A Multicenter, Randomized, Double-Blind, Placebo-controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Dapagliflozin as an Add-on to Insulin Therapy in Subjects With Type 1 Diabetes Mellitus - Study Two
Phase: PHASE3
Conditions: Type 1 Diabetes Mellitus
Sponsor: AstraZeneca

Page:
1
Protocol Number:
MB102230
IND Number:
68,652
Ex-US
Non-IND
EUDRACT Number
2014-004599-49
Date:
05-Feb-2015
Revised Date:
18-May-2016
Clinical Protocol MB102230
A Multicenter, Randomized, Double-Blind, Placebo-controlled, Parallel Group, Phase 3 Study to 
Evaluate the Efficacy and Safety of Dapagliflozin as an Add-on to Insulin Therapy in Subjects 
with Type 1 Diabetes Mellitus - Study Two
Revised Protocol Number: 02
Incorporates amendment: 05
Study Director/Medical Monitor
Lars Hansen, MD, PhD
Route 206 & Province Line Road
Lawrenceville, NJ 08543
24-hr Emergency Telephone Number
Emergency Telephone Number
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Study being conducted by Bristol-Myers Squibb on behalf of AstraZeneca AB
Bristol-Myers Squibb Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
Route 206 & Province Line Road
Lawrenceville, NJ 08543
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 
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Revised Protocol No.: 02
Date:  18-May-2016
2
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).
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.
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Revised Protocol No.: 02
Date:  18-May-2016
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 
02
18-May-2016
Incorporates Amendment 05
Amendment 05
18-May-2016
The primary purpose of this amendment is to provide study visit 
scheduling flexibility by allowing optional phone visits to be done at 
week -4, week 2 and for the Continuous Glucose Monitoring visits (weeks 
10/11 and weeks 22/23) during the 24 week double blinded short term 
treatment period. 
Additional changes in this amendment include:

Adding an exploratory endpoint to compare the number of non-severe 
hypoglycemic events per subject in those achieving a HbA1c 
reduction of >0.5% on dapagliflozin 5 mg or 10 mg plus adjustable 
insulin versus placebo plus adjustable insulin from baseline to Week 
24 visit.

Updating the guidance on DKA assessments and reporting to include 
the following:

Reductions in insulin doses of more than 20% are not 
recommended regardless of glucose values. If blood glucose is 
repeatedly low and a 20% reduction in total daily insulin dose 
cannot be avoided the daily dietary carbohydrate intake should 
be increased,   as well as during and/or after elevated physical 
activity.  

Investigators are recommended to advise subjects to take extra 
insulin and extra carbohydrates if elevated ketones are registered 
and to continue to measure blood ketones.  Study medication 
should be interrupted during sick days if necessary

For subjects who report elevated ketones/ketosis or a DKA, it is 
recommended that the investigator consider reeducation 
concerning DKA at the next scheduled visit, at an un-scheduled 
visit or by telephone contact 

Adding that if total daily insulin dose is reduced upon initiation of 
study medication, attempts must be made to titrate insulin back to 
baseline total daily insulin dose. It is not recommended to reduce 
total daily insulin dose by more than 20% compared to baseline at 
any time during the study unless medically indicated and close 
attention should be paid, especially in these subjects, to symptoms of, 
and risk factors for developing DKA.

Revising the upper range of the Week -1 Visit: Central laboratory 
HbA1c to 10.5%

Adding multiple statistically related changes including:

Adding the ITT estimand analysis and sensitivity analyses for the 
primary efficacy endpoint.

Replacing the single-step Dunnett procedure with the Dunnett 
and Tamhane step-up procedure for improved power and greater 
emphasis on primary endpoint.

Replacing “Randomized subjects dataset” with “Full analysis 
dataset”.  

Replacing the Zhang et al method with a general logistic 
regression model for implementation considerations. 

Adding statistical method to model the added exploratory 
endpoint, number of number of non-severe hypoglycemic events 
per subject in those achieving a HbA1c reduction of 0.5%
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Revised Protocol No.: 02
Date:  18-May-2016
4
Document
Date of Issue
Summary of Change

Indicating that Tubal Ligation in this protocol is not considered 
surgical sterilization

Removing the PK Sampling required at the Day 1 visit

Confirming that subjects are to record day and time of CGM sensor 
insertion if performed at home at week 11 and week 23

Reinforcing that all results recorded in subject diary are to be 
reviewed by site staff during each study visit and that determination 
of a DKA event must be assessed and documented by the Principal 
Investigator or by a qualified sub-investigator

Adding guidance on recording blood ketone and glucose values 
associated with events that are deemed not to be a DKA event 

Including local injections such as intramuscular or intra-articular in 
the systemic corticosteroid therapy exclusion criteria as well as 
adding drops to the topical corticosteroids that are allowed in the 
study

Clarifying that the Data Monitoring Committee will periodically 
evaluate the incidence of hypoglycemia and DKA events, as well as 
AEs, laboratory measurements, and safety assessments to ensure the 
ongoing safety of study subjects.

Adding multiple updates, confirmations and additions in the Study 
Flowchart
Revised Protocol 
01
06-May-2015
Incorporates Amendment 03
Amendment 03
06-May-2015
The primary purpose of the amendment was to modify the Inclusion and 
Exclusion Criteria based on feedback from the European Medicines 
Agency (EMA). Specifically, the EMA has endorsed removing the 
requirement that HbA1c may not drop more than 0.5% during the lead-in 
phase. 
Additional changes in the amendment include:

Adding guidance around requirements for performing the continuous 
glucose monitoring (CGM) assessments, recording meal information, 
and performing the 6-point self monitoring blood glucose (SMBG) 
for subjects who are lead-in failures or who discontinue study 
medication

Harmonizing the criteria for monitoring and discontinuing subjects 
with elevated liver function tests with the hepatic adjudication criteria

Providing guidance on allowing subjects to rescreen if they did not 
fail any of the screening or lead-in criteria and were not subsequently 
randomized within the applicable study visit windows (e.g. due to a 
planned medical procedure, vacation plans, or employment 
commitments) 

Added a 7 day window to the current Lead-in Period window of 56 + 
5 days for subjects who have a one-time HbA1c retest at Week -1
Original Protocol
05-Feb-2015
Not applicable
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
SYNOPSIS
Clinical Protocol MB102230
Protocol Title: A Multicenter, Randomized, Double-Blind, Placebo-controlled, Parallel Group, Phase 3 Study to 
Evaluate the Efficacy and Safety of Dapagliflozin as an Add-on to Insulin Therapy in Subjects with Type 1 Diabetes
Mellitus - Study Two
Investigational Products, Dose and Mode of Administration, Duration of Treatment with Investigational 
Products:

Blinded dapagliflozin tablets 5 mg, and 10 mg administered orally for the 24-week double-blind short-term 
treatment period, and the 28-week subject- and site-blinded long-term treatment period of the study

Matching placebo administered orally for the 24-week double-blind short-term treatment period, and the 
28-week subject and site blinded long-term treatment period of the study.
Study Phase: 3
Research Hypothesis: After 24 weeks of oral administration of double-blind treatment, the change from baseline in 
hemoglobin A1c (HbA1c) with dapagliflozin plus insulin will be greater than placebo plus adjustable insulin in 
subjects with type 1 diabetes mellitus (T1DM) who have inadequate glycemic control. In this study, adjustments of 
insulin dose can be made as deemed appropriate to be consistent with good medical practice.
Objectives:
Primary Objective 
The primary objective of this study is to compare the change from baseline in HbA1c after 24 weeks of 
double-blinded treatment with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable 
insulin.
Secondary Objectives:
Efficacy

Compare the percent change from baseline in total daily insulin dose with dapagliflozin 5 mg or 10 mg plus 
adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Compare the percent change from baseline in body weight with dapagliflozin 5 mg or 10 mg plus adjustable 
insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Compare the change from baseline in the mean value of 24-hour glucose readings obtained from continuous 
glucose monitoring (CGM) with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus 
adjustable insulin after 24 weeks of double-blinded treatment

Compare the change from baseline in mean amplitude of glucose excursion (MAGE) of 24-hour glucose 
readings obtained from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus 
adjustable insulin after 24 weeks of double-blinded treatment

Compare the change from baseline in the percent of 24-hour glucose readings obtained from CGM that falls 
within the target range of 70 mg/dL and 180 mg/dL with dapagliflozin 5 mg or 10 mg plus adjustable 
insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Compare dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin for the 
proportion of subjects achieving an HbA1c reduction from baseline to Week 24 visit 0.5% without severe 
hypoglycemia events
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Safety

To assess the proportion of subjects with hypoglycemia events and the frequency and severity of the 
hypoglycemia events with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable 
insulin

To evaluate the safety and tolerability by assessment of adverse events (AE), vital signs, diabetic ketoacidosis 
(DKA) events, physical examination findings, ECG, and laboratory values
Other/Exploratory Objectives:

Assess the proportion of subjects with HbA1c reduction of at least 0.5% (0.5%) from baseline with 
dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of 
double-blinded treatment

Assess the proportion of subjects with HbA1c < 7.0% with dapagliflozin 5 mg or 10 mg plus adjustable insulin 
versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Assess the change from baseline in fasting plasma glucose (FPG) with dapagliflozin 5 mg or 10 mg plus 
adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Assess the change from baseline in the percent of 24-hour glucose readings obtained from CGM that is within 
the hypoglycemic range of 70 mg/dL with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo 
plus adjustable insulin after 24 weeks of double-blinded treatment

Assess the change from baseline in seated systolic blood pressure with dapagliflozin 5 mg or 10 mg plus 
adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment among 
subjects with hypertension at baseline, defined as seated SBP 140 mmHg and/or seated DBP 90 mmHg

Assess the change from baseline in average glucose values measured by 6-point self monitored blood glucose 
(SMBG) with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 
24 weeks of double-blinded treatment

Assess the change from baseline in postprandial glucose values measured by 6-point SMBG with dapagliflozin 
5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded 
treatment

Assess the change from baseline in postprandial glucose values measured by CGM with dapagliflozin 5 mg or 
10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Assess the change from baseline in standard deviation of 24-hour glucose readings obtained from CGM with 
dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of 
double-blinded treatment

Assess the change from baseline to Week 24 in health status, as measured by the Euro Quality of life 5 
dimensions 3 levels (EQ-5D-3L) questionnaire, between dapagliflozin 5 mg or 10 mg plus adjustable insulin 
versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment 

Assess the changes from baseline to Week 24 in the summary score for treatment satisfaction and scores for 
perceived frequency of hyperglycemia and perceived frequency of hypoglycemia, respectively, as measured by 
the Diabetes Treatment Satisfaction Questionnaire status (DTSQs) between the dapagliflozin 5 mg or 10 mg 
plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Assess the change from baseline to Week 24 in the fear of hypoglycemia as measured by the Hypoglycemia 
Fear Survey (HFS-II) Worry Subscale score between the dapagliflozin 5 mg or 10 mg plus adjustable insulin 
versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

To explore the relationship between observed and/or model estimated pharmacokinetic measures of exposure 
(eg, AUCss, Cmax, Cmin) and efficacy and/or safety endpoints by using model-based approaches. This analysis 
will be provided in a separate report

Compare the number of non-severe hypoglycemic events per subject in those achieving an HbA1c reduction of 
0.5% on dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin from 
baseline to Week 24 visit.
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Study Design: This trial is a randomized, double-blinded, three-arm, parallel-group, placebo-controlled, multicenter 
trial to evaluate the efficacy and safety of dapagliflozin, when added to ongoing insulin therapy, in subjects with 
T1DM and inadequate glycemic control. Approximately 768 subjects will be randomized in this trial. Due to 
regulatory requirements, approximately 160 subjects (of the 768 subjects) are planned to be be included from Japan.
Potential subjects will be assessed for eligibility criteria at the screening visit. Eligible subjects will enter an 8-week 
lead-in period in order to optimize their diabetes management based on individual subject challenge to glycemic 
control (including hyperglycemia, hypoglycemia, erratic meal/exercise patterns, as defined by the investigator) and 
to assess the variability in blood glucose profiles and frequency of hypoglycemic episodes at baseline. No placebo or 
study medication will be provided during the lead-in period. On Day 1, subjects who meet all the protocol-specific 
enrollment and randomization criteria will be randomized into one of the 3 blinded treatment arms (dapagliflozin 
5 mg QD, dapagliflozin 10 mg QD, or placebo QD) in a 1:1:1 ratio. Randomization will be stratified to ensure equal 
representation across all treatment groups by the following: 1) current use of CGM (this refers to an 
unblinded/personal device which may already be in use before using the blinded device as part of the study and will 
be categorized as yes vs no); 2) method of insulin administration at baseline (multiple daily injections ([MDI] vs 
continuous subcutaneous insulin infusion [CSII]); and 3) baseline A1C 7.5% and < 9.0% vs 9.0% and 10.5%. 
Subjects will receive dapagliflozin 5 mg QD, 10 mg QD, or placebo QD for 24 weeks, followed by a 28-week 
subject- and site-blinded long-term treatment period. Besides study medications, subjects will be treated with MDI 
(three or more injections per day of basal and prandial insulin) or CSII. It is recommended that subjects reduce their 
daily insulin dose by up to 20% for both basal and bolus insulin after the first dose of study drug on Day 1 to reduce 
the risk of hypoglycemia, although in some cases it may be necessary to reduce insulin (particularly basal insulin) in 
advance of study drug administration. It is at the discretion of the investigator to determine the extent to which to 
reduce the insulin doses. Throughout the study (from the beginning of the lead-in period to the end of the long-term 
treatment period), insulin dose may be adjusted as deemed appropriate to be consistent with good medical practice 
according to SMBG readings, local guidance and individual circumstances. Subjects will be monitored closely with 
regard to safety parameters, including vital signs, safety laboratory tests, ECGs, and AEs.
Figure -1:
Study Schematic
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Notes:

Eligible subjects should have the Day 1 randomization visit within 56 5 days of the Week -8 entry into lead-in 
period visit

Subjects will receive the last dose of study medications on Week 52 visit and they will have the last follow-up 
visit on Week 56 visit (30 days after Week 52 visit)
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for MB102230
Medication
Potency
IP/Non-IP
Dapagliflozin Film Coated Tablets
5mg
IP
Background Insulin
Varies
Non-IP
Study Population:
Key Inclusion Criteria: 

Diagnosis of T1DM. In addition, a central laboratory C-peptide < 0.7 ng/mL (0.23 nmol/L) is required

Ages 18 to 75 years, inclusive

Insulin use for at least 12 months prior to screening per subject reported or medical records and:
R
Method of insulin administration (MDI or CSII) must have been unchanged for at least 3 months prior to 
screening per subject reported or medical records. Subjects must be taking a total insulin dose of 
0.3 U/kg/day for at least 3 months prior to screening
R
If using MDI, the subject must be taking 3 injections per day

HbA1c eligibility criteria include:
R
Screening Visit: Central laboratory HbA1c 7.7% and 11.0% 
Note: a one-time repeat HbA1C is allowed for subjects in screening if their initial result is within 0.2% of 
the cut off values
R
Week -1 Visit: Central laboratory HbA1c 7.5 % and 10.5%
Note: a one-time repeat HbA1C is allowed for subjects in lead-in if their test result is within 0.2% of the 
cut off values

BMI 18.5 kg/m2

Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product

WOCBP must agree to follow instructions for method(s) of contraception as outlined in the study

Women must not be breastfeeding
Key Exclusion Criteria:

Target Disease Exceptions
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History of T2DM 
Note: subjects with a previous misdiagnosis of T2DM in their medical history must have one of the following in 
order to be eligible for this trial:
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin

Positive autoantibodies for GAD65, phosphatase IA-2/IA2β, or zinc transporter 8 (ZnT8) 
(eg, autoimmune diabetes) 

Fasting c-peptide value below the lower limit of detection performed by the Central Laboratory
R
History of maturity onset diabetes of young (MODY)
R
Pancreatic surgery, chronic pancreatitis, or other pancreatic disorders that could result in decreased -cell 
capacity (eg, pancreatogenous diabetes)
R
Previous use of dapagliflozin and/or any other SGLT-2 inhibitors
R
Use of insulin-sensitizing agents, such as metformin and/or thiazolidinediones, within 2 months prior to the 
screening visit
R
Use of any GLP-1 receptor agonist within the following timeframe prior to the screening visit:
i)
1 month for once or twice daily administration (eg, liraglutide)
ii)
2 months for once weekly administration
R
Any non-insulin, antihyperglycemic agent use within 1 month prior to the Screening visit
R
History of diabetes ketoacidosis (DKA) requiring medical intervention (eg, emergency room visit and/or 
hospitalization) within 1 month prior to the screening visit
R
History of hospital admission for glycemic control (either hyperglycemia or hypoglycemia) within 1 month 
prior to the Screening visit
R
Frequent episodes of severe hypoglycemia as defined by more than one episode requiring medical 
assistance, emergency care (paramedics or emergency room care), and/or glucagon therapy administered by 
a third-party individual within 1 month prior to the screening visit
R
Symptoms of poorly controlled diabetes that would preclude participation in this trial including but not 
limited to marked polyuria and polydipsia with greater than 10% weight loss during the 3 months prior to 
screening, or other signs and symptoms
R
History of Addison’s disease or chronic adrenal insufficiency
R
History of diabetes insipidus

Medical History and Concurrent Diseases
R
Any of the following cardiovascular (CV)/vascular diseases within 6 months of the screening visit:

Myocardial infarction

Cardiac surgery or revascularization (coronary artery bypass surgery [CABG]/percutaneous 
transluminal coronary angioplasty [PTCA]) 

Unstable angina

Unstable congestive heart failure (CHF)

CHF New York Heart Association (NYHA) Class III or IV

Transient ischemic attack (TIA) or significant cerebrovascular disease 

Unstable or previously undiagnosed arrhythmia
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Renal Disease:

History of unstable or rapidly progressing renal disease

Conditions of congenital renal glucosuria

Renal allograft
R
Hepatic Diseases:

Significant hepatic disease, including, but not limited to, chronic active hepatitis and/or severe hepatic 
insufficiency
R
Hematological and Oncological Disease/Conditions:

History of hemoglobinopathy, with the exception of sickle cell trait (SA) or thalassemia minor; or 
chronic or recurrent hemolysis
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin

Known immunocompromised status, including but not limited to, individuals who have undergone 
organ transplantation or who are positive for the human immunodeficiency virus

Donation of blood or blood products to a blood bank, blood transfusion, or participation in a clinical 
study requiring withdrawal of > 400 mL of blood during the 8 weeks prior to the screening visit

Malignancy within 5 years of the screening visit (with the exception of treated basal cell or treated 
squamous cell carcinoma)

History of bladder cancer

History of radiation therapy to the lower abdomen or pelvis at any time

Physical and Laboratory Test Findings
R
Aspartate aminotransferase (AST) > 3x upper limit of normal (ULN)
R
Alanine aminotransferase (ALT) > 3x ULN
R
Serum total bilirubin > 2.0x ULN unless exclusively caused by Gilbert’s Syndrome
R
Calculated creatinine clearance (CrCl) < 60 mL/min as estimated by the Cockcroft-Gault formula, using 
laboratory measurements of serum creatinine collected at the screening visit [Creatinine clearance = 
[[140 - age(yr)]*weight(kg)/[72*serum Cr(mg/dl)] (multiply by 0.85 for women]
R
Hemoglobin 11.0 g/dL (110 g/L) for men; hemoglobin 10.0 g/dL (100 g/L) for women
R
Positive for hepatitis B surface antigen or anti-hepatitis C virus antibody
R
Abnormal Free T4
Note: abnormal TSH value at screening will be further evaluated for free T4. Subjects with abnormal free 
T4 values will be excluded. A one-time retest may be allowed after a minimum of 6 weeks following the 
adjustment of thyroid hormone replacement therapy in subject who have had a prior diagnosis of a thyroid 
disorder and who are currently receiving thyroid replacement therapy. Such cases should be discussed with 
the Sponsor prior to re-testing

Allergies and Adverse Drug Reaction
R
Allergies or contraindication to the contents of dapagliflozin tablets or insulin

Sex and Reproductive Status
R
Women who are pregnant or breastfeeding  

Other Exclusion Criteria
R
Prisoners or subjects who are involuntarily incarcerated
R
Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious 
disease) illness
R
Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise 
program
R
History of bariatric surgery or lap-band procedure within 12 months prior to screening
R
Replacement or chronic systemic corticosteroid therapy, defined as any dose of systemic corticosteroid 
(including local injections such as intramuscular or intra-articular,etc.) taken for > 4 weeks within 3 months 
prior to the Day 1 visit
NOTE: Topical (including drops) or inhaled corticosteroids are allowed
R
Any unstable endocrine, psychiatric or rheumatic disorders as judged by the investigator
R
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
R
Subject who, in the judgment of the investigator, is found to be unlikely to comply with the protocol, or is 
unable to correctly self-administer subcutaneous insulin injections and/or manage their insulin pump, or has 
any severe concurrent medical or psychological condition that may affect the interpretation of efficacy or 
safety data (including during the lead-in period)
R
Subject is currently abusing alcohol or other drugs or has done so within the last 6 months prior to the 
Day 1 visit
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Discontinuation of Subjects from Treatment:
Subjects MUST discontinue study treatment for any of the following reasons:

Withdrawal of informed consent (subject’s decision to withdraw for any reason)

Any 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

Pregnancy

Termination of the study by the Sponsor

Loss of ability to freely provide consent through imprisonment or involuntary incarceration for treatment of 
either a psychiatric or physical (eg, infectious disease) illness

CrCl < 30 mL/min
R
If at any time the subject´s CrCl (based on Cockroft-Gault) falls below 30 mL/min calculated at the central 
laboratory and confirmed at a repeated central laboratory measurement (to be obtained within 4 days, 
whenever possible) the subject should be discontinued from study medication

Subjects experience at least one protocol-defined hypoglycemia episode that leads to a loss of consciousness 
and/or seizure as determined by the investigator

Change of insulin administration method (eg, switch from MDI to CSII, or vice versa)
R
Subjects are not allowed to change their insulin administration methods (eg, from MDI to CSII or vice 
versa) throughout the study. Under certain situations (eg, the replacement of an insulin pump), the subjects 
who are on CSII may be on temporary use of MDI. They should restart CSII administration as early as 
feasible. The period of time when a subject on temporary use of MDI should not be more than 2 weeks

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 results. Subjects should be discontinued from study if the initial and repeat 
laboratory tests meet any of the following criteria:
R
ALT and/or AST are > 3x ULN and total bilirubin (TB) > 2x ULN
R
ALT and/or AST are > 5x ULN for 14 consecutive days, at any time after initial confirmatory results
R
ALT and/or AST are > 10x ULN
Study Assessments:
Primary Assessment:

Change from baseline in HbA1c
Secondary Assessments:

Percent change from baseline to Week 24 in total daily insulin dose

Percent change from baseline to Week 24 in body weight

Change from baseline to Week 24 in the mean value of 24-hour glucose readings obtained from CGM

Change from baseline to Week 24 in mean amplitude of glucose excursion of 24-hour glucose readings obtained 
from CGM

Change from baseline to Week 24 in the percent of 24-hour glucose readings obtained from CGM that falls 
within the range of > 70 mg/dL and 180 mg/dL

