Clinical trial NCT03338855
Conditions: Diabetes Mellitus, Type 2 Skeletal Muscle Insulin Sensitivity
Keywords: T2DM, insulin resistance, skeletal muscle, mitochondria, dapagliflozin
Sponsor: AstraZeneca
Start date: 2018-03-05; Completion date: 2019-11-04
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to investigate the effects of 5 weeks treatment with dapagliflozin in type 2 diabetes patients on how the hormone insulin acts on sugar uptake in muscles.

Detailed description:
To investigate if dapagliflozin improves skeletal muscle insulin sensitivity expressed as corrected glucose disposal rate (cGDR) in comparison with placebo after 5-week double blind treatment. Insulin sensitivity will be determined using a 2-step euglycemic hyperinsulinemic clamp (EHC) procedure

Arms: arm 1: Patients will receive dapagliflozin 10 mg in tablet for a maximum of 40 days based on randomization sequence in Period 1.

Patients that received 10 mg dapagliflozin in the first treatment period will receive matching placebo in the second treatment period for a maximum of 40 days. arm 2: Patients will receive matching placebo in tablet for a maximum of 40 days based on randomization sequence.

Patients who received placebo in the first treatment will receive 10 mg dapagliflozin in the second treatment period, for a maximum of 40 days
Interventions: intervention 1: Dapagliflozin
Intervention descriptions: intervention 1: The study consist of 5 weeks treatment period 1, 6-8 weeks wash-out period and 5 weeks treatment period 2.

The patient will be administered dapagliflozin 10 mg during Period 1 or Period 2.

Protocol documents:
Prot_000.pdf: 
AstraZeneca AB
Clinical Study Protocol
Study code: D1690C00047
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Investigational product: Dapagliflozin 
Final 5.0
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DAPAMAAST: A Double-blind, Randomized, Phase IV, Mechanistic, Placebo-
controlled, Cross-over, Single-center Study to Evaluate the Effects of 5 Weeks 
Dapagliflozin Treatment on Insulin Sensitivity in Skeletal Muscle in Type 2 
Diabetes Mellitus Patients 
Sponsor:
AstraZeneca AB
SE-151 85 Södertälje
Sweden
Principal Coordinating Investigator:
 
 
 Maastricht 
The Netherlands
Sponsor Protocol No.:
D1690C00047
EudraCT No.:
2016-003991-27
Study Drug Name:
Dapagliflozin
Development Phase:
IV
Date of Protocol:
12 September 2018 Version 5.0 
Date of Previous Protocol:
13 August 2018 Version 4.0
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki1, and with other applicable 
regulatory requirements.
This document contains confidential information of AstraZeneca AB.
Do not copy or distribute without written permission from the Sponsor.
CONFIDENTIAL


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SIGNATURE PAGE
Declaration of Sponsor or Responsible Medical Officer
Title: A double-blind, randomized, phase IV, mechanistic, placebo-controlled, 
cross-over, single-center study to examine the effects of 5 weeks dapagliflozin treatment 
on insulin sensitivity in skeletal muscle in Type 2 diabetes mellitus patients
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, 20131, and the guidelines on Good Clinical 
Practice.
_____________________________________
_____________________
Anna Maria Langkilde
Date
Global Clinical Leader
AstraZeneca R&D Gothenburg, Sweden


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Declaration of the Principal Coordinating Investigator
Title: A double-blind, randomized, phase IV, mechanistic, placebo-controlled, 
cross-over, single-center study to examine the effects of 5 weeks dapagliflozin treatment 
on insulin sensitivity in skeletal muscle in Type 2 diabetes mellitus patients
This study protocol was subjected to critical review and has been approved by the 
Sponsor. The information it contains is consistent with the current risk/benefit evaluation 
of the investigational product as well as with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, as amended in 20131
and the guidelines on Good Clinical Practice.
Principal or Global Coordinating Investigator: 
_____________________________________
_____________________
 
 
Maastricht | The Netherlands
Qualified Physician Sub Investigator:
_____________________________________
_____________________
 Maastricht


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PROTOCOL SYNOPSIS
Title
DAPAMAAST: A double-blind, randomized, phase IV, mechanistic, 
placebocontrolled-, cross-over, single-center study to examine the effects of 
5 weeks dapagliflozin treatment on insulin sensitivity in skeletal muscle in 
Type 2 diabetes mellitus patients
Sponsor Study No.
D1690C00047
Phase
IV
Sponsor
AstraZeneca AB
SE-151 85 Södertälje
Sweden
Principal Coordinating 
Investigator
 
Maastricht | The Netherlands
Study Center
It is planned to enrol subjects at one center in Maastricht:
Maastricht University Medical Center +
Department of Human Biology and Human Movement Sciences, 
6200 MD Maastricht, The Netherlands
 


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Study code: D1690C00047
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Investigational product: Dapagliflozin 
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Objectives
Primary:
To investigate if dapagliflozin improves skeletal muscle insulin sensitivity 
expressed as corrected glucose disposal rate (cGDR) in comparison with 
placebo after 5-week double blind treatment. Insulin sensitivity will be 
determined using a 2-step euglycemic hyperinsulinemic clamp (EHC) 
procedure. 
Exploratory:

To investigate if dapagliflozin changes Endogenous Glucose 
Production (EGP) in comparison with placebo after 5 weeks of double 
blind treatment

To investigate if dapagliflozin improves metabolic flexibility as 
compared to placebo, determined by the change in respiratory 
exchange ratio (RER) from fasted state to insulin stimulated state 
during EHC after 5-week double blind treatment 

To investigate if dapagliflozin changes RER and energy expenditure as 
well as plasma metabolites such as beta-hydroxybutyrate and glucose 
as compared to placebo, before and after meals in the metabolic 
chamber after 5-week double blind treatment

To investigate if dapagliflozin improves maximal capacity to form 
acetylcarnitine following exercise and carnitine acetyltransferase 
(CRAT) activity and citrate synthase activity in muscle biopsy, as 
compared to placebo after 5-week double blind treatment

To investigate if dapagliflozin improves in vivo mitochondrial function 
as measured by phosphocreatinine recovery following exercise, as 
compared to placebo after 5-week double blind treatment

To investigate if dapagliflozin improves ex vivo mitochondrial function 
in permeabilized muscle fibers using high resolution respirometry, as 
compared to placebo after 5-week double blind treatment

To investigate if dapagliflozin changes body composition, skeletal 
muscle and liver fat content, as compared to placebo after 5-week 
double blind treatment

To investigate if dapagliflozin changes blood biomarkers such as 
glucagon, insulin and FGF21 in comparison with placebo after 5 weeks 
of double blind treatment

To investigate if dapagliflozin changes expression of mRNA and/or 
proteins involved in metabolic regulation in muscle tissue in 
comparison with placebo after 5-weeks of double blind treatment. 

To investigate if dapagliflozin changes body weight, BMI and systolic 
and diastolic blood pressure in comparison with placebo after 5-weeks 
of double blind treatment.
Safety:
To evaluate the safety and tolerability of dapagliflozin by assessment of 
DAEs/SAEs, including laboratory values and clinically significant findings 
after 5-week double blind treatment.


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Design
This is a double-blind, randomized, mechanistic, placebocontrolled-, 
cross-over study, to evaluate the effect of 5 weeks dapagliflozin treatment 
in Type 2 Diabetes Mellitus (T2DM) patients.
The maximum duration for each treatment period will be 40 days and the 
study will include the following:

Screening within Day -21 to Day -0

A 5 weeks treatment period 1: Day 1 to Day 29±3 (+ 6–8 days for end 
of treatment assessments at site)

A 5–10 days safety follow-up after last dose of treatment (this will be a 
part of the 6–8 weeks wash-out period mentioned below)

A 6–8 weeks wash-out period

A 5 weeks treatment period 2: Day 1 to Day 29±3 (+ 6–8 days for end 
of treatment assessments at site)

A 5–10 days safety follow-up after last dose of treatment.
Treatment
There will be two treatment periods in this study:
Period 1: Patients will receive either dapagliflozin 10 mg or matching 
placebo for a maximum of 40 days based on randomization 
sequence.
Period 2: Patients that received 10 mg dapagliflozin in the first treatment 
period will receive matching placebo in the second treatment 
period and subjects who received placebo in the first treatment 
will receive 10 mg dapagliflozin in the second treatment period, 
for a maximum of 40 days.
Number of Patients
A total of 26 patients are planned to be randomized to have at least 22 
completers in two equal sized treatment sequences. In case of more than 4 
drop-outs, another 4 patients will be randomized and if this occurs a total of 
30 patients will be randomized.
Population
The study population will consist of patients with diagnosed T2DM who 
have been on stable dose of metformin for at least last 3 months or are drug 
naive.
The main inclusion criteria:

Women are post-menopausal (defined as at least 1 year post cessation 
of menses) and aged ≥ 45 and ≤ 70 years. Males are aged ≥ 40 years 
and ≤70 years. Patients should have suitable veins for cannulation or 
repeated venipuncture.

Patients are diagnosed with T2DM for at least the last 6 months, based 
on ADA 2016 standards.

Patients are on no anti-diabetic drug treatment or on stable metformin 
treatment for at least the last 3 months: maximum 3000 mg metformin 
daily dose.

Hemoglobin A1c (HbA1c) levels between 6.0% (=42 mmol/mol) and 
9.0% (75 mmol/mol).


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Criteria for Evaluation 
of Efficacy
Primary:
Comparison of dapagliflozin versus placebo after 5 weeks treatment in 
skeletal muscle insulin sensitivity measured as cGDR using a 2-step EHC 
procedure.
Exploratory:
Comparison of dapagliflozin versus placebo after 5 weeks treatment for the 
following variables:

Endogenous Glucose Production (EGP) in comparison with 
placebo after 5 weeks of double blind treatment

Metabolic flexibility, as determined by the RER from fasted state 
to insulin stimulated state during EHC

RER and energy expenditure as well as plasma metabolites such as 
beta-hydroxybutyrate and glucose before and after meals, as 
measured in metabolic chambers

Maximal capacity to form acetylcarnitine following exercise as 
measured using 1H-magnetic resonance spectroscopy (1H-MRS) 
and by CRAT and citrate synthase activities (muscle biopsy) 

In vivo mitochondrial function as measured post-exercise by 
phosphocreatinine recovery using 31P- magnetic resonance 
spectroscopy

Ex vivo mitochondrial function in permeabilized muscle fibers 
using high resolution respirometry (muscle biopsy)

Body composition as measured by dual-energy X-ray 
absorptiometry (DEXA), and skeletal muscle and liver fat content 
as measured by 1H-MRS.

Blood biomarkers such as glucagon, insulin and FGF21 in 
comparison with placebo after 5 weeks of double blind treatment

Expression of mRNA and/or proteins involved in metabolic 
regulation in muscle tissue in comparison with placebo after 5 
weeks of double blind treatment.

To investigate if dapagliflozin changes body weight, BMI and 
systolic and diastolic blood pressure in comparison with placebo 
after 5-weeks of double blind treatment.
Criteria for Evaluation 
of Safety
Safety and tolerability of dapagliflozin by assessment of the following: 

Incidence of AEs (Discontinuation Adverse Events and Serious 
Adverse Events)

Incidence of independently adjudicated Diabetic Ketoacidosis 
events if any

Clinical chemistry/hematology/urine parameters

Vital signs

Physical examination


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Statistical Methods
The following analysis sets will be defined:

The Enrolled Analysis Set will consist of all patients who sign the 
informed consent form.

The Randomized Analysis Set will consist of all randomized 
patients. 

The Safety Analysis Set will consist of all patients who received at 
least one dose of study drug.

The Evaluable Analysis Set will be the primary analysis set for 
efficacy, and is a subset of the Randomized Analysis Set. This is 
also known as the Per-Protocol population. Relevant protocol 
deviations may lead to certain data points to be excluded from this 
analysis. All decisions to exclude data from the Evaluable 
Analysis Set will be made prior to the database lock of the study.
Efficacy:
The analysis of efficacy will be based on the evaluable analysis set. 
Comparison of cGDR between 5 weeks dapagliflozin and placebo 
treatment will be analyzed using a mixed effect Analysis Of Variance
model. The model will include terms for treatment, sequence and period. A 
term representing patient nested within sequence will be included as a
random effect. Least Square Mean (LSM) estimates, and 95% confidence 
limits will be generated from the fitted model for each treatment. For the 
primary comparison, the difference in LSM estimate of dapagliflozin versus 
placebo treatment, the corresponding 95% confidence interval and 
pvalue- will be generated. Statistical significance will be inferred at a (two-
sided) 0.05 level.
Safety:
The analysis of safety will be based on the safety analysis set. Safety data 
during the treatment period will be evaluated and variables will only be 
summarized descriptively. DAEs and SAEs will be summarized by system 
organ class and preferred term. AEs will be listed for each patient.
Safety laboratory, vital signs, physical examination and ECG findings will 
be listed by patient. Descriptive statistics will be presented by treatment for 
both absolute values and changes from baseline.
Schedule of Procedures
Refer to Section 7.1.


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LIST OF STUDY PERSONNEL
Sponsor
AstraZeneca AB
SE-151 85 Södertälje
Sweden
Principal Coordinating 
Investigator
Dr. Patrick Schrauwen, PhD
 
 
 Maastricht | The Netherlands
 
Qualified Physician Sub 
Investigator
 
 
 
 Maastricht 
Adverse Event Reporting
AstraZeneca
Central Laboratory
Covance Central Laboratory Services Sàrl
7 Rue Moïse-Marcinhes, 1217 Geneva, Meyrin, 
Switzerland
 


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TABLE OF CONTENTS
LIST OF STUDY PERSONNEL ...........................................................................9
LIST OF ABBREVIATIONS...............................................................................14
1
INTRODUCTION.....................................................................................16
1.1
Background...........................................................................................16
1.1.1
Skeletal muscle insulin resistance ..............................................16
1.1.2
Data from previous studies investigating effects of SGLT2 
inhibitors ...................................................................................17
1.2
Rationale for the study and justification of study design....................18
1.3
Risk Assessment....................................................................................19
2
STUDY OBJECTIVES.............................................................................22
2.1
Primary Objective ................................................................................22
2.2
Exploratory Objectives.........................................................................22
2.3
Safety Objective....................................................................................23
3
OVERALL DESIGN AND PLAN OF THE STUDY...............................24
3.1
Overview ...............................................................................................24
3.2
Criteria for Evaluation of the Study....................................................27
3.2.1
Primary Endpoint.......................................................................28
3.2.2
Exploratory endpoints................................................................28
3.2.3
Safety endpoint..........................................................................28
4
STUDY POPULATION............................................................................29
4.1
Inclusion Criteria .................................................................................29
4.2
Exclusion Criteria.................................................................................29
4.3
Discontinuation of Investigational product .........................................31
4.4
Criteria for withdrawal........................................................................31
4.5
Planned Sample Size and Number of Study Centers ..........................31
4.6
Patient Identification and Randomization...........................................32
4.6.1
Patient Identification..................................................................32
4.6.2
Randomization Scheme .............................................................32
4.6.3
Allocation/Randomization of Patients to Treatment ...................32
5
STUDY DRUG..........................................................................................33
5.1
Identity..................................................................................................33
5.1.1
Investigational Products.............................................................33
5.1.2
Non-Investigational Medicinal Product......................................33
5.2
Administration......................................................................................33
5.3
Packaging, Labeling and Storage.........................................................34
5.4
Blinding and Unblinding......................................................................34
5.5
Drug Accountability .............................................................................35
5.6
Compliance ...........................................................................................35
5.7
Previous and Concomitant Medications..............................................35
5.7.1
Permitted concomitant medication.............................................36


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5.7.2
Prohibited concomitant medication............................................36
6
VARIABLES AND METHODS OF ASSESSMENT ..............................37
6.1
Efficacy variables .................................................................................37
6.1.1
Maximal knee-extension test......................................................37
6.1.2
Maximal VO2 cycling test..........................................................37
6.1.3
Euglycemic hyperinsulinemic clamp, indirect calorimetry and 
muscle biopsy............................................................................37
6.1.4
Body composition......................................................................39
6.1.5
24h energy expenditure, 24h RER..............................................39
6.1.6
1H-MRS.....................................................................................39
6.1.7
31P-MRS....................................................................................40
6.1.8
Muscle biopsy from the m. vastus lateralis.................................40
6.1.9
Laboratory blood assessments during Visits 4 and 7...................41
6.1.10
Laboratory urine assessments.....................................................41
6.2
Safety variables.....................................................................................41
6.2.1
Laboratory safety assessments ...................................................41
6.2.2
Physical examinations................................................................42
6.2.3
Vital signs..................................................................................42
6.2.4
Other safety assessments............................................................43
6.3
Safety reporting....................................................................................43
6.3.1
Definition of AEs.......................................................................43
6.3.2
Definitions of serious adverse event...........................................43
6.3.3
Recording of AEs ......................................................................44
6.3.3.1
Time period for collection of AEs.........................................44
6.3.3.2
Follow-up of unresolved AEs ...............................................44
6.3.3.3
Variables .............................................................................44
6.3.3.4
Causality collection .............................................................45
6.3.3.5
AEs based on signs and symptoms........................................45
6.3.3.6
AEs based on examinations and tests ...................................45
6.3.4
Reporting of serious adverse events ...........................................46
6.3.5
Overdose ...................................................................................46
6.3.6
Pregnancy..................................................................................47
6.3.6.1
Maternal Exposure...............................................................47
6.4
Medication Error..................................................................................47
6.5
Demographic and Baseline Characteristics.........................................48
6.6
Medical and surgical history:...............................................................48
6.7
Volume of blood to be collected ...........................................................49
6.8
Storage and destruction of Biological Samples....................................49
6.9
Withdrawal of Informed Consent for Donated Biological Samples ...49
7
STUDY CONDUCT..................................................................................50
7.1
Study plan.............................................................................................50
7.2
Procedures by Visit...............................................................................55
7.2.1
Treatment period 1.....................................................................55
7.2.1.1
Screening (Visit 1) ...............................................................55
7.2.1.2
Randomization (Visit 2)........................................................55


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7.2.1.3
Safety (Visit 3) .....................................................................56
7.2.1.4
End of treatment (Visit 4).....................................................56
7.2.1.5
Wash out period...................................................................57
7.2.2
Treatment period 2.....................................................................57
8
STATISTICAL ANALYSES....................................................................59
8.1
Statistical considerations......................................................................59
8.2
Sample size estimation..........................................................................59
8.2.1
Definition of analysis sets..........................................................59
8.3
Outcome measures for analyses...........................................................60
8.4
Methods for statistical analyses ...........................................................60
8.4.1
Primary Analysis .......................................................................60
8.4.2
Exploratory Analyses.................................................................60
8.4.3
Baseline characteristics..............................................................60
8.5
Safety Analyses .....................................................................................60
8.6
Interim Analyses...................................................................................61
9
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ..................62
9.1
Data Quality Assurance........................................................................62
9.1.1
Database Management and Quality Control ...............................62
9.2
Case Report Forms and Source Documentation .................................62
9.2.1
Data collection...........................................................................63
9.3
Access to Source Data...........................................................................63
9.4
Data Processing ....................................................................................63
9.5
Archiving Study Records .....................................................................64
9.6
Good Clinical Practice..........................................................................64
9.7
Informed Consent.................................................................................64
9.8
Protocol Approval and Amendment....................................................64
9.9
Duration of the Study...........................................................................65
9.10
Premature Termination of the Study...................................................65
9.10.1
Stopping Rules for an Individual Patient....................................65
9.10.2
Stopping Rules for the Study .....................................................65
9.11
Confidentiality......................................................................................65
9.12
Other Ethical and Regulatory Issues...................................................65
9.13
Publication Policy .................................................................................66
10
APPENDICES...........................................................................................67
10.1
Additional Safety Information.............................................................67
11
REFERENCE LIST..................................................................................69


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Tables in Text
Table 1:
Identity of the Study Treatment .............................................................. 33
Table 2
Laboratory safety assessments................................................................ 42
Table 3:
Total blood volume to be collected per Visit .......................................... 49
Table 4: Study procedures.................................................................................... 51
Figures in Text
Figure 1: Study Design.......................................................................................... 25
Figure 2: Overview of the examinations taking place at Visit 4 and Visit 7............ 26


