Conditions: Type 2 Diabetes
Keywords: Diabetes Mellitus Dapagliflozin Placebo Insulin resistance Metabolic Diseases
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 72
Healthy volunteers: no

Brief summary:
A trial of patients aged 10-24 years with type 2 diabetes mellitus to evaluate the comparative efficacy and safety between dapagliflozin and Placebo.

Detailed description:
A 24 Week, Multicenter, Randomized, Double-Blind, Parallel Group, Phase 3 Trial with a 28 Week Long Term Safety Extension Period Evaluating the Safety and Efficacy of Dapagliflozin 10 mg in T2DM Patients aged 10-24 years

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Dapagliflozin intervention 2: Dapagliflozin placebo
Intervention descriptions: intervention 1: Dapagliflozin 10 mg tablets administered orally once daily, for the 24-week blinded treatment period. Dapagliflozin 10mg tablets administered orally once daily, for the 28-week site and subject blinded long term extension. intervention 2: matching placebo tablets, administered orally once daily, for the 24-week blinded treatment period. Dapagliflozin 10mg tablets administered orally once daily,for the 28-week site and subject blinded long term extension.

Protocol document:
Prot_000.pdf: 
Page:
1
Protocol Number:
MB102138
IND Number:
68,652
EUDRACT Number
2015-005041-31
Date:
15-Jan-2016
Revised Date:
20-Sep-2017
Clinical Protocol MB102138
(AZ study number: D1690C00017)
A 24 Week, Multicenter, Randomized, Double-Blind, Parallel Group, Phase 3 Trial with a 
28 Week Long Term Safety Extension Period Evaluating the Safety and Efficacy of 
Dapagliflozin 10 mg in T2DM Patients aged 10-24 years.
Revised Protocol Number: 03
Incorporates amendments: 01 & 02 & 03
Medical Monitor
 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


Clinical Protocol
MB102138
BMS-512148
dapagliflozin
Revised Protocol No: 03
Date: 20-Sep-2017
2
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
This submission document contains confidential commercial information, disclosure of which is 
prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca Standard 
procedures. The clinical study protocol is publicly registered and the results are disclosed and/or 
published according to the AstraZeneca Global Policy on Bioethics and in compliance with all 
prevailing laws and regulations.
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.


Clinical Protocol
MB102138
BMS-512148
dapagliflozin
Revised Protocol No: 03
Date: 20-Sep-2017
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 03
20-Sep-2017
Incorporates Amendment 03
Amendment 03
20-Sep-2017
The purpose of this protocol amendment is to increase the number of 
subjects randomized in the study to ensure that at least 50 subjects will 
complete the 24-week treatment period on investigational product and 
the Week 24 assessment.
Revised 
Protocol 02
13-Feb-2017
Incorporates Amendment 02
Amendment 02
13-Feb-2017
The purpose of this protocol amendment is to reflect the end of 
Bristol-Myers Squibb’s role in the study, and to update the details of the 
Medical Monitor. The duration of the screening period has been 
extended, and details relating to the masking of spot urine glucose, the 
study weeks relating to lack of glycemic control criteria for initiation of 
rescue medication, and the use of third party vendors for Lost to 
Follow-Up subjects have been clarified. 
The 24-hour emergency telephone numbers and SAE reporting details 
have been updated to PRA numbers.
Revised 
Protocol 01
15-Jan-2016
Incorporates Amendment 01
Amendment 01
15-Jan-2016
The purpose of this amendment is to incorporate new safety information 
related to diabetic ketoacidosis (DKA) as reflected in Dapagliflozin IB 
version 12, and correct typographical errors and discrepancies within the 
protocol.
Original 
Protocol
09-Nov-2015
Not applicable


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Revised Protocol No: 03
Date: 20-Sep-2017
4
TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................................... 3
SYNOPSIS
........................................................................................................................................ 7
1 INVESTIGATIONAL PLAN ............................................................................................................... 13
1.1
Study Rationale ......................................................................................................................... 14
1.2
Research Hypothesis ................................................................................................................. 15
1.3
Objectives(s).............................................................................................................................. 15
1.3.1 Primary Objectives .............................................................................................................. 15
1.3.2 Secondary Objectives........................................................................................................... 15
1.3.3 Safety Objectives.................................................................................................................. 15
1.3.4 Exploratory Objectives ........................................................................................................ 16
1.4
Product Development Background............................................................................................ 16
1.5
Overall Risk/Benefit Assessment.............................................................................................. 17
2 ETHICAL CONSIDERATIONS.......................................................................................................... 17
2.1
Good Clinical Practice............................................................................................................... 17
2.2
Institutional Review Board/Independent Ethics Committee ..................................................... 17
2.3
Informed Consent...................................................................................................................... 18
3 INVESTIGATIONAL PLAN ............................................................................................................... 19
3.1
Study Design and Duration ....................................................................................................... 19
3.2
Post Study Access to Therapy ................................................................................................... 20
3.3
Study Population ....................................................................................................................... 20
3.3.1 Inclusion Criteria................................................................................................................. 20
3.3.2 Exclusion Criteria................................................................................................................ 23
3.3.3 Women of Childbearing Potential ....................................................................................... 25
3.4
Concomitant Treatments ........................................................................................................... 25
3.4.1 Prohibited and/or Restricted Treatments............................................................................. 25
3.4.2 Other Restrictions and Precautions..................................................................................... 25
3.5
Discontinuation of Subjects following any Treatment with Study Drug................................... 26
3.5.1 Procedures for handling patients incorrectly enrolled or randomized ............................... 27
3.5.2 Rescue Guidelines for Subjects with Protocol-Defined Lack of Glycemic Control............. 27
3.5.3 Discontinuation Guidelines due to Protocol-Defined Hypoglycemia Episodes .................. 28
3.5.4 Discontinuation Guidelines due to Diabetic Ketoacidosis (DKA)....................................... 29
3.6
Post Study Drug Study Follow-up............................................................................................. 30
3.6.1 Withdrawal of Consent ........................................................................................................ 30
3.6.2 Lost to Follow-Up................................................................................................................ 30
3.6.3 Survey of Subject Vital Status .............................................................................................. 31
4 STUDY DRUG ...................................................................................................................................... 32
4.1
Investigational Product.............................................................................................................. 33
4.2
Non-investigational Product...................................................................................................... 33
4.3
Storage and Dispensing............................................................................................................. 33
4.4
Method of Assigning Subject Identification.............................................................................. 34
4.5
Selection and Timing of Dose for Each Subject........................................................................ 34
4.6
Blinding/Unblinding.................................................................................................................. 35
4.7
Treatment Compliance .............................................................................................................. 35
4.8
Destruction of Study Drug......................................................................................................... 36
4.9
Return of Study Drug ................................................................................................................ 36
4.10 Retained Samples for Bioavailability / Bioequivalence............................................................ 36
5 STUDY ASSESSMENTS AND PROCEDURES ................................................................................ 37
5.1
Flow Chart/Time and Events Schedule..................................................................................... 37
5.1.1 Retesting During Screening or Lead-in Period ................................................................... 46


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5.2
Study Materials.......................................................................................................................... 46
5.3
Safety Assessments ................................................................................................................... 47
5.3.1 Self-Monitored Blood Glucose (SMBG), Self-Monitored blood Ketones and Guidance on 
Management and Reporting of Hypoglycemia Episodes..................................................... 47
5.3.2 Guidance on Assessment of Urinary Tract Infections & Hematuria................................... 49
5.3.3 Guidance on Assessment of Hepatic Laboratory Abnormalities ......................................... 50
5.3.4 Physical Examination .......................................................................................................... 51
5.3.5 Blood Pressure and Heart Rate........................................................................................... 51
5.3.6 Guidance on Volume Depletion........................................................................................... 52
5.3.7 Supplemental Visits.............................................................................................................. 52
5.3.8 Imaging Assessment for the Study ....................................................................................... 52
5.4
Efficacy Assessments................................................................................................................ 52
5.5
Pharmacokinetic Assessments................................................................................................... 52
5.6
Biomarker Assessments............................................................................................................. 53
5.7
Outcomes Research Assessments.............................................................................................. 53
5.8
Other Assessments..................................................................................................................... 53
5.8.1 Diet and Exercise Counseling.............................................................................................. 53
5.8.2 Weight and Height ............................................................................................................... 54
5.9
Results of Central Assessments................................................................................................. 54
6 ADVERSE EVENTS ............................................................................................................................. 54
6.1
Serious Adverse Events............................................................................................................. 55
6.1.1 Serious Adverse Event Collection and Reporting................................................................ 56
6.2
Nonserious Adverse Events....................................................................................................... 57
6.2.1 Nonserious Adverse Event Collection and Reporting.......................................................... 58
6.3
Laboratory Test Result Abnormalities ...................................................................................... 58
6.4
Pregnancy.................................................................................................................................. 58
6.5
Overdose.................................................................................................................................... 59
6.6
Potential Drug Induced Liver Injury (DILI).............................................................................. 59
6.7
Other Safety Considerations...................................................................................................... 59
7 DATA MONITORING COMMITTEE AND OTHER COMMITTEES......................................... 59
7.1
Data Monitoring Committees.................................................................................................... 59
7.2
Hepatic Adjudication Committee.............................................................................................. 59
7.3
Diabetic Ketoacidosis (DKA) Adjudication Committee........................................................... 60
8 STATISTICAL CONSIDERATIONS ................................................................................................. 60
8.1
Sample Size Determination....................................................................................................... 60
8.2
Populations for Analyses........................................................................................................... 60
8.3
Endpoints................................................................................................................................... 61
8.3.1 Primary Endpoint(s) ............................................................................................................ 61
8.3.2 Secondary Endpoint(s)......................................................................................................... 61
8.3.3 Exploratory Endpoint(s) ...................................................................................................... 61
8.4
Analyses .................................................................................................................................... 61
8.4.1 Demographics and Baseline Characteristics....................................................................... 61
8.4.2 Efficacy Analyses................................................................................................................. 61
8.4.3 Safety Analyses .................................................................................................................... 62
8.4.4 Pharmacokinetic Analyses................................................................................................... 63
8.4.5 Biomarker Analyses............................................................................................................. 63
8.4.6 Outcomes Research Analyses .............................................................................................. 63
8.4.7 Other Analyses..................................................................................................................... 63
8.5
Interim Analyses........................................................................................................................ 63
9 STUDY MANAGEMENT..................................................................................................................... 63
9.1
Compliance................................................................................................................................ 63


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Date: 20-Sep-2017
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9.1.1 Compliance with the Protocol and Protocol Revisions....................................................... 63
9.1.2 Monitoring........................................................................................................................... 64
9.1.3 Investigational Site Training ............................................................................................... 65
9.2
Records...................................................................................................................................... 65
9.2.1 Records Retention................................................................................................................ 65
9.2.2 Study Drug Records............................................................................................................. 65
9.2.3 Case Report Forms.............................................................................................................. 66
9.3
Clinical Study Report and Publications..................................................................................... 66
10
GLOSSARY OF TERMS................................................................................................................. 68
11
LIST OF ABBREVIATIONS........................................................................................................... 69
12
REFERENCES.................................................................................................................................. 72
APPENDIX 1
CENTRAL LABORATORY ASSESSMENTS....................................................... 74
APPENDIX 2
SUSTAINED ELEVATED LIVER SAFETY ABNORMALITIES FLOW 
CHART ....................................................................................................................... 78
APPENDIX 3
TANNER ASSESSMENT SCALE ........................................................................... 79
APPENDIX 4
APPENDIX REFERENCES ..................................................................................... 81


Clinical Protocol
MB102138
BMS-512148
dapagliflozin
Revised Protocol No: 03
Date: 20-Sep-2017
7
SYNOPSIS
Clinical Protocol MB102138 (AZ study number: D1690C00017)
Protocol Title: A 24 Week  Multicenter, Randomized, Double-Blind, Parallel Group, Phase 3 Trial with a 28 Week 
Long Term Safety Extension Period Evaluating the Safety and Efficacy of Dapagliflozin 10 mg in T2DM Patients 
aged 10-24 years.
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Dapagliflozin 10 mg or placebo tablets administered orally once daily for the 24-week double-blinded 
short-term treatment period and dapagliflozin 10 mg tablets administered orally once daily for the 28-week open-label 
safety extension.
Study Phase: 3b
Research Hypothesis: Dapagliflozin results in a greater mean reduction from baseline in glycated hemoglobin 
(HbA1c) compared to placebo after 24 weeks of double-blind add-on treatment in patients aged 10 to less than 25 years 
with T2DM who have inadequate glycemic control on diet and exercise with metformin or insulin metformin.
Objectives:
Primary Objective:
To compare the mean change from baseline in HbA1c achieved with dapagliflozin against the mean achieved with 
placebo after 24 weeks of double-blind add-on treatment in patients aged 10 to less than 25 years with T2DM who 
have inadequate glycemic control on diet and exercise with metformin or insulin metformin.
Secondary Objectives:

To compare the mean change from baseline in Fasting Plasma Glucose (FPG) achieved with dapagliflozin against 
the mean achieved with placebo after 24 weeks of double-blind add-on treatment in patients aged 10 to less than 
25 years with T2DM who have inadequate glycemic control on diet and exercise with metformin or insulin 
metformin.

To compare the percentage of subjects who require glycemic rescue or discontinuation due to lack of glycemic 
control with dapagliflozin against the percentage with placebo over the 24 weeks of double-blind add-on treatment 
in patients aged 10 to less than 25 years with T2DM who have inadequate glycemic control on diet and exercise 
with metformin, or insulin metformin.

To compare the percentage of subjects with baseline HbA1c > 7% who achieve a HbA1c level < 7% with 
dapagliflozin against the percentage achieved with placebo after 24 weeks of double-blind add-on treatment in 
patients aged 10 to less than 25 years with T2DM who have inadequate glycemic control on diet and exercise 
with metformin, or insulin metformin.
Safety Objectives:

To assess the safety and tolerability of dapagliflozin as add-on treatment in patients aged 10 to less than 25 years 
with T2DM who have inadequate glycemic control on diet and exercise with metformin or insulin metformin 
when administered for up to 24 weeks of short-term therapy and 52 weeks of total therapy.

To assess the percentage of subjects who experience hypoglycemia with dapagliflozin against the percentage 
achieved with placebo as add-on treatment in patients aged 10 to less than 25 years with T2DM who have 
inadequate glycemic control on diet and exercise with metformin, or insulin metformin when administered for 
up to 24 weeks.

To assess markers of growth and maturation, the incidence of diabetic ketoacidosis (DKA), and changes in 
markers of bone health with dapagliflozin against those observed with placebo as add-on treatment in patients 
aged 10 to less than 25 years with T2DM who have inadequate glycemic control on diet and exercise with 
metformin, or insulin metformin when administered for up to 24 weeks.


Clinical Protocol
MB102138
BMS-512148
dapagliflozin
Revised Protocol No: 03
Date: 20-Sep-2017
8
Exploratory Objectives:

To explore the pharmacokinetics (PK) and exposure-response relationship of dapagliflozin in patients aged 10 to 
less than 25 years with T2DM based on the collection of population PK samples.

To explore the mean change from baseline in HbA1c achieved with dapagliflozin after 52 weeks of add-on 
treatment in patients aged 10 to less than 25 years with T2DM who have inadequate glycemic control on diet and 
exercise with metformin or insulin metformin.

To explore the mean change from baseline in FPG achieved with dapagliflozin after 52 weeks of add-on treatment 
in patients aged 10 to less than 25 years with T2DM who have inadequate glycemic control on diet and exercise 
with metformin or insulin metformin.

To explore the percentage of subjects who require glycemic rescue or discontinuation due to lack of glycemic 
control with dapagliflozin over the 52 weeks of add-on treatment in patients aged 10 to less than 25 years with 
T2DM who have inadequate glycemic control on diet and exercise with metformin or insulin metformin.

To explore the percentage of subjects with baseline HbA1c > 7% who achieve a HbA1c level < 7% with 
dapagliflozin after 52 weeks of add-on treatment in patients aged 10 to less than 25 years with T2DM who have 
inadequate glycemic control on diet and exercise with metformin or insulin metformin.
Study Design: The study will be a prospective, multi-center, 24-week, placebo controlled, double-blind randomized 
study with a 28-week open-label safety extension. Subjects 10 years and < 25 years of age, with confirmed diagnosis 
of T2DM, who are being treated with diet and exercise and a stable dose of metformin immediate release (IR) or 
extended release (XR) (at least 1000 mg daily) for a minimum of 8 weeks prior to screening, or a stable dose of insulin 
for a minimum of 8 weeks prior to screening, or a stable combination of metformin and insulin for a minimum of 
8 weeks prior to screening, will be screened against the inclusion and exclusion criteria. Eligible subjects meeting all 
criteria will enter a 4-week placebo lead-in period. Subjects will be instructed to follow a diet and exercise program 
(in accordance with the American Diabetes Association [ADA] or similar national guidelines) for the duration of the 
study. Subjects will maintain their baseline types of antidiabetic therapy throughout the study. 
Recruitment (randomization) of subjects 18 and < 25 years old will be limited to < 40% of subjects. Recruitment 
(randomization) of subjects 10 and 15 years old will include at least 20% of subjects. 
After the lead-in period, at least 66 subjects with HbA1c 6.5% and 11% at screening will be randomized 1:1 to 
receive oral blinded dapagliflozin 10 mg or placebo, stratified by gender, age (< 18 vs. 18 years and 15 years vs. 
> 15 to < 18 years) and baseline medication (metformin alone, insulin metformin). After completion of the 24-week 
short-term treatment period, all subjects will enter the 28-week open-label safety extension period for safety 
monitoring. All subjects will receive dapagliflozin 10 mg for the duration of this period. This will be followed by a 
4-week post-treatment safety follow-up period.
Subjects who discontinue study drug before the end of the study treatment period will enter a non-treatment, follow-up 
phase, in which subjects will follow their visit schedules with modified assessments until study completion.
Safety measures will be collected throughout the study. This will include regular self-monitored blood glucose 
(SMBG) levels, self-monitored blood ketone levels, and monitoring of growth and development. 
Population PK samples will be collected pre-dose and approximately 2 hours post-dose (1 hour) during the 
Week 16 and 24 visits.


