Conditions: Type 1 Diabetes Mellitus
Keywords: Japanese patients with type 1 diabetes with inadequate glycemic control on insulin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 151
Healthy volunteers: no

Brief summary:
This study will enroll eligible subjects into a long-term safety study (Part B).

Japanese male and female patients with T1DM and age 18 to 75 years, with inadequate glycemic control on insulin defined as HbA1c ≥ 7.5% and ≤ 10.5% at screening visit. As a condition of enrollment, subjects must be on a total daily insulin dose of ≥ 0.3 U/kg/day for at least 3 months prior to the screening visit. The study design of Part B is a randomized, open-label, 2 arm, parallel-group design. 140 Japanese subjects in total will be randomized in a 1:1 ratio into one of the two treatment arms; dapagliflozin 5 mg or dapagliflozin 10 mg.

Detailed description:

Arms:
arm 1: dapagliflozin tablet 5mg + adjustable insulin arm 2: dapagliflozin tablet 10mg + adjustable insulin

Interventions: intervention 1: Dapagliflozin 5 mg intervention 2: Dapagliflozin 10mg
Intervention descriptions: intervention 1: Dapagliflozin, a blood glucose lowering drug. Oral dose intervention 2: Dapagliflozin, a blood glucose lowering drug. Oral dose

Protocol document:
Prot_001.pdf: 
 
 
Clinical Study Protocol 
 
Drug Substance 
dapagliflozin (BMS-512148) 
 
Study Code 
D1695C00001 
 
Version 
3 
 
Date 
14 December 2016 
 
A clinical pharmacology and long term study to evaluate the safety, efficacy, 
pharmacokinetics and pharmacodynamics of dapagliflozin therapy in 
combination with insulin in Japanese subjects with type 1 diabetes who have 
inadequate glycemic control 
 
Sponsor: 
AstraZeneca KK, 3-1, Ofuka-cho, Kita-ku Osaka 530-0011, Japan 
 
 


Clinical Study Protocol 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
2(110) 
VERSION HISTORY 
Version 3, 14th December 2016 
Changes to the protocol are summarised below. 
Sections 
Revision Summary 
Reason for Revision 
Synopsis/Objectives 
From outcome measures for secondary objective (Part 
B), the parenthetic notes related excluding/insulin up-
titration were deleted. 
After reconsideration, it 
was concluded that 
efficacy analyses should 
primarily be based on all 
available data regardless 
of insulin up-titration. 
Synopsis/Objectives 
7-point SMBG for Part A was added to the 
Exploratory Objectives. 
Additional data collection 
of 7-point SMBG in the 
eCRF for Part A has been 
decided as follows; 
As for Part A, last 
subject has completed the 
study in June 2016 and 
analysis of the result was 
performed. Sponsor 
judged the 7-point SMBG 
data which has already 
been collected in the 
subject diary was 
necessary to interpret the 
result of the PD variables 
more precisely and 
decided to collect the data 
exploratively. 
2.2 Secondary 
objectives 
From outcome measures for secondary objective (Part 
B), the parenthetic notes related to excluding/insulin 
up-titration were deleted. 
After reconsideration, it 
was concluded that 
efficacy analyses should 
primarily be based on all 
available data regardless 
of insulin up-titration. 
2.4 Exploratory 
objectives 
7-point SMBG for Part A was added to the 
Exploratory Objectives. 
Additional data collection 
of 7-point SMBG in the 
eCRF for Part A has been 
decided as follows; 
As for Part A, last 
subject has completed the 
study in June 2016 and 
analysis of the result was 
performed. Sponsor 
judged the 7-point SMBG 
data which has already 
been collected in the 


Clinical Study Protocol 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
3(110) 
Version 3, 14th December 2016 
Changes to the protocol are summarised below. 
Sections 
Revision Summary 
Reason for Revision 
subject diary was 
necessary to interpret the 
result of the PD variables 
more precisely and 
decided to collect the data 
exploratively. 
5.3.1.1 Self Monitored 
Blood Glucose (SMBG) 
The underlined parts (normal font) were added in the 
following paragraph; 
In part A, subjects should self-monitor their blood 
glucose whenever possible at least 7 times per day 
(before and after each meal and before going to bed) 
from Day -1 to Day 7 and in the occurrence of 
hypoglycemic symptoms, and contact the 
Investigators in the event of an unusually high or low 
blood glucose value. Study sites will review these 
diary entries and record these data on the eCRF. 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 investigator blood glucose values 
and/or signs and symptoms suggestive of a 
hypoglycemic episode.  Subjects must report the 
values to the investigator on Day 3 to 5 by telephone 
(fax or email) at least once a day. 
Additional data collection 
of 7-point SMBG in the 
eCRF for Part A has been 
decided as follows; 
As for Part A, last 
subject has completed the 
study in June 2016 and 
analysis of the result was 
performed. Sponsor 
judged the 7-point SMBG 
data which has already 
been collected in the 
subject diary was 
necessary to interpret the 
result of the PD variables 
more precisely and 
decided to collect the data 
exploratively. 