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LIST OF ABBREVIATIONS
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase
AMPK
AMP-activated Protein Kinase
ANOVA
Analysis Of Variance
AST
Aspartate aminotransferase
BMI
Body Mass Index
cGDR
corrected Glucose Disposal Rate
CRAT
Carnitine Acetyltransferase
CS
Citrate Synthase
DAE
Discontinuation Adverse Events
DRL
Drug Reference List
DEXA
Dual-Energy X-ray Absorptiometry
DKA
Diabetic Ketoacidosis
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EGP
Endogenous Glucose Production
EHC
Euglycemic Hyperinsulinemic Clamp
FGF21
Fibroblast Growth Factor 21
GCP
Good Clinical Practice
GDR
Glucose Disposal Rate
GMP
Good Manufacturing Practice
Hb
Hemoglobin
HbA1c
Hemoglobin A1c 
hsCRP
high-sensitivity C-Reactive Protein
IB
Investigator’s Brochure
ICF
Informed Consent Form
IEC
Independent Ethics Committee
ICH
International Conference on Harmonization
IMCL
Intramyocellular Lipids


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IR
Insulin Resistance
IRB
Institutional Review Board
ITT
Intent-To-Treat
LSM
Least Square Mean
MedDRA
Medical Dictionary for Regulatory Activities
Mtfn
Mitofusin
mTOR
mechanistic Target Of Rapamycin
MRI
Magnetic Resonance Imaging
MRS
Magnetic Resonance Spectroscopy
NEFA
Non-Esterified Fatty Acids
NIMP
Non-Investigational Medicinal Product
NSAIDS
Nonsteroidal Anti-Inflammatory Drugs
PCr
Phospho Creatinine
RER
Respiratory Exchange Ratio
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SGLT2
Sodium Glucose co-Transporter-2
T2DM
Type 2 Diabetes Mellitus
VO2max
Maximal Oxygen consumption
WHO
World Health Organization
Wmax
Maximum work rate
1H-MRS
1H-Magnetic Resonance Spectroscopy
31P-MRS
31P-Magnetic Resonance Spectroscopy


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1
INTRODUCTION
1.1
Background
The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin was associated 
with lower cardiovascular (CV) mortality in the EMPA-REG study (Zinman et al., 
2015[2]). 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  CV death and disease in the recently presented 
CANVAS study (Neal et al., 2017[3]). There are a number of potential mechanisms that 
could help to explain the reported CV benefits. 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. A complementary hypothesis is 
enhanced night-time catabolism due to the increased urinary glucose excretion by 
dapagliflozin, which will lead to increased glycogenolysis and gluconeogenesis. 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, Cohen & Lippincott-Schwartz, 2015[4]). Therefore, this study will 
investigate the effect of dapagliflozin on energy metabolism with focus on mitochondrial 
function in skeletal muscle, which is more accessible for controlled and invasive 
investigations of mitochondrial function than the heart.  
1.1.1
Skeletal muscle insulin resistance
Type 2 diabetes mellitus (T2DM) results from combined derangements of insulin 
sensitivity and beta-cell function. The main tissues contributing to reduced whole body 
insulin resistance (IR) are the liver, skeletal muscles and adipose tissues. One of the 
earliest changes in first degree relatives to T2DM patients is reduced skeletal muscle 
insulin sensitivity. The degree of IR in skeletal muscle is typically investigated using an 
euglycemic hyperinsulinemic clamp (EHC) technique and given as glucose disposal rate 
(GDR). This study will aim to investigate if treatment with dapagliflozin improves 
skeletal muscle insulin sensitivity by measuring changes in corrected glucose disposal 
rate (cGDR) taking into account the glucose losses in urine and determined using the 
EHC procedure. 
The cause of the IR associated with T2DM has not yet been fully understood (Samuel & 
Shulman, 2016[5]).
The lipotoxicity hypothesis is based on the association between IR and increased 
amounts of ectopic fat in the liver (liver steatosis) and skeletal muscles, also known as 
intramyocellular lipids (IMCL). Increased levels of various lipids, mainly 
diacylglycerols, ceramides and acyl-CoA in skeletal muscles have been associated with 
IR. In this study, liver fat and IMCL will be assessed to determine if dapagliflozin 
treatment changes the amount of ectopic fat.


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Another focus on this study is to investigate the mitochondrial function in skeletal 
muscle. A decreased mitochondrial function has been associated with skeletal muscle IR 
in several studies (Meex et al, 2010[6]; van de Weijer et al, 2013[7]). However, it has been 
unclear if reduced mitochondrial function is a cause or a consequence of  IR. A possible 
causal relationship between mitochondrial function and skeletal muscle insulin 
sensitivity is the ability of the mitochondria to export excess acetyl-CoA as 
acetylcarnitine by the action of carnitine acetyltransferase (CRAT). Reducing acetyl-CoA 
levels alleviate the allosteric inhibition of the pyruvate dehydrogenase complex and 
allow oxidation of glucose to occur in the mitochondria (Muoio et al, 2012[8]); Noland et 
al, 2009[9]). A strong association between levels of acetylcarnitine in skeletal muscles and 
insulin sensitivity has been shown in subjects with various levels of insulin resistance, 
indicating that decreased mitochondrial formation of acetylcarnitine could explain 
skeletal muscle insulin resistance (Lindeboom et al, 2014[10]).
T2DM and IR are associated with metabolic inflexibility as first described by Kelly et al 
(Kelley et al, 1999[11]). Metabolic inflexibility is likely to be caused by nutrient overload 
resulting in substrate competition at the level of the mitochondria (Muoio, 2014[12]). 
Exercise intervention studies have shown improvement in metabolic flexibility, 
mitochondrial function and insulin sensitivity (Meex et al, 2010[6]).
Therefore, this study will also aim to investigate if treatment with dapagliflozin improves 
mitochondrial function and improves metabolic flexibility, including increased 
production of acetylcarnitine during exercise and phosphocreatinine recovery following 
exercise.
1.1.2
Data from previous studies investigating effects of SGLT2 inhibitors
Dapagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor indicated for the 
treatment of T2DM. The SGLT2 inhibition results in a loss of glucose and its associated 
energy (about 50–70 g/day) via urine. This mechanism results in a reduction in 
Hemoglobin A1c (HbA1c) and body weight. In a 2-year study, it was shown that 
dapagliflozin reduces HbA1c by 0.3%, weight by 4.5 kg and fat mass by 2.8 kg (Bolinder 
et al, 2014[13]). It has also been shown that the reduction in body weight is faster over the 
first few weeks, followed by a more gradual decline that plateaus between 24 and 
50 weeks of therapy (Bolinder et al, 2012 [14]). 
An effect on insulin sensitivity, measured as a 17.5% increase in cGDR, has been 
demonstrated after 12 weeks of treatment with 5 mg dapagliflozin (Mudaliar et al, 
2014[15]). This finding was repeated in a study with a treatment period of about 2 weeks 
where cGDR increased by 16% in the dapagliflozin group but remained unchanged in the 
placebo treated group (p<0.05 vs baseline and placebo). This study also showed that 
endogenous glucose production (EGP) increased as a result of dapagliflozin treatment. 
The increase in EGP was associated with an increase in fasting glucagon levels and 
decrease in fasting insulin levels (Merovci et al, 2014[16]). An increased glucagon/insulin 
ratio is expected to reduce hepatic de novo lipogenesis and in parallel increase hepatic 
fatty acid oxidation and ketone body production. In a 4-week empagliflozin study, an 
increase in plasma free fatty levels and fatty acid oxidation was observed. The increase in 
fatty acid oxidation was associated with a decrease in both glucose oxidation and 
nonoxidative glucose disposal. In the same study, it was shown that the increase in EGP 
was exactly balancing the glucose loss in urine (Ferrannini et al, 2014[17]). 


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Another more recent randomized placebo controlled study also investigated insulin 
stimulated glucose disposal in T2DM patients, in which a 36% increase in cGDR after 
2 weeks in the dapagliflozin group and a 12% increase in cGDR after 2 weeks in the 
placebo group was observed (Daniele et al, 2016[18]). The increase in cGDR was 
associated with increased non-oxidative glucose uptake, but no change in glucose 
oxidation; carbohydrate oxidation remained depressed in the presence of a sustained 
increase in whole body lipid oxidation. 
In summary, 3 studies have investigated the effect of 2–12 weeks of treatment with 
SGLT2 inhibitors on insulin sensitivity and found 16-24% net improvements in cGDR.
1.2
Rationale for the study and justification of study design
Treatment with SGLT2 inhibitors increases glucose excretion via the urine, which results 
in energy losses. Increased glucagon/insulin ratio explains increased hepatic glucose 
production, while indirect mechanisms explaining improved skeletal muscle insulin 
sensitivity are not known.
The aim of the study is foremost to understand the mechanisms responsible for the 
improved insulin sensitivity as a consequence of the increased urinary excretion of 
glucose during treatment with dapagliflozin. Another aim is to understand changes in 
energy metabolism with emphasis on mitochondrial function that could help to better 
understand the significant effects observed in the EMPA-REG (Zinman et al., 2015 [2] )
and CANVAS (Neal et al., 2017 [3])  studies on cardiovascular outcome for the future 
development of new medicines to treat type 2 diabetes. 
For this purpose, T2DM patients on metformin or on no pharmacological treatment for 
T2DM will be recruited and randomized to 5 weeks of treatment with 10 mg 
dapagliflozin or placebo in a doubleblind- cross-over study. The placebo tablets will look 
exactly the same as the dapagliflozin containing tablets but will not contain any active 
ingredient. Placebo controlled studies are the best possible way to define the effect of the 
active ingredient. This short-term study will be conducted in well-controlled T2DM 
patients and therefore comparing the effects of dapagliflozin with placebo will be 
associated with limited risks.
The cross-over design was chosen so that fewer patients are needed to detect a significant 
difference in cGDR as compared to a parallel group design.
Significant improvement in cGDR for dapagliflozin treatment over the placebo treatment 
will be quantified and demonstrated in primary efficacy analysis, and the expected 
difference between treatment groups is the basis for the size of the study. All other 
end-points are considered as exploratory.
A potential draw back with cross-over designs is the risk of losing the patient in case 
he/she does not turn up for the second period of treatment. The risk for drop-outs will be 
managed by recruiting only those patients who are very motivated and this risk is 
therefore not regarded as very high. The patient will be contacted regularly throughout 
the study by telephone. Main reason for the telephone contacts is to keep the patients 
motivated to continue the study. Another risk associated with the cross-over design is the 
carrying over effects of the first treatment. Studies on the effects of sedentary lifestyle, 
exercise and dieting on insulin sensitivity have shown that overall these interventions 


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result in transient effects, which are gone within a few weeks. Considering a halflife of 
dapagliflozin of 12.9 hours as well as 6–8 week wash-out period and 5 weeks of 
treatment before the next examination, the risk for carry over effects are regarded as very 
small. 
1.3
Risk Assessment
Dapagliflozin is approved in > 80 countries 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. Details regarding potential risks associated with administration 
of dapagliflozin once a day are provided in the Investigator’s Brochure (IB).
Drug related risks and protection against risks
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. The potential risks 
for the treatment with dapagliflozin and other SGLT2 inhibitors are described in the IB.
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. 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 and T2DM, 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 or temporary interruption of dapagliflozin should be 
considered and the patient should be promptly evaluated.
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting 
from pancreatic disorders (e.g., Type 1 diabetes, history of pancreatitis, or pancreatic 
surgery), insulin dose reduction, reduced caloric intake, or increased insulin requirements 
due to infections, illness or surgery and alcohol abuse. Dapagliflozin should be used with 
caution in these patients.
Procedure related risks and protection against risks
Muscle biopsies will be performed by a skilled person under the supervision of a medical 
doctor. The muscle biopsy will be taken under local anaesthesia of the skin; 
however patients may report dull pain during the sampling of muscle material. Patients 
can perform normal activities after the muscle biopsy, however patients will be instructed 
to refrain from heavy physical labor and not remove the pressure bandage from the leg 


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where the biopsy was taken within the first 24 hours. In rare occasions, the patients need 
an oral pain killer such as paracetamol to reduce pain after the muscle biopsy. The patient 
will be informed that a small scar can occur where the muscle biopsy is taken.
Magnetic Resonance Spectroscopy (MRS) and Dual-Energy X-ray Absorptiometry 
(DEXA) (0.001 mSv) are both safe procedures, with no health risks as long as none of 
the exclusion criteria are met. There could be a chance that Magnetic Resonance Imaging 
(MRI) reveals an unexpected medical condition, of which the patient and his/ her 
physician will be informed.
The exercise test can cause discomfort and muscle pain. During the maximal oxygen 
consumption (VO2max) cycling test, an increase in heart rate is expected which will be 
monitored using an ECG. This test will be performed under the supervision of trained 
medical staff.
EHC is a procedure performed routinely in the site laboratory without notable 
complications. In rare occasions, subjects could exhibit symptoms of hypoglycemia 
(even if their blood glucose levels are > 3 mmol/l). After successfully performing the 
clamp procedure, blood glucose values will be monitored for an additional 60 minutes 
with glucose infusion as a stand-by, in case glucose levels happen to drop. Solid food and 
sugar drinks will be provided after completing the clamp procedure to avoid 
hypoglycemia.
This study has been designed with appropriate measures in place to monitor and 
minimize any of the potential health risks to participating patients. In order to ensure the 
safety of all patients participating in this study, AstraZeneca will conduct a real-time 
review of all safety information from all ongoing clinical dapagliflozin studies as they
become available.
Safety signal detection will include the integration of all available sources of safety 
information, including clinical study data, adverse events (AE) reports, pre-clinical data, 
epidemiological studies and literature reports, to identify and characterize unrecognized 
safety risks or changes in those which are currently expected Adverse Drug Reactions.
Any information that may affect the benefit-risk profile of dapagliflozin will be 
immediately communicated to relevant Health Authorities and appropriate actions will be 
taken regarding the clinical programme as needed. Thus real-time, active safety 
surveillance will be conducted during the entire duration of this study. 
Informed consent and alternatives to participation
All prospective participants will be fully informed of the possible risks associated with 
this study and their consent will be obtained prior to performing any study-specific 
activity. Should a prospective participant elect to not participate in the study or to 
withdraw from the study, other medications are available to treat their T2DM, and other 


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possible concomitant diseases will be treated according to the discretion of their health 
care professional; the patient will not be disadvantaged in any way.
Conclusion
Considering the pre-clinical and clinical experience with dapagliflozin and the 
precautions included in the study protocol, participation in this study presents a minimal 
and thus acceptable risk to patients who meet the inclusion/exclusion criteria and consent 
to take part in the study.


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2
STUDY OBJECTIVES
2.1
Primary Objective
To investigate if dapagliflozin improves skeletal muscle insulin sensitivity expressed as 
corrected glucose disposal rate (cGDR) in comparison with placebo after 5-week double 
blind treatment. Insulin sensitivity will be determined using a 2-step euglycemic 
hyperinsulinemic clamp (EHC) procedure.
2.2
Exploratory Objectives
The exploratory objectives to be evaluated are:

To investigate if dapagliflozin changes Endogenous Glucose Production (EGP) in 
comparison with placebo after 5-weeks of double blind treatment.

To investigate if dapagliflozin improves metabolic flexibility as compared to 
placebo, determined by the change in respiratory exchange ratio (RER) from 
fasted state to insulin stimulated state during EHC after 5-week double blind 
treatment

To investigate if dapagliflozin changes RER and energy expenditure as well as 
plasma metabolites such as beta-hydroxybutyrate and glucose as compared to 
placebo, before and after meals in the metabolic chamber after 5-week double 
blind treatment

To investigate if dapagliflozin improves maximal capacity to form acetylcarnitine 
following exercise and CRAT and CS activities in muscle biopsy, as compared to 
placebo after 5-week double blind treatment

To investigate if dapagliflozin improves in vivo mitochondrial function as 
measured by phosphocreatinine recovery following exercise, as compared to 
placebo after 5-week double blind treatment

To investigate if dapagliflozin improves ex vivo mitochondrial function in 
permeabilized muscle fibers using high resolution respirometry, as compared to 
placebo after 5-week double blind treatment

To investigate if dapagliflozin changes body composition, skeletal muscle and 
liver fat content, as compared to placebo after 5-week double blind treatment.

To investigate if dapagliflozin changes blood biomarkers such as glucagon, 
insulin and FGF21 in comparison with placebo after 5-weeks of double blind 
treatment.

To investigate if dapagliflozin changes expression of mRNA and/or proteins 
involved in metabolic regulation in muscle tissue in comparison with placebo 
after 5-weeks of double blind treatment. 

To investigate if dapagliflozin changes body weight, BMI and systolic and 
diastolic blood pressure in comparison with placebo after 5-weeks of double blind 
treatment.


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2.3
Safety Objective
To evaluate the safety and tolerability of dapagliflozin by assessment of DAE/SAEs, 
including laboratory values and clinically significant findings after 5-week double blind 
treatment. 


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3
OVERALL DESIGN AND PLAN OF THE STUDY
3.1
Overview
This is a double-blind, randomized, mechanistic, placebo-controlled, cross-over study, to 
evaluate the effect of 5 weeks dapagliflozin treatment in T2DM patients, either 
drugnaïve- or on metformin and/or a DPPIV inhibitor.
A total of 26 patients are planned to be randomized to have at least 22 completers in two 
equal sized treatment sequences. In case of more than 4 drop-outs, another 4 patients will 
be randomized and if this occurs a total of 30 patients will be randomized.
Before visit 1, each patient is contacted by telephone to explain the study. During this 
phone call, the patient will also be asked some questions related to the inclusion and 
exclusion criteria to verify eligibility, this is regarded a so-called pre-screening.
There will be two treatment periods in this study:
Period 1: Patients will receive either dapagliflozin 10 mg or matching placebo for a 
maximum of 40 days based on randomization sequence.
Period 2: Patients that received 10 mg dapagliflozin in the first treatment period will 
receive matching placebo in the second treatment period and patients who 
received placebo in the first treatment will receive 10 mg dapagliflozin in the 
second treatment period, for a maximum of 40 days.
The maximum duration for each treatment period will be 40 days and the study will 
include the following:

Screening within Day -21 to Day -0

A 5 weeks treatment period 1: Day 1 to Day 29±3 (+ 6–8 days for end of 
treatment assessments at site)

A 5–10 days safety follow-up after last dose of treatment (this will be a part of 
the 6–8 weeks wash-out period mentioned below)

A 6–8 week wash-out period

A 5 weeks treatment period 2: Day 1 to Day 29±3 (+ 6–8 days for end of 
treatment assessments at site)

A 5–10 days safety follow-up after last dose of treatment.


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The study design is presented in Figure 1.
Figure 1: Study Design
Visit 1: Screening Visit, including C-peptide assessment, Visit 2: Randomization Visit, including VO2 max cycling 
test, maximal knee-extension test and drug dispensing, Visit 3: safety, Visit 4: end of treatment efficacy assessments
and drug dispensing, Visit 5: drug dispensing and safety visit, Visit 6: safety visit. Visit 7: end of treatment efficacy
assessments, drug dispensing.  Safety follow up (FU) visits taking place after end of Visit 4 and Visit 7 are telephone 
meetings for safety follow-up that should be made about 1 week (5-10 days) after the last dose of treatment in each 
period. Alternately, a visit can be made by a nurse or if needed, this visit can also take place at the site and include 
physical examination and laboratory assessments.
n=26 randomized 
Treatment Period 1: 
Visit 1: 
Screening (total 1 hour)
Patients will need to sign the informed consent form and thereafter been screened to 
assess eligibility. During the screening, a fasted blood sample will be obtained to 
measure routine blood parameters including basal C-peptide, a urine sample will be 
obtained. Physical examination, vital signs, body weight and height will be measured and 
an ECG will be performed. Thereafter, medical status and history of the patients will be 
checked. 
Only eligible patients will be included for participation in the study.
Visit 2 (Day 1): 
Randomization + VO2-max cycling test (total 1 hour) and maximal knee-extension 
test (total 1.5 hours)
Eligibility criteria will be checked. The blood pressure, pulse rate and weight of 
randomized patients will be recorded. A maximal aerobic cycling test (VO2 max) will be 
performed to characterize the patient population and to ensure standardized cycling 
intensity during the acetylcarnitine MRS measurement scheduled for Visits 4 and 7; for 
the latter 70% of maximal performance (Wmax) will be used . Also maximal knee 
extension test will be performed to ensure standardized knee extension intensity during 
the phosphocreatine recovery 31P-MRS measurements scheduled for Visits 4 and 7. 


