Conditions: Diabetes Mellitus, Type 2 Kidney Function Tests
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate how dapagliflozin mechanism of action is impacted by Type 2 Diabetes Mellitus status and kidney function

Detailed description:

Arms:
arm 1: T2DM subjects with an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 at the Screening Visit. arm 2: T2DM subjects with an eGFR (CKD-EPI) between \>90 and ≤130 mL/min/1.73m2 for patients aged 59 or younger, between \>85 and ≤130 mL/min/1.73m2 for patients aged 60 to 69, and between \>75 and ≤130 mL/min/1.73m2 for patients aged 70 or older at the Screening Visit. arm 3: Non-diabetic subjects with an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 at the Screening Visit.

Interventions: intervention 1: Dapagliflozin
Intervention descriptions: intervention 1: The study consists of a 2-week, open label, dapagliflozin (10mg) treatment period.

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
DAPASALT: An Open Label, Phase IV, Mechanistic, Three-Arm Study to 
Evaluate the Natriuretic Effect of 2-Week Dapagliflozin treatment in Type 2 
Diabetes Mellitus Patients with Either Preserved or Impaired Renal Function 
and Non-Diabetics with Impaired Renal Function 
 
 
ClinicalTrials.gov Identifier: NCT03152084 
 
 
 
Date of Protocol: 10 January 2020 


AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
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DAPASALT: An Open Label, Phase IV, Mechanistic, Three-Arm Study to Evaluate 
the Natriuretic Effect of 2-Week Dapagliflozin treatment in Type 2 Diabetes 
Mellitus Patients with Either Preserved or Impaired Renal Function and 
Non-Diabetics with Impaired Renal Function 
 
Sponsor: 
AstraZeneca AB 
SE-151 85 Södertälje 
Sweden 
Clinical Research Organisation: 
PAREXEL International (IRL) Limited, 
70 Sir John Rogerson’s Quay, Dublin 2, 
Ireland  
Sponsor Protocol No.: 
D1690C00049 
EudraCT No.: 
2016-002961-79 
Study Drug Name: 
Dapagliflozin 
Development Phase: 
IV 
Date of Protocol: 
10 Jan 2020, Version 6.0 
Date of Previous Protocol: 
23 Apr 2018, Version 5.0 
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki [1], 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 
 


AstraZeneca AB 
Study code: Dl690C00049 
Investigational product: Dapagliflozin 
SIGNATURE PAGE 
Declaration of Sponsor or Responsible Medical Officer 
Clinical Study Protocol 
CONFIDENTIAL 
Title: DAPASALT: An Open Label, Phase IV, Mechanistic, Three-Arm Study to 
Evaluate the Natriuretic Effect of 2-Week Dapagliflozin treatment in Type 2 Diabetes 
Mellitus Patients with Either Preserved or Impaired Renal Function and Non-Diabetics 
with Impaired Renal Function. 
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, 2013 [1], and the guidelines on Good Clinical 
Practice. 
 
Date 
AstraZeneca R&D Gothenburg, Sweden 
Final6.0 
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10 Jan 2020 
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Declaration of the Investigator 
 
Title: DAPASALT: An Open Label, Phase IV, Mechanistic, Three-Arm Study to 
Evaluate the Natriuretic Effect of 2-Week Dapagliflozin treatment in Type 2 Diabetes 
Mellitus Patients with Either Preserved or Impaired Renal Function and Non-Diabetics 
with Impaired Renal Function. 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, electronic data capture (EDC) system, and other 
scientific data. 
The study will not be commenced without the prior written approval of a properly 
constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). 
No changes will be made to the study protocol without the prior written approval of the 
Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to 
the patients. 
I have read and understood and agree to abide by all the conditions and instructions 
contained in this protocol. 
 
Responsible Investigator of the local study centre 
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
_____________________________________ 
Name (block letters) 
 
_____________________________________ 
Title (block letters) 
 
_____________________________________ 
Institution (block letters) 
 
_____________________________________ 
Phone number 


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PROTOCOL SYNOPSIS 
Title 
DAPASALT: An Open Label, Phase IV, Mechanistic, Three-Arm 
Study to Evaluate the Natriuretic Effect of 2-Week Dapagliflozin 
treatment in Type 2 Diabetes Mellitus Patients with Either Preserved 
or Impaired Renal Function and Non-Diabetics with Impaired Renal 
Function. 
Sponsor Study No. 
D1690C00049 
Phase 
IV 
Sponsor 
AstraZeneca AB 
SE-151 85 Södertälje 
Sweden 
Study Centre(s) 
It is planned to enroll patients at up to 5 centres in Europe.  
Objective(s) 
Primary: 
To investigate change in 24-hr sodium excretion during dapagliflozin 
treatment between Baseline (average of Days −3 to −1) and average 
of Days 2 to 4 within each study group in patients with 
type 2 diabetes mellitus (T2DM) with preserved or impaired renal 
function and in non-diabetics with impaired renal function. 
Secondary: 
The secondary objectives to be evaluated within each study group 
during or following dapagliflozin treatment are: 
• 
To evaluate the change in 24-hr sodium excretion during 
dapagliflozin treatment from Baseline to end of treatment, and 
during follow-up.  
• 
To evaluate the change in 24-hr glucose excretion. 
• 
To evaluate the change in mean 24-hr systolic blood pressure. 
• 
To evaluate the change in plasma volume. 
• 
To evaluate the change in extracellular volume. 
• 
To evaluate pharmacokinetics of dapagliflozin. 
• 
To evaluate the change in 24-hr urine albumin: creatinine ratio 
(UACR) 
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Safety: 
• To evaluate the safety and tolerability of dapagliflozin in each of 
the target patient populations. 
Design 
This is an open label, mechanistic, three-arm study to evaluate the 
natriuretic effect of 2 weeks dapagliflozin treatment in T2DM 
patients with either preserved or impaired renal function and in 
non-diabetic patients with impaired renal function. The study 
population will comprise 3 groups of patients as described in study 
population below. The maximum duration of the study will be 
62 days including the allowed window periods for the study (±1 day 
for Visit 7 at Day 13). The study will allow for an up to 6-week 
Screening and Run-in Period. The Run-in Period should always last 
6 days (Day -6 to Day -1) for patients not on insulin (Group 2 and 3); 
however, for patients on insulin (Group 1) the Run-in Period may be 
longer (Day –20 to Day −1). Patients on insulin may require a longer 
Run-in Period in order to be able to adjust their insulin requirements 
according to the caloric content of the food boxes, if needed. 
However, it is not mandatory for the patient on insulin to use the 
entire extended Run-in Period. Based on the Investigator’s 
judgement, the Run-in Period may be shortened once each patient (on 
insulin) has had sufficient time to adapt to the food boxes, and it is 
determined that the patient’s insulin requirement has stabilised 
sufficiently to continue in the study. The study will then include a 
2-week Treatment Period (Day 1 to Day 14) and a 5-day Follow-up 
Period: Day 15 to Day 19. Patients will consume food from 
standardised food boxes (with sodium content 150 mmol) starting on 
Day −6 (patients not on insulin) or Day −20 at the earliest (patients 
on insulin) of the study until Day 18 (inclusive). Eligibility will be 
confirmed on Day −1 based on 24-hr urinary assessments performed 
on Days −3 and −2 (stable urinary sodium excretion on 2 successive 
24-hr urinary sodium excretion measurements ie, <20% difference 
between Days −3 and −2). Eligible patients will receive 
dapagliflozin 10 mg tablets once daily for 14±1 days starting on Day 
1. This will be followed by a Follow-up Period of 5 days.  
Treatment 
Patients will receive dapagliflozin 10 mg tablets once daily for 
14±1 days. 
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Number of Patients 
We plan to enroll a total of 51 patients in the study, with 17 patients 
in each group.  
Population 
The study population will consist of Caucasian, Asian or Middle 
Eastern patients, but Sub-Saharan patients are not eligible. Patients 
are to be aged between 18 years and ≤80 years, able to provide a 
written informed consent, and who have one of the following:  
Group 1: T2DM with an estimated glomerular filtration rate (eGFR) 
Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) 
between ≥25 and ≤50 mL/min/1.73m2 at the Screening Visit or  
Group 2: T2DM with an eGFR (CKD-EPI) between >90 and 
≤130 mL/min/1.73m2 for patients aged 59 or younger, between >85 
and ≤130 mL/min/1.73m2 for patients aged 60 to 69, and between 
>75 and ≤130 mL/min/1.73m2 for patients aged 70 or older at the 
Screening Visit or  
Group 3: Non-diabetic with an eGFR (CKD-EPI) between ≥25 and 
≤50 mL/min/1.73m2 at the Screening Visit. 
The main inclusion criteria are: 
1. In the diabetic arms - a diagnosis of T2DM with 
glycosylated haemoglobin (HbA1c) ≥6.5% (≥48 mmol/mol) 
and <10% (<86 mmol/mol); and eGFR (CKD-EPI) between 
≥25 and ≤50 mL/min/1.73m2 or between >90 and 
≤130 mL/min/1.73m2 for patients aged 59 or younger, 
between >85 and ≤130 mL/min/1.73m2 for patients aged 60 
to 69, and between >75 and ≤130 mL/min/1.73m2 for 
patients aged 70 or older at the Screening Visit (Visit 1). 
2. In the non-diabetic arm, HbA1c <6.5% (<48 mmol/mol) and 
an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 
at the Screening Visit (Visit 1). 
3. Patient-specific optimal antihypertensive dose (as per 
Investigator’s judgement) of an angiotensin receptor blocker 
(ARB) or Angiotensin Converting Enzyme Inhibitor (ACEi) 
for at least 6 weeks prior to Visit 4 (Day 1). All patients 
have to use an ARB or ACEi.  
4. In the diabetic arm (Group 2) an appropriate stable dose of 
metformin or sulphonylurea, or metformin+sulphonylurea as 
anti-diabetic therapy for the last 12 weeks prior to Visit 4 
(Day 1).  
5. In the diabetic arm with impaired renal function (Group 1) a 
stable insulin dosing (intermediate, long‐acting, premixed 
insulin, basal bolus insulin) for the last 12 weeks prior to 
Visit 4 (Day 1) as judged by the Investigator. Metformin or 
sulphonylurea, or metformin+sulphonylurea together with 
insulin would be accepted, but is not mandatory. If used, 
stable dose of metformin or sulphonylurea, or 
metformin+sulphonylurea as anti-diabetic therapy for the 
last 12 weeks prior to Visit 4 (Day 1) is required. 
6. Stable urinary sodium excretion on 2 successive 24-hr 
urinary sodium excretion measurements (<20% difference 
between Days −3 and −2). 
Criteria for Evaluation of 
Efficacy 
Primary: 
• 
Average change in 24-hr sodium excretion from average 
Baseline to average values at Day 2 to 4 within each study 
group. 
Secondary: 


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The secondary endpoints to be evaluated during or following 
dapagliflozin treatment within each study group are: 
• 
Average change in 24-hr sodium excretion from average 
Baseline values to average end of treatment values (Day 12 to 
14); and from average end of treatment values (Day 12 to 14) to 
average values during follow-up (Day 15 to 17). 
• 
Average change in 24-hr glucose excretion from average 
Baseline values to average values at Day 2 to 4; from average 
Baseline values to average end of treatment values (Day 12 to 
14); and from average end of treatment values (Day 12 to 14) to 
average values during follow-up (Day 15 to 17).  
• 
Change in mean 24-hr systolic blood pressure from Baseline to 
Day 4; from Baseline to end of treatment (Day 13); and from end 
of treatment (Day 13) to end of follow-up (Day 18). 
• 
Change in plasma volume from Baseline to Day 4; from Baseline 
to end of treatment (Day 14); and from end of treatment (Day 
14) to end of follow-up (Day 18). 
• 
Change in extracellular volume from Baseline to Day 4; from 
Baseline to end of treatment (Day 14); and from end of treatment 
(Day 14) to end of follow-up (Day 18). 
• 
Dapagliflozin pharmacokinetics on Day 4 and Day 14. 
• 
Average change in mean 24-hr UACR from average Baseline to 
Day 4; from average Baseline values to average end of treatment 
values (Day 12 to 14)
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Criteria for Evaluation of 
Safety 
• 
Adverse events (AEs) starting from first dose throughout the 
study. 
• 
Serious adverse events (SAEs) starting from Visit 1 throughout 
the study. 
• 
Laboratory variables. 
• 
Vital signs. 
• 
Physical examination.  
Statistical Methods 
The following analysis sets will be defined: 
Enrolled Set (ENS): All patients who provided informed consent 
will be included in the ENS. 
Run-in Set: All patients who are provided with the standard food 
boxes.  
Medication Dispensed Set (MDS): All patients who dispensed at 
least one dose of study drug. 
Evaluable Subjects Data Set: This will be a subset of the MDS. It 
will exclude primary efficacy variable data which may have been 
affected by protocol deviations as determined by the medical monitor 
or agreed by the study team. All decisions to exclude data from the 
Run-in Set to form the Evaluable Subjects Analysis Data Set will be 
made prior to the database lock of the study. 
Safety Set (SAF): All patients who received at least 1 dose of study 
drug and who have data from at least one post-dose safety assessment 
available. 
Efficacy: 
The primary efficacy endpoint is the average change in 24-hr sodium 
excretion from average Baseline to average values at Days 2 to 4 
within each study group.  
The primary analysis will be performed separately for each study 
group using a longitudinal repeated-measures analysis for the 
“change from average Baseline” as dependent variable, with a term 
for Baseline value. Point estimates and 95% confidence intervals will 
be calculated for the adjusted mean changes within each study group.  
Safety: 
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All AEs will be summarised by system organ class and preferred 
term. All AEs will be listed for each patient. 
Safety laboratory, vital signs, and physical examination findings will 
be listed by patient and time point including changes from Baseline. 
Descriptive statistics will be presented by patient status for both 
absolute values and changes from Baseline. 
Partial Analysis: 
As recruitment rate for Group 1 is slower than expected, a partial 
analysis based on all patients from Group 2 and Group 3, but none 
from Group 1, might be conducted. If such an analysis takes place, a 
formal Data Review Meeting (DRM) will be held prior to its 
initiation. At the DRM, all protocol deviations related to the patients 
in these two groups will be discussed and the impact on the analysis 
sets to be used for the partial analysis will be assessed. The partial 
analysis will include all the evaluations originally planned to be 
conducted, and reported, for all three groups simultaneously. 
Study Plan 
Refer to Section 7.1. 
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LIST OF STUDY PERSONNEL 
 
Sponsor 
AstraZeneca AB 
SE-151 85 Södertälje 
Sweden  
Sponsor Protocol 
Signatories 
Sponsor’s Medical Expert 
Scientific Coordinator 
Contract Research 
Organisation 
PAREXEL International (IRL) Limited, 70 Sir John 
Rogerson’s Quay, Dublin 2, Ireland 
Adverse Event Reporting 
AstraZeneca 
PAREXEL Medical Services 
Refer to the Safety Handling Plan for details. 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .......................................................................................... 4 
LIST OF STUDY PERSONNEL ............................................................................ 11 
TABLE OF CONTENTS ........................................................................................ 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...................... 16 
1 
INTRODUCTION........................................................................................ 18 
1.1 
Background .............................................................................................. 18 
1.2 
Rationale for the Study and Justification of Study Design ................. 19 
1.2.1 
Study Rationale ............................................................................ 19 
1.2.2 
Study Design ................................................................................ 20 
1.2.3 
Safety Monitoring ........................................................................ 21 
1.3 
Risk-Benefit Assessment ......................................................................... 22 
2 
STUDY OBJECTIVES ................................................................................ 25 
2.1 
Primary Objective ................................................................................... 25 
2.2 
Secondary Objectives .............................................................................. 25 
 
 
2.4 
Safety Objectives ..................................................................................... 26 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ............................... 27 
3.1 
Overview .................................................................................................. 27 
3.2 
Criteria for Evaluation of the Study ...................................................... 30 
3.2.1 
Primary Endpoint ......................................................................... 30 
3.2.2 
Secondary Endpoints ................................................................... 30 
 
 
3.2.4 
Safety Endpoints .......................................................................... 32 
4 
STUDY POPULATION .............................................................................. 33 
4.1 
Inclusion Criteria .................................................................................... 33 
4.1.1 
Inclusion Criteria at Screening Visit (Visit 1) ............................. 33 
4.1.2 
Inclusion Criteria at End of Run-in Period (Visit 3) .................... 34 
4.2 
Exclusion Criteria ................................................................................... 34 
4.2.1 
Exclusion Criteria at Screening Visit (Visit 1) ............................ 34 
4.3 
Rescreening .............................................................................................. 36 
4.4 
Study Restrictions ................................................................................... 37 
4.5 
Patient Withdrawal and Discontinuation ............................................. 38 
4.6 
Planned Sample Size and Number of Study Centres ........................... 39 
4.7 
Patient Identification and Randomisation ............................................ 39 
4.7.1 
Patient Identification .................................................................... 39 
4.7.2 
Randomisation Scheme ................................................................ 39 
4.7.3 
Allocation of Patients to Treatment ............................................. 39 
5 
STUDY DRUG ............................................................................................. 40 
5.1 
Identity ..................................................................................................... 40 
C
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5.1.1 
Investigational Products ............................................................... 40 
5.2 
Administration ......................................................................................... 40 
5.3 
Packaging, Labelling, and Storage ........................................................ 40 
5.4 
Blinding and Breaking the Blind ........................................................... 41 
5.5 
Drug Accountability ................................................................................ 41 
5.6 
Compliance .............................................................................................. 41 
5.7 
Previous and Concomitant Medications ............................................... 41 
5.7.1 
Allowed Concomitant Medications ............................................. 42 
5.7.2 
Prohibited Concomitant Medications .......................................... 42 
5.7.3 
Non-investigational Product ........................................................ 42 
6 
VARIABLES AND METHODS OF ASSESSMENT ............................... 43 
6.1 
Efficacy Variables ................................................................................... 43 
6.1.1 
24-hr Urine Measurement ............................................................ 43 
6.1.2 
24-hr BP Monitoring .................................................................... 43 
6.1.3 
Plasma Volume Measurements .................................................... 43 
6.1.4 
Bioimpedance Spectroscopy Measurements (Extracellular 
Volume, 
 
)................................................................. 44 
6.1.5 
Efficacy Laboratory Assessments ................................................ 45 
6.2 
Safety Variables and Safety Reporting ................................................. 47 
6.2.1 
Definition of Adverse Events ....................................................... 47 
6.2.2 
Definitions of Serious Adverse Event.......................................... 47 
6.2.3 
Recording of Adverse Events ...................................................... 47 
6.2.4 
Reporting of Serious Adverse Events .......................................... 49 
6.2.5 
Laboratory Variables ................................................................... 50 
6.2.6 
Vital Signs .................................................................................... 51 
6.2.7 
Physical Examination................................................................... 51 
6.2.8 
Electrocardiogram ........................................................................ 51 
6.2.9 
Overdose ...................................................................................... 52 
6.2.10 
Pregnancy ..................................................................................... 52 
6.2.11 
Volume Depletion ........................................................................ 53 
6.2.12 
Diabetic Ketoacidosis .................................................................. 53 
6.3 
Demographics and Baseline Characteristics ........................................ 54 
6.4 
Pharmacokinetics .................................................................................... 54 
6.4.1 
Collection of Samples .................................................................. 54 
6.4.2 
Determination of Drug Concentration ......................................... 54 
6.4.3 
Storage and Destruction of Pharmacokinetic Samples ................ 54 
6.5 
Volume of Blood to be Collected ............................................................ 55 
6.6 
Labelling and Shipment of Biohazard Samples ................................... 57 
6.7 
Storage and Destruction of Biological Samples .................................... 57 
6.8 
Withdrawal of Informed Consent for Donated Biological Samples ... 57 
7 
STUDY CONDUCT ..................................................................................... 58 
7.1 
Study Plan ................................................................................................ 58 
7.2 
Procedures by Visit ................................................................................. 71 
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7.2.1 
Screening Period: Day −28 to Day −7 (Patients not on Insulin) and 
Day −42 to Day −21 (Patients on Insulin) ................................... 71 
7.2.2 
Run-in Period: Day −6 to Day −1 (Patients not on Insulin) and 
Day −20 (at the earliest) to Day −1 (Patients on Insulin) ............ 72 
7.2.3 
Treatment Period (Day 1 to Day 14) ............................................ 73 
7.2.4 
Follow-up Period (Day 15 to Day 19) ......................................... 77 
7.2.5 
Unscheduled Visits ...................................................................... 77 
7.2.6 
Early Termination Visit ............................................................... 78 
8 
STATISTICAL METHODS ....................................................................... 79 
8.1 
Study Patients .......................................................................................... 79 
8.1.1 
Analysis Sets ................................................................................ 79 
8.2 
General Considerations .......................................................................... 79 
8.3 
Efficacy Analyses ..................................................................................... 80 
8.3.1 
Primary Efficacy Analysis ........................................................... 80 
8.3.2 
Secondary Efficacy Analyses ...................................................... 80 
 
 
8.3.4 
Food Intake Questionnaires ......................................................... 80 
8.4 
Safety Analyses ........................................................................................ 80 
8.4.1 
Adverse Events ............................................................................ 80 
 
 
8.5 
Partial Analyses ....................................................................................... 81 
8.6 
Determination of Sample Size ................................................................ 81 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS .................. 82 
9.1 
Data Quality Assurance .......................................................................... 82 
9.1.1 
Database Management and Quality Control ................................ 82 
9.2 
Case Report Forms and Source Documentation .................................. 82 
9.2.1 
Data Collection ............................................................................ 83 
9.3 
Access to Source Data ............................................................................. 83 
9.4 
Data Processing ....................................................................................... 84 
9.5 
Archiving Study Records ........................................................................ 84 
9.6 
Good Clinical Practice ............................................................................ 84 
9.7 
Informed Consent .................................................................................... 84 
9.8 
Protocol Approval and Amendment ...................................................... 85 
9.9 
Duration of the Study .............................................................................. 85 
9.10 
Premature Termination of the Study .................................................... 85 
9.10.1 
Stopping Rules for an Individual Patient ..................................... 85 
9.10.2 
Stopping Rules for the Study ....................................................... 85 
9.11 
Confidentiality ......................................................................................... 85 
10 
REFERENCE LIST ..................................................................................... 87 
11 
APPENDICES .............................................................................................. 89 
11.1 
Additional Safety Information ............................................................... 89 
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11.2 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ................................................................................ 91 
 
 
Tables in Text 
Table 1: Identity of the Study Drug ..........................................................................40 
Table 2:  Efficacy Laboratory Variables ...................................................................46 
Table 3: Laboratory Assessments .............................................................................50 
Table 4: Total Blood Volume to be Collected .........................................................56 
Table 5: Study Plan with Assessments Schedule: Group 1 (Patients on Insulin) ....59 
Table 6: Study Plan with Assessments Schedule: Group 2 and Group 3 (Patients not 
 
on Insulin) ..................................................................................................65 
 
 
Figures in Text 
Figure 1: Study Design ...............................................................................................29 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABPM 
Ambulatory blood pressure monitoring 
ACEi 
Angiotensin converting enzyme inhibitor 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
 
 
ARB 
Angiotensin receptor blocker  
AST 
Aspartate aminotransferase 
 
  
CKD 
Chronic kidney disease  
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CSR 
Clinical study report 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate  
ENS 
Enrolled Set 
FAS 
Full Analysis Set  
 
 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate  
GMP 
Good Manufacturing Practice 
HbA1c 
Glycosylated haemoglobin 
IATA 
International Airline Transportation Association 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MDS 
Medication Dispensed Set  
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MedDRA 
Medical Dictionary for Regulatory Activities 
NHE3 
Sodium-hydrogen exchanger-3 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
 
  
PPS 
Per Protocol Analysis Set 
PSSR 
Project Specific Safety Requirements 
 
 
 
 
SAE 
Serious adverse event 
SAF 
Safety Set 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SGLT2 
Sodium glucose co-transporter-2  
SOC 
System organ class 
SPC 
Summary of Product Characteristics 
T1DM 
Type 1 diabetes mellitus  
T2DM 
Type 2 diabetes mellitus 
TCAs 
Tricyclic antidepressants  
UACR 
Urine albumin:creatinine ratio  
  