Clinical Protocol
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dapagliflozin
Revised Protocol No: 03
Date: 20-Sep-2017
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Study Schematic:
During the course of the trial, subjects may be eligible for the addition of open-label rescue medication to their blinded 
treatment regimen in order to treat ongoing hyperglycemia. Insulin will be initiated or up-titrated as rescue.
Pre-specified glycemic criteria (see Table 1 below), based upon SMBG FPG, or single central laboratory FPG and 
repeat confirmatory FPG have been established during the treatment period, starting at Day 1, and up to the Week 52 
visits to determine eligibility for open-label rescue medication. For subjects on baseline insulin, persistently increased 
doses of insulin 20% or more above baseline dose, despite advice and counsel to keep the insulin dose stable, may be 
considered another potential manifestation of poor glycemic control, and should be evaluated for rescue. Any 
permanent changes in dose of basal insulin should be done after evaluation of rescue criteria, including both SMBG 
and central laboratory FPG values. 
Table 1:
Lack of Glycemic Control Criteria for Initiation of Rescue Medication
Study week
Rescue criterion
From Day 1 visit up to and 
including Week 24 visit
FPG > 13.3 mmol/L (240 mg/dL) based on SMBG for 3 consecutive days 
followed by a confirmatory central laboratory FPG or
Single central laboratory FPG followed by a confirmatory central laboratory 
FPG
Following Week 24 visit up to 
and not including Week 52 
visit
FPG > 10 mmol/L (180 mg/dL) based on SMBG for 3 consecutive days 
followed by a confirmatory central laboratory FPG or
Single central laboratory FPG followed by a central laboratory FPG or
HbA1c > 8.0%
Study Population: For entry into the study, the following criteria MUST be met. The full inclusion/exclusion criteria 
are found in Section 3.3 of the protocol.
Key Inclusion Criteria:

Provision of informed consent prior to any study-specific procedures

Males and females, ages 10 years of age, up to but not including 25 years of age at the time of randomization

Previously diagnosed as having T2DM for at least 2 months by World Health Organization (WHO)/ADA 
diagnostic criteria

HbA1c 6.5% and 11% obtained at screening visit


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
Currently on diet and exercise and a stable dose of metformin (at least 1000 mg daily) for a minimum of 8 weeks, 
or stable dose of insulin for a minimum of 8 weeks, or a stable combination of metformin (at least 1000 mg daily) 
and insulin for a minimum of 8 weeks prior to screening

FPG 255 mg/dL (14.2 mmol/L) obtained at screening visit
Key Exclusion Criteria:

Previous diagnosis of Type 1 diabetes

Diabetes ketoacidosis (DKA) within 6 months of screening

Current use of the following medications for the treatment of diabetes, or use within the specified timeframe prior 
to screening for the main study:
-
Eight weeks: sulfonylureas, alpha glucosidase inhibitors, metiglinide, oral or injectable incretins or incretin 
mimetics or other antidiabetes medications not otherwise specified
-
Sixteen weeks: thiazolidinediones
-
Any previous history or current use of a sodium glucose cotransporter-2 (SGLT-2) inhibitor, including
dapagliflozin

Initiation or discontinuation of prescription or non-prescription weight loss drugs within 8 weeks of screening. 
Use of prescription or non-prescription weight loss drugs must be stable during the study.

Pregnant, positive serum pregnancy test, planning to become pregnant during the clinical trials, or breastfeeding

History of unstable or rapidly progressive renal disease

History of unresolved vesico-ureteral reflux

Replacement or chronic systemic corticosteroid therapy, defined as any dose of systemic corticosteroid taken for 
> 4 weeks within 3 months prior to the Day 1 visit
Note: Topical, nasal, or inhaled corticosteroids are allowed

Abnormal renal function, which is defined in subjects < 18 years of age as an estimated glomerular filtration rate 
(eGFR) calculated by the Schwartz Formula < 80 mL/min/1.73 m2 (1.33 mL/s), and in subjects 18 years as an 
eGFR calculated by the Modified Diet in Renal Disease (MDRD) Formula < 60 mL/min/1.73 m2 (1.33 mL/s)

Presence of either: antibodies to glutamic acid decarboxylase (GAD) or protein tyrosine phosphatase-like protein 
antibodies (IA-2)

An abnormal thyroid stimulating hormone (TSH) value at screening will be further evaluated for free T4. Subjects 
with abnormal free T4 values will be excluded.

Hematuria (confirmed by microscopy at screening) with no explanation as judged by the Investigator up to 
randomization

Anemia of any etiology defined as hemoglobin 10.7 g/dL (107 g/L) for females and 11.3 g/dL (113 g/L) for 
males. Subjects who are considered to have anemia according to local guidelines should be excluded.

Volume-depleted subjects. Subjects at risk for volume depletion due to co-existing conditions or concomitant 
medications, such as loop diuretics, should carefully monitor their volume status.
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for BMS-512148
Medication 
Potency 
IP/Non-IP
Dapagliflozin
10 mg
IP
Placebo Matching 
Dapagliflozin
0 mg
IP


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Revised Protocol No: 03
Date: 20-Sep-2017
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Study Assessments:
Dose and Treatment Regimens 
Dapagliflozin 10 mg tablets or matching placebo tablets, administered orally once daily, will be provided for the 
24-week blinded treatment period. Dapagliflozin 10 mg tablets administered orally once daily, will be provided for 
the 28-week site and subject blinded long-term extension.
During the study, diet and exercise will be reinforced at each visit.
Safety Assessments
Self-monitored blood glucose (SMBG) and reporting of hypoglycemia
Glucose meters will be supplied to each study site. Subjects should be asked to self-monitor their blood glucose at 
least once per day and when symptoms suggestive of hypoglycemia occur. The Investigator may require more frequent 
readings based on local clinical practice. The glucose values should be reviewed by the site to identify any unusual 
high or low values.
Self-monitored blood ketones and reporting of DKA
Subjects and their family members must be aware of the possibility that DKA may occur, the signs and symptoms and 
the dangers associated with DKA. Subjects will receive a combined glucose and ketone meter and sufficient supplies 
for testing at the entry into Lead-In (Week -4 visit). Subjects will also be trained in the procedure of conducting blood 
ketone testing according to the manufacturer’s specifications. The blood ketone values should be recorded and will be 
reviewed by the site to identify any unusual high values.
Assessment of growth and maturation
Growth and maturation will be assessed through the collection of relevant physical measurements and specific 
laboratory tests,
Laboratory Safety Assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will be taken at the times 
indicated in the protocol.
The Investigator should make an assessment of the available results with regard to clinically relevant abnormalities.
Statistical Considerations:
Sample Size:
Given the anticipated challenges to recruitment with this population, a partial extrapolation approach was used to 
better inform the sample size determination.
A probability estimate was determined using clinical trial simulation from a non-linear mixed effects model for the 
relationship between dapagliflozin PK and HbA1c response in adult T2DM subjects. Adjustments were made to the 
model for expected differences in the covariate effects on PK and pharmacodynamic (PD) parameters due to the 
differences in baseline characteristics between adult and pediatric T2DM subjects. The simulation allowed for the 
sample size to be reduced while maintaining 85% probability of demonstrating superiority to placebo for dapagliflozin 
10 mg. In order to inform the design of this study, a Bayesian approach was employed to predict the potential efficacy 
of dapagliflozin on HbA1c in pediatric patients from the existing data and knowledge in adult T2DM patients.
Simulation results suggest a difference versus placebo in HbA1c of -0.78% for dapagliflozin 10 mg. Based on this 
estimated treatment difference of 0.78% and assuming a standard deviation of 0.9% for change from baseline in 
HbA1c at Week 24, a sample size of 25 per treatment group has 85% power to demonstrate the superiority of 
dapagliflozin 10 mg to placebo (where superiority is defined as a placebo-corrected HbA1c at 24 weeks indicating 
greater improvement that is statistically significant) at a two-sided alpha level of 5 percent. To ensure that at least 
50 subjects will complete the 24-week treatment period on investigational product and the Week 24 assessment, at 
least 66 subjects will be randomized.


Clinical Protocol
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dapagliflozin
Revised Protocol No: 03
Date: 20-Sep-2017
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Endpoints:
Primary endpoint
1.
Change from baseline in HbA1c at Week 24
Secondary endpoints
2.
The change from baseline in FPG at Week 24
3.
The percentage of subjects who require glycemic rescue medication or discontinuation due to lack of glycemic 
control over 24 weeks double-blind treatment
4.
The percentage of subjects with baseline HbA1c > 7% who achieve HbA1c level < 7% at Week 24
Safety endpoints
The assessment of safety will be based on the analyses of adverse events (AEs), vital signs, physical examinations, 
electrocardiograms (ECGs), hypoglycemia, elevated plasma ketone level, and clinical laboratory evaluations. All 
safety analyses will be performed using the Treated Subjects Data Set.
Analyses:
Statistical Approach and Assumptions
The primary analysis of the primary endpoint, change in HbA1c from baseline to Week 24, will be based on a mixed 
model with repeated measures (MMRM) including all scheduled time points following randomization up to and 
including Week 24. The primary analysis will only include measurements prior to the administration of rescue 
medication. Measurements made following rescue administration will be included in sensitivity analysis. Various 
sensitivity analyses will be specified in the Statistical Analysis Plan to assess the robustness of the primary analyses, 
including sensitivity analyses of all data pre-and post-rescue.
Point estimates and 95% confidence intervals for the mean change in HbA1c for each treatment group as well as the 
difference in the estimated mean change between the dapagliflozin treatment group and placebo will be calculated. 
The p-value of the difference in Week 24 estimates between dapagliflozin and placebo will be presented.
Safety Analyses
Safety analyses will include treatment group summaries of the incidence of AEs and marked laboratory abnormalities, 
the percentages of subjects experiencing hypoglycemia as well as the number and severity of hypoglycemic events, 
the incidence of elevated plasma ketone level, vital signs, and laboratory test parameters. 
Summaries will include the number of patients with events by specified system organ classes and preferred terms.


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1
INVESTIGATIONAL PLAN
Type 2 diabetes mellitus (T2DM) is a complex and multifactorial metabolic disorder with 
contributions from genetic, behavioral, and environmental risk factors. Despite a wealth of 
information concerning T2DM in adults, data unique to the pediatric age group regarding the 
pathophysiology and therapy for T2DM are limited.1
As in adults, T2DM in children is characterized by hyperglycemia associated with initial relative 
insufficiency of insulin secretion and increased insulin resistance, and is ultimately often followed 
by pancreatic β-cell failure.2,3,4 A potentially important difference between adults and pediatric 
patients with T2DM is that in the natural course of T2DM in pediatric patients, the glucose 
dysregulation may develop over a much more rapid time frame than is seen in adults.5 This may 
be a contributing factor to the tendency for poorer prognosis for microvascular and macrovascular 
diabetic complications for pediatric patients with T2DM as they become adults.6 An additional 
factor unique to the development of T2DM in the pediatric age range is the potential additive 
contribution and impact of the insulin resistance of puberty, which, although a natural phenomenon 
during pubertal development, may have a negative influence on and potentially exacerbate 
glycemic dysregulation in susceptible children.5
As with adults, it is expected that children and adolescents with T2DM are at risk for eventually 
developing diabetes-related micro- and macrovascular complications with higher glycemic levels.1
Data from a number of small studies conducted in limited ethnic groups have confirmed an 
increased risk of microvascular complications1,7 in pediatric patients with T2DM compared with 
children and adolescents without diabetes. For example, microalbuminuria, macroalbuminuria, 
and hypercholesterolemia have all shown an increased tendency to develop in Pima Indian children 
with T2DM. Among Japanese pediatric patients, retinopathy has been observed at a similar rate in 
those with type 1 and T2DM, although it appears to be less common in pediatric patients compared 
with adults with T2DM. A study in Australia found that pediatric patients with T2DM have 
significantly higher rates of microalbuminuria and hypertension than those with type 1 diabetes, 
despite shorter duration of disease and lower glycosylated hemoglobin (HbA1c).8 Additional small 
studies have shown an increased occurrence of renal disease (Japanese), non-alcoholic fatty liver 
disease (the Manitoba Cree), and cardiovascular mortality associated with hypertension and 
dyslipidemia in pediatric patients with T2DM.9
There is evidence in adults from the UK Prospective Diabetes Study (UKPDS) that normalization 
of blood glucose substantially decreases the frequency of microvascular complications of T2DM
(UKPDS Group 1998), consistent with what has been noted with type 1 diabetes.10 It is assumed 
that a management regimen based on adequate glycemic control, via lifestyle changes with 
modification of diet and physical activity and, as appropriate, medical treatment, should help to 
reduce the risk of complications in younger persons as well as adults with the disease.
Current therapeutic agents have limited efficacy and are associated with side effects including 
hypoglycemia, weight gain, edema and gastrointestinal effects. While there are several oral 
glucose lowering medications approved for adults with T2DM, the only oral glucose lowering 


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medication approved for use in pediatric patients age 10 and older is metformin. Agents with new 
mechanisms of action for the treatment of T2DM are being studied.
Given the need for additional oral glucose lowering therapy options for pediatric patients with 
T2DM, it is appropriate to test the hypothesis that dapagliflozin, an orally active sodium glucose 
cotransporter-2 (SGLT-2) inhibitor, will confer the therapeutic benefits of glucose-lowering and 
some weight loss, without adding the risk of hypoglycemia, in this population. This program will 
investigate the efficacy, safety, and tolerability of dapagliflozin versus placebo for the treatment 
of patients with pediatric or early age onset T2DM.
1.1
Study Rationale
This protocol will be performed to meet the requirements of the European Union (EU) Pediatric 
Investigations Plan (PIP) for Type 2 Diabetes, and aims to allow for the extended use of 
dapagliflozin in appropriate pediatric patients. 
Dapagliflozin has been shown to be effective in lowering HbA1c in adult patients with T2DM, 
when studied as monotherapy and in combination with insulin or oral antidiabetic (OAD) 
medications. Overall, through its development program, dapagliflozin has been shown to improve 
HbA1c with a low risk of hypoglycemia, while also demonstrating positive trends for common 
comorbidities (weight gain and systolic hypertension) associated with increased cardiovascular 
risk in T2DM adult patients.
A number of studies have demonstrated that the rising prevalence of T2DM in pediatric patients 
parallels the growing obesity problem in this population as it does in adults.9,11,12 However, studies 
from Germany, the United Kingdom (UK), and Sweden indicate that T2DM remains a rarity 
among children in Europe.13,14,15 Also, the recruitment of pediatric patients with T2DM into 
clinical trials has proven very difficult for a number of reasons. Innovative methods are therefore 
required to ensure that new novel treatments, such as dapagliflozin, are studied and made available 
to this population. 
Given the anticipated challenges to recruitment with this population, a partial extrapolation 
approach was used to better inform the sample size determination. Full extrapolation was not 
pursued because the criteria for full extrapolation were deemed not to have been met for this 
disease. This partial extrapolation approach entails that the pediatric outcome and design is 
informed by extrapolation from adult data, and the actual data from the trial proposed will be used 
to validate the extrapolation.
A probability estimate was determined using clinical trial simulation from a non-linear mixed 
effects model for the relationship between dapagliflozin pharmacokinetics (PK) and HbA1c 
response in adult T2DM subjects. Adjustments were made to the model for expected differences 
in the covariate effects on PK and pharmacodynamic (PD) parameters due to the differences in 
baseline characteristics between adult and pediatric T2DM subjects. The simulation allowed for 
the sample size to be reduced, while maintaining 85% probability of demonstrating superiority to 
placebo for dapagliflozin 10 mg. 