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About 60% of the individual maximal weight obtained will be used during the 31P-MRS 
measurements during Visits 4 and 7.
Patients will start the treatment and will receive dapagliflozin 10 mg per day or placebo 
depending on randomized allocation. Patients will continue dapagliflozin or placebo until 
end of study period; Day 29±3 (+ 6–8 days for final assessments).
The patient will be given a lifestyle card.  This is a card with a set of lifestyle advices for 
the patient to adhere to during the course of the study, including keeping their eating 
pattern, alcohol consumption and physical exercise behaviour  during the study.
Visit 3 (Day 15±3): 
Safety 
The blood pressure, pulse rate and weight of patients will be recorded and occurrence of 
any DAEs and SAEs will be reported. 
Visit 4 and Visit 7 [Day 29±3 (+6–8 days for final assessments)]: 
End of treatment period
An overview of the examinations taking place at Visit 4 and Visit 7 is presented in 
Figure 2.
Figure 2: Overview of the examinations taking place at Visit 4 and Visit 7
Visit 4 and Visit 7 will take place over 6–8 days. Four days (Day 1-3 and Day 6, 7 or 8) will be at the site. Two to four 
days after Day 3 will be spent at home or at the hotel. Fasting blood samples for biomarker analyses and muscle biopsy 
will take place in the morning of Day 3.
15:00h, 20:00h, 8:00h, 17:00h, 16:00h, and 17:00h denote the time of the day when the examination are taking place.
The end of treatment visit will take place over 6–8 days: four days (Days 1–3 and Day 6, 
7 or 8) will be spent at the site and 2–4 days after Day 3 will be spent either at home or at 
the hotel. The last dose will be given on the last day of the end of treatment visit (at 
Visit 4 or Visit 7).
On Day 1 of the end of treatment visit, physical examination, the blood pressure, pulse 
rate and weight of patients will be recorded and occurrence of any DAEs and SAEs will 


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be reported. Blood samples will be collected to determine safety parameters. After this, 
the intramyocellular lipid content will be measured using 1H-MRS and PCr recovery 
measurement will be done using 31P-MRS methodology.
From the end of Day 1 until the morning of Day 3 of the end of treatment visit 
(36 hours), the patients will stay in the metabolic chamber. During this stay, whole body 
energy expenditure, sleeping metabolic rate and substrate metabolism will be measured. 
On Day 2 of the end of treatment visit when the patients are in the metabolic chamber, 
blood samples will be drawn at 7 occasions and urine will be collected for 24 hours, 
volumes will be measured and aliquots may be frozen for later analyses. 
On Day 3, the 2-step EHC will be performed to determine whole body and hepatic 
insulin sensitivity. During this clamp, when tracer infusion has started but before insulin 
infusion (basal state), 1H-MRS to determine liver lipid content will be done and a muscle
biopsy will be taken from the m. vastus lateralis. Indirect calorimetry will be performed 
before and after the start of insulin infusion.
After the assesments the patients can take a break of 2-4 days,  which can be spent at 
home (or in a hotel if needed).
On Day 6, 7 or 8 of the end of treatment visit, a DEXA scan will be performed to 
determine whole body composition and 1H-MRS will be performed to measure 
acetylcarnitine levels before and after 30 minutes of cycling (at 70% of maximum work 
rate (Wmax) as pre-determined at Visit 2). The study drug accountability will be assessed 
on this day.
Wash-out Period:
After the last day of the end of treatment visit, treatment with dapagliflozin or placebo 
will be discontinued and patients will enter a 6–8 weeks wash-out period. 
A safety follow- up will be performed about 1 week (5-10 days) after the end of 
treatment visit for reporting of DAEs and SAEs.
Treatment period 2:
After a 6–8 week wash-out period, the cross over will take place and patients having 
received dapagliflozin will receive the placebo and patients having received placebo will 
receive dapagliflozin over a 5-week treatment period.
The study procedures detailed for Visit 2, Visit 3 and Visit 4 from treatment period 1 will 
be performed again at Visit 5 (with additional physical examination, blood and urine 
sampling for laboratory safety assessment with the exception of VO2 cycling test and 
maximal knee-extension testing), Visit 6 and Visit 7 during the treatment period 2. A 
safety follow-up will again be performed 5–10 days post-last dose.
Guidelines for individual patient withdrawal are described in Section 4.4. Guidelines for 
study ending are described in Section 9.10.
Refer to the Study Plan (Table 4) for details on the timing of planned assessments and 
Section 6.1 for details on the methodology of assessments.
3.2
Criteria for Evaluation of the Study
Refer to the study objectives in Sections 2.1, 0, and 2.3.


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3.2.1
Primary Endpoint
Comparison of dapagliflozin versus placebo after 5 weeks treatment in skeletal muscle 
insulin sensitivity measured as cGDR using a 2-step EHC procedure.
3.2.2
Exploratory endpoints
Comparison of dapagliflozin versus placebo after 5 weeks treatment for the following 
variables:

Change of Endogenous Glucose Production (EGP)

Metabolic flexibility, as determined by the RER from fasted state to insulin 
stimulated state during EHC

RER and energy expenditure as well as plasma metabolites such as 
betahydroxybutyrate and glucose before and after meals, as measured in 
metabolic chambers

Maximal capacity to form acetylcarnitine following exercise as measured using 
1H-MRS and by CRAT activity (muscle biopsy) 

In vivo mitochondrial function as measured post-exercise by phosphocreatinine 
recovery using 31P-MRS

Ex vivo mitochondrial function in permeabilized muscle fibers using high 
resolution respirometry (muscle biopsy)

Body composition as measured by DEXA, and skeletal muscle and liver fat 
content as measured by 1H-MRS

Change of blood biomarkers such as glucagon, insulin and FGF21

Change of expression of mRNA and/or proteins involved in metabolic regulation 
in muscle tissue.

Changes in body weight, BMI and systolic and diastolic blood pressure.
3.2.3
Safety endpoint
Safety and tolerability of dapagliflozin by assessment of the following: 

Incidence of DAEs and SAEs

Incidence of independently adjudicated DKA events, if any

Clinical chemistry/hematology/urine parameters

Vital signs

Physical examination


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4
STUDY POPULATION
The study population will consist of patients with diagnosed T2DM who have been on 
stable dose of metformin for at least the last 3 months or are drug naive. 
Patients must be able to provide written informed consent, meet all the inclusion criteria 
and none of the exclusion criteria.
4.1
Inclusion Criteria
Patients will be entered into this study only if they meet all of the following criteria at 
screening:
1. Patients are able to provide signed and dated written informed consent prior to any 
study specific procedures.
2. Women are post-menopausal (defined as at least 1 year post cessation of menses) and 
aged ≥ 45 and ≤ 70 years. Males are aged ≥ 40 years and ≤ 70 years. Patients should 
have suitable veins for cannulation or repeated venipuncture.
3. Patients are diagnosed with T2DM for at least the last 6 months, based on American 
Diabetes Association 2016 standards (Diabetes Care, 2016 [19]).
4. Patients are on no other anti-diabetic drug treatment, or on stable maximum 3000 mg 
daily dose metformin treatment and/or on stable dose of a DPPIV inhibitor treatment 
for at least the last 3 months.
5. HbA1c levels ≥6.0% (=42 mmol/mol) and ≤9.0% (75 mmol/mol).
6. Have a body mass index (BMI) ≤ 38 kg/m2.
4.2
Exclusion Criteria
Patients will not be entered into this study if they meet any of the following criteria at the 
time of screening:
Study-related:
1. Involvement in the planning and conduct of the study (applies to both AstraZeneca 
staff and staff at third party vendor or at the investigational sites).
2. Previous enrolment in the present study or participation in another clinical study with 
an investigational product during the last 3 months or as judged by the Investigator.
General health-related:
3. History of or presence of any clinically significant disease or disorder including a 
recent (< 3 months) cardiovascular event which, in the opinion of the Investigator, 
may either put the patient at risk because of participation in the study or influence the 
results or the patient’s ability to participate in the study.
4. Clinical diagnosis of Type 1 diabetes, maturity onset diabetes of the young, 
secondary diabetes or diabetes insipidus.
5. Unstable/rapidly progressing renal disease or estimated Glomerular Filtration Rate < 
60 mL/min (Cockcroft-Gault formula).


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Males:
Creatinine clearance (mL/min) = Weight (kg) X (140-Age) X 1.23
     Serum creatinine (µmol/l)
Females:
Creatinine clearance (mL/min) = Weight (kg) X (140-Age) X 1.04
     Serum creatinine (µmol/l)
6. Clinically significant out of range values of serum levels of either alanine 
aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase 
(ALP) in the Investigator’s opinion.
7. Contraindications to dapagliflozin according to the local label.
8. Use of antidiabetic drugs other than metformin within 3 months prior to screening.
9. Weight gain or loss > 5 kg in the last 3 months, ongoing weight-loss diet 
(hypocaloric diet) or use of weight loss agents.
10. History of drug abuse or alcohol abuse in the past 12 months. Alcohol abuse is 
defined as > 14 drinks per week for women and > 21 drinks per week for men 
(1 drink = 35 cl beer, 14 cl wine or 4 cl hard liquor) or as judged by the Investigator.
11. Any clinically significant abnormalities in clinical chemistry, hematology or 
urinalysis or other condition the Investigator believes would interfere with the 
patient’s ability to provide informed consent, comply with study instructions, or 
which might confound the interpretation of the study results or put the patient at 
undue risk.
12. Plasma donation within one month of screening or any blood donation/blood loss 
> 500 mL within 3 months prior to screening or during the study.
13. Anemia defined as Hemoglobin (Hb) < 115 g/L (7.1 mM) in women and < 120 g/L 
(7.5 mM) in men.
14. Use of anti-coagulant treatment such as heparin, warfarin, platelet inhibitors, 
thrombin and factor X inhibitors.
15. Use of medication such as oral glucocorticoids, anti-estrogens or other medications 
that are known to markedly influence insulin sensitivity.
16. Use of loop diuretics.
17. Regular smoking and other regular nicotine use.
18. Any contra-indication to magnetic resonance imaging scanning. These 
contra-indications include patients with following devices:
-
Central nervous system aneurysm clip
-
Implanted neural stimulator
-
Implanted cardiac pacemaker of defibrillator
-
Cochlear implant
-
Metal containing corpora aliena in the eye or brain.


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19. Patients, who do not want to be informed about unexpected medical findings, or do 
not wish that their physician be informed about coincidental findings, cannot participate 
in the study. 
4.3
Discontinuation of Investigational product 
Patients may be discontinued from study treatment and assessments at any time in the 
following situations:

Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.

Severe non-compliance to protocol, as judged by the Investigator and/or 
AstraZeneca.

Safety reasons, e.g., AE that warrants discontinuation, as judged by the 
Investigator and/or AstraZeneca.

Patient meets the required exclusion criteria.

Patient lost to follow-up.

Pregnancy.
4.4
Criteria for withdrawal
In all cases, the reason(s) for withdrawal, and the primary reason, must be recorded on 
the electronic case report form (eCRF). If a patient is prematurely withdrawn from the
study drug for any reason, the Investigator must make every effort to perform the safety 
evaluations and refer the patient to further treatment if it becomes necessary.
A patient may be withdrawn from study drug by the Sponsor, Regulatory Authorities, or 
Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs).
Patients will also be withdrawn if the entire study is terminated prematurely as described 
in Section 9.10.
A subject may be re-tested during the screening window, provided any inclusion or 
exclusion criteria the subject fails is expected to resolve prior to the randomisation 
visit. If the criteria are not expected to resolve, the subject should be screen failed and 
withdrawn from the study. A subject may be re-screened once if they have failed to meet 
the inclusion exclusion criteria at a previous attempt. A re-screening can be done if at 
least 21 days have passed after the initial screening visit. Rescreened subjects should be 
assigned a different subject number than in the initial screening and sign another ICF.
However, rescreening should be documented so that its effect on study results, if any, can 
be assessed.Patients who are discontinued from the study drug will not be replaced. If the 
number of discontinued patients exceeds four patients, additional four patients will be 
randomized. The maximum number of additional patients randomized will be four, i.e., 
the total number of randomized patients will not exceed 30. 
 


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4.6
Patient Identification and Randomization
4.6.1
Patient Identification
Upon enrolment, each patient will receive a unique screening number. Enrolled patients 
who drop out of the study before randomization will retain their screening number. The 
enrolment number will be in the following format: E code format (E_Site ID_Patient ID), 
e.g., E0001001 and will be recorded in the eCRF.
The enrolment number will serve as the patient identifier throughout the study and will 
be required in all communication between the Investigator or designee regarding a 
particular patient.
4.6.2
Randomization Scheme
Randomization codes will be assigned strictly sequentially as patients become eligible 
for randomization, starting from 1001. Randomization will be used to assign each subject 
to a specific treatment sequence (dapagliflozin: placebo or vice-versa), and the 
randomization schedule will assign sequences using blocks of equal and fixed size. 
Blocks as well as sequence will both be randomized within the randomization list.
Once a randomization number has been allocated to a patient, it may not be assigned to 
another patient. 
The randomization scheme will be set-up by the AstraZeneca randomization solution 
(AZRand).
4.6.3
Allocation/Randomization of Patients to Treatment
Study drug will be prepared and packed by AstraZeneca supply chain (to be unblinded) 
and then provided to the onsite pharmacy, based on the randomization list. The label will 
contain the random number and visit associated with the randomization list. The onsite 
pharmacy (to remain blinded) will coordinate the dispensing of study drug based on the 
random number and visit.


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5
STUDY DRUG
5.1
Identity
Dapagliflozin is a highly potent, selective and reversible inhibitor of SGLT2.
5.1.1
Investigational Products
For this study, study treatment refers to dapagliflozin 10 mg tablets or placebo tablets.
Details of the study treatment can be found in Table 1. Dapagliflozin 10 mg tablets and 
matching placebo tablets will be supplied by AstraZeneca in labelled bottles containing 
35 tablets each.
Table 1:
Identity of the Study Treatment
IMP
Dosage form and strength
Manufacturer
Dapagliflozin
Plain, green, diamond-shaped, film-coated tablet
AstraZeneca
Placebo
Plain, green, diamond-shaped, film-coated tablet
AstraZeneca
Details of the batch numbers will be included in the Trial Master File and the final 
clinical study report.
5.1.2
Non-Investigational Medicinal Product
During the study the following commercial available Non-Investigational Medicinal 
Products (NIMP) will be sourced from the local pharmacy and used during the study 
related procedures. All NIMPs will be stored, prepared and handled by the site according 
to standard practice, with the exception of D-glucose [6,6-D2] infusion (see below).
Euglycemic hyperinsulinemic clamp:

Glucose Intravenous Infusion BP 20% w/v.

NovoRapid 100 U/ml solution for injection

D-Glucose [6,6-D2] infusion 16.8 mg/ml (stable isotope), (prepared by the 
pharmacy of Radboud University Medical Center, in Nijmegen, the Netherlands 
and stored and handled by the site).
Muscle biopsy (local anaesthetics): 

Lidocaine Hydrochloride 1% w/v Solution for Injection
5.2
Administration
Patients will be provided with dapagliflozin or matching placebo tablets at Visits 2 and 4 
to last for up to 40 days. 


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Minimum duration of treatment will be 32 days (26 +6 days) and maximum duration of 
treatment will be 40 days (32 + 8 days). 
After a 6–8 week wash-out period, the cross over will take place and patients having 
received dapagliflozin will receive the placebo tablets and patients having received 
placebo will receive the dapagliflozin tablets at Visits 5 and 7 for the next 5 weeks of 
treatment period 2.
The tablet will be taken orally once daily in the morning and at approximately the same 
time of the day during the treatment periods. On the days of visits for the clamp, the 
tablet will be taken after fasting blood samples have been collected. 
There are no restrictions regarding timing in relation to food. Dapagliflozin tablets 
contain lactose, which may cause discomfort in lactose-intolerant individuals. 
The first dose of study treatment will be taken by the patients the day after 
randomization.
The patients will be asked to bring their bottles with tablets for the study visits.
5.3
Packaging, Labeling and Storage
The study drug will be packaged by AstraZeneca or designee according to Good 
Manufacturing Practice (GMP).
Labels will be prepared in accordance with GMP and local regulatory guidelines. The 
labels will fulfil GMP Annex 13 requirements for labelling. Label text will be translated 
into local language.
The study drug should be kept in a secure place under appropriate storage conditions. 
The study drug label on the bottle specifies the appropriate storage.
5.4
Blinding and Unblinding
The study will be performed in a double-blind manner. All study drugs will be supplied 
in identical bottles and will be similar in color, smell, taste, and appearance, thereby 
enabling double-blind conditions.
The study blind should not be broken except in a medical emergency (where knowledge 
of the study drug received would affect the treatment of the emergency) or regulatory 
requirement. 
All attempts must be made to contact the Sponsor/Medical Monitor before the actual 
treatment dispensed can be provided. These attempts must be documented. If there is an 
emergency and no contact is possible, an unblinding may be needed.
If unblinded, the date, time and reason must be recorded in the patient’s eCRF, and any 
associated AE report. 
If an Investigator, site personnel performing assessments, or patient, is unblinded, the 
patient must be listed as major protocol deviation. 
The overall randomization code will be broken only for reporting purposes. This will 
occur once all final clinical data have been entered onto the database and all data queries 
have been resolved, and the assignment of patients to the analysis sets has been 
completed.


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5.5
Drug Accountability
The study drugs provided for this study will be used only as directed in the study 
protocol.
The study personnel will account for all study drugs dispensed to and returned from the 
patient at the end of each treatment period.
The Investigator is responsible for making sure:

That the study drugs are handled and stored safely and properly (see Section 5.3).

That the study drugs are only dispensed to study patients in accordance with this 
protocol.
Patients should return all unused study drugs and empty containers to the Investigator.
At the termination of the clinical study or at the request of AstraZeneca, the Investigator 
will either return any unused study drugs to AstraZeneca or its designee, or destroy study 
drugs at the site depending on local regulations. If the study drugs are destroyed at the 
site, the site personnel will account for all unused study drugs and for appropriate 
destruction. If the study drugs are returned to AstraZeneca or its designee, the study site 
personnel or the AstraZeneca monitor will account for all study drugs received at the site, 
unused study drugs and for appropriate destruction. Certificates of delivery, destruction 
and return should be signed and archived. 
Each dispensation of the study drug will be documented in the eCRF.
5.6
Compliance
Patients will be instructed on proper use of study drug. 
Compliance with study treatment will be monitored via the drug accountability 
assessments (tablet counts). Tablet counts will be recorded in the eCRF. 
Compliance with study treatment will be calculated as specified in the statistical analysis 
plan.
5.7
Previous and Concomitant Medications
Any medication the patient takes other than the study drug, including herbal and other 
non-traditional remedies, food and vitamin supplements, etc. are considered a 
concomitant medication. 
All concomitant medications must be recorded in the eCRF. The following information 
must be recorded in the eCRF for each concomitant medication: generic name, route of 
administration, start date, stop date, dosage, and indication. 
Any changes in the dosage or regimen of a concomitant medication must be recorded in 
the eCRF.
At screening, patients will be asked what medications they have taken during the last 
3 months. At each subsequent study visit, patients will be asked if there have been any 
changes to their concomitant medications or standard of care medication for T2DM, and 
whether they have taken any other medications since the previous visit.


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5.7.1
Permitted concomitant medication
Patients with T2DM will continue on metformin and/or a DPPIV inhibitor therapy at the 
same dose that they were on prior to start of the study. Metformin treatment should be 
taken at the same time as the IP if possible.
At each visit, the Investigator will reassess whether the concomitant medication that the 
patient is taking is part of the original maintenance for T2DM or whether the patient has 
started taking extra concomitant medication. The status of each concomitant medication 
(i.e., preexisting- or new) will be documented in the eCRF.
Therapies for treatment of other comorbidities are allowed with the exception of 
medications listed in Section 5.7.2.
All efforts should be made to keep the dose of study medication stable throughout the 
study.
5.7.2
Prohibited concomitant medication
Refer to Section 4.2 for exclusion criteria relating to prohibited medications.
The following medications are prohibited during the study:

Use of antidiabetic drugs other than metformin or DPPIV inhibitors. 

Use of anti-coagulant treatment such as heparin, warfarin, platelet inhibitors, 
thrombin and factor X inhibitors.

Use of medication such as oral glucocorticoids, anti-estrogens or other 
medications that are known to markedly influence insulin sensitivity.