Clinical Study Protocol 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
4(110) 
Version 3, 14th December 2016 
Changes to the protocol are summarised below. 
Sections 
Revision Summary 
Reason for Revision 
5.3.2 
Self-Monitored 
Blood Ketone Testing 
and Guidance on 
Management and 
Reporting of Diabetic 
Ketoacidosis (DKA) 
Episodes 
The following paragraph was added; 
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, their 
carbohydrate intake should be re-valuated and those 
who have insufficient amount of carbohydrate 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 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. 
How to manage the DKA 
was added and 
clarification was made 


Clinical Study Protocol 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
5(110) 
Version 3, 14th December 2016 
Changes to the protocol are summarised below. 
Sections 
Revision Summary 
Reason for Revision 
The underlined parts were added in the following 
paragraph; 
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. Investigator(s) 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, 
investigator(s) 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 
investigator are unsuccessful and if they are in urgent 
need of medical attention, e.g. sings/symptoms, 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 SGLT2 inhibitor 
dapagliflozin in addition to their insulin treatment. 
How to manage the DKA 
was added and 
clarification was made 


Clinical Study Protocol 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
6(110) 
Version 3, 14th December 2016 
Changes to the protocol are summarised below. 
Sections 
Revision Summary 
Reason for Revision 
5.3.3 
Insulin Dosing 
Adjustment and Data 
Collection Guidelines  
The underlined parts were added in the following 
paragraph; 
 In part B, it is recommended that subjects reduce their 
daily insulin dose by up to 20% for both basal and 
bolus insulin after 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 
(particular 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 5.3.2). 
Subjects are to be instructed to document their daily 
individual insulin doses and at least 4-time self 
monitored glucose values (before breakfast, lunch, 
dinner, and bedtime) every day during the treatment 
period in part B and during the treatment period in 
part A.  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. 
How to adjust insulin 
dose was added and 
clarification was made 
8.4.2 Secondary 
endpoints 
From outcome measures for secondary objective (Part 
B), the parenthetic notes related to excluding/insulin 
up-titration were deleted. 
After reconsideration, it 
was concluded that 
efficacy analyses should 
primarily be based on all 
available data regardless 
of insulin up-titration. 


Clinical Study Protocol 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
7(110) 
Version 3, 14th December 2016 
Changes to the protocol are summarised below. 
Sections 
Revision Summary 
Reason for Revision 
8.4.3 Exploratory 
Endpoints 
The following exploratory endpoint of Part A was 
added;  
The relationship between changes in 7-point SMBG 
measurements, 24-hr urinary glucose excursion and 
total daily insulin dose will be explored. 
Additional data collection 
of 7-point SMBG in the 
eCRF for Part A has been 
decided as follows; 
As for Part A, last 
subject has completed the 
study in June 2016 and 
analysis of the result was 
performed. Sponsor 
judged the 7-point SMBG 
data which has already 
been collected in the 
subject diary was 
necessary to interpret the 
result of the PD variables 
more precisely and 
decided to collect the data 
exploratively. 
8.4.5 LOCF 
The strike-through parts were deleted in the following 
paragraph; 
For LOCF, if no measurement is available at a time 
point, the last post-baseline measurement prior to the 
specific time-point will be used instead for analysis. 
Unless otherwise specified, if a subject up-titrates the 
insulin dose, the last value taken on or before the first 
up-titration of insulin dose will be used for analysis. 
After reconsideration, it 
was concluded that 
efficacy analyses should 
primarily be based on all 
available data regardless 
of insulin up-titration. 
8.5.2. Analyses of 
secondary variable(s) 
Clarified that efficacy analysis is primarily conducted 
based on available data regardless of insulin up-
titration.  
After reconsideration, it 
was concluded that 
efficacy analyses should 
primarily be based on all 
available data regardless 
of insulin up-titration. 


Clinical Study Protocol 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
8(110) 
Version 3, 14th December 2016 
Changes to the protocol are summarised below. 
Sections 
Revision Summary 
Reason for Revision 
8.5.3 Exploratory 
analyses 
It is now clarified that analysis plan for exploratory 
endpoint will be documented in the SAP.  The 
subsequent subsection number is changed accordingly.  
Additional data collection 
of 7-point SMBG in the 
eCRF for Part A has been 
decided as follows; 
As for Part A, last 
subject has completed the 
study in June 2016 and 
analysis of the result was 
performed. Sponsor 
judged the 7-point SMBG 
data which has already 
been collected in the 
subject diary was 
necessary to interpret the 
result of the PD variables 
more precisely and 
decided to collect the data 
exploratively. 
8.5.4 Interim Analyses 
It was clarified the interim analyses occurs only after 
Part A and there will be no interim DBL for Part B. 
 
Reconsideration of 
timeline/submission 
strategy  
 
Version 2, 10th February 2016 
Changes to the protocol are summarised below. 
Sections 
Revision Summary 
Reason for Revision 
Synopsis/Study site(s) 
and number of subjects 
planned 
The number of subjects for Part A was changed from 
30 to 42.  
The number of subjects 
planned for Part A has 
been changed as follows; 
Sponsor received a recall 
notice on tubes and 
confirmed that recalled 
tubes had been used for 
all 12 subjects who 
participated in Part A. As 
for the 12 subjects, 
plasma concentration 
might not be measured 
properly. Therefore, 
sponsor judged additional 
12 subjects are necessary. 
Synopsis/Study design 
Number of subjects for Part A was changed from 30 to 
42. 
The number of subjects 
planned for Part A has 
been changed. 