Proportion of subjects achieving an HbA1c reduction from baseline to Week 24 visit 0.5% without severe 
hypoglycemia events
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Safety Assessments: Safety assessments will be based on medical review of AE reports and the results of vital sign 
measurements, ECGs, physical examinations, and clinical laboratory tests. The incidence of observed AEs will be 
tabulated and reviewed for potential significance and clinical importance. Both hypoglycemia and DKA during the 
24-week double-blinded short-term treament period and the 28-week subject- and site-blinded long-term period 
(the Sponsor will be unblinded during the long-term treatment period) will be assessed.
Subjects will receive a combined blood glucose and ketone meter, supplies and instructions on their use. Subjects 
should self-monitor their blood glucose consistent with local treatment guidelines (typically 4 times daily or when 
experiencing symptoms suggestive of hypoglycemia) and contact the investigator in the event of an unusually high 
or low blood glucose value. 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, and to confirm that the 
values are obtained from the subject.
Subjects will be advised to measure their blood ketones using a combined blood glucose and ketone meter provided 
by the Sponsor when they have potential symptoms/signs of DKA (eg, excessive thirst, nausea and vomiting, 
frequent urination, weakness or fatigue, fruity-scented breath, confusion, and/or consistently elevated blood glucose) 
and/or during acute illness. Subjects should be instructed to measure their ketones if symptoms occur, regardless of 
plasma glucose values. Subjects should contact the site for assistance with diabetes management in the event that the 
blood ketone reading is 0.6 mmol/L or above in accordance with the ketone meter user guide provided.
Subjects must also be instructed that if attempts to contact the site are unsuccessful or if they are in urgent need of 
medical attention, that they should seek medical attention. They should provide information to the health care 
provider on their participation in a placebo controlled clinical study evaluating the effects of the SGLT2i 
dapagliflozin in addition to their insulin treatment.
Exploratory Assessments:
Subjects will be instructed to perform 6-point SMBG profiles according to the schedule presented in the study flow 
charts. 6-point SMBG profiles will be taken on any 3 days within one week before the scheduled visits, with 
three glucose measurements obtained preprandially (within 15 minutes prior to meal) and three glucose 
measurements obtained postprandially (1.5- 2 hours after start of the meal) for the three main meals of the day. 
Subjects will be provided with a diary to record their SMBG measurements and mealtimes.
CGM will be used periodically to measure the subject’s interstitial glucose level according to the schedule presented 
in Study Flow Charts. A CGM sensor will be inserted subcutaneously at the Week -2 visit, Week -1 visit, Week 10 
visit and Week 22 visit to allow monitoring for 2 weeks (for example: the Week -2 visit to the Day 1 visit [baseline];
the Week 10 office visit until the Week 12 office visit; and the Week 22 office visit until the Week 24 office visit.). 
The data will remain blinded to the subject, the investigator, and to the Sponsor during the recording and will be 
downloaded into a data file. Detailed procedures (including calibration) will be described in an operations manual 
and site staff will be fully trained on the use of CGM. Subjects will wear the sensor and perform calibration 
according to manufacturer’s instructions. If a subject uses a CGM device prior to entry into the study, he/she may 
continue to use the device during the study in accordance with their usual diabetes management care. Such a subject 
will be required to also use the blinded CGM device according to protocol procedures.
Outcomes Research Assessments:
Patient reported outcomes (PROs) will be assessed at the Day 1 visit (prior to first dose), the Week 24 visit, and the 
Week 52 visit by EQ-5D-3L for generic health status, DTSQs for treatment satisfaction, and the HFS-II Worry 
subscale for worry about hypoglycemia and its negative consequences. The instruments/questions will be 
self-administered using paper and pencil questionnaires. The EQ-5D-3L is a generic, preference-based utility
questionnaire and consists of two parts, the EQ visual analogue scale (VAS) and the EQ-5D-3L index. The EQ VAS 
ranges from 0 = worst possible health to 100 = best possible health. The EQ-5D-3L index is a questionnaire with 
five dimensions, which include mobility, self-care, usual activity, pain/discomfort and anxiety/depression. Each item 
has three levels: no problems, some problems and severe problems. The DTSQ has been developed to assess 
subjects’ satisfaction with treatment and perception of change in hyper- and hypoglycaemia. The DTSQ status 
version (DTSQs) has 8 items. The HFS-II Worry Subscale is an 18-item questionnaire, in which responses are made 
on a 5-point Likert scale (where 0 = Never and 4 = Always). The HFS-II Worry Subscale has a score ranging from 
0 to 72, with higher scores indicating increased fear of hypoglycaemia.
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Data Monitoring Committees:
An external data monitoring committee (DMC) with multidisciplinary representation will be established to evaluate,
on a periodic basis, the incidence of hypoglycemia and DKA events, as well as AEs, laboratory measurements, and 
safety assessments to ensure the ongoing safety of study subjects. An independent reporting statistician not involved 
in the conduct of the study will be designated by BMS to provide the DMC with essential safety data during the 
study. The DMC responsibilities, authorities, and procedures will be documented in a DMC charter.
Statistical Considerations:
Sample Size:
With 243 subjects per treatment group with both baseline and at least one post baseline measurement, there is 
approximately 90% power to detect a difference in means of 0.35% between each dapagliflozin treatment group and 
placebo at the two-sided 0.0262 significance level (based on Dunnett and Tamhane step-up procedure), assuming a 
standard deviation (SD) of 1.1%. Assuming that 5% of subjects do not have a post-baseline assessment, a total of 
768 subjects (256 subjects per treatment arm) need to be randomized to each dapagliflozin or placebo group in 1:1:1 
ratio.
Among those 768 subjects, approximately 160 of them will be from Japan in order to support population specific 
analyses. 
A reduction in the primary endpoint of change from baseline in HbA1c of 0.35% was used to determine sample size 
as this represents a clinically meaningful improvement in glycemic control under the current study design with 
adjustable background insulin dose. A lesser degree of reduction in HbA1c in combination with other beneficial 
outcomes in secondary endpoints may also be clinically important.
Endpoints:
Statistical Approach / Assumptions
The primary endpoint is the change in HbA1c from baseline to Week 24. The primary estimand for the primary 
endpoint is treatment difference at Week 24 if subjects did not discontinue randomized treatment. In order to 
maintain an overall Type I error rate of 5% for the endpoint, a Dunnett and Tamhane step-up procedure will be used, 
which allows for the correlation of 0.5 between the standard normal deviate for each comparison (Dunnett and 
Tamhane 1992). Applying the Dunnett and Tamhane procedure, statistical significance will be declared for both 
doses at the two-sided 5% level if the two-sided p-values from both pairwise comparisons are smaller than 5%. If 
the larger p-value among the two pairwise comparisons is greater than 5% and the smaller p-value is below 2.62%, 
then statistical significance will be declared for the latter comparison. The primary analysis of the change in HbA1c 
from baseline to Week 24 will be based on a longitudinal repeated measures analysis using ‘direct likelihood’. The 
analysis will be based on the full analysis dataset who have a baseline assessment and any post-baseline double-
blind treatment period assessment. The analysis will include all available data up to Week 24 or until premature 
discontinuation of randomized treatment, whichever occurs first. The analysis will be conducted regardless of 
insulin up-titration. The model is based on a missing at random (MAR) assumption with respect to missing data.
The SAS procedure PROC MIXED will be used. The preferred model will include the fixed categorical effects of 
treatment, week, randomization stratification factor (ie, one term for each combination of all stratification factors) 
and treatment-by-week interaction, as well as the continuous fixed covariates of baseline measurement and baseline 
measurement-by-week interaction. An unstructured matrix for the within-subject 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 within each treatment group, as well 
as the difference in mean change between the dapagliflozin treatment group and placebo will be calculated. P-values 
for the difference in Week 24 estimates between each dapagliflozin group and placebo will be calculated
The ITT estimand, i.e., treatment difference at Week 24 regardless of treatment discontinuation, will be evaluated as 
the secondary estimand of the primary endpoint. The analysis of the ITT estimand will include all available data up 
to Week 24, regardless of insulin up-titration and regardless of premature discontinuation of randomized treatment.
Sensitivity analyses will be conducted for the primary efficacy endpoint to assess the robustness of the primary 
efficacy results, including sensitivity analysis with respect to the ITT estimand, sensitivity analyses based on 
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missing-not-at-random (MNAR) assumptions with respect to missing data, and sensitivity analysis with respect to 
insulin up-titration.
Statistical tests for secondary efficacy endpoints will be only conducted if there is a statistically significant 
difference in the primary endpoint for both pairwise comparisons, i.e., dapagliflozin 5mg vs. placebo and 
dapagliflozin 10mg vs. placebo. The same Dunnett and Tamhane step-up procedure will be applied to each 
secondary efficacy endpoint. Secondary efficacy endpoints will be tested in the order that they appear in the 
objectives section of the protocol and protocol synopsis.  Statistical tests will be only performed for a given 
secondary endpoint if both comparisons for a proceeding secondary endpoint are significant. Otherwise, the testing 
procedure will stop at the secondary endpoint that does not reach statistical significance.
The percent change (using logarithmic transformation for the endpoint in the model) from baseline to Week 24 in 
total daily insulin dose and total body weight, the change from baseline to Week 24 in the mean value of 24-hour 
glucose readings obtained from CGM, mean amplitude of glucose excursion of 24-hour glucose readings obtained 
from CGM, and the percent of 24-hour glucose readings obtained from CGM that fall within the range of 
> 70 mg/dL and 180 mg/dL will be analyzed using a longitudinal repeated measures analysis, similarly to the 
model used for the primary efficacy analysis. The proportion of subjects achieving an HbA1c reduction from 
baseline to Week 24 0.5% without severe hypoglycemia events will be analyzed using a logistic regression model 
with adjustment for baseline values. In addition to point estimates and 2-sided 95% confidence intervals, p-values 
will be calculated for all endpoints. Nominal p-values will be presented for endpoints where type 1 error is not 
controlled All secondary efficacy analyses will use subjects in the primary efficacy dataset (ie, full analysis dataset) 
who have a baseline assessment and any post-baseline double-blind treatment period assessment.
Analysis and Reporting:
There will be one study report at the end of short-term period and a second study report at the end of short-term plus 
long-term period.
The PK analysis may be provided in a separate report.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Unmet Medical Need in Type 1 Diabetes Mellitus .................................. 
1.1.2 Introduction of Dapagliflozin and Study Rationale ................................. 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.2.1 Efficacy ........................................................................................... 
1.3.2.2 Safety ............................................................................................... 
1.3.3 Other/Exploratory Objectives .................................................................. 
1.4 Product Development Background ................................................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ........ 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects from Treatment .................................................... 
3.5.1 Discontinuation Guidelines due to Protocol-Defined Hypoglycemia 
Episode or Recurrent Hypoglycemia Episodes ........................................... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.4.1 Subjects entering the 24-week double-blinded short-term treatment 
period .......................................................................................................... 
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4.4.2 Subjects entering the 28-week long-term subject and site blinded 
treatment period .......................................................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction and Return of Study Drug ............................................................. 
4.8.1 Destruction of Study Drug ....................................................................... 
4.9 Return of Study Drug ........................................................................................ 
4.10 Retained Samples for Bioavailability / Bioequivalence ................................. 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.3.2 Self-Monitored Blood Glucose (SMBG) and Guidance on Management 
and Reporting of Hypoglycemia Episodes .................................................. 
5.3.2.1 Self-Monitored Blood Glucose (SMBG) ......................................... 
5.3.2.2 Guidance on Management and Reporting of Hypoglycemia 
Episodes ................................................................................................ 
5.3.3 Self-Monitored Blood Ketone Testing and Guidance on Management and 
Reporting of Diabetic Ketoacidosis Episodes ............................................. 
5.3.4 Insulin Dosing Adjustment and Data Collection Guidelines ................... 
5.3.5 Guidance on Assessment of Urinary Infections and Hematuria .............. 
5.3.5.1 Guidance on Assessment of Urinary Infections .............................. 
5.3.5.2 Guidance on Assessment of Hematuria .......................................... 
5.3.6 Guidance on Assessment of Cardiovascular Events ................................ 
5.3.7 Guidance on Assessment of Hepatic Laboratory Abnormalities ............. 
5.3.8 Physical Examination .............................................................................. 
5.3.9 Blood Pressure and Heart Rate ............................................................... 
5.3.10 Electrocardiograms ............................................................................... 
5.3.11 Guidance on Volume Depletion ............................................................. 
5.3.12 Guidance on Monitoring Renal Function .............................................. 
5.3.13 Supplemental Visits ................................................................................ 
5.3.13.1 Early Treatment Discontinuation Visit ......................................... 
5.3.13.2 Early Treatment Discontinuation Follow-up (Off Treatment 
Procedures) ........................................................................................... 
5.3.13.3 Other Supplemental (Unscheduled) Visits .................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.6 Pharmacogenomic/Pharmacogenetic Assessements ......................................... 
5.7 Biomarker Assessments .................................................................................... 
5.8 Outcomes Research Assessments ..................................................................... 
5.8.1 EQ-5D-3L ................................................................................................ 
5.8.2 Diabetes Treatment Satisfaction Questionnaire ...................................... 
5.8.3 Hypoglycemia Fear Survey ...................................................................... 
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5.9 Other Assessments ............................................................................................ 
5.9.1 Weight ...................................................................................................... 
5.9.2 Height and Body Mass Index (BMI) ........................................................ 
5.9.3 Diet and Exercise Counseling .................................................................. 
5.9.4 Pharmacodynamic Assessments ............................................................... 
5.9.4.1 Fasting Plasma Glucose ................................................................. 
5.9.4.2 6-point SMBG profiles .................................................................... 
5.9.4.3 Continuous Glucose Monitoring (CGM) ........................................ 
5.10 Results of Central Laboratory Assessments ................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
6.7.1 AEs of Special Interest ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
7.1 Cardiovascular Adjudication Committee .......................................................... 
7.2 Hepatic Adjudication Committee ..................................................................... 
7.3 DKA Adjudication Committee ......................................................................... 
7.4 Data Monitoring Committee (DMC) ................................................................ 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint..................................................................................... 
8.3.2 Secondary Endpoints ............................................................................... 
8.3.3 Safety ........................................................................................................ 
8.3.4 Exploratory Endpoints ............................................................................. 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Efficacy Analyses .............................................................. 
8.4.2.2 Secondary Efficacy Analyses .......................................................... 
8.4.2.3 Exploratory Efficacy Analyses ........................................................ 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
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9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 NEW YORK HEART ASSOCIATION FUNCTIONAL CLASS ....... 
APPENDIX 2 CENTRAL LABORATORY ASSESSMENTS ................................... 
APPENDIX 3 SUSTAINED ELEVATED LIVER SAFETY ABNORMALITIES 
FLOW CHART ....................................................................................................... 
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1
INTRODUCTION AND STUDY RATIONALE
1.1
Study Rationale
1.1.1
Unmet Medical Need in Type 1 Diabetes Mellitus
Type 1 diabetes mellitus (T1DM) is a serious chronic disorder that results in the destruction of 
insulin-producing pancreatic -cells. T1DM accounts for approximately 5-10% of all cases of 
diabetes worldwide, and its incidence continues to increase.1 Patients with T1DM require 
lifelong insulin therapy due to their inability to produce endogenous insulin. Insulin requirements 
in these subjects vary widely and depend on several factors including body weight, activity level, 
and food intake.
People with T1DM must balance the goal of long-term glycemic control and reduction of 
complications of the disease with the day-to-day challenges of insulin therapy. The major 
limiting factor for restoring euglycemia is insulin-related hypoglycemia.2 Unfortunately, recent 
data suggest hypoglycaemia remains a common event, with 11.8% of subjects in a clinic registry 
study experiencing at least one episode of severe hypoglycemia resulting in seizure or loss of 
consciousness within the past 12 months.3 The occurrence of severe hypoglycemia did not 
appear to be related to hemoglobin A1C (HbA1c). However, the risk of recurrent hypoglycemia 
episodes in T1DM can be related to the degree of glycemic variability,4 which suggests that 
reducing the swings in glucose may be of importance in this population.
Intensive insulin therapy is also associated with weight gain and insulin resistance, as evidenced 
in the Diabetes Control and Complications Trial,5,6 where subjects in the intensive treatment arm 
gained an average of 4.6 kg more than the control group over the 5 year study. It has been 
postulated that the weight gain associated with intensive insulin treatment is related to reductions 
in urinary glucose excretion, increased appetite, and the ingestion of excess calories to manage or 
avoid hypoglycemia. Weight gain and insulin resistance may have a significant deleterious 
impact upon cardiovascular risk factors,7 at least in some people with T1DM, and has recently 
contributed to the concept of ‘double diabetes.8
Average HbA1c values greater than 8% have been reported in several large studies in people 
with T1DM,9,10 suggesting a large proportion of the population are unable to achieve 
recommended glycemic levels with insulin alone because of the challenges associated with 
insulin therapy. Novel therapies used as an adjunct to insulin that improve glycemic control and 
provide important secondary benefits, such as reductions in insulin dose, hypoglycemia and 
glycemic variability, and attenuation of weight gain associated with insulin, address important 
unmet needs for people with T1DM.
1.1.2
Introduction of Dapagliflozin and Study Rationale
This Phase 3 study is designed to evaluate the efficacy and safety of dapagliflozin 5 mg and 
10 mg as an add-on to insulin therapy when used in subjects with T1DM with inadequate 
glycemic control.
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Dapagliflozin is a stable, competitive, reversible, highly selective, and orally active inhibitor of 
sodium glucose cotransporter 2 (SGLT-2), the major transporter responsible for renal glucose 
reabsorption. Dapagliflozin has been recently approved for the treatment of type 2 diabetes 
mellitus (T2DM). Dapagliflozin is marketed in 40 countries/regions, including the European 
Union (EU; 5 or 10 mg dapagliflozin), United States (5 or 10 mg dapagliflozin), and Australia 
(10 mg dapagliflozin only), and is under investigation for marketing in numerous countries 
around the world. 
The mechanism of action (MOA) for dapagliflozin is different from and complementary to the 
mechanisms of existing medications in other drug classes for T2DM, resulting in the direct, and 
insulin-independent, elimination of glucose by the kidney. Furthermore, as SGLT-2 is almost 
exclusively expressed in the kidney, the highly selective nature of dapagliflozin minimizes the 
risk of off-target (ie, non-kidney) effects. Therefore, no effects are observed on glucose and/or 
other carbohydrate transport or absorption in any other organs, including the gut, and no other 
transporters are affected. As such, dapagliflozin offers an important additional strategy for 
improving glycemic control as an add-on to insulin in patients with T1DM.
Urinary glucose excretion induced by dapagliflozin depends upon the amount of glucose filtered 
by the kidney (Figure 1.1.2-1). This filtered load is the product of the plasma glucose 
concentration and the glomerular filtration rate (GFR). Therefore, the action of dapagliflozin is 
dependent upon the patient’s plasma glucose and renal function, and is independent of the 
patient’s beta cell function or insulin sensitivity, which translates into a relatively low risk of 
hypoglycemia. Furthermore, because the mechanism reduces hyperglycemia independently of 
insulin secretion or action, this approach to antidiabetic therapy provides an opportunity to 
achieve clinically important glycemic efficacy as an add-on to insulin in patients with T1DM.
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Figure 1.1.2-1:
How Dapagliflozin Works (Mechanism of Action)
Multiple Phase 2 and Phase 3 studies, where dapagliflozin was used as monotherapy or in 
combination with other oral hypoglycemic agents or insulin in subjects with T2DM, have shown 
that there is a dose-dependent decrease in fasting plasma glucose (FPG) from baseline to 
Week 12 (Phase 2 studies) and Week 24 (Phase 3 studies) with dapagliflozin treatment. 
Dapagliflozin is also associated with a significant reduction of HbA1c from baseline compared 
to placebo (0.4-0.56% and 0.54-0.68% for the 5 and 10 mg doses, respectively11).
In addition, dapagliflozin as add on therapy to insulin is now being investigated as a potential 
treatment for patients with T1DM with inadequate glycemic control (defined as HbA1c 7.5%). 
Dapagliflozin may be a clinically relevant adjunctive therapy for patients with T1DM given its 
insulin-independent mechanism of action. Because patients with T1DM are insulin deficient, 
insulin treatment is required for preventing ketoacidosis and ultimately for survival. Thus, 
dapagliflozin would not be a replacement for insulin therapy in the setting of T1DM. However, 
dapagliflozin reduces blood glucose levels by an insulin-independent mechanism and may be 
effective in improving glycemic control in patients with T1DM when used in combination with 
insulin. In the T1DM population, the inhibition of urinary glucose reabsorption via SGLT-2 
inhibition is expected to produce a glucose lowering similar to that observed in the T2DM 
population, as well as the modest reductions in blood pressure and body weight. Furthermore, the 
amount of urinary glucose excreted following treatment with dapagliflozin is dependent upon the 
plasma glucose concentration,12 which may serve to blunt the excursions of glucose values over 
the course of the day (reduce glycemic variability).
The potential of dapagliflozin as a treatment option for the T1DM population was explored in a 
Phase 2a pilot study (MB102072). The MB102072 study was a randomized, double-blind, 5-arm, 
parallel-group, placebo-controlled exploratory trial to evaluate the safety, tolerability, 
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pharmacokinetics (PK) and pharmacodynamics (PD) of dapagliflozin in subjects with T1DM 
who had inadequate glycemic control on insulin therapy. Subjects taking insulin monotherapy 
who met the central laboratory enrollment requirement of HbA1c 7.0% and 10.0% were 
randomly assigned in a 1:1:1:1:1 ratio to one of 5 blinded treatment arms: placebo, 1 mg, 2.5 mg, 
5 mg, or 10 mg of dapagliflozin once daily. Subjects received dapagliflozin or matching placebo 
for a total of 14 days and remained confined to the inpatient unit from Day -3 to Day 7, at which 
point they were discharged. Subjects then had outpatient visits on Day 10, Day 14, and a 
discharge visit on Day 21. In this pilot study, dapagliflozin was generally well tolerated at all 
doses in subjects with T1DM. Hypoglycemia events were frequent in this population during 
study treatment. Events were relatively balanced across treatment groups. Consistent with the 
known mechanism of action of dapagliflozin, dose-related increases in 24 hour urinary glucose 
were observed. Based upon the similar PK characteristics in subjects with T1DM compared to 
T2DM or healthy subjects, the exposure response relationship in terms of urinary glucose 
excretion appeared to be virtually identical in this T1DM population to that previously described 
in T2DM subjects, correcting for baseline differences in glycemic control and eGFR between the 
studies. Because dapagliflozin 5 mg was established as the minimally effective dose in T2DM
and the marked similarities in the PK and PD response that drives efficacy, it is expected that 
dapagliflozin 5 mg will also be the minimally effective dose in subjects with T1DM. Evaluation 
of exploratory endpoints suggests a potential for dapagliflozin to improve glycemic control in 
subjects with T1DM as evidenced by:

Dose-related trends toward reduction in FPG at Day 7

Dose-related trends toward reduction in average daily glucose at Day 7 from continuous 
glucose monitoring (CGM)

Trends to reduce glycemic variability over the day as evidenced by reduction in the standard 
deviation of 24-hour glucose values and reduction in the mean amplitude of glucose 
excursion (MAGE) determined from CGM at Day 7

Trends towards increased percentage of CGM readings at Day 7 in the target range 
(> 70 mg/dl to 180 mg/dl)