Use of loop diuretics.

NSAIDS should not be used within 3 days of Visit 4 and 7.


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6
VARIABLES AND METHODS OF ASSESSMENT
6.1
Efficacy variables
Assessments will be performed in accordance with the Study Plan (Table 4).
6.1.1
Maximal knee-extension test
A maximal knee extension test will be performed at Visit 2 to ensure standardized knee 
extension intensity during the PCr 31P-MRS measurements scheduled for Visits 4 and 7. 
This test will be performed on a magnetic-resonance compatible knee-extension exercise 
devise, with incremental weight put on the left leg (500 g every 30 seconds) till 
exhaustion is reached. During the actual 31P-MRS test (Visits 4 and 7) 60% of this 
individual maximal weight will be used.
6.1.2
Maximal VO2 cycling test
A maximal aerobic cycling test will be performed at Visit 2 to characterize the 
participant population and to ensure a standardized cycling intensity during the 
acetylcarnitine 1H-MRS measurements at Visits 4 and 7. Subjects are requested to refrain 
from strenuous exercise for the last two days before these visits.
Subjects will come to the laboratory in the overnight fasted state and will be provided 
with a light breakfast before subjects’ maximal oxygen uptake (VO2max) will be measured 
by a cycling test to determine maximal aerobic capacity. An ECG will be performed by 
the experienced staff at the site during the VO2 max cycling test. To determine maximal 
aerobic capacity, VO2max and Wmax will be measured on an electronically braked cycle 
ergometer during an incremental exhaustive exercise test. In order to do so, O2
consumption and CO2 production will be measured using an Omnical system. In 
addition, RER will be monitored as a verification of their maximal effort. The following 
protocol will be used: after a warming-up period of five minutes with a start workload of 
55 watt for females and 75 watt for males, the workload will be increased with 50 watt 
every 2.5 minutes. When the heart rate of patients reaches 80% of their predicted 
maximal heart rate (220-age), the workload will be increased with 25 watt until 
exhaustion is reached or until they are no longer able to keep their speed of rotation 
above 60 times per minute.
6.1.3
Euglycemic hyperinsulinemic clamp, indirect calorimetry and muscle biopsy
Two step 5.5 hour EHC (3 hour 10 mU/m2/min and 2.5 hour 40 mU/m2/min insulin 
infusion) in combination with infusion of D-glucose (6,6-D2) glucose to determine rates 
of EGP, and whole body GDR and urine glucose excretion to be able to calculate cGDR. 
The clamp will be performed in the post-absorptive state beginning at about 8 am after an 
overnight fast (in the respiration chamber), and subjects are asked to refrain from 
physical exercise for the two days proceeding the clamp test. Study medication will be 
taken in the morning before the clamp. A teflon cannula will be inserted into the 
antecubital veins of one arm for the infusion of glucose tracer, insulin and glucose. 
Another cannula will be inserted in a retrograde manner into a superficial dorsal hand 
vein. This venous blood will be arterialized by placing the hand into a hotbox, which 
blows warm air (55ºC). Blood samples will be taken (approximately 167 mL) throughout 


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the EHC test. Urine volume will be determined during the clamp procedure, and urine 
aliquots frozen for later analyses of glucose concentrations.
Before the insulin infusion starts, there will be a baseline period of 3 hours including 
pre-infusion of D-glucose [6,6-D2] (priming dose: 2.4 mg/kg; continuous infusion: 0.04 
mg/kg-1/min-1) to reach equilibrium in the plasma pool. This is a naturally occurring 
isotope, which is not harmful.
Within this baseline period, a muscle biopsy will be taken from the m. vastus lateralis
(see 6.1.8) and a measurement with indirect calorimetry (ventilated hood) will be 
performed.
During the indirect calorimetry, respiratory gas exchange will be measured using open 
air circuit respirometry with an automated ventilated hood system. These indirect 
calorimetry measurements will be repeated in the last 30 minutes during the 
10 mU/m2/min clamp as well as during the last 30 minutes of the 40 mU/m2/min clamp. 
These 30 minute periods are the so-called ‘steady-state’ periods in which exogenous 
glucose infusion equals glucose uptake. With the indirect calorimetry measurements, 
metabolic flexibility will be determined, reflected by the change in RER from baseline to 
insulin stimulation. 
After 150 minutes of isotopic equilibration, four blood samples will be obtained at 10 
minute intervals (T=150, 160, 170 and 180 minutes) for the determination of basal blood 
substrates, whole body glucose disposal and hepatic glucose production. 
Indirect calorimetry (ventilated hood) will be performed during this last half hour of the 
baseline equilibration period to determine substrate oxidation (T150 – 180 minutes). 
At T=180 minutes, a 3-hour low primed constant infusion of insulin will be initiated 
(10 mU/m2/min) to asses hepatic insulin resistance. Plasma glucose levels will be 
clamped at ~5 mmol/L by variable co-infusion of 20% glucose. At regular time points 
(every 5 to 10 minutes), a small volume of blood (0.9 mL) will be sampled for immediate 
determination of plasma glucose concentration. When necessary, glucose infusion rate 
will be adjusted to obtain plasma glucose levels of ~5 mmol/L (euglycemia). 
Indirect calorimetry will be performed at T=330-360 minutes. During this time period, 
four blood samples will be obtained at 10 minute intervals for the determination of whole 
body glucose disposal and hepatic glucose production (T=330, 340, 350 and 360
minutes). At T=360 minutes, the 2.5 hour high primed constant insulin infusion will take 
place (40 mU/m2/min), in order to fully stop the hepatic glucose production and only 
study the rate of disappearance (Rd) as a measure for skeletal muscle insulin sensitivity. 
Plasma glucose levels will be clamped at ~5 mmol/L by variable co-infusion of 20% 
glucose. At regular time points (every 5 to 10 minutes), a small volume of blood (0.9 
mL) will be sampled for immediate determination of plasma glucose concentrations. 
When necessary, glucose infusion rate will be adjusted to obtain plasma glucose levels of 


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~5 mmol/L (euglycemia). Indirect calorimetry will be performed at T=480–510 minutes. 
During this time period, four blood samples will again be drawn at 10 minute intervals 
(T=480, 490, 500 and 510 minutes). 
6.1.4
Body composition
DEXA scan will be used to determine body composition. DEXA assesses total body 
bone mineral density and accurately measures body soft tissue composition (muscle mass 
and fat mass). By measuring the body’s muscle mass, fat mass and bone mineral density, 
total body fat percentage can be determined.
6.1.5
24h energy expenditure, 24h RER
This will involve a 36-hour stay in a whole-body room calorimetry chamber, of which 
the last 24 hours will be used for measurements (to determine sleeping metabolic rate as 
well as energy expenditure, 24-hour RER fasting-fed state and substrate metabolism). 
Diurnal blood samples will be taken at 7 occasions during the stay in the chamber (before 
and after meals as well as before bedtime) to determine a.o. plasma levels of glucose, 
Non-Esterified Fatty Acids (NEFA), beta-hydroxybutyrate, insulin, glucagon and 
Fibroblast Growth Factor 21 (FGF21).
6.1.6
1H-MRS
Acetylcarnitine levels are measured in the muscle using 1H-MRS (before and after 
exercise at 70% of Wmax). Lipid quantification of the liver and skeletal muscles will 
also be performed using 1H-MRS. The post-exercise PCr recovery measurement will be 
performed using phosphor-MRS (31P-MRS) to assess in vivo mitochondrial function. 
MRS and MRI are modern diagnostic tools that do not imply significant risks (no 
ionizing radiation). MRI will be used to guide the spectroscopic measurements to the 
correct location. All scans will be performed on a 3.0 T clinical MRI scanner.
All patients will be in the supine position. For the intramyocellular lipid content, 
acetylcarnitine and PCr recovery measurements, the patients will be shifted by the legs 
into the bore of the magnet and the head will stay outside the bore. For the intrahepatic 
lipid measurement, the patients will again be in a supine position, but the other way 
around (head first). The patients will be asked to lie still during the whole measurement, 
unless otherwise instructed during the post-exercise PCr recovery measurement. During 
this measurement, knee-extension exercise will be performed for 5 minutes, while being 
in the magnet. During the scans, the patients will receive a buzzer to let the Investigator 
know when they are uncomfortable. Additionally, they will stay in contact with the 
Investigator via an intercom communication system. As the acquisition of MRI images is 
accompanied by a 'clanging' noise, the patients will be provided with protective 
headphones. There is a chance that the MRI may reveal an unexpected medical 
condition, of which the patient and the treating physician will be informed. 
Hepatic lipid accumulation:
An 18 cm3 volume will be selected within the right lobe of the liver as per the MRI 
images of the upper abdomen and the 1H-MRS spectra will be acquired from this region. 
To prevent motion artefacts, patients will be asked to breathe in the rhythm of the 
spectroscopic measurement. In the 1H-MRS spectra, the water signal that is dominating 


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the proton spectra will be suppressed using frequency-selective pre-pulses and the 
spectra will be fitted to quantify the lipid peak. The lipid/water ratio will be used as the 
parameter of intrahepatic lipid content. Patients will need to breath as per the 4s-rhythm 
for about 6 minutes. Total acquisition time (with positioning of patient and imaging) 
should be about 45 minutes.
Intramyocellular lipid content:
A volume of interest will be selected within the tibialis anterior muscle as per the MRI 
images of the leg and the 1H-MRS spectra will be acquired from this region. Patients will 
be able to breathe freely during the whole measurement. In the 1H-MRS spectra, the 
water signal that is dominating the proton spectra will be suppressed using 
frequencyselective- pre-pulses and the spectra will be fitted to quantify the lipid peak. 
The lipid/water ratio will be used as the parameter of intramyocellular lipid content. 
Total acquisition time is estimated to be about 30 minutes.
Muscle acetylcarnitine levels:
Acetylcarnitine quantification will be performed by 1H-MRS during rest and directly 
after exercise. Exercise is well known to increase acetylcarnitine concentrations and a 
high-intensity cycling protocol for 30 minutes would result in quasi-maximal 
acetylcarnitine levels. Therefore, this will enable investigation of the maximal capacity to 
form acetylcarnitine. During the 30 min cycling test blood will be drawn at 3 time-points: 
T=0 min, T=15 min and T=30 min for measurement of lactate.
A volume of interest will be selected within the vastus lateralis as per the MRI images 
and the 1H-MRS spectra will be acquired from this region. The 1H-MRS spectra will 
allow quantification of the amount of acetylcarnitine in the muscle relative to creatine. A 
30-minute cycling protocol will be used where patients will be required to cycle at 70% 
of their individual maximal wattage (determined during the maximal aerobic capacity 
test). The exercise intensity is relatively high to maximize the acetylcarnitine production. 
A fixed duration and wattage will be chosen to prevent variation in exercise intensity and 
duration among patients. The cycling will be performed on an ergometer located in the 
room next to the MRI scanner. The total scanning time including exercise would be 
about 1.5 hours.
6.1.7
31P-MRS
In vivo mitochondrial function using 31P-MRS methodology will be performed. Level of 
PCr will be measured for 5 minutes during rest, 5 minutes during 
kneeextension- exercise (at 60% of maximal weight as pre-determined during Visit 3) 
and during 5 minutes after exercise, during the recovery phase.
6.1.8
Muscle biopsy from the m. vastus lateralis
A percutaneous muscle biopsy will be obtained from the vastus lateralis muscle during 
the EHC procedure once every treatment period. After local anaesthesia, a side-cutting 
needle of 5 mm diameter will be passed through a 7 mm skin incision, as per the 
technique by Bergström J (Bergström et al, 1967[20]). 
Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be used 3 days before 
muscle biopsies.
Biopsies will be performed for assessment of the following:


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
Ex vivo mitochondrial function in permeabilized muscle fibers (using high 
resolution respirometry)

CRAT and CS activities and acylcarnitine levels

Ribonucleic acid/protein extraction and measurements of relevant mRNA and/or 
proteins involved in metabolic regulation [such as but not limited to FGF21, 
PCG1 alpha, Mitofusin (Mtfn) 1 and 2, AMP-activated protein kinase (AMPK)/
mammalian target of rapamycin (mTOR) pathway]

For assessment of size and appearance of the mitochondria, a small fragment of 
muscle will be processed for electron microscopy (EM)provided that muscle 
biopsy size allows doing so.
6.1.9
Laboratory blood assessments during Visits 4 and 7

Fasting plasma/serum samples (+ one extra vial of serum and plasma Biobank 
samples)

Insulin, glucagon, glucose, NEFA, betahydroxybutyrate and FGF21 (7 different 
occasions during 24-hours in the metabolic chamber)

HbA1c (assessed also at Visit 1 (screening) and 5 (restart treatment))

Uric acid

Acylcarnitines and amino acids

Lactate (during 1H-MRS acetylcarnitine exercise test)

High-sensitivity Creactive protein (hsCRP-)
6.1.10 Laboratory urine assessments
Urine collection during clamp and 24-hour urine collection (in 6 hour aliquots) in the 
metabolic chamber will be followed by measurement of volume and glucose. The urine 
samples from the metabolic chamber will also be analyzed for nitrogen and creatinine. 
Samples for measurement of glucose, nitrogen, creatinine and a sample for later 
exploratory measurements will be stored frozen until analysis. Analysis of glucose in 
urine collected during the clamp in the metabolic chamber must be performed after the 
randomization code has been broken to avoid unblinding. 
6.2
Safety variables
6.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, and 
pregnancy testing will be taken in accordance with the Study Plan (Table 4) and sent to a 
local Laboratory for analysis. 
Self-Monitoring of Blood Glucose will be allowed but not reported.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. A retest performed by the Central Laboratory is preferred. However, in case 
of safety concerns and urgency, the Investigator may decide to perform the retest locally 
according to local rules. If local retesting occurs, the date, time of retesting and results 


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(values, units and reference ranges) will be recorded in the appropriate section of the 
eCRF. 
Instructions for collection, storage, and shipment of samples will be provided in the 
Laboratory Manual. 
Table 2 specifies the laboratory safety assessments to be determined.
Table 2
Laboratory safety assessments
Hematology/Hemostasis (whole 
blood)
Clinical Chemistry [serum (S) 
or plasma (P)]
B-Hemoglobin (Hb)
S-Aspartate transaminase (AST)
B-Hematocrit
S-Alanine transaminase (ALT)
S-Alkaline phosphatase (ALP)
S-Bilirubin, total
S-Creatinine
S/P-Glucose
Urine analysis (dipstick)
S/P-Potassium
Pregnancy test
For information on how AEs based on laboratory tests should be recorded and reported, 
see Section 6.3.3.6.
For information regarding labelling, storage and shipment of the laboratory samples, see 
the Laboratory Manual. 
6.2.2
Physical examinations
Physical examinations will be performed in accordance with the Study Plan (Table 4). 
A physical examination will be performed at the baseline and at the end of treatment 
visits of both treatment periods and will include an assessment of the following: general 
appearance, abdomen, cardiovascular and respiratory systems. 
Documentation (yes/no) that the examination was performed will be entered in the eCRF. 
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE  only if 
they are SAEs or lead to discontinuation of the study treatment(see Section 6.3.3.6).
6.2.3
Vital signs
The following vital signs will be assessed in accordance with the Study Plan (Table 4):

Pulse (beats per minute).

Blood pressure (systolic blood pressure and diastolic blood pressure; mmHg).
Pulse (beats/minute, during 30 seconds) will be measured before blood pressure and in a 
lying position after minimum 5 minutes (preferably 10 minutes) of rest. Thereafter, 
systolic blood pressure and diastolic blood pressure (mmHg, the cuff method on the arm 
opposite to the one used for blood sampling) will be measured using the same cuff, 
appropriate for arm circumference, and in the same position, throughout the study. 
For information on how AEs based on vital signs measurements should be recorded and 
reported, see Section 6.3.3.6.


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Abnormal vital signs values should be reported as AEs only if they are SAEs or lead to 
discontinuation of the study treatment (see Section 6.3.3.6). 
6.2.4
Other safety assessments
Diabetic ketoacidosis:
Patients treated with dapagliflozin who present with signs and symptoms consistent with 
ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of 
breath, should be assessed for ketoacidosis, even if blood glucose levels are < 14 mmol/l 
(250 mg/dl). If ketoacidosis is suspected, discontinuation or temporary interruption of 
study drug should be considered and the patient should be promptly evaluated. All 
potential events of DKA will be reported in the eCRF and sent to an independent DKA 
committee.
A separate DKA manual will define and describe the procedures for the collection of 
DKA information, handling, adjudication criteria and reporting of these events/cases.
6.3
Safety reporting
The Principal Investigator is responsible for ensuring that all staff involved in the study 
are familiar with the content of this section.
6.3.1
Definition of AEs
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical 
condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged 
liver) or the abnormal results of an investigation (e.g., laboratory findings, 
electrocardiogram). In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.3.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, wash-out, 
follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity or substantial disruption 
of the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above.


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For further guidance on the definition of an SAE, see Section 10.1.
6.3.3
Recording of AEs
6.3.3.1
Time period for collection of AEs
Discontinuation AEs (DAEs) will be collected throughout the study, from the time of 
enrolment excluding the wash-out period. SAEs will be collected from the time of 
signing the informed consent form, throughout the treatment period and including the 
follow-up period (see Table 4). 
6.3.3.2
Follow-up of unresolved AEs
Any AEs that are unresolved at follow-up are followed up by the Investigator for as long 
as medically indicated, but without further recording in the eCRF. AstraZeneca retains 
the right to request additional information for any subject with ongoing DAE(s)/SAE(s) 
at the end of the study, if judged necessary.
6.3.3.3
Variables 
The following variables will be collect for each DAE/SAE;

AE (verbatim)

The date  when the AE started and stopped

Maximum Intensity

Whether the AE is serious or not

Investigator causality rating against the study drug (yes or no)

Action taken with regard to study drug

AE caused patient’s withdrawal from study (yes or no)

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for a serious AE

Date Investigator became aware of the SAE

AE is serious due to

Date of hospitalization (if applicable)

Date of discharge (if applicable)

Probable cause of death (if applicable)

Date of death (if applicable)

Autopsy performed (if applicable)

Causality assessment in relation to Study procedure(s)

Causality assessment in relation to other medication (e.g., concomitant 
medication, background therapy)

Description of SAE.
The intensity of the reported AEs will be assessed according to the following scale:


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
Mild (awareness of sign or symptom, but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities).
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.3.2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.3.2. On the other hand, a stroke that results in only a limited degree 
of disability may be considered a mild stroke but would be a SAE when it satisfies the 
criteria shown in Section 6.3.2.
6.3.3.4
Causality collection
The Investigator will assess causal relationship between study drug and each DAE/SAE, 
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 study drug?’
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 Section 11.1.
6.3.3.5
AEs based on signs and symptoms
All DAEs/SAEs spontaneously reported by the patient or reported in response to the 
open question from the study personnel: Have you had any health problems since the 
previous visit/you were last asked?, or revealed by observation will be collected and 
recorded in the eCRF. When collecting DAEs/SAEs, the recording of diagnoses is 
preferred (when possible) to recording a list of signs and symptoms. However, if a 
diagnosis is known and there are other signs or symptoms that are not generally part of 
the diagnosis, the diagnosis and each sign or symptom will be recorded separately.
6.3.3.6
AEs based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarized 
in the clinical study report. Deterioration as compared to baseline in protocol-mandated 
laboratory values, 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 study treatment.
If deterioration in a laboratory value/vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/vital sign will be considered as additional information. Wherever possible the 
reporting Investigator uses the clinical, rather than the laboratory term (e.g., anaemia 
versus low hemoglobin value). In the absence of clinical signs or symptoms, clinically 
relevant deteriorations in non-mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE only if 
they are SAEs or lead to discontinuation of the study treatment.


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6.3.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the study 
drug, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel 
inform the appropriate AstraZeneca representatives within one day i.e., immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site 
within 1 calendar day of initial receipt for fatal and life threatening events and within 5 
calendar days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the eCRF, an 
automated email alert is sent to the designated AstraZeneca representative.
If the electronic data capture (EDC) system is not available, then the Investigator or other 
study site personnel reports a SAE to the appropriate AstraZeneca representative by 
telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed.
The reference document for definition of expectedness/listedness is in the Investigator’s 
brochure for the AstraZeneca drug.
6.3.5
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 T2DM. 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 eCRF 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/DAEs/SAEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the eCRF and on the Overdose eCRF 
module.
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours after 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.


