximation of the variability of measurement differences between baseline and end of 
treatment, leads to approximately 80-90% power with 40 randomized patients (at a two-sided 
alpha level 0.05 and assuming 15% non-evaluable rate).


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2.
ANALYSIS SETS
2.1
Definition of analysis sets
Following the CSP, the main analysis sets are defined as follows.
Analysis set
Description
Enrolled Analysis Set
The Enrolled Analysis Set will consist of all subjects who 
signed informed consent.
Randomized Analysis Set
The Randomized Analysis Set will consist of all randomized
subjects who received at least one dose of study medication 
during the treatment period. In analyses of the Randomized 
Analysis Dataset, subjects will be summarized by the treatment 
group to which they were randomized (even if the treatment 
they received is different).
Evaluable Analysis Set
The Evaluable Analysis Set will be the primary analysis dataset 
and is a subset of the Randomized Analysis Set. This is also 
known as the Per-Protocol population. All data points after an 
important protocol deviation will be excluded from this 
analysis. Important protocol deviations are defined as 
deviations which could potentially affect the interpretability of 
the study results. The overall criteria for important protocol 
deviations is defined in section 2.2 and details further specified 
in the protocol deviations process document (Appendix 8.5). 
Subjects will be presented according to the randomized 
treatment assignment, irrespective of the treatment actually 
received.
Safety Analysis Set
The Safety Analysis Set will consist of all subjects who 
received at least one dose of study medication during the 
treatment period. Subjects will be presented by randomized
treatment group, except if information indicates that a subject 
received a different treatment for the entire course of their 
participation in the treatment period. In this case, the safety 
data for such a subject will be presented according to the 
treatment actually received.
PK Analysis Set
The PK analysis set will include subjects for whom PK data are 
evaluable (with no important protocol deviations thought to 
significantly affect the pharmacokinetics of the drug). PK data 
may be reported separately from the clinical study report.


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In addition, three subsets of the Evaluable Analysis Set will be defined, namely: MRI Analysis 
Set, 11C-Acetate Analysis Set and 18F-FTHA Analysis Set. These subsets will consist of 
subjects that, in addition to not having any important protocol deviations, also to a sufficient 
degree fulfil the measurement-specific requirements (have fasted and abstained from nicotine, 
alcohol and caffeine, see Section 2.2.2). Specifically:
Analysis Set
Description
MRI Evaluable Analysis Set
Patients in the Evaluable Analysis Set that, as per clinical 
judgement, sufficiently fulfilled the 4 conditions specified in 
Section 2.2.2 at both of the times when MRI measurements 
were taken.
11C-Acetate Evaluable 
Analysis Set
Patients in the Evaluable Analysis Set that, as per clinical 
judgement, sufficiently fulfilled the 4 conditions specified in 
Section 2.2.2 at both of the times when PET-11C-Acetate
measurements were taken.
18F-FTHA Evaluable 
Analysis Set
Patients in the Evaluable Analysis Set that, as per clinical 
judgement, sufficiently fulfilled the 4 conditions specified in 
Section 2.2.2 at both of the times when PET-18F-FTHA 
measurements were taken.
The efficacy analyses will be performed using one of these three sets, the choice of a set 
determined by the measurement method that provided the analysed endpoint. For an exact 
specification of which endpoint corresponds to which set, see Table 3.4 “Source” column.
The number of patients included in the sets will be tabulated, for each treatment group separately 
and in total. In addition, for the Safety Analysis Set, the Evaluable Analysis Set, and the three 
subsets defined above, the reasons for exclusion of patients from the respective sets will be 
provided. 
2.2
Violations and deviations
2.2.1
General protocol deviations
A protocol deviation (PD) occurs when a patient fails to adhere to pre-specified protocol 
eligibility criteria, and/or compliance during the course of the trial.
In this study, we will distinguish between general protocol deviations and procedure-specific 
deviations. General protocol deviations include all deviations except for the procedure-specific 
ones as defined in Section 2.2.2 and can be classified as either important or not important. 
Important protocol deviation is defined as a PD that “may significantly impact the completeness, 
accuracy, and/or reliability of the study data or that may significantly affect a subject’s rights, 
safety or wellbeing”. Important protocol deviations (IPD) will lead to exclusion of a subject 