Trend towards reduction in total daily insulin dose with all dapagliflozin treatment
In completed clinical studies in subjects with both T2DM and T1DM, dapagliflozin was 
generally safe and well-tolerated. No clinically relevant changes from baseline were seen in 
either renal function or serum electrolytes in subjects treated with dapagliflozin. In Phase 2/3 
studies in subjects with T2DM, the frequency of overall AEs was similar to placebo. In the 
Phase 2 study in subjects with T1DM (MB102072), the frequency of overall AEs was similar to 
placebo. Compared to subjects with T2DM, hypoglycemia was more frequent in subjects with 
T1DM, but the frequency of hypoglycemia was relatively balanced across dapagliflozin 
treatment and placebo groups. Urine ketone tests revealed frequent positive urine ketones in this 
study, with a possibly slight increase in subjects receiving dapagliflozin 10 mg. No diabetic 
ketoacidosis (DKA) was observed during the study period (from the start of study drugs to the 
end of follow-up).
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It is expected that dapagliflozin will exhibit an efficacy and safety profile in subjects with T1DM 
that will be similar to that observed in T2DM. In fact, dapagliflozin may be a potentially novel 
adjunct to insulin therapy for the treatment of T1DM. Dapagliflozin potently decreases HbA1c 
and may provide important secondary benefits, such as reductions in total daily insulin dose, 
hypoglycemia, and glycemic variability and may attenuate the weight gain associated with 
insulin use to address important unmet needs for people with T1DM.
1.2
Research Hypothesis 
In subjects with T1DM that have inadequate glycemic control with insulin alone, the addition of 
dapagliflozin to adjustable insulin will result in a greater mean reduction in HbA1c after 
24 weeks of double-blind treatment, as opposed to placebo plus adjustable insulin. In this study, 
adjustments of insulin dose can be made as deemed appropriate to be consistent with good 
clinical practice.
1.3
Objectives
1.3.1
Primary Objectives
The primary objective of this study is to compare the change from baseline in HbA1c between 
dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 
24 weeks of double-blinded treatment.
1.3.2
Secondary Objectives
1.3.2.1
Efficacy
Six secondary efficacy objectives are identified:
1) Compare the percent change from baseline in total daily insulin dose with dapagliflozin 5 mg 
or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of 
double-blinded treatment
2) Compare the percent change from baseline in body weight with dapagliflozin 5 mg or 10 mg 
plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of 
double-blinded treatment
3) Compare the change from baseline in the mean value of 24-hour glucose readings obtained 
from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus 
adjustable insulin after 24 weeks of double-blinded treatment
4) Compare the change from baseline in mean amplitude of glucose excursions (MAGE) of 
24-hour glucose readings obtained from CGM with dapagliflozin 5 mg or 10 mg plus 
adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded 
treatment
5) Compare the change from baseline in the percent of 24-hour glucose readings obtained from 
CGM that falls within the target range of > 70 mg/dL and 180 mg/dL with dapagliflozin 
5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks 
of double-blinded treatment
6) Compare dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable 
insulin for the proportion of subjects achieving an HbA1c reduction from baseline to 
Week 24 visit 0.5% without severe hypoglycemia events
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1.3.2.2
Safety
1) To assess the proportion of subjects with hypoglycemia events and the frequency and 
severity of the hypoglycemia events with dapagliflozin 5 mg or 10 mg plus adjustable insulin 
versus placebo plus adjustable insulin
2) To evaluate the safety and tolerability by assessment of AEs, vital signs, DKA events, 
physical examination findings, ECGs, and laboratory values
1.3.3
Other/Exploratory Objectives
1) Assess the proportion of subjects with HbA1c reduction of at least 0.5% (0.5%) from 
baseline with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus 
adjustable insulin after 24 weeks of double-blinded treatment
2) Assess the proportion of subjects with HbA1c < 7.0% with dapagliflozin 5 mg or 10 mg plus 
adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded 
treatment
3) Assess the change from baseline in FPG with dapagliflozin 5 mg or 10 mg plus adjustable 
insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
4) Assess the change from baseline in the percent of 24-hour glucose readings obtained from 
CGM that is in the hypoglycemic range of 70 mg/dL with dapagliflozin 5 mg or 10 mg plus 
adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded 
treatment
5) Assess the change from baseline in seated systolic blood pressure with dapagliflozin 5 mg or 
10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of 
double-blinded treatment among subjects with hypertension at baseline, defined as seated 
SBP 140 mmHg and/or seated DBP 90 mmHg
6) Assess the change from baseline in average glucose values measured by 6-point (SMBG) 
with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable 
insulin after 24 weeks of double-blinded treatment
7) Assess the change from baseline in postprandial glucose values measured by 6-point self 
SMBG with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus 
adjustable insulin after 24 weeks of double-blinded treatment
8) Assess the change from baseline in postprandial glucose values measured by CGM with 
dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin 
after 24 weeks of double-blinded treatment
9) Assess the change from baseline in standard deviation of 24-hour glucose readings obtained 
from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus 
adjustable insulin after 24 weeks of double-blinded treatment
10) Assess the change from baseline to Week 24 in health status, as measured by the Euro 
Quality of life 5 dimensions 3 levels (EQ-5D-3L) questionnaire, between dapagliflozin 5 mg 
or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of 
double-blinded treatment
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11) Assess the changes from baseline to Week 24 in the summary score for treatment satisfaction 
and scores for perceived frequency of hyperglycemia and perceived frequency of 
hypoglycemia, respectively, as measured by the Diabetes Treatment Satisfaction 
Questionnaire status (DTSQs) between the dapagliflozin 5 mg or 10 mg plus adjustable 
insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
12) Assess the change from baseline to Week 24 in the summary score of fear of hypoglycemia 
as measured by the Hypoglycemia Fear Survey (HFS-II) Worry Subscale between the 
dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin 
after 24 weeks of double-blinded treatment
13) To explore the relationship between observed and/or model estimated pharmacokinetic 
measures of exposure (eg, AUCss, Cmax, Cmin) and efficacy and/or safety endpoints by 
using model-based approaches. This analysis will be provided in a separate report
14) Compare the number of non-severe hypoglycemic events per subject in those achieving an 
HbA1c reduction of 0.5% on dapagliflozin 5 mg or 10 mg plus adjustable insulin versus 
placebo plus adjustable insulin from baseline to Week 24 visit.
1.4
Product Development Background
Dapagliflozin has been designed as a potent and selective inhibitor of the renal sodium-glucose 
transporter, SGLT-2. Multiple Phase 2 and Phase 3 studies, where dapagliflozin was used as 
monotherapy or in combination with other oral hypoglycemic agents or insulin in subjects with 
T2DM, have shown that dapagliflozin is associated with a significant reduction of HbA1c from 
baseline compared to placebo (0.4-0.56% and 0.54-0.68% for 5 and 10 mg doses, respectively). 
Results from the MB102009 and D1690C00006 studies, where dapagliflozin was added in 
subjects with T2DM receiving high doses of insulin, confirmed that dapagliflozin was effective 
in lowering HbA1c when combined with insulin in this population (HbA1c reduction of 
0.6% relative to placebo). 
Overall, dapagliflozin as monotherapy and in combination with other antidiabetic agents
(metformin, sulfonylurea, thiazolidinedione, or insulin) was generally safe and well tolerated in 
subjects with T2DM. In Phase 2/3 studies, the frequency of overall AEs was similar to placebo. 
Most AEs were mild or moderate in intensity and resolved while continuing treatment. No 
clinically relevant changes from baseline were seen in either renal function or serum electrolytes 
in subjects treated with dapagliflozin. The frequency of genital infections and urinary tract 
infections was higher in subjects treated with dapagliflozin. Most of the genital infections and 
urinary tract infections were mild-to-moderate and easily treatable. 
Besides data obtained from subjects with T2DM, results from MB102072, where dapagliflozin 
was added to insulin therapy in subjects with T1DM, showed that dapagliflozin 5 mg and 10 mg 
may improve glycemic control during a 2-week study period while reducing total daily insulin 
dose. In this pilot study, adverse events, including hypoglycemia and genitourinary infections, 
were generally balanced across treatment groups.
Additional clinical safety and efficacy information is available in the Investigator Brochure. 
Revised Protocol No.: 02
Date: 18-May-2016
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1.5
Overall Risk/Benefit Assessment
Dapagliflozin is being developed as a potential new therapy for hyperglycemia in subjects with 
T1DM. Considering the mechanism of action of dapagliflozin, the design features of this study
(ie, the inclusion, exclusion, and discontinuation criteria), and the planned safety procedures, 
participation in this study presents a minimal risk.
As noted above, dapagliflozin has been effective at lowering glucose and HbA1c in subjects with 
T2DM, when studied as monotherapy, as well as in combination with insulin or oral antidiabetic 
medications. In a recently concluded Phase 2a study, the combination therapy of dapagliflozin 
with insulin was assessed in subjects with T1DM with inadequate glycemic control. In that 
study, dapagliflozin was found to be well-tolerated. Results from the study also suggested that 
treatment with dapagliflozin as add-on to insulin may have potential to reduce glucose levels, 
decrease glycemic variability based on CGM, and reduce total daily insulin dose. Similar results 
were also reported in an 8-week study in which empagliflozin was added as an adjunct to insulin 
therapy in subjects with T1DM.13
Potential risks
The potential risks associated with dapagliflozin have been identified based upon the mechanism 
of action, the preclinical results, and the extensive clinical experience to date, including a study 
combining it with insulin when used in subjects with T1DM. The benefits and risks associated 
with the investigational drug and insulin are well established and presented in their approved 
Investigator Brochure and prescribing information respectively. No study procedure will put 
subjects at a risk beyond those ordinarily encountered during the performance of routine medical 
examinations or tests.
Protection against risks
The present study has been designed with appropriate measures in place to monitor and minimize 
any of the potential health risks to participating subjects. In order to ensure the safety of all 
subjects participating in this study, the Sponsor will conduct a real-time review of all safety 
information from all ongoing clinical dapagliflozin studies as it becomes available. Safety signal 
detection will include the integration of all available sources of safety information, including 
clinical study data, AE reports, pre-clinical data, epidemiological studies and literature reports,
and post-marketing reports to identify and characterize unrecognized safety risks or changes in 
those which are currently expected Adverse Drug Reactions. Any information that may affect the 
benefit-risk profile of dapagliflozin will be immediately communicated to relevant health 
authorities and appropriate actions will be taken regarding the clinical program as needed. 
Given the potential increased risk of hypoglycemia when dapagliflozin is added on to insulin, it 
is recommended that subjects reduce their daily insulin doses by up to 20% for both basal and 
bolus insulin after the first dose of study drug on Day 1 following randomization to reduce the 
risk of hypoglycemia. In some cases it may be necessary to reduce insulin (particularly basal 
insulin) in advance of study drug administration. During the study, insulin dose may be adjusted 
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as deemed appropriate to be consistent with good clinical practice according to (SMBG)
readings, local guidance and individual circumstances.
Safety will also be monitored by an external Data Monitoring Committee (DMC) with 
multidisciplinary representation, which will periodically evaluate the incidence of AEs 
(especially events of hypoglycemia and DKA), laboratory measurements, and safety assessments 
to ensure the ongoing safety of study subjects. An independent reporting statistician not involved
in the conduct of the study will be designated by Bristol-Myers Squibb (BMS) to provide the 
DMC with essential safety data during the study. The DMC responsibilities, authorities, and 
procedures will be documented in a DMC charter. 
All studies which include dapagliflozin are subject to a carefully designed subject risk 
management plan. Investigators are also provided guidance on appropriate management of 
potential risks such as hypoglycemia, urinary tract infections and decreased renal function as 
mentioned in the plan. In addition, for this trial, investigators are provided guidance on 
appropriate managements and potentials risks associated with DKA.
Potential benefits to subjects
As noted above, dapagliflozin added to background insulin therapy was well-tolerated in the 
Phase 2 study in subjects with T1DM (MB102072) and had a PK profile similar to the healthy 
and T2DM populations studied previously. Therefore, it is expected that the efficacy and safety 
profile of dapagliflozin in subjects with T1DM will be similar to that observed in T2DM 
subjects. Furthermore, because its mechanism is independent of insulin, dapagliflozin provides 
an opportunity to achieve clinically important glycemic efficacy in subjects with T1DM. In 
addition, all subjects will continue to receive insulin (dose can be adjusted) as active background 
therapy.
Subjects are also expected to receive some benefit in the form of increased medical care/attention 
when participating in study procedures, which includes multiple clinic visits and physical 
examinations over the 52 week study. Subjects will also receive counseling on diet and exercise. 
It is commonly observed that even subjects receiving placebo in diabetes studies show some 
improvement in glycemic control, likely due to their increased compliance to dietary and 
exercise counseling while they are participating in a clinical study. 
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 European Union Directive 2001/20/EC and the United States 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 form will receive Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
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All potential serious breaches must be reported to BMS immediately. A serious breach is defined 
as a violation 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 validity 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 (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
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 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS/AZ should provide the IRB/IEC with reports, updates and other 
information (eg, 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. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form 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 most 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. 
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4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form 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 HIPAA Authorization.
The consent form must also include a statement that BMS 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 informed consent 
form 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.
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
This trial is a randomized, double-blinded, three-arm, parallel-group, placebo-controlled, 
multicenter trial to evaluate the efficacy and safety of dapagliflozin, when added to ongoing 
insulin therapy, in subjects with T1DM and inadequate glycemic control. 
Potential subjects will be assessed for eligibility criteria at the screening visit. Eligible subjects 
will enter an 8-week lead-in period in order to optimize their diabetes management and assess 
the variability in blood glucose profiles and frequency of hypoglycemic episodes at baseline. No 
placebo or study medication will be provided during the lead-in period. On Day 1, subjects who 
meet all the protocol-specific enrollment and randomization inclusion criteria and meet none of 
the exclusion criteria will be randomized into one of the three blinded treatment arms 
(dapagliflozin 5 mg QD, dapagliflozin 10 mg QD, or placebo QD) in a 1:1:1 ratio. 
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Randomization will be stratified by the following factors to ensure equal representation across all 
treatment groups:

Current use of CGM (this refers to an unblinded/personal device already being used, in 
addition to the blinded CGM device that will be required for participation in the study. 
Current use of CGM will be categorized as yes vs no)

Method of insulin administration at baseline (multiple daily injections [MDI] defined as three 
or more injections per day vs continuous subcutaneous insulin infusion [CSII])

Week -1 Visit (Baseline) A1C 7.5% and < 9.0% vs 9.0% and 10.5%
Subjects will receive dapagliflozin 5 mg QD, 10 mg QD, or placebo QD for 24 weeks, followed 
by a 28-week subject and site blinded long-term treatment period. Besides study medications, 
subjects will be treated with MDI (3 or more injections per day of basal and prandial insulin) or 
CSII. 
It is recommended that subjects reduce their daily insulin dose by up to 20% for both basal and 
bolus insulin after the first dose of study medication to minimize the risk of hypoglycemia. In 
some cases it may be necessary to reduce insulin (particularly basal insulin) in advance of study 
drug administration. It is at the discretion of the investigator to determine the extent to 
which to reduce the insulin doses. Throughout the study (from the beginning of the lead-in 
period to the end of the long-term treatment period), insulin dose may be adjusted as deemed 
appropriate to be consistent with good clinical practice according to SMBG readings, local 
guidance, and individual circumstances. Subjects will be monitored closely with regard to safety 
parameters, including vital signs, safety laboratory tests, ECGs, and AEs.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
Notes:

Eligible subjects should have the Day 1 randomization visit within 56 5 days of the 
Week -8 entry into lead-in period visit

Subjects will receive the last dose of study medications at the Week 52 Visit and they will 
have the follow-up visit at Week 56 (30 days after the Week 52 visit)
3.2
Post Study Access to Therapy
At the end of the study, BMS/AZ will not continue to provide BMS supplied study drug to 
subjects/investigators unless BMS/AZ 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 their legally responsible representatives must be willing and able to give 
signed and dated written informed consent
b) Not applicable per Protocol Amendment 03 - Subjects from Japan 18 years old and 
< 20 years old must have assent forms signed and dated by their parents or guardians
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2) Target Population
a) Diagnosis of T1DM. In addition, the following criteria also needs to be met;
i)
Central laboratory test of C-peptide < 0.7 ng/ml (0.23 nmol/L)
b) Subject re-enrollment: This study does not permit the re-enrollment of a subject who has 
discontinued the study as a screen or lead-in failure
Note: Subjects who did not fail any of the screening or lead-in criteria and are not 
subsequently randomized within the applicable study visit windows (e.g. due to a planned 
medical procedure, vacation plans, or employment commitments) may rescreen after 
discussion and approval by the Sponsor.
3) Insulin use for at least 12 months prior to screening per subject report or medical records and
a) Method of insulin administration (MDI or CSII) must have been unchanged for at least 
3 months prior to the screening visit per subject reported or medical records. Subjects 
must be taking a total insulin dose of 0.3 U/kg/day for at least 3 months prior to the 
screening visit
b) If on MDI insulin administration, subject must be taking 3 injections per day
4) HbA1c eligibility criteria include:
a) Screening visit: Central laboratory HbA1c 7.7% and 11.0% 
Note: a one-time repeat HbA1C is allowed for subjects in screening if their initial result 
is within 0.2% of the cut off values 
b) Week -1 Visit: Central laboratory HbA1c 7.5 % and 10.5%
Note: a one-time repeat HbA1C is allowed for subjects in lead-in if their test result is 
within 0.2% of the cut off values
To ensure adequate time is given to complete the repeat Week -1 A1C, a 7 day window 
(added to the current lead-in period window of 56 + 5 days) will be allowed
5) Body mass index (BMI) 18.5 kg/m²
6) Age and reproductive status
a) Men and women, ages 18 to 75 years, inclusive
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of investigational product
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with dapagliflozin plus 4 days (> 5 half-lives of dapagliflozin) plus 30 days 
(duration of ovulatory cycle) for a total of 34 days post-treatment completion
e) Males who are sexually active with WOCBP must agree to the following instructions for 
the duration of treatment with dapagliflozin plus 4 days (>5 half-lives of dapagliflozin) 
plus 90 days (duration of sperm turnover) for a total of 94 days post-treatment completion
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Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of one method of highly effective contraception 
listed below:

Male condoms with spermicide14

Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirenaby WOCBP 
subject or male subject’s WOCBP partner. Female partners of male subjects participating in 
the study may use hormone-based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug

Non-hormonal IUDs, such as ParaGard®

Tubal ligation (not considered surgically sterile, see section 3.3.3)

Vasectomy

Complete abstinence*
*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.
Azoospermic males and WOCBP who are continuously not heterosexually active are exempt 
from contraceptive requirements. However, females must still undergo pregnancy testing as 
described in this section.
3.3.2
Exclusion Criteria
1) Target Disease Exceptions
a) History of T2DM
Note: subjects with a previous misdiagnosis of T2DM in their medical history must have one 
of the following in order to be eligible for this trial:

Positive autoantibodies for GAD65, phosphatase IA-2/IA2β, or zinc transporter 8 (ZnT8) 
(eg, autoimmune diabetes) 

Fasting c-peptide value below the lower limit of detection performed by the Central 
Laboratory 
b) History of maturity-onset diabetes of the young (MODY)
c) Pancreatic surgery, chronic pancreatitis, or other pancreatic disorders that could result in 
decreased -cell capacity (eg, pancreatogenous diabetes)
d) Previous use of dapagliflozin and/or any other SGLT-2 inhibitors
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e) Use of insulin-sensitizing agents, such as metformin and/or thiazolidinediones, within 
2 months prior to the screening visit
f)
Use of any GLP-1 receptor agonist within the following timeframe prior to the screening 
visit:

1 month for once or twice daily administration (eg, liraglutide)

2 months for once weekly administration
g) Use of any non-insulin antihyperglycemic agent within 1 month prior to the screening 
visit
h) History of DKA requiring medical intervention (eg, emergency room visit and/or 
hospitalization) within 1 month prior to the screening visit
i)
History of hospital admission for glycemic control (either hyperglycemia or 
hypoglycemia) within 1 month prior to the screening visit
j)
Frequent episodes of severe hypoglycemia as defined by more than one episode requiring 
medical assistance, emergency care (paramedics or emergency room care), and/or 
glucagon therapy administered by a third-party individual within 1 month prior to the 
screening visit
k) Symptoms of poorly controlled diabetes that would preclude participation in this trial 
including, but not limited to, marked polyuria and polydipsia with greater than 
10% weight loss during the 3 months prior to the screening visit, or other signs and 
symptoms of poor glycemic control
l)
History of Addison’s disease or chronic adrenal insufficiency
m) History of diabetes insipidus
2) Medical History and Concurrent Diseases
a) Any of the following cardiovascular (CV)/vascular disease within 6 months of the 
screening visit:
1. Myocardial infarction
2. Cardiac 
surgery 
or 
revascularization 
(coronary 
artery 
bypass 
surgery 
[CABG]/percutaneous transluminal coronary angioplasty [PTCA])
3. Unstable angina
4. Unstable congestive heart failure (CHF)
5. New York Heart Association (NYHA) CHF Class III or IV
6. Transient ischemic attack (TIA) or significant cerebrovascular disease 
7. Unstable or previously undiagnosed arrhythmia
b) Renal disease:
1. History of unstable or rapidly progressing renal disease
2. Conditions of congenital renal glucosuria
3. Renal allograft
c) Hepatic diseases:
1. Significant hepatic disease, including, but not limited to, chronic active hepatitis 
and/or severe hepatic insufficiency
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d) Hematological and oncological disease/conditions:
1. History of hemoglobinopathy, with the exception of sickle cell trait (SA) or 
thalassemia minor; or chronic or recurrent hemolysis
2. Known immunocompromised status, including but not limited to, individuals who 
have undergone organ transplantation or who are positive for the human 
immunodeficiency virus
3. Donation of blood or blood products to a blood bank, blood transfusion, or 
participation in a clinical study requiring withdrawal of > 400 mL of blood during the 
8 weeks prior to the screening visit
4. Malignancy within 5 years of the screening visit (with the exception of treated basal 
cell or treated squamous cell carcinoma)
5. History of bladder cancer
6. History of radiation therapy to the lower abdomen or pelvis at any time
3) Physical and Laboratory Test Findings
a) Aspartate aminotransferase (AST) > 3x upper limit of normal (ULN)
b) Alanine aminotransferase (ALT) > 3x ULN
c) Serum total bilirubin (TB) > 2x ULN unless exclusively caused by Gilbert’s Syndrome
d) Calculated creatinine clearance (CrCl) < 60 mL/min as estimated by the Cockcroft-Gault 
formula, using laboratory measurements of serum creatinine collected at the screening 
visit [Creatinine clearance = [[140 - age(yr)]*weight(kg)/[72*serum Cr(mg/dl)] (multiply 
by 0.85 for women)]
e) Hemoglobin 11.0 g/dL (110 g/L) for men; hemoglobin 10.0 g/dL (100 g/L) for 
women
f)
Positive for hepatitis B surface antigen or anti-hepatitis C virus antibody
g) Abnormal Free T4
NOTE: abnormal TSH value at enrollment will be further evaluated for free T4. Subjects 
with abnormal free T4 values will be excluded. A one-time retest may be allowed, as 
determined by the investigator, after a minimum of 6 weeks following the adjustment of 
thyroid hormone replacement therapy in subjects who have had a prior diagnosis of a thyroid 
disorder and who are currently receiving thyroid 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.
4) Allergies and Adverse Drug Reaction
a) Allergies or contraindication to the contents of dapagliflozin tablets or insulin
5) Sex and Reproductive Status
a) Women who are pregnant
6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
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b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Subjects on a commercial weight loss program with ongoing weight loss, or on an 
intensive exercise program
d) History of bariatric surgery or lap-band procedure within 12 months prior to screening
e) Replacement or chronic systemic corticosteroid therapy, defined as any dose of systemic 
corticosteroid (including local injections such as intramuscular or intra-articular, etc.) 
taken for > 4 weeks within 3 months prior to the Day 1 visit
NOTE: Topical (including drops) or inhaled corticosteroids are allowed
f)
Any unstable endocrine, psychiatric or rheumatic disorders as judged by the investigator
g) Volume-depleted subjects. Subjects at risk for volume depletion due to co-existing 
conditions or concomitant medications, such as loop diuretics who cannot carefully 
monitor their volume status should be excluded from the study
h) Subject who, in the judgment of the investigator, is found to be unlikely to comply with 
the protocol, or is unable to correctly administer subcutaneous insulin injections and/or 
manage their insulin pump, or has any severe concurrent medical or psychological 
condition that may affect the interpretation of efficacy or safety data (including during 
the lead-in period)
i)
Subject with any condition which, in the judgment of the investigator, may render the 
subject unable to complete the study or which may pose a significant risk to the subject
j)
Subject is currently abusing alcohol or other drugs or has done so within the last 
6 months prior to the Day 1 visit
k) Subject is a participating investigator, study coordinator, employee of an investigator or 
immediate family member of any of the aforementioned
l)
Employee of BMS, AstraZeneca (AZ), or their relatives
m) Administration of any other investigational drug within 30 days of the screening visit
n) No clinical conditions or clinically significant abnormalities in any laboratory value(s) 
collected after screening and prior to randomization which, in the investigator’s 
judgment, should preclude entry into the treatment period
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 (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of 
amenorrhea in a woman over age 45 years in the absence of other biological or physiological 
causes. In additional, women under the age of 55 years must have a serum follicle stimulating 
hormone, (FSH) level > 40mIU/mL to confirm menopause.*
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*Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and investigators should use their judgment 
in checking serum FSH levels. If the washout period exceeds 4 weeks, the subject must have all 
enrollment procedures and laboratory assessments repeated and all of these must meet 
enrollment eligibility criteria. The subject’s number will however remain the same as initially 
assigned. If the serum FSH level is > 40 mIU/ml at any time during the washout period, the 
woman can be considered postmenopausal:

1 week minimum for vaginal hormonal products, (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
Once enrolled, subjects may not receive any of the following for the duration of the screening 
(qualification period), lead-in, double-blinded short-term and subject and site blinded long-term 
treatment periods:

Antihyperglycemic medication (other than protocol required medication)

Weight loss medication

Newly initiated treatment with any systemic corticosteroid therapy (including local injections 
such as intramuscular or intra-articular,etc.) that will involve 5 days of therapy is not 
permitted (inhaled and topical, including drops, are allowed). The Medical Monitor should be 
consulted prior to beginning therapy with corticosteroids for subjects who require systemic 
corticosteroid treatment

Acetaminophen (paracetamol) containing medications (such as Tylenol) while using the 
CGM device and 24 hours prior to insertion
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 medication or 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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
Subjects must make every attempt to adhere to the diet and exercise counseling 
(see Section 5.9.3) and to the study flow chart/time and event schedule (see Section 5.1)

Women of child-bearing 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 
(see Section 6.4)
3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Withdrawal of informed consent (subject’s decision to withdraw for any reason)

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 Bristol-Myers Squibb (BMS)/AstraZeneca (AZ)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Unblinding a subject for any reason (emergency or non-emergency)

Pregnancy

Creatinine clearance < 30 mL/min

If at any time the subject´s CrCl (based on Cockroft-Gault) falls below 30 mL/min 
calculated at the central laboratory and confirmed at a repeated central laboratory 
measurement (to be obtained within 4 days, whenever possible), the subject should be 
discontinued from study medication.