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1.2
Research Hypothesis 
Dapagliflozin results in a greater mean reduction from baseline in HbA1c compared to placebo 
after 24 weeks of double-blind add-on treatment in patients aged 10 to less than 25 years with 
T2DM who have inadequate glycemic control on diet and exercise with metformin or insulin 
metformin.
1.3
Objectives(s)
1.3.1
Primary Objectives
To compare the mean change from baseline in HbA1c achieved with dapagliflozin against the 
mean achieved with placebo after 24 weeks of double-blind add-on treatment in patients aged 10 to 
less than 25 years with T2DM who have inadequate glycemic control on diet and exercise with 
metformin or insulin metformin.
1.3.2
Secondary Objectives

To compare the mean change from baseline in Fasting Plasma Glucose (FPG) achieved with 
dapagliflozin against the mean achieved with placebo after 24 weeks of double-blind add-on 
treatment in patients aged 10 to less than 25 years with T2DM who have inadequate glycemic 
control on diet and exercise with metformin or insulin metformin.

To compare the percentage of subjects who require glycemic rescue or discontinuation due to 
lack of glycemic control with dapagliflozin against the percentage with placebo over the 
24 weeks of double-blind add-on treatment in patients aged 10 to less than 25 years with T2DM 
who have inadequate glycemic control on diet and exercise with metformin, or insulin 
metformin.

To compare the percentage of subjects with baseline HbA1c > 7% who achieve a HbA1c level 
< 7% with dapagliflozin against the percentage achieved with placebo after 24 weeks of 
double-blind add-on treatment in patients aged 10 to less than 25 years with T2DM who have 
inadequate glycemic control on diet and exercise with metformin, or insulin metformin.
1.3.3
Safety Objectives

To assess the safety and tolerability of dapagliflozin as add-on treatment in patients aged 10 to 
less than 25 years with T2DM who have inadequate glycemic control on diet and exercise with 
metformin or insulin metformin when administered for up to 24 weeks of short-term therapy 
and 52 weeks of total therapy.

To assess the percentage of subjects who experience hypoglycemia with dapagliflozin against 
the percentage achieved with placebo as add-on treatment in patients aged 10 to less than 
25 years with T2DM who have inadequate glycemic control on diet and exercise with 
metformin, or insulin metformin when administered for up to 24 weeks.

To assess markers of growth and maturation, the incidence of diabetic ketoacidosis (DKA), 
and changes in markers of bone health with dapagliflozin against those observed with placebo 
as add-on treatment in patients aged 10 to less than 25 years with T2DM who have inadequate 
glycemic control on diet and exercise with metformin or insulin metformin when 
administered for up to 24 weeks.


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1.3.4
Exploratory Objectives

To explore the PK and exposure-response relationship of dapagliflozin in patients aged 10 to 
less than 25 years with T2DM based on the collection of population PK samples.

To explore the mean change from baseline in HbA1c achieved with dapagliflozin after 
52 weeks of add-on treatment in patients aged 10 to less than 25 years with T2DM who have 
inadequate glycemic control on diet and exercise with metformin or insulin metformin.

To explore the mean change from baseline in FPG achieved with dapagliflozin after 52 weeks 
of add-on treatment in patients aged 10 to less than 25 years with T2DM who have inadequate 
glycemic control on diet and exercise with metformin or insulin metformin.

To explore the percentage of subjects who require glycemic rescue or discontinuation due to 
lack of glycemic control with dapagliflozin over the 52 weeks of add-on treatment in patients 
aged 10 to less than 25 years with T2DM who have inadequate glycemic control on diet and 
exercise with metformin or insulin metformin.

To explore the percentage of subjects with baseline HbA1c 7% who achieve a HbA1c level 
< 7% with dapagliflozin after 52 weeks of add-on treatment in patients aged 10 to less than 
25 years with T2DM who have inadequate glycemic control on diet and exercise with 
metformin or insulin metformin.
1.4
Product Development Background
Dapagliflozin is a rationally designed, stable, competitive, reversible, highly selective and orally 
active inhibitor of SGLT-2, the major transporter responsible for renal glucose reabsorption. 
Dapagliflozin inhibits human SGLT-2 (Ki = 0.55 nM) selectively (1400-fold selective), and is also 
highly selective vs. other facilitative glucose transporters. Dapagliflozin’s mechanism of action is 
different and complementary to the mechanisms of currently available medicines, resulting in the 
direct and insulin-independent elimination of glucose by the kidney. Further, as SGLT-2 is almost 
exclusively expressed in the kidney, the highly selective nature of dapagliflozin minimizes the risk 
of off target (i.e., non-kidney) effects. As such, dapagliflozin offers an important additional 
strategy for improving glycemic control in patients with T2DM.
Dapagliflozin has been shown to be effective in lowering HbA1c in adult patients with T2DM, 
when studied as monotherapy and in combination with insulin or OAD medications. Results from 
secondary glycemic efficacy endpoints (including FPG, 2-hour postprandial glucose [PPG], and 
change in HbA1c in patients with baseline HbA1c 9.0%) are consistent with the main HbA1c 
results and further support the role of dapagliflozin as a glucose lowering agent. Importantly, 
dapagliflozin has been shown to improve glycemic control with a low intrinsic risk for 
hypoglycemia. Furthermore, the steady excretion of glucose due to SGLT-2 inhibition results in a 
continual loss of calories that ultimately leads to a decrease in weight and adiposity. The inhibition 
of sodium and glucose transport in the proximal tubule also causes a mild diuretic effect, leading 
to a modest lowering of blood pressure (BP). Overall, dapagliflozin has been shown to improve 
HbA1c with a low risk of hypoglycemia, while also demonstrating positive trends for common 
comorbidities (weight gain and systolic hypertension) associated with increased cardiovascular 
risk in T2DM adult patients.


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1.5
Overall Risk/Benefit Assessment
Dapagliflozin is approved for use in adults in approximately 40 countries including the United 
States (US) and EU. Prior to approval, dapagliflozin was evaluated in 5 core Phase 2b studies, 
16 core Phase 3 studies, and 3 regional Phase 3 studies. These studies established that dapagliflozin 
is effective in reducing HbA1c in a broad range of adult subjects, regardless of disease 
progression/duration or concomitant use of antidiabetic therapies. Dapagliflozin consistently 
demonstrated statistically and clinically significant mean reductions in HbA1c versus placebo 
among the three doses typically studied (2.5, 5, and 10 mg). Overall, the dose of 10 mg provided 
better efficacy than the two lower doses. Effects on secondary glycemic efficacy parameters, 
including FPG and PPG, support the primary HbA1c efficacy findings. Dapagliflozin also resulted 
in a modest reduction in total body weight relative to placebo or comparator, largely attributable 
to a decrease in body fat mass, as well as reductions in systolic BP. Placebo-controlled data for up 
to 2 years indicate that the beneficial effects on glycemic and non-glycemic parameters were 
maintained.
Overall, dapagliflozin has been well tolerated in clinical studies.
For an overall risk/benefit assessment of dapagliflozin, see the Investigator’s Brochure (IB).
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying EU Directive 2001/20/EC and the US Code of Federal Regulations, Title 21, 
Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment).
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the Investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(e.g., advertisements), and any other written information to be provided to subjects. The 


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Investigator or Sponsor (or designee) should also provide the IRB/IEC with a copy of the IB or 
product labeling information to be provided to subjects and any updates.
The Investigator or Sponsor (or designee) should provide the IRB/IEC with reports, updates and 
other information (e.g., expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate.
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate.
Sponsor or designee will provide the Investigator with an appropriate (i.e., Global or Local) sample 
informed consent form (ICF) which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample ICF will adhere to the ethical principles that have their origin 
in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language in 
which the subject is proficient prior to clinical study participation. The language must be 
non-technical and easily understood.
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written ICF and any other 
information to be provided to the subjects, prior to the beginning of the study, and after any 
revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The Investigator, or a person designated by the Investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented.
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed Health Insurance Portability and Accountability Act of 1996 (HIPAA)
Authorization.


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The consent form must also include a statement that the Sponsor or designee and regulatory 
authorities have direct access to subject records.
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the ICF approved for the study prior to 
clinical study participation. The explicit wish of a minor, who is capable of forming an opinion 
and assessing this information, to refuse participation in, or to be withdrawn from, the clinical 
study at any time should be considered by the Investigator.
Minors who are judged to be of an age of reason must also give their written assent.
Subjects unable to give their written consent may only be enrolled in the study with the consent of 
a legally acceptable representative. The subject must also be informed about the nature of the study 
to the extent compatible with his or her understanding, and should this subject become capable, he 
or she should personally sign and date the consent form as soon as possible. The explicit wish of 
a subject who is unable to give his or her written consent, but who is capable of forming an opinion 
and assessing information to refuse participation in, or to be withdrawn from, the clinical study at 
any time should be considered by the Investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
The study will be a prospective, multi-center, 24-week, placebo controlled, double-blind 
randomized study with a 28-week open-label safety extension. Subjects 10 years and < 25 years 
of age, with confirmed diagnosis of T2DM, who are being treated with diet and exercise and a 
stable dose of metformin immediate release (IR) or extended release (XR) (at least 1000 mg daily) 
for a minimum of 8 weeks prior to screening, or a stable dose of insulin for a minimum of 8 weeks 
prior to screening, or a stable combination of metformin and insulin for a minimum of 8 weeks 
prior to screening, will be screened against the inclusion and exclusion criteria, as per Section 3.3. 
Eligible subjects meeting all criteria will enter a 4-week placebo lead-in period. Subjects will be 
instructed to follow a diet and exercise program (in accordance with the American Diabetes 
Association [ADA] or similar national guidelines) for the duration of the study. Subjects will 
maintain their baseline types of antidiabetic therapy throughout the study. 
Recruitment (randomization) of subjects 18 and < 25 years old will be limited to < 40% of 
subjects. Recruitment (randomization) of subjects 10 and 15 years old will include at least 
20% of subjects. 
After the lead-in period, at least 66 subjects with HbA1c 6.5% and 11% at screening will be 
randomized 1:1 to receive oral blinded dapagliflozin 10 mg or placebo, stratified by gender, age 
(< 18 vs. 18 years and ≤ 15 years vs. >15 to < 18 years) and baseline medication (metformin 
alone, insulin metformin). After completion of the 24-week short-term treatment period, all 
subjects will enter the 28-week open-label safety extension period for safety monitoring. All 
subjects will receive dapagliflozin 10 mg for the duration of this period. This will be followed by 


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a 4-week post-treatment safety follow-up period. The study will end when all evaluable subjects 
complete the 56 weeks of study.
Subjects who discontinue study drug before the end of the study treatment period will enter a 
non-treatment, follow-up phase, in which subjects will follow their visit schedules with modified 
assessments until study completion. Discontinued subjects will not be replaced. 
Glycemic rescue parameters are included for subjects who meet the criteria for lack of glycemic
control in both the 24-week short-term treatment period and the 28-week safety extension period. 
Investigators will use insulin as rescue. Rescued subjects will continue treatment on study drug.
Safety measures will be collected throughout the study. This will include regular self-monitored 
blood glucose (SMBG) levels, self-monitored blood ketone levels, and monitoring of growth and 
development. 
Population PK samples will be collected pre-dose and approximately 2 hours post-dose (1 hour) 
during the Week 16 and 24 visits. The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
3.2
Post Study Access to Therapy
At the end of the treatment period (at Week 52 visit) or early discontinuation, the Sponsor or 
designee will not continue to provide Sponsor supplied study drug to subjects/investigators unless 
the Sponsor or designee chooses to extend the study. The Investigator should ensure that the 
subject receives appropriate standard of care to treat the condition under study.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects (or designee) must be willing and able to give signed and dated written informed 
consent. Minor’s parents or legally acceptable representatives must give fully informed 


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written consent. Assent should be obtained according to local regulations and if child is 
capable.
2. Target Population
a) Previously diagnosed with T2DM by World Health Organization (WHO)/ADA diagnostic 
criteria
b) HbA1c 6.5% and 11% obtained at screening visit
c) Currently on diet and exercise and a stable dose of metformin (at least 1000 mg daily) for 
a minimum of 8 weeks, or stable dose of insulin for a minimum of 8 weeks, or a stable 
combination of metformin (at least 1000 mg daily) and insulin for a minimum of 8 weeks 
prior to screening
d) FPG 255 mg/dL (14.2 mmol/L) obtained at screening visit
e) Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (i.e., subject has not been randomized / 
has not been treated).
Note: If re-enrolled, the subject must be re-consented. All screening procedures will be 
repeated. Subjects may only be re-enrolled once.
3. Age and Reproductive Status
a) Males and females, ages 10 years of age, up to but not including 25 years of age at the time 
of randomization. 
i)
Recruitment (randomization) of subjects 18 and < 25 years old will be limited to 
< 40% of subjects. 
ii) Recruitment (randomization) of subjects 10 and 15 years old will include at least
20% of subjects.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic 
gonadotrophin) within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) Women of childbearing potential must agree to follow instructions for method of 
contraception for the duration of treatment with study drug, plus 5 half-lives of study drug 
or 30 days (whichever is longer), plus 30 days (duration of ovulatory cycle), for a total of 
60 days post-treatment completion.
e) Women of childbearing potential who are continuously not heterosexually active are 
exempt from contraceptive requirements. However, they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy. Investigators shall advise WOCBP on the use of highly 
effective methods of contraception. Highly effective methods of contraception have a failure rate 
of < 1% when used consistently and correctly.


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At a minimum, subjects must agree to use one highly effective OR one less effective method of 
contraception as listed below:
A. HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. Women of childbearing potential are expected to use one of the highly effective methods 
of contraception listed below. Contraception methods are as follows:
1. Progestogen-only hormonal contraception associated with inhibition of ovulation
2. Hormonal methods of contraception including oral contraceptive pills containing 
combined estrogen + progesterone, vaginal ring, injectables, implants and intrauterine 
devices (IUDs) such as Mirena
3. Nonhormonal IUDs, such as ParaGard
4. Bilateral tubal occlusion
5. Vasectomised partner with documented azoospermia 90 days after procedure
a.
Vasectomised partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the surgical success.
6. Intrauterine hormone-releasing system
7. Complete abstinence
a.
Complete abstinence is defined as the complete avoidance of heterosexual 
intercourse (refer to Glossary of Terms).
b. Complete abstinence is an acceptable form of contraception for all study drugs and 
must be used throughout the duration of the study treatment (plus 5 half-lives of the 
investigational drug plus 30 days).
c.
It is not necessary to use any other method of contraception when complete 
abstinence is elected.
d. Subjects who choose complete abstinence must continue to have pregnancy tests. 
e.
Acceptable alternate methods of highly effective contraception must be discussed 
in the event that the subject chooses to forego complete abstinence.
f.
The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the subject.
B. LESS EFFECTIVE METHODS OF CONTRACEPTION
1. Diaphragm with spermicide
2. Cervical cap with spermicide
3. Vaginal sponge with spermicide
4. Male or female condom with or without spermicide.16,17 A male and a female condom must 
not be used together.
5. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
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C. UNACCEPTABLE METHODS OF CONTRACEPTION
a) Periodic abstinence (calendar, symptothermal, post-ovulation methods)
b) Withdrawal (coitus interruptus)
c) Spermicide only
d) Lactation amenorrhea method
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Previous diagnosis of Type 1 diabetes
b) Previous diagnosis of monogenic etiology of T2DM such as maturity onset diabetes of the 
young (MODY), genetic disorders with strong associations with insulin resistance/diabetes 
and/or obesity such as Turner’s Syndrome and Prader-Willi, or secondary diabetes (steroid 
use, Cushing’s disease, acromegaly)
c) Diabetic ketoacidosis within 6 months of screening
d) Current use of the following medications for the treatment of diabetes, or use within the 
specified timeframe prior to screening for the main study:
i)
Eight weeks: sulfonylureas, alpha glucosidase inhibitors, metiglinide, oral or injectable 
incretins or incretin mimetics or other antidiabetes medications not otherwise specified
ii) Sixteen weeks: thiazolidinediones
iii) Any previous history or current use of an SGLT-2 inhibitor, including dapagliflozin
e) Initiation or discontinuation of prescription or non-prescription weight loss drugs within 
8 weeks of screening. Use of prescription or non-prescription weight loss drugs must be 
stable during the study.
2. Medical History and Concurrent Diseases
a) Pregnant, positive serum pregnancy test, planning to become pregnant during the clinical 
trials, or breastfeeding
b) History of unstable or rapidly progressive renal disease
c) History of unresolved vesico-ureteral reflux
d) History of hemoglobinopathy, with the exception of sickle cell trait or thalassemia minor; 
or chronic or recurrent hemolysis
e) Malignancy within 5 years of the screening visit (with the exception of treated basal cell 
or treated squamous cell carcinoma)
f)
Significant co-morbidity that, in the opinion of the investigators, will increase the risk to 
the subject such as coronary artery disease, any heart disease that increases risk associated 
with exercise, or immune-suppression
g) Replacement or chronic systemic corticosteroid therapy, defined as any dose of systemic 
corticosteroid taken for > 4 weeks within 3 months prior to the Day 1 visit
NOTE: Topical, nasal, or inhaled corticosteroids are allowed


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3. Physical and Laboratory Test Findings
a) Abnormal renal function, which is defined in subjects < 18 years of age as an estimated 
glomerular 
filtration 
rate 
(eGFR) 
calculated 
by 
the 
Schwartz 
Formula 
< 80 mL/min/1.73 m2 (1.33 mL/s)18, and in subjects 18 years as an eGFR calculated by 
the Modified Diet in Renal Disease (MDRD) Formula < 60 mL/min/1.73 m2 (1.33 mL/s)19
b) Presence of either: antibodies to glutamic acid decarboxylase (GAD) or protein tyrosine 
phosphatase-like protein antibodies (IA-2)
c) An abnormal thyroid stimulating hormone (TSH) value at screening will be further 
evaluated for free T4. Subjects with abnormal free T4 values will be excluded.
Note: In subjects who have had a prior diagnosis of a thyroid disorder and who are currently 
receiving thyroid replacement therapy, a one-time retest of TSH may be allowed, as 
determined by the Investigator, after a minimum of 6 weeks following the adjustment of 
thyroid hormone replacement therapy. Such cases should be discussed with the Sponsor 
prior to re-testing. The subject must have all enrollment procedures and laboratory 
assessments performed as part of this re-test, and all of these must meet enrollment 
eligibility criteria. The subject’s number will however remain the same as initially 
assigned.
d) Hematuria (confirmed by microscopy at screening) with no explanation as judged by the 
Investigator up to randomization. 
e) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2× upper limits of 
normal (ULN), or clinically significant hepatic disease.
f)
Serum total bilirubin (TB) 2x ULN, unless exclusively caused by Gilbert’s syndrome
g) History of positive serologic evidence of current infectious liver disease including 
anti-hepatitis A virus (HAV) (Immunoglobulin M [IgM]), hepatitis B surface antigen 
(HBsAg), or anti-hepatitis C virus (HCV). Patients who may have isolated positive 
hepatitis B surface antibodies may be included.
h) Anemia of any etiology defined as hemoglobin 10.7 g/dL (107 g/L) for females and 
11.3 g/dL (113 g/L) for males. Subjects who are considered to have anemia according to 
local guidelines should be excluded.
i)
Volume-depleted subjects. Subjects at risk for volume depletion due to co-existing 
conditions or concomitant medications, such as loop diuretics, should carefully monitor 
their volume status.
j)
Clinically significant abnormalities in any pre-randomization laboratory analyses or 
electrocardiogram (ECG)
that, in the Investigator’s opinion, would preclude 
randomization.
4. Allergies and Adverse Drug Reaction
a) Known allergy, sensitivity or contraindication to any study drug or its excipient/vehicle.