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from the Evaluable Analysis Set. A non-important protocol deviation will, by itself, not lead to 
subject exclusion. However, a combination of non-important PDs might lead to such an 
exclusion, as per clinical judgement.
Important protocol deviations
Important protocol deviations include, but are not limited to:
-
Randomized but did not meet the eligibility criteria
-
Developed criteria for discontinuation of treatment but were not discontinued
-
Received wrong study drug
-
Received disallowed concomitant medication(s)
-
Suspected study drug compliance less than 90% or more than 120%
-
Severe non-compliance to the protocol
-
Other
Protocol deviations will be further defined in a separate protocol deviations process document, 
see Appendix 8.5. PDs will be identified partly through programmed checks and partly through
examination performed by e.g. monitors prior to database lock. A detailed list of both important 
and non-important protocol deviations will be provided in a separate document.
Number of patients with important protocol deviations will be tabulated for each treatment 
group separately and in total. No such tabulation will be made for non-important protocol 
deviations. However, subjects excluded from the analysis due to an important protocol 
deviation, or due to a combination of non-important protocol deviations, if such exist, will be 
listed.
2.2.2
Procedure-specific protocol deviations
These deviations refer to the fulfilment of conditions that the patients are required to adhere to 
when taking MRI and PET measurements. These conditions are as follows:
1) Patient should have been fasting for at least 6 hours 
2) Patient should have abstained from products containing nicotine for at least 6 hours 
3) Patient should have abstained from products containing alcohol for at least 6 hours
4) Patient should have abstained from products containing caffeine for at least 6 hours 
A failure to fulfil at least one of these conditions might lead to removal of the patient from the 
respective analysis set. Whether a condition (or several) was violated to a degree that would 
require a patient to be excluded from the analysis will be determined by clinical judgement, and 
this will be done prior to database lock and study unblinding.  
The number, and percentage, of patients who fail to fulfil the above criteria for any of the 
performed measurements (MRI, 11C-Acetate or 18F-FTHA) will be tabulated, regardless of 
whether a patient was, or was not, removed from the analysis due to such a failure. 


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3.
PRIMARY AND SECONDARY VARIABLES
3.1
Study endpoints
3.1.1
Adjudication of clinical endpoints
Adjudication will be performed only for potential events of diabetic ketoacidosis (DKA). These 
will be recorded in the CRF and submitted to an independent DKA Adjudication Committee 
(see CSP Section 8.2.6.1 for details). No other endpoints will be adjudicated.
3.1.2
Baseline demographics and patient characteristics
The values for the baseline demographics and patient characteristics, as listed below, will be 
obtained at the screening visit. The characteristics will be summarized descriptively, as is 
detailed in Section 4.1.1. The following demographics characteristics will be captured:
Table 3.1 Demographics
Demographics
Possible values / units
Measurement type
Derived
Sex
Male, Female
Categorical
No
Age
Years
Numerical
Yes
Age, categorized
<65 years
∀65 years
Categorical
Yes
Ethnicity
Hispanic or Latino 
Not Hispanic or Latino 
Categorical
No
Race
White 
Black or African American 
Asian 
Other 
Categorical
No
Also, the following patient characteristics will be captured:
Table 3.2 Patient characteristics
Patient characteristic
Possible values / units
Measurement type
Derived
Height
cm
Numerical
No
Weight
kg
Numerical
No
Weight, categorized
< 70 kg
∀70 - < 90 kg
∀90 kg
Categorical
Yes


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BMI
kg/m2
Numerical
Yes
BMI, categorized
< 25 kg/m2
∀25 and < 30 kg/m2 
∀30 kg/m2
Categorical
Yes
ECG
Normal
Abnormal
Categorical
No
Pulse Rate
Beats / min
Numerical
No
Blood Pressure
mmHg
Numerical
No
The derivation of the baseline characteristics, when applicable, will be performed according to 
the following rules:
Patient characteristic
Derivation principle
Age
Derived by taking the difference between screening visit date and the 
date of birth. Explicitly, 
(1 + consent date - birth date) / 365.25
BMI
Weight / Height2
The categorization of weight and BMI will be performed using the numerical values of the 
respective measurements. 
The following measurements will be performed at randomization visit and treated as baseline 
characteristic:
Measurement
Unit
Measurement type
Source
S-Cholesterol
S-Triglycerides
S-HDL-Cholesterol 
Direct
mmol/L
mmol/L
mmol/L
Numerical
Blood sample