If at any time the subject´s CrCl (based on Cockroft-Gault) falls below 30 mL/min 
calculated at local laboratory, a central laboratory CrCl should be obtained promptly. If 
the CrCl is confirmed by the central laboratory and persists at a repeated central 
laboratory measurement (to be obtained within 4 days, whenever possible), the subject 
should be discontinued from study medication.

Subjects experience at least one protocol-defined hypoglycemia episode that leads to a loss 
of consciousness and/or seizure as determined by the investigator (see Section 3.5.1)

Change of insulin administration method (eg, switch from MDI to CSII or vice versa)
Note: Subjects are not allowed to change their insulin administration methods (MDI or CSII) 
throughout the study. Under certain situations (eg, the replacement of an insulin pump), the 
subjects who are on CSII may be on temporary use of MDI. They should restart CSII 
administration as early as feasible. The period of time when a subject is on temporary use of 
MDI should not be more than 2 weeks
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
Subjects with a central laboratory ALT and/or AST > 3x ULN will be scheduled for a 
follow-up visit within 3 days following the receipt of the result (see Appendix 3 for further 
guidance). Subjects should be discontinued from study if the initial and repeat laboratory 
tests meet any of the following criteria:

ALT and/or AST are > 3x ULN and total bilirubin (TB) > 2x ULN

ALT and/or AST are > 5x ULN for 14 consecutive days, at any time after initial 
confirmatory results

ALT and/or AST are 10x ULN
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5 with the exception of the study drug and PK procedures. The 
only exception to this requirement is when a subject withdraws consent for all study procedures 
including post-treatment study follow-up or loses the ability to consent freely (ie, 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 case report form (CRF) page.
3.5.1
Discontinuation Guidelines due to Protocol-Defined Hypoglycemia 
Episode or Recurrent Hypoglycemia Episodes
Subjects should not be discontinued from any treatment phase based on single episodes of 
hypoglycemia or symptoms of hypoglycemia unless clinically indicated (see the criteria below). 
The assessment of a single capillary glucose measurement (eg, fingerstick) or central laboratory 
glucose value should not be the sole assessment used to determine subject discontinuation due to 
hypoglycemia.
Subjects should be discontinued from study drug if they meet any of the following criteria:

At least one hypoglycemia episode that leads to loss of consciousness and/or seizure

Severe/recurrent hypoglycemia episodes where the possibility of down-titration of 
contributing concomitant medication(s) (other than double-blind study medication), and/or 
contributing factors (eg, excessive physical activity) have been evaluated and corrected. 
NOTE: Dose titration of double-blind study drug is not permitted at any time during the 
short-term and long-term treatment period.
Section 5.3.2.2 provides additional guidance on management and reporting of hypoglycemia.
3.6
Post Study Drug Study Follow up
In this study, safety is a key endpoint of the study. Post treatment 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 outcomes and/or 
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survival follow-up data as required and in line with Section 5 until death or the conclusion of the 
study.
Therefore as such, all subjects who discontinue investigational product in the 24-week 
double-blinded short-term treatment period or in the subject- and site-blinded long-term 
treatment period should be asked to continue study participation for each scheduled visit for the 
remaining length of the study and complete all procedures as outlined in the Section 5 study 
flowchart, with the exception of study drug management and PK sampling. If continued study 
participation according to the protocol schedule is not possible, the investigator should contact 
the subject to discuss alternatives (eg, return to the clinic 30 days after discontinuation of study 
drug to perform the Week 56 visit post-treatment follow-up procedures as outlined in the 
Section 5 study flowchart or be contacted by telephone 30 days after discontinuation of study 
drug to evaluate the following safety assessments: AEs, hypoglycemia events, and DKA 
episodes. Please note that after the discontinuation of study drug, management of a subject’s 
diabetes would be under the care and direction of the investigator and/or subject’s healthcare 
providers.
The only exception to any of these follow-up methods are when a subject withdraws consent for 
all study procedures, including post-treatment study follow-up, or loses the ability to consent 
freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or 
physical illness).
Please utilize the Off-Treatment Short-Term and Off-Treatment Long-Term eCRF pages for this 
data completion.
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 the subject to provide this information withdraws consent. 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.
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 is defined as 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.
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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 subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. 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.
4
STUDY DRUG
Study drugs include both non-investigational medicinal products (NIMP) and investigational 
medicinal products (IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)
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Table 4-1:
Study Drug for MB102230 - Product Description - Double-blinded Short-term Treatment and Subject 
and Site Blinded Long-term Treatment Period
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging/ Appearance
Storage Conditions
(per label)
Dapagliflozin film-coated 
tablet a
5 mg
IP
Blinded
Green, plain, diamond 
shaped, film coated tablet
(reference footnote below for 
packaging)
Store at 15-25 degrees Celsius 
(59-77 degrees Fahrenheit); store 
in tightly closed container
Placebo for dapagliflozin 
film- coated tablets b
0 mg
IP
Blinded
Green, plain, diamond 
shaped, film coated tablet
(reference footnote below for 
packaging)
Store at 15-25 degrees Celsius 
(59-77 degrees Fahrenheit); store 
in tightly closed container
Insulin
Varies
Non-IMP
Open Label
Based on manufactured 
product specifications
Based on manufactured product 
specifications
a Blinded 
dapagliflozin 
10 mg 
kit 
contains 
2 
bottles 
of 
dapagliflozin 
5 mg 
film-coated 
tablets 
(35 count)
Blinded dapagliflozin 5 mg kit contains 1 bottle of dapagliflozin 5 mg film-coated tablets (35 count) and 1 bottle of placebo for dapagliflozin film-coated 
tablets (35 count)
b Blinded placebo kit contains 2 bottles of placebo for dapagliflozin film-coated tablets (35 count)
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product (IMP) in some 
regions, is defined as 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 investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational products are: (also described in Table 4-1) dapagliflozin 5 mg 
and matching placebo tablets; insulin will not be provided by the Sponsor since it is part of the 
subject’s standard of care.

Blinded dapagliflozin 5 mg and 10 mg dose administered orally for the 24-week
double-blinded short-term treatment period, and the 28-week subject- and site-blinded 
long-term treatment period of the study

Matching placebo dose administered orally for the 24-week double-blinded short-term 
treatment period, and the 28-week subject- and site-blinded long-term treatment period of the 
study.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventive, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
In this protocol, non-investigational product is: insulin.
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 BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS 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 (eg, required diluents, administration sets).
4.4
Method of Assigning Subject Identification
 
 
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4.4.1
Subjects entering the 24-week double-blinded short-term treatment 
period 
Following completion of the lead-in period, subjects who meet the criteria will be randomly 
assigned by the IVRS at the Day 1 (randomization) visit, to one of the following 3 double-blind 
treatment arms in a 1:1:1 ratio using a centralized blocked randomization schedule: 
1) Blinded dapagliflozin 5 mg
2) Blinded dapagliflozin 10 mg
3) Blinded placebo
Randomization will be stratified by:

Current use of CGM (this refers to an unblinded/personal device already being used, in 
addition to the blinded CGM device that will be required for participation in the study. 
Current use of CGM will be categorized as yes vs no)

Method of insulin administration at baseline (multiple daily injections [MDI] three or more 
injections per day vs continuous subcutaneous insulin infusion [CSII])

Week -1 Visit (Baseline) HbA1c 7.5% and < 9.0% vs 9.0% and 10.5%
Randomization schedules for both subject treatment and kits will be generated and kept by BMS.
4.4.2
Subjects entering the 28-week long-term subject and site blinded 
treatment period 
Following completion of the 24-week double-blinded treatment period, subjects eligible for the 
long-term subject- and site-blinded treatment period will be continue in their same randomization 
assignment based on their original randomization grouping. Subjects that were assigned to the 
blinded dapagliflozin 5 mg arm will continue to receive blinded dapagliflozin 5 mg. Subjects that 
were assigned to the blinded dapagliflozin 10 mg arm will continue to receive blinded 
dapagliflozin 10 mg and subjects that were assigned to the blinded placebo arm will continue to 
receive blinded placebo. At all study visits when study drug is dispensed, each subject will be 
assigned a kit number by the IVRS. Kit numbers will be assigned non-sequentially and will 
correspond to the numbers printed on the containers and bottles containing study drug, and will 
be recorded on the appropriate eCRF. The IVRS will be available 24 hours per day, 7 days a 
week. Randomization schedules for both subject treatment and kits will be generated and kept by 
BMS.
4.5
Selection and Timing of Dose for Each Subject
Dapagliflozin 5 mg, 10 mg, or placebo will be administered orally, once daily for the 24-week 
double-blinded short-term treatment period and the 28-week subject- and site-blinded long-term 
treatment period.
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Date: 18-May-2016
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CCI

Clinical Protocol
MB102230
BMS-512148
dapagliflozin
4.6
Blinding/Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product 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 (ie, that it will alter the subject's immediate 
management). In many cases, particularly when the emergency is clearly not related to the 
investigational product, 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 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 the IVRS.
For information on how to unblind in case of an emergency, consult the IVRS manual.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
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 the subject’s interview and a count of the 
tablets returned. Compliance should be between 80% and 120%. The investigator 
(or designee) will record the amounts of study medication dispensed and returned at each visit, as 
well as document the 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. If the subject is not 80% compliant, the period of non compliance should be noted as a 
protocol deviation and the Sponsor should be notified. The subject should be re-educated 
regarding treatment compliance and/or recording dose.
4.8
Destruction and Return of Study Drug
4.8.1
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site.
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics).
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
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 (SOPs) and a copy provided to BMS 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 of the containers. 
The method of disposal (ie, 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 BMS/Contract Research Organization 
(CRO) Study Monitor will make arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty and partially full 
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.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible BMS/CRO Study Monitor.
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.
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Flow chart for Protocol MB102230 - Qualification and Lead-in Period
Procedure
Qualification Period 
Screening Visita
Lead-in Period (8 Weeks) 
Notes
Week -8b
Week-4b,c
Week -2 b
Week -1d
Eligibility Assessments
Subject reports to site
X
X
X
X
X
Obtain informed consent
X
Review inclusion/exclusion 
criteria
X
X
Review medical history
X
General Procedures
Complete physical exam
X
Includes general appearance, head, eyes, 
ears, nose, throat, neck, cardiovascular, 
lungs, abdomen, lymph nodes, extremities, 
neurological, skin, and musculoskeletal.
Brief physical exam
X
X
Includes cardiovascular, lungs, abdomen, 
and extremities, and any organ systems 
pertinent to the subject’s signs, symptoms, 
or AEs
Body weight
X
X
X
Height
X
Body mass index (BMI)
X
Electrocardiogram (ECG)
X
Blood pressure and heart rate
X
X
X
3 replicate measurements obtained at least 1 
minute apart
Review concomitant 
medications/procedures
X
X
X
X
X
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-1:
Flow chart for Protocol MB102230 - Qualification and Lead-in Period
Procedure
Qualification Period 
Screening Visita
Lead-in Period (8 Weeks) 
Notes
Week -8b
Week-4b,c
Week -2 b
Week -1d
Contact IVR system
X
X
Provide dietary and exercise 
counseling
X
X
X
X
Dispense subject diaries and 
provide instructions
X
X
X
X
Review subject diaries 
X
X
X
Adjust insulin dose (as needed)
X
X
X
X
Dispense glucose and ketone 
meter and strips and provide 
training 
X
Dispense glucose and ketone 
strips 
X
Insert/calibrate CGM
Xe
If a lead-in subject fails lead-in prior to the 
Day 1 visit, the CGM will not be required to 
be completed between the week-2 visit and 
the Day 1 visit  (Please refer to Section 
5.9.4.3)
Replace CGM sensor, 
download data to review 
compliance, and provide 
training
Xe
Record Meals for 7 days -
Second week of CGM.
Xe
If a lead-in subject fails lead-in prior to the 
Day 1 visit, the CGM will not be required to 
be completed between the week-2 visit and 
the Day 1 visit  (Please refer to Section 
5.9.4.3)
6-point SMBG profiles 
X
If a lead-in subject fails prior to the Day 1 
visit, the 6-point SMBG profile will not be 
required between the week -1 visit and the 
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-1:
Flow chart for Protocol MB102230 - Qualification and Lead-in Period
Procedure
Qualification Period 
Screening Visita
Lead-in Period (8 Weeks) 
Notes
Week -8b
Week-4b,c
Week -2 b
Week -1d
Day 1 visit
Please refer to Section 5.9.4.2 in protocol
Safety Assessmentsf
Assess AEs
X
X
X
X
Assess hypoglycemia episodes
X
X
X
X
Assess DKA
X
X
X
X
Laboratory Assessments
Blood standard safety 
laboratory panel
X
Urine standard safety panel 
(dipstick)
X
X
Pregnancy test (serum) 
WOCBP only
X
Pregnancy test (urine) WOCBP 
only
Xg
Xg
Spot urine for glucose, albumin 
and creatinine quantification 
and determination of glucose: 
creatinine and 
albumin:creatinine ratios
X
Fasting plasma glucose
X
C-peptide
X
HbA1c
X
X
Hepatitis screen panel
X
TSH
X
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-1:
Flow chart for Protocol MB102230 - Qualification and Lead-in Period
Procedure
Qualification Period 
Screening Visita
Lead-in Period (8 Weeks) 
Notes
Week -8b
Week-4b,c
Week -2 b
Week -1d
Fasting serum lipids
X
a Screening visit may consist of 2 days. Second day is to collect lab work. The length of the Qualification period is 28 days.
b Week -8 visit needs to be within 28 days of screening visit. Week -4 visit and Week -2 visit may be scheduled 3 days to allow flexibility of scheduling.
c Optional Phone Visit - Week -4 visit can be done as a phone visit to allow flexibility for the subject in visit scheduling. If a phone visit is done, the home 
pregnancy kit and new week -4 visit diary should be given to the subject at the week -8 visit as well as additional glucose and ketone strips, if needed. Copies 
of completed diaries must be sent (scan, photo, fax) into the site prior to the phone visit so discussions can occur between the subject and site personnel about 
the data captured in the diaries.
d Week -1 visit should be scheduled at least 7 days but not longer than 10 days after Week -2 visit to accommodate for CGM data collection.
e If a lead-in subject fails lead-in prior to the Day 1 visit, the CGM and Meal Recording will not be required to be completed
f These safety assessments; review of AEs, hypoglycemia events, and DKA episodes to be performed throughout the study according to the visit schedule as 
noted via “X”
g If an optional phone visit is planned for week -4, the home pregnancy kit should be given to the subject at the week -8 visit.
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-2:
Flow chart for Protocol MB102230 - 24-week Double-blinded Short-term Treatment Period
Procedure
24-week Double-blinded Short-term Treatment Period
Notes
Day 1a
Day 2
(Phone Visit)
Day 4
(Phone Visit)b
Week 1b
Day 10
(Phone Visit)b
Week 2c,d
Week 4c
Week 8 c
Week 10 c,e
Week 12f
Week 18c
Week 22c, e
Week 24/Early 
Term Visitg
Eligibility 
Assessments
Subject reports to site
X
X
X
X
X
X
X
X
X
X
Review 
inclusion/exclusion 
criteria
X
Review medical history
X
General Procedures
Brief physical exam
X
X
Includes 
cardiovascular, 
lungs, abdomen, 
and extremities, 
and any organ 
systems 
pertinent to the 
subject’s signs, 
symptoms, or 
AEs
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-2:
Flow chart for Protocol MB102230 - 24-week Double-blinded Short-term Treatment Period
Procedure
24-week Double-blinded Short-term Treatment Period
Notes
Day 1a
Day 2
(Phone Visit)
Day 4
(Phone Visit)b
Week 1b
Day 10
(Phone Visit)b
Week 2c,d
Week 4c
Week 8 c
Week 10 c,e
Week 12f
Week 18c
Week 22c, e
Week 24/Early 
Term Visitg
Complete physical 
exam
X
X
Includes general 
appearance, 
head, eyes, ears, 
nose, throat, 
neck, 
cardiovascular, 
lungs, abdomen, 
lymph nodes, 
extremities, 
neurological, 
skin, and 
musculoskeletal.
Body weight
X
X
X
X
X
X
X
X
Blood pressure and 
heart rate
X
X
X
X
X
X
X
X
3 replicate 
measurements 
obtained at least 
1 minute apart
ECG
X
X
Review concomitant 
medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-2:
Flow chart for Protocol MB102230 - 24-week Double-blinded Short-term Treatment Period
Procedure
24-week Double-blinded Short-term Treatment Period
Notes
Day 1a
Day 2
(Phone Visit)
Day 4
(Phone Visit)b
Week 1b
Day 10
(Phone Visit)b
Week 2c,d
Week 4c
Week 8 c
Week 10 c,e
Week 12f
Week 18c
Week 22c, e
Week 24/Early 
Term Visitg
Insert/calibrate CGM
Xh
Xh
At Week 10 & 
22. If subject is 
an early 
termination, 
then CGM is not 
required. If 
week 10 and 
week 22 are 
optional phone 
visits, please 
refer to footnote 
e below and 
Section 5.9.4.3
CGM.
CGM Data collection, 
data upload, and 
review
X
Xh
Xh
At Week12 & 
24. CGM Data 
Collection not 
needed if at 
Week 10/22 
visit CGM 
insertion was 
not completed
Please refer to 
Section 5.9.4.3
Record Meals for 7 
days - Second week of 
CGM.
Xh
Xh
Please refer to 
Section 5.9.4.3
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-2:
Flow chart for Protocol MB102230 - 24-week Double-blinded Short-term Treatment Period
Procedure
24-week Double-blinded Short-term Treatment Period
Notes
Day 1a
Day 2
(Phone Visit)
Day 4
(Phone Visit)b
Week 1b
Day 10
(Phone Visit)b
Week 2c,d
Week 4c
Week 8 c
Week 10 c,e
Week 12f
Week 18c
Week 22c, e
Week 24/Early 
Term Visitg
6-point SMBG profiles 
X
Xh
Xh
See Section 
5.9.4.2
Provide dietary and 
exercise counseling
X
X
X
X
X
X
X
X
Dispense subject 
diaries and provide 
instructions
X
X
X
X
Xi
X
X
Xi
X
X
At Day 1, 
collect Lead-In 
Period diaries 
and dispense the 
first diaries in 
the Short Term 
Treatment 
Period
Re-dispense blood 
glucose and ketone 
strips and provide 
training (as needed)
X
X
X
X
X
X
Review subject diaries 
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust insulin dose (as 
needed)
Xj
X
X
X
X
X
X
X
X
X
X
X
X
Collection of short-
term diaries. Dispense 
long-term diaries.
X
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-2:
Flow chart for Protocol MB102230 - 24-week Double-blinded Short-term Treatment Period
Procedure
24-week Double-blinded Short-term Treatment Period
Notes
Day 1a
Day 2
(Phone Visit)
Day 4
(Phone Visit)b
Week 1b
Day 10
(Phone Visit)b
Week 2c,d
Week 4c
Week 8 c
Week 10 c,e
Week 12f
Week 18c
Week 22c, e
Week 24/Early 
Term Visitg
Administer EQ-5D-3L,
DTSQs, and HFS-II
X
X
Completed prior 
to any other 
procedures. For 
Day 1 visit 
assessment to be 
completed prior 
to first dose
Safety Assessmentsk
Assess AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess hypoglycemia 
episodes
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess DKA
X
X
X
X
X
X
X
X
X
X
X
X
X
Revised Protocol No.: 02
Date: 18-May-2016
55
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-2:
Flow chart for Protocol MB102230 - 24-week Double-blinded Short-term Treatment Period
Procedure
24-week Double-blinded Short-term Treatment Period
Notes
Day 1a
Day 2
(Phone Visit)
Day 4
(Phone Visit)b
Week 1b
Day 10
(Phone Visit)b
Week 2c,d
Week 4c
Week 8 c
Week 10 c,e
Week 12f
Week 18c
Week 22c, e
Week 24/Early 
Term Visitg
Laboratory 
Assessments
Pregnancy test (urine) 
WOCBP only
X
X
X
X
X
X
X
Home 
pregnancy test 
kits sent home 
with WOCBP 
subjects to 
perform 
monthly 
pregnancy tests 
between visits 
and record 
results
Blood standard safety 
laboratory panel
X
X
X
X
X
X
Urine standard safety 
panel (dipstick)
X
X
X
X
Spot urine for glucose, 
albumin and creatinine 
quantification and 
determination of 
glucose: creatinine and 
albumin:creatinine 
ratios
X
X
X
X
FPG
X
X
X
X
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-2:
Flow chart for Protocol MB102230 - 24-week Double-blinded Short-term Treatment Period
Procedure
24-week Double-blinded Short-term Treatment Period
Notes
Day 1a
Day 2
(Phone Visit)
Day 4
(Phone Visit)b
Week 1b
Day 10
(Phone Visit)b
Week 2c,d
Week 4c
Week 8 c
Week 10 c,e
Week 12f
Week 18c
Week 22c, e
Week 24/Early 
Term Visitg
FFA
X
X
A1C
X
X
X
X
X
Fasting serum lipids
X
X
X
PK sampling
X
X
Xl
Refer to Section 
5.5
Clinical Drug Supply
Randomize
X
Dispense study drug
X
X
X
X
X
Contact IVR system
X
Xm
Xm
Xm
Xm*
*Also, call if 
subject is 
having an early 
termination visit
Review study 
medication compliance
X
X
X
X
X
X
X
X
Review study drug 
dosing 
X
X
X
a Day 1 visit should be within 56 days +/- 5 days of the Week -8 visit. If a retest of A1C is done at Week -1, a 7 day window (added to the current lead-in period 
window of 56+5 days) will be allowed
b Visits may be scheduled 1 days to allow flexibility of scheduling.
c Visits may be scheduled 3 days to allow flexibility of scheduling.
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
d Optional Phone Visit - Week 2 visit can be done as a phone visit to allow flexibility for the subject in visit scheduling. If a phone visit is done, the blood 
pressure, heart rate and body weight will not be done. A new week 2 diary should be given to the subject at the week 1 visit. Copies of completed diaries must 
be sent (scan,photo,fax) into the site prior to the phone visit so discussions can occur between the subject and site personnel about the data captured in the 
diaries
e Optional Phone Visit - Week 10 visit and/or Week 22 visit can be done as a phone visit to allow flexibility for the subject in visit scheduling. If a phone visit is 
done, the week 10 visit will move to be performed at week 11and/or week 22 visit will move to be performed at week 23. CGM sensors (4) should be given to 
the subject at week 8 and/or week 18. The CGM sensor should be self inserted by the subject at home at week 11 for the first CGM wear in the short term 
period and/or at week 23 for the second CGM wear in the short term period and should be worn for 7 days. In those subjects having optional phone visits, this 
means that the CGM device would be worn for 7 days instead of the full 14 days Site personnel should call the subject for the week 11 visit and/or week 23 
visit to confirm the insertion was done correctly. If the self-insertion is not done or no data is on the device at the week 12 and/or week 24 visit, then the 
subject gets a new sensor inserted at the site and wears it for 7 days.  After the 7 days of CGM wear is completed, following the week 12 visit, the subject will 
retain the sensor until returning to the site for the week 18 visit.  After the week 24 visit, the subject will return the sensor to the site within 7 days of removal. 
If an optional phone visit is to be done, a new week 10 diary should be given at week 8 and/or a new week 22 diary should be given at week 18.
f Week 12 visit should be scheduled at least 14 days after Week 10 visit in order to collect a full 14-day CGM data, but not longer than 17 days. Sensors need 
to be changed 7 days after insertion. Subjects will be trained at the Week-1 visit to change the sensor. An ad-hoc visit may be performed if assistance is 
needed. If a subject performs sensor change on his/her own, the site should call to remind the subject to change the sensor 7 days after insertion.
g Week 24 visit should be scheduled at least 14 days after Week 22 visit in order to collect full 14-day CGM data, but not longer than 17 days. Sensors need to 
be changed 7 days after insertion. Subjects will be trained at the Week-1visit to change the sensor. An ad-hoc visit may be performed if assistance is needed. If 
a subject performs sensor change on his/her own, the site should call to remind the subject to change the sensor 7 days after insertion.
h If a randomized subject terminates the study any time prior to the Week 24 visit, the CGM, Recording Meals, and 6-point SMBG will not be required for the 
early termination visit. However, CGM, Recording Meals, and 6-point SMBG are expected to be performed at Week 12 and 24 off treatment visit, if the 
subject decides to continue with the study procedures
i
If an optional phone visit is to be done at week 10, the subject diary should be given to the subject at week 8 and/or a new week 22 diary should be given at 
week 18
j
For the Day 1 visit - it will be recommended that subjects reduce their daily insulin dose by up to 20% for both basal and bolus insulin after the first dose of 
study drug, although in some cases it may be necessary to reduce insulin (particularly basal insulin) in advance of study drug administration.
k These safety assessments; review of AEs, hypoglycemia events, and DKA episodes to be performed throughout the study according to the visit schedule as 
noted via “X.”
l
PK samples should be collected if the visit is being used as an early termination visit or if it is the subject’s regularly scheduled week 24 visit and the subject is 
currently taking study medication. In the event that the subject discontinues study medication but continues in the study, any PK samples required at visits 
should not be done
m If visit is during the “off-treatment” or the Post Study Drug Study Follow-up phase (Section 3.6), the IVRS does not have to be contacted
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-3:
Flow chart for Protocol MB102230 - 28-week Subject- and Site-Blinded Long-term Treatment Period
Procedure
28-week Subject and Site blinded Long-term Treatment Period
Notes
Week 32a
Week 40a
Week 48a
Week 52a / ET
Visit For 
Long- term
Week 56a
Follow-up (for 
both ST and LT
periods)
Subject reports to site
X
X
X
X
X
General Procedures
Brief physical exam
X
X
Includes cardiovascular, lungs, 
abdomen, and extremities, and any 
organ systems pertinent to the 
subject’s signs, symptoms, or AEs
Complete physical exam
X
Includes general appearance, head, 
eyes, ears, nose, throat, neck, 
cardiopvascular, lungs, abdomen, 
lymph nodes, extremities, 
neurological, skin, and 
musculoskeletal.
Body weight
X
X
X
X
X
Blood pressure and heart rate
X
X
X
X
X
ECG
X
Review concomitant 
medications/procedures
X
X
X
X
X
Provide dietary and exercise 
counseling
X
X
X
X
Dispense study diaries and provide 
instructions
X
X
X
X
Re-dispense blood glucose and 
ketone strips and provide retraining 
(as needed)
X
X
X
X
Review subject diaries
X
X
X
X
X
Revised Protocol No.: 02
Date: 18-May-2016
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Clinical Protocol
MB102230
BMS-512148
dapagliflozin
Table 5.1-3:
Flow chart for Protocol MB102230 - 28-week Subject- and Site-Blinded Long-term Treatment Period
Procedure
28-week Subject and Site blinded Long-term Treatment Period
Notes
Week 32a
Week 40a
Week 48a
Week 52a / ET
Visit For 
Long- term
Week 56a
Follow-up (for 
both ST and LT
periods)
Adjust insulin dose (as needed)
X
X
X
X
Collection of long-term treatment 
period diaries
X
Administer EQ-5D-3L, DTSQs, and 
HFS-II
X
Completed prior to any other 
procedures
Safety Assessmentb
Assess AEs
X
X
X
X
X
Assess hypoglycemia episodes
X
X
X
X
X
Assess DKA
X
X
X
X
X
Laboratory Assessments
Pregnancy test (urine) WOCBP only
X
X
X
X
X
Home pregnancy test kits and 
pregnancy logs sent home with 
WOCBP to perform monthly 
pregnancy tests between visits and 
record results in log book.
Blood standard safety laboratory 
panel
X
X
X
Urine standard safety (dipstick)
X
X
X
Spot urine for glucose, albumin and 
creatinine quantification and 
determination of glucose: creatinine 
and albumin:creatinine ratios
X
X
FPG
X
X
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Table 5.1-3:
Flow chart for Protocol MB102230 - 28-week Subject- and Site-Blinded Long-term Treatment Period
Procedure
28-week Subject and Site blinded Long-term Treatment Period
Notes
Week 32a
Week 40a
Week 48a
Week 52a / ET
Visit For 
Long- term
Week 56a
Follow-up (for 
both ST and LT
periods)
A1C
X
X
X
X
X
FFA
X
Fasting lipid panel
X
Clinical Drug Supply
Dispense study drug
X
X
Contact IVR system
Xc
Xc
Xc*
X
*Also, call if subject is having an 
early termination visit
Review study medication 
compliance
X
X
X
X
a Visits may be scheduled 5 days to allow flexibility of scheduling with the exception of Week 56 visit. Week 56 visit cannot be scheduled earlier than
30 days of week 52 visit or last dose of study drug but can have a longer window of 5 days.
b These safety assessments; review of Adverse Events, hypoglycemia events, and DKA episodes, to be performed throughout the study according to the visit 
schedule as noted via “X.”
c If visit is during the “off-treatment” the Post Study Drug Study Follow-up phase (Section 3.6), the IVRS does not have to be contacted
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments during the Screening or Lead-in 
period will not be permitted (this does not include parameters that require a confirmatory result).
Retesting is limited to HbA1C and free T4 as described in Section 3.3.
Any new result will override the previous result (ie, 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. 
5.2
Study Materials
BMS will supply the sites with the following materials as allowed per local regulations.