WHO-DD 
World Health Organisation - Drug Dictionary 
 
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1 
INTRODUCTION 
1.1 
Background 
Dapagliflozin is a stable, reversible, highly selective, and orally active inhibitor of human 
renal sodium glucose co-transporter 2 (SGLT2), the major transporter responsible for 
glucose reabsorption in the kidney. Dapagliflozin’s mechanism of action results in the 
direct and insulin-independent elimination of glucose by the kidneys. Results from 
nonclinical and clinical studies have shown that dapagliflozin can be used to promote 
urinary excretion of glucose as a well-tolerated and effective method of reducing blood 
glucose levels in type 2 diabetes mellitus (T2DM) patients. The persistent loss of glucose 
with associated calories in the urine, results in a consistent and maintained reduction of 
the total body weight, in addition to the improved glycemic control. Moreover, 
dapagliflozin also has been shown to reduce blood pressure and albuminuria, 2 essential 
prognostic risk factors for progression of renal disease. 
Notably, the total amount of glucose excreted in the urine by dapagliflozin, declines with 
decreasing kidney function. In a recent meta-analysis of placebo controlled clinical trials 
from the dapagliflozin programme it was confirmed that the glycosylated haemoglobin 
(HbA1c) lowering effect was smaller in patients with an estimated glomerular filtration 
rate (eGFR) between 45 and 60 mL/min/1.73m2 compared to patients with an eGFR 
> 90 mL/min/1.73m2 (Sjöström et al, 2016 [2]). Intriguingly however, the effects of 
dapagliflozin on body weight, blood pressure, albuminuria, and haematocrit were similar 
regardless of the eGFR level (Sjöström et al, 2016 [2]), and may therefore be 
independent of glycemic effects of SGLT2 inhibitors. 
T2DM is associated with an elevated risk of cardiovascular morbidity and mortality as 
well as renal failure. The cardiovascular benefit of SGLT2 inhibition was demonstrated 
in the EMPA-REG study by showing a lower rate of the primary composite 
cardiovascular outcome and of death in the active empagliflozin treatment arm (Zinman 
et al, 2015 [3]). There is also a growing body of evidence indicating that SGLT2 
inhibition is nephroprotective. Post-hoc analysis from the dapagliflozin phase II and 
phase III programme have shown in T2DM patients with moderate renal impairment on 
top of renin-angiotensin-aldosterone system (RAAS) blockade reduction around 40% in 
albuminuria and stabilization of eGFR decline for up to 1 year (Sjöström et al, 2015 [4]) 
and 2 years (Fioretto et al, 2015 [5]). After an initial drop in eGFR, kidney function was 
stable over time while a progressive decrease in eGFR was seen in the placebo group. In 
another trial with the SGLT2 inhibitor empagliflozin, a 38%, 44% and 55% risk 
reduction was found in new onset of macroalbuminuria, doubling of serum creatinine and 
initiation of dialysis treatment respectively. Moreover, the overall risk reduction in 
cardiovascular death was 22% in patients with chronic kidney disease (CKD) 3 
(eGFR 30 to 59 mL/min) (Wanner et al, 2016 [6]). 
The nephroprotective effect is thought to be achieved by mechanisms independent of 
blood glucose reduction (Rajasekeran et al, 2016 [7]), such as by reduced 
intra-glomerular pressure through an enhanced tubuloglomerular feedback mechanism 
(De Nicola, et al 2014 [8] and Thomas, 2014 [9]), reduced glucose and sodium transport 
over the proximal tubule cells (Pollock, et al 1991 [10] and Komala, et al 2013 [11]), 


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increased natriuresis (Heerspink et al, 2013 [12]) and reduced systemic blood pressure 
(Baker et al, 2015 [13]). 
Since the sodium/volume related effects are believed to be independent of HbA1c 
reduction this trial will include both patients with and without T2DM.  
1.2 
Rationale for the Study and Justification of Study Design 
1.2.1 Study Rationale 
The central hypothesis of this study is that dapagliflozin drives a natriuretic effect 
independently of renal function level and diabetic status. Hence, the study will evaluate 
average 24-hr sodium excretion during dapagliflozin treatment in patients with T2DM 
with preserved or impaired renal function or non-diabetics with impaired renal function. 
In the majority of healthy individuals blood pressure falls (dips) at night. These 
individuals are classified as dippers. Those who do not exhibit this nocturnal fall in blood 
pressure are referred to as non-dippers. In populations with CKD, non-dippers are 
overrepresented due to reduced natriuretic capacity (Spencer et al, 2015 and references 
therein [14]). Decreased natriuresis leads to sodium retention and volume expansion with 
clinical consequences. Patients with T2DM often have increased extracellular volume as 
a result of increased glucose and sodium reabsorption in the kidney (Novikov et al, 2016 
[15]). We hypothesise that SGLT2 inhibition enables improved natriuresis and diuresis 
as both sodium and glucose excretion contribute to osmotic diuresis. The mechanisms 
downstream of natriuresis and diuresis have distinct impact on a number of clinically 
important parameters. Enhanced natriuresis enables improved systemic sodium balance, 
which directly impacts both volume expansion as well as systemic sodium load. The 
failure to maintain natriuretic and fluid balance also results in increased demand to drive 
natriuresis to a greater extent. Consequently, blood pressure is increased as well as 
maintained at raised levels during the full 24-hr period generating the non-dipping 
phenotype. This has clear consequence on cardiovascular fitness via demand placed on 
cardiac and vascular tissues. In particular sodium and fluid accumulation are associated 
with impaired endothelial function, vascular stiffening and consequent left ventricular 
hypertrophy.  
As described in the background there is an apparent disconnect between HbA1c lowering 
and the other effects of SGLT2 inhibition by dapagliflozin (eg, blood pressure, body 
weight) which may be in part consequent on volume contraction or changes in 
tubuloglomerular feedback. Tubuloglomerular feedback is the process whereby the 
macular densa which sits downstream of the proximal tubule senses the delivery of 
sodium and chloride and provides feedback to the glomerulus to alter afferent and 
efferent pressure via several mechanisms including renin activity and adenosine 
production. 
 
 At the same time diuresis leads to decrease 
arterial pressure and volume. Dapagliflozin is hypothesised to work through both these 
mechanisms to reduce renal renin activity with concomitant reductions in angiotensin II 
and its metabolites and alter the production of adenosine. Recent studies have also 
suggested a cross-talk between the SGLT2 transporter and the sodium-hydrogen 
exchanger-3 (NHE3) (Novikov et al 2016 [15]). NHE3 is located in the proximal tubule 
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and responsible for approximately 30% of the reabsorption of sodium in the kidney. 
Inhibition of SGLT2 results in down regulation of NHE3 sodium transport activity, 
which may also contribute to the natriuretic effects of dapagliflozin. As a result of the 
interaction between SGLT2 and NHE3, as well as potential effects (both direct and 
indirect, eg, via altered renal RAAS activity) on other transporters, the effect of 
dapagliflozin on electrolyte and fluid related parameters may persist to a significant 
extent in patients with lower eGFR levels. 
 
 
(Schey et al, 2015 [16]). 
This study will further clarify the dapagliflozin mechanisms of action by investigating if 
and how the effect of dapagliflozin on natriuresis, blood pressure regulation, plasma 
volume, extracellular volume, 
 
 are 
impacted by T2DM status and level of kidney function. 
1.2.2 Study Design 
This study is an open label study to evaluate the changes in average 24-hr sodium 
excretion during dapagliflozin treatment in patients with T2DM with preserved or 
impaired renal function and in non-diabetics with impaired renal function. 
Optimization of Patient Population: 
The study will include 3 groups of patients; T2DM patients with either impaired renal 
function (an eGFR by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] 
between ≥25 and ≤50 mL/min/1.73m2); or with normal renal function (an eGFR 
[CKD-EPI] between >90 and ≤130 mL/min/1.73m2 for patients aged 59 years or 
younger, between >85 and ≤130 mL/min/1.73m2 for patients aged 60 to 69 years, and 
between >75 and ≤130 mL/min/1.73m2 for patients aged 70 years or older [Coresh et al, 
2003 17]); and non-diabetic patients with impaired renal function as defined above. 
Details of eGFR estimation using CKD-EPI are provided in Section 3.1. 
All patients will be required to be on patient-specific optimal antihypertensive dose (as 
per Investigator’s judgement) of an angiotensin receptor blocker (ARB) or angiotensin 
converting enzyme inhibitor (ACEi) prior to being considered for the study. During the 
study, all patients will be provided with food in standard food boxes which contain in 
total 150 mmol sodium per day, starting in the Run-in Period prior to treatment initiation 
and to be continued throughout the duration of the study. Patients in whom 24-hr sodium 
excretion does not differ by more than 20% at Day −3 and −2 will be allowed to 
participate in the Treatment Period. This will allow a homogenous stable population to 
be enrolled in the study for evaluation of the study objective.  
Patients with T2DM (Group 2) will be required to be on a stable dose of metformin or 
sulphonylurea, or metformin+sulphonylurea as anti-diabetic therapy for 12 weeks prior 
to start of treatment with dapagliflozin. In the diabetic arm with impaired renal function 
(Group 1), a stable insulin dosing (intermediate, long‐acting, premixed insulin, basal 
bolus insulin) for the last 12 weeks prior to start of treatment with dapagliflozin is 
required. In this group metformin or sulphonylurea, or metformin+sulphonylurea 
together with insulin would be accepted but is not mandatory. If used, stable dose of 
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metformin or sulphonylurea, or metformin+sulphonylurea as anti-diabetic therapy for the 
last 12 weeks prior to start of treatment with dapagliflzoin is required. 
Dapagliflozin Dose and Regimen: 
Patients will receive one tablet dapagliflozin 10 mg per day for a total period of 
14±1 days. This dose is the recommended dose for monotherapy and for add-on 
combination therapy with other glucose-lowering medicinal products including insulin to 
improve glycaemic control in T2DM. 
Study Endpoints: 
The primary endpoint of the study is the average change in 24-hr sodium excretion 
during dapagliflozin treatment from average Baseline to average values at Day 2 to 4 
within each study group. This endpoint will provide information on acute changes in 
sodium excretion in patients based on their renal function and will enable comparison in 
patients with T2DM as well as non-diabetic patients. Additionally urinary sodium 
excretion at Days 12 to 14 will provide information on the effect of 10 mg dapagliflozin 
on steady state natriuresis, and Days 15 to 17 will provide data on the effect of treatment 
withdrawal. Additionally, changes in urinary glucose excretion, urine albumin:creatinine 
ratio (UACR), plasma volume, extracellular volume, and 24-hr systolic blood pressure 
will also be evaluated in the 3 study groups. Pharmacokinetics of dapagliflozin will also 
be studied in the 3 study groups. 
 
 
 
 
 
 
 
 
 
 
 
 
  
1.2.3 Safety Monitoring 
Assessment of adverse events (AEs) is part of the study procedures. All serious adverse 
events (SAEs) will be assessed from the time of signing of informed consent and AEs 
will be assessed from first dose administration throughout the study including the 
Follow-up Period.  
Patients at risk of volume depletion due to co-existing conditions or concomitant 
medications, will be carefully monitored for their status. Events of potential diabetic 
ketoacidosis will be monitored as per Section 6.2.12. 
Safety laboratory assessments will be performed at Screening, immediately prior to 
dosing, 4 days after treatment initiation (for evaluation of serum creatinine), and at the 
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completion of Treatment Period (Day 14). Vital signs and physical examination will also 
be monitored in the study. 
1.3 
Risk-Benefit Assessment 
Dapagliflozin has global market approval and based on global cumulative sale figures up 
to March 2016 it is estimated that dapagliflozin has been administered during 
>1000000 patient years. 
Potential risks 
The potential risks for the treatment with dapagliflozin and other SGLT2 inhibitors are 
described in the Investigator’s Brochure (IB). Due to its mode of action resulting in 
increased urinary glucose excretion an increased risk of urinary tract infections (slightly 
higher compared to placebo in the phase III studies) and genital infections has been seen. 
Higher proportions of patients with marked laboratory abnormalities of 
hyperphosphataemia were reported in dapagliflozin vs placebo. The magnitude and 
clinical significance of this in patients with CKD is unclear. 
After the introduction of dapagliflozin and other SGLT2 inhibitors, there have been 
post-marketing reports of ketoacidosis, including diabetic ketoacidosis, in patients with 
type I diabetes mellitus (T1DM) 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, should be 
assessed for ketoacidosis, irrespective of blood glucose levels. If ketoacidosis is 
suspected by the Investigator, discontinuation or temporary interruption of dapagliflozin 
should be considered and the patient should be promptly evaluated. 
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting 
from pancreatic disorders (eg, T1DM, 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. 
There is no reason to believe that dapagliflozin poses an undue risk of hypoglycemia in 
non-diabetic patients. The amount of glucose excreted in the urine depends on the total 
filtered glucose load (blood glucose concentration x GFR). Thus, at blood glucose levels 
in the low normal range, the amount of glucose excreted into the urine is not sufficient to 
induce hypoglycaemia (Defronzo et al, 2013 [18]). In Clinical Pharmacology studies in 
healthy subjects single doses up to 500 mg and multiple oral doses of 2.5 to 100 mg up to 
14 days have been evaluated and have shown that dapagliflozin does not induce even a 
single case of hypoglycemia in non-diabetic subjects.  
Patients on sulphonylurea and/or insulin at the onset of the study treatment have an 
increased risk of experiencing hypoglycaemic events. Blood glucose is therefore 
monitored at Day 4. Once patients on insulin enter the study, they will be carefully 
followed once starting on food boxes. Additionally, insulin dosing will be adjusted, if 
needed, to avoid hypoglycaema/hyperglycaemia. 
In this study, indocyanine green will be used to assess changes in plasma volume. 
Indocyanine green has been used for decades for this purpose and has a short half-life of 


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only approximately 3 min (Jacob et al, 2007 [19]). The risk profile of indocyanine green 
is considered good (Jacob et al, 2007 [18]), but there are reports of allergic reactions 
including anaphylactic reactions (Speich et al, 1988 [20] and Garski et al, 1978 [21]). In 
patients with terminal renal insufficiency, the possibility that an anaphylactic reaction 
occurs seems to be increased (Summary of Product Characteristics [SPC] Verdye [22]). 
Assessment of 
 (including extracellular and 
) will 
be conducted with bioimpedance spectroscopy. This is an easy to use and non-invasive 
technique not considered to cause any risk to the patient if following the manufacturer’s 
instructions. 
No other study procedure is considered putting the patients at risk beyond those 
ordinarily encountered during the performance of routine medical examinations or 
routine tests.  
Protection against risks 
This study has been designed with appropriate measures in place to monitor and 
minimise any of the potential health risks to participating patients. 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. 
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 judgement of the Investigator, may be at risk for dehydration or volume 
depletion due to co-existing conditions or concomitant medications, such as loop 
diuretics, should have careful monitoring of their volume status. For this study, patients 
with current treatment with diuretics will not be included. In hypovolaemic patients 
starting treatment with dapagliflozin, there is a potential risk for increased serum 
creatinine levels. Patients who show a greater than 50% increase in serum creatinine 
should therefore be discontinued on the study drug. 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 should be based on clinical judgement 
Safety signal detection will include the integration of all available sources of safety 
information, including clinical study data, AE reports, pre-clinical data, epidemiological 
studies and literature reports, to identify and characterise unrecognised safety risks or 
changes in those which are currently expected Adverse Drug Reactions. Any information 
that may affect the benefit-risk profile of dapagliflozin 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.  
In addition, all dapagliflozin studies are subject to a carefully designed patient risk 
management plan that includes the temporary and if necessary permanent discontinuation 
of the investigational product in individual patients in whom a potential health risk or a 
laboratory abnormality of clinical concern has been identified. 
Due to a potential risk of allergic reactions, the use of indocyanine green should be 
performed under supervision of a physician. Symptoms related to an allergic reaction 
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may include unrest, feeling of warmth, pruritus, urticarial, acceleration of heart rate, fall 
in blood pressure, shortness of breath, bronchospasm, flush, cardiac arrest, 
laryngospasm, facial oedema, and nausea.  
Patients with a known hypersensitivity to indocyanine green, sodium iodide, or iodine, or 
patients who have poorly tolerated indocyanine green in the past should not use 
indocyanine green again (see Section 4.2 Exclusion Criteria). Additionally, patients with 
hyperthyroidism or with autonomic thyroid adenomas are excluded (see SPC [21]). Some 
medicinal products and substances can reduce or increase absorption of indocyanine 
green and should thus be avoided (see Section 4.2, Exclusion Criteria). 
Due to the risk of allergic reactions including anaphylactic reactions, emergency 
equipment should be available to immediately start treatment of an allergic reaction if 
needed. 
For the bioimpedance spectroscopy measurements, patients should not be pregnant, have 
a pacemaker or other implanted electronic devices (see Section 4.2, Exclusion Criteria). 
Potential benefits to patients 
In this study, the dose of dapagliflozin 10 mg was chosen based on previous clinical 
experience. This mechanistic study is non-therapeutic; therefore, it has limit or no direct 
clinical benefit for the subjects. In studies of longer duration, in patients randomised to 
active drug, dapagliflozin is expected to reduce progression of renal failure and reduce 
cardiovascular mortality. Dapagliflozin is known to decrease body weight (or prevent 
weight gain) as well as lower blood pressure. 
Patients are also expected to receive some benefit in the form of increased medical 
care/attention when participating in study procedures. 
Informed consent and alternatives to participation 
All prospective participants will be fully informed of the possible risks and benefits 
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 CKD, 
and other possible concomitant diseases according to the discretion of their health care 
professional, and 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 with respect to other study procedures, 
participation in this study presents a small 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 change in 24-hr sodium excretion during dapagliflozin treatment between 
Baseline (average of Days −3 to −1) and average of Days 2 to 4 within each study group 
in patients with T2DM with preserved or impaired renal function and in non-diabetics 
with impaired renal function. 
2.2 
Secondary Objectives 
The secondary objectives to be evaluated within each study group during or following 
dapagliflozin treatment are: 
• To evaluate the change in 24-hr sodium excretion during dapagliflozin treatment 
from Baseline to end of treatment, and during follow-up.  
• To evaluate the change in 24-hr glucose excretion. 
• To evaluate the change in mean 24-hr systolic blood pressure. 
• To evaluate the change in plasma volume. 
• To evaluate the change in extracellular volume. 
• To evaluate the pharmacokinetics of dapagliflozin. 
• To evaluate the change in 24-hr UACR. 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
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2.4 
Safety Objectives 
• To evaluate the safety and tolerability of dapagliflozin in each of the target patient 
populations. 
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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
This is an open label, mechanistic, three-arm study to evaluate the natriuretic effect of 
2-week dapagliflozin treatment in T2DM patients with either preserved or impaired renal 
function and in non-diabetics with impaired renal function.  
The study population will comprise 3 groups of patients: 
Group 1: T2DM patients with impaired renal function (an eGFR [CKD-EPI] between 
≥25 and ≤50 mL/min/1.73m2) 
Group 2: T2DM patients with normal renal function (an eGFR [CKD-EPI] between >90 
and ≤130 mL/min/1.73m2 for patients aged 59 years or younger, between >85 
and ≤130 mL/min/1.73m2 for patients aged 60 to 69 years, and between >75 
and ≤130 mL/min/1.73m2 for patients aged 70 years or older) 
Group 3: Non-diabetic patients with impaired renal function (an eGFR [CKD-EPI] 
between ≥25 and ≤50 mL/min/1.73m2) 
Estimated GFR using CKD-EPI equation is given below (Levey et al, 2009 [23]):   
 
eGFR (mL/min/1.73m2) = 141 x min (SCr/κ,1)α x max (SCr/κ,1)−1.209 x 
0.993Age x [1.018 if female] x [1.159 if black] 
 
SCr = serum creatinine (in mg/dL), κ is 0.7 for females and 0.9 for males, α is 
−0.329 for females and −0.411 for males, min indicates the minimum of SCr/κ 
or 1, and max indicates the maximum of SCr/κ or 1. 
 
We plan to enroll a total of 51 patients in the study, with 17 patients in each group.  
The maximum duration of the study will be 62 days including the allowed window 
periods for the study (±1 day for Visit 7 at Day 13). The study periods and schedule of 
visits are presented in Table 5 for patients on insulin (Group 1) and Table 6 for patients 
not on insulin (Group 2 and Group 3). 
Screening (Day −28 to Day −7 [patients not on insulin] and Day −42 to Day −21 
[patients on insulin]); Run-in Period (Day −6 to Day −1 [patients not on insulin] and 
Day −20 to Day −1 [patients on insulin):  
All patients will undergo study procedures as listed in Table 5 and Table 6 at the 
Screening Visit (Visit 1), after signing the informed consent. At this visit, the patients 
will also have a discussion with the study dietician regarding specific dietary 
requirements to be adhered to during the study from Day −6 (patients not on insulin) or 
Day –20 at the earliest (patients on insulin) of the study. Patients on insulin may require a 
longer Run-in Period in order to be able to adjust their insulin requirements according to 
the caloric content of the food boxes, if needed. However, it is not mandatory for the 
patient on insulin to use the entire extended Run-in Period. During this Run-in Period, 
there will be regular contacts between the Investigators and patients to ensure that their 
blood glucose is adequately controlled (by potentially adjusting/optimising their insulin 
doses) and to confirm that their insulin regime remains stable while on food boxes. 


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Patient consultation with Investigator may occur at several times from Day -20 to Day -1. 
Exact dates will be decided on an as needed basis by patient and Investigator. Patients 
will be contacted by the study dietician by telephone on Day −7 (patients not on insulin) 
or Day −21 at the earliest (patients on insulin) to remind them about the dietary 
requirements to be followed from Day −6 (patients not on insulin) or Day −20 at the 
earliest (patients on insulin) of the study, respectively, and about the food boxes that will 
be provided to them from Day −6 (patients not on insulin) or Day −20 at the earliest 
(patients on insulin), respectively.  
Following the Screening Visit eligible patients (eligible based on available investigations 
from Screening Visit) will enter the Run-in Period beginning on Day −6 (patients not on 
insulin) or Day –20 at the earliest (patients on insulin). Based on the Investigator’s 
judgement, the Run-in Period may be shortened once each patient (on insulin) has had 
sufficient time to adapt to the food boxes, and it is determined that the patient’s insulin 
requirement has stabilised sufficiently to continue in the study. Patients will receive food 
boxes with a daily sodium content of approximately 150 mmol, starting on Day −6 
(patients not on insulin) or Day –20 at the earliest (patients on insulin), throughout the 
study until Day 18 (inclusive). All patients will be required to adhere to the dietary 
requirements throughout the period of the study until Day 18 (inclusive). Patients will be 
required to complete food questionnaires starting Day −6 (patients not on insulin) or Day 
–20 at the earliest (patients on insulin) until Day 18, wherein they will record daily 
adherence to the dietary requirements and record liquid intake and any deviation from the 
recommended diet. Patients will also record study treatment intake daily in the food 
questionnaires. 
During the Run-in Period, clinic visits are scheduled on Day −2 (Visit 2) and Day −1 
(Visit 3). Patients will collect 24-hr urine samples on Day −3, and −2. Patients, in whom 
24-hr sodium excretion does not differ by more than 20% from Day −3 to Day −2, will be 
considered eligible to proceed to the Treatment Period starting Day 1 (Dosing Initiation 
Visit).  
The patients will commence 24-hr ambulatory blood pressure monitoring (ABPM) on 
Day −1 (ie, the day before the start of dosing). The patients will also collect the 24-hr 
urine sample on Day −1. 
In case the patients are not eligible for the study based on the 24-hr sodium excretion 
results, the patients will be informed and the 24-hr blood pressure monitoring and 
24-hr urine collection will be discontinued. 
Treatment Period (Day 1 to Day 14):  
On Day 1 (Dosing Initiation Visit), patients will start the administration of one 
dapagliflozin 10 mg tablet per day. Patients will continue with dapagliflozin until 
Day 14, following which they will enter a Follow-up Period from Day 15 to Day 19.  
During the Treatment Period, the following clinic visits are scheduled: Visit 4 (Day 1: 
Dosing Initiation Visit), Visit 5 (Day 4), Visit 6 (Day 5), Visit 7 (Day 13) and Visit 8 
(Day 14: end of treatment). There will be 4 consecutive 24-hr urine collections on 
Days 1, 2, 3, and 4 followed by 3 consecutive 24-hr urine collections on Days 12, 13, 
and 14. Initiation of 24-hr blood pressure monitoring will be done on Days 4 and 13. 


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Plasma volume assessment and bioimpedance spectroscopy for extracellular volume, 
 will be performed on Days 1, 4 and 14. On 
Day 1, 
, plasma volume and bioimpedance spectroscopy 
measurements will be done prior to the first dose of dapagliflozin. 
 
 Blood samples for 
pharmacokinetics of dapagliflozin will be collected on Days 4 and 14.  
A window period of ±1 day is allowed for Visit 7 at Day 13. Urine collection on Day 12 
should start 1 day before Visit 7. Visit 8 will occur 1 day after Visit 7 and the follow-up 
period of 5 days (Day 15 to Day 19) will start 1 day after Visit 8. 
Follow-up Period (Day 15 to Day 19): 
On Day 15, treatment with dapagliflozin will be discontinued (last dose to be taken on 
Day 14) and patients will enter a 5-day Follow-up Period between Day 15 and Day 19. A 
clinic visit is scheduled on Day 18 to provide the last 24-hr urine samples and participate 
in the investigations detailed in Table 5 and Table 6. 
 
. The patients will return to the clinic for the 
last study visit on Day 19 and return equipment provided.  
There will be 3 consecutive 24-hr urine collections on Days 15, 16, and 17. On Day 18, 
24-hr blood pressure monitoring will be initiated. Plasma volume assessment and 
bioimpedance spectroscopy for extracellular volume, 
 
will be performed as well.  
After the end of the study, patients will return to their normal clinical care plan. 
Stopping rules for individual patients are described in Section 4.5. Stopping rules for the 
study are described in Section 9.10. 
The study design is presented in Figure 1. Refer to the Study Plan (Table 5 and Table 6) 
for further details of the timings of planned assessments. 
 