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For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 6.3.4 For other overdoses, reporting must occur within 30 days.
6.3.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
6.3.6.1
Maternal Exposure 
Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the investigational product should be discontinued immediately 
and the pregnancy reported to AstraZeneca.
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 during 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 after 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.
6.4
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 drug that either causes harm to 
the subject or has the potential to cause harm to the subject. 
A medication error is not due to lack of efficacy of the drug, but rather a human or 
process related failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error: 

Occurred

Was identified and intercepted before the subject received the drug

Did not occur, but circumstances were recognize that could have led to an error.
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 subject

Drug not administered as indicated, for example, wrong route or wrong site of 
administration


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
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 subject received the medication 

Wrong drug administered to subject.
Examples of events that do not require reporting as medication errors in clinical studies:

Subject accidentally missed drug dose(s) e.g. forgot to take medication

Accidental overdose (will be captured as an overdose)

Subject 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.
If an 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 or 5 calendar days if there is an SAE 
associated with the medication error (see Section 6.4) and within 30 days for all other 
medication errors.
6.5
Demographic and Baseline Characteristics
Demographic and baseline characteristics are assessed at screening. These include:

Demographics (as appropriate to country regulations): sex, date of birth, race, ethnic 
group

Height (in cm) and weight (in kg)

Previous and concomitant medications at Visit 1 (see Section 5.7).
6.6
Medical and surgical history:

Confirmation of diagnosis of T2DM prior to 6 months

Other concomitant diseases within the last 3 months before Visit 1, with date of 
diagnosis.
The medical history will be obtained by interviewing the patient or by inspecting his/her 
medical records. For coding of medical history, see Section 9.4.


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6.7
Volume of blood to be collected
The total blood volume to be collected from each patient during the study will be 
approximately 624 mL, as summarized in Table 3.
Additional blood samples for safety analyses may be taken as required in the study. 
Table 3:
Total blood volume to be collected per Visit
6.8
Storage and destruction of Biological Samples
Biological samples (i.e. urine, serum and plasma) for future research will be retained at 
AstraZeneca or its designee for a maximum of 15 years following the last visit of the last 
patient in the study, after which they will be destroyed. The results of this biomarker 
research may be reported in the clinical study report itself, 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 involving the study drug to generate hypotheses 
to be tested in future research.
6.9
Withdrawal of Informed Consent for Donated Biological Samples
If a patient withdraws consent to the use of donated biological samples, the samples will 
be disposed if not already analyzed and the action documented. As collection of donated 
biological samples is an integral part of the study, these patients will be withdrawn from 
further study participation.
AstraZeneca will ensure the laboratory holding the samples is informed about the 
withdrawn consent immediately and that samples are disposed of or destroyed, the action 
documented, and the signed document returned to the clinical site.
Visit
Description
Total blood volume per 
visit (mL)
Visit 1- screening
Fasting blood
21
Visit 4
Fasting blood
36
Metabolic chamber
84
EHC
167
Cycling
6
Visit 5 – day 1 period 2
Fasting blood 
17
Visit 7
Fasting blood
36
Metabolic chamber
84
EHC
167
Cycling
6
Total blood volume (maximum)
624


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7
STUDY CONDUCT
7.1
Study plan
The study plan displaying assessments/tasks and time points is presented in Table 4. 


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Table 4: 
Study procedures
Visit
1
Screening
2
Random
ization
3
Safety
4
End of 
treatmenta
Wash Out period
5
Re-start 
treatment
6
Safety 
7
End of 
treatmenta
Safety 
Follow-
upb
5–10 days 
post last 
IP dose
Treatment period
1
–
2
Week
(-3) -0
0
2
5 
6-8 weeks
0
2
5 
6
Day 
1
15 ± 3 
days
29 ± 3
(+6-8 days 
for final 
assessments)
Safety 
Follow-upb
5–10 days 
post last IP 
dose
1
15 ± 3 
days
29 ± 3
(+6-8 days 
for final 
assessments)
5–10 days 
post last 
IP dose
Signing informed consent 
X
Inclusion/exclusion criteria
X
X
Demographic data 
X
Medical and surgical history 
X
Electrocardiogram
X
Physical examination 
X
X
X
X
Vital signs, body weight and 
other assessments c
X
X
X
X
X
X
X
HbA1c, Clinical chemistry, 
hematology, urine dip-stick 
(pregnancy test)d,g
X e
X 
X 
X 
The lifestyle card release
X
Maximal VO2 cycling test
Xi


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Visit
1
Screening
2
Random
ization
3
Safety
4
End of 
treatmenta
Wash Out period
5
Re-start 
treatment
6
Safety 
7
End of 
treatmenta
Safety 
Follow-
upb
5–10 days 
post last 
IP dose
Treatment period
1
–
2
Week
(-3) -0
0
2
5 
6-8 weeks
0
2
5 
6
Day 
1
15 ± 3 
days
29 ± 3
(+6-8 days 
for final 
assessments)
Safety 
Follow-upb
5–10 days 
post last IP 
dose
1
15 ± 3 
days
29 ± 3
(+6-8 days 
for final 
assessments)
5–10 days 
post last 
IP dose
Drug dispensation
X
X
X
X
Maximal kneeextension- test 
Xi
Body composition (DEXA)
X
X
Euglycemic 
hyperinsulinemic clamp 
(incl. urine collection)g
X
X
36-hour metabolic chamber 
(incl. 24-hour collection of 
blood samples and urine)h
X
X
1H-MRS (lipids) and 31P-
MRS (PCr recovery)
(60% maximal kneeextension-)
X
X
1H-MRS acetylcarnitine at 
70% VO2 max (and plasma 
lactate g)
X
X


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Visit
1
Screening
2
Random
ization
3
Safety
4
End of 
treatmenta
Wash Out period
5
Re-start 
treatment
6
Safety 
7
End of 
treatmenta
Safety 
Follow-
upb
5–10 days 
post last 
IP dose
Treatment period
1
–
2
Week
(-3) -0
0
2
5 
6-8 weeks
0
2
5 
6
Day 
1
15 ± 3 
days
29 ± 3
(+6-8 days 
for final 
assessments)
Safety 
Follow-upb
5–10 days 
post last IP 
dose
1
15 ± 3 
days
29 ± 3
(+6-8 days 
for final 
assessments)
5–10 days 
post last 
IP dose
Muscle biopsy
X
X
Biomarkersf
X
X
Exploratory samples for 
future analysis (serum, 
plasma and urine)g
X
X
Current and concomitant 
medication
X
X
X
X
X
X
X
Discontinuation adverse 
events
X
X
X
X
X
X
X
X
Serious adverse events
X
X
X
X
X
X
X
X
X
X
Study drug accountability
X
X
IP= Investigational Product, VO2= Volume Oxygen, 31P-MRS=31P-magnetic resonance spectroscopy, PCr= Phospho Creatinine, 1H-MRS= 1H-Magnetic 
Resonance Spectroscopy, DEXA= Dual-Energy X-ray Absorptiometry, AEs= Adverse Events
a The end of treatment visits (Visit 4 and Visit 7) will need to take place over 6–8 days. Four days (Day 1–3 and Day 6, 7 or 8) will be spent at the site and 
2-4 days after Day 3 will be spent at home or at the hotel. The last dose will be given on the last day of the end of treatment visit (Visit 4 and Visit 7). Minimum 
duration of treatment will therefore be 32 days (26 +6 days) and maximum duration of treatment will be 40 days (32 + 8 days).


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b Telephone meeting for safety follow-up should be made about 1 week (5–10 days) after each end of treatment visit. The visit can be made by a nurse and if 
needed, this visit can also take place at the site and include physical examination and laboratory assessments. 
c Blood pressure, pulse rate, weight, height (height only at screening). 
d U-pregnancy test using dip-stick should only be done at Visits 1 and 5.
e C-peptide is measured at Visit 1.
f HbA1c, uric acid, hsCRP and acylcarnitines will be measured in a lab to be determined
g To be stored at the central lab
h To be analyzed in blood:glucose, insulin, glucagon, betahydroxybutyrate, NEFA, FGF21 and to be analysed in urine: glucose, nitrogen and creatinine
i In case it is needed Maximal kneeextension- test and Maximal VO2 cycling test can be performed at the Visit 3


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7.2
Procedures by Visit
Visit 1 can take place up to three weeks before Visit 2 (i.e. randomization and start of 
treatment). All times should be recorded using the 24-hour clock (e.g., 23:20, not 
11:20 pm).
Patients are advised to continue their normal eating and drinking pattern during the entire 
study period and to maintain their normal activity and sleeping pattern throughout the 
study. Before specific test days, restrictions in physical activity apply.
7.2.1
Treatment period 1
7.2.1.1
Screening (Visit 1)
At the Screening Visit (Visit 1), potentially suitable patients for the study will provide 
informed consent and will be assessed to ensure that they meet the eligibility criteria. 
Patients who do not meet these criteria must not be entered into the study. All 
assessments for Visit 1 will be performed as listed in Table 4. 
All SAEs are collected from time of signing the informed consent and throughout the 
study, including the wash-out period and cross-over period. 
The following procedures are performed at Visit 1:

Signing of informed consent

Check of eligibility criteria

Assignment of enrolment number 

Demographic data collection

Medical and surgical history 

ECG

Physical examination 

Vital signs (blood pressure and pulse), weight and height 

Blood and urine dip-stick sampling for laboratory safety assessment 

Prior and current medication

SAEs. 
Patients will be advised to bring extra clothes and equipment needed for the maximal 
VO2 cycling test and the maximal knee-extension test to be performed at Visit 2.
7.2.1.2
Randomization (Visit 2)
Patients meeting all eligibility criteria will be randomized into the study.
The following procedures will be performed at Visit 2 (Day 1):

Check of eligibility criteria

Vital signs (blood pressure and pulse) and weight

Maximal knee-extension test

Maximal VO2 cycling test


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
Randomization into two sequences to receive either treatment with dapagliflozin 
10 mg/day or placebo for 5 weeks starting from the day after randomization

Drug dispensation

Concomitant medication

DAEs and SAEs. 
7.2.1.3
Safety (Visit 3)
The following procedures will be performed at Visit 3 (Day 15 ± 3):

Vital signs (blood pressure and pulse) and weight

Concomitant medication

DAEs and SAEs. 
Patients will be asked to perform no physical activity like exercise training or other extra 
physical activity beyond their routine daily activity and will be given diet instructions 
three days before Visit 4.
7.2.1.4
End of treatment (Visit 4)
The end of treatment visit (Visit 4) will need to take place over 6–8 days, of which four 
days (Day 1–3 and Day 6, 7 or 8) will be spent at the site and 2–4 days after Day 3 will 
be spent at home or at the hotel. 
At the site, meals will be served according to a standardized schedule. At about 8 am, 
patients will be required to consume a regular breakfast with cheese and/or ham 
sandwiches, glass of orange juice and/or a cup of coffee or tea, provided at the site. A 
similar meal will be provided during lunch at about 12 pm, after which the patients will 
be required to fast until the acetylcarnitine measurement has been finalized. 
The following procedures will be performed during Visit 4 [Day 29 ± 3 (+ 6–8 days for 
final assessments)]:
Day 1

Physical examination

Vital signs (blood pressure and pulse) and weight 

Drug dispensation

Blood and urine sampling for laboratory safety assessment 

1H-MRS (muscle fat)

31P-MRS (PCr recovery) 

Concomitant medication

DAEs and SAEs

Entering the metabolic chamber.
Day 2

36-hour stay in a whole-body room calorimetry chamber (to determine 24-hour 
energy expenditure, 24 hour RER fasting-fed state). Diurnal blood samples will 
be taken during the stay in the chamber (before and after meals and before 
bedtime, in total 7 occasions) to determine a.o. plasma levels of glucose, NEFA, 


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betahydroxybutyrate, insulin, glucagon and FGF21. A cannula may be used to 
draw these blood samples. 

Urine collection during clamp and 24-hour urine collection (in 6 hour aliquots) in 
the whole-body room calorimetry chamber for measurement of glucose, nitrogen 
and creatinine

DAEs and SAEs.
Day 3

Fasting plasma/serum samples (+ one extra vial of serum and plasma)
o
HbA1c 
o
Uric acid
o
Acylcarnitines and amino acids
o
hsCRP

Muscle biopsy from the m. vastus lateralis

Indirect calorimetry

1H-MRS (liver fat)

EHC

DAEs and SAEs.
Day 6, 7 or 8

Body composition using DEXA

1H-MRS (acetylcarnitine) including lactate

DAEs and SAEs

Drug accountability.
Refer to Figure 2 for an overview of the examinations taking place at Visit 4 and 7. 
The last treatment dose will be given on the last day of the end of treatment visit 
(Visit 4).
7.2.1.5
Wash out period
A safety followup will be performed in Week 7 (5–10 days -postlast- assessment).
A telephone follow-up should be performed, else a visit may be made by a nurse or study 
personel and if needed, this visit can also take place at the site and include physical
examination and laboratory assessments as specified in Section 6.2.1, at the discretion of 
the Investigator.
After the last day of the end of treatment visit, treatment with dapagliflozin or placebo 
will be discontinued and patients will enter a 6–8 weeks wash out period. 
7.2.2
Treatment period 2
After a 6–8 week wash-out period, the cross over will take place and patients having 
received dapagliflozin will receive the placebo and patients having received placebo will 
receive dapagliflozin over a 5 week treatment period.


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Re-start treatment (Visit 5):

Physical examination

Vital signs (blood pressure and pulse) and weight

Blood sampling for laboratory safety assessment and urine dip-stick sampling for 
pregnancy testing

Drug dispensation

Concomitant medication

DAEs and SAEs. 
The study procedures detailed for Visit 3 and Visit 4 from treatment period 1 will be 
performed again at Visit 6 (with the exception of maximal oxygen consumption test and 
maximal knee-extension testing) and Visit 7 during the treatment period 2.
Patients who discontinue early from the study should, if possible, have an early 
termination visit. This visit should take place as soon as possible after the patient stops 
taking the study drug/as soon as possible after it was learned that the patient will not be 
able to complete followup- (See also Section 4.4). If the patient is in agreement, the 
safety profile and vital signs will be assessed and physical examination will be 
performed.


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8
STATISTICAL ANALYSES
8.1
Statistical considerations

All personnel involved with the analyses of the study will remain blinded until 
database lock and identification of protocol violators.

Analyses will be performed by AstraZeneca or its representatives.
The Statistical Analysis Plan (SAP) will include further details of the analyses.
 
 
 
  
 
 
 
 
8.2.1
Definition of analysis sets
The following analysis sets will be defined for this study. Further details regarding the 
inclusion and exclusion of patients from each of these analysis sets will be described in 
the SAP.

The Enrolled Analysis Set will consist of all patients who sign the informed 
consent form.

The Randomized Analysis Set will consist of all randomized patients. This is also 
known as the intent to treat (ITT) population. In analyses of the Randomized 
Analysis Set, patients will be represented using the treatment to which they were 
randomized (even if the treatment they received is different).

The Safety Analysis Set will consist of all patients who received at least one dose 
of study drug.

The Evaluable Analysis Set will be the primary analysis set for efficacy, and is a 
subset of the Randomized Analysis Set. This is also known as the 
PerProtocol- population. Relevant protocol deviations may lead to certain data 
points to be excluded from this analysis. Important protocol deviations are defined 
as deviations which could potentially affect the interpretability of the study 
results. Patients’ data will be represented using the treatment they received. All 


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decisions to exclude data from the Evaluable Analysis Set will be made prior to 
the database lock of the study.
8.3
Outcome measures for analyses
Refer to Section 3.2.
8.4
Methods for statistical analyses
8.4.1
Primary Analysis
The analysis of efficacy will be based on the evaluable analysis set. Comparison of 
cGDR between dapagliflozin and placebo after 5 weeks of treatment will be performed 
using a mixed effect Analysis Of Variance (ANOVA) model. The model will include 
terms for treatment, sequence and period. A term representing patient nested within 
sequence will be included as a random effect. Model assumptions will be checked using 
conventional methods (residual plots and tests for the normal distribution of model 
residuals).
Least Square Mean (LSM) estimates and 95% confidence limits will be generated from 
the fitted model for each treatment. For the primary comparison, the difference in LSM 
estimate of dapagliflozin versus placebo treatment will be generated for the 
corresponding 95% confidence interval and p-value. Statistical significance will be 
inferred at a (twosided-) 0.05 level.
8.4.2
Exploratory Analyses
Analysis of exploratory variables will be performed using the evaluable analysis set. The
same random effect ANOVA model as described for the primary variable will be applied, 
where appropriate. Statistical significance will be inferred at a (two-sided) 0.05 level, and 
nominal p-values will be reported.
Benjamini and Hochberg (Devan VM and Joseph FH, 2004[21]) false discovery rate may 
be applied to interpret p-values from exploratory analyses.
8.4.3
Baseline characteristics
Demographic and other baseline characteristics will be summarized by the treatment 
sequence group and overall. For qualitative variables, frequency counts (number of 
patients [n] and percentages) will be made. For quantitative variables, descriptive 
statistics that include n, mean, standard deviation, median, minimum and maximum will 
be presented, if not otherwise specified in the SAP. The statistics will be presented for the 
Evaluable Analysis Set. No formal comparison of the baseline characteristics using 
statistical testing procedures is planned.
8.5
Safety Analyses
The analysis of safety will be based on the safety analysis set. Safety data during the 
treatment period will be evaluated and variables will only be summarized descriptively. 
DAEs and SAEs will be summarized by system organ class and preferred term and will 
be listed for each patient. The number and percent of subjects that discontinue due to 


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adverse events (DAE) and, separately, that experience at least one SAE will be 
summarized for each treatment. 
Safety laboratory, vital signs, physical examination and ECG findings will be listed by 
patient. Descriptive statistics will be presented by treatment for both absolute values and 
changes from baseline.
8.6
Interim Analyses
No interim analysis is planned for this study.


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9
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS
9.1
Data Quality Assurance
The Sponsor or Sponsor’s designee will conduct a site visit to verify the qualifications of 
each Investigator, inspect the site facilities, and inform the Investigator of responsibilities 
and the procedures for ensuring adequate and correct documentation.
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded on the eCRF for this study must be consistent with 
the patients’ source documentation (i.e., medical records).
9.1.1
Database Management and Quality Control
All data generated by the site personnel will be captured electronically at the study center 
using eCRFs. Data from external sources (such as laboratory data) will be imported into 
the database. Once the eCRF clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail. 
The reason for change, the name of the person who performed the change, together with 
the time and date will be logged to provide an audit trail. 
If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the EDC application. The appropriate staff at the study site will answer queries 
sent to the Investigator. The name of the staff member responding to the query, and time 
and date stamp will be captured to provide an audit trail. Once all source data verification 
is complete and all queries are closed, the monitor will freeze the eCRF page.
The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual. In addition, site 
personnel will receive training on the EDC system/eCRF.
9.2
Case Report Forms and Source Documentation
All data obtained during this study should be entered in the eCRFs promptly. All source 
documents from which eCRF entries are derived should be placed in the patient’s 
medical records. Measurements for which source documents are usually available include 
laboratory assessments, medical files, etc. 
Data that will be entered directly into the eCRF (i.e., for which there is no prior written or 
electronic record of data) are considered to be source data.
The original eCRF entries for each patient may be checked against source documents at 
the study site by the site monitor. 
After review by the site monitor, completed eCRF entries will be uploaded. Instances of 
missing or uninterpretable data will be discussed with the Investigator for resolution. 
The specific procedures to be used for data entry and query resolution using eCRF will be 
provided to study sites in a training manual. In addition, site personnel will receive 
training on the eCRF.