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3.1.3
Disease history
Relevant medical and surgical history will be collected at the screening visit. History of diabetes 
will include information about duration of diabetes (in years, continuous and categorized), 
possible complications and current antidiabetic medication. Explicitly, the following diabetes 
history related variables will be collected:
Table 3.3 Disease history
Measurement
Possible values / units
Measurement type
Derived
Duration of Type 2 Diabetes
Years
Numerical
Yes
Duration of Type 2 
Diabetes, categorized
< 3 years
∀3 and # 10 years
> 10 years
Categorical
Yes
Presence of complications
Yes
No
Categorical
No
Type of complication
Retinopathy
Neuropathy Autonomic
Neuropathy Peripheral
Nephropathy
Angiopathy
Other
Categorical
No
Metformin dose
# 500 mg
> 500 and # 1000 mg
> 1000 and # 2000 mg
> 2000 mg
Categorical
No
Out of these, duration of Type 2 Diabetes will be derived as follows:
Duration of Type 2 
Diabetes
Derived by taking the difference between screening visit date and the 
date T2D was diagnosed. Explicitly, 
(1 + consent date - diagnosis date) / 365.25.
Other than the history of diabetes, medical history of special interest, such as myocardial 
infarction and atrial fibrillation, will be registered (see Appendix 8.2 for a complete list of 
medical history of special interest). Additional medical and surgical history will also be 
collected as free text, later coded according to the version of Medical Dictionary for Regulatory 
Activities (MedDRA version 21.1) which is current at the time of data base lock.


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In addition, the following measurements will be treated similarly to baseline patient 
characteristic (disease characteristics):
Measurement
Unit
Measurement type
Source
B-HbA1c 
%
Numerical
Blood sample
B-HbA1c, categorized
<7%
∀7% – <8%, 
∀8%
Categorical
Blood sample
LV 
global 
longitudinal 
strain (GLSLV)
%
Numerical
MRI
Myocardial efficiency
%
Numerical
PET-[11C]-Acetate
P-Glucose
mmol/L
Numerical
Blood sample
P-Insulin
pmol/L
Numerical
Blood sample
P-Glucagon
pmol/L
Numerical
Blood sample
P-Glucagon/Insulin
Ratio
Numerical
Blood sample
3.1.4
Prior and/or concomitant medications
Prior medications are defined as medications taken with start and stop date that fall before 
randomization. Concomitant medications are defined as treatments that are ongoing during the 
study period (i.e. after and including the randomization day). The use of prior and concomitant 
medications in the study will be collected as free text, later coded according to World Health 
Organization Drug Dictionary (WHODD).
In addition, the concomitant usage of metformin will be tabulated as part of the disease 
characteristics. The tabulation will be done for each treatment group and in total and include the 
total daily metformin dosage at the time of screening visit and duration of metformin treatment.
3.1.5
Efficacy
The efficacy endpoints in the study are changes observed in measurements listed below between 
the time of randomization (visit 2) and end of the 6-week treatment period (visit 4). All the 
endpoints are quantitative and can be viewed as measurements on a continuous scale. All the 
endpoints will be analysed in the same manner, described in detail in Section 4.2, which includes 
both a descriptive summary and a formal statistical analysis. For details about measurement 
procedures, see CSP Section 8.1. 


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In the table below, the efficacy variables are grouped according to their clinical similarity. 
Table 3.4 Efficacy endpoints
Variable group
Endpoints in the group
Source
Primary 
LV global longitudinal 
strain (GLSLV)
GLSLV (%)
MRI
Secondary
Myocardial efficiency 
Myocardial efficiency (%)
PET-[11C]-
Acetate (d)
Exploratory
[11C]-ACETATE
Wash-out in the myocardium (Kmono) (l/min)
Myocardial perfusion (mL/min/g)
Wash-out in the myocardium (Kmono) / myocardial 
perfusion 
PET-[11C]-
Acetate
[18F]-FTHA
Myocardial fatty acid uptake (μmol/g/min)
Fatty acid uptake in liver (μmol/g/min)
Fatty acid uptake in kidney cortex (μmol/g/min)
Fatty acid uptake in brain (μmol/g/min)
PET-[18F]-
FTHA
LV global strain
LV global radial strain (%)
LV global circumferential strain (%)
MRI
LV global systolic strain 
rate
LV global systolic longitudinal strain rate (s-1)
LV global systolic radial strain rate (s-1)
LV global systolic circumferential strain rate (s-1)
MRI
LV global diastolic 
strain rate
LV global diastolic longitudinal strain rate (s-1)
LV global diastolic radial strain rate (s-1) 
LV global diastolic circumferential strain rate (s-1)
MRI
LV volume
LV end-diastolic volume (mL)
LV end-systolic volume (mL)
LV stroke volume (mL)
LV ejection fraction (%)
MRI
LV mass
LV mass (g)
LV mass/end-diastolic volume (g/mL)
MRI
Left atrial volumes and 
compliance measures
Left atrial min volume (mL)
Left atrial max volume (mL)
MRI