Figure 1: Study Design 
 
 
T2DM=Type 2 diabetes mellitus 
Note: lines indicate days on which 24-hr urine is collected. 
Note: Day −6 indicates the start of the Run-in Period for patients not on insulin; Day −20 indicates the 
earliest start of the Run-in Period for patients on insulin. 
Patients will be required to adhere to dietary advice and consume food only from the food boxes until 
Day 18 (inclusive). 
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3.2 
Criteria for Evaluation of the Study 
Refer to the study objectives in Sections 2.1, 2.2, 2.3, and 2.4. 
3.2.1 Primary Endpoint 
• Average change in 24-hr sodium excretion from average Baseline to average 
values at Day 2 to 4 within each study group. 
3.2.2 Secondary Endpoints 
The secondary endpoints to be evaluated during or following dapagliflozin treatment 
within each study group are: 
• Average change in 24-hr sodium excretion from average Baseline values to 
average end of treatment values (Day 12 to 14); and from average end of treatment 
values (Day 12 to 14) to average values during follow-up (Day 15 to 17). 
• Average change in 24-hr glucose excretion from average Baseline values to 
average values at Day 2 to 4; from average Baseline values to average end of 
treatment values (Day 12 to 14); and from average end of treatment values 
(Day 12 to 14) to average values during follow-up (Day 15 to 17).  
• Change in mean 24-hr systolic blood pressure from Baseline to Day 4; from 
Baseline to end of treatment (Day 13); and from end of treatment (Day 13) to end 
of follow-up (Day 18). 
• Change in plasma volume from Baseline to Day 4; from Baseline to end of 
treatment (Day 14); and from end of treatment (Day 14) to end of follow-up 
(Day 18). 
• Change in extracellular volume from Baseline to Day 4; from Baseline to end of 
treatment (Day 14); and from end of treatment (Day 14) to end of follow-up 
(Day 18). 
• Dapagliflozin pharmacokinetics on Days 4 and 14. 
• Average change in mean 24-hr UACR from average Baseline to Day 4; and from 
average Baseline values to average end of treatment values (Day 12 to 14). 
 
 
 
 
 
 
 
 
 
 
 
 
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3.2.4 Safety Endpoints 
• AEs starting from first dose throughout the study. 
• SAEs starting from Visit 1 throughout the study. 
• Laboratory variables. 
• Vital signs. 
• Physical examination.  
 
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4 
STUDY POPULATION 
The study population will consist of patients with one of the following:  
• T2DM with an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 at the 
Screening Visit or  
• T2DM with an eGFR (CKD-EPI) between >90 and ≤130 mL/min/1.73m2 for 
patients aged 59 years or younger, between >85 and ≤130 mL/min/1.73m2 for 
patients aged 60 to 69 years, and between >75 and ≤130 mL/min/1.73m2 for 
patients aged 70 years or older at the Screening Visit or  
• Non-diabetic with an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 at 
the Screening Visit.  
Patients must be able to provide written consent and meet all the inclusion criteria and 
none of the exclusion criteria. 
4.1 
Inclusion Criteria  
 
4.1.1 Inclusion Criteria at Screening Visit (Visit 1) 
Patients will be entered into this study only if they meet all of the following criteria: 
1. Provision of signed and dated, written informed consent prior to any study-specific 
procedures. 
2. Caucasian, Asian or Middle Eastern (sub-Saharan patients are not eligible); female 
and/or male aged between 18 years and ≤80 years. 
3. In the diabetic arms - a diagnosis of T2DM with HbA1c ≥6.5% (≥48 mmol/mol) and 
<10% (<86 mmol/mol); and eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 
or between >90 and ≤130 mL/min/1.73m2 for patients aged 59 years or younger, 
between >85 and ≤130 mL/min/1.73m2 for patients aged 60 to 69 years, and between 
>75 and ≤130 mL/min/1.73m2 for patients aged 70 years or older at the Screening 
Visit (Visit 1). 
4. In the non-diabetic arm, HbA1c <6.5% (<48 mmol/mol) and an eGFR (CKD-EPI) 
between ≥25 and ≤50 mL/min/1.73m2 at the Screening Visit (Visit 1). 
5. Patient-specific optimal antihypertensive dose (as per Investigator’s judgement) of an 
ARB or ACEi for at least 6 weeks prior to Visit 4 (Day 1). 
6. In the diabetic arm (Group 2) an appropriate stable dose of metformin or 
sulphonylurea, or metformin+sulphonylurea as anti-diabetic therapy for the last 
12 weeks prior to Visit 4 (Day 1).  
7. In the diabetic arm with impaired renal function (Group 1) a stable insulin dosing 
(intermediate, long‐acting, premixed insulin, basal bolus insulin) for the last 12 weeks 
prior to Visit 4 (Day 1) as judged by the Investigator. Metformin or sulphonylurea, or 
metformin+sulphonylurea together with insulin would be accepted but is not 
mandatory. If used, stable dose of metformin or sulphonylurea, or 
metformin+sulphonylurea as anti-diabetic therapy for the last 12 weeks prior to Visit 
4 (Day 1) is required. 


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8. Suitable veins for cannulation or repeated venepuncture 
9. Female patients must be 1 year post-menopausal, surgically sterile, or using an 
acceptable method of contraception (an acceptable method of contraception is 
defined as a barrier method in conjunction with a spermicide) for the duration of the 
study (from the time they sign consent) and for 3 months after the last dose of study 
drug to prevent pregnancy. In addition, oral contraceptives, approved contraceptive 
implant, long-term injectable contraception, intrauterine device, or tubal ligation are 
allowed. Oral contraception alone is not acceptable; additional barrier methods in 
conjunction with spermicide must be used. 
4.1.2 Inclusion Criteria at End of Run-in Period (Visit 3) 
Patients must fulfil the following criteria in order to continue participation in the 
study. 
10. Patient-specific optimal antihypertensive dose (as per Investigator’s judgement) of an 
ARB or an ACEi for at least 6 weeks prior to Visit 4 (Day 1).  
11. In the diabetic arm (Group 2) an appropriate stable dose of metformin or 
sulphonylurea, or metformin+sulphonylurea as anti-diabetic therapy for the last 12 
weeks prior to Visit 4 (Day 1). 
12. In the diabetic arm with impaired renal function (Group 1) a stable insulin dosing 
(intermediate, long‐acting, premixed insulin, basal bolus insulin) for the last 12 weeks 
prior to Visit 4 (Day 1) as judged by the Investigator. Metformin or sulphonylurea, or 
metformin+sulphonylurea together with insulin would be accepted but is not 
mandatory. If used, stable dose of metformin or sulphonylurea, or 
metformin+sulphonylurea as anti-diabetic therapy for the last 12 weeks prior to Visit 
4 (Day 1) is required. 
13. Stable urinary sodium excretion on 2 successive 24-hr urinary sodium excretion 
measurements (<20% difference between Days −3 and −2). 
4.2 
Exclusion Criteria 
4.2.1 Exclusion Criteria at Screening Visit (Visit 1) 
Patients will not be entered into this study if they meet any of the following criteria: 
Study-related: 
1. Previous enrolment in the present study or participation in another clinical study with 
an investigational product during the last 6 months prior to Screening Visit (Visit 1). 
2. 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). 
3. Hypersensitivity to dapagliflozin, indocyanine green, sodium iodide, or iodine, or 
patients who have poorly tolerated indocyanine green in the past. 
4. Pacemaker or other implanted electronic devices. 


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5. Pregnancy. 
6. Breastfeeding. 
General health-related: 
7. Known clinically significant disease or disorder; or clinically relevant abnormal 
findings in physical examination, clinical chemistry, haematology, and urinalysis; or 
unstable or rapidly progressing renal disease; or any other condition or minor medical 
complaint, 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 and comply with study procedures, restrictions and 
requirements. 
8. Diagnosis of T1DM. 
9. Hyperthyroidism or autonomic thyroid adenomas. 
10. Abnormal vital signs, after 10 minutes supine rest, defined as any of the following 
(Visit 1): 
- 
Systolic blood pressure above 180 mmHg. 
- 
Diastolic blood pressure above 110 mmHg. 
- 
Pulse <50 bpm or >100 bpm 
11. Any of the following cardiovascular/vascular diseases within 3 months prior to 
signing the consent at Visit 1, as assessed by the Investigator: myocardial infarction, 
cardiac surgery or revascularization (coronary artery bypass graft [CABG]/ 
percutaneous transluminal coronary angioplasty [PTCA]), unstable angina, unstable 
heart failure, heart failure New York Heart Association Class IV, transient ischemic 
attack or significant cerebrovascular disease, unstable or previously undiagnosed 
arrhythmia. 
12. Patients with severe hepatic impairment (Child-Pugh C). 
13. Ongoing weight-loss diet (hypocaloric diet) or use of weight-loss agents, unless the 
diet or treatment has been stopped at least 3 months before Screening Visit, ensuring 
patients having a stable body weight with no verified body weight variability of 
>3 kg during the 3 months before Screening Visit. 
Renal failure-related: 
14. Symptoms/complaints suggestive of established neurogenic bladder and/or 
incomplete bladder emptying. 
15. History of bladder cancer. 
16. Diagnosis of polycystic kidney disease. 
17. History of or current lupus nephritis. 
18. UACR >1000 mg/g per day at the Screening Visit based on spot urine sample 
(quantitative assessment). 


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Concomitant Medication and/or study treatment-related: 
19. Current/chronic use of the following medication: any anti-diabetic medication with 
the exception of metformin, sulphonylurea, insulin (insulin only allowed in Group 1),  
oral glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immune 
suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and 
monoamine oxidase inhibitors.  
20. Receiving immunosuppressive or other immunotherapy for primary or secondary 
renal disease within 6 months prior to Screening Visit (Visit 1). 
21. Current treatment or treatment within the last 2 weeks prior to Screening Visit 
(Visit 1) with diuretics including loop diuretics, thiazides, and mineralocorticoid 
antagonists. 
22. A metformin dose which is outside the specified dose range for renal impairment 
according to local guidelines and/or Investigator’s judgement. 
23. Medicinal products and substances that can reduce or increase absorption of 
indocyanine green: anticonvulsants, bisulphite compounds, haloperidol, heroin, 
meperidine, metamizol, methadone, morphium, nitrofurantoin, opium alkaloids, 
phenobarbital, phenylbutazone (reduced absorption), and cyclopropane, probenecid, 
rifamycin (increased absorption). 
4.3 
Rescreening 
Rescreening in this study will be allowed once per patient only under the following 
circumstances: 
• If a patient consents to participate, meets the eligibility criteria but is no longer 
able to be enrolled on a certain date due to personal reasons (eg, family crisis, 
vacation, etc.). 
• If the Investigator discovers during the Screening Period, that a patient requires an 
adjustment of their regular medication, in line with the local standard of care, for 
instance, any changes required with regard to their antihypertensive (ARB or 
ACEi) or anti-diabetic (metformin, sulphonylurea, metformin+sulphonyurea or 
insulin) treatment, such a patient may be rescreened once the patient’s medical 
condition has stabilised, as judged by the Investigator. The time required before 
such a patient is rescreened will be assessed on a case-by-case basis as per the 
judgement of the Investigator.  
• In case errors occurred during the 24-hr urine collection process, for instance urine 
spillage/loss of urine/not used the correct amount of salt sticks, etc. In such a case, 
the patient may be retested to accurately assess the sodium excretion. This is done 
by restarting the urinary sampling days with start from Day −3 again. The new 
urinary collections should be used for analysis.  
• In case a patient previously failed screening based on older inclusion and 
exclusion criteria in previous versions of the protocol but may now be eligible 
based on amended inclusion and exclusion criteria (e.g. age-specific eGFR ranges, 
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• Retesting of patients will be allowed in the Screening Visit window period at the 
discretion of Investigator in case there is a single laboratory measurement that is 
out of range. In case of multiple laboratory parameters out of range and considered 
not clinically significant, retesting will be allowed. 
• In case the eGFR performed at Screening is out of range and the Investigator is of 
the opinion that the patient is eligible based on local laboratory values, a single 
repeat of the eGFR test is allowed. 
4.4 
Study Restrictions 
Patients entered into the study must: 
1. Patients should strictly adhere to the dietary requirement including drinks in the study 
and consume food only from the food boxes provided to them throughout the study 
starting Day -6 (patients not on insulin) or Day –20 at the earliest (patients on 
insulin), and up to Day 18 (included). Patients on insulin may require a longer Run-in 
Period in order to be able to adjust their insulin requirements according to the caloric 
content of the food boxes, if needed. However, it is not mandatory for the patient on 
insulin to use the entire extended Run-in Period. Based on the Investigator’s 
judgement, the Run-in Period may be shortened, once each patient (on insulin) has 
had sufficient time to adapt to the food boxes, and it is determined that the patient’s 
insulin requirement has stabilised sufficiently to continue in the study. During this 
Run-in Period, there will be regular contacts between Investigators and patients to 
ensure that their blood glucose is adequately controlled (by potentially 
adjusting/optimising their insulin) and to confirm that their insulin regime remains 
stable while on food boxes. Patient consultation with Investigator may occur at 
several times from Day -20 to Day -1. Exact dates will be decided on an as needed 
basis by patient and Investigator. 
2. Not use drugs of abuse during the entire study. One alcoholic beverage a day is only 
allowed between Visit 1 and Day −7 (patients not on insulin) / Day −21 at the earliest 
(patients on insulin). Alcohol should not be consumed on days when urine samples 
are collected. 
3. Women of childbearing potential: use contraception as specified in inclusion 
criteria 9, in Section 4.1.  
Restrictions for clinic visit days: 
4. 
 
 
 
 
.  
Restrictions prior to measurements for plasma volume and bioimpedance spectroscopy:  
5. Plasma volume assessment and bioimpedance spectroscopy measurements will be 
done at Day 1, Day 4, Day 14 and Day 18. Prior to the test, patients should adhere to 
non-caffeinated drinks.  
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6. During the measurement procedure, patients are allowed to move around, to eat a 
snack and to drink non-caffeinated drinks. 
4.5 
Patient Withdrawal and Discontinuation 
Patients may be discontinued from study treatment and assessments at any time in the 
following situations.  
• Patient decision. The patient is free at any time to discontinue treatment, without 
prejudice to further treatment. 
• Severe non-compliance to protocol, as judged by the Investigator and/or 
AstraZeneca. 
• Safety reasons, eg, AE that warrants discontinuation, as judged by the Investigator 
and/or AstraZeneca. 
• Incorrect enrolment (ie, the patient does not meet the required inclusion/exclusion 
criteria) for the study. 
• Patient lost to follow-up. 
• Pregnancy. 
• Major hypoglycaemic events. 
Subjects should not be discontinued from any treatment phase based on single 
episodes of hypoglycaemia or symptoms of hypoglycaemia unless clinically indicated 
(see the criteria below). The assessment of a single fingerstick or local laboratory 
glucose value should not be the sole assessment used to determine patient 
discontinuation due to hypoglycemia. 
Subjects should be discontinued from study drug if they experience severe 
hypoglycaemia as defined by the American Diabetes Association: 
- 
Requires assistance of another person to actively administer carbohydrates, 
glucagon, or take other corrective actions.  
- 
Plasma glucose concentrations may not be available during an event, but 
neurological recovery following the return of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma 
glucose concentration. 
• Suspected/potential diabetic ketoacidosis based on Investigator’s judgement. 
• Patients who show a greater than 50% increase in serum creatinine on Day 4 
should be discontinued from the study drug. 
In all cases, the reason(s) for withdrawal and the primary reason must be recorded on 
electronic case report form (eCRF). If a patient is prematurely withdrawn from the study 
treatment for any reason, the Investigator must make every effort to perform the 
evaluations described for Visit 8. 
Patients will also be withdrawn if the entire study is terminated prematurely as described 
in Section 9.10. 
Refer to Section 4.3 for rescreening of patients for the study. 


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4.6 
Planned Sample Size and Number of Study Centres  
We plan to enroll a total of 51 patients at up to 5 study centres in 3 equal sized groups. 
Each group will enroll 17 patients. It is planned to enroll patients in Europe. Refer to 
Section 8.6 for sample size justification. 
4.7 
Patient Identification and Randomisation 
4.7.1 Patient Identification 
At Screening, each patient will receive a unique enrolment number. Patients who drop 
out of the study before dosing will retain their assigned enrolment number. 
The enrolment number will be in the following format and will be recorded in the eCRF:  
E code format (E_Site ID_Patient ID), eg, E0010001. 
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. 
4.7.2 Randomisation Scheme 
There is no randomisation in the study.  
4.7.3 Allocation of Patients to Treatment 
Start of treatment will occur at Visit 4 (Day 1) after all Screening procedures have been 
performed and eligibility for the study confirmed. Patients will be enrolled to specific 
groups based on their diagnosis. When 17 patients have been enrolled to each specific 
patient group enrolment into that group will stop. 


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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. 
Details of the study treatment can be found in Table 1. Dapagliflozin 10 mg tablets will 
be supplied by AstraZeneca in labelled bottles containing 35 tablets. 
Table 1: 
Identity of the Study Drug 
Study drug 
Dosage form and strength 
Manufacturer 
Dapagliflozin 
Plain, green, diamond-shaped, film 
coated tablet, 10 mg 
AstraZeneca 
Details of the batch numbers will be included in the Trial Master File and the final 
clinical study report (CSR). 
5.2 
Administration 
The study consists of a 2-week, open label, Treatment Period. Patients will be provided 
with one bottle of dapagliflozin tablets on Day 1 (Visit 4) to last for the 14±1 days of the 
Treatment Period.  
The tablet is taken orally once daily in the morning and at approximately the same time 
of the day.  
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 dapagliflozin will be administered at Visit 4 (Day 1) at the study site 
after all baseline assessments (including laboratory tests, plasma volume assessments, 
and bioimpedance spectroscopy measurement) have been performed. 
On days of study site visits where blood sampling is scheduled, ie, Visit 5 and Visit 8, 
the patients will be required to bring the bottle of dapagliflozin tablets to site. At Visit 5 
(Day 4), the patient will consume the tablet together with breakfast after fasting blood 
sampling is completed at the site. At Visit 8 (Day 14), the patient will consume the tablet 
together with breakfast after pre-dose bioimpedance spectroscopy measurements, 
pharmacokinetics blood sampling, 
. 
5.3 
Packaging, Labelling, and Storage 
Patients will be provided with study drug according to the study plan Table 5 (Group 1) 
and Table 6 (Group 2 and Group 3). 
The study drug will be packaged by AstraZeneca or designee according to Good 
Manufacturing Practice (GMP). 
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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 Breaking the Blind 
This is an open label study and hence blinding is not applicable. 
5.5 
Drug Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all study drugs dispensed to and returned from the 
patient. 
The Investigator is responsible for making sure: 
• That the study drug is handled and stored safely and properly (see Section 5.3). 
• That the study drug is only dispensed to study patients in accordance with this 
protocol. 
Patients should return all unused study drug and empty containers to the Investigator. 
At the termination of the clinical study or at the request of AstraZeneca, remaining drug 
and packaging of used study drug after final drug accountability, are to be destroyed 
locally in line with local regulations. On destruction of the study drug at the site, the site 
personnel will account for all unused study drug and for appropriate destruction 
documentation. Certificates of delivery, destruction and return should be signed and 
archived.  
Each dispensing and returning of 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 at Visit 8) and patient diary entries (ie, patients will record 
study drug intake daily in the food questionnaires and this will be reviewed at the clinic 
visits during the Treatment Period).  
5.7 
Previous and Concomitant Medications 
Any medication the patient takes other than the study treatment, including herbal and 
other non-traditional remedies, is 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, dose, regimen, and indication.  
Any changes in the dosage or regimen of a concomitant medication must be recorded in 
the eCRF. 


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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 or 
renal failure (as applicable), and whether they have taken any other medications since the 
previous visit. 
5.7.1 Allowed Concomitant Medications 
Background therapy for T2DM and renal failure: 
All patients will continue to use their ARB or ACEi at the same dose that they were on 
prior to start of the study. 
Diabetic patients will continue on metformin or sulphonylurea, or 
metformin+sulphonylurea therapy at the same dose that they were on prior to start of the 
study. For patients on insulin (Group 1), recording of total insulin doses will be done 
during the study. 
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 renal failure or whether 
the patient has started taking extra concomitant medication. The status of each 
concomitant medication (ie, pre-existing or new) will be documented on the eCRF. 
Therapies for treatment of other comorbidities are allowed as long as the dose regimen is 
stable in the 3 months prior to first dose and is not a prohibited medication 
(Section 5.7.2). All efforts should be made to keep the dose of study drug stable 
throughout the study. 
5.7.2 Prohibited Concomitant Medications 
Refer to Section 4.2 for exclusion criteria relating to prohibited medications. 
The following medications are prohibited during the study: 
• Immunosuppressive or other immunotherapy for primary or secondary renal 
disease. 
• Diuretic drugs including loop diuretics, thiazides, mineralocorticoid receptor 
antagonists. 
• Use of any anti-diabetic medications with the exception of metformin, 
sulphonylurea and insulin (insulin only allowed in Group 1), oral glucocorticoids, 
NSAIDs, immune suppressants, chemotherapeutics, antipsychotics, TCAs and 
monoamine oxidase inhibitors. 
• Use of medicinal products and substances that can reduce or increase absorption of 
indocyanine green: anticonvulsants, bisulphite compounds, haloperidol, heroin, 
meperidine, metamizol, methadone, morphium, nitrofurantoin, opium alkaloids, 
phenobarbital, phenylbutazone (reduced absorption), and cyclopropane, 
probenecid, rifamycin (increased absorption). 
5.7.3 Non-investigational Product 
The product used for plasma volume measurements (indocyanine green) is considered a 
non-investigational product (see Section 6.1.3 for details). 


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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 5 [Group 1] 
and Table 6 [Group 2 and Group 3]). 
6.1.1 24-hr Urine Measurement 
24-hr urine collection will be performed as per schedule provided in Table 5 and Table 6. 
The patients will be provided with equipment for collection and storage of urine samples. 
Patients receive empty 24-hr urine collection containers preceding the collection days 
according to instructions. At the Screening Visit, patients will be instructed to start 
collection of urine samples starting Day −3. The morning the patient starts with the 24-hr 
urine collection, the bladder is emptied. The 24-hr urine collection starts after the first 
morning urine is voided in the toilet. The urine is collected in the container for 24 hrs. 
The date and time of the start and end of the urine collection should be written on the 
designated labels. Patients will be advised to store the urine in the refrigerator after 
finishing the 24-hr urine collection until he/she delivers the urine to the clinic. The 
carefully sealed container will be delivered to the research nurse/physician at the day of 
the next clinic visit. The importance of obtaining a complete urine collection will be 
stressed. The patients will return the equipment on the days specified in Table 5 and 
Table 6. 
The local laboratory will receive the urine samples and will record the volume of urine 
collected for every 24-hr urine sample. 
For premenopausal women, the Investigator will estimate the menstrual timing and aim 
to avoid the 2 urine collection periods (Day −3 to 4 and Day 12 to 17) during 
menstruation. 
6.1.2 24-hr BP Monitoring 
Ambulatory blood pressure monitoring will be performed to record 24-hr systolic and 
diastolic blood pressure at Days −1, 4, 13, and 18.  
The ABPM manual will contain more detail on the specific device and method of data 
capture/transfer. 
6.1.3 Plasma Volume Measurements 
Plasma volume will be assessed using indocyanine green distribution in the circulation. 
Measurements will be performed prior to dosing on Day 1 (Baseline) and following 
dosing on Days 4 and 14. Plasma volume will also be assessed on Day 18.  
6.1.3.1 Dosage, Form Strength and Storage of Indocyanine Green 
Indocyanine green (tradename Verdye, manufacturer Diagnostic Green) 5mg /mL is 
provided as powder for solution. Single doses of 0.25 mg/kg body weight will be 
administered as bolus injection. For details on storage of indocyanine green see 
SPC [21]. 


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6.1.3.2 Administration of Indocyanine Green 
Indocyanine green is to be reconstituted with water for injection (not solutions containing 
salt). See SPC [21] for more information. 
After the patient is weighed, a catheter will be positioned for example in an anticubital 
vein for the injection of indocyanine green. A second catheter will be positioned in the 
contralateral arm for blood sampling.  
Blood collections will start exactly 2 minutes after injection of indocyanine green and 
will be collected for a 3-minute period at 30 sec intervals (7 blood samples). The 
administration of indocyanine green is of critical importance for the quality of the plasma 
volume measurements. It is important that the exact time of the samples is noted. Further 
details can be found in the manual for plasma volume measurements. 
6.1.3.3 In Case of Anaphylactic Reactions due to Indocyanine Green 
The risk profile of indocyanine green is considered good, but there are reports of allergic 
reactions including anaphylactic reactions (see Section 1.3). Since severe anaphylactic 
reactions might occur, indocyanine green must only be applied under supervision of a 
physician. If an anaphylactic reaction should occur, immediate emergency treatment 
should be initiated and may include below actions as judged necessary by the physician: 
• Stop further administration of indocyanine green, leave injection catheter or 
cannula in the vein. 
• Keep airways open. 
• Inject 100 to 300 mg hydrocortisone or a similar preparation by rapid intravenous 
injection. 
• Substitute volume with isotonic electrolyte solution. 
• Give oxygen, monitor circulation. 
• Slowly administer antihistamines intravenously. 
 