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9.2.1
Data collection
The Investigators (and appropriately authorized staff) will be given access to an online 
web-based EDC) system which is 21 CFR Part 11 compliant. This system is specifically 
designed for the collection of the clinical data in electronic format. Access and right to 
the EDC system will be carefully controlled and configured according to each 
individual’s role throughout the study. In general, only the Investigator and authorized 
staff will be able to enter data and make corrections in the eCRFs.
The eCRF should be completed for each patient included in the study and should reflect 
the latest observations on the patients participating in the study. Therefore, the eCRFs are 
to be completed as soon as possible during or immediately after the patient’s visit or 
assessment. The Investigator must verify that all data entries in the eCRF are accurate 
and correct. If some assessments cannot be done, or if certain information is unavailable, 
not applicable or unknown, the Investigator should indicate this in the eCRF. 
Computerized data-check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and 
the site will be informed about new issues to be resolved on-line. All discrepancies will 
be solved online directly by the Investigator or by authorized staff. Off-line edit checks 
will be done to examine relationships over time and across panels to facilitate quality 
data.
After completion, the Investigator will be required to electronically sign off the clinical 
data.
Data about all study drug dispensed to the patient and any dosage changes will be tracked
on the eCRF. 
9.3
Access to Source Data
During the study, a monitor will make site visits to review protocol compliance, compare 
eCRF entries and individual patient’s medical records, assess drug accountability, and 
ensure that the study is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained.
Checking of the eCRF entries for completeness and clarity, and cross-checking with 
source documents, will be required to monitor the progress of the study. Moreover, 
Regulatory Authorities of certain countries, IRBs, IECs, and/or AstraZeneca’s Clinical 
Quality Assurance Group may wish to carry out such source data checks and/or on-site 
audit inspections. Direct access to source data will be required for these inspections and 
audits; they will be carried out giving due consideration to data protection and medical 
confidentiality. The Investigator assures AstraZeneca of the necessary support at all 
times.
9.4
Data Processing
All data will be entered by site personnel into the eCRF (as detailed in Section 9.2.1).
The data-review and data-handling document, to be developed during the initiation phase 
of the study, will include specifications for consistency and plausibility checks on data 
and will also include data-handling rules for obvious data errors. Query/correction sheets 


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for unresolved queries will be sent to the study monitors for resolution with the 
Investigator. The database will be updated on the basis of signed corrections. 
Previous and concomitant medications will be coded using the latest available version of 
World Health Organisation - Drug Dictionary (WHO-DD). Medical history/current 
medical conditions and adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology.
Previous and concomitant diseases as well as AEs will be coded with latest available 
version of MedDRA.
The versions of the coding dictionaries will be provided in the CSR. 
9.5
Archiving Study Records
According to International Council for Harmonization (ICH) guidelines, essential 
documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. However, these documents 
should be retained for a longer period if required by the applicable legal requirements.
9.6
Good Clinical Practice
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the Good Clinical Practice guidelines of the ICH, 
and of the Declaration of Helsinki (2013)[1]. The study also will be carried out in keeping 
with local legal requirements and according to WMO (Wet Medisch-wetenschappelijk
Onderzoek met mensen, i.e. scientific medical research).
9.7
Informed Consent
Before each patient is admitted to the study, informed consent will be obtained from the 
patient according to the regulatory and legal requirements of the participating country. 
This consent form must be dated and retained by the Investigator as part of the study 
records. The Investigator will not undertake any investigation specifically required only 
for the clinical study until valid consent has been obtained. The terms of the consent and 
when it was obtained must also be documented in the eCRF.
If a protocol amendment is required, the informed consent form may need to be revised to 
reflect the changes to the protocol. If the consent form is revised, it must be reviewed and 
approved by the appropriate IEC/IRB, and signed by all patients subsequently enrolled in 
the study as well as those currently enrolled in the study.
9.8
Protocol Approval and Amendment
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/IRB/Competent Authorities, in accordance with local legal 
requirements. The Sponsor and the Investigator must ensure that all ethical and legal 
requirements have been met before the first patient is enrolled in the study.


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This protocol is to be followed exactly. To alter the protocol, amendments must be 
written, receive approval from the appropriate personnel, and receive 
IRB/IEC/Competent Authority approval prior to implementation (if appropriate). 
All amendments will be distributed to all protocol recipients, with appropriate 
instructions.
9.9
Duration of the Study
For each individual patient, the maximum duration for each of the 2 treatment periods 
will be 40 days, separated by a wash out period of 6–8 weeks. 
The study will close when all patients have completed the final safety follow-up.
9.10 Premature Termination of the Study
9.10.1 Stopping Rules for an Individual Patient
Withdrawal criteria for an individual patient are specified in Section 4.4.
9.10.2 Stopping Rules for the Study
If the Investigator or AstraZeneca becomes aware of conditions or events that suggest a 
possible hazard to patients if the study continues, the study may be terminated after 
appropriate consultation between the relevant parties. The study may also be terminated 
early at AstraZeneca’s discretion in the absence of such a finding.
Conditions that may warrant termination include, but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study;

Failure to enroll patients at an acceptable rate;

A decision on the part of AstraZeneca to suspend or discontinue development of 
the drug.
9.11 Confidentiality
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior 
written approval from AstraZeneca.
The anonymity of participating patients must be maintained. Patients will be identified on 
eCRF and other documents submitted to the Sponsor by their patient number and/or birth 
date, not by name. Documents not to be submitted to Sponsor that identify the patient 
(e.g., the signed informed consent) must be maintained in confidence by the Investigator. 
9.12 Other Ethical and Regulatory Issues 
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the Sponsor will issue prompt notification to all parties – Regulatory 
Authorities, Investigators, and IRB/IECs.


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A significant safety issue is one that has a significant impact on the course of the clinical 
study or program (including the potential for suspension of the development program or 
amendments to protocols) or warrants immediate update of informed consent.
9.13 Publication Policy
By signing the study protocol, the Investigator agrees with the use of results of the study 
for the purposes of national and international registration, publication and information for 
medical and pharmaceutical professionals. If necessary, Regulatory Authorities will be 
notified of the Investigator's name, address, qualifications and extent of involvement.
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with AstraZeneca in advance. Details are provided in a separate document.


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10
APPENDICES
10.1 Additional Safety Information
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS ADVERSE 
EVENT (SAE)
Life-threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (e.g., hepatitis that resolved without hepatic 
failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the 
reasons for it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or 
surgical operations planned before or during a study are not considered AEs if the illness 
or disease existed before the subject was enrolled in the study, provided that it did not 
deteriorate in an unexpected way during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgement should be exercised in deciding whether a case is 
serious in situations where important medical events may not be immediately life-
threatening or result in death, hospitalization, disability or incapacity but may jeopardise 
the subject or may require medical intervention to prevent one or more outcomes listed in 
the definition of serious. These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; 
medical judgement must be used.

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 hospitalization.

Development of drug dependency or drug abuse.
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.


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11
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World Medical Association Declaration of Helsinki. Recommendations guiding 
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WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 48th WMA General Assembly, Somerset West, Republic of South 
Africa, October 1996, the 52nd WMA General Assembly, Edinburgh, Scotland, 
October 2000, Note of Clarification on Paragraph 29 added by the WMA General 
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WMA General Assembly, Tokyo 2004, and 59th WMA General Assembly, Seoul, 
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Bolinder J, Ljunggren O, Kullberg J, et al. Effects of dapagliflozin on body weight, 
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Investigation, 2014; 124: 499–08.
18
Daniele G, Xiong J, Solis-Herrera C, et al. Dapagliflozin enhances fat oxidation 
and ketone production in patients with type 2 diabetes. Diabetes Care, 2016. DOI: 
10.2337/dc15-2688.
19
American Diabetes Association. Diabetes Care, 2016; 39 (Supplement 1): S1-S2. 
http://dx.doi.org/10.2337/dc16-S001.
20
Bergstrom J, , Hultman E et al. Diet, muscle glycogen and physical performance. 
Acta Physiol Scand, 1967; 71 (2): 140–50.
21
Devan VM and Joseph FH. Use of the false discovery rate for evaluating clinical 
safety data. Statistical Methods in Medical Research, 2004; 13: 227–38.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Title:
D1690C00047 Clinical Study Protocol Version 5
Signed by
Meaning of Signature
Anna Maria Langkilde
Content Approval
Daniel Reyner
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D1690C00047
Edition Number
2.0
Date
18th December 2019
DAPAMAAST: A Double-blind, Randomized, Phase IV, Mechanistic, 
Placebo-controlled, Cross-over, Single-center Study to Evaluate the Effects
of 5 Weeks Dapagliflozin Treatment on Insulin Sensitivity in Skeletal 
Muscle in Type 2 Diabetes Mellitus Patients






Statistical Analysis Plan
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
DAPAMAA$T: A Double-blind, Randomized, Phase IV, Mechanistic, Placebo-
controlled, Cross-over, Single-center Study to Evaluate the Effects of 5 Weeks
Dapagliflozin Treatment on Insulin Sensitivity in Skeletal Muscle in Type 2
Diabetes Mellitus Patients
IQVIA Statistician
ZODEC2a
Date
4


Statistical Analysis Plan 
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
5
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
SIGNATURE OF STUDY STATISTICIAN........................................................4
TABLE OF CONTENTS.....................................................................................5
LIST OF ABBREVIATIONS ..............................................................................7
AMENDMENT HISTORY..................................................................................9
1.
STUDY DETAILS............................................................................................. 12
1.1
Study objectives.................................................................................................12
1.1.1
Primary objective............................................................................................... 12
1.1.2
Safety objectives................................................................................................ 12
1.1.3
Exploratory objectives ....................................................................................... 12
1.2
Study design ......................................................................................................13
1.3
Number of subjects ............................................................................................ 16
2.
ANALYSIS SETS ............................................................................................. 16
2.1
Definition of analysis sets .................................................................................. 16
2.1.1
Enrolled analysis set........................................................................................... 16
2.1.2
Randomized analysis set .................................................................................... 16
2.1.3
Evaluable analysis sets....................................................................................... 16
2.1.4
Safety analysis set.............................................................................................. 17
2.2
Violations and deviations ................................................................................... 17
2.2.1
Protocol deviation monitoring............................................................................17
2.2.2
Protocol deviation reporting............................................................................... 17
3.
PRIMARY AND EXPLORATORY VARIABLES............................................18
3.1
General Definitions............................................................................................ 18
3.1.1
Definition of baseline......................................................................................... 18
3.1.2
Absolute change from baseline...........................................................................18
3.1.3
Study day...........................................................................................................19
3.1.4
Definition of end of treatment ............................................................................19
3.2
Calculation or derivation of efficacy variables.................................................... 19
3.2.1
Primary efficacy endpoint .................................................................................. 19
3.2.2
Exploratory efficacy endpoints...........................................................................19


Statistical Analysis Plan 
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
6
3.3
Calculation or derivation of safety variable(s) .................................................... 20
3.3.1
Adverse events...................................................................................................21
3.3.1.1
Diabetic ketoacidosis events............................................................................... 21
3.3.2
Clinical laboratory safety assessments................................................................ 22
3.3.2.1
Strip Sign for Selected Laboratory Data ............................................................. 22
3.3.3
ECGs ................................................................................................................. 23
3.3.4
Physical examination ......................................................................................... 23
3.3.5
Vital signs..........................................................................................................23
3.3.6
Medical and Surgical History............................................................................. 23
3.3.6.1
Diabetes History ................................................................................................ 23
3.3.6.2
Specific Medical and/or Surgical History........................................................... 23
4.
ANALYSIS METHODS.................................................................................... 24
4.1
General principles.............................................................................................. 24
4.1.1
Statistical notations and presentation..................................................................24
4.1.2
Statistical analyses ............................................................................................. 24
4.2
Analysis methods............................................................................................... 25
4.2.1
Subject disposition, demography data and subject characteristics ....................... 25
4.2.1.1
Subject disposition............................................................................................. 25
4.2.1.2
Demographic and baseline characteristics .......................................................... 25
4.2.2
Prior and Concomitant Medications ...................................................................26
4.2.3
Treatment Compliance ....................................................................................... 27
4.2.4
Efficacy analyses ............................................................................................... 27
4.2.4.1
Analysis of the primary efficacy variable ........................................................... 27
4.2.4.2
Analysis of exploratory variables .......................................................................29
4.2.5
Safety and tolerability analyses ..........................................................................30
4.2.5.1
Adverse events...................................................................................................30
4.2.5.2
Laboratory data..................................................................................................31
4.2.5.3
ECG................................................................................................................... 31
4.2.5.4
Vital Signs .........................................................................................................31
5.
INTERIM ANALYSES ..................................................................................... 32
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 32
7.
REFERENCES ..................................................................................................32
8.
APPENDIX .......................................................................................................33


Statistical Analysis Plan 
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AC
Acetylcarnitine 
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANOVA
Analysis Of Variance
AST
Aspartate Aminotransferase
AUC
Area under the curve
BH
Benjamini-Hochberg
BMI
Body Mass Index
cGDR
corrected Glucose Disposal Rate
CRA
Clinical Research Associate
CRAT
Carnitine Acetyltransferase
CS
Citrate Synthase
DAE
Discontinuation of Investigational Product due to Adverse Event
DEXA
Dual-Energy X-ray Absorptiometry
DKA
Diabetic Ketoacidosis
DPPIV
Dipeptidyl peptidase IV
EAS
Evaluable Analysis Set
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EGP
Endogenous Glucose Production
EHC
Euglycemic Hyperinsulinemic Clamp
EOT
End of treatment
FA
Fatty acid
FDR
False discovery rate
FGF21
Fibroblast Growth Factor 21
GDR or RD
Glucose Disposal Rate or Rate of Disposal
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HL
Hy’s Law


Statistical Analysis Plan 
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Edition Number 2.0
Date 18th December 2019
8
Abbreviation or 
special term
Explanation
hsCRP
High-sensitivity C-Reactive Protein
IHLC
Intrahepatic lipid content
IMCL
Intramyocellular lipids
IP
Investigational Product
IPD
Important protocol deviation
ITT
Intent-to-Treat
LSM
Least Square Mean
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MRS
Magnetic Resonance Spectroscopy
NEFA
Non-esterified fatty acids
NOGD
Non-oxidative glucose disposal
PCr
Phosphocreatine recovery 
PD
Protocol deviation
PHL
Potential Hy’s Law
RER
Respiratory Exchange Ratio
RQ
Respiratory Quotient 
SAE
Serious Adverse Event
SD
Standard Deviation
SE
Standard Error
T2DM
Type 2 Diabetes Mellitus
VO2max
Maximal Oxygen consumption
WHO
World Health Organisation


Statistical Analysis Plan 
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
9
AMENDMENT HISTORY
Date
Brief description of change
N/A
20th February 2019
Section 1.2 – Text added for clarity on defining drop-outs.
Section 3.3.1 - Adverse event windowing updated to remove 5-10 days follow-
up window due to site collection dates being longer than protocol outlined.
Section 4.2.2 - Prior medication definition updated from stop date to start date. 
Section 4.2.3 – Compliance reporting clarified to specify missing calculations in 
treatment period and overall if a return bottle is missing.
Section 4.2.4.1 – Detail added on residuals being assessed for normality during 
model checking. Clarification on response variable of change between 
Dapagliflozin and Placebo being modelled for the linear regression model.
Section 4.2.5.1 – Imputation rules for missing intensity, causality and 
seriousness updated in line with the Dapa Mech program.
Appendix B updated with amendment to efficacy endpoints collected.
21st October 2019
Section 2.1.3 – Evaluable analysis set updated to clarify subject exclusions for 
procedure specific PDs will lead to exclusion of the subject from both periods 
for an endpoint if at least one period is missing data. Use of planned treatment 
instead of treatment received for outputs.
Section 3.1.3 – Definition for study day calculation separated to distinguish 
between on or after first dose of IP and prior to first dose of IP.
Section 3.2.1 – Text added to clarify discrepancy in terminology used in the 
protocol for the primary efficacy endpoint and data to be received from the site. 
Section 3.3.1 – Removed off-treatment definition from AEs and reference to 
combined period.
Section 3.3.6.1 and 4.2.1.2 – Reference to addition of baseline metformin dose 
categorization in outputs and categories to be summarized.
Section 4.2.1.1, 4.2.1.2, 4.2.2 and 4.2.3 – Update to analysis populations used 
for outputs and reference to those used in shells already, stated in the relevant 
sections.
Section 4.2.1.2 – Clarity added for medical and surgical history tables to include
specific medical history in them as well. 
Section 4.2.4.1 – Model assumption checks reduced due to update in efficacy 
approach removing treatment-, period- and sequence- heterogeneous analyses 
from sensitivity.
Section 4.2.4.2 – Additional text for vital signs outputs to model change from 
baseline separately for day’s 15 and 30. Multiplicity sort order clarified for p-
values feeding into Benjamini-Hochberg analysis.
Section 4.2.5.1 – Reference to adverse events clarified to state only serious 
adverse events (SAEs), AEs causing discontinuation of IP (DAEs) and potential 
DKA events will be presented for in outputs.
Appendix B updated with amendment to efficacy endpoints collected.


Statistical Analysis Plan 
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
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Date
Brief description of change
20th November
2019
Section 1 – Protocol version updated from 4 to 5.
Section 1.2 – Text amended to reference end of treatment visits only in
determining drop outs needing replacement.
Section 2.1.3 – EAS MRS Lactate subset added to list. Details about a separate
populations report mentioned. Change from planned treatment to treatment
received.
Section 3.2.2 – Exploratory endpoint list updated and derivation for urine
chamber parameters daytime and night-time calculations added over 24 hours.
Section 3.3.1.1 – Guidance document for DKA reporting referenced.
Section 4.2.1.2 – Updated to outline demographic and baseline characteristic
outputs to be summarized by Randomized analysis set as well as EAS.
Section 4.2.2 – Prior medications changed from start date less than or equal to
first day of IP to just less than first day of IP.
Section 4.2.3 – Clarification added to state extent of exposure is calculated for
each treatment period using the same formula.
Section 4.2.4.1 – Within-subject difference for linear regression model updated.
Section 4.2.4.2 – Information on lactate parameter analysis added, outlining
model to be performed as well as summary statistics and boxplot to be
presented. Area under the curve for calculating the trapezoidal method on
chamber blood parameters incorporated, including how to handle missing
samples.
Section 4.2.5.1 – Reference to AE counts being presented, removed.
Clarification around DKA events to be listed.
Section 6 – Text on AUC as a change from protocol outlined.
Appendix B – Additional endpoints added for lactate, glucose urine loss (24h),
protein oxidation (24h) and creatinine daytime (12h), night-time (12h) and
(24h).
3rd December 2019
Section 2.1.3 – Text added outlining update in process by the site determining
invalid results not to be used for analysis.
Section 2.2.1 – Process of programmed deviations used for monitoring in the
study clarified.
Section 3.1.2 – Derivation for within-subject difference added.
Section 3.1.4 – Wording update to explain clearly EOT derivation for each
subject.
Section 3.2.1 and 4.2.4.1 – Primary endpoint updated to align with Appendix B.
Section 3.3 – Clarified pulse will not be assessed as efficacy as per CSP.
Double blind changed to double-blind throughout for consistency.


Statistical Analysis Plan 
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
11
Date
Brief description of change
11th December
2019
Section 3.2.2 - Change in daytime and night-time calculations for laboratory
urine assessments.
Section 4.2.1.2 – Baseline characteristic VO2 max/lean body mass updated to be
divided by total body mass.
Appendix B – reference to 12h for laboratory urine assessments removed.
Reference to SMR day 1 and day 2 removed. Addition of first acetylcarnitine
(AC)/after exercise.


Statistical Analysis Plan 
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
12
1.
STUDY DETAILS
This is the statistical analysis plan (SAP) for study D1690C00047. The SAP describes the 
statistical analyses specified in Version 5 of the clinical study protocol (CSP) in more detail; 
any changes with regards to what is already specified in the CSP will be described in Section
6.
1.1
Study objectives
1.1.1
Primary objective
To investigate if dapagliflozin improves skeletal muscle insulin sensitivity expressed as
corrected glucose disposal rate (cGDR) in comparison with placebo after 5-week double-blind 
treatment. Insulin sensitivity will be determined using a 2-step euglycemic hyperinsulinemic 
clamp (EHC) procedure.
1.1.2
Safety objectives
To evaluate the safety and tolerability of dapagliflozin by assessment of discontinuation of 
Investigational Product (IP) due to adverse event (DAE)/serious adverse events (SAE),
including laboratory values and clinically significant findings after 5-week double-blind
treatment.
1.1.3
Exploratory objectives
1. To investigate if dapagliflozin changes Endogenous Glucose Production (EGP) in
comparison with placebo after 5-weeks of double-blind treatment.
2. To investigate if dapagliflozin improves metabolic flexibility as compared to placebo,
determined by the change in respiratory exchange ratio (RER) from fasted state to 
insulin stimulated state during EHC after 5-week double-blind treatment.
3. To investigate if dapagliflozin changes RER and energy expenditure as well as plasma
metabolites such as beta-hydroxybutyrate and glucose as compared to placebo, before 
and after meals in the metabolic chamber after 5-week double-blind treatment.
4. To investigate if dapagliflozin improves maximal capacity to form acetylcarnitine
following exercise, and *Carnitine Acetyl Transferase (CRAT) and citrate synthase 
activities in muscle biopsy, as compared to placebo after 5-week double-blind 
treatment.
5. To investigate if dapagliflozin improves in vivo mitochondrial function as measured 
by phosphocreatine recovery following exercise, as compared to placebo after 5-week
double-blind treatment.