Clinical Study Protocol 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
9(110) 
Version 2, 10th February 2016 
Changes to the protocol are summarised below. 
Sections 
Revision Summary 
Reason for Revision 
1.4.1 
PK and PD 
evaluation part (Part A) 
Number of subjects for Part A was changed from 30 to 
42. 
The number of subjects 
planned for Part A has 
been changed. 
5.3.8 
Resting 12-
Lead ECG 
A term “initiated”, changed in the Clinical Study 
Protocol Amendment 1 as a typo, was changed back to 
“initialed”.  
Typo 
8.2.1 
PK and PD 
evaluation part (Part A) 
Number of subjects for Part A was changed from 30 to 
42. 
The number of subjects 
planned for Part A has 
been changed. 
The underlined parts were added in the following 
paragraph; 
In terms of key PD evaluation (mean change in 24-
hour urinary glucose [g/24h]), the half width of 95% 
confidence interval for treatment difference based on 
10-14 evaluable patients/arm are estimated to be 
approximately 42-50 [g/24h], assuming the common 
standard deviation of 56 [g/24h]. 
The rationale for sample 
size estimation was added 
and clarification was 
made to explain why the 
number of subjects 
planned for Part A was 
changed. 
The following paragraph was added; 
In addition, PK-PD relationships will be evaluated 
exploratory to compare between those of Japanese 
T1DM patients and those of non-Japanese T1DM 
patients.  For this evaluation, 10 patients per arm are 
considered sufficient. 
Originally, in the initial version of the Clinical Study 
Protocol issued at 9th July 2015, about 30 patients 
were planned to be randomized to the study.  
However, 12 patients in Part A were judged to be 
unevaluable for PK data due to issue related to 
sampling tube.  It is considered that the revised sample 
size (randomization of about 42 patients) would lead 
to sufficient number of patients for evaluating PK 
profile, as well as exploratory evaluating PK-PD 
relationships, without the 12 patients.  
The rationale for sample 
size estimation was added 
and clarification was 
made to explain why the 
number of subjects 
planned for Part A was 
changed. 


Clinical Study Protocol 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
10(110) 
Version 2, 10th February 2016 
Changes to the protocol are summarised below. 
Sections 
Revision Summary 
Reason for Revision 
10.5 
Changes to the 
protocol and informed 
consent form 
 
The following paragraph was amended as below 
(added part is indicated as underlined, deleted as strike 
through); 
Study procedures will not be changed without the 
mutual agreement of the Principal Investigator and 
AstraZeneca.  If it is necessary for the study protocol 
Clinical Study Protocol to be amended, the 
amendment amended Clinical Study Protocol should 
be submitted to the Head of the Study Site.  If the 
changes are of an administrative nature, it is submitted 
to the IRB.  If the changes have a significant impact 
on the safety of the subjects, the scientific value of the 
study, the conduct and management of the study, and 
the quality of any investigational product used in the 
study, it should be approved by the IRB.  If 
applicable, AstraZeneca should submit a notification 
to the regulatory authority before it is implemented. If 
a protocol amendment the amended Clinical Study 
Protocol requires a change to a particular centre's 
Informed Consent Form, then AstraZeneca and the 
centre's IRB should be notified by the Principal 
Investigator.  Approval of the revised Informed 
Consent Form by AstraZeneca and by the IRB is 
required before the revised form is used.  If an 
administrative change is required, such a change 
should be notified to or approved by each IRB 
according to local requirements. 
Due to the revision of the 
Japan template for the 
Clinical Study Protocol to 
reflect the updated 
Standard Operational 
Procedure, SOP, of the 
Sponsor 
The whole document 
List of abbreviations and definition of terms was 
updated. 
Editorial changes due to 
updates. 
 “gluccuronide” to “glucuronide” 
“glucemic” to “glycemic” 
“SMBG 4 point” to “4-point SMBG” 
 “6 point SMBG” to “6-point SMBG” 
Typo and editorial 
changes for the sake of 
terminology consistency 
 
Administrative change 2, 5th January 2016 
For changes to the protocol, refer to the document. 
 


Clinical Study Protocol 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
11(110) 
Amendment 2, 25th November 2015 
For changes to the protocol, refer to the document. 
 
Administrative change 1, 30th September 2015 
For changes to the protocol, refer to the document. 
 
Amendment 1, 12th August 2015 
For changes to the protocol, refer to the document. 
 
Version 1, 9th July 2015 
Initial creation 
 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
12(110) 
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 
 


Clinical Study Protocol Synopsis 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
13(110) 
PROTOCOL SYNOPSIS 
 
A clinical pharmacology and long term study to evaluate the safety, efficacy, 
pharmacokinetics and pharmacodynamics of dapagliflozin therapy in 
combination with insulin in Japanese subjects with type 1 diabetes who have 
inadequate glycemic control 
 
Principal Investigator 
The names of the principal investigators are described in Japan Addendum - Investigators and 
Study Administrative Structure. 
Study site(s) and number of subjects planned 
Study Centres: Approximately 40 centres are planned for participation 
Number of Subjects: [Part A] 42 randomized Japanese subjects. [Part B] 140 randomized 
Japanese subjects. 
Study period 
 
Phase of development 
Estimated date of first subject enrolled 
October 2015 
Phase I/III 
Estimated date of last subject completed 
October 2017 
 
 
Study design 
The study design of Part A is a randomized, single-blind, 3 arm, parallel-group, placebo-
controlled design.  Forty-two Japanese subjects in total will be randomized in a 1:1:1 ratio into 
one of the three single-blinded treatment arms; dapagliflozin 5 mg, dapagliflozin 10 mg or 
placebo. 
The study design of Part B is a randomized, open-label, 2 arm, parallel-group design.  One 
hundred forty Japanese subjects in total will be randomized in a 1:1 ratio into one of the two 
treatment arms; dapagliflozin 5 mg or dapagliflozin 10 mg. 