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5. Other Exclusion Criteria
a) Subject is currently abusing alcohol or other drugs or has done so within the last 6 months 
prior to the screening visit.
b) Prisoners or subjects who are involuntarily incarcerated
c) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness
d) Psychiatric or cognitive disorder that will, in the opinion of investigators, limit the subject’s 
ability to comply with the study medications and monitoring.
e) Subjects who have contraindications to therapy as outlined in the dapagliflozin IB or local 
package inserts
f)
Participation and receiving investigational product (IP) in another clinical study during the 
prior 3 months
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A woman of childbearing potential is defined as any female who has experienced menarche and 
who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not 
postmenopausal.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments

Once consented, subjects may not receive any prescription antihyperglycemic medication other 
than study drug, metformin and/or insulin.

Once consented, subjects should not begin treatment with any systemic corticosteroid therapy 
lasting 5 days (inhaled and topical are allowed). Subjects who require systemic corticosteroid 
therapy should be discussed with the medical monitor prior to starting therapy whenever 
possible.

Once consented, subjects should not commence or modify therapy with any prescription or 
over the counter weight loss medications.

Once consented, subjects should not undergo any bariatric surgery.
3.4.2
Other Restrictions and Precautions

Subjects must comply with their prescribed dosing regimen to preserve study integrity and 
ensure subject safety.

Subjects should be cautioned that any new prescription, over-the-counter or herbal/nutritional 
therapies should be discussed thoroughly with the Investigator as concomitant use could result 
in alterations to their glycemic control and may place them at risk for significant hypoglycemic 
episodes.


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
Medication other than those which are protocol prohibited as described above, considered 
necessary for the patient’s safety and well-being, may be given at the discretion of the 
Investigator and must be recorded in the appropriate sections of the case report form (CRF).

Subjects must make every attempt to adhere to the diet and exercise counseling and to the study 
flow chart/time and events schedule (see Section 5.1).

Women of childbearing potential must immediately contact the Investigator if they suspect 
they might be pregnant and if they have changed or plan to change their birth control method.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue IP (and non-investigational product [non-IP] at the discretion of the 
Investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the Investigator, indicates that continued participation in the study is not in the best 
interest of the subject

Termination of the study by Sponsor

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness

Unblinding a subject for any reason (emergency or non-emergency)

Severe non-compliance to protocol, as judged by the Investigator and/or Sponsor

Safety reasons as judged by the Investigator and/or Sponsor

Pregnancy

Subjects experiencing decreased renal function must be evaluated as per Investigator’s 
discretion. 
o
Subjects with eGFR < 50 mL/min/1.73 m2 (by Schwarz formula18 for subjects
< 18 years and by MDRD formula19 for subjects 18 years) for a sustained period of 
time (12 to 16 weeks) must be discontinued.

Subjects with a central laboratory ALT and/or AST > 3xULN will be scheduled for a follow-up 
visit within 3 days following the receipt of the result (see Appendix 1 and Appendix 2 for 
further guidance). Subjects should be discontinued from study drug if the initial repeat 
laboratory tests meet any of the following criteria:
o
ALT and/or AST are > 3x ULN and TB > 2x ULN. 
o
ALT and/or AST are > 5x ULN for 14 consecutive days, at any time after initial 
confirmatory results.
o
ALT and/or AST are 10x ULN.
In the case of pregnancy, the Investigator must immediately notify the Sponsor’s Medical 
Monitor/designee of this event. The study drug will be permanently discontinued in an appropriate 
manner.
All subjects who discontinue study drug should comply with protocol-specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 


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withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate CRF page.
3.5.1
Procedures for handling patients incorrectly enrolled or randomized
Subjects who fail to meet the inclusion/exclusion criteria must not, under any circumstances, be 
enrolled or randomized. There can be no exceptions to this rule.
Subjects who are incorrectly enrolled, but are not yet randomized, should be withdrawn from the 
study. The procedures included in the protocol for the discontinuation of such subjects must be 
followed. Study medication should be permanently stopped and the subject should be further 
treated according to the Investigator’s judgment and local therapy tradition.
If a subject not meeting the study criteria is randomized in error, and if the error is identified after 
randomization, a discussion must occur between the Sponsor Medical Monitor or designee and the 
Investigator regarding whether to continue or discontinue the subject from the study drug. If 
agreement to continue in the study is reached, the subject should complete the study unless there 
are safety concerns or if the subject withdraws the consent. In situations in which an agreement 
cannot be reached, the subject should have the randomized therapy stopped and be discontinued 
from the study. The procedures included in the protocol for the discontinuation of such subjects 
must be followed. The Sponsor Medical Monitor is to ensure all such contacts with the Investigator
and such decisions are appropriately documented. 
Withdrawn subjects will not be replaced.
3.5.2
Rescue Guidelines for Subjects with Protocol-Defined Lack of Glycemic 
Control
During the course of the trial, subjects may be eligible for the addition of open-label rescue 
medication to their blinded treatment regimen in order to treat ongoing hyperglycemia. Insulin will 
be initiated or up-titrated as rescue.
Pre-specified glycemic criteria (see Table 3.5.2-1), based upon SMBG FPG, or single central 
laboratory FPG and repeat confirmatory FPG have been established during the treatment period, 
starting at Day 1, and up to the Week 52 visit, to determine eligibility for open-label rescue 
medication. For subjects on baseline insulin, persistently increased doses of insulin 20% or more 
above baseline dose, despite advice and counsel to keep the insulin dose stable, may be considered 
another potential manifestation of poor glycemic control, and should be evaluated for rescue. Any 
permanent changes in dose of basal insulin should be done after evaluation of rescue criteria, 
including both SMBG and central laboratory FPG values. 


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Table 3.5.2-1:
Lack of Glycemic Control Criteria for Initiation of Rescue 
Medication
Study week
Rescue criterion
From Day 1visit up to and 
including Week 24 visit
FPG > 13.3 mmol/L (240 mg/dL) based on SMBG for 3 consecutive 
days followed by a confirmatory central laboratory FPG or
Single central laboratory FPG followed by a confirmatory central 
laboratory FPG
Following Week 24 visit up 
to and not including Week 
52 visit
FPG > 10 mmol/L (180 mg/dL) based on SMBG for 3 consecutive days 
followed by a confirmatory central laboratory FPG or
Single central laboratory FPG followed by a central laboratory FPG or
HbA1c > 8.0%
Subjects must be rescued following one of these scenarios:

Subjects with a SMBG FPG value meeting the lack of glycemic control criterion at any time 
during the pre-specified study period will be instructed to repeat FPG measurements on 
2 further consecutive days. If all 3 daily values meet the relevant lack of glycemic control 
criterion subjects should be scheduled for a follow-up visit (within 1 - 5 days) to obtain a 
central laboratory FPG value and review of the subject’s glucose meter readings. If the central 
laboratory FPG value meets the criterion, the subject must be rescued.

Subjects with a central laboratory FPG value meeting the lack of glycemic control criterion at 
a pre-specified visit will be scheduled for a follow-up visit (within 3 - 5 days) to obtain a second 
central laboratory FPG value and review of the subject’s glucose meter readings. If the second 
central laboratory FPG value also meets the criterion, the subject must be rescued.

Subjects with a central laboratory HbA1c value meeting the lack of glycemic control criterion 
following the pre-specified Week 24 visit must be rescued.
Subjects who meet rescue criteria must first complete the Rescue Visit procedures before receiving 
open-label rescue medication to ensure that important trial endpoint measurements are collected.
Following completion of the Rescue Visit, rescued subjects will either initiate or up-titrate 
open-label insulin as rescue medication. Insulin should be initiated at the lowest starting dose and 
titrated in accordance with the approved product label in the applicable country at the discretion 
of the Investigator, in addition to their study medication. Additional visits for titration of rescue 
medication should be scheduled as per the Investigator’s judgment in accordance with the 
approved product label for that country and by the subject’s glycemic response. Rescued subjects 
will then continue in the study according to their original visit schedule.
Note: Rescue medication will NOT be provided by the Sponsor in this study.
3.5.3
Discontinuation Guidelines due to Protocol-Defined Hypoglycemia 
Episodes
Subjects should not be discontinued from any treatment phase based on single episodes of 
hypoglycemia or symptoms of hypoglycemia unless clinically indicated. The assessment of a 


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single finger-stick or central laboratory glucose value should not be the sole assessment used to 
determine subject discontinuation for hypoglycemia. Clinical indications for discontinuation 
because of hypoglycemia may include the following:

Multiple occasions of episodes outlined below that, in the opinion of the Investigator, indicate 
that continued treatment with study therapy is not in the best interest of the subject. This 
includes, but is not limited to:
o
Recurrent symptoms suggestive of hypoglycemia (e.g., sweating, shakiness, increased 
heart rate (HR), confusion, dizziness, light-headedness, or hunger) in the absence of 
environmental factors known to contribute to hypoglycemia (i.e., excess physical 
activity, concurrent illness, or missed or delayed meal).
o
Recurrent documented capillary or plasma blood glucose values < 54 mg/dL 
(< 3.0 mmol/L).

A subject may also be discontinued from the study because of severe hypoglycemia as 
determined by the Investigator.
Down-titration of blinded study drug and/or background antihyperglycemic agent during 
the study
Down-titration of blinded study drug and/or background metformin will not be allowed at any time 
during the study.
Subjects on background insulin treatment who experience multiple or severe episodes of 
hypoglycemia may down-titrate insulin treatment during the study. The down-titration should be 
minimized, but is at the Investigator’s discretion.
3.5.4
Discontinuation Guidelines due to Diabetic Ketoacidosis (DKA)
There have been post-marketing reports of ketoacidosis, including DKA, in patients with type 1 
and T2DM taking dapagliflozin and other SGLT-2 inhibitors, although a causal relationship has 
not been established. 
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). 
A subject with any symptoms that may be consistent with an event of DKA should measure blood 
ketone levels, using the provided ketone and glucose meter, interrupt study drug and contact the 
Investigator. Treatment with the study drug may resume when the symptoms resolve or at the 
Investigator’s discretion. In the case of an established DKA, study drug should be interrupted until 
the event has resolved.
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from
pancreatic disorders (e.g., type 1 diabetes, history of pancreatitis, or pancreatic surgery), insulin
dose reduction, reduced caloric intake, or increased insulin requirements due to infections, illness 
or surgery and alcohol abuse.


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3.6
Post Study Drug Study Follow-up
In this study, safety is a key endpoint of the study. Post study follow-up is of critical importance 
and is essential to preserving subject safety and the integrity of the study. Subjects who discontinue 
study drug must continue to be followed for collection of outcome and/or survival follow-up data 
as required and in line with Section 5 until death or the conclusion of the study.
Please note that after the discontinuation of study drug, the management of the subject’s diabetes 
will be under the care and direction of the Investigator. 
The only exception to any of these follow-up methods is when a subject withdraws consent for all 
study procedures, including post-treatment study follow-up or loses the ability to consent freely 
(i.e., is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical 
illness).
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol-specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the Investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the Investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post-treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
destroyed, and the action documented. If samples are already analyzed, the Sponsor is not obliged 
to destroy the results of this research.
The Investigator must ensure:

Subject’s withdrawal of informed consent to the use of donated samples is notified 
immediately to the Sponsor.

Biological samples from that subject, if stored at the study site, are immediately identified, 
destroyed, and the action documented.

The laboratory holding the samples is informed about the withdrawn consent immediately and 
that samples are destroyed, and the action documented.

The subject and Sponsor are informed about the sample disposal.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 


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is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If the Investigator’s use of a third-party representative to assist in the follow-up portion of the 
study has been included in the subject’s informed consent, then the Investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining the subject’s contact 
information or other vital status data necessary to complete the follow-up portion of the study. The 
site staff and representative will conduct searches in a legally permissible manner that may include 
public records and database research, social media research and genealogical research. Physical 
research of local municipal resources, as allowed by local laws and regulations, may be conducted.
If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the Investigator should be reported and documented in the subject’s medical 
records.
3.6.3
Survey of Subject Vital Status
Subjects who prematurely discontinue from the study may be contacted after discontinuation from 
the study to collect vital status and safety information.


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4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational [Medicinal] Product (Non-IP/
Non-IMP) and can consist of the following:
Table 4-1:
Study Drugs for MB102138: Product Description: Short-term Double-Blind 
Treatment and Long-term Open Label Treatment Period
Product Description / 
Class and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Manufacturer
Storage Conditions
(per label)
Dapagliflozin Film Coated 
Tablet
10 mg
IP
Blinded
AstraZeneca
Storage conditions (per label), 
printed on IP bottles
Placebo for Dapagliflozin 
Film Coated Tablets
0 mg
IP
Blinded
AstraZeneca
Storage conditions (per label), 
printed on IP bottles
Dapagliflozin Film Coated 
Tablet
10 mg
IP
Open-Label
AstraZeneca
Storage conditions (per label), 
printed on IP bottles


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4.1
Investigational Product
An IP also known as investigational medicinal product (IMP) in some regions, is defined a 
pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) differently than the authorized form, or used for an unauthorized 
indication, or when used to gain further information about the authorized form.
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the Investigator to ensure that IP is only dispensed to study subjects. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations.
In this protocol, the IP is dapagliflozin 10 mg and placebo (also described in Table 4-1). 
Background therapy metformin and/or insulin (as appropriate) will not be provided by the Sponsor, 
since it is part of patients’ standard of care prior to enrollment.
Dapagliflozin 10 mg and corresponding placebo tablets may contain lactose, which may cause 
discomfort in lactose-intolerant individuals.
Labeling: Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and 
local regulatory guidelines. The labels will fulfill GMP Annex 13 requirements for labeling. Label 
text will be translated into local language according to the regional regulatory requirements.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-IPs. 
Subjects are expected to be on background medication of metformin IR or XR and / or insulin. 
Insulin, as per local labeling and standard of care, will be used for rescue as described in 
Section 3.5.2.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the Sponsor or 
designee. If concerns regarding the quality or appearance of the study drug arise, the study drug 
should not be dispensed and the sponsor or designee should be contacted immediately. All study 
drugs should be kept in a secure place under appropriate storage conditions. The IP label on the 
bottle specifies the appropriate storage.
Study drug not supplied by the Sponsor or designee will be stored in accordance with the package 
insert.
Investigational product documentation (whether supplied by the Sponsor or not) must be 
maintained that includes all processes required to ensure drug is accurately administered. This 
includes documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., required diluents, administration sets).