The following additional measures may be indicated in cases of anaphylactic shock: 
• Place patient in recumbent position with legs raised. 
• Rapidly substitute volume with eg, isotonic electrolyte solution (pressure 
infusion), plasma expanders. 
• Immediately administer 0.1 to 0.5 mg adrenaline (epinephrine) diluted to 10 mL 
with 0.9% saline intravenously (repeat after 10 min if necessary). 
6.1.4 Bioimpedance Spectroscopy Measurements (Extracellular Volume, 
 
Bioimpedance spectroscopy will be performed prior to dosing on Day 1 (Baseline) and 
following dosing on Days 4 and 14. Bioimpedance spectroscopy will also be performed 
in the Follow-up Period on Day 18. 
 
 
 Bioimpedance spectroscopy will be assessed using the SFB7 
device produced by ImpediMed. 
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For the bioimpedance spectroscopy, patients should void their bladder and add to the 
ongoing 24-hr urine collection. Patients should abstain from exercising 2 hr prior to the 
assessment. 
An alcohol swab is used to clean the skin, allowing the alcohol to dry completely before 
placing the electrodes on the skin. If there is excess hair on the sites where the electrodes 
will be attached, not allowing proper electrode adherence, these sites will be shaved. 
The patient should be put in the supine position for 5 min before the measurement. The 
patient should not touch any metal surfaces while in the supine position. It has to be 
ensured that the patient’s limbs are not crossed and that the legs are completely 
separated. For patients who cannot effectively separate their inner thighs, it may be 
necessary to place insulating material (eg, a towel) between them. It has to be ensured 
also that the patient’s arms are not touching the torso. The bioimpedance spectroscopy 
should be set to make 3 repeat measurements (see manual instructions for SFB7 device). 
The patient has to remain still and relaxed during the measurement. 
When several measurements are made on the same day, the patient should not remain 
supine between readings. The amount of time in supine position should be the same on 
each assessment day and at each assessment time. 
The points of contact for the electrodes should be marked on the patient‘s skin and the 
same positions used at all occasions. Preferably, electrodes should be connected to the 
right side of the body (hand and foot according to the manual instructions for SFB7). 
It has to be ensured that the bioimpedance spectroscopy machine is charged and not 
connected to mains power during use.  
6.1.5 Efficacy Laboratory Assessments 
Table 2 presents the laboratory assessments that will be performed for evaluation of the 
endpoints. Refer to Table 5 and Table 6 study plan for schedule of assessments. 
. 
Instructions for collection, storage, and shipment of samples will be provided in the 
Laboratory Manual for samples collected at central laboratories. 
 
 
 
 
 
 
  
 
 
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Table 2:  
Efficacy Laboratory Variables 
UACR=urine albumin: creatinine 
ratio  
 
 
 
Local Laboratory 
Central Laboratories 
Primary and Secondary Variable 
24-hr urinary sodium excretion 
- Sodium 
- 
Secondary Variables 
24-hr urinary glucose excretion 
- Glucose 
- 
Changes in plasma volume 
- 
- Plasma volume 
Dapagliflozin pharmacokinetics 
- 
- Plasma concentration of 
dapagliflozin 
Change in 24-hr UACR 
- UACR 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
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6.2 
Safety Variables and Safety Reporting 
The Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.  
Assessments will be performed in accordance with the Study Plan (Table 5 [Group 1] 
and Table 6 [Group 2 and Group 3]) 
6.2.1 Definition of Adverse Events 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical 
condition can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged 
liver) or the abnormal results of an investigation (eg, laboratory findings, 
electrocardiogram). In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including during Run-in or Wash-out Periods, even if no 
study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
6.2.2 Definitions of Serious Adverse Event 
An SAE is an AE occurring during any study phase (ie, 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 hospitalisation or prolongation of existing hospitalisation. 
• Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions. 
• Is a congenital abnormality or birth defect. 
• Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of an SAE, see Section 11.1. 
6.2.3 Recording of Adverse Events 
6.2.3.1 Time Period for Collection of Adverse Events 
All AEs will be collected from the time of first dose throughout the study, including the 
Follow-up Period. 
All SAEs will be collected from the time of signing the informed consent throughout the 
study, including the Run-in and Follow-up Periods. 
6.2.3.2 Follow-up of Unresolved Adverse Events 
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 patient with ongoing AE(s)/SAE(s) at 
the end of the study, if judged necessary. 


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6.2.3.3 Variables  
The following variables will be collected for each AE: 
• AE (verbatim). 
• The date and time when the AE started and stopped. 
• 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 hospitalisation (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 (eg, concomitant medication, 
background therapy). 
• Description of SAE. 
The intensity of the reported AEs will be assessed according to the following scale: 
• 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 6.2.2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2.2. On the other hand, a stroke that results in only a limited degree 
of disability may be considered a mild stroke but would be a SAE when it satisfies the 
criteria shown in Section 6.2.2. 
6.2.3.4 Causality Collection 
The Investigator will assess causal relationship between the study treatment and each 
AE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?’ 


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For SAEs the 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. 
6.2.3.5 Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the patient or reported in response to the open 
question from the study personnel: ‘Have you had any health problems since the previous 
visit/you were last asked?’, or revealed by observation will be collected and recorded in 
the eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) 
to recording a list of signs and symptoms. However, if a diagnosis is known and there are 
other signs or symptoms that are not generally part of the diagnosis, the diagnosis and 
each sign or symptom will be recorded separately. 
6.2.3.6 Adverse Events Based on Examinations and Tests 
The results from protocol-mandated laboratory tests and vital signs will be summarised 
in the CSR. Deterioration as compared to Baseline in protocol-mandated laboratory 
values, or vital signs should therefore only be reported as AEs if they fulfil any of the 
SAE criteria or are the reason for discontinuation of 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 (eg, anaemia 
versus low haemoglobin value). In the absence of clinical signs or symptoms, clinically 
relevant deteriorations in non-mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE. 
6.2.4 Reporting of Serious Adverse Events 
All SAEs have to be reported, whether or not considered causally related to the 
investigational product, or to the study procedure(s). All SAEs will be recorded in the 
eCRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel 
inform the appropriate AstraZeneca representatives (PAREXEL Medical services team) 
within one day, ie, immediately but no later than 24 hours of when he or she becomes 
aware of it. 
The designated AstraZeneca representative (PAREXEL Medical services team) 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 
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information on a previously reported SAE within one calendar day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the eCRF, an 
automated email alert is sent to the designated AstraZeneca representative (PAREXEL 
Medical services team). 
If the electronic data capture (EDC) system is not available, then the Investigator or other 
study site personnel reports an SAE to the appropriate AstraZeneca representative 
(PAREXEL Medical services team) by telephone. 
The AstraZeneca representative (PAREXEL Medical services team) will advise the 
Investigator/study site personnel how to proceed. 
The reference document for definition of expectedness/listedness is the IB for the 
AstraZeneca drug. 
6.2.5 Laboratory Variables 
Blood and urine samples for determination of clinical chemistry, haematology, and 
urinalysis will be taken in accordance with the Study Plan (Table 5 and Table 6) and sent 
to the local laboratory for analysis. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. If local retesting occurs, the date, time of retesting and results (values, units 
and reference ranges) will be recorded in the appropriate section of the eCRF. Blood 
samples will be collected after at least 8 hr overnight fasting (except for the Screening 
Visit where fasting is not required). 
Table 3 specifies the safety laboratory variables to be determined. 
Standardised and validated laboratory reference ranges will be provided by the local 
laboratory performing the assessments. 
Table 3: 
Laboratory Assessments 
Haematology/ haemostasis (whole blood): 
Clinical Chemistry (serum [S] or 
plasma [P]) 
B-Haemoglobin  
B-Haematocrit a 
HbA1cb 
S-Creatinine a 
S-Bilirubin, total  
P-Glucose a 
S-ALP  
S-AST  
S-ALT 
 
Pregnancy testing 
Urinalysis 
Women: 
Urine pregnancy testb –for women of childbearing 
potential (HCG minimum sensitivity of 25 IU/L), dipstick 
analysed at the study centre 
Serum βHCG (if urine pregnancy dipstick result is 
positive) 
Dipstick: 
U-Blood  
U-Albumin  
U-Glucose 
Spot urine sample: 
U-Albumin/U-Creatinineb 
ALP=alkaline phosphatase, ALT=alanine transaminase, AST=aspartate transaminase, B=blood, 
HCG=human chorionic gonadotropin, S=serum, P=plasma, U=urine 


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a. 
 
b. These tests will be performed for verifying inclusion/exclusion criteria and not as a safety measure. 
 
For information on how AEs based on laboratory tests should be recorded and reported, 
see Section 6.2.3.6. 
6.2.6 Vital Signs 
The following vital signs will be assessed in accordance with the Study Plan (Table 5 and 
Table 6): 
• Pulse (beats/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 
supine 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 6.2.3.6. 
6.2.7 Physical Examination 
Physical examinations will be performed in accordance with the Study Plan (Table 5 and 
Table 6).  
An abbreviated physical examination will be performed at the Screening Visit (Visit 1) 
and at Visit 9, and include an assessment of the following: general appearance, abdomen, 
cardiovascular, respiratory systems, and assessment of the volume status.  
Body weight will be measured as indicated in Study Plan (Table 5 and Table 6). It will 
be assessed in the morning after an overnight fast (except for the Screening Visit where 
fasting is not required) and a lavatory visit in underwear/light dressing on the same 
calibrated scale at each occasion. 
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 (see 
Section 6.2.3.6). 
6.2.8 Electrocardiogram 
Standard 12-lead electrocardiogram (ECG) will be performed in accordance with the 
Study Plan (Table 5 and Table 6).  
Either a digital or a paper ECG will be performed after 10 minutes supine rest.  
The Investigator will judge the overall interpretation as normal or abnormal. If abnormal, 
it will be decided as to whether or not the abnormality is clinically significant and the 
reason for the abnormality will be recorded. Only the overall evaluation 
(normal/abnormal) will be recorded in the eCRF. 
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The Investigator may add extra 12-lead paper ECG safety assessments if there are any 
abnormal findings or if the Investigator considers it is required for any other safety 
reason. These assessments should be entered as an unscheduled assessment. 
The printout of the ECG is to be signed, dated and filed in the Investigator study file 
along with a signed and dated copy (if the printouts are not on archive-quality paper). 
6.2.9 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 type 2 diabetes. Suspected single intake of less than 
50 tablets of 10 mg dapagliflozin tablets or repeated intake of less than 10 tablets of 
10 mg dapagliflozin tablets should not 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 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, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative (PAREXEL Medical services team) works 
with the Investigator to ensure that all relevant information is provided to the 
AstraZeneca Patient Safety data entry site. 
For overdoses associated with an SAE, the standard reporting timelines apply, see 
Section 6.2.4. For other overdoses, reporting must occur within 30 days. 
6.2.10 Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
6.2.10.1 Maternal Exposure 
Women of childbearing potential are allowed to be included in this study as long as they 
agree to use the contraceptive methods specified in inclusion criterion 9 in Section 4.1.  
Should a pregnancy occur, the study drug should be discontinued immediately and the 
pregnancy reported to AstraZeneca. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or 
congenital abnormality) should be followed up and documented even if the patient was 
discontinued from the study. 


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If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives (PAREXEL Medical 
services team) within 1 day, ie, immediately but no later than 24 hours of when he or 
she becomes aware of it. 
The designated AstraZeneca representative (PAREXEL Medical services team) works 
with the Investigator to ensure that all relevant information is provided to the 
AstraZeneca Patient Safety data entry site within 1 or 5 calendar days for SAEs (see 
Section 6.2.4) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The pregnancy module (PREGREP) in the eCRF is used to report the pregnancy and the 
pregnancy outcome report (PREGOUT) is used to report the outcome of the pregnancy. 
6.2.11 Volume Depletion 
Patients at risk of volume depletion due to co-existing conditions or concomitant 
medications, such as loop diuretics (exclusion criteria in this study), should have careful 
monitoring of their volume status as judged by the Investigator. 
6.2.12 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 below 
14 mmol/l (250 mg/dl). If ketoacidosis is suspected by the Investigator, discontinuation 
of study drug and withdrawal of the patient should be considered, and the patient should 
be promptly evaluated. 
 
Adjudication of potential events of diabetic ketoacidosis:  
An independent Diabetic Ketoacidosis Adjudication Committee T2DM will assess 
available information on each potential diabetic ketoacidosis event and will classify the 
event in accordance with the definitions in the Diabetic Ketoacidosis Adjudication 
Charter T2DM, as follows: 
• Definite diabetic ketoacidosis 
• Probable diabetic ketoacidosis 
• Possible diabetic ketoacidosis 
• Not diabetic ketoacidosis 
The Diabetic Ketoacidosis Adjudication Committee will be kept blinded to the study 
drug treatment received by each patient with a potential diabetic ketoacidosis event in the 
clinical study. A separate Diabetic Ketoacidosis Adjudication Manual will define and 
describe the procedures for the collection of diabetic ketoacidosis information, handling, 
adjudication criteria and reporting of these events/cases. 
The decision of withdrawal of patient due to potential diabetic ketoacidosis event will be 
based on Investigator’s judgement and will not be dependent on adjudication of these 
events by the Adjudication Committee. 


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The outcome of the classification of potential diabetic ketoacidosis cases by the 
Adjudication Committee will not be reported in the CSR. 
6.3 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics are assessed at Screening. These include: 
• Demographics (as appropriate to country regulations): sex, date of birth, race, 
ethnic group. 
• Medical and surgical history: 
- 
Confirmation of diagnosis of T2DM. 
- 
Disease history (T2DM and renal impairment) including date of diagnosis. 
- 
Other previous and concomitant diseases within the last 6 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. 
• Height (in cm) and weight (in kg). 
• Previous and concomitant medications at Visit 1 (see Section 5.7). 
• eGFR at Screening, based on serum creatinine levels and CKI-EPD method. 
• HbA1c at Screening. 
6.4 
Pharmacokinetics 
6.4.1 
Collection of Samples 
Blood samples for determination of dapagliflozin concentration in plasma will be taken 
at the times presented in the study plan Table 5 [Group 1] and Table 6 [Group 2 and 
Group 3]. 
On Day 4, a single pre-dose sample will be obtained. On Day 14, samples will be 
obtained pre-dose, 1, 2 and 4 hr post-dose. It is important that the exact time of the 
sample is noted. 
Samples will be collected, labelled stored and shipped as detailed in the Laboratory 
Manual. 
6.4.2 
Determination of Drug Concentration 
Samples for determination of drug concentration in plasma will be analysed by Covance 
on behalf of AstraZeneca, using an appropriate bioanalytical method. Full details of the 
analytical method used will be described in a separate bioanalytical report. 
6.4.3 Storage and Destruction of Pharmacokinetic Samples 
Pharmacokinetic samples will be disposed of after the bioanalytical report finalisation or 
6 months after issuance of the draft bioanalytical report (whichever is earlier), unless 
requested for future analyses. 
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic 


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samples to further evaluate and validate the analytical method. Any results from such 
analyses may be reported separately from the CSR. 
Incurred sample reproducibility analysis, if any, will be performed alongside the 
bioanalysis of the test samples. The results from the evaluation will not be reported in the 
CSR but separately in a bioanalytical report. 
6.5 
Volume of Blood to be Collected 
 
, as summarised in Table 4, and may change due to transfer of 
assay, validation, etc. 
Additional blood samples for safety analyses may be taken as required in the study.  
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Table 4: Total Blood Volume to be Collected  
Assay 
Volume per 
sample (mL) 
Total number of 
samples 
Total blood 
volume 
(mL) 
Local Laboratory 
Haematology (including haemoglobin, 
haematocrit, HbA1c) 
2 
5 
10 
haemoglobin 
 
3 
 
haematocrita 
 
5 
 
HbA1c 
 
1 
 
Clinical chemistry + Eyrthropoietin 
5 
5 
25 
AST, ALT, ALP, TBL,  
 
2 
 
creatininea  
 
5 
 
glucosea 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Central Laboratories 
 and 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dapagliflozin pharmacokinetics 
2 
5 
10 
Plasma volume  
14 
4 
56 
Total blood volume (maximum) 
 
 
ALP=alkaline phosphatase, ALT=alanine transaminase, AST=aspartate transaminase, 
 
; 
, ECG=electrocardiogram, 
 
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 HbA1c=glycosylated haemoglobin, 
 
TBIL=total bilirubin.  
 
 
 
 
 
 
6.6 
Labelling and Shipment of Biohazard Samples 
Samples will be labelled and shipped in accordance with the Laboratory Manual and the 
Biological Substance, Category B regulations (materials containing or suspected to 
contain infectious substances that do not meet Category A criteria), see Appendix 11.2 of 
this Clinical Study Protocol ‘International Airline Transportation Association (IATA) 6.2 
Guidance Document’. 
Any samples identified as Infectious Category A materials will not be shipped and no 
further samples will be taken from the patient unless agreed with AstraZeneca and 
appropriate labelling, shipment and containment provisions are approved. 
6.7 
Storage and Destruction of Biological Samples 
Biological samples for future research will be retained at AstraZeneca or its designee for 
a maximum of 15 years following the finalisation of the CSR, after which they will be 
destroyed. 
 
 
 
 
6.8 
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 analysed and the action documented. 
As collection of donated biological samples is an integral part of the study, the patient 
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. 
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AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0 
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10 Jan 2020 
7 
STUDY CONDUCT 
7.1 
Study Plan 
The Study Plan displaying assessments/tasks and time points is presented in Table 5 
(Group 1) and Table 6 (Group 2 and Group 3).  


AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
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Investigational product: Dapagliflozin  
 
Final 6.0  
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Table 5: 
Study Plan with Assessments Schedule: Group 1 (Patients on Insulin)  
Study Plan 
Screening 
Period 
Run-in Period 
Treatment Period 
Follow-up Period 
Visits (Clinic) 
1 
 
 
 
2 
3 
4 
 
 
5 
6 
 
7 
8 
 
 
 
9 
10 
Day  
−42 
to -22 
−21a 
−20a 
−3 
−2 
−1 
1 
2 
3 
4 
5 
12 
 
13 
±1d 
14b 
15 
16 
17 
18 
19 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm final eligibility 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsd 
X 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Height and weighte 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Briefing of patients by the 
study dietician regarding food 
boxes 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone call by dieticianf  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient consultation with the 
Investigator with respect to 
food boxes introductiong 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
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Study Plan 
Screening 
Period 
Run-in Period 
Treatment Period 
Follow-up Period 
Visits (Clinic) 
1 
 
 
 
2 
3 
4 
 
 
5 
6 
 
7 
8 
 
 
 
9 
10 
Day  
−42 
to -22 
−21a 
−20a 
−3 
−2 
−1 
1 
2 
3 
4 
5 
12 
 
13 
±1d 
14b 
15 
16 
17 
18 
19 
Dietary advicee 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Consumption of food from 
food boxes 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sampling  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For clinical chemistry 
and haematologyh 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
  
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Dapagliflozin PKj 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine sample for 
urinary albumin and 
creatinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
61 of 91 
10 Jan 2010 
Study Plan 
Screening 
Period 
Run-in Period 
Treatment Period 
Follow-up Period 
Visits (Clinic) 
1 
 
 
 
2 
3 
4 
 
 
5 
6 
 
7 
8 
 
 
 
9 
10 
Day  
−42 
to -22 
−21a 
−20a 
−3 
−2 
−1 
1 
2 
3 
4 
5 
12 
 
13 
±1d 
14b 
15 
16 
17 
18 
19 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
(Dipstick): U-albumin, 
U-glucose, U-bloodl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
x 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Pregnancy testn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
24-hr urineo 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
24-hr urine collection 
instructions/dispensing of 
containersp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hr blood pressureq 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Plasma volumer 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Bioimpedance spectroscopyr, s 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
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AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
62 of 91 
10 Jan 2010 
Study Plan 
Screening 
Period 
Run-in Period 
Treatment Period 
Follow-up Period 
Visits (Clinic) 
1 
 
 
 
2 
3 
4 
 
 
5 
6 
 
7 
8 
 
 
 
9 
10 
Day  
−42 
to -22 
−21a 
−20a 
−3 
−2 
−1 
1 
2 
3 
4 
5 
12 
 
13 
±1d 
14b 
15 
16 
17 
18 
19 
Dispense study drugt 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Verify drug intake and drug 
accountabilityu 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
Review of concomitant 
medications 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
 
X 
X 
Collection of AE/SAEv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Food intake questionnairew 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ABPM=ambulatory blood pressure monitoring, AE=adverse event, DBP=diastolic blood pressure, 
 
 
 HbA1c=glycosylated haemoglobin, hr=hour, 
 PK=pharmacokinetics, 
 
SAE=serious adverse event, SBP=systolic blood pressure, UACR=urine albumin: creatinine ratio, 
  
a. The indicated days are the earliest days for the assessments listed. 
b. In case of early discontinuation, patient will attend an Early Termination Visit. This visit should take place as soon as possible after the patient stops taking 
study treatment. If patients can continue the study treatment up to the day of the Early Termination Visit, the observations and procedures scheduled for 
Visit 8 should be performed. If not, the Early Termination Visit should be handled as Visit 9. 
c. Selection of a patient in the study to be done only after results of clinical chemistry, haematology, and urinalysis have been reviewed. Stable urinary sodium 
excretion to be confirmed on 2 successive 24-hr urinary sodium excretion measurements (<20% difference between Days −3 and −2 Inclusion criterion #13; 
Section 4.1.2). 
d. Vital signs include heart rate and blood pressure. 
e. Height to be measured only at Screening Visit. Body weight to be assessed in the morning after an overnight fast (except for Visit 1 where fasting is not 
required) and a visit to the lavatory in underwear/light clothing on the same calibrated scale for each individual.  
f. Telephone call by dietician within 24 hours as a reminder for food boxes to be consumed from Day –20 (at the earliest) onwards and to complete food 
questionnaire. Dietary advice and food boxes with a daily sodium content of approximately 150 mmol sodium content will start at Day –20 at the earliest and 
continue throughout the study (until Visit 9).  
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AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
63 of 91 
10 Jan 2010 
g. During the Run-in Period, there will be regular contacts between Investigators and patients to ensure that their blood glucose is adequately controlled and to 
confirm that their insulin regime remains stable while on food boxes. Patient consultation with Investigator may occur at several times from Day -20 to 
Day −1. Exact dates will be decided on an as needed basis by patient and Investigator. Patients may have their insulin requirements adjusted according to the 
caloric content of the food boxes, if needed. 
h. 
 
Samples should be obtained prior to dosing. At the Screening Visit and on Day 14, all safety laboratory assessments specified in Table 3 will be performed; 
on Day 1, only haemoglobin, creatinine, haematocrit, glucose will be assessed; and on Day 4 and Day 18, only creatinine, haematocrit, glucose will be 
assessed. At the Screening Visit HbA1c will be assessed for confirmation of inclusion criterion. 
 
 
 
 
 
j. On Day 4, a single pre-dose sample will be obtained. On Day 14, samples will be obtained pre-dose, 1, 2 and 4 hrs post-dose. 
 
 
l. Urine dipstick parameters to be evaluated are blood, glucose and albumin.  
 
n. A positive urine pregnancy test (dipstick analysed at the study centre) should be confirmed with a serum pregnancy test. 
o. Patients will be given instructions on how to collect and store 24-hr urine samples. From the 24-hr urine samples, following parameters will be analysed at all 
timepoints: 24-hr 
 
 glucose, sodium, 
 and UACR; and 
 will be analysed only on Days −1, 4, 14, and 17. For premenopausal women, the Investigator will estimate the menstrual timing and 
aim to avoid the 2 urine collection periods (Day −3 to 4 and Day 12 to 17) during menstruation. For the second collection period (Day 12 to 17), the urine 
collection will start 1 day before Visit 7 (Day 13±1 day) and end 4 days after Visit 7 (Day 13±1 day). 
p. Patients will receive empty 24-hr urine collection containers preceding the collection days according to instructions. Dispensing of 24-hr urine containers may 
occur at several occasions during the study period. 
q. ABPM will be used to record 24-hr SBP and DBP. Specific instructions will be provided to the patients as per the ABPM manual. 
r. Assessments of plasma volume and bioimpedance spectroscopy should be done in the following order: 1) 
. On 
Day 1, plasma volume assessment and bioimpedance spectroscopy will be performed pre-dose, while on Days 4 and 14, it will be assessed post dose. 
2) Intake of study drug and other medications and breakfast (The time when dapagliflozin is taken should be noted as t=0). 3) One hr after dapagliflozin 
intake, bioimpedance spectroscopy is performed (Days 4 and 14). The timing of the assessment relative to the dapagliflozin dose should be consistent across 
visits for each patient. 4) Approximately 1.5 hr after dapagliflozin intake, the plasma volume assessment will be done. The timing of the assessment relative 
to the dapagliflozin dose should be consistent across visits for each patient. 5) On Day 14, the bioimpedance spectroscopy measurement will be conducted 
also at pre-dose, as well as 2 and 4 hr after dapagliflozin dose (in addition to 1 hr post-dose noted above), that is, the bioimpedance spectroscopy 
measurement will be done at the same time as pharmacokinetics sampling on Day 14. The bioimpedance spectroscopy measurement is always to be done 
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AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
64 of 91 
10 Jan 2010 
before pharmacokinetics sampling. On Days 1 and 18, bioimpedance spectroscopy is conducted 1 hr after intake of breakfast and non-study drugs (but not 
dapagliflozin) and plasma volume is assessed 1.5 hr after breakfast and non-study drug intake. 
s. Bioimpedance spectroscopy measurements include assessment of extracellular volume, 
 
  
t. Study drug administration should start in the morning at Day 1 (Visit 4) and last dose should be taken by the patient on Visit 8. 
u. Intake of study treatment will be confirmed based on the completion of record of drug intake by the patient in the food questionnaire on Days 4, 5, 13, and 14. 
Drug accountability (tablet count) will be performed on Visit 8. 
v. AEs are collected from time of first dose and SAEs are collected from provision of informed consent throughout the study. 
w. Patient will record compliance with recommended food intake, liquid intake daily in the food questionnaire. Any other food and drink consumed will also be 
recorded. Study treatment intake will also be recorded daily during the Treatment Period. 
 