Clinical Study Protocol Synopsis 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
14(110) 
Objectives 
Primary Objective: 
Outcome Measure: 
[Part A] 
To evaluate the pharmacokinetics (PK) and 
pharmacodynamics (PD) of 7 days repeated 
doses of dapagliflozin in Japanese patients 
with type 1 diabetes mellitus (T1DM) with 
inadequate glycemic control under standard 
insulin therapy. 
PK variables: Cmax, Tmax, AUCτ for dapagliflozin and 
dapagliflozin 3-O-glucuronide, and ratio of 
dapagliflozin 3-O-glucuronide AUCτ to dapagliflozin 
AUCτ. 
PD variables: Change from baseline in 24-hour 
urinary glucose excretion on Day 7. 
[Part B] 
To evaluate safety and tolerability of long-
term treatment (52 weeks) of dapagliflozin 
5mg and 10 mg in Japanese patients with 
T1DM with inadequate glycemic control 
under standard insulin therapy. 
Adverse event (including AEs of hypoglycemia and 
diabetic ketoacidosis (DKA) events), physical 
examination, vital signs (blood pressure, heart rate), 
ECG, and clinical laboratory measures, urine test. 
 
Secondary Objective: 
Outcome Measure: 
[Part A] 
To evaluate the PD of 7 days repeated doses of 
dapagliflozin in Japanese patients with T1DM 
with inadequate glycemic control under 
standard insulin therapy. 
Change from baseline in fasting plasma glucose 
(FPG) on Day 7, daily insulin dose, Systolic blood 
pressure (SBP) 
[Part A] 
To assess the safety and tolerability of 7 days 
repeated doses of dapagliflozin in Japanese 
patients with T1DM with inadequate glycemic 
control under standard insulin therapy. 
Adverse event (including AEs of hypoglycemia and 
DKA events), physical examination, vital signs 
(blood pressure, heart rate), ECG and clinical 
laboratory measures, urine test. 


Clinical Study Protocol Synopsis 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
15(110) 
Secondary Objective: 
Outcome Measure: 
[Part B] 
To assess the efficacy of long-term treatment 
(52 weeks) of dapagliflozin 5mg and 10 mg in 
Japanese patients with T1DM inadequately 
controlled on insulin therapy. 
Change from baseline in HbA1c  at Week 24 and 52 
Change from baseline in GA at Week 24 and 52 
Change from baseline in average glucose values 
measured by 6-point SMBG  at Week 24 and 52 
Change from baseline in postprandial glucose values 
measured by 6-point SMBG  at Week 24 and 52 
Percent change from baseline in total daily insulin 
dose  at Week 24 and 52 
Percent change from baseline in body weight  at 
Week 24 and 52 
Proportion of subjects with HbA1c reduction from 
baseline of at least 0.5% without severe 
hypoglycemia events at Week 24 and 52  
Proportion of subjects with HbA1c reduction from 
baseline of at least 0.5% at Week 24 and 52  
Proportion of subjects with HbA1c < 7.0% at Week 
24 and 52  
Change from baseline to Week 24 and 52 in seated 
SBP among subjects with hypertension at baseline, 
defined as seated SBP ≥ 140 mmHg and/or seated 
DBP ≥ 90 mmHg 
 
Safety Objective: 
Outcome Measure: 
Not applicable 
Not applicable 
 
Exploratory Objective: 
Outcome Measure: 
[Part A]  
Explore relationship between 7-point SMBG 
measurements and other PD variables 
7-point SMBG measurements, 24-hr urinary glucose, 
total daily insulin dose and their changes from 
baseline  
[Part B] 
The efficacy evaluation will be made by 
comparing subgroups BMI <25.0 kg/m2 or 
BMI ≥ 25.0 kg/m2. 
Change from baseline in HbA1c, GA, average/post-
prandial glucose values measured by 6-point SMBG, 
and percent change from baseline in body weight, 
total daily insulin dose by subgroup defined by BMI. 