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4.4
Method of Assigning Subject Identification
At the screening visit each subject will be assigned a unique sequential subject number by the 
Interactive Web / Voice Response System (IWRS). This number will be used for identification 
throughout the study and will not be used for any other participant.
Randomized schedules will be generated and kept by the Sponsor or designee. Subjects will be 
randomly assigned to 1 of 2 blinded treatment groups by the IWRS in a 1:1 ratio. Randomization 
will be stratified by gender, age (< 18 vs. 18 years and 15 years vs. > 15 to < 18 years) and 
baseline medication (metformin alone vs. insulin metformin).
Subjects entering the 4-week placebo lead-in period
Following completion of the Screening activities, subjects who meet all the inclusion and none of 
the exclusion criteria will be registered by the IWRS into the lead-in period, and receive blinded 
placebo treatment.
Subjects entering the 24-week double-blinded short-term treatment period
Following completion of the placebo Lead-In period, subjects who meet the criteria will be 
randomly assigned by the IWRS at the Day 1 Randomization visit, to one of the following two 
double-blind treatment arms in a 1:1 ratio:

Blinded dapagliflozin 10 mg

Blinded placebo to match dapagliflozin 10 mg
Subjects entering the 28-week long-term extension period
Following completion of the 24-week double-blinded treatment period, subjects will enter the 
long-term open-label treatment period. All subjects will receive open-label dapagliflozin 10 mg, 
i.e., subjects that were assigned to be on the blinded dapagliflozin 10 mg arm will receive 
open-label dapagliflozin 10 mg and subjects that were assigned to be on the blinded placebo arm 
will receive open-label dapagliflozin 10 mg. 
At all study visits when study drug is dispensed, each subject will be assigned one or several Kit 
ID numbers by the IWRS. Kit ID numbers will be assigned non-sequentially and will correspond 
to the numbers printed on the bottles containing study drug, and will be recorded on the appropriate 
electronic case report form (eCRF). The IWRS will be available 24 hours per day, 7 days a week.
4.5
Selection and Timing of Dose for Each Subject
Subjects successfully completing the lead-in period and meeting all eligibility criteria will be 
randomized (1:1) to receive either dapagliflozin 10 mg or placebo for the 24-week double-blinded 
short-term treatment period. All subjects completing the 24-week double-blind treatment period 
will then receive open-label dapagliflozin 10 mg for the subsequent 28-week long-term extension 
period.
Dapagliflozin 10 mg tablets or matching placebo tablets, will be administered orally once daily for 
the duration of the study.


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4.6
Blinding/Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study.
Methods used to ensure blinding include: 

Investigational product will be labeled using a unique material kit ID, which is linked to the 
randomization code

The IWRS will assign the bottle of study material to be dispensed to each patient

This is a double-blind study wherein each patient will receive either the active drug or matching 
placebo. The active drug and placebo tablets will be identical and presented in identical 
packaging to ensure blinding of the medication
However, in the event of a medical emergency or pregnancy in an individual subject in which 
knowledge of the IP is critical to the subject's management, the blind for that subject may be broken 
by the Investigator. The subject’s safety takes priority over any other considerations in determining 
if a treatment assignment should be unblinded.
Before breaking the blind of an individual subject's treatment, the Investigator should determine 
that the unblinded information is necessary, i.e., that it will alter the subject's immediate 
management. In many cases, particularly when the emergency is clearly not related to the IP, the 
problem may be properly managed by assuming that the subject is receiving active product. It is 
highly desirable that the decision to unblind treatment assignment be discussed with the Medical 
Monitor, but the Investigator always has ultimate authority for the decision to unblind. The 
Principal Investigator should only call in for emergency unblinding AFTER the decision to 
discontinue the subject has been made.
For this study, the method of unblinding for emergency purposes is via the IWRS.
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
The exception is for those personnel analyzing the PK data, the AstraZeneca Supply Chain Study 
Management (SCSM) team and the responsible personnel carrying out the packaging and labeling 
of IPs. The randomization information will be provided to ensure appropriate treatment allocation 
and that only PK samples from patients who were on the active study treatment are analyzed.
4.7
Treatment Compliance
Each time study medication is dispensed, compliance will be reinforced. When study medication 
is returned, compliance will be assessed based upon subject’s interview and a count of the tablets 
returned. Compliance should be between 70% and 130% of that prescribed. The Investigator
(or designee) will record the amounts of study medication dispensed and returned at each visit, as 
well as document reasons for non-compliance in the source document. The dates of all study 
medication dosing, including interruptions, missed doses or overdose, must be recorded on the 
eCRF.


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If the subject is not 70% compliant with study drug doses during the study, then the period of 
non-compliance should be noted as a significant protocol deviation and the sponsor should be 
notified. The subject should be re-educated regarding the importance of study drug compliance.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by the Sponsor or sourced by the Investigator) such as 
partially used study drug containers, vials and syringes are to be destroyed locally at a site 
approved by the local regulatory authority in accordance with local regulations. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (e.g., cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s standard operating procedures and a copy provided to the Sponsor/designee
upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met, the responsible Study Monitor will make arrangements 
for return of study drug to a designated facility for destruction.
4.9
Return of Study Drug
It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.10
Retained Samples for Bioavailability / Bioequivalence
Not applicable.


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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (MB102138)
Procedure
Screening
Week
-12 / -8a
Lead-In
Week -4b
Notes
Eligibility Assessments
Informed Consent
X
Obtain written Assent (If applicable)
X
Inclusion/Exclusion Criteria
X
Medical History
X
Review Concomitant Medication
X
X
ECG
X
Safety Assessments
Physical Examination
X
Targeted Physical Examination
X
Tanner Staging (Investigator determined/Self-reported)
X
See Appendix 3
Vital Signs
X
X
Height
X
Body Weight
X
BMI
X
Serious Adverse Events Assessment
X
X
Adverse Events Assessment
X


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Table 5.1-1:
Screening Procedural Outline (MB102138)
Procedure
Screening
Week
-12 / -8a
Lead-In
Week -4b
Notes
Laboratory Tests
Standard Safety Laboratory Panel (Blood/Urine)
X
See Appendix 1
GAD/IA2 Autoantibodies
X
Fasting Plasma Glucose (FPG)
X
HbA1c
X
Pregnancy Test (WOCBP only)
X
For WOCBP only urine test with reflex serum test, if positive.
TSH, (reflex to FT4)
X
Hepatitis Screening Panel
X
Includes hepatitis screen panel (anti-HAV [IgM], HbsAg, and 
anti-HCV)
Study Drug / IWRS
Contact IWRS
X
X
Dispense Study Drug
X
General
Provide Dietary and Exercise Counseling
X
Provide glucose meter and supplies / instructions
X
Provide logs / instructions
X
Assessment of signs and symptoms of hypoglycemia 
episodes
X
a The range in duration of the screening period, from Week -12 to Week -8, is due to the possibility of considerable delays in the performance and delivery of 
results of GAD/IA2 antibodies testing in some countries. Therefore, if all other screening procedures have been completed during the first 4 weeks of screening, 
but a final decision cannot be made due to a delay in results of GAD/IA2 testing, up to 4 additional weeks, i.e, up to a total of 8 weeks for all screening procedures, 
will be allowed until a decision of compliance with inclusion/exclusion criteria is made. 
b Lead-in visit can be performed as soon as screening laboratory results have been reviewed, but within 56 days from Screening visit. 


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Table 5.1-2:
Short-term Procedural Outline (MB102138)
Procedure
Day 
1a
Wk 
2a,b
Wk 
4a
Wk 
8a
Wk
12a,b
Wk 
16a
Wk 
20a,b
Week 24 /
ETD (early 
treatment 
discontinuation)
/ Rescuea
Notes
Eligibility Assessments
Inclusion/Exclusion Criteria
X
Review concomitant medications / 
procedures
X
X*
X
X
X*
X
X*
X
*Assessed by Phone
Safety Assessments
Physical Examination
X
Targeted Physical Examination
X
X
X
X
Tanner Staging (Investigator
determined/Self-reported)
X
See Appendix 3
Vital Signs
X
X
X
X
X
Height
X
X
X
X
Body Weight
X
X
X
X
ECG
X
Assessment of signs and symptoms 
of hypoglycemia episodes
X
X*
X
X
X*
X
X*
X
*Assessed by Phone
DKA Assessment
X
X*
X
X
X*
X
X*
X
*Assessed by Phone
Serious Adverse Event Assessment
X
X*
X
X
X*
X
X*
X
*Assessed by Phone 
Adverse Events Assessment
X
X*
X
X
X*
X
X*
X
*Assessed by Phone
Laboratory Tests
Standard Safety Laboratory Panel 
(Blood/Urine)
X
X
X
X
X
See Appendix 1


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Table 5.1-2:
Short-term Procedural Outline (MB102138)
Procedure
Day 
1a
Wk 
2a,b
Wk 
4a
Wk 
8a
Wk
12a,b
Wk 
16a
Wk 
20a,b
Week 24 /
ETD (early 
treatment 
discontinuation)
/ Rescuea
Notes
Fasting Lipid panel
X
X
Total cholesterol, triglycerides, HDL, and 
LDL
Fasting Plasma Glucose (FPG)
X
X
X
X
HbA1c
X
X
X
X
X
Results masked
Pregnancy Test (WOCBP only)
X*
X
X
X**
X
X**
X
*To be performed prior to administration 
of first dose. 
**If appropriate, parent will provide result 
over the phone.
Home pregnancy kits will be provided
Spot Urine Glucose
X
X
X
X
Results masked
Growth / maturation markers / Bone 
biomarkers
X
X
Thyroid-stimulating hormone (TSH), free 
thyroxine, luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
estradiol, total testosterone, insulin-like 
growth factor-1 (IGF-1), insulin-like 
growth factor binding protein-3) 
(IGFBP3), calcitonin, 25-hydroxy 
vitamin D, bone alkaline phosphatase, and 
osteocalcin, parathyroid hormone (PTH).
Blood PK Sampling
PK Panel
X
X*
Samples to be taken pre-dose and 2 hours 
post-dose (± 1 hour)
*Not to be collected at ETD visits
Study Drug / IWRS
Contact IWRS
X
X
X
X


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Table 5.1-2:
Short-term Procedural Outline (MB102138)
Procedure
Day 
1a
Wk 
2a,b
Wk 
4a
Wk 
8a
Wk
12a,b
Wk 
16a
Wk 
20a,b
Week 24 /
ETD (early 
treatment 
discontinuation)
/ Rescuea
Notes
Randomize
X
Dispense Study Drug
X
X
X
X*
*No drug dispensed during ETD or Rescue 
visit
Rescued subjects will continue with their 
current assigned IP regimen.
Study Drug Compliance Review
X
X
X
X
General
Provide diet and exercise counseling
X
X
X
X
X
Dispense Meter Supplies
X
X
X
X
X
Review daily diary of finger-stick 
glucose values
X
X*
X
X
X*
X
X*
X
*Assessed by Phone
Provide logs / instructions
X
X
X
X
X
Assess Rescue
X
X
X*
X
X*
X
*Assessed by Phone
a Visits may be scheduled 7 days (of original schedule) to allow flexibility of scheduling.
b Phone assessments


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Table 5.1-3:
Long-term Procedural Outline (MB102138)
Procedure
Wk 
28a,b
Wk 
32a
Wk 
36a,b
Wk 
40a
Wk 
46a,b
Week 52 /
ETD / 
Rescuea
Wk 56
Follow
-up
Notes
Eligibility Assessments
Review concomitant medications / 
procedures
X*
X
X*
X
X*
X
X*
*Assessed by Phone
Safety Assessments
Physical Examination
X
Targeted Physical Examination
X
X
Tanner Staging (Investigator 
determined/Self-reported)
X
See Appendix 3
Vital Signs
X
X
X
Height
X
X
X
Body Weight
X
X
X
ECG
X
Assessment of signs and 
symptoms of hypoglycemia 
episodes
X*
X
X*
X
X*
X
*Assessed by Phone
DKA Assessment
X*
X
X*
X
X*
X
*Assessed by Phone
Serious Adverse Event 
Assessment
X*
X
X*
X
X*
X
X*
*Assessed by Phone
Adverse Events Assessment
X*
X
X*
X
X*
X
X*
*Assessed by Phone
Laboratory Tests
Standard Safety Laboratory Panel 
(Blood/Urine)
X
X
X
See Appendix 1


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Revised Protocol No: 03
Date: 20-Sep-2017
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Table 5.1-3:
Long-term Procedural Outline (MB102138)
Procedure
Wk 
28a,b
Wk 
32a
Wk 
36a,b
Wk 
40a
Wk 
46a,b
Week 52 /
ETD / 
Rescuea
Wk 56
Follow
-up
Notes
Fasting Lipid panel
X
Total cholesterol, triglycerides, HDL, and LDL
Fasting Plasma Glucose (FPG)
X
X
X
HbA1c
X
X
X
Pregnancy Test (WOCBP only)
X*
X
X*
X
X*
X
*If appropriate, parent will provide result over 
the phone.
Home pregnancy kits will be provided. 
Growth/ maturation markers / 
Bone biomarkers
X
Thyroid-stimulating hormone (TSH), free 
thyroxine, luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), estradiol, 
total testosterone, insulin-like growth factor-1 
(IGF-1), insulin-like growth factor binding 
protein-3) (IGFBP3), calcitonin, 25-hydroxy 
vitamin D, bone alkaline phosphatase, and 
osteocalcin , parathyroid hormone (PTH).
Study Drug / IWRS
Contact IWRS
X
X
X
Dispense Study Drug
X
X
*No drug dispensed during ETD or Rescue visit
Rescued subjects will continue with their current 
assigned IP regimen.
Study Drug Compliance Review 
X
X
X
General
Provide diet and exercise 
counseling
X*
X
X*
X
X*
*Assessed by Phone
Dispense Meter Supplies
X
X
Review daily diary of finger-stick 
glucose values
X*
X
X*
X
X*
X
*Assessed by Phone


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Revised Protocol No: 03
Date: 20-Sep-2017
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Table 5.1-3:
Long-term Procedural Outline (MB102138)
Procedure
Wk 
28a,b
Wk 
32a
Wk 
36a,b
Wk 
40a
Wk 
46a,b
Week 52 /
ETD / 
Rescuea
Wk 56
Follow
-up
Notes
Provide logs / instructions
X
X
Assess Rescue
X*
X
X*
X
X*
X
*Assessed by Phone
a Visits may be scheduled 7 days (of original schedule) to allow flexibility of scheduling.
b Phone assessments


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Revised Protocol No: 03
Date: 20-Sep-2017
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Table 5.1-4:
Early Treatment Discontinuation (ETD) Follow-up - Non-Treatment Phase
Procedure
Non-treatment 
Short-term
Follow-up (up to and 
including Week 24)
Office Visita,b
Non-treatment 
Longterm
Follow-up (after 
Week 24, up to and 
including Week 52)
Office Visita,b
Short-term and 
Long-term 
Non-treatment 
Follow-up
Phone Assessmentb,c
Notes
Safety Assessments
Targeted physical examination
X
X
Vital signs
X
X
Body weight and height
X
X
Review concomitant medications
X
X
X
AE assessment
X 
X 
X 
Standard safety laboratory panel 
(Blood/Urine)
X
X
Appendix 1
HbA1c
X
X
a In-office assessments to occur at time points corresponding to originally scheduled Short-term (up to and including Week 24) and Long-term (after 
Week 24, up to and including Week 52) visits
b Visits may be scheduled 7 days (of original schedule) to allow flexibility of scheduling
c Phone assessments only to occur at time points corresponding to originally scheduled that is not identified above as an in office visit


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5.1.1
Retesting During Screening or Lead-in Period
The laboratory parameters listed below may be repeated once in an effort to find all possible 
well-qualified subjects. Consultation with the Medical Monitor may be needed to identify whether 
repeat testing of any particular parameter is clinically relevant.
Retesting of screening laboratory tests will only be allowed under the following circumstances, 
and must be performed within 10 days from the original screening visit:

Repeat HbA1c testing if results fall 0.3% from inclusion range

Repeat FPG testing if results fall + 9 mg/dL (0.5 mmol/L) from inclusion range
Any new result will override the previous result (i.e., the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Other individual laboratory screening tests for which the results are in error, borderline, or 
indeterminate for inclusion in the study may be repeated once for confirmation during the 
Screening period if they are within 25% of the exclusion limit. Upon retesting, subjects whose 
results remain outside this threshold should not be randomized.
5.2
Study Materials
The Sponsor or designee will supply the sites with the following materials:

Blood glucose and ketone meters. One (1) meter will be provided to each study subject at 
enrollment and one (1) meter will be provided to each investigative site.