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AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
65 of 91 
10 Jan 2010 
Table 6: 
Study Plan with Assessments Schedule: Group 2 and Group 3 (Patients not on Insulin) 
Study Plan 
Screening 
Period 
Run-in Period 
Treatment Period 
Follow-up Period 
Visits (Clinic) 
1 
 
 
 
2 
3 
4 
 
 
5 
6 
 
7 
8 
 
 
 
9 
10 
Day  
−28 to -8 
−7 
−6 
−3 
−2 
−1 
1 
2 
3 
4 
5 
12 
 
13 
±1d 
14a 
15 
16 
17 
18 
19 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm final eligibility 
 
 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsc 
X 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Height and weightd 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Briefing of patients by the 
study dietician regarding food 
boxes 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone call by dieticiane  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dietary advicee 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Consumption of food from 
food boxes 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sampling  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For clinical chemistry 
and haematologyf 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 


AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
66 of 91 
10 Jan 2010 
Study Plan 
Screening 
Period 
Run-in Period 
Treatment Period 
Follow-up Period 
Visits (Clinic) 
1 
 
 
 
2 
3 
4 
 
 
5 
6 
 
7 
8 
 
 
 
9 
10 
Day  
−28 to -8 
−7 
−6 
−3 
−2 
−1 
1 
2 
3 
4 
5 
12 
 
13 
±1d 
14a 
15 
16 
17 
18 
19 
 
 
 
 
  
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Dapagliflozin PKh 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine sample for 
urinary albumin and 
creatinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
(Dipstick): U-albumin, 
U-glucose, U-bloodj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
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AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
67 of 91 
10 Jan 2010 
Study Plan 
Screening 
Period 
Run-in Period 
Treatment Period 
Follow-up Period 
Visits (Clinic) 
1 
 
 
 
2 
3 
4 
 
 
5 
6 
 
7 
8 
 
 
 
9 
10 
Day  
−28 to -8 
−7 
−6 
−3 
−2 
−1 
1 
2 
3 
4 
5 
12 
 
13 
±1d 
14a 
15 
16 
17 
18 
19 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
x 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Pregnancy testl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
24-hr urinem 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
24-hr urine collection 
instructions/dispensing of 
containersn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hr blood pressureo 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Plasma volumep 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Bioimpedance spectroscopyp, 
q 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
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AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
68 of 91 
10 Jan 2010 
Study Plan 
Screening 
Period 
Run-in Period 
Treatment Period 
Follow-up Period 
Visits (Clinic) 
1 
 
 
 
2 
3 
4 
 
 
5 
6 
 
7 
8 
 
 
 
9 
10 
Day  
−28 to -8 
−7 
−6 
−3 
−2 
−1 
1 
2 
3 
4 
5 
12 
 
13 
±1d 
14a 
15 
16 
17 
18 
19 
Dispense study drugr 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Verify drug intake and drug 
accountabilitys 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
Review of concomitant 
medications 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
 
X 
X 
Collection of AE/SAEt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Food intake questionnaireu 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ABPM=ambulatory blood pressure monitoring, AE=adverse event, DBP=diastolic blood pressure, 
, 
 
, HbA1c=glycosylated haemoglobin, hr=hour, 
PK=pharmacokinetics, 
 
SAE=serious adverse event, SBP=systolic blood pressure, UACR=urine albumin: creatinine ratio, 
  
a. In case of early discontinuation, patient will attend an Early Termination Visit. This visit should take place as soon as possible after the patient stops taking 
study treatment. If patients can continue the study treatment up to the day of the Early Termination Visit, the observations and procedures scheduled for 
Visit 8 should be performed. If not, the Early Termination Visit should be handled as Visit 9. 
b. Selection of a patient in the study to be done only after results of clinical chemistry, haematology, and urinalysis have been reviewed. Stable urinary sodium 
excretion to be confirmed on 2 successive 24-hr urinary sodium excretion measurements (<20% difference between Days −3 and −2 Inclusion criterion #13; 
Section 4.1.2). 
c. Vital signs include heart rate and blood pressure. 
d. Height to be measured only at Screening Visit. Body weight to be assessed in the morning after an overnight fast (except for Visit 1 where fasting is not 
required) and a visit to the lavatory in underwear/light clothing on the same calibrated scale for each individual.  
e. Telephone call by dietician as a reminder for food boxes to be consumed from Day -6 onwards and to complete food questionnaire. Dietary advice and food 
boxes with a daily sodium content of approximately 150 mmol sodium content will start at Day -6 and continue throughout the study (until Visit 9).  
f. Blood samples to be obtained in the morning at the same time for each individual after fasting for at least 8 hr (except at Visit 1 where fasting is not required). 
Samples should be obtained prior to dosing. At the Screening Visit and on Day 14, all safety laboratory assessments specified in Table 3 will be performed; 
on Day 1, only haemoglobin, creatinine, haematocrit, glucose will be assessed; and on Day 4 and Day 18, only creatinine, haematocrit, glucose will be 
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AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
69 of 91 
10 Jan 2010 
assessed. At the Screening Visit HbA1c will be assessed for confirmation of inclusion criterion. 
 
. 
 
 
h. On Day 4, a single pre-dose sample will be obtained. On Day 14, samples will be obtained pre-dose, 1, 2 and 4 hrs post-dose. 
i. 
 
 
j. Urine dipstick parameters to be evaluated are blood, glucose and albumin.  
 
l. A positive urine pregnancy test (dipstick analysed at the study centre) should be confirmed with a serum pregnancy test. 
m. Patients will be given instructions on how to collect and store 24-hr urine samples. From the 24-hr urine samples, following parameters will be analysed at all 
timepoints: 24-hr 
, glucose, sodium, 
, and UACR; and 
 will be analysed only on Days −1, 4, 14, and 17. For premenopausal women, the Investigator will estimate the menstrual timing and 
aim to avoid the 2 urine collection periods (Day −3 to 4 and Day 12 to 17) during menstruation. For the second collection period (Day 12 to 17), the urine 
collection will start 1 day before Visit 7 (Day 13±1 day) and end 4 days after Visit 7 (Day 13±1 day). 
n. Patients will receive empty 24-hr urine collection containers preceding the collection days according to instructions. Dispensing of 24-hr urine containers may 
occur at several occasions during the study period. 
o. ABPM will be used to record 24-hr SBP and DBP. Specific instructions will be provided to the patients as per the ABPM manual. 
p. Assessments of plasma volume and bioimpedance spectroscopy should be done in the following order: 1) 
. On 
Day 1, plasma volume assessment and bioimpedance spectroscopy will be performed pre-dose, while on Days 4 and 14, it will be assessed post dose. 
2) Intake of study drug and other medications and breakfast (The time when dapagliflozin is taken should be noted as t=0). 3) One hr after dapagliflozin 
intake, bioimpedance spectroscopy is performed (Days 4 and 14). The timing of the assessment relative to the dapagliflozin dose should be consistent across 
visits for each patient. 4) Approximately 1.5 hr after dapagliflozin intake, the plasma volume assessment will be done. The timing of the assessment relative 
to the dapagliflozin dose should be consistent across visits for each patient. 5) On Day 14, the bioimpedance spectroscopy measurement will be conducted 
also at pre-dose, as well as 2 and 4 hr after dapagliflozin dose (in addition to 1 hr post-dose noted above), that is, the bioimpedance spectroscopy 
measurement will be done at the same time as pharmacokinetics sampling on Day 14. The bioimpedance spectroscopy measurement is always to be done 
before pharmacokinetics sampling. On Days 1 and 18, bioimpedance spectroscopy is conducted 1 hr after intake of breakfast and non-study drugs (but not 
dapagliflozin) and plasma volume is assessed 1.5 hr after breakfast and non-study drug intake. 
q. Bioimpedance spectroscopy measurements include assessment of extracellular volume, 
 
  
r. Study drug administration should start in the morning at Day 1 (Visit 4) and last dose should be taken by the patient on Visit 8. 
s. Intake of study treatment will be confirmed based on the completion of record of drug intake by the patient in the food questionnaire on Days 4, 5, 13, and 14. 
Drug accountability (tablet count) will be performed on Visit 8. 
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AstraZeneca AB 
Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
70 of 91 
10 Jan 2010 
t. AEs are collected from time of first dose and SAEs are collected from provision of informed consent throughout the study. 
u. Patient will record compliance with recommended food intake, liquid intake daily in the food questionnaire. Any other food and drink consumed will also be 
recorded. Study treatment intake will also be recorded daily during the Treatment Period. 
 
 


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Clinical Study Protocol 
Study code: D1690C00049 
CONFIDENTIAL 
Investigational product: Dapagliflozin  
 
Final 6.0  
71 of 91 
10 Jan 2020 
7.2 
Procedures by Visit 
Visit 1 should occur a maximum of 42 days before Visit 4 (ie, start of dosing). All times 
should be recorded using the 24-hr clock (eg, 23:20, not 11:20 pm). 
7.2.1 Screening Period: Day −28 to Day −7 (Patients not on Insulin) and Day −42 to 
Day −21 (Patients on Insulin) 
7.2.1.1 Visit 1: Screening Visit 
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 assessment 
for Visit 1, as listed in Table 5 (patients on insulin) and Table 6 (patients not on insulin) 
will be performed.  
At the Screening Visit, the study dietician will discuss with the patient regarding the food 
boxes to be provided from Day −6 (patients not on insulin) or Day –20 at the earliest 
(patients on insulin). The dietician will emphasise the importance of adherence to the 
dietary requirements in the study. The patients will be explained that they should 
consume food only from the food boxes that will be provided on a weekly basis. The 
patients will be explained to record adherence to food requirements and liquid 
consumption throughout the day in the food questionnaires from Day -6 (patients not on 
insulin) or Day –20 at the earliest (patients on insulin) onwards until Visit 9 (inclusive). 
Patients on insulin may require a longer Run-in Period in order to be able to adjust their 
insulin requirements according to the caloric content of the food boxes, if needed. 
However, it is not mandatory for the patient on insulin to use the entire extended Run-in 
Period. Based on the Investigator’s judgement, the Run-in Period may be shortened once 
each patient (on insulin) has had sufficient time to adapt to the food boxes, and it is 
determined that the patient’s insulin requirement has stabilised sufficiently to continue in 
the study. 
All SAEs are collected from time of signing the informed consent and throughout the 
study, including the Run-in Period and the Follow-up Period. Adverse events will be 
collected from the time of first dose throughout the study, including the Follow-up 
Period. 
For premenopausal women, the Investigator will estimate the menstrual timing and aim 
to avoid the 2 urine collection periods (Day −3 to 4 and Day 12 to 17) during 
menstruation. 
The following procedures are performed at Visit 1: 
• Signing of informed consent 
• Receive enrolment number  
• Eligibility criteria 
• Demographics 
• Medical and surgical history 


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Clinical Study Protocol 
Study code: D1690C00049 
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Investigational product: Dapagliflozin  
 
Final 6.0  
72 of 91 
10 Jan 2020 
• Vital signs (blood pressure and pulse)  
• Physical examination 
• Weight and height 
• ECG 
• Discussion with study dietician regarding food boxes 
• Blood sampling 
- 
Safety laboratory assessments (haematology and clinical chemistry) 
- 
HbA1c 
• Urine samples 
- 
Spot urine sampling for estimation of urinary albumin excretion (UACR) 
- 
Urine dipstick for safety laboratory assessments 
- 
Urine pregnancy test for women of childbearing potential  
• Concomitant medication 
• SAEs  
• Dispense equipment for 24-hr urine collection 
7.2.2 Run-in Period: Day −6 to Day −1 (Patients not on Insulin) and Day −20 (at the 
earliest) to Day −1 (Patients on Insulin) 
Patients meeting all eligibility criteria (based on available investigations) will be 
scheduled for the Run-in Period starting on Day −6 (patients not on insulin) or Day −20 
at the earliest (patients on insulin). 
• Patients will receive a phone call from the dietician on Day −7 (patients not on 
insulin) or Day –21 at the earliest (patients on insulin) as a reminder for the food 
boxes that they will have to start using from Day −6 or Day −20 (at the earliest) 
onwards, respectively, until the end of study; and to remind them to complete the 
food questionnaire starting Day −6 (patients not on insulin) or Day –20 at the 
earliest (patients on insulin) 
• There will be regular contacts between Investigators and patients to ensure that 
their blood glucose is adequately controlled (by potentially adjusting/optimising 
their insulin doses) and to confirm that their insulin regime remains stable while 
on food boxes. Patient consultation with Investigator may occur at several times 
from Day -20 to Day -1. Exact dates will be decided on an as needed basis by 
patient and Investigator. 
• Dietary advice and food boxes with a daily sodium content of approximately 
150 mmol will start at Day −6 (patients not on insulin) or Day –20 at the earliest 
(patients on insulin) 
• Patients will also start completing food questionnaires starting at Day −6 (patients 
not on insulin) or Day –20 at the earliest (patients on insulin) 
• Patients will start collection of first 24-hr urine sample on Day −3 


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7.2.2.1 Visit 2: Day −2 
• Patient to start collection of 24-hr urine sample 
• Obtain 24-hr urine sample from previous day  
• Dietary advice  
• Concomitant medications 
• SAEs  
• Review of food questionnaires completed by the patient 
7.2.2.2 Visit 3: Day −1 
Following procedures will be performed at this visit: 
• Eligibility criteria check:  
At this visit the inclusion criterion pertaining to stable urinary sodium excretion on 
2 successive 24-hr urinary sodium excretion measurements will be confirmed, based 
on <20% difference between samples obtained on Day −3 and Day −2 (inclusion 
criterion 13, Section 4.1.2). 
• Vital signs (blood pressure and pulse)  
• Obtain 24-hr urine sample from previous day  
• Patient to start collection of 24-hr urine sample  
• Start 24-hr ABPM 
• Dietary advice 
• Concomitant medication 
• SAEs  
• Review of food questionnaires completed by the patient 
Patients will be instructed the following: 
- 
 
7.2.3 Treatment Period (Day 1 to Day 14) 
7.2.3.1 Visit 4: Day 1 (Dosing Initiation Visit) 
Treatment with dapagliflozin 10 mg/day will be initiated on Day 1 for eligible patients 
after blood sampling. 
• Obtain 24-hr urine sample from previous day (ie, Day −1)  
• Patient to start collection of 24-hr urine sample  
• Discontinue 24-hr ABPM 
• Vital signs (blood pressure and pulse)  
• Body weight 
• Pre-dose blood and urine samples 
- 
Safety laboratory assessments (haemoglobin, creatinine, haematocrit, and glucose 
all of which [except haemoglobin] are also 
) 
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- 
 
 
- 
 
• Patient will have breakfast at the study site along with non-study drugs  
• Bioimpedance spectroscopy measurement (pre-dose; 1 hr after food intake) 
• Measurements for plasma volume (pre-dose; approximately 1.5 hr after food 
intake) 
• Administration of first dose of study drug at the study site  
• Dietary advice  
• Concomitant medication 
• AEs/SAEs  
• Review of food questionnaires completed by the patient 
• Dispensation of study drug sufficient for up to 15 days of treatment duration  
Patients will be asked to follow the procedures below until the next clinic visit: 
- 
collect 24-hr urine samples on Day 2 and Day 3 
- 
follow dietary advice daily 
- 
complete food questionnaires daily 
- 
 for the next clinic visit on Day 4 
and to bring the study drug to the clinic for consumption after the blood sampling 
7.2.3.2 Visit 5: Day 4 
Following procedure will be performed at this visit: 
• Obtain 24-hr urine sample from previous days (ie, Days, 1, 2 and 3)  
• Patient to start collection of 24-hr urine sample  
• Vital signs (blood pressure and pulse)  
• Body weight 
• Pre-dose blood and urine samples  
- 
Safety laboratory assessments (creatinine, haematocrit, and glucose all of which 
are 
) 
- 
 
 
- 
Pre-dose blood sample for dapagliflozin pharmacokinetics 
- 
 
• Patient will have breakfast at the study site along with study drug (t=0) and 
non-study drugs 
• Bioimpedance spectroscopy measurement (1 hr after study drug intake) 
• Measurements for plasma volume (approximately 1.5 hr after study drug intake) 
• Start 24-hr ABPM 
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• Verify study treatment intake from diaries 
• Dietary advice 
• Concomitant medication 
• AEs/SAEs  
• Review of food questionnaires completed by the patient 
7.2.3.3 Visit 6: Day 5 
Following procedure will be performed at this visit 
• Obtain 24-hr urine sample from previous day (ie, Day 4)  
• Discontinue 24-hr ABPM  
• Verify study treatment intake from diaries 
• Dietary advice 
• Concomitant medication 
• AEs/SAEs  
• Review of food questionnaires completed by the patient 
Patients will be asked to follow the procedures below until the next clinic visit (Visit 7): 
- 
collect 24-hr urine samples starting 1 day before Visit 7. 
- 
follow dietary advice daily 
- 
complete food questionnaires daily 
7.2.3.4 Visit 7: Day 13 
A window of ± 1 day is allowed for this visit; however, 24-hr urine sample collection 
should be started a day prior to the visit. 
The following procedure will be performed at this visit: 
• Obtain 24-hr urine sample from previous day 
• Patient to start collection of 24-hr urine sample  
• Start 24-hr ABPM 
• Verify study treatment intake from diaries 
• Dietary advice 
• Concomitant medication 
• AEs/SAEs  
• Review of food questionnaires completed by the patient 
Patients will be instructed the following: 
- 
) for the next clinic visit on the next 
day and to bring the study drug to the clinic for consumption after the blood 
sampling 
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7.2.3.5 Visit 8: Day 14 
Visit 8 is the final Treatment Period Visit and will occur 1 day after Visit 7 (Day 13 
±1 day). Patients will take their last dose of dapagliflozin on Visit 8.  
The following procedure will be performed at this visit: 
• Obtain 24-hr urine sample from previous day 
• Patient to start collection of 24-hr urine sample  
• Discontinue 24-hr ABPM  
• Vital signs (blood pressure and pulse) 
• Body weight 
• Pre-dose blood and urine samples  
- 
Safety laboratory assessments (haematology and clinical chemistry) 
 
 
- 
 
- 
Urine dipstick 
- 
Urine pregnancy test for women of childbearing potential 
- 
Pre-dose blood sample for dapagliflozin pharmacokinetics 
• Pre-dose bioimpedance spectroscopy measurement 
• Patient will have breakfast at the study site along with study drug (t=0) and 
non-study drugs 
• Bioimpedance spectroscopy measurement (1 hr post-dose) 
• Blood sample for dapagliflozin pharmacokinetics (1 hr post-dose) 
• Measurements for plasma volume (approximately 1.5 hr post-dose) 
• Bioimpedance spectroscopy measurement (2 hr post-dose) 
• Blood sample for dapagliflozin pharmacokinetics (2 hr post-dose) 
• Bioimpedance spectroscopy measurement (4 hr post-dose) 
• Blood sample for dapagliflozin pharmacokinetics (4 hr post-dose) 
• Verify study treatment intake from diaries 
• Drug accountability (based on tablet counts) 
• Dietary advice 
• Concomitant medication 
• AEs/SAEs  
• Review of food questionnaires completed by the patient 
Patients will be asked to follow the procedures below until the next clinic visit: 
- 
collect 24-hr urine samples on Day 15, Day 16, and Day 17 
- 
follow dietary advice daily 
- 
complete food questionnaires daily 
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- 
 for the next visit on Day 18  
7.2.4 Follow-up Period (Day 15 to Day 19) 
The patients will have a Follow-up Period for 5 days starting 1 day after Visit 8. 
7.2.4.1 Visit 9: Day 18 
Visit 9 will occur on the 4th day of the Follow-up Period.  
Following procedures will be performed at this visit: 
• Obtain 24-hr urine sample from previous days (ie, Days 14, 15, 16, and 17)  
• Vital signs (blood pressure and pulse) 
• Physical examination 
• Body weight 
• 
 and urine samples 
 
 
- 
 
• Patient will have breakfast at the study site along with non-study drugs 
• Bioimpedance spectroscopy measurement (1 hr after food intake) 
• Measurements for plasma volume (approximately 1.5 hr after food intake) 
• Start 24-hr ABPM 
• Dietary advice 
• Concomitant medication 
• AEs/SAEs  
• Review of food questionnaires completed by the patient 
7.2.4.2 Visit 10: (End of Study) Day 19 
Visit 10 is the final visit in the study and will occur on the 5th day of the Follow-up 
Period. Following procedures will be performed at this visit: 
• Discontinue 24-hr ABPM  
• Return equipment 
• Concomitant medication 
• AEs/SAEs  
7.2.5 Unscheduled Visits 
An unscheduled visit can be performed as required for evaluation of a safety concern or 
any other reason.  
The following will be performed at unscheduled visit. Additional 
investigations/procedures can be performed as per the Investigator’s clinical judgement.  
• AEs 
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• Concomitant medication 
• Vital signs (blood pressure and pulse) 
7.2.6 Early Termination Visit 
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 study treatment. If patients can continue the study treatment up to the day of the 
Early Termination Visit, the observations and procedures scheduled for Visit 8 including 
repeated PK and BIS (Section 7.2.3.5) should be performed. If not, the Early Termination 
Visit should be handled as Visit 9 (Section 7.2.4.1). 


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8 
STATISTICAL METHODS 
The statistical considerations summarised in this section outline the plan for data analysis 
of this study.  
A separate statistical analysis plan (SAP) will be finalised prior to database lock.  
Any deviations from the planned analyses will be described in a SAP amendment. Any 
deviations from the planned analyses will be described and justified in the final 
integrated CSR. 
 
 
8.1 
Study Patients 
8.1.1 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. 
Analysis Set  
 
Definition 
Enrolled Set (ENS): 
All patients who provided informed consent will be 
included in the ENS. 
Run-in Set: 
All patients who are provided with the standard food 
boxes. 
Medication Dispensed Set (MDS): All patients who dispensed at least one dose of study 
drug. 
Evaluable Subjects Data Set:  
This will be a subset of the MDS. It will exclude 
primary efficacy variable data which may have been 
affected by protocol deviations as determined by the 
medical monitor or agreed by the study team. All 
decisions to exclude data from the Run-in Set to form 
the Evaluable Subjects Analysis Data Set will be 
made prior to the database lock of the study. 
Safety Set (SAF): 
All patients who received at least 1 dose of study 
drug and who have data from at least one post-dose 
safety assessment available. 
All safety analyses will be based on the SAF. 
Demographic and baseline characteristics will be summarised for the SAF. 
8.2 
General Considerations 
Statistical analyses will be performed using SAS® (SAS Institute Inc., Cary, NC, US) 
Version 9.3 or higher unless otherwise specified. 
All statistical tests will be 2-sided and will be performed at the 5% level of significance, 
unless otherwise stated. 
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8.3 
Efficacy Analyses 
The Baseline for 24-hr urinary related endpoints is the average of the daily urinary 
sodium excretion from Days −3, −2 and −1 assessments prior to the date of the first dose 
of the study treatment (with the exception of 
 for which the Baseline 
is the urinary assessment from Day −1). 
8.3.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the average change in 24-hr sodium excretion from 
average Baseline to average values at Day 2 to 4 within each study group. This will be 
analysed as follows “average change in 24-hr sodium excretion during dapagliflozin 
treatment between Baseline (average of Days −3 to −1) and average of Days 2 to 4 within 
each study group”. 
The primary analysis will be performed separately for each study group using a 
longitudinal repeated-measures analysis for the “change from average Baseline” as 
dependent variable, with a term for Baseline value. Point estimates and 95% confidence 
intervals will be calculated for the adjusted mean changes within each study group.  
The primary analysis will be based on the Evaluable Subjects Analysis Set. 
8.3.2 Secondary Efficacy Analyses 
The secondary analyses will be based on the Evaluable Subjects Analysis Set. 
The endpoints listed in Section 3.2.2 will be analysed using the same model and 
presentation as for the primary efficacy analysis. 
8.3.2.1 Secondary Pharmacokinetic Analyses 
Plasma concentrations of dapagliflozin will be listed, summarised and plotted vs time 
relative to intake of dapagliflozin. A population pharmacokinetic analysis of data may be 
performed as outlined in a separate population pharmacokinetic analysis plan. 
 