Blood glucose/ketone meters. One (1) meter will be provided to each study subject at lead-in 
and one meter will be provided to each investigative site

Glucose and ketone test strips

Lancets

Glucose control solutions

CGM devices and software to download data (see paragraph at the end of this section)

Subject education and site support materials (eg, CGM instruction manuals)

Electronic case report forms (eCRFs) (Serious Adverse Event [SAE] Forms, Pregnancy 
Surveillance Forms, Events of Special Interest]

Subject alert cards

Study drug inventory control forms

Site file

Subject diary:

Full diary review by site staff is required for this study during each visit

Use of subject diaries are mandatory for the study and will be maintained by each study 
subject for documentation of 6-point SMBG results and SMBGs from the Day 1 visit to 
the Week 2 visit, insulin doses, meal times during specific weeks of CGM monitoring,
day/time of CGM sensor insertion if performed at home at Weeks 11 and 23, study 
medication dosing, ketone testing, DKA symptoms, hypoglycemia episodes, and if 
applicable WOCBP urine pregnancy results
6-point SMBG profiles: see Section 5.9.4.2
SMBG: see Section 5.3.2.1
Subjects are to be instructed to document their insulin dose in their study diaries 
during the protocol-defined time period as outlined in Section 5.3.4. eCRF pages will 
be provided to the sites so they can record the data obtained from the diaries in the 
study database
R
Subjects who have not recorded all of their insulin doses should be assessed by 
the study staff for their ability to comply with the protocol. The diaries are to be 
maintained to ensure subject safety and must be completed by the subject 
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throughout the study. Compliance with prescribed insulin administration and 
diary completion should be assessed and re-enforced at every visit
Subjects are to record their meal times in their diary during the following time 
periods:
R
Week -1 to Day 1 prior to randomization
R
Week 11 to Week 12
R
Week 23 to Week 24
Subjects are to record day and time of CGM sensor insertion if performed at home at 
week 11 and week 23
The dates, time, and number of tablets of study medication taken by the subject are to 
be recorded in the study diary. Electronic CRF pages will be provided to the sites so 
they can record the data obtained from the diaries in the study database
Subjects are to record any hypoglycemic symptoms they may experience and SMBG 
values if they conducted the test when they had symptoms in their diaries. All events 
recorded in subject diary will be reviewed by site staff according to Section 5.3.2
Any ketone testing performed by the subject, symptoms potentially associated with 
DKA, and relevant events (Section 5.3.3) are to be recorded in the diary. All results 
recorded in subject diary will be reviewed by site staff during each study visit.  
Determination of a DKA event must be assessed and documented by the Principal 
Investigator or by a qualified sub-investigator.

Any other materials as locally required or agreed upon
The central laboratory will provide all laboratory-related materials including home pregnancy 
testing kits for WOCBP to the study sites.
Materials related to the CGM will be provided by a central vendor. Dexcom Inc is planned to be 
the provider of these devices; however, the Sponsor may change the provider as needed. Below 
is a summary of selected information related to the specifications of the planned CGM system:
Model No (range)/Name:

STK-GL-(00l to 099) / mg/dL, Dexcom G4 PLATINUM Receiver Kit

STK-GL-(101 to 199) / mmol/L, Dexcom G4 PLATINUM Receiver Kit

STR-GL-(002 to 099) / mg/dL, Dexcom G4 PLATINUM Replacement Receiver Kit

STR-GL-(101 to 199) / mmol/L, Dexcom G4 PLATINUM Replacement Receiver Kit

STT-GL-(00l to 010) / Dexcom G4 PLATINUM Transmitter Kit

STS-GL-(00l to 144) / Dexcom G4 PLATINUM Sensor

MT21190 / Dexcom Studio
All the information for devices used in this study is available from the vendor(s).
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5.3
Safety Assessments
Safety assessments will include adverse event reporting, as well as marked abnormalities in 
clinical laboratory tests. Please refer to Appendix 2 for details on central laboratory assessments.
The procedures described in the sections that follow will also be completed to ensure subject’s 
safety.
5.3.1
Imaging Assessment for the Study
Not applicable.
5.3.2
Self-Monitored Blood Glucose (SMBG) and Guidance on Management 
and Reporting of Hypoglycemia Episodes
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the investigator as per standard 
medical/clinical judgment.
5.3.2.1
Self-Monitored Blood Glucose (SMBG)
Combination glucose and ketone meters will be supplied to each study site. At the entry into the 
lead-in period, subjects will receive a glucose and ketone meter, supplies and instruction on their 
use. Testing supplies will be provided to allow for blood glucose and ketone testing for the 
duration of the study. Subjects should bring their glucose meter with them to each study visit to 
ensure that it is functioning properly and for review of SMBG results. Subjects may keep the 
glucose meters at the end of the study. It is strongly preferred that subjects use the meter 
provided by the Sponsor. If a subject uses another meeting to perform this test, these results 
will be captured on an eCRF page.
Subjects should self-monitor their blood glucose at least 4 times per day (generally before 
breakfast, lunch, dinner, and bedtime), and in the occurrence of hypoglycemic symptoms, and to 
contact the investigator in the event of an unusually high or low blood glucose value. In addition, 
study subjects should comply with the site’s instructions with regard to self-monitoring of blood 
glucose and insulin adjustments accordingly and should report to the site blood glucose values 
and/or signs and symptoms suggestive of a hypoglycemic episode.
Subjects should attempt to enter all valid SMBG values into the CGM in order for the calibration 
of the system.
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 and ketone meter’s memory and/or from the 
subject’s hypoglycemia portion in the diary) were obtained from the subject. If fingerstick 
glucose 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.
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5.3.2.2
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 the 
dangers associated with low blood sugar.
Study subjects must be properly instructed on the recognition and management of hypoglycemia. 
Subjects should record any hypoglycemic symptoms in their diaries. 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.
Hypoglycemia eCRF pages will be used to document all reported episodes of hypoglycemia. 
The investigator is responsible for questioning the subject about all symptoms reported on the 
hypoglycemia portion of the diary 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 episodes 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.
5.3.3
Self-Monitored Blood Ketone Testing and Guidance on Management 
and Reporting of Diabetic Ketoacidosis Episodes
Diabetic ketoacidosis is an expected event in subjects with T1DM. Subjects and their family 
members must be aware of the possibility that DKA may occur and the dangers associated with 
DKA. 
Dapagliflozin reduces blood glucose by urinary excretion of glucose, thus representing a daily 
removal of a substantial amount of carbohydrate from the body. We estimate (from 
insulin:carbohydrate ratios) that the amount of glucose excreted in the urine in subjects on 
dapagliflozin may correspond to the glycemic effect achieved from as much as 20% of a 
subject’s total daily insulin dose and, therefore, insulin dose reductions will have opposite 
glycemic effects compared to those of dapagliflozin. Furthermore, since DKA is caused by gross 
insulin deficiency and is mechanistically unrelated to glucose levels per se (as can be seen in 
euglycemic DKA), reductions in insulin doses of more than 20% are not recommended 
regardless of glucose values. If subjects have repeatedly low blood glucose and could otherwise 
not avoid a 20% reduction in total daily insulin dose, they are recommended to increase their 
daily dietary carbohydrate intake. Similarly, subjects should be reminded that during/after 
elevated physical activity/exercise, dapagliflozin continues to remove glucose in addition to what 
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is being consumed by the physical activity. Therefore, additional (re-) fueling with carbohydrates 
is important and should generally be preferred over higher than usual reductions in subjects’ 
insulin doses.
As noted above, subjects will receive a combined glucose and ketone meter and sufficient 
supplies for testing at the entry into the lead-in period. Subjects will also be trained in the 
procedure of conducting blood ketone testing according to the manufacturer’s specifications. 
Subjects will be advised to measure their blood ketones using the glucose and ketone meter 
provided by the Sponsor when they have 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, and/or during acute 
illness. Subjects should be instructed to measure their ketones if symptoms occur, regardless of 
plasma glucose values. Blood ketone test results, symptoms potentially associated with DKA,
and relevant risk factors (eg, missed insulin injection, insulin pump malfunction, infection, heart 
attack, etc) should be recorded in the subject diary.
Study subjects must be properly instructed on the recognition and management of DKA. Subjects 
should contact the site for assistance with diabetes management in the event that the blood 
ketone reading is 0.6 mmol/l or above according to the glucose/ketone meter user guide. The 
investigator is recommended to advise the subject to take extra insulin and extra carbohydrate if 
elevated ketones are registered and continue to measure blood ketones. If deemed necessary, 
dosing of study medication should be interrupted during sick days. The action, follow-up, and 
monitoring plan will be at the discretion of the investigator and will depend on his/her 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). ). It is recommended that for subjects who report 
elevated ketones/ketosis, the investigator considers re-education concerning DKA at the next 
scheduled visit, at an un-scheduled visit or by telephone contact, as appropriate.
Subjects must also be instructed that if attempts to contact the site are unsuccessful or if they are 
in urgent need of medical attention, that they should seek medical attention. They should provide 
information to the health care provider on their participation in a placebo controlled clinical 
study evaluating the effects of the SGLT2i dapagliflozin in addition to their insulin treatment.
The blood ketone values should 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 fingerstick 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 
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this event to the Sponsor. Blood ketone and glucose values associated with events deemed not to 
be a DKA event should be recorded on the non-DKA eCRF log page.
In addition the Sponsor will utilize Standardized Medical Dictionary for Regulatory Activities 
(MedDRA) Queries (SMQs) based on a list of pre-defined terms in MeDRA to identify potential 
DKA events. The list of these terms are included in the Data Monitoring Committee (DMC) 
Charter. Investigators will further evaluate these cases and if the event is determined to be DKA, 
the investigator will complete the DKA eCRF.
Regarding the reporting of DKA events, it is important to distinguish ketosis from DKA.
Low levels of ketosis, in which blood or urine ketone values are elevated, can occur in 
individuals who follow a low-carbohydrate, high-fat diet (eg, dietary ketosis) or after prolonged 
periods of fasting. However, ketosis is a benign condition if symptoms are absent and the blood 
pH remains buffered within normal limits (eg, no acidosis). In contrast, DKA episode may be 
confirmed when subjects have potential symptoms/signs of DKA (polyuria, polydipsia, weight 
loss, vomiting, abdominal pain, signs of volume depletion on physical examination), marked 
hyperglycemia (although DKA has been reported in individuals with normal or mildly elevated 
plasma glucose levels as well), elevated blood/urine ketone values, and a metabolic acidosis 
characterized by low arterial blood pH values, decreased serum bicarbonate, and an increased
anion gap. The combination of specific symptoms/signs of DKA and elevated blood/urine ketone 
values may be suggestive of DKA, recognizing that some subjects may not have lab test results 
(eg, blood gas measurement) to confirm acidosis.
During clinical trials, subjects frequently report symptoms of DKA when asked, even when 
treated with placebo or medications not otherwise associated with DKA. The investigator is 
responsible for questioning the subject about all DKA related symptoms reported on the subject 
diary and for determining if they meet the clinical definition of DKA. Only the episodes deemed 
by the investigator to meet the definition of DKA should be reported on the DKA eCRF pages. 
Signs and symptoms of DKA, DKA episodes, or discontinuation due to DKA 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 DKA eCRF 
pages. If a DKA episode occurs in a subject that fails screening, the DKA eCRF pages do not 
need to be completed. However, if the event meets the protocol criteria for an SAE, the SAE 
form must be completed. . For subjects who experience a DKA it is recommended that the 
investigator schedules a telephone or site visit for re-education in prevention of ketosis and 
DKA.
A DKA Adjudication Committee, blinded to the treatment of the subjects, will independently 
adjudicate all the DKA events reported by investigators during the study period. A separate 
Adjudication Manual will define and describe the procedure for the handling, reporting, and 
classification of these cases.
The key goals of treating DKA include correcting dehydration, hyperglycemia, and electrolyte 
imbalance, and identifying and appropriately treating comorbid precipitating events. Subjects 
with DKA should be carefully monitored until significant improvement in the symptoms, 
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normalization of blood acidity (eg, pH > 7.3), and improvement/absence of ketones in blood or 
urine.
5.3.4
Insulin Dosing Adjustment and Data Collection Guidelines
Adjustment of a subject’s pre-existing insulin dosing regimen may be required during the 
conduct of this study, due to changes in diet, activity, emotional stress during the study, as well 
as potential effects of dapagliflozin to reduce blood glucose and thereby insulin requirements.
During the lead-in period, subjects will be advised to self-monitor their blood glucose consistent 
with local treatment guidelines. The method of documentation for glucose results will be based 
on local clinic practice. Glucose control will be reviewed by the investigator at each visit. Insulin 
dose may be adjusted as deemed appropriate to be consistent with good medical practice 
according to SMBG readings, local guidance and individual circumstances.
It is recommended that subjects reduce their daily insulin dose by up to 20% for both basal and 
bolus insulin after the first dose of study drug to minimize the risk of hypoglycemia. It is at the 
discretion of the investigator to determine the extent to which to reduce the insulin doses.
In some cases it may be necessary to reduce insulin (particularly basal insulin) in advance of 
study drug administration. If total daily insulin dose is reduced upon initiation of study 
medication, attempts must be made to titrate insulin back to baseline total daily insulin dose. It is 
not recommended to  reduce  total daily insulin dose by more than 20% compared to baseline at 
any time during the study unless medically indicated and close attention should be paid, 
especially in these subjects, to symptoms of, and risk factors for developing DKA (See also 
Section 5.3.3). Subjects are to be instructed to document their daily individual insulin doses and 
self-monitor glucose values at least 4-times every day (before breakfast, lunch, dinner, and 
bedtime) during the first 2 weeks. This information will be used to facilitate appropriate insulin 
dose adjustment and ensure subject safety. For the rest of the study period (both short-term and 
long-term), subjects will be advised to continue self-monitoring their blood glucose as per local 
guidelines. Glucose control will be reviewed by the investigator at each visit. Insulin dose may 
be adjusted as deemed appropriate to be consistent with good medical practice according to 
SMBG readings, local guidance, and individual circumstances. The glycemic control goals may 
be individualized based upon a subject’s personal target and stability of glycemic control at 
baseline.
Subjects are not allowed to change their insulin administration methods (MDI or CSII) 
throughout the study unless a subject using an insulin pump needs to replace the pump. Under 
this situation, the subject may temporarily use MDI and should restart CSII administration as 
early as feasible. The period of time a subject is on temporary use of MDI should not be more 
than 2 weeks. 
Insulin Dosing Recording
At the following time periods the subjects will be instructed to record all their individual doses of 
(basal and bolus) insulin in their study diary. 