Glucose and ketone test strips

Lancets

Glucose control solutions

Subject education and site support materials

Electronic case report forms (eCRFs) [Serious Adverse Event (SAE) Forms, Pregnancy 
Surveillance Forms]

Subject Alert Cards

Study Drug inventory control forms

Subject Diary:
o
Full diary review by site staff is required for this study
o
Use of subject diaries is mandatory for the study and will be maintained by each study 
subject for documentation of SMBG results, ketone results, study medication dosing, 
hypoglycemia episodes (if applicable), symptoms potentially associated with DKA and 
relevant risk factors, WOCBP urine pregnancy test results (if applicable).
-
eCRF pages will be provided to the sites so they can record the relevant data 
obtained from the diaries into the study database. 
-
Subjects are to record any hypoglycemic symptoms and symptoms potentially 
associated with DKA they may experience and SMBG and ketone values if they 


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conducted the test when they have symptoms in their diaries. All events recorded 
in subject diary are to be reviewed by site staff according to Section 5.3.1

Any other materials as locally required or agreed.
The central laboratory will provide all laboratory-related materials including home pregnancy 
testing kits for WOCBP to the study sites.
5.3
Safety Assessments
Safety assessments will include AE reporting as well as marked abnormalities in clinical laboratory 
tests. Please refer to Appendix 1 for details on central laboratory assessments.
The procedures described in the sections that follow will also be completed to ensure subject’s 
safety.
It is the Investigator's responsibility to report, as applicable based on the Investigator's judgment 
and the subject's medical history, related AEs as defined in Section 6. Additional information, 
including but not limited to completion of supplemental eCRFs or questionnaires may be requested 
for certain AEs and/or laboratory abnormalities which are reported/identified during the course of 
the study.
5.3.1
Self-Monitored Blood Glucose (SMBG), Self-Monitored blood Ketones 
and Guidance on Management and Reporting of Hypoglycemia 
Episodes
5.3.1.1
Self-Monitoring of Blood Glucose (SMBG)
Glucose meters will be supplied to each study site. At the entry into Lead-In (Week -4 visit), 
subjects will receive a glucose meter, supplies and instruction on their use. Supplies will be 
provided to allow for approximately 60 blood glucose assessments per month for the duration of 
the study. Subjects should be encouraged to measure and record fasting blood glucose levels at 
least once per day. The Investigator may require more frequent readings based on local clinical 
practice. Subjects should bring their glucose meter with them to each study visit to ensure that it 
is functioning properly. Subjects may keep the glucose meters at the end of the study, but the 
Sponsor will not continue to provide glucose meter supplies once the study is complete.
In the occurrence of hypoglycemic symptoms or in the event of an unusually high or low blood 
glucose value, subjects should contact the Investigator. In addition, study subjects should comply 
with site’s instructions with regard to self-monitoring of blood glucose and should report to the 
site blood glucose values and/or signs and symptoms suggestive of a hypoglycemia episode. 
The memory of the glucose meter should be reviewed to compare with the subject’s hypoglycemia 
episode log, as applicable. The glucose values should be reviewed by the site to identify any 
unusual high or low values, and to confirm that the values (from the glucose meter’s memory 
and/or from the subject’s hypoglycemia log) were obtained for the subject. If finger-stick glucose 
values are discordant from glycemic control assessed by the central laboratory or with clinical 
symptoms, the subject’s glucose meter should be tested and the procedure for using it reviewed 
with the subject.


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5.3.1.2
Self-Monitored Blood Ketone Testing and Guidance on Management 
and Reporting of Diabetic Ketoacidosis Episodes
Diabetic ketoacidosis has been identified as a potential risk in subjects with diabetes receiving 
SGLT-2 inhibitors. Subjects and their family members must be aware of the possibility that DKA 
may occur, the signs and symptoms and the dangers associated with DKA. Subjects will receive a 
combined glucose and ketone meter and sufficient supplies for testing at the entry into Lead-In 
(Week -4 visit). Subjects will also be trained in the procedure of conducting blood ketone testing 
according to the manufacturer’s specifications. 
Subjects will be instructed to measure their blood ketones using the glucose and ketone meter 
provided by the Sponsor at least at the following frequency:

Between Randomization (Day 1 visit) and Week 4 visit: once a day

Between Week 4 visit and Week 24 visit: at least once every 2 weeks

Between Start of open-label extension period (Week 24 visit) and Week 28 visit: once a day

Between Week 28 visit and Week 52 visit: at least once every 2 weeks

When experiencing potential symptoms/signs of DKA, including but not limited to; excessive 
thirst, nausea and vomiting, frequent urination, weakness or fatigue, fever, fruity-scented 
breath, confusion, and/or consistently elevated blood glucose: at least once a day

During an acute illness: at least once a day
Blood ketone test results, symptoms potentially associated with DKA and relevant risk factors 
(e.g., missed insulin injection, infection, etc) should be recorded in the subject diary. As DKA may 
present differently and occur at lower glucose values than expected, particular attention should be 
paid to episodes of nausea and vomiting as indicative DKA symptoms, particularly in subjects 
requiring insulin therapy. Subjects should contact the site for assistance with diabetes management 
in the event that they develop such symptoms or when the blood ketone reading is 0.6 mmol/L or 
above, even if their blood glucose levels are not elevated at that time. 
The action, follow-up and monitoring plan will be at the discretion of the Investigator and will 
depend on their judgment of severity based on signs/symptoms of DKA, risk factors, relevant 
contributing factors, and blood glucose (with the caveat that the blood glucose may be lower than 
would be otherwise expected given elevated ketone levels). 
The blood ketone values should be recorded and will be reviewed by the site to identify any 
unusual high values, and to confirm that the values (from the glucose and ketone meter’s memory 
and/or from the subject’s diary) were obtained from the subject. If finger-stick blood values are 
discordant from glycemic control assessed by the central laboratory or with clinical symptoms, the 
subject’s glucose and ketone meter should be tested and the procedure for using it reviewed with 
the subject. Investigators will examine if any of the elevated ketone values from the subject’s diary 
are associated with a DKA event. If yes, investigators will document all DKA related symptoms, 
relevant risk factors, and available laboratory test results (including blood ketone values and blood 
glucose values measured by the glucose/ketone meter) on the DKA eCRF pages and report this 
event to the Sponsor. Signs and symptoms associated with DKA events should not be reported on 


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the AE eCRF page, unless the event fulfills protocol criteria for an SAE (see Section 6.1.1), in 
which case an SAE form must be completed in addition to the DKA eCRF pages.
5.3.1.3
Guidance on Management and Reporting of Hypoglycemia Episodes
Hypoglycemia may be an expected event in subjects who are treated for diabetes. Subjects and 
their family members must be aware of the possibility that hypoglycemia may occur and of the 
dangers associated with low blood sugar. Study subjects must be properly instructed on the 
recognition and management of hypoglycemia. Subjects should record in their log books any 
hypoglycemic symptoms. They should be encouraged to measure, when possible, their blood 
glucose values when they have symptoms of hypoglycemia. Subjects should carry with them easily 
ingestible forms of carbohydrate at all times in order to treat an event of hypoglycemia should it 
occur.
During clinical trials, subjects frequently report symptoms of hypoglycemia when asked, even 
when treated with placebo or medications not otherwise associated with hypoglycemia. As 
hypoglycemia is an important event associated with diabetes therapy, all episodes which could be 
consistent with the clinical definition of hypoglycemia as assessed by the Investigator should be 
documented and reported on the appropriate eCRF page.
The Investigator is responsible for questioning the subject about all symptoms reported on the 
hypoglycemia log and for determining if they meet the clinical definition of hypoglycemia. Only 
symptoms and/or blood glucose values deemed by the Investigator to meet the definition of 
hypoglycemia should be reported on the hypoglycemia eCRF pages. Signs and symptoms of 
hypoglycemia, hypoglycemia episode or discontinuation due to hypoglycemia should not be 
reported on the AE eCRF page, unless the event fulfills protocol criteria for an SAE (see Section 
6.1.1), in which case an SAE form must be completed in addition to the hypoglycemia eCRF pages 
for hypoglycemia.
Hypoglycemia episodes will be classified in the clinical study report (CSR) according to the 
International Society for Pediatric and Adolescent Diabetes (ISPAD) criteria20 and the ADA 
criteria.21
5.3.2
Guidance on Assessment of Urinary Tract Infections & Hematuria
5.3.2.1
Guidance on Assessment of Urinary Tract Infections
The following is presented to assist in the classification and management of urinary tract infections
(UTIs). It is not intended to supplant investigators’ clinical judgment:
Study drug should be withheld in subjects with clinical evidence of upper tract UTI 
(e.g., pyelonephritis) or presumed urosepsis until the course of treatment of the infection has 
been completed and clinical recovery has occurred.
It is recommended that a follow-up urine culture be obtained within 7 days of clinical 
recovery from all urinary tract infections. Whether or not additional therapy is prescribed 
because of culture results should be determined by Investigator judgment, after consultation 
with the Medical Monitor.


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It is the Investigator's responsibility to report, as applicable based on Investigator's 
judgment and subject's medical history, related AEs as defined in Section 6.
Additional information, including but not limited to completion of supplemental eCRFs or 
questionnaires may be requested for certain AEs and/or laboratory abnormalities which are 
reported/identified during the course of the study.
Asymptomatic bacteriuria 
During enrollment, treatment, and follow-up of patients in this trial, the Investigator may discover 
a patient with asymptomatic bacteriuria. Asymptomatic bacteriuria is defined as the presence of 
105 colony forming units/mL of bacteria, in a properly collected voided urine specimen, without 
signs or symptoms typically attributed to UTI. In this study, the central laboratory will report 
urinary dipstick test results for hemoglobin but will not routinely report the results of urinary 
dipstick tests for leukocyte esterase as a screening test for pyuria in surveillance urine 
examinations.
5.3.2.2
Guidance on Assessment of Hematuria
All events of hematuria (microscopic and/or macroscopic) during the study should be worked up 
for a possible cause as per local guidelines.
5.3.3
Guidance on Assessment of Hepatic Laboratory Abnormalities
An independent Hepatic Adjudication Committee, blinded to the treatment of the subjects, will 
determine the probability that drug-induced liver injury (DILI) is the cause of liver-related 
abnormalities, including, but not limited to:

Hepatic events related or leading to death (occurring within 30 days before death)

Liver laboratory abnormalities such as:
o
elevated AST and/or ALT 3x ULN and TB 2x ULN (within 14 days of the AST 
and/or ALT elevation) 
o
AST and/or ALT 10x ULN
A separate Adjudication Charter will define and describe the procedure for the handling, reporting,
and classification of these cases.
The following is presented to assist in the evaluation and management of hepatic laboratory values. 
It is not intended to supplant Investigator’s clinical judgment. Subjects who experience ALT 
and/or AST values > 3X ULN confirmed with a repeated test will have the following performed 
within 3 days of the confirmed laboratory results:

Adverse event assessment

Physical examination for jaundice and other signs of liver diseases

Review of relevant risk factors and current history focusing on possible causes of the increased 
ALT and/or AST and/or TB, including:
o
Use of suspect concomitant medication (including over-the-counter 
[i.e., acetaminophen/paracetamol], herbal and vitamin preparations)


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o
Recent alcohol consumption or recreational drug/narcotic use
o
Recent unaccustomed physical exertion
o
Occupational or environmental exposure to hepatotoxins
o
Other conditions which may cause liver diseases or which may cause abnormal test 
results
o
Specialized Liver Laboratory Panel (see Appendix 1)
Additional information, including but not limited to completion of supplemental eCRFs or 
questionnaires, may be requested for certain AEs and/or laboratory abnormalities which are 
reported /identified as part of the hepatic safety surveillance.
For subjects who are discontinued from study medication as a result of sustained elevated liver 
safety abnormalities, as described in Section 3.5, additional blood sampling must be done within 
3 days of the confirmed laboratory results (see Appendix 2), in conjunction with an Early 
Treatment Discontinuation (ETD) visit, in addition to the procedures noted above. A referral 
consultation to a hepatologist or gastroenterologist (specializing in liver abnormalities) should be 
obtained. Any additional tests and/or examinations should be carried out at the discretion of 
the Investigator. Any further investigations and laboratory results for subjects with 
abnormal laboratory values at the follow-up visit should be made available to the Sponsor 
upon request.
5.3.4
Physical Examination

A targeted physical examination should include cardiovascular, lungs, abdomen, and 
extremities, and any organ systems pertinent to the subject’s signs, symptoms, or AEs

A full physical examination should include general appearance, head, eyes, ears, nose, throat, 
neck, cardiovascular, lungs, abdomen, lymph nodes, extremities, neurological, skin, and 
musculoskeletal
The individual performing the physical examinations must be licensed by state law (or 
applicable local law) to perform this procedure.
5.3.5
Blood Pressure and Heart Rate
Blood pressure and HR measurements must be taken consistently throughout the study. Only use 
either the right or the left arm when measuring these parameters. Document which arm was used 
along with the observer’s initials; the same arm and position should be used at each visit. The 
subject should be allowed at least 5 minutes of rest before measurement. Blood pressure should be 
measured with the subject’s arm resting on a table, and with the subject’s back supported and feet 
flat on the floor.
Blood pressure and HR will be determined from three replicate measurements obtained at least 
1 minute apart. The average BP and HR will be determined from these 3 replicate measurements 
and reported in the eCRF.
All measurements should occur at least 8 hours after the last ingestion of caffeine, alcohol, or 
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It is critical that the BP and HR measurements are obtained prior to the administration of blinded 
study medication.
5.3.6
Guidance on Volume Depletion
Dapagliflozin has a modest diuretic effect. The risk of volume depletion is enhanced when two 
diuretics are used in combination and in patients that otherwise are at risk for volume depletion. 
Therefore, caution should be exercised when administering to patients at risk for volume depletion 
due to co-existing conditions or concomitant medications, such as loop diuretics. These patients 
should be carefully monitored for volume status, electrolytes, and renal function.
5.3.7
Supplemental Visits
5.3.7.1
Rescue or Early Treatment Discontinuation Visit 
Any subject who qualifies for rescue or discontinues during the study periods must have all 
Rescue/ETD visit procedures performed at the time of study discontinuation or rescue. The IWRS
must be called to record the subject status (i.e., rescue, or discontinuation status). All subjects who 
are rescued or who discontinue study drug should remain in the study and follow the visit schedule.

For subjects qualifying for rescue: Rescue procedures will be performed and the subject will 
then continue in the treatment period according to the regular visit schedule. The Rescue/ETD 
supplemental eCRF will need to be completed to collect Rescue-related endpoint data.

Subjects who discontinue study medication should have all ETD procedures performed 
(Rescue/ETD visit) and recorded in the Rescue/ETD supplemental eCRF. Subjects will then 
continue in the study and undergo non-treatment follow-up visit assessments according to their 
original visit schedule (Table 5.1-4).
5.3.7.2
Other Supplemental (Unscheduled) Visits
At any time during the trial, the Investigator may at his/her discretion arrange for a subject to have 
an unscheduled (supplemental) assessment(s), especially in the case of AEs that require follow-up. 
If a subject is seen for an unscheduled assessment, the appropriate Supplemental Pages of the 
eCRF must be completed.
5.3.8
Imaging Assessment for the Study
Not applicable.
5.4
Efficacy Assessments
Assessments consist of the central laboratory measurement of the HbA1c, and other relevant 
laboratory tests collected during the study.
5.5
Pharmacokinetic Assessments
Blood samples for determination of the level of dapagliflozin in plasma will be taken at the times 
presented in Table 5.5-1. Samples will be collected, labeled, stored and shipped as detailed in 
Laboratory Manual.
Samples for determination of drug concentration in plasma will be analyzed by appointed 
laboratory on behalf of the Sponsor or designee using appropriate bioanalytical methods. Full 


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details of the analytical methods used will be described in a separate bioanalytical report. Only 
samples from patients on relevant active study drug will be analyzed. Samples from patients not 
dosed with the relevant active study treatment will only be analyzed on a ‘for cause’ basis, for 
example, if there is a suspicion that a patient has been dosed incorrectly.
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested 
for future analyses. All samples still within the known stability of the analyses of interest at the 
time of receipt by the bioanalytical laboratory will be analyzed. Pharmacokinetic samples may be 
disposed of or destroyed and anonymized by pooling. Additional analyses may be conducted on 
the anonymized, pooled PK 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.
Table 5.5-1:
Sampling Schedule
Study Day
Time 
(Relative to 
Dosing)
Hour
Time 
(Relative to Dosing)
Hour: Min
PK
Blood Sample
Week 16
0 (predose)
2 hours post-dose (1 hour)
X
Week 24
0 (predose)
2 hours post-dose (1 hour)
X
Rescue visita
0 (predose)
2 hours post-dose (1 hour)
X
a If applicable during the short-term treatment period only.
5.6
Biomarker Assessments
Not applicable
5.7
Outcomes Research Assessments
Not applicable
5.8
Other Assessments 
5.8.1
Diet and Exercise Counseling 
Starting at entry into Lead-In (Week -4), subjects will be instructed on a diet and exercise program 
in accordance with the ADA or similar local guidelines to be followed for the study duration.
A Registered Dietitian, Registered Nurse, Physician, Certified Diabetes Educator, Nutritionist, or 
other qualified member of the study team who has appropriate documented training, will provide 
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5.8.2
Weight and Height
Body weight and height will be measured according to the schedule presented in the study flow 
chart/time and event schedule (see Section 5.1) and will be recorded in the eCRF. 
The study-site staff should use a digital precision scale if possible, and record the weight to the 
first decimal point (e.g., 69.3 kg). The subject should wear a standard hospital-type gown or 
equivalent light indoor clothing, shoes removed, and bladder empty for the body weight 
measurement at each visit. Subjects should be weighed on the same scale at all visits.
Measurement of height should be performed with the subject’s shoes removed. The subject’s knees 
should be straightened, head held erect and eyes forward.
Method of Body Mass Index (BMI) calculation:

Use actual height and weight

To calculate BMI:
o
Convert pounds (lbs) to kilograms (kg = lb / 2.2)
o
Convert inches (in) to centimeters (cm = in X 2.54)
o
BMI = (weight in kg) / (height in cm/100)2
o
Round to one decimal place (if 0.05 or greater, round up)
5.9
Results of Central Assessments 
Blood and urine samples will be obtained at specified time points for laboratory evaluations 
(see Appendix 1). The central laboratory for this study will perform the analysis of all scheduled 
laboratory tests and will provide reference ranges for these tests. The central laboratory will 
provide specific instructions for collection, processing, packaging, and shipping of all samples.
For the duration of the double-blind treatment period (Day 1 to Week 24), the HbA1c and the 
urinary glucose values, including the urinary glucose:creatinine ratio, will be masked to the 
Sponsor and will not be available to the Investigator. During the open-label long-term extension 
period (after the Week 24 visit to Week 52), the above measurements will be unmasked and 
available to the Sponsor and the Investigator.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
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The causal relationship to study drug is determined by a physician and should be used to assess all 
AEs. The causal relationship can be one of the following:

Related: There is a reasonable causal relationship between study drug administration and 
the AE

Not related: There is not a reasonable causal relationship between study drug 
administration and the AE
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of 1 or more AEs.)
The Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and Food and Drug 
Administration (FDA) Code of Federal Regulations 21 CFR Parts 312 and 320.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential DILI is also considered an important medical event. (See Section 6.6
for the definition of potential DILI.)
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential DILI are not always serious by regulatory 
definition, these events must be handled as SAEs. (See Section 6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (e.g., death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as an SAE (see Section 6.1.1 for reporting details).