Statistical Analysis Plan 
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6. To investigate if dapagliflozin improves ex vivo mitochondrial function
in
permeabilized muscle fibers using high resolution respirometry, as compared to
placebo after 5-week double-blind treatment.
7. To investigate if dapagliflozin changes body composition, skeletal muscle and liver fat
content, as compared to placebo after 5-week double-blind treatment.
8. To investigate if dapagliflozin changes blood biomarkers such as glucagon, insulin and 
FGF21 in comparison with placebo after 5-weeks of double-blind treatment.
9. *To investigate if dapagliflozin changes expression of mRNA and/or proteins involved 
in metabolic regulation in muscle tissue in comparison with placebo after 5-weeks of
double-blind treatment.
10. To investigate if dapagliflozin changes body weight, body mass index (BMI) and 
systolic and diastolic blood pressure in comparison with placebo after 5-weeks of 
double-blind treatment.
A full list of exploratory endpoints associated with the objectives can be found in Appendix B.
*Note: These exploratory end-points are not planned to be reported in the CSR since these 
analyses are exploratory and will be done by an external partner and/or will be done after all 
other analyses are performed. Further descriptions of analyses associated with these endpoints 
are not covered in this SAP.
1.2
Study design
This is a double-blind, randomized, mechanistic, placebo-controlled, cross-over study, to 
evaluate the effect of 5-weeks dapagliflozin treatment in Type 2 Diabetes Mellitus (T2DM) in 
subjects either on a stable dose of metformin and/or a dipeptidyl peptidase IV (DPPIV)
inhibitor for at least the last 3 months or are drug naïve.
A total of 26 subjects are planned to be randomized to have at least 22 completers in two 
equal sized treatment sequences. In case of more than 4 drop-outs, not attending both end of
treatment visits (visit 4 and visit 7), another 4 subjects will be randomized and if this occurs, a 
total of 30 subjects will be randomized.
Subjects will participate in two treatment periods. In period 1 subjects will receive either
dapagliflozin 10 mg or matching placebo for a maximum of 40 days based on randomization
sequence. For period 2, subjects that received 10 mg dapagliflozin in the first treatment period 
will receive matching placebo in the second treatment period and subjects who received 
placebo in the first treatment will receive 10 mg dapagliflozin in the second treatment period,
for a maximum of 40 days.
All potentially eligible subjects will be asked to provide informed consent and thereafter be 
screened to assess eligibility criteria at Screening (Visit 1). Subjects who meet eligibility 


Statistical Analysis Plan 
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
14
criteria will be randomized to one of two treatment sequences. The first 5-week treatment 
period will involve the first dose of dapagliflozin/placebo administered via tablet at Week 0
(this is considered to be Day 1, for the purpose of analysis). Subjects will continue 
dapagliflozin or placebo until end of study period, Day 29±3 (+ 6–8 days for final 
assessments). After the last day of the end of treatment (EOT) visit, treatment with 
dapagliflozin or placebo will be discontinued and subjects will enter a 6–8 weeks wash-out 
period. A safety follow- up will be performed about 1 week (5-10 days) after the EOT visit.
After completion of the 6–8-week wash-out period, the cross over will take place and subjects 
having received dapagliflozin will receive the placebo and subjects having received placebo 
will receive dapagliflozin over a 5-week treatment period. A safety follow-up will again be 
performed 5–10 days post-last dose. A graphical view of the study is shown in Figure 1. For a 
detailed overview of study design and the performed assessments, see CSP Table 4.


15
Figure 1
Study flow chart


16
 
 
 
 
 
 
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Enrolled analysis set
This analysis set consists of all subjects who sign the informed consent form and will be used 
for the reporting of disposition and screening failures.
2.1.2
Randomized analysis set
The Randomized analysis set will consist of all randomized subjects. This is also known as the 
intent to treat (ITT) population. In analyses using the Randomized analysis set, subjects will 
be represented using the treatment to which they were randomized (even if the treatment they 
received is different). This analysis set will be used for reporting important protocol 
deviations (IPD), analysis sets and disallowed medications.
2.1.3
Evaluable analysis sets
The Evaluable analysis set (EAS) will be the primary analysis set for efficacy and is a subset 
of the Randomized analysis set, consisting of subjects who received at least 1 dose of IP. This
analysis set will exclude subjects with IPDs that may greatly impact the completeness, 
accuracy, and/or reliability of the study data or that may significantly affect a subject’s rights, 
safety, or well-being. This is also known as the Per-Protocol (PP) population. 
To evaluate the primary and exploratory endpoints, relevant protocol deviations (PDs) that are
procedure specific will also be assessed. These PDs may lead to subjects being excluded from 
particular analyses (but not from all of them). Examples of such PDs are insufficient quality of 
a sample, or a subject failing to fulfil a procedure-specific requirement such as fasting for 6 
hours. To evaluate each endpoint effectively the following subsets of the Evaluable analysis 
set are to be utilised:

EAS Clamp 

EAS Chamber

EAS Biomarkers

EAS Indirect Calorimetry

EAS MRS Acetylcarnitine

EAS MRS Liver Lipid (IHLC)


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
EAS MRS Muscle Lipid (IMCL)

EAS MRS Mitochondrial (PCr recovery rate)

EAS MRS Lactate

EAS DEXA (body composition)

EAS Muscle Biopsy (high resolution respirometry using muscle fibers)
All values for the efficacy endpoints will be evaluated for validity prior to judgement on PDs,
where invalid results are noted and will not be used in analysis. Subjects for whom both the 
data from the first and second period is judged to be unreliable due to PDs will be excluded 
from the data set corresponding to the measurement in question. Subjects for whom the data 
from only one endpoint is judged to be unreliable for a procedure will be included in the 
population total for the EAS subset, but the subject will be excluded from the analyses for the
endpoint. All decisions to exclude data from the Evaluable analysis sets will be made prior to 
the database lock of the study and treatment unblinding and will be documented in a separate
populations report.
Subjects’ data will be represented using the actual treatment received.
2.1.4
Safety analysis set
The Safety analysis set will consist of all subjects who received at least one dose of study 
drug, with subjects being analyzed and presented by treatment received, rather than as 
randomized.
2.2
Violations and deviations
2.2.1
Protocol deviation monitoring
During study conduct, protocol deviations will be closely monitored and identified from two 
sources:

Manually entered protocol deviations identified by Clinical Research Associate 
(CRA) during the study conduct.

Statistically programmed protocol deviations. These are deviation checks will be
generated by execution of programs written using the predefined deviator 
descriptions in the SAP and protocol. Any potential PDs will be fed back to the
study team to be manually entered into IMPACT prior to unblinding.
2.2.2
Protocol deviation reporting
The description of different types of PDs, as well as the classification of the PDs will be 
provided in a separate protocol deviation document outside of the SAP. Briefly, the PDs 
include, but are not limited to:

Subjects who do not meet the inclusion criteria


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
Subjects who meet any of the exclusion criteria

Subjects who use one or more prohibited medication

Subjects who received the incorrect investigational treatment or dose at any time

Protocol-required procedures not adhered to

Incorrectly unblinded to treatment during study participation

General study conduct
All reported PDs will be reviewed, and IPDs will be identified and documented by the AZ 
study physician and statisticians prior to unblinding of the data. Protocol deviations that the 
study team considers to be important will be tabulated or listed.
The summaries of IPDs will be done by treatment sequence and overall. Separate listings of 
all subjects with important protocol deviations will also be produced. All data removed due to 
protocol deviations will also be listed.
3.
PRIMARY AND EXPLORATORY VARIABLES
3.1
General Definitions
3.1.1
Definition of baseline 
For safety and efficacy endpoints, where applicable, the last measurement prior to first dose of 
study treatment at Visits 2 and 5 will serve as the baseline measurements for the two treatment 
periods, omitting unscheduled visits.
3.1.2
Absolute change from baseline
Absolute change from baseline outcome variables is computed separately for each treatment
period as 
(post-treatment value – baseline value). 
If either the post-treatment value or the baseline value is missing, then the absolute change 
from baseline value will also be set to missing.
A similar derivation will be used for the within-subject difference, regardless of treatment
sequence, calculated as
(dapagliflozin – placebo)


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3.1.3
Study day
Study day will be defined relative to the first dose of IP in the given treatment period and will 
be calculated as
If on or after the first dose of IP in Periods 1 or 2: (date of assessment/event – date of first 
dose of IP in the given treatment period) + 1.
If before the first dose of IP in Period 1: (date of assessment/event – date of first dose of IP in 
the given treatment period).  
Day 1 will be reset for each treatment period, with washout and follow-up periods being 
calculated relative to the previous treatment period. Treatment period will be indicated where 
study day is presented.
3.1.4
Definition of end of treatment
End of treatment (EOT) assessments are defined as assessments captured at Visits 4 or 7. For 
overall EOT assessments for a subject this will be the last of Visits 4 and 7 assessments
regardless of treatment sequence. Where either visit is missing for an efficacy endpoint, the
EOT value for a subject will not be imputed. For evaluation of changes in safety endpoints, if 
the scheduled EOT within a study period for a subject is not performed, not evaluable or is
missing, but an unscheduled assessment is available, then the last unscheduled assessment in
the period will be used.
3.2
Calculation or derivation of efficacy variables
3.2.1
Primary efficacy endpoint
The primary endpoint is the skeletal muscle insulin sensitivity measured as cGDR, which will 
now be referred to as delta RD (basal vs high insulin), using a 2-step EHC procedure after 5 
weeks of treatment. For the primary analysis, the response variable is the delta RD (basal vs
high insulin) measured at the end of treatment period 1 and 2, captured at Visits 4 and 7 
respectively. Delta RD (basal vs high insulin) will be calculated and provided by the site.
3.2.2
Exploratory efficacy endpoints
Comparison of dapagliflozin versus placebo after 5 weeks treatment will be given for the
following:
1. Change of Endogenous Glucose Production (EGP) during EHC.
2. Metabolic flexibility, as determined by the RER using indirect calorimetry from fasted 
state to insulin (high insulin) stimulated state during EHC.
3. RER 
and
energy 
expenditure 
as 
well 
as 
plasma 
metabolites 
such 
as
betahydroxybutyrate and glucose before and after meals, as measured in metabolic 
chambers.


Statistical Analysis Plan 
Study Code D1690C00047
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4. Maximal capacity to form acetylcarnitine following exercise as measured using 1H-
MRS, and *CRAT and CS activities from muscle biopsy.
5. In vivo mitochondrial function as measured post-exercise by phosphocreatine recovery 
using 31P-MRS.
6. Ex vivo mitochondrial function in permeabilized muscle fibers using high resolution 
respirometry (muscle biopsy).
7. Body composition as measured by DEXA, and skeletal muscle and liver fat content as 
measured by 1H-MRS.
8. Change of blood biomarkers such as glucagon, insulin and FGF21.
9. *Change of expression of mRNA and/or proteins involved in metabolic regulation in 
muscle tissue.
10. Change from baseline in body weight, BMI and systolic and diastolic blood pressure.
*Note: These exploratory end-points are not planned to be reported in the CSR since these 
analyses will be done by an external partner and/or will be done after all other analyses are 
performed. Further descriptions of analyses associated with these endpoints are not covered in 
this SAP.
A comprehensive list of efficacy endpoints with analysis sets is given in Appendix B.
All calculated exploratory endpoints will be provided by the site.
BMI will be calculated from the height (in meters) and weight (in kilograms) as follows: 
BMI = kg/m2
The 24-hour laboratory urine assessment parameters, glucose, creatinine and nitrogen (used to
calculate protein oxidation), from the metabolic chamber are collected over 6-hour periods but
will be summarised as daytime and night-time. The following samples will be grouped:
Daytime = 0-6 hours + 6-12 hours + 12-18 hours
Night-time = 18-24 hours
3.3
Calculation or derivation of safety variable(s)
Safety outcome variables are:

Incidence of SAEs and DAEs.


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
Incidence of independently adjudicated diabetic ketoacidosis (DKA) events, if any.

Change from baseline in vital signs (pulse, diastolic blood pressure, systolic blood 
pressure, weight, and BMI). Note: These will also be regarded as efficacy variables,
except for pulse.

Change from baseline in hematology parameters (Hemoglobin and Hematocrit). Note: 
These will also be regarded as efficacy variables.

Change from baseline in clinical chemistry parameters namely AST, ALT, ALP, Total 
Bilirubin, Creatinine, Glucose (fasting and non-fasting), and Potassium. Note: Fasting 
glucose is also regarded as an efficacy variable.
Safety data will also be collected during the study for:

Physical examination, where any new or aggravated clinically relevant abnormal 
medical finding will be reported as an AE only if that are SAEs, DAEs or a suspected 
DKA event occurred.

Pregnancy urine testing.
3.3.1
Adverse events
SAEs and DAEs experienced by the subjects will be collected throughout the entire study and 
will be coded by the AstraZeneca designee using the agreed upon version of the Medical 
Dictionary for Regulatory Activities (MedDRA).
AE data will be categorized according to their onset date into the following periods:

AEs occurring pre-treatment: (onset date ≥ Visit 1 and before the first day of
administration of IP) 

AEs occurring during treatment: (onset date ≥ the first day of administration of IP in
treatment period 1) or (onset date ≥ the first day of administration of IP in treatment 
period 2)
If an AE start date is fully missing, the start date will be imputed as the date of first dose of 
study medication in treatment period 1. Guidance for partial start dates for AEs is given in 
Appendix A. Imputed dates will not appear on the listings. Fully missing and partial AE stop 
dates will not be imputed. AEs ongoing at the end of the study will be highlighted in listings.
AEs occurring in the pre-treatment period will be listed, but not summarized.
3.3.1.1
Diabetic ketoacidosis events
A DKA Adjudication Committee, blinded to the treatment of the subjects, will independently 
adjudicate all the suspected DKA events reported by the investigators, as well as those 
identified based on pre-defined algorithm during the study period.  A separate Adjudication 
Manual, “Guidance for reporting Diabetic Ketoacidosis (DKA) for AstraZeneca Dapagliflozin 


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Program”, will define and describe the procedure for the handling, reporting, and
classification of these cases.
3.3.2
Clinical laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology and pregnancy 
testing will be taken in accordance with the CSP and sent to laboratory for analysis. 
Additional safety samples may be collected if clinically indicated at the discretion of the
Investigator. The parameters outlined in Table 2 in Section 6.2.1 of the CSP will be assessed.
Changes in hematology and clinical chemistry variables between baseline and EOT
assessment will be calculated. No conversion from the reported units will take place.
Absolute values will be compared to the relevant reference range and classified as low (below 
range), normal (within range or on limits) or high (above range). The reference ranges will be 
collected in the electronic case report form (eCRF). All values falling outside the reference 
ranges will be flagged.
For the following liver function tests, the multiple of the upper limit of normal (ULN) range 
will be calculated for each data point: aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin (TBL), and alkaline phosphatase (ALP).
Multiple = value / ULN
e.g., if the ALT value is 72 IU/L and the ULN 36 IU/L, then the multiple is 2.
Hy’s Law
A potential Hy’s Law (PHL) case is defined as any subject with elevations in AST or ALT ≥3 
x ULN together with total bilirubin ≥2 x ULN at any point during the study following the start 
of study treatment, irrespective of an increase in ALP.
A Hy’s Law (HL) case is defined as any subject with elevations in AST or ALT ≥3 x upper 
limit of normal (ULN) together with total bilirubin ≥2 x ULN, where no other reason can be 
found to explain the combination of increases.
For PHL and HL, the elevation in AST or ALT must precede or occur on the same day as the 
elevation in total bilirubin, but there is no specified timeframe in which the elevations must 
occur. Hy’s Law cases will be identified programmatically and through medical monitoring.
3.3.2.1
Strip Sign for Selected Laboratory Data
For selected laboratory test values that have been received with an operator sign as a part of 
the result (>, , <, or ), a process to strip the operator sign will be applied and the resulting 
numeric values will be used for summary data. The raw value with operator will remain as 
entered in the database and presented as collected in listings. 


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3.3.3
ECGs
Electrocardiogram (ECG) measurements will be recorded at the Screening visit.
The outcome of the overall evaluation is to be recorded as normal/abnormal in the eCRF, with 
any abnormalities being recorded as not clinically significant or clinically significant.
3.3.4
Physical examination
Physical examinations will be performed in accordance with Table 4 in the CSP and will 
include an assessment of the following: general appearance, abdomen, cardiovascular and 
respiratory systems.
Any new finding(s), or aggravated existing finding(s), judged as clinically significant by the 
Investigator, will be reported as an AE only if they are SAEs, DAEs or suspected DKA 
events.
3.3.5
Vital signs
Vital signs (pulse, systolic blood pressure, diastolic blood pressure, height, and weight) will be 
obtained in accordance with the schedule provided in Table 4 in the CSP.
Changes in vital signs variables between baseline and scheduled or EOT assessments within 
the corresponding period will be calculated. Abnormal vital signs values will be reported as 
AEs only if they are SAEs, DAEs or suspected DKA events.
3.3.6
Medical and Surgical History
Medical history/current medical conditions, as well as surgical history, will be coded using the 
agreed upon version of MedDRA.
3.3.6.1
Diabetes History
Medical history related to diabetes will be collected at Screening (Visit 1). Information on 
duration of diabetes, type of diabetes, any complications associated with diabetes, type of 
complication (Retinopathy, Nephropathy, Neuropathy autonomic or peripheral, Angiopathy
and other), and baseline metformin dose category (≤500 mg, >500 - ≤1000 mg, >1000 - ≤2000
mg, >2000 mg), will be tabulated.
3.3.6.2
Specific Medical and/or Surgical History
In addition, specific medical and/or surgical histories that have occurred prior to Visit 1, will 
have information collected on date of diagnosis, date of first treatment and most recent 
episode/procedure.


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4.
ANALYSIS METHODS
4.1
General principles
All statistical evaluation, as well as summaries and tabulations, will be done by qualified 
personnel at IQVIA. Before breaking the treatment codes following clean file declaration 
(database lock), all decisions on the evaluability of the data for each individual subject will be 
made and documented, and each subject will be assigned to the appropriate analysis data sets.
Statistical Analysis Software (SAS) version 9.4 or higher will be used to generate all statistical 
analyses, data summaries and listings.
4.1.1
Statistical notations and presentation
Summary data will be presented in tabular format by treatment group, as well as sequence 
and/or period where applicable. Categorical data will be summarized by the number and 
percentage of subjects in each category. Unless otherwise stated, percentages will be 
calculated out of the population total for the treatment group or sequence. Continuous data 
will be summarized by descriptive statistics including n (number of subjects with available 
data), mean, SD, median, minimum and maximum, as well as first and third quartile where 
warranted. All screening and safety data will be listed, where applicable. For efficacy 
endpoints, data only pertaining to the primary variable will be listed. Data listings will be 
sorted by subject number and treatment sequence. 
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, SD and 
confidence intervals (CIs) will be reported to one further degree of precision. Percentages will 
be rounded to 1 decimal place.
All hypothesis testing will be performed using 2-sided tests at the 5% significance level. 
P-values will be rounded to 4 decimal places.
No analysis visit windows will be derived. All by-visit data will be presented by protocol 
scheduled nominal visits, apart from EOT visits where unscheduled assessments could be used 
as per Section 3.1.4. Listings will include unscheduled visits.
4.1.2
Statistical analyses
The main focus for the statistical analyses is to compare the effect of dapagliflozin as 
compared to placebo after 5 weeks of treatment with regards to primary and exploratory
endpoints. All variables will be analyzed using a linear mixed effects model. For the primary 
endpoint, model assumptions will be checked using conventional methods discussed in 
Section 4.2.4.1.