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Left atrial ejection fraction (%)
E/A (I) 
E (cm/s)
A (cm/s)
DT (ms)
Glucose control 
biomarkers (a)
P-Glucose (mmol/L) (c)
B-HbA1c (%) (e)
P-Lactate (mmol/L)
P-Insulin (pmol/L)
P-Glucagon (pmol/L)
P-Glucagon/Insulin, (Ratio) (b)
Blood sample
Fatty acid blood 
biomarkers (a)
S-Free Fatty Acids, NEFA (mmol/L)
P-Beta-hydroxybutyrate (umol/L)
Blood sample
Red blood cell 
biomarkers (a, c)
B-Erythrocyte, Volume Fraction (Ratio) 
B-Haemoglobin (g/L)
Laboratory, 
haematology/
haemostasis
Heart blood biomarkers
(a)
S-N-Terminal Pro-Brain Natriuretic Peptide (pmol/L)
P-Fibroblast Growth Factor 21 (ng/L)
S-C-Reactive Protein (mg/L)
P-high-sensitivity Troponin I (ug/L)
Blood sample
Other biomarkers (a)
S-Urate (μmol/L)
Blood sample
Vital Signs (a)
Weight (kg)
Systolic Blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Physical 
examination
a
No evaluation of within-group dependencies will be done for this group.
b 
Derived by dividing the glucagon value from the Glucose control biomarkers group with insulin value 
from the same group.
c 
Also part of the safety analysis.
d 
Variables obtained from MRI examination (stroke volume) and vital signs examination (blood pressure
and pulse rate) on the corresponding visit are also used in calculation of myocardial efficiency.
e 
If data are not received in % following derivation should be applied,
HbA1c (%) = [ HbA1c (mmol/mol) +24]/11
3.1.6
Safety 
The safety will be assessed through collection and examination of laboratory values and adverse 
events.
3.1.6.1
Safety, laboratory and vital signs
The following safety measurements will be done prior to treatment initiation (screening and 
randomization visits) and at the end of treatment:


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Measurement
Unit
Source
B-Haemoglobin
B-Erythrocyte, Volume Fraction
g/L
Ratio
Laboratory, 
haematology/haemostasis
P-Creatinine
P-Bilirubin, total
P-Alkaline Phosphatase (ALP)
P-Aspartate transaminase (AST)
P-Alanine transaminase (ALT)
P-Glucose
μmol/L
μmol/L
μkat/L 
μkat/L
μkat/L
mmol/L
Laboratory, clinical chemistry
Systolic blood pressure
Diastolic blood pressure
Pulse
mmHg
mmHg
bpm
Physical examination
The safety measurements will be presented descriptively, as is detailed in Section 4.1.3.1.
Observe that B-Haemoglobin, B-Erythrocyte, systolic blood pressure and diastolic blood 
pressure will also be part of the efficacy analyses. 
In addition, the following safety variables will be derived:
Measurement
Possible values / units
Derivation principle
ALP, grouped
Abnormal, low
Normal
Abnormal, high
The classification is performed by relating the 
ALP 
measurement 
to 
the 
corresponding 
reference limits of the local labs (see Appendix 
8.4).
AST, grouped
Abnormal, low
Normal
Abnormal, high
The classification is performed by relating the 
AST 
measurement 
to 
the 
corresponding 
reference limits of the local labs.


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ALT, grouped
Abnormal, low
Normal
Abnormal, high
The classification is performed by relating the 
ALT 
measurement 
to 
the 
corresponding 
reference limits of the local labs.
Total bilirubin, 
grouped
Abnormal, low
Normal
Abnormal, high
The classification is performed by relating the 
total bilirubin measurement to the corresponding 
reference limits of the local labs.
3.1.6.2
Safety, adverse events
Serious adverse events (SAE) and adverse events leading to discontinuation (DAE) will be 
captured. All possible events of diabetic ketoacidosis (including non-serious) will also be 
collected.
AE type
Definition
AE 
An adverse event is the development of any untoward medical occurrence in a subject 
or clinical study subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavourable and unintended sign (e.g. an abnormal laboratory finding), 
symptom (for example nausea, chest pain), or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal 
product. The term AE is used to include both serious and non-serious AEs and can 
include a deterioration of a pre-existing medical occurrence. An AE may occur at 
any time, including run-in or washout periods, even if no Study treatment has been 
administered.
SAE
An SAE is an AE occurring during any study phase (screening, randomization, 
treatment, follow-up) that fulfils one or more of the following criteria:
-
Results in death.
-
Is immediately life-threatening.
-
Requires 
in-patient 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation.
-
Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions.
-
Is a congenital abnormality or birth defect.
-
Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above.
DAE
Discontinuation of Investigational Product due to Adverse Event