Clinical Study Protocol Synopsis 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
16(110) 
Target subject population 
Patients are divided in two parts in this study.  
[Part A] 
Japanese male and female patients with T1DM and age 18 to 65 years, with inadequate 
glycemic control on insulin defined as HbA1c ≥ 7.0% and ≤ 10.0% at screening visit. 
[Part B] 
Japanese male and female patients with T1DM and age 18 to 75 years, with inadequate 
glycemic control on insulin defined as HbA1c ≥ 7.5% and ≤ 10.5% at screening visit. 
[Part A and B] 
Method of insulin administration (MDI or CSII) must have been unchanged for at least 3 
months prior to the screening visit per subject report or medical records.  Subjects must be on 
a total daily insulin dose of ≥ 0.3 U/kg/day for at least 3 months prior to the screening visit. In 
part A, CSII user are excluded. 
Duration of treatment 
[Part A] 
The treatment period will be 7 days.  Patients will have a screening period up to 14 days and a 
follow-up period of 7 days off of study medication.  The 7 days follow-up period allows for a 
further understanding of any changes in physical signs and symptoms or laboratory 
parameters that can be potentially attributed to the use of the investigational product. 
[Part B] 
The treatment period will be 52 weeks.  Patients will have a screening period of 14 days, a 
wash-out period of 7 days if needed, and a follow-up period of 4 weeks off of study 
medication.  The 4 weeks follow-up period allows for a further understanding of any changes 
in physical signs and symptoms or laboratory parameters that can be potentially attributed to 
the use of the investigational product. 
Investigational product, dosage and mode of administration 
[Part A] 
Each dose will be composed of 2 tablets. Investigational drug should be taken once daily in 
the morning. 
dapagliflozin 5 mg dose: dapagliflozin 5 mg 1 tablet + dapagliflozin 10 mg placebo 1 tablet 
dapagliflozin 10 mg dose: dapagliflozin 5 mg placebo 1 tablet + dapagliflozin 10 mg 1 tablet 
placebo dose: dapagliflozin 5 mg placebo 1 tablet + dapagliflozin 10 mg placebo 1 tablet 


Clinical Study Protocol Synopsis 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
17(110) 
[Part B] 
Dapagliflozin 5 mg or 10 mg tablet administered orally once daily in much around the same 
time for the 52-week open-label treatment period.  Study drug for 5 mg and 10 mg dose 
groups should be stated separately. 
Statistical methods 
[Part A] 
PK: summary statistics for Cmax, Tmax, AUCτ for both dapagliflozin and its major metabolite 
dapagliflozin 3-O-glucuronide, and ratio of metabolite (MR) to parent AUCτ will be provided 
by arm. Geometric mean and CV (coefficient of variation) will be presented for Cmax, AUCτ, 
and Ratio of metabolite to parent AUCτ.  Medians and ranges will be presented for Tmax.  
PD: change from baseline to Day 7 in 24-hour urinary glucose will be summarized by arm. 
Also difference of dapagliflozin vs. placebo and 95%CIs will be summarized if appropriate.  
No formal statistical testing will be performed.  For other PD parameters to be assessed by 
change from baseline (ie, FPG and SBP), similar analysis like 24-hour urinary glucose will be 
carried out.  For PD parameters to be assessed by percent change from baseline (ie, daily basal 
insulin dose, daily bolus insulin dose, total daily dose of insulin), similar analysis will be 
carried out with exception that mean percent change from baseline will be calculated from the 
exponentiated values of estimates obtained on the natural logarithmic scale.  
[Part B] 
Adverse events (including hypoglycemia events and DKA events), serious adverse events 
(SAEs) and adverse event leading to discontinuation of study drug (DAEs) will be 
summarized by treatment group (dapagliflozin 5 mg or 10 mg). 
Efficacy analyses on change from baseline in HbA1c, GA, average glucose values measured 
by 6-point SMBG and post-prandial glucose values measured by 6-point SMBG, are to be 
analysed by Mixed Model with Repeated Measures (MMRM) to provide point estimate and 
95% confidence intervals (95% CIs) for each dapagliflozin group.  Efficacy analyses on 
percent change from baseline in total daily insulin dose and body weight will be conducted by 
MMRM on log-transformed values.  No confirmatory statistical testing is planned and hence 
no multiplicity adjustment will be done in this study. 


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TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
PROTOCOL SYNOPSIS ....................................................................................... 13 
TABLE OF CONTENTS ....................................................................................... 18 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 24 
1. 
INTRODUCTION ................................................................................................. 27 
1.1 
Background and rationale for conducting this study ............................................. 27 
1.1.1 
Unmet Medical Need in Type 1 Diabetes Mellitus ............................................... 27 
1.1.2 
Introduction of dapagliflozin and Study Rationale ................................................ 28 
1.1.3 
Product Development Background ........................................................................ 31 
1.2 
Rationale for study design, doses and control groups ............................................ 31 
1.2.1 
Research Hypothesis .............................................................................................. 31 
1.3 
Benefit/risk and ethical assessment........................................................................ 32 
1.4 
Study Design .......................................................................................................... 33 
1.4.1 
PK and PD evaluation part (Part A) ....................................................................... 33 
1.4.2 
Long term treatment part (Part B) .......................................................................... 36 
2. 
STUDY OBJECTIVES .......................................................................................... 38 
2.1 
Primary objective ................................................................................................... 38 
2.2 
Secondary objectives ............................................................................................. 38 
2.3 
Safety objectives .................................................................................................... 39 
2.4 
Exploratory objectives ........................................................................................... 39 
3. 
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 40 
3.1 
Inclusion criteria .................................................................................................... 40 
3.1.1 
Women of Childbearing Potential ......................................................................... 41 
3.2 
Exclusion criteria ................................................................................................... 42 
3.3 
Subject enrolment and randomization ................................................................... 46 
3.4 
Procedures for handling incorrectly enrolled or randomized subjects ................... 46 
3.5 
Methods for assigning treatment groups ................................................................ 47 
3.5.1 
PK and PD evaluation part (Part A) ....................................................................... 47 
3.5.2 
Long term treatment part (Part B) .......................................................................... 47 