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NOTE: 
The following hospitalizations are not considered SAEs in the Sponsor’s clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases.

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).

admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the IB represent the Reference Safety Information to determine 
expectedness of SAEs for expedited reporting. Following the subject’s written consent to 
participate in the study, all SAEs, whether related or not related to study drug, must be collected, 
including those thought to be associated with protocol-specified procedures. All SAEs must be 
collected that occur during the screening period and within 28 days of discontinuation of dosing. 
If applicable, SAEs must be collected that relate to any later protocol-specified procedure (e.g., a 
follow-up skin biopsy). 
The Investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the Investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to the 
Sponsor within 24 hours of awareness of the event. 
All SAEs will be recorded in the CRF. If any SAE occurs in the course of the study, then 
investigators or other site personnel must inform the appropriate AstraZeneca representatives 
within 1 day i.e., immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data site within 1 calendar 
day of initial receipt for fatal and life-threatening events and within 5 calendar days of initial 
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For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up must be undertaken immediately. Investigators or other site personnel must inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
1 calendar day, i.e., immediately but no later than 24 hours of when he or she becomes aware of 
it.
Serious adverse events must be recorded on the SAE Report Form; pregnancies on a Pregnancy 
Surveillance Form (electronic or paper forms). The preferred method for SAE data reporting 
collection is through the eCRF. The paper SAE/pregnancy surveillance forms are only intended as 
a back-up option when the eCRF system is not functioning. In this case, the paper forms are to be 
transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: 
USA
SAE Telephone Number: 
SAE Facsimile Number: 
Europe
SAE Telephone Number:
SAE Facsimile Number: 
For studies capturing SAEs through electronic data capture, electronic submission is the required 
method for reporting. In the event the electronic system is unavailable for transmission, paper 
forms must be used and submitted immediately. When paper forms are used, the original paper 
forms are to remain on site.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to the Sponsor 
using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
Intensity will be graded according to the following definitions:

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)


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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 6.1. 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 6.1. 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 6.1.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the Investigator must immediately notify the Medical 
Monitor or appropriate AstraZeneca representatives of this event and complete and forward a 
Pregnancy Surveillance Form to AstraZeneca or designee within 24 hours of awareness of the 
event and in accordance with SAE reporting procedures described in Section 6.1.1.
If pregnant the study drug shall be immediately discontinued.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.


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6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential DILI is defined as: 
1. Aminotransferases (AT) (ALT or AST) elevation > 3 times ULN
AND
2. Total bilirubin (TB) > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECG, x-ray 
filming, any other potential safety assessment required or not required by protocol should also be 
recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER COMMITTEES
7.1
Data Monitoring Committees
An independent Data Monitoring Committee (DMC) comprised of pediatric and endocrine 
therapeutic area specialists and statisticians will be formed and will convene on a regular basis to 
review trial data. The DMC will be responsible for safeguarding the interests of the subjects in the 
trial by assessing the safety and efficacy of the interventions during the trial, and for reviewing the 
overall conduct of the clinical trial. The DMC will provide recommendations about stopping or 
continuing the trial and will be governed by a separate DMC Charter.
7.2
Hepatic Adjudication Committee
An independent Hepatic Adjudication Committee, blinded to the treatment of the subjects, will 
determine the probability that DILI is the cause of liver-related abnormalities, including but not 
limited to, hepatic disorders leading to death, and liver laboratory abnormalities such as elevated 
AST and/or ALT with or without TB elevations (see Section 5.3.3 for more details). 
A separate Adjudication Charter will define and describe the procedure for the handling, reporting 
and classification of these events.


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7.3
Diabetic Ketoacidosis (DKA) Adjudication Committee
An independent DKA Adjudication Committee, blinded to the treatment of the subjects, will 
adjudicate all potential events of DKA. 
A separate Adjudication Charter will define and describe the procedure for the handling, reporting 
and classification of these events.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
In order to inform the design of this study, a Bayesian approach was employed to predict the 
potential efficacy of dapagliflozin on HbA1c in pediatric patients from the existing data and 
knowledge in adult T2DM patients.
Simulation results suggest a difference versus placebo in HbA1c of -0.78% for dapagliflozin 
10 mg. Based on this estimated treatment difference of 0.78% and assuming a standard deviation 
of 0.9% for change from baseline in HbA1c at Week 24, a sample size of 25 per treatment group 
has 85% power to demonstrate the superiority of dapagliflozin 10 mg to placebo (where superiority 
is defined as a placebo-corrected HbA1c at 24 weeks indicating greater improvement that is 
statistically significant) at a two-sided alpha level of 5 percent. To ensure that at least 50 subjects 
will complete the 24-week treatment period on IP and the Week 24 assessment, at least 66 subjects 
will be randomized.
8.2
Populations for Analyses

The Enrolled Subjects Data Set will consist of all subjects who sign informed consent.

The Randomized Subjects Data Set will consist of all randomized subjects who receive at least 
one dose of study medication during the treatment period. This is also known as the Intent to 
Treat population. This will be the primary efficacy data set. Data in this data set will be 
analyzed based on randomized treatment group.

The Evaluable Subjects Data Set will be a subset of the Randomized Subjects, with all data 
points collected after relevant protocol deviations are excluded from the data set. Relevant 
protocol deviations are defined as deviations that could potentially affect the interpretability of 
the study results. This is also known as the per-protocol population. This data set will be used 
for sensitivity analyses of the primary efficacy endpoint if > 10% of subjects in any treatment 
group have relevant protocol deviations.

The Treated Subjects Data Set will consist of all subjects who receive at least one dose of study 
medication during the treatment group. This will be the primary safety data set. Data in this 
data set will be analyzed based on randomized treatment, except in cases where a subject 
received a different treatment for the entire course of his/her participation in the treatment 
period. In this case, safety data for such a subject will be analyzed based on the first treatment 
the subject actually received.

Pharmacokinetic Analysis Data Set will include all patients who received a dapagliflozin dose 
and have collected at least 1 PK sample.


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8.3
Endpoints
8.3.1
Primary Endpoint(s)
Change from baseline in HbA1c at Week 24.
8.3.2
Secondary Endpoint(s)

The change from baseline in FPG at Week 24

The percentage of subjects who require glycemic rescue medication or discontinuation due to 
lack of glycemic control over 24 weeks double-blind treatment.

The percentage of subjects with baseline HbA1c > 7% who achieve HbA1c level < 7% at 
Week 24.
8.3.3
Exploratory Endpoint(s) 

The PK and exposure-response relationship of dapagliflozin based on the collection of 
population PK samples

The mean change from baseline in HbA1c achieved with dapagliflozin at Week 52

The mean change from baseline in FPG achieved with dapagliflozin at Week 52

The percentage of subjects who require glycemic rescue medication or discontinuation due to 
lack of glycemic control during 52 weeks treatment period.

The percentage of subjects with baseline HbA1c > 7% who achieve a HbA1c level < 7% at 
Week 52
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized using frequency distributions and 
descriptive statistics using the Randomized Subjects Data Set, for each treatment group as well as 
for all subjects combined. No statistical tests will be performed to compare treatment groups at 
baseline.
8.4.2
Efficacy Analyses
8.4.2.1
Primary Analysis
The primary analysis of the primary endpoint, change in HbA1c from baseline to Week 24, will 
be based on a mixed model with repeated measures (MMRM) including all scheduled time points 
following randomization up to and including Week 24. This model will include patients in the 
Randomized Subjects Data Set who have a baseline measurement and at least one post-baseline 
measurement. The primary analysis will only include measurements prior to the administration of 
rescue medication. Measurements made following rescue administration will be included in 
sensitivity analysis. Various sensitivity analyses will be specified in the Statistical Analysis Plan 
to assess the robustness of the primary analyses, including sensitivity analyses of all data pre-and 
post-rescue.
The SAS procedure PROC MIXED will be used for primary analyses. The primary analysis model 
will include the fixed categorical effects of treatment, week, randomization stratification factor (as 
warranted), and treatment-by-week interaction as well as the continuous fixed covariates of 


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baseline measurement and baseline measurement-by-week interaction. An unstructured matrix for 
the within-patient error variance-covariance will be used. The denominator degrees of freedom 
will be calculated according to the Kenward-Roger method. A number of back-up models will be 
defined in the Statistical Analysis Plan in case of non-convergence of the preferred model or other 
issues. 
Point estimates and 95% confidence intervals for the mean change in HbA1c for each treatment 
group as well as the difference in the estimated mean change between the dapagliflozin treatment 
group and placebo will be calculated. The p-value of the difference in Week 24 estimates between 
dapagliflozin and placebo will be presented.
8.4.2.2
Secondary Analyses
The family-wise Type I error rate related to the primary and secondary efficacy endpoints will be 
controlled at the 2-sided 0.05 level by using a hierarchical closed testing procedure. 
Specifically, if the primary comparison in change in HbA1c between the dapagliflozin 10 mg 
treatment group and the placebo group is significant at the 0.05 level, then the statistical testing 
for the secondary efficacy endpoints will be performed. In order to control the family-wise Type I 
error rate across the primary and secondary endpoints, the interpretation of the statistical 
significance of treatment comparison for each secondary efficacy endpoint will be done using a 
hierarchical closed testing procedure which will be defined in the Statistical Analysis Plan, prior 
to unblinding of the treatment assignments.
Similar methods to the primary analysis will be used in analyses of continuous secondary 
endpoints. The methodology of Zhang, Tsiatis and Davidian22 and Tsiatis, Davidian, Zhang, and 
Lu23 with adjustment for baseline measurement and randomization strata will be used in analyses 
of categorical secondary endpoints, and details will be provided in the Statistical Analysis Plan.
8.4.2.3
Exploratory Analyses
Similar methods to the primary and secondary analyses will be used for analyses of exploratory 
endpoints. Between group differences in the mean change from baseline for continuous 
exploratory variables (HbA1c and FPG) will not be generated for the long-term (LT) period in 
short-term (ST) + LT analyses, and statistical comparisons will not be performed. Similarly, 
between group differences in proportions of dichotomous exploratory variables will not be 
generated for the LT period in ST + LT analyses, and statistical comparisons will also not be 
performed.
Analysis of the PK endpoint is described in Section 8.4.4.
8.4.3
Safety Analyses
Safety analyses will include treatment group summaries of the incidence of AEs and marked 
laboratory abnormalities, the percentages of subjects experiencing hypoglycemia as well as the 
number and severity of hypoglycemic events, the incidence of elevated plasma ketone level, vital 
signs, and laboratory test parameters. 


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The assessment of safety will be based on the analyses of AEs, vital signs, physical examinations, 
ECGs, hypoglycemia, elevated plasma ketone level, and clinical laboratory evaluations. All safety 
analyses will be performed using the Treated Subjects Data Set. 
The number and percent of patients with at least one AE will be summarized by treatment group, 
including summaries of AEs, SAEs, AEs leading to discontinuation of study medication, and AEs
of special interest. Summaries will include the number of patients with events by specified system 
organ classes and preferred terms. 
Summary statistics will be presented at each assessment visit for the continuous safety parameters. 
Descriptive statistics of changes from baseline by study visits will also be presented. A frequency 
table of results of categorical safety parameters will be produced. Furthermore, laboratory/ECG 
abnormalities will be analyzed by shift tables. The number and percent of subjects with values 
meeting marked/notable abnormality criteria will be summarized for each treatment group for vital 
signs, lab, and ECG parameters.
8.4.4
Pharmacokinetic Analyses
Dapagliflozin plasma concentration will be listed and summarized by sample collection day and 
time. The analyses will be performed using the Pharmacokinetic Analysis Data Set.
8.4.5
Biomarker Analyses
Not applicable
8.4.6
Outcomes Research Analyses
Not applicable
8.4.7
Other Analyses 
Not applicable
8.5
Interim Analyses
Not applicable
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, the Sponsor or designee. The Investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to 
eliminate an immediate hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:

IRB/IEC for review and approval/favorable opinion


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
the Sponsor/Designee

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to the Sponsor or designee.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
The Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records.
Representatives of the Sponsor or designee must be allowed to visit all study site locations 
periodically to assess the data quality and study integrity. On site they will review study records 
and directly compare them with source documents, discuss the conduct of the study with the
Investigator, and verify that the facilities remain acceptable.
In addition, the study may be evaluated by the Sponsor or designee internal auditors and 
government inspectors who must be allowed access to CRFs, source documents, other study files, 
and study facilities. The Sponsor or designee audit reports will be kept confidential.
The Investigator must notify the Sponsor or designee promptly of any inspections scheduled by 
regulatory authorities, and promptly forward copies of inspection reports to the Sponsor or 
designee. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
AE tracking/reporting, protocol required assessments, and/or drug accountability records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 


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9.1.3
Investigational Site Training
AstraZeneca or designee will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The Investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by the Sponsor or designee, whichever is longer. The Investigator must contact the 
Sponsor or designee prior to destroying any records associated with the study.
The Sponsor or designee will notify the Investigator when the study records are no longer needed.
If the Investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, IRB). Notice of such 
transfer will be given in writing to the Sponsor or designee.
9.2.2
Study Drug Records 
It is the responsibility of the Investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include IP and the following 
non-IP(s). Records or logs must comply with applicable regulations and guidelines and should 
include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (e.g., lost, wasted)

amount destroyed at study site, if applicable

amount returned to the Sponsor or designee

retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for IP dispensing/accountability, as per the Delegation 
of Authority Form
The Sponsor or designee will provide forms to facilitate inventory control if the investigational 
site does not have an established system that meets these requirements.


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9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor’s electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the electronic SAE form and Pregnancy Surveillance form, respectively. If an electronic SAE form 
is not available, a paper SAE form can be used.
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The Investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the Investigator or qualified physician who is a subinvestigator and 
who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review and 
approval/signature is completed electronically through the Sponsor’s electronic data capture tool. 
The Investigator must retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet the Sponsor’s training 
requirements and must only access the Sponsor or designee’s electronic data capture tool using the 
unique user account provided by the Sponsor. User accounts are not to be shared or reassigned to 
other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the CSR.
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (e.g., among the top quartile of enrollers)

Involvement in trial design

Regional representation (e.g., among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)


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The data collected during this study are confidential and proprietary to the Sponsor or designee. 
Any publications or abstracts arising from this study must adhere to the publication requirements 
set forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation 
in the study. These requirements include, but are not limited to, submitting proposed publications 
to the Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.


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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete Abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Female subjects must continue 
to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to 
forego complete abstinence.
If two forms of contraception is required, Complete abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as complete 
avoidance of heterosexual intercourse is an acceptable form of 
contraception for all study drugs. This also means that abstinence is the 
preferred and usual lifestyle of the patient. This does not mean periodic 
abstinence (e.g., calendar, ovulation, symptothermal, profession of 
abstinence for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of contraception. Subjects 
who choose complete abstinence are not required to use a second method 
of contraception, but female subjects must continue to have pregnancy 
tests. Acceptable alternate methods of highly effective contraception must 
be discussed in the event that the subject chooses to forego complete 
abstinence.