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AEs (for this study, SAEs and DAEs) will be classified by Primary System Organ Class (SOC) 
and Preferred Term (PT) according to the version of Medical Dictionary for Regulatory 
Activities (MedDRA) which is current at the time of data base lock.
For details regarding AE collection and follow-up, see CSP v2 Section 8.3.
3.1.7
Duration of exposure and treatment compliance
Compliance, as a percentage, will be calculated as 100 times the ratio of the total number of 
tablets taken (numerator) and the total number that should have been taken (denominator). The 
total number of tablets taken is the difference between total number of tablets dispensed minus 
total number of tablets returned over the entire randomized treatment period. The total number 
of tablets that should have been taken is calculated as the date of the last IP dose minus the date 
of first IP dose during randomized treatment period plus one (one tablet a day is the study 
dosing).
3.2
Management of missing data 
All the analyses (both descriptive and formal) will be conducted using the available data. No 
imputation of values of endpoints, laboratory values, or patient characteristics will be 
performed. Missing start/stop dates for AE will appear as missing in the listings but will, 
however, be imputed for the tabulated summaries. Missing dates for T2D first diagnosed will 
likewise be imputed for the tabulated summaries but appear as missing, or partially missing, in 
the listings. Missing start/stop date of prior and concomitant medications will also be reported 
as missing in the listings, but imputation will be performed to allow the classification into prior 
and concomitant. Missing dates related to medical history (e.g. date of the most recent episode)
will be reported as missing. For details in the imputation algorithms, see Appendix 8.3.
4.
ANALYSIS METHODS
4.1
General principles
The SAS software version 9.4 or higher will be used for production of the statistical outputs.
For continuous measurements (e.g. age, pulse, blood pressure) the summary statistics will 
include number of subjects with non-missing values (n), minimum, maximum, median, mean 
and SD. For categorical measurements (e.g. sex, race, ethnicity) they will include frequencies
and the percentage of subjects in the respective category. For the percentages, the denominator 
will be the number of patients in each treatment arm and in total.
Minimum and maximum values will be reported to the same degree of precision as the raw


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data up to a maximum of 3 decimal places. Mean, first quartile, median, third quartile and SD 
will be reported to one further degree of precision. Percentages will be rounded to 1 decimal 
place. In general, baseline will be defined as the last value prior to the date of the first dose. 
For insulin and vital status two measurements are taken with a few minutes apart. The average 
of those measurements will be used in the calculations. 
In general, the laboratory results from the blood biomarkers will be used for the efficacy 
endpoints and the clinical safety laboratory assessments will be used for the safety endpoints. 
4.1.1
Baseline characteristics
The baseline demographics, patient characteristics and relevant medical history will be 
summarized for the Evaluable analysis set.
Descriptive statistics will be tabulated for each treatment arm and in total, but no formal 
statistical tests of equivalence of distributions of baseline characteristics in the two treatment
groups will be performed. 
Medical history
The variables related to diabetes history collected at screening, as well as medical history of 
special interest, will be tabulated in the same manner as patient characteristics, as described 
above. Additional medical and surgical history of interest will be tabulated by SOC and PT.
Concomitant medications
Concomitant medications will be classified according to ATC classification/ (generic) drug 
name. Concomitant medications will be tabulated using the same principle as for categorical 
baseline characteristics (number and percentage of patients for each treatment group separately 
and in total). In addition, all patients with changes in medication regimen occurring during the 
study will be listed.  
Duration of exposure and treatment compliance
Compliance will be summarized through tabulation of summary statistics (mean, SD, min, max, 
median, Q1, Q3) for each treatment arm separately. In addition, the number and percentage of 
patients with compliance below 90%, between 90 and 120%, and above 120% will also be 
presented. This will be done both for Evaluable Analysis Set and the Randomized Analysis Set. 
Duration of exposure will be summarized in a similar manner using Safety Analysis Set.
4.1.2
Efficacy
The efficacy analyses (with the exception of PK) will be performed using the Evaluable 
Analysis Set, as well as the three subsets of the Evaluable Analysis Set, as described in 
Section 2.1.