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3.6 
Methods for ensuring blinding (in Part A) ............................................................. 47 
3.7 
Methods for unblinding (in Part A)........................................................................ 47 
3.8 
Restrictions ............................................................................................................ 48 
3.9 
Discontinuation of investigational product ............................................................ 48 
3.9.1 
Procedures for discontinuation of a subject from investigational product ............ 50 
3.9.1.1 
Discontinuation Guidelines due to Protocol-Defined Hypoglycemia 
Episode or Recurrent Hypoglycemia Episodes ...................................................... 50 
3.10 
Criteria for withdrawal ........................................................................................... 50 
3.10.1 
Screen failures ........................................................................................................ 50 
3.10.2 
Withdrawal of the informed consent ...................................................................... 50 
3.11 
Discontinuation of the study .................................................................................. 51 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 51 
4.1 
Enrolment/screening period (2weeks) ................................................................... 61 
4.1.1 
Retesting During Screening ................................................................................... 61 
4.1.1.1 
Study Materials ...................................................................................................... 61 
4.2 
Wash-out period only for part B (1 week, it is applicable exclusively for 
subjects receiving α-GI on top of insulin).............................................................. 62 
4.3 
Treatment period .................................................................................................... 63 
4.3.1 
PK and PD evaluation part (Part A) ....................................................................... 63 
4.3.2 
Long term treatment part (Part B) .......................................................................... 64 
4.4 
Follow-up period .................................................................................................... 64 
4.4.1 
PK and PD evaluation part (Part A) ....................................................................... 64 
4.4.2 
Long term treatment part (Part B) .......................................................................... 64 
4.5 
Supplemental Visits ............................................................................................... 64 
4.5.1 
Early Treatment Discontinuation Visit .................................................................. 64 
4.5.2 
Other Supplemental (Unscheduled) Visits ............................................................. 65 
5. 
STUDY ASSESSMENTS ..................................................................................... 65 
5.1 
Efficacy assessments .............................................................................................. 65 
5.1.1 
Efficacy assessments .............................................................................................. 65 
5.1.2 
HbA1c and glycoalbumin ...................................................................................... 65 
5.1.3 
6-point SMBG profiles .......................................................................................... 66 
5.1.4 
Weight and height .................................................................................................. 66 
5.1.5 
Blood pressure ....................................................................................................... 66 
5.2 
PD assessment (Part A only) .................................................................................. 66 
5.2.1 
Analysis of 24-hour urinary glucose excretion ...................................................... 66 
5.2.2 
FPG ........................................................................................................................ 67 
5.3 
Safety assessments ................................................................................................. 67 
5.3.1 
Self Monitored Blood Glucose (SMBG) and Guidance on Management 
and Reporting of Hypoglycemia Episodes ............................................................ 67 


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5.3.1.1 
Self Monitored Blood Glucose (SMBG) ............................................................... 67 
5.3.1.2 
Guidance on Management and Reporting of Hypoglycemia Episodes ................. 68 
5.3.2 
Self-Monitored Blood Ketone Testing and Guidance on Management and 
Reporting of Diabetic Ketoacidosis (DKA) Episodes ........................................... 69 
5.3.3 
Insulin Dosing Adjustment and Data Collection Guidelines ................................. 72 
5.3.4 
Guidance on Assessment of Urinary Infections & Hematuria ............................... 74 
5.3.4.1 
Guidance on Assessment of Urinary Infections ..................................................... 74 
5.3.4.2 
Guidance on Assessment of Hematuria ................................................................. 74 
5.3.5 
Guidance on Assessment of Hepatic Laboratory Abnormalities ........................... 75 
5.3.6 
Physical Examination ............................................................................................. 76 
5.3.7 
Blood Pressure and Heart Rate .............................................................................. 76 
5.3.8 
Resting 12-Lead ECG ............................................................................................ 76 
5.3.9 
Guidance on Volume Depletion ............................................................................. 77 
5.3.10 
Other safety assessments ........................................................................................ 77 
5.4 
Other assessments .................................................................................................. 77 
5.4.1 
Height and Body Mass Index (BMI) ..................................................................... 77 
5.4.2 
Diet and Exercise Counselling ............................................................................... 78 
5.5 
Results of Central Laboratory Assessments .......................................................... 78 
5.5.1 
Blood Standard Safety Laboratory Panels: ............................................................ 79 
5.5.1.1 
Hematology ............................................................................................................ 79 
5.5.1.2 
Serum Chemistry ................................................................................................... 80 
5.5.1.3 
Urine Analyses ....................................................................................................... 80 
5.5.2 
Screening-Specific Safety Panel ............................................................................ 81 
5.6 
Pharmacokinetics (PK) in part A ........................................................................... 81 
5.6.1 
Collection of samples ............................................................................................. 81 
5.6.2 
Determination of drug concentration ..................................................................... 81 
5.7 
Pharmacodynamics (Not Applicable) .................................................................... 82 
5.8 
Pharmacogenetics (Not Applicable) ...................................................................... 82 
5.9 
Biomarker analysis (Not Applicable) .................................................................... 82 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 82 
6.1 
Definition of adverse events .................................................................................. 82 
6.2 
Definitions of serious adverse event ...................................................................... 82 
6.3 
Recording of adverse events .................................................................................. 83 
6.3.1 
Time period for collection of adverse events ......................................................... 83 
6.3.2 
Follow-up of unresolved adverse events ................................................................ 83 
6.3.3 
Variables ................................................................................................................ 83 
6.3.4 
Causality collection ................................................................................................ 84 
6.3.5 
Adverse events based on signs and symptoms....................................................... 84 
6.3.6 
Adverse events based on examinations and tests ................................................... 84 
6.3.7 
Other Safety Considerations .................................................................................. 85 
6.4 
Reporting of serious adverse events....................................................................... 85 