 
  
8.3.4 Food Intake Questionnaires 
Results from patients’ food intake questionnaire will be listed. 
8.4 
Safety Analyses 
8.4.1 Adverse Events 
The analysis of safety will be based on the SAF. Safety data gained during the study 
period will be evaluated and variables will only be summarised descriptively. 
Adverse events will be presented by preferred term and system organ class. 
Continuous data will be summarised with number of observations, mean, standard 
deviation, minimum and maximum value, and median. 
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Categorical data will be summarised with absolute and relative frequency. 
 
 
 
8.5 
Partial Analyses 
As recruitment rate for Group 1 is slower than expected, a partial analysis based on all 
patients from Group 2 and Group 3, but none from Group 1, might be conducted. If such 
an analysis takes place, a formal Data Review Meeting (DRM) will be held prior to its 
initiation. At the DRM, all protocol deviations related to the patients in these two groups 
will be discussed and the impact on the analysis sets to be used for the partial analysis 
will be assessed. The partial analysis will include all the evaluations originally planned to 
be conducted, and reported, for all three groups simultaneously. 
Further details on the planned analyses will be given in the study SAP. 
8.6 
Determination of Sample Size 
With a sample size of 15 patients per group and assuming a conservative standard 
deviation (SD) of 25 mEq/24 hrs in change from average Baseline in 24-hr sodium 
excretion, at an assumed increase of 20 mEq/24 hrs (delta), the study will have 80% 
power to detect an increase of at least 20 mEq/24 hrs in average change from average 
Baseline 24-hr sodium excretion with dapagliflozin within each group at a two-sided 
alpha level of 0.05. Under these conventions the minimum detectable difference in 
change from average Baseline in 24-hr sodium excretion is approximately 
13.6 mEq/24 hrs. Similarly, under sample size conventions when fixing the change from 
average Baseline in 24-hr sodium excretion (delta) of 20 mEq/24 hrs, the maximum SD 
at which statistical significance can be demonstrated is approximately 37 mEq/24 hrs.  
It is assumed that approximately 10% of the enrolled patients will not provide evaluable 
data with regards to the primary endpoint, leading to 17 patients to be enrolled in each of 
the groups. If the non-evaluable rate is higher than expected, additional patients might be 
enrolled in order to ensure 15 evaluable patients. 
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9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1 
Data Quality Assurance 
AstraZeneca or 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 (ie, medical records). 
9.1.1 Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each study 
centre 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 centre, 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.  
Data that will be entered directly into the eCRF (ie, 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 PAREXEL site monitor. After review by the site monitor, completed 
eCRF entries will be uploaded and forwarded to PAREXEL. 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 the 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 authorised staff) will be given access to an online 
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 authorised 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.  
Computerised 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 online. All discrepancies will be 
solved online directly by the Investigator or by authorised 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 treatment dispensed and returned from the patient will be tracked on 
the eCRF.  
Data from external sources (such as central laboratory data and data for blood pressure 
measurements from 24-hr ABPM) will be imported into the database using SAS. 
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, Institutional Review Boards (IRBs), 
Independent Ethics Committees (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 PAREXEL and AstraZeneca of the necessary support at all times. 


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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 
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 AEs will be coded using the latest available version of 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 Harmonisation (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 AstraZeneca and 
Investigator abide by the principles of the Good Clinical Practice (GCP) 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.  
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 Informed consent form (ICF) 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 ICF may need to be revised to reflect the 
changes to the protocol. If the ICF 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. 


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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. AstraZeneca must ensure that all ethical and legal requirements have been 
met before the first patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be 
written and approval obtained from the appropriate personnel and IRB/IEC/Competent 
Authority prior to implementation (if appropriate).  
Administrative changes (not affecting the patient benefit/risk ratio) may be made without 
the need for a formal amendment. 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 of the study will be up to 62 days 
(including up to 6 weeks for Screening and Run-in Period, 2-week Treatment Period, and 
5-day Follow-up Period, and 1 additional day for allowed window periods).  
The study will close when all patients have completed the last visit (Visit 10). 
9.10 Premature Termination of the Study 
9.10.1 Stopping Rules for an Individual Patient 
Withdrawal criterial for an individual patient are specified in Section 4.5. 
9.10.2 Stopping Rules for the Study 
If the Investigator, AstraZeneca, or the medical monitor 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 study 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 eCRFs and other documents submitted to PAREXEL by their patient number, not by 


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name. Documents not to be submitted to PAREXEL that identify the patient (eg, the 
signed informed consent) must be maintained in confidence by the Investigator.  


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10 REFERENCE LIST 
1 
World Medical Association Declaration of Helsinki. Recommendations guiding 
physicians in biomedical research involving human subjects. Adopted by the 18th 
WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 29th 
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 
Assembly, Washington 2002, Note of Clarification on Paragraph 30 added by the 
WMA General Assembly, Tokyo 2004, 59th WMA General Assembly, Seoul, 
South Korea, October 2008, and 64th WMA General Assembly, Fortaleza, Brazil, 
October 2013.  
2 
Sjöström CD, Greasley PJ, Xu J, Heerspink HJL. Differential effects of 
dapagliflozin on cardiovascular risk factors at varying degrees of renal function. 
EASD abstract 2016. 
3 
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E et al. Empagliflozin, 
cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 
373:2117-28. 
4 
Sjöström CD, Johansson P, Sugg J, Johnsson E. Dapagliflozin reduces albuminuria 
on top of renin angiotensin system blockade in diabetic patients with moderate 
renal impairment. Abstr. SAT-461 ISN World Congress of Nephrology, March 
2015, Cape Town. 
5  
Fioretto P, Giaccari A and Sesti G. Efficacy and safety of dapagliflozin, a sodium 
glucose cotransporter 2 (SGLT2) inhibitor, in diabetes mellitus. Cardiovasc 
Diabetol. 2015;14:142. 
6  
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney 
disease in type 2 diabetes; EMPA-REG OUTCOME Investigators. N Engl J Med. 
2016;375:323-34. 
7  
Rajasekeran H, Lytvyn Y, Cherney DZI. Sodium–glucose cotransporter 2 
inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the 
emerging role of natriuresis. Kidney International. 2016;89:524–6. 
8 
De Nicola L, Gabbai FB, Liberti ME, et al. Sodium/glucose cotransporter 2 
inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in 
diabetes. Am J Kidney Dis. 2014;64:16-24. 
9  
Thomas MC. Renal effects of dapagliflozin in patients with type 2 diabetes. Ther 
Adv Endocrinol Metab. 2014;5:53-61. 
10  
Pollock CA, Field MJ, Bostrom TE, et al. Proximal tubular cell sodium 
concentration in early diabetic nephropaty assessed by electron microprobe 
analysis. Pflügers Archiv. 1991;418:14-7. 
 
 


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Investigational product: Dapagliflozin  
 
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10 Jan 2020 
 
11  
Komala MG, Panchapakesan U, Pollock C, et al. Sodium glucose cotransporter 2 
and the diabetic kidney. Curr Opin Nephrol Hypertens. 2013;22:113–9. 
12  
Heerspink HJL, de Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug 
with diuretic properties in subjects with type 2 diabetes. Diabetes, Obesity and 
Metabolism. 2013;15:853–62. 
13  
Baker WL, Smyth LR, Rich DM, et al. Effects of sodium-glucose co-transporter 2 
inhibitors on BP: A systematic review and meta-analysis. J Am Soc Hypertens. 
2014;8:262-75. 
14 
Spencer AG, Greasley PJ. Pharmacologic inhibition of intestinal sodium uptake: a 
gut centric approach to sodium management. Curr Opin Nephrol Hypertens. 
2015;24:410-6. 
15  
Novikov A, Vallon V. Sodium glucose cotransporter 2 inhibition in the diabetic 
kidney: an update. Curr Opin Nephrol Hypertens. 2016;25:50-8. 
16  
Schey KL, Luther JM, Rose KL. Proteomics characterization of exosome cargo. 
Methods. 2015;87:75-82. 
17  
Coresh J, Astor BC, Greene T, et al. Prevalence of Chronic Kidney Disease and 
Decreased Kidney Function in the Adult US Population: Third National Health and 
Nutrition Examination Survey. Am J Kidney Dis. 2003; 41:1-12. 
18  
De Fronzo, Hompesch M, Kasichayanula S, et al. Characterization of Renal 
Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and 
Subjects with Type 2 Diabetes. Diabetes Care. 2013;36:3169-76. 
19  
Jacob M, Conzen P, Finsterer U, et al. Technical and physiological background of 
plasma volume measurement with indocyanine green: a clarification of 
misunderstandings. J Appl Physiol. 2007;102(3):1235-42. 
20  
Speich R, Saesseli B, Hoffmann U, et al. Anaphylactoid reactions after 
indocyanine-green administration. Ann Intern Med. 1988;109(4):345-6. 
21  
Garski TR, Staller BJ, Hepner G, et al. Adverse reactions after administration of 
indocyanine green. JAMA. 1978;240(7):635. 
22  
Summary of Product Characteristics (SPC) Verdye. Available at 
http://www.mhra.gov.uk/spc-
pil/?prodName=VERDYE&subsName=INDOCYANINE%20GREEN&pageID=S
econdLevel. Accessed on 14 December 2016. 
23  
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009;150(9):604-12. 


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11 APPENDICES 
11.1 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 (eg, hepatitis that resolved without hepatic 
failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the 
reasons for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or 
surgical operations planned before or during a study are not considered AEs if the illness 
or disease existed before the subject was enrolled in the study, provided that it did not 
deteriorate in an unexpected way during the study. 
Important Medical Event or Medical Intervention 
Medical and scientific judgement should be exercised in deciding whether a case is 
serious in situations where important medical events may not be immediately life-
threatening or result in death, hospitalisation, disability or incapacity but may 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 intravenous 
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 (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation. 
• 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? 


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• Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the 
same pharmacological class? Or could the AE be anticipated from its 
pharmacological properties? 
• 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 recognised 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 judgement. 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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11.2 International Airline Transportation Association (IATA) 6.2 Guidance 
Document 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents 
into 3 categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). 
For transport purposes the classification of infectious substances according to risk groups 
was removed from the Dangerous Goods Regulations in the 46th edition (2005). 
Infectious substances are now classified either as Category A, Category B or Exempt. 
There is no direct relationship between risk groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when 
exposure to it occurs, is capable of causing permanent disability, life-threatening or fatal 
disease in otherwise healthy humans or animals. Category A pathogens are eg, Ebola, 
Lassa fever virus: 
• are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria 
for inclusion in Category A. Category B pathogens are e.g., hepatitis A, B, C, D, and E 
viruses, human immunodeficiency virus (HIV) types 1 and 2. They are assigned the 
following UN number and proper shipping name: 
• UN 3373 – Biological Substance, Category B 
• are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
• Clinical trial samples will fall into Category B or exempt under IATA regulations 
• Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm) 
• Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
• IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable 
• Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail 
transport is used. 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
DAPASALT: An Open Label, Phase IV, Mechanistic, Three-Arm Study to 
Evaluate the Natriuretic Effect of 2-Week Dapagliflozin treatment in Type 2 
Diabetes Mellitus Patients with Either Preserved or Impaired Renal Function 
and Non-Diabetics with Impaired Renal Function 
 
 
ClinicalTrials.gov Identifier: NCT03152084 
 
 
 
Date of Statistical Analysis Plan: 25 October 2019 


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STATISTICAL ANALYSIS PLAN  
 
 
 
 
 
D1690C00049 
 
DAPASALT: An Open Label, Phase IV, Mechanistic, Three-Arm Study to 
Evaluate the Natriuretic Effect of 2-Week Dapagliflozin Treatment in Type 
2 Diabetes Mellitus Patients with Either Preserved or Impaired Renal 
Function and Non-Diabetics with Impaired Renal Function 
 
 
Version:  Final 3.0 
Date: 25 Oct 2019 
 
 
 
 
 
 
 
 
 
 
 


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REVISION HISTORY 
Version 
Version Date 
Author 
Summary of Changes 
Made 
Final 1.0 
28Jun2017 
NA 
Final 2.0 
06 Nov2018 
NA 
Final 3.0  
25 Oct 2019 
Updated according to 
Dry Run comments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
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TABLE OF CONTENTS 
 
 
REVISION HISTORY ............................................................................................................. 2 
SIGNATURE PAGE - ASTRAZENECA ................................................................................ 4 
SIGNATURE PAGE - PAREXEL ........................................................................................... 5 
TABLE OF CONTENTS ......................................................................................... 6 
STATISTICAL ANALYSIS PLAN ...................................................................... 11 
1. 
STUDY OBJECTIVES .......................................................................................... 12 
1.1 
Primary Objective .................................................................................................. 12 
1.2 
Secondary Objectives ............................................................................................. 12 
1.4 
Safety Objectives ................................................................................................... 13 
2. 
STUDY DESIGN ................................................................................................... 13 
3. 
STATISTICAL BASIS FOR SAMPLE SIZE ....................................................... 15 
4. 
RANDOMISATION .............................................................................................. 15 
5. 
STATISTICAL ANALYSIS CONVENTIONS .................................................... 16 
5.1 
Analysis variables .................................................................................................. 16 
5.1.1 
Demographic and baseline variables...................................................................... 16 
5.1.2 
Prior and concomitant medication ......................................................................... 16 
5.1.3 
Safety variables ...................................................................................................... 16 
5.1.3.1 
Adverse events ....................................................................................................... 16 
5.1.3.2 
Clinical laboratory tests ......................................................................................... 16 
5.1.3.3 
Vital signs .............................................................................................................. 17 
5.1.3.4 
12-lead safety electrocardiogram ........................................................................... 17 
5.1.3.5 
Physical examination ............................................................................................. 18 
5.1.4 
Pharmacokinetic variables ..................................................................................... 18 
5.1.5 
Efficacy variables ................................................................................................... 18 
5.1.5.1 
Primary Efficacy Endpoint .................................................................................... 18 
5.1.5.2 
Secondary Efficacy Endpoints ............................................................................... 18 
5.2 
Analysis sets ........................................................................................................... 21 
5.2.1 
Enrolled Set ............................................................................................................ 21 
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5.2.2 
Run-in Set .............................................................................................................. 21 
5.2.3 
Medication Dispensed Set ...................................................................................... 21 
5.2.4 
Evaluable Subjects Data Set .................................................................................. 21 
5.2.5 
Pharmacokinetic analysis set ................................................................................. 21 
5.2.6 
Safety Set ............................................................................................................... 21 
5.3 
Statistical analysis methods, general principles ..................................................... 21 
5.3.1 
Listings and descriptive statistics ........................................................................... 22 
5.3.2 
Handling of repeat and unscheduled measurements .............................................. 22 
5.3.3 
Statistical significance level ................................................................................... 22 
5.3.4 
Software ................................................................................................................. 23 
5.3.5 
Missing and censored data ..................................................................................... 23 
5.3.6 
Laboratory data reported above or below a threshold............................................ 23 
5.3.7 
Center pooling strategy .......................................................................................... 23 
5.3.8 
Coding dictionaries ................................................................................................ 23 
5.3.9 
Study population characteristics ............................................................................ 23 
5.3.9.1 
Patient disposition .................................................................................................. 23 
5.3.9.2 
Protocol deviations ................................................................................................. 24 
5.3.10 
Demographics, medical history and baseline data ................................................. 24 
5.3.11 
Pregnancy testing ................................................................................................... 25 
5.3.12 
Prior and concomitant medication ......................................................................... 26 
5.3.13 
Exposure to investigational product ....................................................................... 26 
5.3.14 
Compliance to investigational product .................................................................. 26 
5.3.15 
Food and fluid consumption .................................................................................. 27 
5.3.16 
Efficacy analysis and reporting, general approach ................................................ 27 
5.3.16.1 Statistical models ................................................................................................... 27 
5.3.16.2 24-hour urine data .................................................................................................. 29 
5.3.16.3 24-hour blood pressure monitoring ........................................................................ 30 
5.3.16.4 Measurements for plasma volume estimates ......................................................... 31 
5.3.16.5 Pharmacokinetic concentrations ............................................................................ 32 
5.3.16.6 Censored data for pharmacokinetic evaluation ...................................................... 32 
5.3.16.7 Bioimpedance spectroscopy ................................................................................... 33 
 
5.3.18 
Safety analysis ....................................................................................................... 35 
5.3.18.1 Adverse events ....................................................................................................... 35 
5.3.18.2 Clinical laboratory ................................................................................................. 37 
5.3.18.3 Hy´s Law ................................................................................................................ 37 
5.3.18.4 Vital signs .............................................................................................................. 37 
5.3.18.5 Physical examination ............................................................................................. 37 
5.4 
Partial Analysis ...................................................................................................... 37 
6. 
APPENDICES ....................................................................................................... 38 
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7. 
AMENDMENT TO THE STATISTICAL ANALYSIS PLAN ............................ 45 
7.1 
Amendment :Version Final 3.0 .............................................................................. 45 
7.1.1 
Rationale for the amendment ................................................................................. 45 
7.1.2 
List of changes ....................................................................................................... 45 
  
 
 


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ABBREVIATION AND ACRONYM LIST 
Abbreviation / Acronym 
Definition / Expansion 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BIS 
bioimpedance spectroscopy  
BLQ 
below the limit of quantification 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
cm 
centimetre 
CSP 
clinical study protocol 
CSR 
clinical study report 
CV 
coefficient of variation 
DRM 
data review meeting 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ET 
end of treatment 
FU 
follow up 
HbA1c 
glycosylated haemoglobin 
ICG 
indocyanine green 
IMP 
Investigational Medicinal Product 
kg 
kilogram(s) 
L 
litre(s) 
LLOQ 
lower limit of quantification 
LSMEANS 
least-squares means 
m 
metre 
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Abbreviation / Acronym 
Definition / Expansion 
MA 
marked abnormality 
MedDRA 
Medical Dictionary for Regulatory Activities 
mEq 
milliequivalent 
min 
minute 
mL 
millilitre 
mmHg 
millimetres of mercury 
n 
number of patients 
NA 
not applicable 
ND 
not determined 
NQ 
not quantifiable 
PK 
pharmacokinetic(s) 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
ST 
Start of treatment 
T2DM 
type 2 diabetes mellitus  
TLFs 
tables, listings and figures 
UACR  
urine albumin to creatinine ratio 
WHO-DD                                World Health Organisation - Drug Dictionary 
 
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STATISTICAL ANALYSIS PLAN 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analysing 
study data and outlines the statistical programming specifications for the Tables, Listings and 
Figures (TLFs). It describes the variables and analysis sets, anticipated data transformations 
and manipulations and other details of the analyses not provided in the Clinical Study Protocol 
(CSP). 
The analyses described are based on the CSP Version 5.0, dated 23 April 2018. The SAP will 
be finalised prior to database lock and describes the statistical analysis as it is foreseen when 
the study is being planned. If circumstances should arise during the study rendering this 
analysis inappropriate, or if improved methods of analysis should arise, updates to the 
analyses may be made in an updated SAP. Any deviations from the SAP after database lock, 
reasons for such deviations and all alternative or additional statistical analyses that may be 
performed, will be described in a SAP Addendum and discussed in the Clinical Study Report 
(CSR). 
The SAP describes Group 1 as it was originally planned in the latest version of the CSP. it was 
decided that no Group 1 subjects will be enrolled onto this study (please see reference in 
Action log on the 22nd of March 2019), so no statistical outputs will contain Group 1 
information. 
 
 


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1. 
STUDY OBJECTIVES 
1.1 
Primary Objective 
The primary objective is to investigate the change in 24-hour sodium excretion during 
dapagliflozin treatment between Baseline (average of Days −3 to −1) and average of Days 2 to 
4 within each study group. 
 
 
Patients with type 2 diabetes mellitus (T2DM) with impaired renal function; 
 
Patients with T2DM with preserved renal function; 
 
Non-diabetic patients with impaired renal function. 
1.2 
Secondary Objectives 
The secondary objectives of the study, to be assessed for each of the groups, are to: 
 
 
Evaluate the change in 24-hour sodium excretion from Baseline to end of treatment, 
and during follow-up; 
 
Evaluate the change in 24-hour glucose excretion; 
 
Evaluate the change in mean 24-hour systolic blood pressure; 
 
Evaluate the change in plasma volume; 
 
Evaluate the change in extracellular volume; 
 
Evaluate the pharmacokinetics of dapagliflozin; 
 
Evaluate the change in 24-hr urine albumin to creatinine ratio (UACR). 
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1.4 
Safety Objectives 
The safety objectives are to evaluate the safety and tolerability of dapagliflozin in each of the 
target patient populations. 
2. 
STUDY DESIGN 
DAPASALT is an open label, mechanistic, three-arm study to evaluate the natriuretic effect of 
two-week dapagliflozin treatment in T2DM patients with either preserved or impaired renal 
function and in non-diabetics with impaired renal function. 
The study population will comprise three groups of patients: 
 
Group 1: T2DM patients with impaired renal function, defined as having an 
estimated glomerular filtration rate (eGFR), defined by Chronic Kidney Disease 
(CKD) 
Epidemiology 
Collaboration 
(CKD-EPI), 
of 
≥ 
25 
and 
≤ 
50 
millilitres/minute/1.73 metres squared (mL/min/1.73m2); 
 
Group 2: T2DM patients with preserved renal function, defined as having an eGFR, 
defined by CKD-EPI, of > 90 and ≤ 130 mL/min/1.73 m2 for patients aged 59 years 
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or younger, between >85 and ≤130 mL/min/1.73 m2 for patients aged 60 to 69 
years, and between >75 and ≤130 mL/min/1.73 m2for patients aged 70 years or 
older; 
 
Group 3: Non-diabetic patients with impaired renal function, defined as eGFR range 
for Group 1. 
A total of 51 patients are planned to be enrolled in the study, with 17 patients in each group.  
The study periods and schedule of visits are presented in Section 7.1 (Tables 5 and 6) of CSP. 
Briefly, the efficacy measurements will, with some exceptions, be collected four times during 
the course of the study: Visit 4 (day 1 relative to start of treatment), Visit 5 (day 4), Visit 8 
(typically, day 14) and Visit 9 (typically, day 18), with the final time point being post-
treatment. A notable exception is the 24-hour urine, which will be collected on three, or four, 
consecutive days during four time periods, with the last day in these periods being day -1, day 
4, day 14 and day 17, and 24-hr blood pressure, which will be collected at Visit 7 (typically, 
day 13) rather than day 14. Blood samples to evaluate pharmacokinetic (PK) properties of 
dapagliflozin in this population will be taken twice during the study, once during Visit 5 (pre-
dose) and four times during Visit 8 (pre-dose and 1, 2, 4 h post-dose). Additional 
bioimpedence spectroscopy measurements will be performed at the same time as PK sampling 
during Visit 8.   
Adverse events (AE), including serious adverse events (SAE) are collected throughout the 
study, with SAE collection starting at the screening visit and AE collection at dosing, both 
ending at the last visit (Visit 10, typically day 19). Laboratory safety assessments will 
generally be done at Screening (Visit 1), Visit 4 and Visit 8 (See Section 5.1.3.2), with some 
exceptions. 
As many of the efficacy measurements will be taken at four distinctive time periods during the 
course of the study, namely baseline, soon after treatment start, at the end of treatment and at 
the end of follow up, when reporting the efficacy results of the study each measurement will 
be assigned to an analysis window:  
 
 
Baseline is the measurement obtained before initiation of treatment, typically 
during Visit 4. For 24-hr blood pressure, the baseline measurement is the 
measurement obtained the day before Visit 4. 
 
Start of Treatment (ST) is the measurement obtained after the patient has been in 
the study for a short time, typically on Visit 5.  
 
End of treatment (ET) is the measurement obtained on the visit corresponding to 
the last day of the treatment period, namely Visit 8, unless the patient attended an 
early termination visit. For 24-hr blood pressure, as well as 
 
measurements in the 24-hr urine, the end of treatment measurement is the 
measurement obtained the day before Visit 8.  
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 
Follow-up (FU) is the measurement obtained after the end of the treatment period, 
namely Visit 9. 
 