Week -2 visit up to the Day 1 visit prior to randomization
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
Day 1 visit after randomization up to the Week 2 visit

Week 10 visit up to the Week 12 visit

Week 22 visit to up the Week 24 visit
The site will review these diary entries and record the total basal and total bolus daily dose of 
insulin the subject received on the eCRF. For statistical analysis purposes the total daily dose is 
defined as the sum of all these individual doses of insulin (both basal and bolus) during a 
24-hour period. 
Subject’s daily individual insulin doses and self-monitored glucose values collected from Day 1 
visit (after randomization) to the Week 2 visit will be used to facilitate appropriate insulin dose 
adjustment and ensure patient safety.
At the following time periods subjects will be instructed to record the minimum and maximum 
total daily insulin dose range (basal plus bolus) taken for each week in their study diary:

Week -8 visit up to the Week -2 visit

Week 2 visit up to the Week 10 visit

Week 12 visit up to the Week 22 visit

Week 24 visit up to the Week 56 visit
The site will review these diary entries and record the weekly ranges subject received of insulin 
on the eCRF.
5.3.5
Guidance on Assessment of Urinary Infections and Hematuria
5.3.5.1
Guidance on Assessment of Urinary Infections
The following is presented to assist in the classification and management of urinary tract 
infections. It is not intended to supplant investigators’ clinical judgment: It is at the discretion of 
an investigator to determine whether and when to send an initial urine culture.
Study drug should be withheld in subjects with clinical evidence of a UTI or presumed urosepsis 
until the course of treatment of the infection has been completed and clinical recovery has 
occurred.
It is recommended that a urine culture be obtained by local laboratory within 7 days of clinical 
recovery from all treated 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.
It is the investigator's responsibility to report, as applicable based on the investigator's judgment 
and the subject's medical history, related adverse events as defined in Section 6. Additional 
information, including but not limited to completion of supplemental eCRFs or questionnaires 
may be requested for certain adverse events and/or laboratory abnormalities which are 
reported/identified during the course of the study.
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Asymptomatic Bacteriuria
During enrollment, treatment and follow up of subjects in this trial, the investigator may discover 
a subject 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 urinary tract infection. Asymptomatic 
bacteriuria is prevalent among diabetic women, and is associated with pyuria in 70% of cases. 
Neither guidelines from the Infectious Diseases Society of America (IDSA), US Preventive 
Services Task Force,15,16 nor the European Association of Urology17 recommend screening for
or treatment of, asymptomatic bacteriuria in non-pregnant diabetic patients. 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.
5.3.5.2
Guidance on Assessment of Hematuria
During the course of the study, hematuria should be investigated according to local standards and 
best clinical practices for a possible cause.
If NO common cause is identified, subjects should be further investigated based on American 
Urological Association (AUA) guidelines or equivalent local standard of care and best practices,
which could include referral to a urologist and undergoing evaluation that may include 
abdominal computed tomography (CT), urine cytology, and an NMP-22 urine test. The subject 
should continue to be randomized/receive investigational product treatment during these 
investigations (unless otherwise contraindicated).
It is the investigator's responsibility to report, as applicable based on the investigator's judgment 
and subject's medical history, related adverse events as defined in Section 6. Additional 
information, including but not limited to completion of supplemental eCRFs or questionnaires 
may be requested for certain adverse events and/or laboratory abnormalities which are 
reported/identified during the course of the study.
5.3.6
Guidance on Assessment of Cardiovascular Events
A Clinical Events Committee (CEC), blinded to the treatment of the subjects, will independently 
adjudicate certain cardiovascular adverse events, and they will operate in accordance with a 
dedicated Clinical Events Committee Charter/Manual of Operations:
Events related to the following will be sent to the CEC for adjudication.
Death, including:

Cardiovascular death

Non-cardiovascular death
Myocardial infarction (MI), including:

ECG and/or cardiac enzymes confirmed MI
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
Sudden death

Percutaneous coronary intervention (PCI)-related MI

Coronary artery bypass graft (CABG)-related MI

MI diagnosed via pathologic criteria

Silent MI
Fatal and non-fatal stroke, including:

Ischemic stroke

Hemorrhagic stroke
Serious Adverse Events of the following:

Heart failure

Cardiac arrhythmia

Unstable angina

Unplanned arterial revascularization (coronary, carotid and peripheral)

Cardiac arrest with successful resuscitation

Deep vein thrombosis (DVT) and pulmonary emboli (PE)

Systemic non-stroke arterial embolism/thrombosis including systemic arterial occlusion

Non-traumatic amputation of the lower limb. Only events above the ankle will be considered 
for adjudication.
In order to provide the independent CEC with appropriate and adequate information for 
adjudication of the listed events, please consult the Adjudication Reference Manual for Primary 
Investigators and Study Staff.
5.3.7
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, included, but not limited to:

AST and/or ALT > 3x ULN and total bilirubin (TB) > 2x ULN (within 14 days of the AST 
and/or ALT elevation)

Hepatic events timely related to death (within 30 days before death)

AST and/or ALT > 10x ULN
Hepatic disorders leading to discontinuation from study drug and/or death
Liver laboratory abnormalities such as elevated AST and/or ALT with or without TB Elevations
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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 the 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:

AE 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:

Use 
of 
suspect 
concomitant 
medication 
[including 
over-the-counter 
(ie, acetaminophen/paracetamol), herbal and vitamin preparations]

Recent alcohol consumption or recreational drug/narcotic use

Recent unaccustomed physical exertion

Occupational or environmental exposure to hepatotoxins

Other conditions which may cause liver diseases or which may cause abnormal test 
results

Specialized liver laboratory panel (see Appendix 2)

should only be done once for elevated liver enzymes per Appendix 3 Sustained Elevated 
Liver Safety Abnormalities Flow Chart unless liver discontinuation panel is required
Additional information, including but not limited to completion of supplemental eCRFs or 
questionnaires, may be requested for certain adverse events 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 3), in conjunction with an Early 
Treatment Discontinuation (End-of-Treatment) 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.
5.3.8
Physical Examination

A brief physical examination should include cardiovascular, lungs, abdomen, and 
extremities, and any organ systems pertinent to the subject’s signs, symptoms, or adverse 
events
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A complete 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 or national
law (or applicable local law) to perform this procedure.
5.3.9
Blood Pressure and Heart Rate
Blood pressure (BP) and heart rate (HR) measurements must be taken consistently throughout 
the study. Only the right or the left arm should be used when measuring these parameters. The
arm that was used should be documented, along with the observer’s initials; the same arm should 
be used at each visit. The subject should be in a seated position, allowing at least 5 minutes of 
rest before measurement. Blood pressure should be measured with the subject’s arm resting on a 
table, and with 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 
nicotine.
5.3.10
Electrocardiograms
Electrocardiograms will be performed as noted in Section 5.1. The investigator should review 
and assess all ECGs for any clinically significant abnormalities, and initial and date the report. 
The screening ECG must be assessed, and initialed and dated by the investigator prior to 
randomizing the subject. In preparation for the ECG, there should be minimal interference 
between the skin surface and the electrode. Alcohol should be used to prepare the skin at each 
electrode site. Thick chest hair should be shaved to ensure sufficient contact. Before attaching 
electrodes to pick-up points, electrode gel should be applied to the electrodes. The electrodes
should be placed on bony areas, avoiding large muscle masses, to achieve better tracings as 
described below. The subject must be supine and should refrain from movement during the ECG 
recording. The subject and the electrodes (including the neutral electrode) should not be exposed 
to conducting objects, even if grounded.

RL: On the right leg (inside calf, midway between knee and ankle)

LL: On the left leg (inside calf, midway between knee and ankle)

RA: Right arm (on the inside)

LA: Left arm (on the inside)

V1: 4th intercostal space, at right sternal margin

V2: 4th intercostal space, at left sternal margin

V3: Midway between V2 and V4

V4: 5th intercostal space at left midclavicular line
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V5: Same transverse level at V4, at anterior axillary line

V6: Same transverse level at V4, at left midaxillary line
One original ECG print-out should be kept in the medical chart and a copy, assessed, initialed 
and dated by the investigator, should be maintained in the source documents for the study.
5.3.11
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 subjects that otherwise are at risk for volume 
depletion. Therefore, caution should be exercised when administering dapagliflozin to subjects at 
risk for volume depletion due to co-existing conditions or concomitant medications, such as loop 
diuretics. These subjects should be carefully monitored for of volume status, electrolytes, and 
renal function.
5.3.12
Guidance on Monitoring Renal Function
Creatinine clearance (CrCl, based on Cockroft-Gault) 45 ml/min and < 60 ml/min:

At all scheduled and unscheduled visits, patients should be asked for symptoms of volume 
depletion, as well as other AEs, and vital signs should be assessed (including blood pressure 
measurement).

Renal function should be monitored by central lab at all scheduled and unscheduled visits.
Creatinine clearance (CrCl, based on Cockroft-Gault) 30 ml/min and < 45 ml/min:

If the creatinine clearance (CrCl, based on Cockroft-Gault) falls below 45 ml/min, the patient 
should be scheduled for a re-test within 4 days, whenever possible.

If the re-test CrCl (based on Cockroft-Gault) is 45 ml/min the patient can resume the 
normal visit schedule. 

If re-test CrCl is still < 45 ml/min, the Investigator should consider re-testing CrCl within 
one to two weeks, whenever possible.

In addition, the Investigator should consider evaluating the subjects for potentially reversible 
causes of renal dysfunction including: concurrent use of NSAIDS, antibiotics, or other 
medications known to affect creatinine clearance; volume depletion; urinary tract infection 
and obstructive uropathy. Further re-testing and evaluation should be done every second 
week until stabilization.
Creatinine clearance (CrCl, based on Cockroft-Gault) 30 ml/min:
See Section 3.5
for re-testing instructions and possible need for study medication 
discontinuation.
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Any subject that is discontinued from study medication due to deterioration in renal functions 
should be monitored closely by the investigator until abnormalities stabilize and the subject is
asymptomatic.
5.3.13
Supplemental Visits
5.3.13.1
Early Treatment Discontinuation Visit
Subjects discontinued from the double-blinded short-term treatment period
Any subject who discontinues study medication during the 24-week double-blinded short-term 
treatment period must
have the Week 24/Early Termination (ET) visit completed. 
The Week24/ET visit eCRF will also need to be completed and a Week 24/ ET visit laboratory 
kit will need to be used to collect ET visit blood and urine samples. The IVRS must be called to 
record the subject status (ie, discontinuation status).
Subjects discontinued from the subject and site blinded long-term treatment period
Any subject who discontinues study medication during the 28-week subject- and site-blinded 
long-term treatment period must have the Week 52/ET visit completed. The IVRS must be called 
to record the subject status (ie, discontinuation status). The Week 52/ET visit eCRF will also 
need to be completed and a Week 52/ET visit laboratory kit will need to be used to collect ET 
Visit blood and urine samples. 
5.3.13.2
Early Treatment Discontinuation Follow-up (Off Treatment Procedures) 
As described in Section 3.6, all subjects who discontinue investigational product during the 
24-week double-blinded short-term treatment period or the subject- and site-blinded long-term 
treatment period are expected to continue study participation for each scheduled visit for the 
remaining length of the study and complete all procedures as outlined in the Section 5.1 study 
flowchart (with the exception of study drug management and PK sampling). If continued study 
participation according to the protocol schedule is not possible, the investigator should contact 
the subject to discuss alternatives (eg, return to the clinic 4 weeks/at least 30 days after 
discontinuation of study drug to perform the week 56 post treatment follow-up procedures as 
outlined in Section 5.1 study flowchart or be contacted by telephone 30 days after 
discontinuation of study drug to evaluate the following safety assessments: AEs, hypoglycemia 
events, and DKA episodes). Please note that after the discontinuation of study drug, management 
of the subject’s diabetes would be under the care and direction of the investigator and/or 
subject’s healthcare providers.
Please utilize the post treatment follow up pages in the eCRF post treatment section for this data 
completion.
5.3.13.3
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.
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5.4
Efficacy Assessments
The procedures described in the sections that follow will completed to capture information for 
efficacy assessments.
5.5
Pharmacokinetic Assessments
PK samples will be obtained prior to dosing at the Weeks 12, 18, and 24 visits.
Please refer to the central laboratory instructions for sample collection and processing
5.6
Pharmacogenomic/Pharmacogenetic Assessements
Pharmacogenetic samples may be collected as covered in the pharmacogenetic blood sample 
amendment (Amendment 01), where applicable.
5.7
Biomarker Assessments
Not applicable.
5.8
Outcomes Research Assessments
Patient-reported outcomes (PROs) will be assessed as indicated in Table 5.1-2 and Table 5.1-3.
The instruments/questions will be self-administered using paper and pencil questionnaires.
The following PROs will be assessed in this trial:

EQ-5D-3L for generic health status

Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) for treatment 
satisfaction

Hypoglycemia Fear Survey (HFS-II) for worries to avoid hypoglycemia and its negative 
consequences
PROs will be filled out prior to any other site activities and encounters with the study physician. 
The subjects will be instructed to complete the PRO questionnaires independently. The site will 
have a designated quiet space for subjects to use when completing the assessments. Each center
should allocate responsibility for PRO assessment to a specified individual (eg, a research nurse). 
The research nurse or appointed individual should stress the information is confidential.
It is important that the value and relevance of health-related quality of life (HRQoL) data are 
explained carefully to participating subjects so that they are motivated to comply with data 
collection. The research nurse or appointed individual should also stress that the information is 
confidential. Therefore, if the subject has any medical problems s/he should discuss them with 
the doctor or research nurse separately from their PRO assessment.
The instructions for completion of questionnaires are:

It should be completed before any investigations or discussions about the status of the 
subject’s disease with the clinic staff

The subject should complete it her/himself without any intervention from family, friends, 
center staff etc
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
Only one answer to every question should be checked

Center personnel should not review the responses to the questionnaire with the subject or 
with any other center staff
Following completion, the nurse or appointed individual may quickly scan the questionnaire 
visually for completeness and should confirm verbally with the subject that the questionnaire has 
been completed fully.
5.8.1
EQ-5D-3L
The EQ-5D-3L is a generic, preference-based utility questionnaire and consists of two parts, the 
EQ visual analogue scale (VAS) and the EQ-5D-3L index. The EQ VAS ranges from 0 = worst 
possible health to 100 = best possible health. The EQ-5D-3L index is a five dimension 
questionnaire. The dimensions consist of mobility, self-care, usual activity, pain/discomfort and 
anxiety/depression. Each item has three levels: no problems, some problems and severe 
problems.
5.8.2
Diabetes Treatment Satisfaction Questionnaire
The Diabetes Treatment Satisfaction Questionnaire (DTSQ) has been developed to assess 
patient´s satisfaction with treatment and perception of change in hyper- and hypoglycaemia18. 
The DTSQ status version (DTSQs) has 8 items.
5.8.3
Hypoglycemia Fear Survey
The Hypoglycemia Fear Survey (HFS-II) includes two subscales, of which one is an 18-item 
Worry Subscale that measures worries about hypoglycemia and its negative consequences 
(ie, describe specific concerns that patients may have about their hypoglycemic episodes). 
Responses are made on a 5-point Likert scale where 0 = Never and 4 = Always. The Worry 
Subscale has a score range of 0 to 72, with higher scores indicating increased fear of 
hypoglycaemia. The HFS-II is a widely used measure in clinical trials, has been translated into 
more than 20 languages, and has demonstrated reliability and validity.19
5.9
Other Assessments 
5.9.1
Weight
Body weight 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 in kilograms or pounds to 
the first decimal point (eg, 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.
5.9.2
Height and Body Mass Index (BMI)

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
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
BMI is used as an index of obesity and is a method of defining normal body weight and 
excess body fat. BMI is determined by weight (kg) divided by height (m) squared
Method of BMI calculation:

Use actual height and weight

To calculate BMI:

convert pounds (lbs) to kilograms (kg = lb / 2.2)

convert inches (in) to meters ( in x 0.0254)

BMI = (weight in kg) / (height in meter) 2
5.9.3
Diet and Exercise Counseling
Starting at entry into the lead-in period (Week -8 visit), subjects will be instructed on a diet and 
an exercise program in accordance with the American Diabetes Association (ADA) or similar 
local guidelines to be followed for the study duration.
A registered dietitian, registered nurse, physician, certified diabetes educator (CDE), nutritionist, 
or other qualified member of the study team who has appropriate documented training, will 
provide this counseling.
5.9.4
Pharmacodynamic Assessments 
5.9.4.1
Fasting Plasma Glucose
Blood samples will be drawn for measurement of fasting plasma glucose concentrations 
according to the schedule presented in study flow chart/time and event schedule 
(see Section 5.1).
5.9.4.2
6-point SMBG profiles
Subjects will be instructed to perform 6-point SMBG profiles as described below. It is strongly 
preferred that subjects use the meter provided by the Sponsor. If a subject uses another 
meter to perform this test, the site must try to determine the medium that the meter reports in 
(ie, plasma glucose vs. whole blood glucose). This information and results will be captured on an 
eCRF page. If subjects do not use the meter provided by the Sponsor, they should be instructed 
to continue using the same meter for all subsequent visits to avoid increasing variability.
Profiles will be obtained on any 3 days within a week before the Week -4 visit, Day 1 visit, 
Week 12 visit, and Week 24 visit, according to the schedules presented in study flow chart/time 
and event schedule (see Section 5.1). Each separate 6-point SMBG profile encompasses 1 day 
within one week before the scheduled visits, with three glucose measurements obtained 
preprandially (within 15 minutes prior to meal) and three glucose measurements obtained 
postprandially (1.5 - 2 hours after the start of the meal) for the three main meals of the day. 
Subjects will be provided with a diary to record these SMBG measurements and mealtimes, and 
eCRFs will available for the investigator sites to capture these results. 
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If a lead-in subject fails prior to the Day 1 visit, the 6-point SMBG profile will not be required 
between the week -1 visit and the Day 1 visit.
If a randomized subject terminates the study any time prior to the Week 24 visit, the 6-point 
SMBG profile will not be required for the early termination visit. However, the 6-point SMBG is
expected to be performed at Week 12 and 24 off treatment visit, if the subject decides to continue 
with the study procedures.
5.9.4.3
Continuous Glucose Monitoring (CGM)
CGM measures the subject’s interstitial glucose level using electrodes that measure an electric 
signal produced by glucose oxidase reaction. The system records data approximately every 
5 minutes. CGM will be used periodically to measure the subject’s interstitial glucose level 
according to the schedule presented in study flow chart/time and event schedule 
(see Section 5.1). 
A CGM sensor will be inserted subcutaneously at the Week - 2 visit, at the Week - 1 visit 
(and removed prior to the first dose on the Day 1 visit), and at the Week 10 and Week 22 visits to 
allow for monitoring of a 2 week time period (for example: the Week -2 visit to the Day 1 visit 
[baseline]; the Week 10 office visit until the Week 12 office visit; and the Week 22 office visit 
until the Week 24 office visit.) During those periods, subjects will document their three main 
meal times in the diary every day. Subjects should be trained to perform sensor replacement at 
Week-1 visit. In addition, at Week -1, sites should upload the sensor data to check subject’s 
compliance with wearing the device. 
The sensor requires at least one SMBG values to be entered every 12 hours for calibration during 
use. At a minimum, a SMBG value obtained in the morning (eg, fasting or pre-breakfast 
measurement) should be entered, as well as a value in the evening (eg, pre- or post-dinner 
measurement). Subjects may be instructed to use results from the 4 daily SMBG measures to 
fulfill this criteria. Every 7 days the sensor needs to be replaced and subjects can return to the 
site for assistance on this, if needed. If the subject needs assistance with sensor replacement, an 
ad-hoc visit should be performed; if this occurs a data upload is also recommended at this time. 
If subjects opt to perform sensor replacement at home, sites should call subject 7 days after 
insertion as a reminder. Please refer to the CGM Manual for further instructions on data uploads 
during an ad-hoc visit.
The data will remain blinded to the subject, the investigator, and to the Sponsor during the 
recording and will be downloaded into a data file. The downloaded file should be printed and 
reviewed by the site for review of monitoring compliance. The subjects should make every 
attempt to be at or greater than 100% compliant with use of the device. If a subject is not 
compliant, the reason should be discussed with the subject, documented in source notes, and the 
subject should be re-educated about the importance of CGM compliance.
Detailed procedures (including calibration) will be described in an operations manual and site 
staff will be fully trained on the use of CGM. Subjects will be instructed on use of the device and 
calibration according to manufacturer’s instructions. Subjects will wear the sensor and perform 
calibration according to manufacturer’s instructions. 
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If a subject uses a CGM device prior to entry into the study, he/she may continue to use their 
personal device during the study in accordance with their usual diabetes management care. Such 
a subject will be required to also use the blinded CGM device according to protocol procedures.
If a lead-in subject fails lead-in prior to the Day 1 visit, the CGM will not be required to be 
completed between the week -2 visit and the Day 1 visit. In addition, the meal recording for 
7 days will not be required between the week -1 visit and the Day 1 visit.
If a randomized subject terminates the study any time prior to the Week 24 visit, the CGM and 
meal recording for 7 days during the second week of CGM will not be required for the early 
termination visit. However, CGM and meal recording is expected to be performed at week 12 
and week 24 off treatment visits, if the subject decides to continue with the study procedures 
after discontinuation of study drug.
5.10
Results of Central Laboratory Assessments
Blood and urine samples will be obtained at specified time points for laboratory evaluations 
(see Appendix 2). 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.  
During the short-term double-blind treatment periods (Day 1 to Week 24), the HbA1c, 
continuous glucose monitoring values, and urinary glucose values, including spot urine for 
glucose, albumin and creatinine quantification, determination of glucose:creatinine and 
albumin:creatinine ratios, and urine glucose dipstick values, will be masked to the Sponsor and 
will not be available to the investigator. During the long-term subject- and site-blinded treatment 
period, (after Week 24 and through Week 56), the above measurements will be unmasked to the 
Sponsor. However, these values will still not be available to the investigator, except for the 
HbA1c values, until after study completion. HbA1c values will be provided to the investigator 
during the subject- and site-blinded treatment period.
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 an investigational 
(medicinal) product 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 investigational product, 
whether or not considered related to the investigational product.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual 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
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The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
AEs 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 one or more AEs.)
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 [eg, 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 drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI).
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. 
(See Section 6.1.1 for additional information on reporting pregnancies).
NOTE:
The following hospitalizations are not considered SAEs in BMS 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 
(eg, routine colonoscopy)
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
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 (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
6.1.1
Serious Adverse Event Collection and Reporting
The Investigator Brochure (IB) includes 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 30 days of discontinuation of dosing.
The investigator should 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 should 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 should 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 
AstraZeneca within 24 hours. SAEs must be recorded on the SAE Report Form and pregnancies 
must be recorded on a Pregnancy Surveillance Form (electronic or paper forms). When using 
paper forms, the reports are to be transmitted via email or confirmed facsimile (fax) transmission 
to:
SAE Email Address:
SAE Facsimile Numbers:
Note:  All numbers redirect to the same recipient – so chose the most convenient number.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Contact should be made 
to AZ or its designee. Refer to provided Contact Information list.
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If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should 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, a follow-up SAE report should be sent within 24 hours to AstraZeneca using 
the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
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 drug 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.
See Section 6.7.1 regarding the collection and reporting of non-serious events necessary to meet 
the post-marketing commitments required by the FDA.
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
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
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 (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, 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 (approximately 3 days) after product administration, the investigator must 
immediately notify the BMS (or designee) Medical Monitor of this event and complete and 
forward a Pregnancy Surveillance Form to AZ (or designee) within 24 hours and in accordance 
with SAE reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS and/or AZ, the pregnant subject may continue study drug, after a 
thorough discussion of benefits and risk with the subject.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcomes and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
AZ. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
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 drug induced liver injury is defined as: 
Aminotransferase (ALT or AST) elevation > 3x upper limit of normal (ULN)
AND
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Total bilirubin (TB) > 2x ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase)
AND
No other immediately apparent possible causes of aminotransferase
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, 
electrocardiograms, 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.
6.7.1
AEs of Special Interest 
Event categories of special interest for this study may include, but are not limited to, 
hypoglycemia, fractures, hepatobiliary adverse events, genital infections, urinary tract infections, 
volume depletion, worsening renal function, hypersensitivity, and DKA.
For the purposes of regulatory reporting, the following events must be reported within 24 hours 
regardless of whether the events are classified as serious or non-serious:
Liver test abnormalities accompanied by jaundice or hyperbilirubinemia
This category of events include all AEs where hepatocellular damage (with elevations of ALT or 
AST > 3x ULN) is combined with hepatic dysfunction (with elevation of total bilirubin > 2x 
ULN) or jaundice. With respect to LFT abnormalities, both central-lab results and adverse events 
will be monitored. 
For each non-serious event in this category, notify the Medical Monitor within 24 hours to 
discuss next steps in reporting.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
7.1
Cardiovascular Adjudication Committee
An Independent Adjudication Committee, blinded to the treatment of subjects, will classify 
cardiovascular adverse events, such as, but not limited to, death, myocardial infarction, and 
stroke reported in the study (see Section 5.3.6 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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7.2
Hepatic Adjudication Committee
An Independent 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:

AST and/or ALT > 3X ULN and TB >2 X ULN (within 14 days of the AST and/or ALT 
elevation)

Hepatic events timely related to death (within 30 days before death)

AST and/or ALT > 10X ULN
A separate Adjudication Charter will define and describe the procedure for the handling, 
reporting, and classification of these events.
7.3
DKA Adjudication Committee
A DKA Adjudication Committee, blinded to the treatment of the subjects, will independently 
adjudicate all the DKA events reported by investigators during the study period.
A separate Adjudication Manual will define and describe the procedure for the handling, 
reporting, and classification of these cases.
7.4
Data Monitoring Committee (DMC)
An external DMC with multidisciplinary representation will be established to evaluate, on a 
periodic basis, the incidence of hypoglycemia and DKA events, as well as AEs, laboratory 
measurements, and safety assessments to ensure the ongoing safety of study subjects. 
An independent reporting statistician not involved in the conduct of the study will be designated 
by BMS to provide the DMC with essential safety data during the study.
The DMC responsibilities, authorities, and procedures will be documented and followed 
according to the DMC charter. 
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The primary endpoint is the change from baseline in HbA1c to Week 24
With 243 subjects per treatment group with both baseline and at least one post baseline 
measurement, there is approximately 90% power to detect a difference in means of 0.35% 
between each dapagliflozin treatment group and placebo at the two-sided 0.0262 significance 
level (based on Dunnett and Tamhane step-up procedure), assuming a standard deviation (SD) of 
1.1%. Assuming that 5% of subjects do not have a post-baseline assessment, a total of 
768 subjects (256 subjects per treatment arm) need to be randomized to each dapagliflozin or 
placebo group in 1:1:1 ratio. 
Among those 768 subjects, approximately 160 of them are planned to be from Japan in order to 
support population specific analyses.
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A reduction in the primary endpoint of change from baseline in HbA1c of 0.35% was used to 
determine the sample size, as this represents a clinically meaningful improvement in glycemic 
control under the current study design with adjustable background insulin dose. A lesser degree 
of reduction in HbA1c in combination with other beneficial outcomes in secondary endpoints 
may also be clinically important.
8.2
Populations for Analyses
The following datasets will be used for analyses:

Enrolled subjects dataset: The enrolled subjects dataset includes data collected from all 
subjects who signed informed consent.