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6.5 
Overdose ................................................................................................................ 86 
6.6 
Pregnancy ............................................................................................................... 86 
6.6.1 
Maternal exposure .................................................................................................. 86 
6.7 
Management of IP related toxicities and dose Reductions- Not Applicable ......... 87 
6.8 
Study governance and oversight ............................................................................ 87 
6.8.1 
Hepatic Adjudication Committee .......................................................................... 87 
6.8.2 
DKA Adjudication Committee .............................................................................. 87 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 87 
7.1 
Identity of investigational product(s) ..................................................................... 87 
7.2 
Dose and treatment regimens ................................................................................. 88 
7.2.1 
PK and PD evaluation part (Part A) ....................................................................... 88 
7.2.2 
Long term treatment part (Part B) .......................................................................... 88 
7.2.3 
Non-investigational Product .................................................................................. 88 
7.3 
Labelling ................................................................................................................ 89 
7.4 
Storage ................................................................................................................... 89 
7.5 
Compliance ............................................................................................................ 89 
7.6 
Accountability ........................................................................................................ 89 
7.7 
Concomitant and other treatments ......................................................................... 89 
7.7.1 
Prohibited and/or Restricted Treatments................................................................ 89 
7.7.2 
Other concomitant treatment .................................................................................. 90 
7.8 
Post Study Access to Study Treatment .................................................................. 90 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA ............................................ 90 
8.1 
Statistical considerations ........................................................................................ 90 
8.2 
Sample size estimate .............................................................................................. 90 
8.2.1 
PK and PD evaluation part (Part A) ....................................................................... 90 
8.2.2 
Long term treatment part (Part B) .......................................................................... 91 
8.3 
Definitions of analysis sets .................................................................................... 91 
8.3.1 
PK and PD evaluation part (Part A) ....................................................................... 91 
8.3.2 
Long term treatment part (Part B) .......................................................................... 91 
8.4 
Outcome measures for analyses ............................................................................. 92 
8.4.1 
Primary Endpoints ................................................................................................. 92 
8.4.2 
Secondary Endpoints ............................................................................................. 92 
8.4.3 
Exploratory Endpoints ........................................................................................... 93 
8.4.4 
Baseline value ........................................................................................................ 93 
8.4.5 
LOCF ..................................................................................................................... 93 
8.4.6 
Calculation of eGFR .............................................................................................. 93 
8.5 
Methods for statistical analyses ............................................................................. 93 
8.5.1 
Analysis of the primary variable (s) ....................................................................... 93 


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8.5.2 
Analysis of the secondary variable(s) .................................................................... 94 
8.5.3 
Exploratory analyses .............................................................................................. 96 
8.5.4 
Interim Analyses .................................................................................................... 96 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA .......................... 96 
9.1 
Training of study site personnel ............................................................................. 96 
9.2 
Monitoring of the study ......................................................................................... 97 
9.2.1 
Source data ............................................................................................................. 97 
9.2.2 
Direct access to source data in Japan ..................................................................... 97 
9.2.3 
Study agreements ................................................................................................... 97 
9.2.4 
Archiving of study documents ............................................................................... 97 
9.3 
Study timetable and end of study ........................................................................... 98 
9.4 
Data management by AstraZeneca ........................................................................ 98 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 99 
10.1 
Ethical conduct of the study ................................................................................... 99 
10.2 
Subject data protection ........................................................................................... 99 
10.3 
Ethics and regulatory review.................................................................................. 99 
10.4 
Informed consent ................................................................................................. 100 
10.5 
Changes to the protocol and informed consent form ........................................... 100 
10.6 
Audits and inspections ......................................................................................... 101 
11. 
LIST OF REFERENCES ..................................................................................... 101 
 
LIST OF TABLES 
Table 1 
Study schedule for Part A ......................................................................... 52 
Table 2 
Time schedule of PK and PD sample collection (Part A) ........................ 56 
Table 3 
Study schedule (Part B) ............................................................................ 57 
Table 4 
Efficacy laboratory variables in part B ..................................................... 65 
Table 5 
Safety laboratory variables (Part A) ......................................................... 78 
Table 6 
Safety laboratory variables (Part B) ......................................................... 79 
Table 7 
Identity of investigational product(s) ....................................................... 87 
Table 8 
Composition of dose and number of tablets ............................................. 88 
Table 9 
Drug dispensing scheme ........................................................................... 88 
 