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4.2
Analysis methods
4.2.1
Subject disposition, demography data and subject characteristics
4.2.1.1
Subject disposition
The subject disposition, including counts and percentages of subjects who completed each of 
the treatment sequences specifying the number of subjects enrolled, re-screened, randomized, 
who received/did not receive treatment, who completed study, and who terminated 
prematurely, including reasons for termination, will be summarized for the Enrolled
population.
Subject listings of disposition will be generated for all screened subjects.
4.2.1.2
Demographic and baseline characteristics
Demographic data such as age, gender, race and ethnicity will be summarized overall and by 
treatment sequence for the EAS and Randomized analysis set.
Various baseline characteristics will also be summarized by treatment sequence for the
Randomized and EAS populations. These include diabetes disease history including
categorization of metformin dose at baseline, weight, height, BMI, diabetes duration and VO2
max/total body mass.
Specific medical and surgical histories as well as current medical conditions will be 
summarized by MedDRA Preferred Term (PT) within the System Organ Class (SOC) level of
MedDRA for the Safety analysis set.
Subject’s age (years) will be presented as collected on the eCRF at Screening.
Duration of diabetes (years) will be calculated using the screening visit date and the date of 
diabetes diagnosis (see below).


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If date of diabetes diagnosis is…
Then duration of diabetes (years) is…
Complete date
(Date of screening
–
Date of diabetes 
diagnosis + 1) / 365.25
Partial date
(a) Year and month are not missing, but day 
is missing
(b) Year is not missing, but month and date 
are both missing
(b1) Year of diabetes diagnosis is 
different from the year of screening
(b2) Year of diabetes diagnosis is the 
same as year of screening
(a) (Number of months between date of 
diabetes diagnosis and date of screening + 1) / 
12
(b1) Difference between year of diabetes 
diagnosis and year of screening
(b2) 2/12 = 0.17 (2 months)
Subject listings of demographic and baseline characteristics, other baseline characteristics of 
interest, diabetes history, specific medical and surgical history, medical history, and surgical 
history will be generated for all randomized subjects.
4.2.2
Prior and Concomitant Medications
The number and percentage of subjects receiving each medication (by ATC classification 
system codes at the 4th level and generic name) will be presented for each treatment group for 
the populations specified below. Medications will be classified as follows:

Prior: Medications with a start date < the first day of IP in treatment period 1.

Concomitant (during treatment): 

Treatment period 1: Medications that are still ongoing on the first day of IP 
and also medications with start date ≥ the first day of IP at Visit 2 and < the 
first day of IP at Visit 5.

Treatment period 2: Medications that are still ongoing on the first day of IP
at Visit 5 and also medications with start date ≥ the first day of IP at Visit 5 
and ≤ the last day of safety follow-up
If a medication has a missing start date then, unless the stop date of the medication indicates 
otherwise, this medication will be considered as both prior and concomitant to both treatment 
period 1 and 2.  Similarly, if a medication has a partial start date, then unless the partial start 
date or the stop date indicate otherwise, this medication will be considered as both prior and 
concomitant.


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Separate tables will be presented for all medications received during the concomitant period 
for allowed and disallowed medications. Disallowed medications will include medications 
defined as prohibited according to Section 5.7.2 of the CSP. They will be defined following a 
physician review (prior to database lock) of the unique combinations of ATC code
classifications and generic terms captured. Disallowed and allowed medications will be 
presented based on the Safety analysis set. Percentages will be calculated relative to the 
number of subjects in the analysis set.
Medications will be classified according to the World Health Organization (WHO) Drug 
Dictionary.
All medications will also be listed by subject for the Randomized analysis set.
4.2.3
Treatment Compliance
Treatment compliance will be assessed by the tablet count, and the information will be 
recorded in the appropriate section of the eCRF. 
Compliance is defined as:
Compliance (%) = (Total number of tablets taken/total number of tablets that should have 
been taken) x 100
The total number of tablets taken will be calculated as the total number of tablets dispensed 
minus total number of tablets returned, based on the subject drug accountability data collected 
in the eCRF. The total number of tablets that should have been taken is the extent of exposure, 
as defined below. Percent compliance will be categorized cumulatively by >90% and >120%
and summarized by treatment group for the Safety analysis set and Evaluable analysis set. 
Note, where a dispensed bottle is not returned, percent compliance for the subject is not 
calculated for the associated treatment period.
Extent of exposure will be defined as the number of days between the start and the end dates 
of study therapy plus 1 day for each treatment period:
Extent of exposure (days) = (Last dosing date - First dosing date) + 1.
Overall exposure will be calculated as the sum of the extent of exposure days corresponding to 
the two treatments, regardless of missing dispensed bottles. Compliance and extent of 
exposure will be presented for each treatment period, treatment total and overall. Treatment 
compliance and extent of exposure will also be listed by subject for the Safety analysis set.
4.2.4
Efficacy analyses
4.2.4.1
Analysis of the primary efficacy variable
The primary efficacy variable is delta RD (basal vs high insulin) and the aim of the primary 
analysis is to compare the delta RD (basal vs high insulin) after 5 weeks of treatment with


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dapagliflozin with delta RD (basal vs high insulin) after 5 weeks of treatment with placebo.
The analysis of the primary endpoint will be performed using the EAS Clamp population.
Summary statistics will be presented by treatment sequence and treatment period, as well as 
overall for each treatment group. A boxplot of values in each sequence/ period combination 
will be presented.
Primary model
The expected difference between treatment groups will be estimated using a linear mixed 
effects model. This model will have treatment group, treatment sequence and period as fixed 
effects, as well as random intercept for each subject. This model will assume independent 
conditional residuals with equal variations in each period and treatment group. In the CSP this 
model is referred to as “mixed Analysis of Variance (ANOVA)”, and the induced covariance 
structure between the two observations belonging to the same subject is equivalent to the 
covariance structure in the repeated measurements model defined by Equation 2 in Mueller-
Cohrs, PhUSE 2006, commonly referred to as a compound symmetry covariance structure.
The model stated above will be implemented using Equation 7 in Mueller-Cohrs, PhUSE 
2006.
The model will be implemented using SAS® MIXED procedure. The Residual/Restricted 
Maximum Likelihood (REML) approach will be applied to estimate the model parameters. 
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom. Missing data will not be imputed.
Model assumption checks
Model assumptions will be checked using conventional methods, i.e. a visual examination of 
standardised residuals generated from the model with both fixed and random effects (OUTP; 
box plots and QQ-plots of residuals) to check for outliers. An outlier will be defined as an 
observation with a standardized residual that is more than three times the interquartile range 
above the 75th percentile or below the 25th percentile. If outliers are present, then additional 
sensitivity analyses will be performed with the outliers excluded, in order to assess their 
impact on the results. 
Presentation of results
The least-squares (LS) means for treatment effect in the respective treatment groups, the 
corresponding standard errors (SE), and the 95% CIs, will be presented. The difference in LS 
means between the two treatments will also be generated, with corresponding SEs, 95% CI 
and p-value tabulated. All LS mean estimates will be obtained from the global mixed effects 
model, and not from stratification by treatment. 
Sensitivity analyses
Sensitivity analyses will be performed using a linear regression model with the within-subject
difference, defined in Section 3.1.2, for each study endpoint as response and sequence will be 
included as a term in the linear model.  In addition, a non-parametric test of treatment 


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difference against zero will be performed (Wilcoxon signed-rank test) using all the data and 
ignoring the sequence membership.
Presentation of results
For the sensitivity analysis utilizing a linear regression model, the estimate of the intercept 
from the model to get the LS means for the treatment difference, together with the 
corresponding SE, 95% CI and p-value, will be presented. For the sensitivity analysis utilizing 
a non-parametric test, the corresponding p-values will be presented. Sensitivity analyses will 
be presented with primary analysis results for the primary and exploratory endpoints.
Subgroup analyses
There are no planned sub-group analyses.
Baseline imbalance
Due to the small sample size, imbalances in baseline characteristics between the two 
sequences are possible. However, it is expected that the cross-over nature of the design, in 
combination with the additional covariates included in the main model (sequence and period) 
will account for the possible influence of such an imbalance. Thus, no sensitivity analyses 
connected to baseline characteristics imbalance will be performed.  
4.2.4.2
Analysis of exploratory variables
The exploratory endpoints will be analyzed based on the subsets of the EAS as specified in 
Appendix B. The analysis approach, and the presentation of the results, will be the same as 
for the primary endpoint, excluding vital signs and lactate. Vital signs parameters will model 
change from baseline at Visit 3 and 6 (day 15) and Visit 4 and 7 (EOT - day 30) separately.
The lactate parameter will model change from time at Visit 4 and 7 for 0 minutes to 15
minutes and 30 minutes separately. The analysis will allow for subjects to be included in the 
model for one timepoint if the other timepoint has missing data. Checks of outliers and 
sensitivity analyses will be performed for all exploratory endpoints. Summary statistics and
boxplots for vital signs parameters will be produced for absolute values and change from
baseline over timepoints as well as by sequence/ period combination. The lactate parameter
will output summary statistics for absolute and change from time 0, at particular visits similar
to vital signs. Boxplots will not be produced for lactate or chamber blood parameters.
Area under the curve
The chamber blood parameters are scheduled to occur at Visit 4 and Visit 7. Blood samples
are drawn before/after breakfast, before/after lunch, before/after dinner and before bedtime.
Area under the curve (AUC) will be calculated using the trapezoidal method using the actual
sample times collected. The AUC will be defined as the area between the x-axis, where the
before breakfast measurement will be equal to time 0, up to the sample collection time for the
before bedtime measurement. The AUC will be calculated using the following formula:


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Where C(i) and C(i+1) are the sample collections at time i and i+1, T(i) and T(i+1) are time at a
given visit. Subject’s with missing data for blood samples at Visit 4 or 7 will be excluded
from the AUC calculations.
Multiplicity
Due to the number of endpoints, the false discovery rate (FDR), i.e. the expected proportion of 
hypotheses for which no treatment effect actually exists despite the p-value in the 
corresponding test being smaller than alpha, might be rather large. In order to illustrate the 
issue and aid the interpretation of the results, Benjamini-Hochberg (BH) adjusted p-values 
(DV Mehrotra and JF Heyse 2004) will be presented alongside the unadjusted p-values (sorted 
from high to low) for all exploratory endpoints in a separate table, the latter obtained from 
mixed effect models as described earlier. The BH-adjustment of p-values controls the FDR in 
the sense that, if FDR is set to 0.1, then rejecting the hypotheses with BH-adjusted p-values
less that 0.1 will lead to a proportion of false rejections that is, on average, less or equal to 
10%. For illustrative purposes, the BH-adjusted p-values that are less than 0.1 will be 
indicated in the tabulation. Note: The alpha of 0.05 for analyses carried out on the primary and 
exploratory endpoints are separate to the FDR procedure. 
4.2.5
Safety and tolerability analyses
All safety and tolerability variables (including AEs, laboratory parameters and vital signs) will 
be summarized descriptively by treatment group for the Safety analysis set.
4.2.5.1
Adverse events
AEs (i.e., SAEs, DAEs and potential DKA events) will be summarized for the on-treatment
period defined in Section 3.3.1.
An overall summary table will be produced showing the number and percentage of subjects
with at least 1 AE in any of the following categories: AEs, AE with outcome of death, SAEs
including event with outcome of death, DKA events verified by adjudication committee, DKA 
events leading to discontinuation of IP, DAEs and AEs leading to withdrawal from study. 
AEs, SAEs, DAEs and AEs with outcome of death will be summarized by SOC and PT 
assigned to the event category using MedDRA. For each PT, the number and percentage of 
subjects reporting at least one occurrence will be presented i.e., a subject with multiple 
occurrences of an AE will only be counted once.
SAEs and DAEs (by PT) will be summarized by maximum intensity. If a subject reports 
multiple occurrence of the same AE, the maximum intensity will be taken as the highest 
recorded maximum intensity for each PT (the order being mild, moderate, and severe). Any 
AEs with unknown intensity, causality or seriousness will be regarded as unknown for 
tabulations.
Independent evaluation of potential DKA events will also be listed.


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A listing of AEs including SAEs, with indicators of death due to AE, discontinuations due to 
AEs, and DKA events will be presented. A separate listing of SAEs with an onset prior to 
randomization will also be provided.
4.2.5.2
Laboratory data
All continuous laboratory parameters will be summarized by absolute value at each visit, 
stratifying by treatment sequence, treatment group and overall treatment group, as per the 
units collected, together with the corresponding changes from baseline. The summary 
statistics presented will be the minimum, first quartile, median, third quartile, maximum, mean 
and SD. 
Local laboratory reference ranges will be used for the identification of individual clinically 
important abnormalities and included in subject listings for each laboratory parameter to allow 
the identification of low, normal, high, and missing values. 
Hy’s Law
To identify potential Hy’s Law cases, a listing of subjects who have ALT or AST ≥3 x ULN 
and total bilirubin ≥ 2 x ULN at any time during the study (i.e., not necessarily at the same 
time) will be provided.  This listing will include all visits for this subset of subjects.
4.2.5.3
ECG
The Investigator’s assessment of the abnormal ECG evaluations collected at Screening visit
with description of abnormality will be included in subject listings of ECG, along with 
detailing whether any abnormalities were clinically significant or not.
4.2.5.4
Vital Signs
All vital signs parameters will be summarized by absolute value at each visit, stratifying by 
treatment sequence, treatment group and overall treatment group, together with the 
corresponding changes from baseline. The summary statistics presented will be the minimum,
1st quartile, median, 3rd quartile, maximum, mean and SD.
All recorded vital signs data will be listed.


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5.
INTERIM ANALYSES
No interim analysis is planned for this study.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
The AUC analysis described in Section 4.2.4.2 was not originally planned as per the
exploratory analyses Section 8.4.2 of the CSP but was determined to be useful based on the
collection of blood parameters over 7 timepoints throughout the day.
7.
REFERENCES
DV Mehrotra and JF Heyse 2004
Devan V Mehrotra and Joseph F Heyse. Use of the false discovery rate for evaluating clinical 
safety data. Statistical Methods in Medical Research 2004;13:227-238.
Jochen Mueller-Cohrs, PhUSE 2006
Jochen Mueller-Cohrs. Analysis of incomplete two-period crossover trials with SAS PROC 
MIXED. PhUSE 2006; Paper ST07.
Timmers et al, Cell Metabolism 2011
Timmer et al. Calorie Restriction-like Effects of 30 Days of Resveratrol Supplementation of 
Energy Metabolism and Metabolic Profile in Obese Humans. Cell Metabolism 14, 612-622, 
November 2, 2011; Elsevier Inc.
Phielix et al, Diabetes 2008
Lower Intrinsic ADP-Stimulated Mitochondrial Respiration Underlies In Vivo Mitochondrial 
Dysfunction in Muscle of Male Type 2 Diabetic Patients. Diabetes, Vol. 57; 2943-2949, 
November 2008.
Lindeboom et al, J Clin Invest. 2014
Long-echo time MR spectroscopy for skeletal muscle acetylcarnitine detection. The Journal of 
Clinical Investigation, Vol. 124(11):4915–4925, November 2014.
Schrauwen-Hinderling et al, Diabetologia 2007
Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients 
with type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia (2007) 50:113–
120.


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8.
APPENDIX
Appendix A
Partial date conventions for AEs
Missing type
Action
If only the day part of the AE onset date is
missing and occurs in the same month and 
year as
1. the first dose of study medication 
within a treatment period,
2. the screening period.
1. The date of first dose of study 
medication in that period will be used 
as the onset date of the AE. 
Otherwise,
2. The start date of the screening period 
will be used as the onset date of the 
AE.
Else, 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 within a 
treatment period.
The date of the first dose of study
medication of the earliest treatment period 
within the year of AE onset will be used as 
the onset date of the AE. 
If the AE onset date is completely missing.
The date of the first dose of study
medication in treatment period 1 will be used 
as the onset date of the AE.


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Appendix B
Efficacy endpoints
Procedure: Two step hyperinsulinemic euglycemic clamp with glucose tracer
Group
Endpoint
Analysis set
Peripheral insulin 
sensitivity
-RD basal
-RD low insulin
-RD high insulin
-delta RD (basal vs high insulin) [primary endpoint 
referred to as cGDR in the CSP]
EAS Clamp
Peripheral insulin 
sensitivity 
corrected for 
insulin levels
-delta RD (basal vs high)/steady-state insulin
Hepatic insulin 
sensitivity
-EGP basal
-EGP low insulin
-EGP high insulin
-delta EGP (basal vs low insulin)
-delta EGP (basal vs high insulin)
Urinary 
parameters
-Glucose excretion rate
Non-oxidative 
glucose disposal
-NOGD basal
-NOGD low insulin
-NOGD high insulin
-delta NOGD (basal vs high insulin)


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Procedure: Indirect calorimetry
Group
Endpoint
Analysis set
Respiratory 
exchange ratio
-RER basal
-RER low insulin
-RER high insulin
-delta RER (basal vs high insulin)
EAS Indirect 
Calorimetry
Insulin-stimulated 
glucose oxidation
-Glucose (CHO) oxidation basal
-Glucose (CHO) oxidation low insulin
-Glucose (CHO) oxidation high insulin
-delta glucose (CHO) oxidation (basal vs high 
insulin)
Insulin-
suppressed fat 
oxidation
-Fatty acid (FA) oxidation basal
-Fatty acid (FA) oxidation low insulin
-Fatty acid (FA) oxidation high insulin
-delta Fatty acid (FA) oxidation (basal vs high 
insulin)
Procedure: High resolution respirometry
Group
Endpoint
Analysis set
Ex vivo 
mitochondrial 
function
- state 3 of complex I
- state 3 of complex I + II
- state 3 of β-oxidation and complex I
- state 3 of β-oxidation and complex I+ II
- state 4o
- state u of β-oxidation
EAS Muscle 
Biopsy (high 
resolution 
respirometry 
using muscle 
fibers)


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Procedure: MR Spectroscopy
Group
Endpoint
Analysis set
PCr recovery 
measurement
-Half time of PCr recovery
EAS MRS 
Mitochondrial
(PCr recovery 
rate)
Muscle fat
- IMCL
EAS Muscle 
Lipid (IMCL)
Acetylcarnitine
-Average acetylcarnitine (AC)/creatine at rest
-Maximal acetylcarnitine (AC)/creatine after exercise
-Average acetylcarnitine (AC)/creatine after exercise
-First acetylcarnitine (AC)/creatine after exercise
EAS MRS 
Acetylcarnitine
Liver fat
-IHLC
EAS MRS 
Liver Lipid
(IHLC)
Lactate
Lactate at 0, 15 and 30 minutes
EAS MRS
Lactate
Procedure: Body composition (DEXA)
Group
Endpoint
Analysis set
-Fat mass
-Lean mass
-Total mass
-Fat mass percentage
-Trunk fat mass
-Trunk lean mass
EAS DEXA
(body 
composition)


Statistical Analysis Plan 
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
37
Procedure: Whole body respirometry (Respiration Chamber)
Group
Endpoint
Analysis set
Substrate 
utilization
-24h energy expenditure
-Sleeping metabolic rate (SMR) 
-Diet induced thermogenesis (DIT)
-24h RQ
-RQ daytime
-RQ night-time
-Glucose urine loss daytime 
-Glucose urine loss night-time 
-Glucose urine loss (24h)
-Protein oxidation daytime 
-Protein oxidation night-time 
-Protein oxidation (24h)
-Urine Creatinine daytime
-Urine Creatinine night-time
-Urine Creatinine (24h)
EAS Chamber
Blood parameters
-Glucose
-Beta-hydroxybutyrate
-NEFA
-Insulin
-Glucagon
-FGF21
Procedure: Fasting and other blood biomarkers
Group
Endpoint
Analysis set
Fasting 
biomarkers
-hsCRP
-Uric acid
EAS 
Biomarkers
Other
-HbA1c
-Hb
-Erythrocytes Volume Fraction


Statistical Analysis Plan 
Study Code D1690C00047
Edition Number 2.0
Date 18th December 2019
38
Procedure: Vital signs
Group
Endpoint
Analysis set
Vital signs
-Body weight
-BMI
-Systolic blood pressure
-Diastolic blood pressure
EAS 
To be listed or summarised only:
Procedure: VO2 Maximal test
Group
Endpoint
Analysis set
VO2 Maximal test
-VO2 Max/lean body mass
EAS
Procedure: Two step hyperinsulinemic euglycemic clamp with glucose tracer
Group
Endpoint
Analysis set
Blood parameters 
measured during 
clamp
-Insulin low
-Insulin high
EAS Clamp
Procedure: Blood parameters
Group
Endpoint
Analysis set
Fasting 
biomarkers
-C-peptide
EAS