 
 
The exception from the rules outlined above is the 24-hr urine, the collection of which will 
take place on consecutive days, rather than on one single day. In this case, Baseline, ST, ET 
and FU used in the analyses will be the averages of these consecutive samples. Explicitly, 
Baseline is the average of measurements obtained on day -3 to day -1, ST the average of 
measurements obtained on day 2 to day 4, ET the average of measurements obtained on day 
12 to day 14 and FU the average of measurements obtained on day 15 to day 17. 
3. 
 STATISTICAL BASIS FOR SAMPLE SIZE 
With a sample size of 15 patients per group and assuming a standard deviation (SD) of 25 
milliequivalent (mEq)/24 hours in change from average Baseline in 24-hour sodium excretion, 
the study will have 80% power to detect an increase of at least 20 mEq/24 hours in average 
change from average Baseline 24-hour sodium excretion with dapagliflozin within each group 
at a two-sided alpha level of 0.05.  
Under these same conventions for the number of patients, the SD and the alpha level, and 
assuming 50% power, the minimum detectable difference in change from average Baseline in 
24-hour sodium excretion is approximately 13.6 mEq/24 hours. 
Similarly, under the same conventions for the number of patients and the alpha level, 50% 
power and fixing the change from average Baseline in 24-hour sodium excretion to 20 
mEq/24 hours, the maximum SD at which statistical significance can be demonstrated is 
approximately 37 mEq/24 hours. 
It is assumed that approximately 10% of the enrolled patients will not provide evaluable data 
with regards to the primary endpoint, leading to 17 patients to be enrolled in each of the 
groups. If the non-evaluable rate is higher than expected, additional patients might be enrolled 
in order to ensure 15 evaluable patients.  
4. 
RANDOMISATION 
Randomisation will not be applied in this study.  Patients will be enrolled to specific groups 
based on their diagnosis. When 17 patients have been enrolled to each specific patient group 
enrolment into that group will stop, and the evaluability of the data evaluated. If less than 15 
evaluable patients in a particular group are found, the recruitment into that group might 
resume. All patients will receive dapagliflozin 10 mg tablets once daily for 14 days. 
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5. 
STATISTICAL ANALYSIS CONVENTIONS 
5.1 
Analysis variables 
5.1.1 
Demographic and baseline variables 
During the screening visit, baseline patient characteristics (e.g. age, gender and race) will be 
collected. Relevant medical and surgical history will be recorded, as well as details of T2DM 
(for T2DM patients) and renal impairment (for patients with impaired renal function). Vital 
signs, such as pulse and blood pressure, will also be registered. For a detailed list of baseline 
assessments, please see Appendix A. 
5.1.2 
Prior and concomitant medication 
Any medications administered other than dapagliflozin or indocyanine green (ICG) will be 
classified as prior or concomitant. The following definitions of prior and concomitant 
medications will be used: 
 
 
Prior medication: medications that have been taken prior to first dapagliflozin dose 
and which have a stop date which indicates that the medication has been stopped 
before first dapagliflozin are considered prior medication. 
 
Concomitant medication: medications with a start date on or after first 
dapagliflozin dose are considered concomitant medications. In addition, 
medications with a start date of administration prior to the date of first dapagliflozin 
administration, but which have an end date (or are ongoing) on or after first 
dapagliflozin administration will be considered as both concomitant and prior 
medication.  
5.1.3 
Safety variables 
5.1.3.1 
Adverse events 
AEs and Serious AEs (SAEs), are defined in Section 6.2.1 of the CSP. SAEs will be collected 
from the time of informed consent until the end of the Follow-up period.  All other AEs will 
be recorded from first dose until the end of the Follow-up period.  
5.1.3.2 
Clinical laboratory tests 
Clinical laboratory tests for safety and eligibility evaluation will be performed pre-dose and 
during the study (refer to Table 5 and Table 6 study plan for schedule of assessments on the 
Clinical Study Protocol). 


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The following variables will be measured: 
Lab 
Screening 
Baseline  
ST 
ET 
FU 
Clinical chemistry 
Creatinine 
x 
x 
x 
x 
x 
Glucose 
x 
x 
x 
x 
x 
Total bilirubin 
x 
 
 
x 
 
AST 
x 
 
 
x 
 
ALT 
x 
 
 
x 
 
ALP 
x 
 
 
x 
 
Haematology (a) 
Haemoglobin 
x 
x 
 
x 
 
Haematocrit 
x 
x 
x 
x 
x 
HbA1C (b) 
x 
 
 
 
 
Urinalysis 
UACR (b) 
x 
 
 
 
 
Dipstick (c) 
x 
 
 
x 
 
Other 
Pregnancy test 
x 
 
 
x 
 
(a) 
Note that haematocrit, glucose and creatinine will also be analysed as efficacy endpoints. If the urine pregnancy test is positive, then a serum pregnancy test 
will also be performed 
(b) 
For evaluation of the inclusion / exclusion criteria 
(c) 
Tests performed are U-albumin, U-glucose and U-blood 
 
5.1.3.3 
Vital signs 
The following measurements will be performed at each time-point: 
 
Blood pressure (systolic and diastolic, measured in millimetres of mercury 
[mmHg]) 
 
Pulse rate (measured in beats per minute) 
 
Weight (kg) 
5.1.3.4 
12-lead safety electrocardiogram  
A 12-lead electrocardiogram (ECG) will be obtained at Screening. 
The Investigator will provide an overall interpretation of the ECG as normal, abnormal or 
borderline and the result will be recorded in the eCRF.  If abnormal, the clinical significance 


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(clinically significant or not clinically significant), and the details of the abnormality, will also 
be recorded in the eCRF.   
5.1.3.5 
Physical examination 
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. 
5.1.4 
Pharmacokinetic variables 
There will be no pharmacokinetic parameters derived.  A population pharmacokinetic analysis 
of data may be performed as outlined in a separate population pharmacokinetic analysis plan 
and the results of this will be reported outside of the CSR and will not be further discussed in 
this SAP. 
5.1.5 
Efficacy variables 
The full list of measurements performed during the study that are used to evaluate efficacy can 
be found in Appendix B  . 
5.1.5.1 
Primary Efficacy Endpoint 
Average change in 24-hr sodium excretion from average Baseline to average values at Day 2 
to 4 within each study group. 
5.1.5.2 
Secondary Efficacy Endpoints 
The secondary endpoints to be evaluated during or following dapagliflozin treatment within 
each study group are: 
 
Average change in 24-hr sodium excretion from average Baseline values to average 
end of treatment values (Day 12 to 14); and from average end of treatment values 
(Day 12 to 14) to average values during Follow-up (Day 15 to 17). 
 
Average change in 24-hr glucose excretion from average Baseline values to average 
values at Day 2 to 4; from average Baseline values to average end of treatment 
values (Day 12 to 14); and from average end of treatment values (Day 12 to 14) to 
average values during Follow-up (Day 15 to 17). 
 
Change in mean 24-hr systolic blood pressure from Baseline to Day 4; from 
Baseline to end of treatment (Day 13); and from end of treatment (Day 13) to end of 
Follow-up (Day 18). 
 
Change in plasma volume from Baseline to Day 4; from Baseline to end of 
treatment (Day 14); and from end of treatment (Day 14) to end of Follow-up 
(Day 18). 


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 
Change in extracellular volume from Baseline to Day 4; from Baseline to end of 
treatment (Day 14); and from end of treatment (Day 14) to end of Follow-up 
(Day 18). 
 
Dapagliflozin pharmacokinetics on Days 4 and 14. 
 
Average change in mean 24-hr UACR from average Baseline to Day 4; and from 
average Baseline values to average end of treatment values (Day 12 to 14). 
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5.2 
Analysis sets 
5.2.1 
Enrolled Set 
All patients who provided informed consent will be included in the Enrolled Set. 
5.2.2 
Run-in Set 
All patients who received standard food boxes will be included in the Run-in Set.  
5.2.3 
Medication Dispensed Set 
All patients who were dispensed at least one dose of study drug will be included in the 
Medication Dispensed Set. 
5.2.4 
Evaluable Subjects Data Set 
This will be a subset of the Medication Dispensed Set. It will exclude primary efficacy 
variable data which may have been affected by protocol deviations as determined by the 
medical monitor or agreed by the study team. All decisions to exclude data from the Evaluable 
Subjects Data Set will be made prior to the database lock of the study during the Data Review 
Meeting (DRM). 
5.2.5 
Pharmacokinetic analysis set  
The Pharmacokinetic (PK) analysis set will consist of all subjects in the medication dispensed 
set for whom at least one of the plasma concentration samples are available and who have no 
important protocol deviations judged to impact the analysis of the PK data.  
 
5.2.6 
Safety Set  
All patients who took at least one dose of study drug and who have data from at least one 
post-dose safety assessment available will be included in the Safety Set. 
5.3 
Statistical analysis methods, general principles 
Statistical evaluation will be performed by PAREXEL. Analysis Data will adhere to CDISC 
(Clinical Data Interchange Standards Consortium) guidance documents for Analysis Data 
Model (ADaM) and follow their AZ interpretation. 
The term “by group” will refer to the grouping of summary data based on the groups as 
defined in Section 2 in all cases, unless otherwise specified: 
 
Group 1: T2DM patients with impaired renal function; 
 
Group 2: T2DM patients with preserved renal function; 
 
Group 3: Non-diabetic patients with impaired renal function. 


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In case of a pre-mature termination of the study, or a request of a report of the current results 
while the study is on-going, all the analyses will be performed on the data available. If there 
are no patients in one of the groups above, the group will be omitted from all the 
presentations.   
5.3.1 
Listings and descriptive statistics 
Data will be summarised using descriptive statistics. 
For each qualitative variable, frequency counts (number of patients [n] and percentages) will 
be made.  The percentages will be calculated with respect to number of patients in each group. 
For continuous variables, descriptive statistics will include n, arithmetic mean, standard 
deviation (SD), median, minimum and maximum, and might include the first and the third 
quartile. Geometric coefficient of variation (geometric CV%), geometric mean and geometric 
SD will also be presented in the descriptive statistics for the PK concentration data.  
General rounding rules will be followed with regard to the number of decimal places and 
presentation of data in the tables and listings unless it is deemed scientifically appropriate to 
display the data in a different format (see Appendix C). 
5.3.2 
Handling of repeat and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the listings. The following 
general rules will apply to all repeated and unscheduled measurements: 
 For repeated measurements obtained prior to the first dose of dapagliflozin the latest 
value (which may be scheduled or unscheduled) will be used in the calculation of 
descriptive statistics 
 For repeated measurements obtained at the designated Baseline visit, the latest value 
(which may be scheduled or unscheduled) will be defined as the Baseline provided that 
this occurred prior to the first dose of dapagliflozin. Repeated measurements designated 
Baseline will be used in descriptive statistics rather than the planned measurement they 
replace 
 For repeated measurements obtained at any time point after the first dose of 
dapagliflozin, the first value of any repeated measurements will be used in the 
calculation of changes from Baseline and for the descriptive statistics. Unscheduled and 
repeated measurements will not be included in the descriptive statistics at time points 
after the first dose of dapagliflozin. 
5.3.3 
Statistical significance level 
All statistical tests will be two-sided and will be performed at the 5% level of significance. No 
multiplicity adjustments will apply. However, it is acknowledged that the issue of false 
positives is very relevant in this study, as the number of tested hypotheses is large. This issue 


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will be taken into consideration when interpreting the results, keeping in mind both the 
expected number of false positives (i.e. rejections of a hypothesis when no effect is in fact 
present) and clinical feasibility of the pattern of seemingly detected effects.   
5.3.4 
Software 
All statistical analyses and production of tables, figures and appendices will be performed 
using SAS software version 9.3 or later.   
5.3.5 
Missing and censored data 
In general, missing data will not be imputed. The only exceptions to this rule are missing dates 
for start or stop of an adverse event, missing dates of start and end of concomitant medications 
and missing dates for onset of a historical medical condition. For details on imputation rules 
regarding dates, see Appendix D. 
5.3.6 
Laboratory data reported above or below a threshold 
Any laboratory variables with results from the laboratory given as '<xx', '>xx', '≤xx' or '≥xx' in 
the database will be imputed with the absolute value of the number without the sign (e.g., < 
2.2 will be imputed as 2.2) for the descriptive statistics, changes from baseline and derivation 
of any derived variables dependent on this value.  Graphical displays will also make use of 
this convention.  Observed value results will be listed as is without any imputation.   
5.3.7 
Center pooling strategy 
It is planned to recruit subjects in different centers. The data from different sites will be 
pooled for all analyses. 
5.3.8 
Coding dictionaries 
All AEs and medical history will be coded for analysis according to the Medical Dictionary 
for Regulatory Activities (MedDRA)® coding dictionary, using the latest version available. 
Prior and concomitant medication will be coded according to the World Health Organisation 
Drug Dictionary Enhanced + Herbal Dictionary March 2017. Medical procedures will not be 
coded. 
5.3.9 
Study population characteristics 
5.3.9.1 
Patient disposition 
An overall disposition will be listed and summarised descriptively, with the descriptive 
summary done per group and organized by population type (e.g. patients enrolled into study). 
All disposition summary tables will be based on the Enrolled Set and the percentages will be 
based on the number of patients in the Medication Dispensed Set. No percentages will be 
presented for the number of patients enrolled or for the number of patients in the Run-in Set. 


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5.3.9.2 
Protocol deviations 
Protocol deviations will be handled in accordance with PAREXEL SOPs.  
 
Deviations from the protocol will be assessed as “not important” or “important”.  Important 
deviations from the protocol may lead to the exclusion of patients from the Evaluable Patients 
Set and include the following: 
 
 
Violation of inclusion and/or exclusion criteria; 
 
Dosing deviations (e.g., non-compliance); 
 
Patients receiving prohibited concomitant medications; 
 
Other procedural and study conduct deviations recorded by the clinical unit on the 
protocol deviation log. 
Compliance will be calculated as specified in Section 5.3.14. Patients will be considered 
non-compliant for a given interval(s) if the compliance is more than 120% or less than 80%. 
 
Only important protocol deviations (as agreed and documented at the DRM prior to database 
hardlock) will be reported in the relevant table and listing. 
 
The complete set of criteria for the assessment and reporting of protocol deviations will be 
stipulated in a separate study-specific protocol deviation specification document. 
 
All important protocol deviations will be listed and summarised by group based on the 
Medication Dispensed Set. Percentages for the summary will be based on the number of 
patients in the Medication Dispensed Set for each study group respectively. 
 
Patients and data excluded from the Evaluable Subjects Set will be listed, including the 
reasons for exclusions. These listings will be based on the Medication Dispensed Set. 
 
5.3.10 
Demographics, medical history and baseline data 
Demographics (including Screening height, weight, age, gender, ethnicity and race) will be 
listed by patient based on the Safety Set. Demographic characteristics (age, gender, race, and 
ethnicity) and patient characteristics (Screening height and weight) will be also summarised 
based on the Safety Set, by group.  The denominator for the percentages will be the number of 
patients in the Safety Set for each group. 
 
Medical history data will be listed by patient, based on the Safety Set and summarised by 
group, system organ class (SOC) and preferred term (PT) based on the Safety Set.  


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Percentages for the summary will be based on the number of patients in the Safety Set for 
each study group respectively. Surgical history will be listed by patient, based on the Safety 
Set, showing the procedure and the date of the procedure. 
 
The following additional listings will be presented, based on the Safety Set: 
 
 
For patients with T2DM: 
 
the date of first diagnosis 
 
duration of T2DM 
 
For patients with renal impairment: 
 
date of first diagnosis 
 
duration of renal impairment 
 
most likely aetiology as detailed in  Appendix A. 
 
if applicable, chronic glomerulonephritis type as detailed in  Appendix A. 
The disease duration will be calculated as follows: 
 
 
(1 + informed consent date - diagnosis date) / 365.25. 
See Appendix D for details the handling of missing or incomplete diagnosis dates. 
The following additional baseline characteristics will be summarised, where applicable: 
 
 
Duration of T2DM and duration of renal impairment, summarised by: 
 
Continuous summary (years) 
 
Categorical summary (years): n (%): < 3, ≥3 - ≤ 10, > 10 
 
HbA1c 
 
Continuous summary (%) 
 
Categorical summary (%): n (%): <6, ≥6 - <6.5, ≥ 6.5 - <7, ≥ 7 - <8, ≥ 8 - <9, ≥ 
9 - <10 
 
eGFR (mL/min/1.73 m^2) 
 
Continuous summary 
 
Categorical summary: n (%): < 30, ≥ 30 - <45, ≥ 45 - <60, ≥ 60 - <90, ≥ 90 
 
UACR (mg/g) 
 
Continuous summary 
 
Categorical summary: n (%): < 30, ≥30 - 300, > 300 - < 2200, ≥2200 
 
Fasting insulin (uU/ml), continuous summary                                                                                       
5.3.11 
Pregnancy testing 
Pregnancy testing results will be listed for each female patient, based on the Safety Set. 
 


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5.3.12 
Prior and concomitant medication 
Missing dates/times for prior/concomitant medications will be handled as described in 
Appendix D.  
Prior and concomitant medication will be listed by patient based on the Safety Set (a flag for 
Evaluable Subjects will be included).  The listing will include the information detailed in 
collected in the eCRF as well as the preferred term, anatomical therapeutic chemical class and 
classification as prior or concomitant (or both where applicable). 
Prior and concomitant medications will be summarised by group, separately for prior and 
concomitant medications, based on the Safety Set. Percentages will be based on the number of 
patients in the Safety Set for each group. 
5.3.13 
Exposure to investigational product 
Exposure to dapagliflozin will be listed for each patient, based on the Safety Set.  The date 
and time (where available) of administration, as well as the duration of exposure will be 
included in the listing. 
Duration of exposure is defined as the number of days exposed to study drug and calculated as 
(last dosing date – first dosing date) + 1. 
The duration of exposure will be summarised by descriptive statistics. 
5.3.14 
Compliance to investigational product 
Compliance will be calculated and expressed as a percentage. Based on the tablet counts, the 
percentage treatment compliance will be calculated as the number of tablets taken (dispensed 
minus returned) relative to expected number of taken tablets: 
 100 x (number of tables taken / expected number of taken tablets) 
The expected number of tablets taken will be calculated as: 
 (number of tablets taken daily) × (number of days between visits, until treatment is 
completed or permanently discontinued). 
The following intervals will be considered for the calculation of compliance: 
 
Overall: based on Day 1 to Day 14; this will only be calculated for patients 
completing the treatment period (Day 1 – Day 14); 
 
Start of Treatment: based on Day 1 to Day 4; 
 
Maintenance Treatment: based on Day 5 to Day 11; 
 
End of Treatment: based on Day 12 to Day 14. 


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Based on drug accountability obtained from the eCRF, the compliance for the overall period 
will be tabulated. The compliance will also be listed by patient including results for both drug 
accountability obtained from eCRF and patient diaries. The safety set will be used.  
5.3.15 
Food and fluid consumption 
Details regarding food and fluid consumption will be listed by patient based on Safety Set. 
5.3.16 
Efficacy analysis and reporting, general approach 
Unless otherwise specified, all listings and individual patient figures in this section will be 
based on the Evaluable Subjects Set; all tables and mean figures in this section will be based 
on the Evaluable Subjects Set.     
5.3.16.1 Statistical models 
For each efficacy variable, and each patient group, two models will be constructed. The first 
will be used to estimate the change from baseline to ST, and from baseline to ET. The second 
will be used to estimate the change from end of treatment to follow-up. 
Model 1 
Due to the likely dependence between within-patient observations, the first model will be a 
linear mixed effect model with time (ST and ET), the baseline value of the variable and the 
interaction between the two as fixed effects. The within-patient dependence is incorporated 
through covariance matrix of the residuals, which is assumed to be unstructured. Least squares 
mean (LSM) estimates of average effect at each one of the two time points will be obtained 
from the model and tabulated, together with the 95% confidence intervals (CI) and p-values.  
Kenward-Rogers method will be used for approximation of degrees of freedom for the tests 
from which the p-values are obtained. 
Explicitly, the following SAS code will be used for the first model: 
 
 
PROC MIXED DATA = <DATA>; 
 
BY <GROUP>; 
CLASS <TIME> <USUBJID>; 
MODEL <CHANGE> = <TIME> <BASE> <TIME> * <BASE> /  DDFM = 
KENWARDROGER; 
REPEATED <TIME> / TYPE = UN SUBJECT = <USUBJID>; 
LSMEANS <TIME> / CL ALPHA = 0.05; 
RUN;  
where <GROUP> is the variable representing the patient group, <CHANGE> refers to the 
variable containing the change versus the baseline for each patient, <TIME> refers to the 


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time-point, <USUBJID> refers to the variable containing the patient numbers, <BASE> refers 
to the baseline value; <TIME> * <BASE> refers to the interaction term.   
 
In case on non-convergence of the model the following alternative will be explored in order, 
as required:  
Each of the groups and each of the timepoints will be considered separately by fitting a linear 
regression model with change between baseline to the specific timepoint (ST, ET) as the 
response and the baseline value of the modelled endpoint as a single covariate. Similarly, to 
the original model, the estimated expected change from baseline for a patient with an average 
baseline value (which can be seen as a form of LSM), as well as the 95% CI and p-value, will 
be tabulated. 
Explicitly, the following SAS code will be used:  
PROC MIXED DATA = <DATA>; 
BY <GROUP> <TIME>; 
CLASS <GROUP>;  
MODEL <CHANGE> = <BASE>  <GROUP>; 
LSMEANS <GROUP>/ CL ALPHA = 0.05; 
RUN;  
 
With variable names as above. 
Model 2 
The model for the change between the ET and the FU timepoints will be a linear regression 
model. This model will be constructed for each group separately and include the baseline 
value of the studied endpoint as a single covariate. Similarly, to the back-up option for Model 
1, the estimated expected change between ET and FU for a patient with an average baseline 
value, as well as the 95% CI and p-value, will be tabulated. 
This will be done using the following SAS code: 
PROC MIXED DATA = <DATA>; 
 
BY <GROUP>; 
 
CLASS <GROUP>; 
MODEL <CHANGE> = <BASE>  <GROUP> ; 
LSMEANS <GROUP> / CL ALPHA = 0.05; 
RUN;  
 
Here, <CHANGE> refers to the change between ET and FU.  
 


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The approach described above will be applied for the analyses of all endpoints, with the 
exception of PK (discussed separately in Section 5.3.16.5).  
 
The formal analyses will be accompanied by listings, tables with summary statistics and Box 
plots. The summary tables for the values observed at each measurement timepoint will be 
presented for each group separately, in general including mean n, SD, median, minimum, 
maximum, as well as the first and third quartiles. For the change from baseline, the summary 
will include n, median, minimum and maximum. 
 
5.3.16.2 24-hour urine data 
A listing of urine sample collection, showing each collection day’s start and stop date/time, 
urine sodium amount excreted, urine glucose concentration, urine glucose amount excreted, 
urine volume and UACR, will be presented.   
A separate listing will be presented showing the by-patient arithmetic mean of the urine 
sodium amount excreted, urine glucose amounts excreted urine volume and UACR taken 
across the following summary periods: 
 
Baseline: Day -3 up to and including Day -1; 
 
Start of Treatment (ST): Day 2 up to and including Day 4 and for UACR ST: Day4; 
 
End of Treatment (ET): Day 12 up to and including Day 14; 
 
Follow-up (FU): Day 15 up to and including Day 17.  
The following by-patient changes will be derived for each urine sodium amount excreted, 
urine glucose amount excreted, urine volume and UACR: 
 
ST average versus the BL average 
 
ET average versus the BL average; 
 
FU average versus the ET average. 
Changes in urine sodium amount excreted, urine glucose amount excreted, urine volume and 
UACR will be listed, for each of the change types specified above. 
Each of the average summary periods (Baseline, ST, ET and FU), as well as the individual 
study day values, will be summarised for urine sodium amount excreted, urine glucose amount 
excreted, urine volume and UACR, by group.   
Calculated by-patient changes, for each of the change types defined above (i.e., each of the 
defined intervals/days where changes are calculated), will be summarised by group and 
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Box-plots for each change type versus time-point will be presented, with all groups overlaid 
on the same plot and separate plots for each of urine sodium amount excreted, urine glucose 
amount excreted, urine volume and UACR. 
5.3.16.3 24-hour blood pressure monitoring 
The results of systolic and diastolic blood pressure will be listed for each of the intervals over 
which this is collected over the 24-hour period.   
The following by-patient averages will be derived and listed for systolic and diastolic blood 
pressure, for each of the collection days as specified in Section 5.1.5.3: 
 
Daily average defined as the average over the entire 24 hours collection; 
The following rules will apply with regards to incomplete blood pressure measurements: 
 
Daily average: a minimum of 40 valid data points will be required for the 
calculation of the daily average; otherwise, no Daily average will be calculated. 
The above rules are based on the following sampling frequencies and the requirement that 
50% of data be non-missing: 
 
a sampling frequency of every 15 minutes (= 0.25 hours) during the day, which 
would result in ~16/0.25 = 64 data points over a 16 hour period is time-period; 
 
a sampling frequency of every 30 minutes (= 0.5 hours) during the night, which 
would result in ~8/0.5 = 16 data points over an eight hours period; 
 
64 + 16 = 80 data points over the whole 24-hour period; 
For each patient, 
 will be derived and listed for systolic and 
diastolic blood pressure. 
Changes in the daily average 
, will be 
derived and listed.  The following changes will be derived: 
 
Change from Baseline (Day -1) to ST (Day 4); 
 
Change from Baseline (Day -1) to ET (Day 13); 
 
Change from ET (Day 13) to FU (Day 18). 
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Daily averages, 
 and the corresponding changes will be summarised by group 
and time-point. 
Boxplots for daily averages, 
 will be presented, with all groups overlaid on the 
same plot and separate plots for systolic and diastolic blood pressure, 
. 
5.3.16.4 Measurements for plasma volume estimates 
The total plasma volume will be estimated based on results from a noncompartmental analysis 
of the plasma ICG-time profile. The derivation of the plasma volume estimates will be 
conducted by AstraZeneca and details regarding the estimation techniques will be documented 
separately. The plasma volume estimates will be provided to PAREXEL for further analysis 
and reporting as described below. 
Presentation of ICG 
The bolus dose of ICG (in mg) administered will be derived based on the administered volume 
(mL) and the confirmed strength (5 mg/mL) of the ICG solution: 
 
bolus dose administered (mg) = volume administered (mL) x 5 mg/mL. 
The details of the bolus dose of ICG administered for each study day will be listed, including 
the dose volume and the date/time of the ICG injection and bolus dose. 
The plasma ICG concentrations will be listed by patient and time-point, including the 
date/time of the sample; and will be summarised using geometric mean, 10th and 90th 
percentiles by group and time-point.  
Presentation of plasma volume 
Changes in the estimated plasma volume will be derived.  The following changes will be 
calculated: 
 
Change from baseline (Day 1, pre-dose) to ST (Day 4); 
 
Change from baseline to ET (Day 14); 
 
Change from ET (Day 14) to FU (Day 18). 
The estimated plasma volume for each patient and study day will be listed and summarised by 
study period and group, including changes specified above. Box plots for the estimated plasma 
volume versus study period by group will be presented. 
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5.3.16.5 Pharmacokinetic concentrations  
All PK presentations will be based on all available data. 
A listing of PK blood sample collection times, as well as derived sampling time deviations 
will be provided. In addition, plasma concentrations of dapagliflozin will be listed by patient 
and time-point.  
Plasma dapagliflozin concentrations will be summarised by group and time-point. Where 
possible, the following descriptive statistics will be presented: n, geometric mean, [geometric 
mean x geometric SD], [geometric mean / geometric SD], geometric CV%, median, minimum 
and maximum.  
 