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4.1.2.1
Evaluation of treatment effect
The main purpose of these analyses is to detect a systematic difference in mean for change in 
measurements obtained at randomization and at the end of treatment between the two treatment 
groups. This will be studied for primary, secondary and all the exploratory endpoints as listed 
in Table 3.4. Thus, for each of the endpoints, the following two-sided hypothesis will be tested:
Null hypothesis: There is no systematic difference in mean change between the two treatment 
groups
Alternative hypothesis: There is a systematic difference in mean change between the two 
treatment groups
For this purpose, a linear model with measurement difference as the dependent variable and the 
treatment group indicator and baseline value of the modelled endpoint as independent variables
(ANCOVA) will be fitted for each of the endpoints (primary, secondary and exploratory). For 
details regarding modelling and presentation of results, see Section 4.2.1.
All the tests will be performed using a two-sided Type I error rate 0.05. As the nature of the 
study is exploratory, with no confirmatory component, no control of family-wise error rate will
be performed. However, due to the large number of considered endpoints, it is likely that several 
of them will be found to be “significant” as a consequence of the Type I error rate allowable by 
the hypothesis testing procedure, even if no effect is truly present. Thus, the interpretation of 
the findings will be done with care, keeping in mind both whether the detected patterns are 
clinically meaningful and the expected number of false discoveries that might occur due to 
chance.
The potential effect of treatment will also be presented descriptively by tabulating summary 
statistics (n, minimum, maximum, mean, SD, Q1, median, Q3) for the change from baseline. 
These will be accompanied by similar summaries describing the distribution of all the efficacy 
measurements obtained at randomization and end of treatment. These summaries will be made 
for each treatment group separately.
4.1.2.2
Evaluation of co-dependence
The purpose of this analysis (corresponding to exploratory objective 15) is to detect, and 
quantify, possible dependence between the endpoints of the study. This includes, partly, 
detecting a possible existence of dependence within groups of endpoints as defined in Table 3.4
(primary, secondary, exploratory), and, partly, quantifying the magnitude of the dependence 
between the primary and secondary endpoints and the exploratory ones. 
The evaluation will be done using Pearson correlation:
1) Between all the endpoints within each group as defined in Table 3.4. 
2) Between the primary endpoint and the other endpoints (secondary and exploratory).


Statistical Analysis Plan 
Study Code D1690C00063
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Date 11/04/2019
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3) Between the secondary endpoint and the exploratory endpoints.
The analyses will be performed for each treatment group separately.
4.1.2.3
PK analysis
The pharmacokinetic concentration data from the pre-dose blood sample at visit 4 will be listed 
for all patients in the PK analysis set. Further analysis may be presented separately from the 
main clinical study report.
4.1.3
Safety
All the safety analyses will be performed using Safety analysis set.
4.1.3.1
Laboratory assessments and vital signs
For all laboratory assessments, descriptive statistics will be presented by treatment group and 
in total for both absolute values at randomization and end of treatment visits, and the change 
between these two visits. The statistics will include n, minimum, maximum, median, Q1, Q3,
mean and SD. For ALT, AST, ALP and total bilirubin changes in evaluation (normal, below 
lower limit, above upper limit) between randomization and end of treatment visits will be 
tabulated using a shift table. If the value of a laboratory assessment obtained at randomization 
is missing, but there exists a corresponding value obtained at an earlier visit (i.e. screening or 
an unscheduled visit) this value will be used in place of the missing one. 
For clinical chemistry and haematology, only fasting values will be analysed. 
4.1.3.2
Adverse events
All collected AEs (which, for this study, consist of DAEs and SAEs) with onset date during the 
treatment period will be summarized using descriptive statistics (number of patients, percentage 
of patients). Such summaries will be created separately for AEs with the outcome of death, 
SAEs and DAEs. 
The summaries will be presented by:
!
SOC and PT (AEs with the outcome of death, SAE, DAE)
!
PT and maximum reported intensity (SAE, DAE)
!
PT and causality assessment (SAE, DAE)
Causality assessment will include “Caused by IP”, “Caused by 11C-Acetate” and “Caused by 
18F-FTHA”.
In addition, key patient information for SAEs, DAEs and AEs with the outcome of death will 
be listed. All SAEs occurring from the time of signature of informed consent up to and including 
the follow-up period will be summarized by system organ class (SOC) and preferred term (PT).


Statistical Analysis Plan 
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Edition Number 2.0
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All instances of DKA AEs will be listed. The listing will include the study day corresponding 
to the start of the AE, symptoms, DKA risk factors, intensity, outcome, a causality assessment
and adjudicated results.
4.2
Analysis methods
Below, the statistical models used for the efficacy analyses, as well as presentation of results, 
are described.
4.2.1
Analysis of the effect of treatment
The main tool for evaluation of treatment effect in this study will be an ANCOVA model (see 
section 4.1.2), with treatment group as the categorical independent variable and baseline value 
of the respective endpoint as the covariate. 
4.2.1.1
Presentation of results
Least Square Mean (LSM) change from baseline estimates, as well as the corresponding 95 
percent confidence limits, will be generated from the fitted model for each treatment group. The 
average value of the difference in LSM between the dapagliflozin and placebo treatment groups, 
the corresponding 95 percent confidence interval and the p-value will also be presented. 
4.2.2
Evaluation of plausibility of model assumptions 
An ANCOVA model has three main assumptions, which will be checked for primary and 
secondary endpoints:
1) The deviations of the single data point from the expected general trend fitted by the 
model (residuals) follow a normal distribution 
2) The relationship of the response to the baseline variable is linear within each treatment 
group
3) The effect of treatment is the same for all possible baseline values of the endpoint under 
study (no treatment-by-baseline value interaction)
The plausibility of the first and second of these assumptions will be evaluated by graphical 
examination of residuals using normal Q-Q-plots and scatter plots of the residuals against the 
baseline value of the respective endpoint. A Shapiro-Wilk normality test may also be performed. 
If strong deviations from normality are discovered, the p-value corresponding to the treatment 
effect will be obtained from an ANCOVA based on ranked response and baseline values (with 
the effect estimates and the corresponding CIs still based on a parametric ANCOVA).
If the relationship of the response to the baseline variable is non-linear, then a suitable 
transformation of the response and the baseline variable (e.g., natural logarithm, square root, 
inverse, quadratic, etc.) may be used for analysis.