Lead-in subjects dataset: The lead-in subjects dataset includes data collected from all 
subjects who have at least one vital sign measurement during the lead-in period.

Full analysis dataset: The full analysis dataset will consist of all randomized subjects who 
took at least one dose of double-blind study medication during the short-term double-blind 
period. Whenever using the full analysis dataset, subjects will be presented in the treatment 
group to which they were randomized at the start of the short-term double-blind treatment 
period (even if the treatment they received was different).

Evaluable subjects dataset: The evaluable subjects dataset will be a subset of the full 
analysis dataset through exclusion of subjects with important protocol deviations. Important 
protocol deviations are those that have the potential to impact the results of the primary 
analysis. Detailed exclusion criteria for the evaluable subjects dataset will be specified in the 
SAP. All decisions to exclude data from the full analysis dataset to form the evaluable 
subjects dataset will be made prior to the unblinding of the study.

Treated subjects dataset: The treated subjects dataset consists of all subjects who received 
at least one dose of double-blind study medication during the short-term double-blind 
treatment period. The treated subjects dataset would include any subject who accidentally 
received double-blind study medication but was not randomized in the study. These subjects 
will be included in analyses using the treated subject dataset in the treatment they received. 
For randomized subjects, all analyses using the treated subject dataset will be presented by 
randomized treatment group, except in cases where information was available which 
indicated that a subject received a different treatment for the entire course of their 
participation in the study (or period). In this case, the safety data for those subjects will be 
presented by the treatment actually received. In cases where a subject never received the 
treatment as assigned by randomization, then the safety data for that subject will be presented 
by the first treatment received.

Short-term completers dataset: The short-term completers dataset will consist of all 
subjects in the full analysis dataset who completed the short-term double-blind treatment 
period. Whenever using the short term completers dataset, subjects will be presented in the 
treatment group to which they were randomized at the start of the short-term double-blind 
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treatment period (even if the treatment they received in the short-term or long-term was 
different).
Efficacy analyses will be performed using the full analysis dataset, which is considered as the 
primary efficacy dataset. Primary efficacy analysis will be reanalyzed using the evaluable 
subjects’ dataset if more than 10% of the subjects in any treatment group are found to 
significantly violate the terms and conditions of the protocol. Otherwise, efficacy analysis will be 
restricted to the primary efficacy dataset.
Safety analyses will be based on the treated subjects dataset which consists of all subjects who 
received at least one dose of double-blind study medication.
8.3
Endpoints
8.3.1
Primary Endpoint
The primary endpoint of this study is the change in HbA1c from baseline to Week 24.
8.3.2
Secondary Endpoints
The secondary efficacy endpoints are:
1. Percent change from baseline to Week 24 in total daily insulin dose
2. Percent change from baseline to Week 24 in body weight
3. Change from baseline to Week 24 in the mean value of 24-hour glucose readings obtained 
from CGM
4. Change from baseline to Week 24 in mean amplitude of glucose excursion (MAGE) of 
24-hour glucose readings obtained from CGM
5. Change from baseline to Week 24 in the percent of 24-hour glucose readings obtained from 
CGM that falls within the range of > 70 mg/dL and 180 mg/dL
6. Proportion of subjects achieving an HbA1c reduction from baseline to Week 24 0.5% and 
without severe hypoglycemia events.
8.3.3
Safety
The safety endpoints include:

The proportion of subjects with hypoglycemia events and the frequency and severity of the 
hypoglycemia events

The proportion of subjects experiencing adverse events (AE), DKA events, and marked 
abnormalities in clinical laboratory tests

The change from baseline at each post-baseline time point of assessment of selected safety 
clinical laboratory parameters, physical measurements, vital signs, and electrocardiogram 
data
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8.3.4
Exploratory Endpoints 
The efficacy exploratory endpoints of the study are:
1) Proportion of subjects with HbA1c reduction from baseline to Week 24 of at least 0.5% 
(0.5%)
2) Proportion of subjects with HbA1C < 7.0% after 24 weeks of double-blinded treatment
3) Change from baseline to Week 24 in FPG
4) Change from baseline to Week 24 in the percent of 24-hour glucose readings obtained from 
CGM that falls within the hypoglycemic range of 70 mg/dL
5) Change from baseline to Week 24 in seated systolic blood pressure among subjects with 
hypertension at baseline, defined as seated SBP 140 mmHg and/or seated DBP 90 mmHg
6) Change from baseline to Week 24 in average glucose values measured by 6-point self 
monitored blood glucose (SMBG)
7) Change from baseline to Week 24 in postprandial glucose values measured by 6-point self 
monitored blood glucose (SMBG)
8) Change from baseline to Week 24 in postprandial glucose values measured by CGM
9) Change from baseline to Week 24 in the standard deviation of 24-hour glucose readings 
obtained from CGM
10) Change from baseline to Week 24 in each of the 5 dimensions, as well as the health status 
index of the EQ-5D-3L questionnaire
11) Changes from baseline to Week 24 in the summary score for treatment satisfaction and 
scores for perceived frequency of hyperglycemia and perceived frequency of hypoglycemia, 
respectively, as measured by the Diabetes Treatment Satisfaction Questionnaire status 
(DTSQs)
12) Changes from baseline to Week 24 in the summary score of the Hypoglycemia Fear Survey 
(HFS-II) Worry Subscale between the dapagliflozin 5 mg or 10 mg plus adjustable insulin 
versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
13) To explore the relationship between observed and/or model estimated pharmacokinetic 
measures of exposure (eg, AUCss, Cmax, Cmin) and efficacy and/or safety endpoints by 
using model-based approaches. This analysis will be provided in a separate report
14) Number of non-severe hypoglycemic events per subject in those achieving a HbA1c 
reduction of 0.5%
8.4
Analyses
Analyses of the data from the short-term period will be conducted once all randomized subjects 
have either completed the short-term double-blind period or discontinued study medication from 
the short-term double-blind period. In addition all relevant queries must be resolved and the 
database must be locked for this period before the blind is broken for analyses.
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Analyses of the data from both short-term double-blinded and long-term subject- and 
site-blinded treatment periods will be performed after all subjects have completed or have been 
discontinued from the study. In addition, all relevant queries must be resolved and the database 
must be locked for this study prior to analyses.
8.4.1
Demographics and Baseline Characteristics
Frequency distributions and summary statistics for demographic and baseline variables 
summarized in efficacy analyses will be computed by treatment group, as well as for all subjects 
combined. No statistical test will be carried out for comparison of any baseline measurement 
among the treatment groups.
8.4.2
Efficacy Analyses
Unless otherwise specified, efficacy analyses will be performed using the full analysis dataset.
8.4.2.1
Primary Efficacy Analyses
The primary endpoint is the change in HbA1c from baseline to Week 24. The primary estimand 
for the primary endpoint is treatment difference at Week 24 if subjects did not discontinue 
randomized treatment. In order to maintain an overall Type I error rate of 5% for the endpoint, a 
Dunnett and Tamhane step-up procedure will be used, which allows for the correlation of 0.5 
between the standard normal deviate for each comparison (Dunnett and Tamhane 1992).20
Applying the Dunnett and Tamhane procedure, statistical significance will be declared for both 
doses at the two-sided 5% level if the two-sided p-values from both pairwise comparisons are 
smaller than 5%. If the larger p-value among the two pairwise comparisons is greater than 5% 
and the smaller p-value is below 2.62%, then statistical significance will be declared for the latter 
comparison. 
The primary analysis of the change in HbA1c from baseline to Week 24 will be based on a 
longitudinal repeated measures analysis using ‘direct likelihood’. The analysis will be based on 
the full analysis dataset who have a baseline assessment and any post-baseline double-blind 
treatment period assessment. The analysis will include all available data up to Week 24 or until 
premature discontinuation of randomized treatment, whichever occurs first. The analysis will be 
conducted regardless of insulin up-titration. The model is based on a missing at random (MAR) 
assumption with respect to missing data.
The SAS procedure PROC MIXED will be used. The preferred model will include the fixed 
categorical effects of treatment, week, randomization stratification factor (ie, one term for each 
combination of all stratification factors) and treatment-by-week interaction, as well as the 
continuous fixed covariates of baseline measurement and baseline measurement-by-week 
interaction. An unstructured matrix for the within-subject 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 within each treatment group as well as the difference in mean 
change between the dapagliflozin treatment group and placebo will be calculated. P-values for 
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the differences in the Week 24 estimates between each dapagliflozin group and placebo will be 
calculated.
The ITT estimand, i.e., treatment difference at Week 24 regardless of treatment discontinuation, 
will be evaluated as the secondary estimand of the primary endpoint. The analysis of the ITT 
estimand will include all available data up to Week 24, regardless of insulin up-titration and 
regardless of premature discontinuation of randomized treatment.
Sensitivity analyses will be conducted for the primary efficacy endpoint to assess the robustness 
of the primary efficacy results, including sensitivity analysis with respect to the ITT estimand, 
sensitivity analyses based on missing-not-at-random (MNAR) assumptions with respect to 
missing data, and sensitivity analysis with respect to insulin up-titration.
8.4.2.2
Secondary Efficacy Analyses
Statistical tests for secondary efficacy endpoints will be only conducted if there is a statistically 
significant difference in the primary endpoint for both pairwise comparisons, i.e., dapagliflozin 
5 mg vs. placebo and dapagliflozin 10mg vs. placebo. The same Dunnett and Tamhane step-up 
procedure will be applied to each secondary efficacy endpoint. Secondary efficacy endpoints will 
be tested in the order that they appear in the objectives section of the protocol and protocol 
synopsis. Statistical tests will be only performed for a given secondary endpoint if both 
comparisons for a proceeding secondary endpoint are significant. Otherwise, the testing 
procedure will stop at the secondary endpoint that does not reach statistical significance.
The percent change (using logarithmic transformation for the endpoint in the model) from 
baseline to Week 24 in total daily insulin dose and total body weight, the change from baseline to 
Week 24 in the mean value of 24-hour glucose readings obtained from CGM, mean amplitude of 
glucose excursions of 24-hour glucose readings obtained from CGM, and the percent of 24-hour 
glucose readings obtained from CGM that fall within the range of 70 mg/dL and 180 mg/dL 
will be analyzed using a longitudinal repeated measures analysis, similarly to the model used for 
primary efficacy analysis. The proportion of subjects achieving an HbA1c reduction from 
baseline to Week 24 visit 0.5% without severe hypoglycemia events will be analyzed using a 
logistic regression model with adjustment for baseline value. In addition to point estimates and 
95% confidence intervals, p-values will be calculated for all endpoints. Nominal p-values will be 
presented for endpoints where type 1 error is not controlled. All secondary efficacy analyses will 
use subjects in the primary efficacy dataset (ie, full analysis dataset) who have a baseline 
assessment and any post-baseline double-blind treatment period assessment.
8.4.2.3
Exploratory Efficacy Analyses
The proportion of subjects with HbA1c reduction from baseline to Week 24 last observation 
carried forward (LOCF) of at least 0.5% (0.5%) and the proportion of subjects with HbA1c at 
Week 24 LOCF < 7.0% will be summarized for each treatment group. For these analyses, LOCF 
refers to the Week 24 value, or the last post-baseline measurement prior to Week 24 if no 
measurement is available at Week 24. Poisson regression will be used to model number of non-
severe hypoglycemic events per subject in those achieving a HbA1c reduction of 0.5%. Point 
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estimates and 2-sided 95% confidence intervals for the proportion in each treatment group and 
for the differences in proportions between each dapagliflozin treatment groups and the placebo 
treatment group will be calculated. No p-values will be generated. 
The change from baseline to Week 24 in the following parameters will be analyzed using a 
longitudinal repeated measures model similar to the primary efficacy analysis:

Fasting plasma glucose

Percent of 24-hour glucose readings obtained from CGM that falls within the range of 
70 mg/dL

Seated systolic blood pressure among subjects with hypertension at baseline, defined as 
seated SBP 140 mmHg and/or seated DBP 90 mmHg

Average glucose values measured by 6-point SMBG

Postprandial glucose values measured by 6-point SMBG

Postprandial glucose values measured by CGM

Standard deviation of 24-hour glucose readings obtained from CGM
8.4.3
Safety Analyses
The incidence of adverse events and of marked abnormalities in clinical laboratory tests will be 
summarized by treatment group.
The proportion of subjects with at least one hypoglycemic episode will be summarized by 
treatment group and by the severity of the events. The frequency of the hypoglycemia will also 
be summarized. Subjects with adjudicated DKA events will also be summarized by treatment 
group.
All AEs that are serious or that result in discontinuation of study therapy will be described in 
depth. Changes from baseline at each of the scheduled time points in each clinical laboratory 
parameter will be summarized by treatment group.
Changes from baseline at each of the scheduled time points in each selected safety clinical 
laboratory parameters, physical measurements, vital signs and electrocardiogram data will be 
summarized by treatment group.
8.4.4
Pharmacokinetic Analyses
The dapagliflozin plasma concentrations obtained by sampling of individual subjects will be 
used to build a population PK (PPK) model to estimate PK parameters (eg, oral clearance 
[CL/F], apparent volume of distribution [Vd/F], and absorption rate constant [ka]). Possible 
covariate effects on PK parameters may be identified and quantified. The estimated parameters 
will be used to derive individual exposure measures (eg, AUC, Cmin). Relationships between
observed exposures, and/or these model-based estimates of exposures, and efficacy/safety 
endpoints (eg, changes from baseline in HbA1c, average daily glucose concentration, 
hypoglycemia) will be explored. The PK data and efficacy endpoint responses derived from this 
study may also be pooled with similar data from other studies to refine the model-based 
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exposure-response relationship. Listings and summary statistics will be reported for the sampled 
pharmacokinetic measurements. The PPK and exposure-response analyses will be described in a 
separate report. 
8.4.5
Biomarker Analyses
Not applicable
8.4.6
Outcomes Research Analyses
The change from baseline to Week 24 LOCF (Week 24 value or the last post-baseline 
measurement prior to Week 24 if no measurement is available at Week 24, [ie, last observation 
carried forward]) in each of the 5 dimensions of the EQ-5D-3L questionnaire will be analyzed 
with shift tables showing difference as to the respective classifications at baseline.
The change from baseline to Week 24 LOCF in the following will be analyzed as continuous 
variables: 1) health status index of the EQ-5D-3L questionnaire; 2) the summary score for 
treatment satisfaction and scores for perceived frequency of hyper- and perceived frequency of 
hypoglycemia, respectively, as measured by the Diabetes Treatment Satisfaction Questionnaire 
status (DTSQs); and 3) the summary score for HFS-II Worry Subscale. These will be analyzed 
using an ANCOVA model with treatment group as effect and baseline value and randomization 
stratification factor (ie, one term for each combination of all stratification factors) as covariates. 
Point estimates and 2-sided 95% confidence intervals for the mean change within each treatment 
group, as well as for the differences in the mean change between each dapagliflozin treatment 
group and the placebo treatment group will be calculated. No p-values will be generated.
All above mentioned analyses will use subjects in the primary efficacy dataset (ie, full analysis 
dataset) who have at least one baseline assessment and any post-baseline double-blind treatment
period assessment.
8.4.7
Other Analyses
Not applicable.
8.5
Interim Analyses
There are no planned interim analyses for this study.
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 BMS. 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.
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If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, the deviation or change will be submitted as 
soon as possible to:

IRB/IEC for review and approval/favorable opinion

BMS

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 BMS.
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
Representatives of BMS/CRO 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. Certain pages and/or electronic files may serve as the 
source documents, including but not limited to: CGM data, fingerstick blood glucose values 
recorded in the diary and meter data (SMBGs and ketones), insulin pump data, and the diary data 
as noted in Section 5.2.
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3
Investigational Site Training
BMS will provide quality investigational staff training prior to study initiation. Training topics 
will include but are not limited to: good clinical practice (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 
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specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study 
drug are inventoried and dispensed. 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 (eg, lost, wasted)

Amount destroyed at study site, if applicable

Amount returned to BMS

Retain samples for bioavailability/bioequivalence, if applicable

Dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
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 BMS 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 paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
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left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS.
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 sub-investigator 
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS 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 BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. 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 clinical study report.
For this protocol, the Signatory Investigator will be selected considering the following criteria:

National Coordinating Investigator

Involvement in trial design
The data collected during this study are confidential and proprietary to AZ. Any publications or 
abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTAg) governing [Study site or Investigator] participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to AZ 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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GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the investigator 
or BMS as related to the investigational product
Unexpected Adverse Reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved investigational 
product)
Serious Adverse Event
Serious adverse event defined as 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; 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 [eg, 
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.). For reporting purposes only, BMS also 
considers the occurrence of pregnancy, overdose (regardless 
of association with an AE), and cancer as important medical 
events.
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LIST OF ABBREVIATIONS
Term
Definition
A1C
Glycosylated Hemoglobin
ADA
American Diabetes Association 
AE
Adverse event
ALK-P
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUA
American Urological Association
AZ
AstraZeneca
BMI
Body mass index
BMS
Bristol-Myers Squibb
BP
Blood pressure
C
Celsius
CABG
Coronary artery bypass graft
CFR
Code of Federal Regulations 
CEC
Clinical event committee
CGM
Continuous Glucose Monitoring 
CHF
Congestive Heart Failure
CK
Creatine kinase
Cm
Centimeter
CPK
Creatine phosphokinase
CrCl
Creatinine Clearance
Cr
Creatinine
CRF
Case Report Form, paper or electronic
CRO
Contract Research Organization
CSII 
Continuous subcutaneous insulin infusion
CT
Computed Tomography
CTAg
Clinical Trial Agreement
CV
Cardiovascular
DBP
Diastolic blood pressure
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Term
Definition
DKA
Diabetic Ketoacidosis
dL
Deciliter
DILI
Drug-induced liver injury
DMC
Data Monitoring Committee
DTSQs
Diabetes Treatment Satisfaction Questionnaire
DVT
Deep Vein Thrombosis
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
Eg
exempli gratia (for example)
EQ-5D-3L
Euro Quality of life 5 dimensions 3 levels
ET
Early Termination
FDA
Food and Drug Administration
FFA
Free Fatty Acid
FPG
Fasting Plasma Glucose
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
g/L
Grams/liter
g/dl
Grams/deciliter
GFR
Glomerular filtration rate
HbA1c
Glycosylated Hemoglobin
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HCG
Human Chorionic Gonadotropin
HFS-II
Hypoglycemia Fear Survey II
HIPAA
Health Insurance Portability and Accountability Act
HR
Heart rate
HRQoL
Health related Quality of Life
HRT
Hormone replacement therapy
ICF
Informed Consent
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Term
Definition
ICH
International Conference on Harmonisation 
Ie
id est (that is)
IEC
Independent Ethics Committee
IMP
Investigational medicinal products
IRB
Institutional Review Board
IU
International Unit
IUD
Intrauterine Device
IVRS
Interactive Voice Response System
Kg
kilogram
Lb
Pound
LFT
Liver function test
LOCF
Last observation carried forward
M
Meter
MAGE
Mean amplitude of glucose excursions
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDI
Multiple daily injections
Mg
milligram
mL
milliliter
MI
Myocardial infarction
Min
minute
Mmol
Millimole
MOA
Mechanism of Action
MODY
Maturity onset diabetes of young
NIMP
Non-investigational medicinal products 
NSAID
Nonsteroidal anti-inflammatory drug
NYHA
New York Heart Association
PCI
Percutaneous Coronary Intervention
PE
Pulmonary Embolism
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Term
Definition
PK
Pharmacokinetics
PPK
Population Pharmacokinetics
PRO
Patient reported outcomes
PT
Prothrombin time
PTCA
Percutaneous transluminal coronary angioplasty
QD, qd
quaque die, once daily
RBC
Red blood cell
SA
Sickle cell trait
SAE
Serious adverse event
SBP
Systolic blood pressure
SD
Standard deviation
SGLT-2
Sodium-dependent glucose transporter 2
SMBG
Self monitored blood glucose
SMQ
Standardized MedDRA Queries
SOP
Standard Operating Procedures
TB
Total bilirubin
TIA
Transient Ischemic Attack
TSH
Thyroid Stimulating Hormone
T1DM
Type 1 Diabetes Mellitus
T2DM
Type 2 Diabetes Mellitus
ULN
Upper limit of normal
UTI
Urinary Tract Infection
VAS
Visual Analogue Scale
WOCBP
women of childbearing potential
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REFERENCES
1
Daneman D. Type 1 Diabetes. Lancet 2006;367:847-58.
2
Cryer PE. Hypoglycaemia: The limiting factor in the glycaemic management of Type 1 and 
Type II Diabetes. Diabetologia 2002;45:937.948.
3
Weinstock RS, Xing D, Maahs DM, Michels A, Rickels MR, Peters AL, et al. Severe 
hypoglycemia and diabetic ketoacidosis in adults with type 1 diabetes: results from the T1D 
Exchange clinic registry. J Clin Endocrinol Metab 2013;98(8):3411-9.
4
Kilpatrick ES, Rigby AS, Goode K, Atkin SL. Relating mean blood glucose and glucose 
variability to the risk of multiple episodes of hypoglycaemia in type 1 diabetes.Diabetologia. 
2007;50(12):2553-61
5
The 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;329:977–986.
6
Kilpatrick ES, Rigby AS, Atkin SL. Insulin resistance, the metabolic syndrome, and 
complication risk in type 1 diabetes: "double diabetes" in the Diabetes Control and 
Complications Trial. Diabetes Care. 2007;30(3):707-12.
7
Ferriss JB, Webb D, Chaturvedi N, Fuller JH, Idzior-Walus B; The EURODIAB Prospective 
Complications Group. Weight gain is associated with improved glycaemic control but with 
adverse changes in plasma lipids and blood pressure in Type 1 diabetes. Diabet Med 
2006;23(5):557-64.
8
Cleland SJ, Fisher BM, Colhoun HM, Sattar N, Petrie JR. Insulin resistance in type 1 
diabetes: what is 'double diabetes' and what are the risks? Diabetologia. 2013;56(7):1462-70.
9
Soedamah-Muthu SS, Chaturvedi N, Witte DR, Stevens LK, Porta M, Fuller JH for the 
EURODIAB Prospective Complications Study Group. Relationship between risk factors and 
mortality in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications 
Study (PCS). Diabetes Care 2008;31(7):1360-6.
10 Beck RW, Tamborlane WV, Bergenstal RM, Miller KM, DuBose SN, Hall CA for the T1D 
Exchange Clinic Network. The T1D exchange clinic registry. J Clin Endocrinol Metab 
2012;97(12):4383-9.
11 Investigator Brochure Version 07: Dapagliflozin (BMS-512148). Bristol-Myers Squibb 
Research and Development and AstraZeneca AB, 22-Dec-2010, BMS Document Control 
Number 930005487.
12 Defronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, Morrow LA, 
Leslie BR, Boulton DW, Ching A, Lacreta FP, Griffen SC. Characterization of renal glucose 
reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 
diabetes. Diabetes Care 2013;36:3169-3176.
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13 Perkins BA, Cherney DZ, Partridge H, Soleymanlou N, Tshirhart H, Zinman B, et al. 
Sodium-glucose cotransporter 2 inhibition and glycemc control in type 1 diabetes: results of 
an 8-week open-label proof-of-concept trial. Diabetes Care 2014;37:1480-83.
14 Kestelman P. et. al., Efficacy of the Simultaneous Use of Condoms and Spermicides Family 
Planning Perspectives.Vol 23 (5); October 1991; 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.
15 Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM. Infectious diseases 
society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria 
inadults. Clin Infect Dis 2005;40:643-54.
16 US Preventative Services Taskforce. Recommendation Statement Screening orAsymptomatic 
Bacteriuria. Revised 2004. Available athttp://www.ahrq.gov/clinic/uspstf/uspsbact.htm
17 European Association of Urology. Guidelines on the management of urinary and male 
genitaltract infections 2008. Available at http://www.uroweb.org/
18 Bradley C (1994) The Diabetes Treatment Satisfaction Questionnaire: DTSQ. In Bradley C 
(ED) (1994) Handbook of Physchology and Dianetes: a guide to Psychological Measurement 
in diabetes research and practice. Chur, Switzerland: Harwood Academic Publishers.
19 Gonder-Frederick L, Schmidt K, Vajda K, Greear M, Singh H, Shepard J, Cox D: 
Psychometric properties of the Hypoglycemia Fear Survey-II for adults with Type 1 diabetes. 
Diabetes Care 2011, 34:801-806.
20 Dunnett CW and Tamhane AC.  A step-up multiple test procedure.  J of the American 
Statistical Association. 1992;87(417):162-170.
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Page:
1
Protocol Number:
MB102230
IND Number:
68,652
EUDRACT Number
2014-004599-49
Date:
18-May-2016
Protocol MB102230: A Multicenter, Randomized, Double-Blind, Placebo-controlled, 
Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Dapagliflozin as an Add-on 
to Insulin Therapy in Subjects with Type 1 Diabetes Mellitus -Study Two
Amendment Number 05
Site Number: All
Study Director/Central Medical Monitor
Lars Hansen, MD, PhD
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Bristol-Myers Squibb Research and Development
Metabolics Clinical Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
Route 206 & Province Line Road
Lawrenceville, NJ 08543
This protocol amendment contains information that is confidential and proprietary to 
Bristol-Myers Squibb (BMS).
This amendment must be maintained with the referenced protocol.
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Protocol Amendment 05
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Amendment Rationale:
The primary purpose of this amendment is to provide study visit scheduling flexibility by
allowing optional phone visits to be done at week -4, week 2 and for the Continuous Glucose 
Monitoring visits (weeks 10/11 and weeks 22/23) during the 24 week double blinded short term 
treatment period.
Additional changes in this amendment include:

Adding an exploratory endpoint to compare the number of non-severe hypoglycemic events 
per subject in those achieving a HbA1c reduction of 0.5% on dapagliflozin 5 mg or 10 mg 
plus adjustable insulin versus placebo plus adjustable insulin from baseline to Week 24 visit.

Updating the guidance on DKA assessments and reporting to include the following:

Reductions in insulin doses of more than 20% are not recommended regardless of 
glucose values. If blood glucose is repeatedly low and a 20% reduction in total daily
insulin dose cannot be avoided the daily dietary carbohydrate intake should be increased,   
as well as during and/or after elevated physical activity.  

Investigators are recommended to advise subjects to take extra insulin and extra 
carbohydrates if elevated ketones are registered and to continue to measure blood 
ketones.  Study medication should be interrupted during sick days if necessary

For subjects who report elevated ketones/ketosis or a DKA, it is recommended that the 
investigator consider reeducation concerning DKA at the next scheduled visit, at an un-
scheduled visit or by telephone contact

Adding that if total daily insulin dose is reduced upon initiation of study medication, attempts 
must be made to titrate insulin back to baseline total daily insulin dose. It is not 
recommended to reduce total daily insulin dose by more than 20% compared to baseline at 
any time during the study unless medically indicated and close attention should be paid, 
especially in these subjects, to symptoms of, and risk factors for developing DKA.

Revising the upper range of the Week -1 Visit: Central laboratory HbA1c to 10.5%

Adding multiple statistically related changes in this amendment including:

Adding the ITT estimand analysis and sensitivity analyses for the primary efficacy
endpoint.

Replacing the single-step Dunnett procedure with the Dunnett and Tamhane step-up 
procedure for improved power and greater emphasis on primary endpoint.

Replacing “Randomized subjects dataset” with “Full analysis dataset”.  

Replacing the Zhang et al method with a general logistic regression model for
implementation considerations. 

Adding statistical method to model the added exploratory endpoint, number of number of 
non-severe hypoglycemic events per subject in those achieving a HbA1c reduction of 
0.5%

Indicating that Tubal Ligation in this protocol is not considered surgical sterilization

Removing the PK Sampling required at the Day 1 visit
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Protocol Amendment 05
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
Confirming that subjects are to record day and time of CGM sensor insertion if performed at 
home at week 11 and week 23

Reinforcing that all results recorded in subject diary are to be reviewed by site staff during 
each study visit and that determination of a DKA event must be assessed and documented by 
the Principal Investigator or by a qualified sub-investigator

Adding that blood ketone and glucose values associated with events that are deemed not to 
be a DKA event should be recorded on the non-DKA eCRF log page 

Including local injections such as intramuscular or intra-articular in the systemic 
corticosteroid therapy exclusion criteria as well as adding drops to the topical corticosteroids 
that are allowed in the study

Clarifying that the Data Monitoring Committee will periodically evaluate the incidence of 
hypoglycemia and DKA events, as well as AEs, laboratory measurements, and safety 
assessments to ensure the ongoing safety of study subjects.

Adding multiple updates, confirmations and additions in the Study Flowchart
The changes included in the amendment apply to all subjects in the study with no impact 
expected on study conduct
Changes to the Protocol:
1. Cover Page, Study Director/Medical Monitor Contact Information: Updated Medical 
Director name and telephone number 
2. Synopsis 
Other/Exploratory 
Objectives, 
14th
objective, 
Protocol 
Section 
1.3.3 
Other Exploratory Objectives, 14th objective:  Added new objective for comparing the 
number of non-severe hypoglycemic events per subject in those achieving an HbA1c 
reduction of 0.5% on dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo 
plus adjustable insulin from baseline to Week 24 visit
3. Synopsis Study Design, end of 2nd paragraph, Protocol Section 3 Investigational Plan, 
Section 3.1 Study Design and Duration, Protocol Section 4.4.1, Subjects entering the 24-
week double-blinded short-term treatment period: Updated the higher end of the range of the 
Week -1 Visit: Central laboratory HbA1c to 10.5% in the third factor for randomization 
stratification
4. Synopsis Study Design, 3rd paragraph: Clarified the recommendation for daily insulin dose 
reduction is to be up to 20%
5. Synopsis, Figure 1, Study Schematic, Protocol 3.1-1 Study Design Schematic:  Added
Optional Phone visits for week -4, 2, 10, and 22
6. Synopsis Study Population, Key Inclusion Criteria, 4th bullet, Protocol Section 3.3.1 
Inclusion Criteria 4b): Updated the higher end of the range of the Week -1 Visit: Central 
laboratory HbA1c to 10.5%
7. Synopsis Study Population, Key Exclusion Criteria, 6th bullet, Other Exclusion Criteria, fifth 
bullet, Protocol Section 3.3.2 Exclusion Criteria, 6) Other Exclusion Criteria, bullet e), 
Protocol Section 3.4.1 Prohibited and/or Restricted Treatments, 3rd bullet: Added local 
injections such as intramuscular or intra-articular,etc. as an example of systemic 
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Protocol Amendment 05
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corticosteroid therapy excluded as well as adding drops to the topical corticosteroids that are 
allowed in the study
8. Synopsis Study Assessments, Safety Assessments: Added guidance that subjects must also be 
instructed that if attempts to contact the site are unsuccessful or if they are in urgent need of 
medical attention that they should seek medical attention. They should provide information 
to the health care provider on their participation in a placebo controlled clinical study 
evaluating the effects of the SGLT2i dapagliflozin in addition to their insulin treatment.
9. Synopsis Data Monitoring Committee, Protocol Section 7.4, Data Monitoring Committee:  
Clarified that DMC would periodically evaluate the incidence of hypoglycemia and DKA 
events, as well as AEs,
10. Synopsis Statistical Considerations, Sample Size, Protocol Section 8 Statistical 
Considerations, Section 8.1 Sample Size Determination: 
a) Removed incorrect text in 2nd paragraph
b) Added new language for 243 subjects per treatment group with both baseline and at least 
one post baseline measurement, there is approximately 90% power to detect a difference 
in means of 0.35% between each dapagliflozin treatment group and placebo at the two-
sided 0.0262 significance level (based on Dunnett and Tamhane step-up procedure), 
assuming a standard deviation (SD) of 1.1%.
11. Synopsis, Statistical Considerations, Statistical Approach / Assumptions, Protocol Section 
8.4.2.1 Primary Efficacy Analyses
a) Removed second sentence in first paragraph and added The primary estimand for the 
primary endpoint is treatment difference at Week 24 if subjects did not discontinue 
randomized treatment. 
b) Added In order to maintain an overall Type I error rate of 5% for the endpoint, a Dunnett 
and Tamhane step-up procedure will be used, which allows for the correlation of 0.5 
between the standard normal deviate for each comparison (Dunnett and Tamhane 1992). 
Applying the Dunnett and Tamhane procedure, statistical significance will be declared 
for both doses at the two-sided 5% level if the two-sided p-values from both pairwise 
comparisons are smaller than 5%. If the larger p-value among the two pairwise 
comparisons is greater than 5% and the smaller p-value is below 2.62%, then statistical 
significance will be declared for the latter comparison.
c) Removed model will use subjects in the primary efficacy dataset (ie, randomized subjects 
dataset) 
d) Added The analysis will be based on the full analysis dataset
e) Removed For subjects whose insulin dose is up-titrated by more than 25% of baseline 
insulin prior to randomization measurements, obtained after meeting the above insulin 
up-titration criteria will be excluded from the primary analysis but included in the 
sensitivity analysis. Multiple sensitivity analyses, including the sensitivity analyses using 
data regardless of insulin dose up-titration, will also be performed for the primary 
efficacy endpoint to assess
f)
Added The analysis will include all available data up to Week 24 or until premature 
discontinuation of randomized treatment, whichever occurs first. The analysis will be 
conducted regardless of insulin up-titration. The model is based on a missing at random 
(MAR) assumption with respect to missing data
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Protocol Amendment 05
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g) Added will be evaluated as the secondary estimand of the primary endpoint. The analysis 
of the ITT estimand will include all available data up to Week 24, regardless of insulin 
up-titration and regardless of premature discontinuation of randomized treatment.
h) Added Sensitivity analyses will be conducted for the primary efficacy endpoint to assess 
the robustness of the primary efficacy results, including sensitivity analysis with respect 
to the ITT estimand, sensitivity analyses based on missing-not-at-random (MNAR) 
assumptions with respect to missing data, and sensitivity analysis with respect to insulin 
up-titration.
12. Synopsis, Statistical Considerations, Statistical Approach / Assumptions, Protocol Section 
8.4.2.2 Secondary Efficacy Analyses
a) Removed the original secondary efficacy analysis description
b) Added Statistical tests for secondary efficacy endpoints will be only conducted if there is 
a statistically significant difference in the primary endpoint for both pairwise 
comparisons, i.e., dapagliflozin 5 mg vs. placebo and dapagliflozin 10mg vs. placebo. 
The same Dunnett and Tamhane step-up procedure will be applied to each secondary 
efficacy endpoint. Secondary efficacy endpoints will be tested in the order that they 
appear in the objectives section of the protocol and protocol synopsis. Statistical tests will 
be only performed for a given secondary endpoint if both comparisons for a proceeding 
secondary endpoint are significant. Otherwise, the testing procedure will stop at the 
secondary endpoint that does not reach statistical significance
c) Replaced the Zhang et al method with a general logistic regression model for 
implementation considerations
d) End of last paragraph replaced However, no claim will be based on endpoints for which 
the statistical testing is not performed as per the testing strategy as described above. No 
claims can be made based on these p-values. A clear distinction will be made between p-
values whereby claims can and cannot be made with Nominal p-values will be presented 
for endpoints where type 1 error is not controlled
e) Replaced randomized subject dataset with full analysis dataset
13. Section 3.3.1 Inclusion Criteria, 6) Age and Reproductive Status:  Clarifed that tubal ligation 
is not considered surgically sterile
14. Section 5, Table 5.1-1 Flow chart for Protocol MB102229, Qualification and Lead-in Period: 
a) Week -4: Added footnote c
b) Insert/calibrate CGM, Record Meals for 7 days - Second week of CGM.:  Added If a 
lead-in subject fails lead-in prior to the Day 1 visit, the CGM will not be required to be 
completed between the week-2 visit and the Day 1 visit  (Please refer to Section 5.9.4.3)
c) 6-point SMBG profiles:  Added If a lead-in subject fails prior to the Day 1 visit, the 6-
point SMBG profile will not be required between the week -1 visit and the Day 1 visit
d) Pregnancy test (urine) WOCBP only:  added footnote g for week -8 and week -4
e) Footnote c:  Added details for Optional Phone Visit at week -4
f)
Footnote g:  Added If an optional phone visit is planned for week -4, the home pregnancy
kit should be given to the subject at the week -8 visit.
15. Section 5, Table 5.1-2 Flow chart for Protocol MB102229, 24-week Double-blinded Short-
term Treatment Period,  
a) Week 2:  Added footnote d
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b) Week 10 and Week 22:  Added footnote e
c) Insert/calibrate CGM:  Added in Notes column If week 10 and week 22 are optional 
phone visits, please refer to footnote e below and Section 5.9.4.3 CGM.
d) Insert/calibrate CGM, CGM Data Collection, data upload, and review, and Record Meals
for7 days - Second week of CGM: Added Note Please refer to Section 5.9.4.3
e) Dispense subject diaries and provide instructions:  Added footnote l in week 8 and week 
18 
f)
Dispense subject diaries and - provide instructions:  Added in Notes column At Day 1, 
collect Lead-In Period diaries and dispense the first diaries in the Short Term Treatment 
Period and added X to indicate the procedure needs to be done at week 10 and week 22 
visits
g) Review subject diaries, Adjust Insulin Dose, as needed, Assess Adverse Events, Assess 
Hypoglycemia Episodes, Assess DKA:  Added X to indicate the procedure needs to be 
done at week 10 and week 22 visits
h) PK sampling:  Removed procedure requirement at Day 1
i)
Contact IVR system:  Added footnote m at week 4, 8, 12, and 24
j)
Footnote d:  Added the footnote with details for Optional Phone Visit at Week 2
k) Footnote e:  Added the footnote with details for Optional Phone Visit at Week 10 and/or 
Week 22
l)
Footnote 1:  Added the footnote If an optional phone visit is to be done at week 10, the 
subject diary should be given to the subject at week 8 and/or a new week 22 diary should 
be given at week 18
m) Footnote m:  Added the footnote to indicate that if visit is during the “off-treatment” or 
the Post Study Drug Study Follow-up phase (Section 3.6), the IVRS does not have to be 
contacted
16. Section 5, Table 5.1-3 Flow chart for Protocol MB102229, 28-week Subject and Site Blinded 
Long-term Treatment Period:
a) Included footnote a at week 52 to allow + 5 day visit window
b) Pregnancy test (urine) WOCBP only:  Added and pregnancy logs to Notes
c) Contact IVR system:  Added footnote c at week 32, 40, and 52
d) Footnote c:  Added the footnote to indicate that if visit is during the “off-treatment” or the 
Post Study Drug Study Follow-up phase (Section 3.6), the IVRS does not have to be 
contacted
17. Section 5.2,  Study Materials, Subject Diary:
a) Added to end of first bullet during each visit
b) Added to second bullet, day/time of CGM sensor insertion if performed at home at 
Weeks 11 and 23
i)
Added fifth bullet Subjects are to record day and time of CGM sensor insertion if 
performed at home at week 11 and week 23
ii) Added at the end of the eighth bullet during each study visit.  Determination of a 
DKA event must be assessed and documented by the Principal Investigator or by a 
qualified sub-investigator.
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18. Section 5.3.3, Self-Monitored Blood Ketone Testing and Guidance on Management and 
Reporting of Diabetic Ketoacidosis Episodes:
a) Added guidance for reductions in insulin doses of more than 20% not recommended 
regardless of glucose values. If blood glucose is repeatedly low and a 20% reduction in 
total daily insulin dose cannot be avoided the daily dietary carbohydrate intake should be 
increased, as well as during and/or after elevated physical activity.  
b) Added recommendation for the investigator to advise the subject to take extra insulin and 
extra carbohydrates if elevated ketones are registered and continue to measure blood 
ketones. If deemed necessary, dosing of study medication should be interrupted during 
sick days
c) Added guidance for the investigator to consider re-education concerning DKA at the next 
scheduled visit, at an un-scheduled visit or by telephone contact, as appropriate for 
subjects who report elevated ketones/ketosis
d) Added blood ketone and glucose values associated with events deemed not to be a DKA 
event should be recorded on the non-DKA eCRF log page.
e) Added reinforcement. that subjects who experience a DKA, it is recommended that the 
investigator schedules a telephone or site visit for re-education in prevention of ketosis 
and DKA
f)
Section 5.3.4 Insulin Dosing Adjustment and Data Collection Guidelines: Added 
guidance that if total daily insulin dose is reduced upon initiation of study medication, 
attempts must be made to titrate insulin back to baseline total daily insulin dose. It is not 
recommended to  reduce  total daily insulin dose by more than 20% compared to baseline 
at any time during the study unless medically indicated and close attention should be 
paid, especially in these subjects, to symptoms of, and risk factors for developing DKA 
(See also Section 5.3.3).
19. Section 5.3.7 Guidance on Assessment of Hepatic Laboratory Abnormalities, Specialized 
Liver Laboratory Panel:  Added clarification the Specialized Liver Lab Panel should only be 
done once for elevated liver enzymes per Appendix 3 Sustained Elevated Liver Safety 
Abnormalities Flow Chart unless liver discontinuation panel is required
20. Section 5.5 Pharmacokinetic Assessments:  Removed PK Sampling at Day 1
21. Section 5.9.4.3 Continuous Glucose Monitoring (CGM):  Added guidance on optional phone 
visits during CGM visits at week 10/11 and 22/23
22. Section 8 Statistical Considerations, Section 8.1 Sample Size Determination: Removed “For 
subjects whose insulin dose is up-titrated by more than 25% of insulin prior to 
randomization, measurements obtained after meeting the above insulin up-titration criteria 
will be excluded from the primary analysis of the primary efficacy endpoint. “
23. Section 8.2 Populations for Analyses, Section 8.2.1 Definition of Analysis Datasets:
a) Randomized subjects dataset: Removed the section
b) Evaluable subjects dataset:
i)
changed randomized subject dataset to full analysis dataset
ii) added through exclusion of subjects with important protocol deviations. Important 
protocol deviations are those that have the potential to impact the results of the 
primary analysis
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iii) removed It will exclude primary efficacy variable data which may have been affected 
by protocol deviations as determined by the medical monitor
iv) added detailed exclusion criteria for the evaluable subjects dataset will be specified in 
the SAP
v) replaced “data” with “subjects”
c) Short-term completers dataset
i)
changed randomized subject dataset to full analysis dataset
ii) deleted “changed randomized subject dataset to full analysis dataset”
24. Section 8.3.1 Primary Endpoint:  removed second paragraph 
25. Section 8.3.2 Secondary Endpoints:  removed last paragraph
26. Section 8.3.4 Exploratory Endpoints: 
a) added new exploratory endpoint of Number of non-severe hypoglycemic events per 
subject in those achieving a HbA1c reduction of > 0.5%
b) removed the last paragraph
27. Section 8.4.2 Efficacy Analyses:  
a) removed first sentence
b) added Unless otherwise specified, efficacy analyses will be performed using the full 
analysis dataset.
28. Section 8.4.2.2 Secondary Efficacy Analyses:  removed last sentence in the section
29. Section 8.4.2.3 Exploratory Efficacy Analyses
a) added Poisson regression will be used to model number of non-severe hypoglycemic 
events per subject in those achieving a HbA1c reduction of > 0.5%
b) removed incorrect text in last paragraph
30. Section 8.4.6 Outcomes Research Analyses
a) changed randomized subject dataset to full analysis dataset
b) removed incorrect text in last paragraph
31. References
a) Deleted references 18) and 19)
b) Added new reference 18) Dunnett CW and Tamhane AC.  A step-up multiple test 
procedure. J of the American Statistical Association. 1992;87(417):162-170
Please maintain a copy of this amendment with your protocol. Please provide a copy to 
your Investigational Review Board / Ethics Committee, unless agreed otherwise with BMS.
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