In all cases, the geometric mean is calculated as follows:  
 
Geometric mean = exp[ML], 
where ML is the mean of natural log-transformed values, and ‘exp’ refers to the natural 
exponential function. 
The geometric CV% is calculated as follows:  
 
Geometric CV% = 100 x sqrt[exp(SL2) – 1], 
where SL is the SD of natural log-transformed values, and ‘sqrt’ refers to the square root 
function. 
 
The geometric SD is calculated as follows:  
 
Geometric SD = exp[SL], 
where SL is defined as above. 
 
The PK profiles will also be illustrated by figures for average PK profile over time on a linear 
and a semi-logarithmic scale.   
 
5.3.16.6 Censored data for pharmacokinetic evaluation 
For the listings, plasma concentrations that are NQ will be listed as “BLQ” – no imputations 
or substitutions will be performed for the listings. For descriptive statistics, plasma 
concentrations that are NQ will be handled as described below.   


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Any dapagliflozin plasma concentration data reported as not quantifiable (NQ), below the 
limit of quantification (BLQ), “<x.xx” or similar will be handled as follows for the descriptive 
statistics: 
 
At a time-point where less than or equal to 50% of the values are NQ, all NQ values 
will be set to the lower limit of quantification (LLOQ), and all descriptive statistics 
will be calculated. 
 
At a time-point where more than half of the values (but not all) are NQ, the 
geometric mean, [geometric mean x geometric SD], [geometric mean / geometric 
SD] and geometric coefficient of variation (CV)% will be set to Not Determined 
(“ND”). The maximum value will be reported from the individual data, and the 
minimum and median will be shown as “BLQ” – below the limit of quantification. 
 
If all values are NQ at a time-point, no descriptive statistics will be calculated for 
that time-point. Not applicable (“NA”) will be written in the field for geometric 
CV% and “BLQ” will be written in all other statistics. 
 
The number of BLQ values (n below LLOQ) and the number of data points (n) will 
be reported for each time-point. 
5.3.16.7 Bioimpedance spectroscopy 
The BIS examination will consist of two parts: an evaluation at Baseline, ST, ET and FU, 
similar to other efficacy endpoints, and acute changes evaluation at ET, aiming to examine the 
changes between a pre-dose measurement and measurements 1, 2 and 4 hours post-dose.  The 
measurements obtained during BIS, and for which the analyses will be performed, are 
 
, extracellular fluid (in litre and %), 
 
 
Part 1 
Changes in the BIS results will be derived.  The following changes will be calculated: 
 
Change from Baseline (Day 1, pre-dose) to ST (Day 4); 
 
Change from Baseline (Day 1, pre-dose) to ET (Day 14, 1 h post-dose); 
 
Change from ET (Day 14, 1 h-post-dose) to FU (Day 18). 
The BIS results for each patient, as well as corresponding changes, will be listed. Results will 
also be summarised by time-point and group, including changes specified above, similarly to 
other efficacy endpoints.  
Corresponding box plots for the BIS results versus study period will be presented, with each 
group overlaid on the same plot. The statistical model from Section 5.3.16.1 will be used to 
analyse the changes more formally, with results presented as described in Section 5.3.16.1.  
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Part 2 
 
 
 
 
 
 
 
 
  
 
 
 
.  
 
 
 
 
 
 
 
 
Following variables will also be listed: 
 
Systolic daily average, 
 
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 
Diastolic daily average, 
, 
 
 
 
Plasma volume 
 
Extracellular fluid (litres and percent), 
 
 
24-hr urinary volume 
 
Sodium excretion (24-hr urine) 
 
5.3.18 
Safety analysis 
All safety TLFs will be based on the Safety Set unless otherwise specified. 
5.3.18.1 Adverse events 
Adverse events will be summarized by SOC and PT. Adverse events will be assigned to a 
study phase (Screening, treatment or follow-up) based on the start date/time of the AE. 
 
Adverse events with missing start and/or end dates and/or times (if applicable) will be handled 
as described in Appendix D. 
All AEs will be listed for each patient. A listing showing AE onset and resolution date/time 
will be presented. Relationship to dapagliflozin (causally related or not causally related) will 
also be listed.  
An overall summary (number of patients and percentage of patients) of all AEs will be 
presented by group. The summary will include the following categories:  
 
Number and percentage of patients with AEs 
 
Number and percentage of patients with AEs judged as causally related to 
dapagliflozin in the opinion of Investigator; 
 
Number and percentage of patients with AEs leading to death; 
 
Number and percentage of patients with SAEs (including outcomes = death); 
 
Number and percentage of patients with any related SAEs (including outcomes = 
death); 
 
Number and percentage of patients with AEs leading to permanent discontinuation 
of dapagliflozin; 
 
 Number and percentage of patients with SAEs leading to permanent 
discontinuation of dapagliflozin; 
 
Number and percentage of patients with hypoglycaemia AEs; 
 
Number and percentage of patients with hypoglycaemia AEs leading to permanent 
discontinuation of dapagliflozin; 
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The AE overall summary as detailed above will be repeated for event counts. 
Adverse related to hypoglycaemia events are specified by the following PTs: 
 
Blood glucose decreased 
 
Hypoglycaemia 
 
Hypoglycaemia unawareness 
 
Hypoglycaemic coma 
 
Hypoglycaemic encephalopathy 
 
Shock hypoglycaemic 
 
Hypoglycaemic seizure 
 
Hypoglycaemic unconsciousness 
Summaries (patient counts and percentages) of AEs by group, SOC and PT will be presented 
for the following: 
 
All AEs by group; 
 
All AEs by group and investigator’s assessment of causality; 
 
All AEs by group and maximum reported intensity; 
 
Serious AEs by group; 
 
Adverse events leading to permanent discontinuation of dapagliflozin, by group. 
The denominator for summaries will be the number of patients in the Safety Set for each 
group. 
An AE summary showing the number of events by group and PT will be presented for all 
on-treatment AEs and SAEs. 
An additional summary of all non-serious AEs which occur in at least 5 percent of patients in 
any group will be presented, the events categorized by SOC and PT, and group.  In addition to 
the number and percentage of patients that experience at least one event, the number of events 
will also be presented.  
All potential events of diabetic ketoacidosis (DKA) will be recorded in the eCRF and 
submitted to an independent DKA Adjudication Committee. Patients with AEs and SAEs 
recorded on the DKA eCRF page will be listed. 
Patients with DKA events reviewed by the adjudication committee will be listed. 
Key information for adverse events leading to death, SAEs and discontinuation will be listed 
separately. These listings will include group, reported term, PT, date of the event, time from 
start of treatment up to the onset of the event, causality and outcome.  Additional details will 
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5.3.18.2 Clinical laboratory 
Clinical chemistry and haematology 
Safety laboratory measurements (clinical chemistry and haematology/haemostasis as specified 
in Section 5.1.3.2) will be listed by patient and time-point, including the date/time of the 
sample, changes from baseline and flags for measurements outside the reference range.  The 
listing will include all repeated and unscheduled measurements.  
Descriptive statistics will be presented by group, time-point and visit for observed values and 
changes from baseline.   
Baseline is defined as the results from assessments performed at pre-dose on Day 1. 
Urinalysis 
The results for qualitative and quantitative urinalysis (as specified in Section 5.1.3.2) will be 
listed separately. 
5.3.18.3 Hy´s Law 
Number and percentage of patients with potential Hy’s Law will be presented per treatment 
group. Potential Hy’s Law is an increase in serum Aspartate Aminotransferase (AST) or 
Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal (ULN) together with Total 
Bilirubin (TBL) ≥ 2xULN, irrespective of serum Alkaline Phosphatase (ALP), at any point 
during the study following the start of the IMP. 
5.3.18.4 Vital signs 
Vital signs measurements will be listed by patient and time-point including the date/time of 
the assessment and changes from baseline. Descriptive statistics will be presented by group 
and time-point for both observed values and changes from baseline. 
Baseline is defined as the results from assessments performed at pre-dose on Day 1. 
5.3.18.5 Physical examination 
Abnormal physical examination findings post-baseline will be recorded as AEs. 
5.4 
Partial Analysis 
A partial analysis based on all patients from Group 2, will be conducted. The partial analysis 
will include all the evaluations originally planned to be conducted, and reported, for all three 
groups simultaneously. 
 


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6. 
APPENDICES 
Appendix A  
Demographic and baseline variables 
Below is a detailed list of the following demographic and background information that will be 
recorded at the Screening visit: 
Demographic characteristics: 
• 
Date of birth (year only) 
• 
Age (years) 
• 
Gender (male / female) 
• 
Race (White, Black or African American, Asian, Other) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
Vital signs 
• 
Height (reported in centimetres [cm]) 
• 
Weight at Screening (reported in kilograms [kg]) 
• 
Supine blood pressure (diastolic and systolic ([mmHg]) 
• 
Pulse (beats/min) 
Disease history 
• 
Medical history, including the condition and start and end date [or status as 
“Ongoing”] of the condition 
• 
Surgical history, including the procedure and the date of the procedure 
• 
For patients with impaired renal function: 
 date of first renal impairment diagnosis 
 most likely aetiology from among the following: cystic kidney disease; diabetic 
nephropathy; ischaemic/hypertensive nephropathy; chronic glomerulonephritis; 
renal artery stenosis; chronic pyelonephritis (infectious); chronic interstitial 
nephritis; obstructive nephropathy; unknown; other: specified 


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 if applicable, chronic glomerulonephritis type from among the following: 
immunoglobulin A nephropathy; focal segmental glomerulosclerosis; membranous 
nephropathy; minimal change; lupus nephritis; other primary or secondary 
glomerulonephritis CKD diagnosis: specified 
• 
For patients with T2DM, date of first T2DM diagnosis 
Screening lab results 
• 
Screening results for HbA1c and eGFR; eGFR to be based on the serum creatinine 
level and CKD-EPI method, and recorded directly on the eCRF 


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Appendix B Efficacy Variables 
Group 
Measurements 
Blood
PK 
- 
Concentrations of dapagliflozin 
Urinalysis
Spot urine sample for urinary 
albumin and creatinine 
- 
Albumin, creatinine 
 
 
U-albumin, U-glucose and U-
blood (Dipstick) 
- 
Albumin, glucose, blood 
24-hr urine (a) 
- 
Sodium excretion, sodium concentration, glucose 
excretion, glucose concentration, 24-hr urinary 
volume, UACR 
Other
- 
24-hr blood pressure 
- 
Systolic daily average, 
 
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- 
Diastolic daily average, 
 
 
 
Plasma volume 
Plasma volume 
Bioimpedance spectroscopy 
- 
 Extracellular 
fluid (litres and percent), 
 
 
- 
 
 
Vital signs 
- 
 
(a) The measurement consists of an average of three (alt, four) measurements taken on consecutive days 
With the exception of PK and hourly BIS, the endpoints of the study are within-patient 
differences in the listed measurements between ST and Baseline measurements, between ET 
and baseline measurements and between FU and ET measurements. For PK, the endpoint is 
the concentrations of dapagliflozin at the time-points at which a PK sample was obtained. For 
BIS, the following additional endpoints will be considered: at Visit 8, the difference between 
1, 2 and 4 hr measurements and the pre-dose measurement.  
Explicitly, the different study endpoints are defined as detailed below. 
 
 
 
 
 
 
 
 
 
 
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Appendix C General rounding rules 
All data will be listed according to the number of decimal places presented in the original 
data, with the exception of data for which the original number of decimals exceeds four 
decimal places; in these cases, the data will be presented to three significant figures. 
When reporting relative frequencies or other percentage values, the following rules apply: 
 
For values where all subjects fulfil certain criteria, the percentage value will be 
displayed as 100 
 
For values where the absolute frequency is zero, there will be no percentage 
displayed at all 
 
All other percentage displays will use 2 decimal places 
Percentages displayed based on continuous data (e.g., percentage changes from baseline) will 
be displayed to 2 decimal places. 
When reporting descriptive statistics, the following rules will apply in general: 
 
n will be an integer 
 
Mean, geometric Mean, SD, geometric SD, median, Q1 and Q3 will use 1 decimal 
place more than the original data 
 
Minimum and maximum will be reported using the same number of decimal places 
as the original value 
 
If no subjects have data at a given time point, for example, then only n=0 will be 
presented. If n<3, then only n, minimum and maximum will be presented. If n=3, 
then only n, mean, median, minimum and maximum will be presented. The other 
descriptive statistics will be left blank. 
 
P-values will be presented to four decimal places (p-values that are smaller than 
0.0001 will be presented as '<0.0001') 
 
An extra digit of precision will be added (four significant digits at most) for 
reporting of the least-squares (LS) means and bounds of all confidence intervals 
(CIs) within inferential analyses 
A maximum of four significant figures will apply to all summary statistics. 


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Appendix D Missing data 
Missing data for adverse events 
If an onset date is incomplete, the derived onset date will be calculated using the following 
algorithm: 
 
Calculate a surrogate date as the first non-missing valid date from the following list 
(in order of precedence): 
 
First active study medication date 
 
Informed consent date 
 
Visit date corresponding to the visit at which the event was reported 
If a valid non-missing date is not available for any of these dates, the surrogate date will be set 
to missing. Any AEs with unknown intensity, causality or seriousness will be regarded as 
unknown for the tabulations.  
There will be no imputation of AE data for the data listings – all data will be listed as recorded 
in source.  
Missing data for prior/concomitant medications 
Missing start or end dates and times of medications other than dapagliflozin and ICG will be 
handled as follows for the purposes of the classification as prior or concomitant: 
 
If the reported start date is missing or invalid and the informed consent date is not 
missing or invalid, then the imputed start date is set equal to the informed consent 
date. If the consent date is missing or invalid and the birth date is not missing or 
invalid, then the imputed start date is set equal to the birth date. If the start date, the 
consent date and the birth date are all invalid or missing, then the imputed start date 
is set equal to missing. 
 
If the reported start date is partially entered, then the imputed start date is set equal 
to the earliest possible reported start date based on the partial entered reported start 
date. 
 
If the reported end date is missing, continuing, unknown or invalid, then the 
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 
If the reported end date of the medication is partial, then the imputed end date is set 
equal to the last possible reported end date based on the partial entered reported end 
date. 
Imputed dates will not appear on the listings. 
Missing data for diagnosis date 
If the date of disease diagnosis is partially missing, the following rules will take effect: 
 
Missing day, but month and year are present: the day will be imputed as the 15th 
day of the month. 
 
Missing day and month, but year is present: the day and month will be imputed as 
30 June of the year (provided that the imputed date is less than the consent date). 
 
Missing year, but day and month are present: No imputations will occur, and the 
patient will be excluded from all summaries related to duration of disease.  
 
Missing day, month and year: No imputations will occur, and the patient will be 
excluded from all summaries related to duration of disease. 
 
If any such imputed date falls after the consent date, then the diagnosis date will be 
taken as equal to the consent date. 
These durations, even if partially imputed, will be listed. However, only the portion of the date 
of diagnosis actually observed, rather than imputed dates, will be displayed in listings. 
Missing data for efficacy evaluation 
There will be no imputation of missing efficacy data.  Data will be used as far as is available 
and listed as reported without imputation.  
Missing data for safety evaluation 
Apart from the missing date/time imputation for adverse event assessments, there will be no 
imputation of missing safety data.  Data will be used as far as is available and listed as 
reported without imputation.  
 
 
 


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7. 
AMENDMENT TO THE STATISTICAL ANALYSIS PLAN  
7.1 
Amendment :Version Final 3.0 
7.1.1 
Rationale for the amendment 
This SAP was amended following Astrazeneca comments after Dry Run. 
7.1.2 
List of changes 
Change #1 
STATISTICAL ANALYSIS PLAN 
The following text was added: 
The SAP describes Group 1 as it was originally planned in the latest version of the CSP. it was 
decided that no Group 1 subjects will be enrolled onto this study (please see reference in 
Action log on the 22nd of March 2019), so no statistical outputs will contain Group 1 
information. 
 
Change #2 
Study Design (Section 2) 
 
Baseline measurement (Baseline) is the measurement obtained before initiation of 
treatment, typically during Visit 4. For 24-hr blood pressure, the baseline 
measurement is the measurement obtained the day before Visit 4. 
 
Short treatment measurement (ST) is the measurement obtained after the patient 
has been in the study for a short time, typically on Visit 5.  
 
End of treatment measurement (ET) is the measurement obtained on the visit 
corresponding to the last day of the treatment period, namely Visit 8, unless the 
patient attended an early termination visit. 
 
in the 24-hr urine, the end of treatment 
measurement is the measurement obtained the day before Visit 8.  
 
Follow-up measurement (FU). Is the measurement obtained after the end of the 
treatment period, namely Visit 9. 
 
 
 
 
The exception from the rules outlined above is the 24-hr urine, the collection of 
which will take place on consecutive days, rather than on one single day. In this 
case, Baseline, ST, ET and FU measurements used in the analyses will be the 
averages of these consecutive samples. Explicitly, Baseline is the average of 
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measurements obtained on day -3 to day -1, ST the average of measurements 
obtained on day 2 to day 4, ET the average of measurements obtained on day 12 to 
day 14 and FU the average of measurements obtained on day 15 to day 17. 
 
Was changed to: 
 
Baseline is the measurement obtained before initiation of treatment, typically 
during Visit 4. For 24-hr blood pressure, the baseline measurement is the 
measurement obtained the day before Visit 4. 
 
Start of Treatment (ST) is the measurement obtained after the patient has been in 
the study for a short time, typically on Visit 5.  
 
End of treatment (ET) is the measurement obtained on the visit corresponding to 
the last day of the treatment period, namely Visit 8, unless the patient attended an 
early termination visit. For 24-hr blood pressure, 
 
 
, the end of treatment measurement is the 
measurement obtained the day before Visit 8.  
 
Follow-up (FU) is the measurement obtained after the end of the treatment period, 
namely Visit 9. 
 
 
 
The exception from the rules outlined above is the 24-hr urine, the collection of which will 
take place on consecutive days, rather than on one single day. In this case, Baseline, ST, ET 
and FU used in the analyses will be the averages of these consecutive samples. Explicitly, 
Baseline is the average of measurements obtained on day -3 to day -1, ST the average of 
measurements obtained on day 2 to day 4, ET the average of measurements obtained on day 
12 to day 14 and FU the average of measurements obtained on day 15 to day 17. 
 
Change #3 
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Change #4 
24-hour urine data (Section 5.3.16.2) 
A listing of urine sample collection, showing each collection day’s start and stop date/time, 
urine sodium amount excreted, urine glucose concentration, urine glucose amount excreted, 
urine volume and UACR, will be presented.   
A separate listing will be presented showing the by-patient arithmetic mean of the urine 
sodium amount excreted, urine glucose amounts excreted urine volume and UACR taken 
across the following summary periods: 
 
Baseline: Day -3 up to and including Day -1; 
 
Short of Treatment (ST): Day 2 up to and including Day 4; 
 
End of Treatment (ET): Day 12 up to and including Day 14; 
 
Follow-up (FU): Day 15 up to and including Day 17.  
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The following by-patient changes will be derived for each urine sodium amount excreted, 
urine glucose amount excreted, urine volume and UACR: 
 
ST average versus the BL average 
 
ET versus the BL average; 
 
FU average versus the ET average. 
 
Was changed to: 
A listing of urine sample collection, showing each collection day’s start and stop date/time, 
urine sodium amount excreted, urine glucose concentration, urine glucose amount excreted, 
urine volume and UACR, will be presented.   
A separate listing will be presented showing the by-patient arithmetic mean of the urine 
sodium amount excreted, urine glucose amounts excreted urine volume and UACR taken 
across the following summary periods: 
 
Baseline: Day -3 up to and including Day -1; 
 
Start of Treatment (ST): Day 2 up to and including Day 4 and for UACR ST:Day4; 
 
End of Treatment (ET): Day 12 up to and including Day 14; 
 
Follow-up (FU): Day 15 up to and including Day 17.  
The following by-patient changes will be derived for each urine sodium amount excreted, 
urine glucose amount excreted, urine volume and UACR: 
 
ST average versus the BL average 
 
ET average versus the BL average; 
 
FU average versus the ET average. 
. 
Change #5 
24-Hour blood pressure monitoring (Section 5.3.16.3) 
 
 
. 
Was changed to: 
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Change #6 
Bioimpedance spectroscopy (Section 5.3.16.7) 
The BIS examination will consist of two parts: an evaluation at Baseline, ET, ST and FU, 
similar to other efficacy endpoints, and a short-term evaluation at ET, aiming to examine the 
changes between a pre-dose measurement and measurements 1, 2 and 4 hours post-dose.  The 
measurements obtained during BIS, and for which the analyses will be performed, are 
 
, extracellular fluid (in litre and %), 
 
 
Part 1 
Changes in the BIS results will be derived.  The following changes will be calculated: 
 
Change from baseline (Day 1, pre-dose) to ST (Day 4); 
 
Change from baseline (Day 1) to ET (Day 14, 1 h post-dose); 
 
Change from ET (Day 14, 1 h post-dose) to FU (Day 18). 
The BIS results for each patient, as well as corresponding changes, will be listed. Results will 
also be summarised by time-point and group, including changes specified above, similarly to 
other efficacy endpoints.  
Corresponding box plots for the BIS results versus study period will be presented, with each 
group overlaid on the same plot. The statistical model from Section 5.3.16.1 will be used to 
analyse the changes more formally, with results presented as described in Section 5.3.16.1.  
Part 2 
 
 
 
 
 
.  
 
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Was changed to: 
The BIS examination will consist of two parts: an evaluation at Baseline, ST, ET and FU, 
similar to other efficacy endpoints, and acute changes evaluation at ET, aiming to examine the 
changes between a pre-dose measurement and measurements 1, 2 and 4 hours post-dose.  The 
measurements obtained during BIS, and for which the analyses will be performed, are 
 
 extracellular fluid (in litre and %), 
 
 
Part 1 
Changes in the BIS results will be derived.  The following changes will be calculated: 
 
Change from Baseline (Day 1, pre-dose) to ST (Day 4); 
 
Change from Baseline (Day 1, pre-dose) to ET (Day 14, 1 h post-dose); 
 
Change from ET (Day 14, 1 h post-dose) to FU (Day 18). 
The BIS results for each patient, as well as corresponding changes, will be listed. Results will 
also be summarised by time-point and group, including changes specified above, similarly to 
other efficacy endpoints.  
Corresponding box plots for the BIS results versus study period will be presented, with each 
group overlaid on the same plot. The statistical model from Section 5.3.16.1 will be used to 
analyse the changes more formally, with results presented as described in Section 5.3.16.1.  
Part 2 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
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Change #7 
Partial Analysis (Section 5.4) 
A partial analysis based on all patients from Group 2 and Group 3, but none from Group 1, 
will be conducted. The partial analysis will include all the evaluations originally planned to be 
conducted, and reported, for all three groups simultaneously. 
 
Was changed to: 
A partial analysis based on all patients from Group 2, will be conducted. The partial analysis 
will include all the evaluations originally planned to be conducted, and reported, for all three 
groups simultaneously.