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
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The plausibility of the third assumption will be evaluated by expanding the ANCOVA model 
by including the interaction between treatment group and baseline value of the endpoint. The 
significance of the effect of the interaction term will be formally assessed through the statistical 
test based on the Wald test using a 0.1 level of significance. If the p-value from a model that 
includes interaction is less than 0.1, then the predicted values for each treatment will be plotted 
against baseline value, and the type of interaction will be assessed.  If the lines do not cross, or 
the crossing is not too severe, then the interaction will be considered quantitative and the 
interaction term will be dropped from the model. Otherwise, the p-value from the model will 
not be reported.
Any impact of the potential outliers and subgroups will also be investigated. An outlier is an 
observation with a residual that is more than three times the interquartile range above the 75th 
percentile or below the 25th percentile. Outliers will be identified using standardized residuals 
from the original ANCOVA model. If outliers are present, then additional sensitivity analyses 
will be performed with the outliers excluded.
The following subgroups will be considered for the primary and the secondary endpoints: site, 
country, age, BMI and gender.
4.2.2.1
Presentation of results
Any marked violations of model assumptions will be discussed in the CSR and the supporting
results will be presented in appendices.
4.2.3
Analysis of co-dependence
The analysis of co-dependence will be done by Pearson correlation, using Fisher transformation
to produce confidence intervals as given in (PASS, Chapter 808).
Co-dependence will be examined:
!
within each group as specified in Table 3.4.
!
between the primary endpoint and the other endpoints (secondary and exploratory)
!
between the secondary endpoint and the other endpoints (exploratory)
4.2.3.1
Presentation of results
The results of the co-dependence will be presented as the estimate of the correlation, with the 
corresponding 95% confidence interval as well as the p-value. Within each group, this will be 
presented in the form of correlation matrices. Between primary/secondary endpoints and the 
exploratory endpoints it will be tabulated. 


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
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5.
INTERIM ANALYSES (NOT APPLICABLE)
6.
CHANGES OF ANALYSIS FROM PROTOCOL (NOT 
APPLICABLE)


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
34
7.
REFERENCES
Gjesdal O, Yoneyama K, Mewton N, Wu C, Gomes AS, Hundley G, et al. (2016). Reduced 
long axis strain is associated with heart failure and cardiovascular events in the multi-ethnic 
study of Atherosclerosis. J Magn Reson Imaging 44: 178-185.
Singh A, Steadman CD, Khan JN, Horsfield MA, Bekele S, Nazir SA, et al. (2015). 
Intertechnique agreement and interstudy reproducibility of strain and diastolic strain rate at 1.5 
and 3 Tesla: a comparison of feature-tracking and tagging in patients with aortic stenosis. J 
Magn Reson Imaging 41: 1129-1137.
Tuunanen H, Engblom E, Naum A, Nagren K, Hesse B, Airaksinen KE, et al. (2006). Free 
fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart 
failure. Circulation 114: 2130-2137.
Tuunanen H, Kuusisto J, Toikka J, Jaaskelainen P, Marjamaki P, Peuhkurinen K, et al. (2007). 
Myocardial perfusion, oxidative metabolism, and free fatty acid uptake in patients with 
hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the alpha-
tropomyosin gene: a positron emission tomography study. J Nucl Cardiol 14: 354-365.
PASS 15 Power Analysis and Sample Size Software (2017), Chapter 808. NCSS, LLC. 
Kaysville, Utah, USA, https://ncss-wpengine.netdna-ssl.com/wp-
content/themes/ncss/pdf/Procedures/PASS/Confidence_Intervals_for_Spearmans_Rank_Corre
lation.pdf