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LIST OF ABBREVIATIONS
Term
Definition
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransferases
AZ
AstraZeneca
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
CFR
Code of Federal Regulations 
CRF
case report form
CSR
Clinical Study Report
CTA
Clinical Trial Agreement
DILI
drug-induced liver injury
DKA
diabetic ketoacidosis
dL
deciliter
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EU
European Union
ETD
early treatment discontinuation
FDA
Food and Drug Administration
FPG
fasting plasma glucose
g
gram
GAD
glutamic acid decarboxylase
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HAV
hepatitis A virus


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Term
Definition
HbA1c
glycosylated hemoglobin
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HR
heart rate
IA-2
protein tyrosine phosphatase-like protein antibodies
IB
investigator brochure
ICF
informed consent form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IP
investigational (medicinal) product
IR
immediate release
IRB
Institutional Review Board
IU
international unit
IUD
intrauterine device
IWRS
Interactive Web / Voice Recognition System
kg
kilogram
L
liter
LT
long-term
MDRD
Modified Diet in Renal Disease, study equation
mg
milligram
min
minute
mL
milliliter
MMRM
Mixed effect Model Repeat Measurement
MODY
maturity onset diabetes of the young
non-IMP
non-investigational medicinal product 
non-IP
non-investigational (medicinal) product
OAD
oral antidiabetic
PD
pharmacodynamics
PK
pharmacokinetics


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Term
Definition
PPG
postprandial glucose
SAE
serious adverse event
SGLT-2
sodium glucose cotransporter-2
SMBG
self-monitored blood glucose
ST
short-term
TB
total bilirubin
T2DM
type 2 diabetes mellitus
TSH
thyroid stimulating hormone
UK
United Kingdom
ULN
upper limit of normal
UKPDS
UK Prospective Diabetes Study
UTI
urinary tract infection 
US
United States (of America)
WHO
World Health Organization
WOCBP
women of childbearing potential
XR
extended release


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12
REFERENCES
1. Alberti G, Zimmet P, Shaw J, Bloomgarden Z, Kaufman F, Silink M, et al. Type 2 diabetes 
in the young: the evolving epidemic. Diabetes Care 2004;27:1798-811
2. International Diabetes Federation Clinical Guidelines Task Force. Global guideline for 
type 2 diabetes. Brussels: International Diabetes Federation; 2005. Available from: 
http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf. Accessed on 13 February 2008.
3. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes 
Care 2000;23:381-9.
4. American Diabetes Association. Standards of medical care in diabetes 2008. Diabetes Care 
2008;31(Suppl 1):S12-54.
5. Goran MI, Ball GDC, Cruz ML. Obesity and risk of type 2 diabetes and cardiovascular 
disease in children and adolescents. J Clin Endocrinol Metab 2003;88:1417-27.
6. Krakoff J, Hanson RL, Kobes S, Knowler WC. Comparison of the effect of plasma glucose 
concentrations on microvascular disease between Pima Indian youths and adults. Diabetes 
Care 2001;24:1023-8.
7. Dean HJ, Sellers EAC. Comorbidities and microvascular complications of type 2 diabetes 
in children and adolescents. Pediatr Diabetes 2007; 8 (Suppl 9):35-41.
8. Eppens MC, Craig ME, Cusumano J, Hing S, Chang AKF, Howard NJ, et al. Prevalence 
of diabetes complications in adolescents with type 2 compared with type 1 diabetes. 
Diabetes Care 2006;29:1300-6.
9. Bloomgarden, ZT. Type 2 diabetes in the young. The evolving epidemic. Diabetes Care 
2004;27:998-1010.
10. Diabetes Control and Complications Trial Research Group. The Effect of Intensive 
Treatment of Diabetes on the Development and Progression of Long-Term Complications 
in Insulin-Dependent Diabetes Mellitus. N Engl J Med 1993;329:977- 86.
11. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. Increased 
incidence of non-insulin-dependent diabetes mellitus among adolescents. J Pediatr 
1996;128(5 Pt 1):608-15.
12. Bingley P, Bonifacio E, Ziegler A, Schatz D, Atkinson M, Eisenbarth G and the 
Immunology of Diabetes Society. Proposed Guidelines on Screening for Risk of Type 1 
Diabetes. Diabetes Care 2001;24(2):398.
13. Ehtisham S, Hattersley AT, Dunger DB, Barrett TG. First UK survey of paediatric type 2 
diabetes and MODY. Arch Dis Child 2004;89:526-9.
14. Neu A, Feldhahn L, Ehehalt S, Hub R, Ranke M. Type 2 diabetes mellitus in children and 
adolescents is still a rare disease in Germany: A population-based assessment of the 
prevalence of type 2 diabetes and MODY in patients aged 0-20 years. Peds Diabetes 
2009;10(7):468-73.


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15. Zachrisson I, Tibell C, Bang P, Ortquist E. Prevalence of type 2 diabetes among known 
cases of diabetes aged 0-18 years in Sweden. J Pediatr Endocrinol Metab 2003;16:919-55.
16. Kestelman P. et. al., Efficacy of the Simultaneous Use of Condoms and Spermicides 
Family Planning Perspectives.Vol 23 (5); October 1991.
17. Gabbay MB, Thomas J, Gibbs A, Hold P. A Randomized Crossover Trial of The Impact 
of Additional Spermicide on Condom Failure Rates. Sex Transm Dis 2008; 35: 862-8.
18. Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New 
Equations to Estimate GFR in Children with CKD. JASN 2009; 20: 629-637.
19. Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F; Chronic 
Kidney Disease Epidemiology Collaboration. Expressing the Modification of Diet in Renal 
Disease Study Equation for Estimating Glomerular Filtration Rate with Standardized 
Serum Creatinine Values. Clin Chem. 2007 Apr;53(4):766-72.
20. Global IDF/ISPAD Guideline for Diabetes in Childhood and Adolescence, available at 
https://www.idf.org/sites/default/files/Diabetes-in-Childhood-and-Adolescence-
Guidelines.pdf
21. http://care.diabetesjournals.org/content/early/2013/04/12/dc12-2480.full.pdf
22. Zhang M., A.A. Tsiatis, and M. Davidian, Improving efficiency of inferences in 
randomized clinical trials using auxiliary covariates. Biometrics, 2008. 64(3): 707-715.
23. Tsiatis, A.A., et al., Covariate adjustment for two-sample treatment comparisons in 
randomized clinical trials: a principled yet flexible approach. Stat Med, 2008. 27(23): 
4658-4677.


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APPENDIX 1
CENTRAL LABORATORY ASSESSMENTS
Blood and urine samples will be obtained at specified time points for laboratory evaluations. The 
central laboratory for this study will perform the analysis of all scheduled laboratory tests and will 
provide reference ranges for these tests. The detailed methods for specimen collection, handling, 
processing, shipping, and storage will be supplied in the Investigator’s Laboratory Manual 
provided by the Central Laboratory. All clinical laboratory tests will be performed by the Central 
Laboratory or designated reference laboratory.
For the duration of the double-blind treatment period (Day 1 to Week 24), the HbA1c and the 
urinary glucose values, including the urinary glucose:creatinine ratio, will be masked to the 
Sponsor and will not be available to the Investigator. 
During the open-label long-term extension period (after the Week 24 visit to Week 52), the above 
measurements will be unmasked and available to the Sponsor and the Investigator.
The following sections indicate the laboratory tests required for this study. For countries using 
conventional units, the results will be reported using conventional units. For countries using 
SI units, the results will be reported using SI units. In cases of differences in the units as listed in 
this protocol compared to the units on the central laboratory reports, the units from the central 
laboratory reports will be used. 
PROTOCOL-SPECIFIC CENTRAL LABORATORY ASSESSMENTS:

HbA1c (%, mmol/mol)

Fasting plasma glucose (FPG) (mg/dL, mmol/L)

Fasting serum lipid profile: 

Total-C (mg/dL, mmol/L)

Calculated LDL-C (mg/dL, mmol/L)
Except screening period, reflex testing will occur for Direct LDL-C if TG > 400 mg/dL 
(4.52 mmol/L)

HDL-C (mg/dL, mmol/L)

TG (mg/dL, mmol/L)
Enrollment-Specific Reflex Testing

Thyroid stimulating hormone (TSH)

Reflex Testing: abnormal TSH value at enrollment will be further evaluated by free T4.

Hepatitis Screen Panel:

Anti-hepatitis C virus antibody

Hepatitis B surface antigen

Anti-hepatitis A virus IgM
Reflex Testing: Low positive and positive results require confirmatory testing.


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Specialized Liver Panel:
For subjects who are being monitored frequently as a result of confirmed aspartate 
aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3X upper limit of normal 
(ULN), additional central laboratory tests will be performed within 3 days of receipt of 
confirmatory results. These laboratory tests will study the possible causes of the increased ALT 
and/or AST and/or TB, and may include, but are not limited to, the following tests:

Hepatitis A IgM

Hepatitis BsAg

Hepatitis B Core Ab IgM

Hepatitis C virus RNA or RIBA

Hepatitis C Ab

Hepatitis E IgM

Epstein-Barr virus (EBV) IgM Ab

Lactate dehydrogenase (LDH)

Gamma-glutamyl-transpeptidase (GGT)

Carbohydrate deficient transferrin (CDT)

Prothrombin time (PT/INR)

Iron panel - iron, ferritin, total iron binding capacity (TIBC)

Immunology panel including antinuclear antibody (ANA), anti-smooth muscle antibody 
(SMA) and anti-liver/kidney microsomal antibody (Anti-LKM)

Anti-tissue transglutaminase antibody
Liver Discontinuation Panel:
For subjects who are discontinued from the study as a result of sustained elevated liver safety 
abnormalities, additional central laboratory tests will be performed at the time of Early 
Termination (End-of-Treatment) visit. Similar to the Specialized Liver Panel, these laboratory tests 
will study the possible causes of the increased ALT and/or AST and/or TB, and may include, but 
are not limited to, the following tests:

Cytomegalovirus (CMV) IgM Ab

Herpes simplex virus (HSV) 1 and 2

Ceruloplasmin

Toxoplasmosis

Alpha-1 antitrypsin
For specific details regarding the Specialized Liver Panel and the Liver Discontinuation Panel 
laboratory tests, refer to the Central Laboratory Manual for this study.


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Standard Safety Laboratory Panels:
Table Appendix 1:
Standard Safety Laboratory Panels
Hematology

Hemoglobin (g/dL, g/L)

Hematocrit (%, V/V)

Red blood cell (RBC) (x106/UL, x1012/L)
RBC count indices: 

Mean Cell Volume (MCV) (fL) 

Mean Cell Hemoglobin (MCH) (pg/cell)

Mean Cell Hemoglobin Concentration (MCHC) (gHb/dL, gHb/L)

White blood cell Count and Differential

Platelet count (x109/L)
Serum Chemistry

AST (IU/L)

ALT (IU/L)

ALK-P (IU/L) 

Total Bilirubin (mg/dL, mol/L)

Serum Creatinine (Scr) used to calculate estimated glomerular filtration rate (eGFR) according to the 
following:

In subjects < 18 years of age: Schwarz formula1 eGFR (mL/min/1.73 m2) = 0.413 *(height (cms)/serum 
creatinine (mg/dL)

In subjects 18 years of age: MDRD Equation2 GFR (mL/min/1.73 m2) = 175 × (Serum creatinine)-
1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)
Results will be reported to the sites and the Sponsor.

Sodium (mEq/L, mmol/L)

Potassium (mEq/L, mmol/L)

Chloride (mEq/L, mmol/L)

Calcium (mg/dL, mmol/L)

Magnesium (mEq/L, mmol/L)

Phosphorus (mg/dL, mmol/L)

Total Protein (g/dL, g/L)

Uric acid (mg/dL, mol/L)
Urine Analyses

Creatinine

Calculated Urinary albumin:creatinine ratio (UACR)

Urine HCG pregnancy test for WOCBP (HCG minimum sensitivity of 25 IU/L; performed at site or at home). 
If a urine HCG test is positive, a blood specimen will be obtained and a serum pregnancy test will be performed 
by the central laboratory for confirmation.


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Table Appendix 1:
Standard Safety Laboratory Panels
Spot urine:

Urinary glucose:creatinine ratio
Urinalysis with microscopy:

Hematuria


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APPENDIX 2
SUSTAINED ELEVATED LIVER SAFETY ABNORMALITIES FLOW CHART
Obtain confirmatory repeat AST, ALT, ALK-P and TB within 
3 days. Do NOT hold study medication
Step 1: Central Laboratory Alert Criteria
ALT and/or AST  3X ULN
. 
.
Step 2a: 
If repeat ALT AND
AST 3X ULN
Step 2b: 
If repeat ALT and/or AST 
3X ULN BUT 5X ULN 
AND TB 2.0X ULNa
Step 2c: 
If repeat ALT and/or AST 
5X ULN BUT 10X 
ULN and TB 2.0X ULN
Step 2d: 
If repeat ALT and/or AST 
3X ULN with a second 
confirmed TB 2.0X ULNa
Step 2e: 
If repeat ALT and/or 
AST 10X ULN
- Continue the subject 
in the treatment period 
according to the 
original visit schedule, 
unless otherwise 
contraindicated.
- Discontinue the subject immediately.
- Notify the Sponsor.
- Perform the end-of-treatment visit and additional assessments, 
including the liver discontinuation panel.b
- Obtain confirmatory repeat AST, ALT, ALK-P and TB 
every 3 days.c
- Continue study medication.
- Perform additional 
assessments, including the 
specialized liver panel.b
- Obtain confirmatory 
repeat AST, ALT, ALK-P 
and TB every 3 days.c
Each time AST, ALT, ALK-P and TB results are received, go 
back to Step 2 to review and implement the appropriate follow-up
- Continue study medication.
- Perform additional 
assessments, including the 
specialized liver panel.b
- Obtain confirmatory 
repeat AST, ALT, ALK-P 
and TB every 3 days.c
If repeat ALT and/or AST 5X ULN for 14 consecutive days, at 
any time after initial confirmatory results
a
In subjects with repeat ALT or AST 3X ULN but 10X ULN, only subjects with TB 2.0X ULN at Step 1 should be followed according to Step 2b. Subjects with an 
initial TB and confirmatory repeat TB 2.0X ULN should be followed according to Step 2d.
b
Refer to section 5.3.4 for details on additional assessments to be performed (AE assessment, PE, review of current medical history including focused review of risk factors 
for liver diseases and collection of blood samples [specialized liver panel or liver discontinuation panel]).
c
Confirmatory repeat AST, ALT, ALK-P and TB should be obtained every 3 days following receipt of prior laboratory results, until the ALT and AST are 2X ULN or until 
ALT and AST are at or below baseline levels. The frequency of retesting can decrease to once a week or less if abnormalities stabilize and the subject is asymptomatic.


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APPENDIX 3
TANNER ASSESSMENT SCALE
The Tanner Scale (also known as Tanner Staging) is a measure of pubertal development (sexual 
maturation) in children and adolescents with components described for each sex, rated separately 
on a scale of stage one to stage five. The stages define physical measurement of development based 
on external primary and secondary sexual characteristics. Females are classified with regard to 
breast and pubic hair characteristics. Males are classified with regard to genitalia and pubic hair 
characteristics. 
A qualitative determination of the subject’s sexual maturity rating on a scale of 1 to 5 will be 
determined according to those criteria established by Tanner3,4 (summarized in Tables 1 and 
2 below). Based on the level of comfort by the Investigator, caregiver, or study subject, the 
measure of sexual maturity may be obtained by 1) visually observing the level of development 
after the subject disrobes or 2) requesting the caregiver or subject point to the level of maturity 
from a description or selection of pictures that exhibit the various stages of maturity.
Table 1:
Classification of Sex Maturity Stages in Girls
Stage
Pubic Hair
Breasts
1
Preadolescent
Preadolescent
2
Sparse growth of long, slightly pigmented downy 
hair, straight or only slightly curled; appears 
chiefly along the labia
Breast bud stage; elevation of breast and 
papilla as a small mound; enlargement of 
areola diameter
3
Darker, beginning to curl, increased amount
Further enlargement of breast and areola with 
no separation of their contours
4
Resembles adult type but the area covered is still 
considerably smaller than in most adults; no 
spread to the medial surface of the thighs
Projection of areola and papilla form a 
secondary mound above the level of the 
breast
5
Adult in quantity and type, spread to medial 
surface of thighs
Mature; projection of papilla only due to 
recession of the areola to the general contour 
of the breast


Clinical Protocol
MB102138
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dapagliflozin
Revised Protocol No: 03
Date: 20-Sep-2017
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Table 2:
Classification of Sex Maturity Stages in Boys
Stage
Pubic Hair
Genitalia
1
None
Preadolescent
2
Sparse growth of long, slightly pigmented downy 
hair, straight or only slightly curled; appears 
chiefly at the base of the penis
Scrotum and testes have enlarged; change in 
texture of the scrotal skin with some 
reddening
3
Darker, coarser, and more curled; spreads sparsely 
over the junction of the pubes
Growth of the penis, mainly in length but 
with some increase in breadth; further growth 
of testes and scrotum
4
Resembles adult type but the area covered is still 
considerably smaller than in most adults; no 
spread to the medial surface of the thighs
Penis further enlarged in length and breadth 
with development of glans. Testes and 
scrotum further enlarged with further 
darkening of the scrotal skin
5
Adult in quantity and type, spread to medial 
surface of thighs
Adult size and shape. No further enlargement 
of testes and scrotum
Additional materials to aid in the Tanner Stage assessment will be provided upon request.









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