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
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8.
APPENDIX
8.1
Overview of the study assessments
Screening
Randomization 
Baseline
Interim visit 
(Phone visit)
End of 
treatment
Safety Follow-up
(Phone visit)
Visit
1
2
3
4
5
Day 
-21 to 0
1
14
42
49
Informed consent 
X
Inclusion /exclusion criteria
X
X
Routine clinical procedures
Demography
X
Physical examination
X
Medical history and comorbid conditions
X
Vital signs
X
X
X
Height
X
Weight
X
X
X
ECG 
X
Echocardiogram
X
Concomitant medication
X
X
X
X
Routine safety measurements
SAE
X
X
X
X
X
DAE
X
X
X
X
Diabetic ketoacidosis events
X
X
X
X
Pregnancy test (serum or urine)
X
X
X
Clinical chemistry and haematology
X
X
X
Blood and Urine analyses (except Safety analyses)
HbA1c (screening)
X
Biomarkers
X
X
Urine sample
X
X
Pharmacokinetic measurements
Pre-dose blood sample
X
Efficacy measurements
MRI (fasting)
X
X
CT-PET/MRI-PET (fasting)
X
X


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
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Screening
Randomization 
Baseline
Interim visit 
(Phone visit)
End of 
treatment
Safety Follow-up
(Phone visit)
Visit
1
2
3
4
5
Day 
-21 to 0
1
14
42
49
Randomisation
X
Study treatment dispensed (daily dosing)
X
Study treatment return
X
8.2
Medical history of special interest
The collected medical history of special interest will consist of the following items:
Dyslipidaemia, Hypertension, Peripheral Arterial Occlusive Disease, Angina Pectoris, Myocardial 
Infarction, Coronary Artery Disease, Percutaneous Coronary Intervention, Heart Failure, Valvular 
Heart Disease, Atrial Fibrillation, Atrial Flutter, Chronic Obstructive Pulmonary Disease, 
Coronary Artery Bypass, Chronic Kidney Disease, Vascular Stent
For each of the above, the presence/absence of the condition will be recorded, as well as, where 
applicable, whether the condition is currently treated and the dates of the most recent episode
and procedure.
8.3
Imputation of missing dates
Every attempt will be made to obtain complete information about dates related to study design, 
e.g. date of informed consent and visit dates. In case of this information is still missing, or 
partially missing, at the time of database lock, the dates will not be imputed but, rather, left as 
unknown. 
For the dates of the diagnosis of diabetes mellitus, AE start / stop date and medications start/stop 
dates, the following conventions will be used:
Date diabetes mellitus first diagnosed
Missing type
Action
Missing day, but month and year are present
The day will be imputed as the 15th day of the 
month.
Missing day and month, but year is present
The day and month will be imputed as 
30 June of the year (provided that the 
imputed date is less than the consent date).


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
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Missing year, but day and month are present
No imputations will occur, and the subject 
will be excluded from all summaries related 
to duration of Type 2 diabetes.
Missing day, month and year
No imputations will occur, and the subject 
will be excluded from all summaries related 
to duration of Type 2 diabetes.
If any such imputed date falls after the 
consent date
The diagnosis date will be taken as equal to 
the consent date.
Partial date conventions for AE
Missing type
Action
If only the day part of the AE onset date is
missing and occurs in the same month and
year as the first dose of study medication
The date of first dose of study medication
will be used as the onset date of the AE.
Otherwise, the first day of the month will be
used to complete the onset date of the AE
If the day and month parts of the AE onset
date are missing and occur in the same year
as the first dose of study medication
The date of the first dose of study
medication will be used as the onset date of
the AE. Otherwise, January 1st will be used
to complete the onset date of the AE.
If the AE onset date is completely missing
The date of the first dose of study
medication will be used as the onset date of
the AE.
If only the day part of the AE end date is
missing and occurs before or in the same
month and year as the first dose of study
medication
The last day of the month will be used to
complete the end date of the AE.
If the day and month parts of the AE end
date are missing
December 31st will be used to complete the
end date of the AE.
If the end date of the AE is completely
missing and the onset date of the AE occurs
after the date of the first dose of study
medication
Then the onset date of the AE will be used
as the AE end date. Otherwise, the date of
the first dose of study medication will be
used as the AE end date


Statistical Analysis Plan 
Study Code D1690C00063
Edition Number 2.0
Date 11/04/2019
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Concomitant medications
!
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.
!
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.
8.4
Reference limits for ALT, AST, ALP and total bilirubin
Parameter
Site
Reference values
Male
Female
Lower 
limit
Upper 
limit
Lower 
limit
Upper 
limit
Units
AST
2201
15
45
15
35
U/L
ALT
2201
-
50
-
35
U/L
ALP
2201
35
105
35
105
U/L
Total 
bilirubin
2201
-
21
-
21
μmol/L
AST
7201
0.25
0.75
0.25
0.60
μkat/L
ALT
7201
0.15
1.1
0.15
0.75
μkat/L
ALP
7201
0.6
1.8
0.6
1.8
μkat/L
Total 
bilirubin
7201
5
25
5
25
μmol/L