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LIST OF FIGURES 
Figure 1 
How dapagliflozin Works (Mechanism of Action) .................................. 29 
Figure 2 
Study Design Schematic (Part A) ............................................................. 35 
Figure 3 
Study Design Schematic (Part B) ............................................................. 37 
Figure 4 
Sustained elevated liver safety abnormalities flow chart ....................... 108 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information ................................................................ 104 
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ............................................................................... 106 
Appendix C 
New York Heart Association (NYHA) Classification ........................... 107 
Appendix D 
Sustained Elevated Liver Safety Abnormalities Flow Chart .................. 108 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADA 
American Diabetes Association 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUCτ 
Area under the plasma concentration time curve from 0 to τ 
BMI 
Body mass index 
BP 
Blood pressure 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CRF 
Case Report Form (electronic/paper) 
CSII 
Continuous subcutaneous insulin infusion 
DAE 
Discontinuation of study drug 
DBP 
Diastolic blood pressure 
DKA 
Diabetic Ketoacidosis 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
ET 
End of Treatment 
FAS-B 
Full analysis set -Part B 
FFA 
Free Fatty Acid 
FPG 
Fasting plasma glucose 
FSH 
Follicle stimulating hormone 
GA 
Glycoalbumin 
GCP 
Good Clinical Practice 
Unless otherwise noted, ‘GCP’ shall mean ‘the International Conference on 
Harmonisation Tripartite Guideline for Good Clinical Practice’ (ICH GCP) 
and the Japanese ‘Good Clinical Practice for Trials on Drugs (Ministry of 
Health, Labour and Welfare [MHLW] Ordinance No. 28, 27 March 1997, 
partially revised by MHLW Ordinance and their related notifications’ (GCP 
Ordinance). 
GFR 
Glomerular filtration rate 


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Abbreviation or 
special term 
Explanation 
HbA1c 
Hemoglobin A1c (glycated hemoglobin) 
HCG 
Human chorionic gonadotropin 
HDL-C 
High-density lipoprotein cholesterol 
HDPE 
High-density polyethylene 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
IATA 
International Airline Transportation Association 
ICH 
International Conference on Harmonisation 
International 
Co-ordinating 
investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally.  
Investigators 
Principal Investigator + Sub-investigator 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LOCF 
Last observation carried forward 
MDI 
Multiple daily injections 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model with Repeated Measures 
MOA 
Mechanism of Action 
NGSP 
National Glycohemoglobin Standardization Program 
PD 
Pharmacodynamics 
PI 
Principal Investigator  
PD-A 
Pharmacodynamic set -Part A 
PK 
Pharmacokinetics 
PK-A 
Pharmacokinetic set -Part A 
QD 
qd quaque die, once daily 
SAE 
Serious adverse event 
SAF-A 
Safety set -Part A 
SAF-B 
Safety set -Part B 
SBP 
Systolic blood pressure 
SGLT 
Sodium-glucose cotransporter 


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Abbreviation or 
special term 
Explanation 
SMBG 
Self monitored blood glucose 
T1DM 
Type 1 diabetes mellitus 
T2DM 
Type 2 diabetes mellitus 
TB 
Total bilirubin 
TC 
Telephone contact 
TG 
Triglycerides 
Tmax 
Time to maximum plasma concentration 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper limit of normal 
WBDC 
Web Based Data Capture 
α-GI 
α-glucosidase inhibitor 
 


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1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
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 β-cells.  T1DM accounts for approximately 5-10% of all cases of 
diabetes worldwide, and its incidence continues to increase (Daneman 2006). 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 (Cryer 2002).  
Unfortunately, recent data suggest hypoglycemia 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 (Weinstock et al 2013).  
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, which suggests that reducing the swings in glucose may be 
of importance in this population (Kilpatrick et al 2007b). 
Intensive insulin therapy is also associated with weight gain and insulin resistance, as 
evidenced in the Diabetes Control and Complications Trial, where subjects in the intensive 
treatment arm gained an average of 4.6 kg more than the control group over the 5 year study 
(Tajima N, Morimoto A 2012, The Diabetes Control and Complications Trial Research Group 
1993, Kilpatrick et al 2007a).  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, at least in some people with T1DM, and has recently contributed to the concept of 
‘double diabetes’ (Ferriss et al 2006, Cleland et al 2013).  
Average HbA1c values greater than 8% have been reported in several large studies in people 
with T1DM, 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 (Soedamah-Muthu et al 2008, Beck et al 2012).  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. 
Reported incidence rate of T1DM among those below 15 years of age is 1.5-2.5 per 100000 
(Tajima N, Morimoto A 2012).  The figure is relatively lower than the rate in Europe and the 
US and calculated population of patients with T1DM including all ages is estimated as from 


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70000 to 80000.  Despite advances in intensive insulin therapy including Multiple Daily 
Injection (MDI) and Continuous Subcutaneous Insulin Injection (CSII) for T1DM, the date 
revealed that most people with T1DM in Japan still fail to meet therapeutic target. 
The national health insurance has been providing coverage for CSII since 2000 and this 
therapy has been used in clinical practice in Japan since then, but less frequently than in the 
U.S. due to several reasons such as financial burden on patients, concerns regarding operation 
and safety of the device, and slower introduction of newest devices.  In addition, α-GI is only 
approved for T1DM as an oral hyperglycemic agent in Japan (used without insulin) 
(Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013), although 
SYMLIN® has been used for patients with T1DM with Insulin in the US since 2005.  Thus, 
finding new possible medication for combination therapy with insulin for T1DM patients is 
required in Japan. 
1.1.2 
Introduction of dapagliflozin and Study Rationale 
The study is designed to evaluate safety, efficacy, pharmacokinetics (PK) and 
pharmacodynamics (PD) of dapagliflozin therapy in combination with insulin in Japanese 
subjects with T1DM who have inadequate glycemic control. 
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 approved for the treatment of type 2 diabetes 
mellitus (T2DM) in Japan on March 2014.  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.  Further, 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).  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 anti-diabetic 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 
How dapagliflozin Works (Mechanism of Action) 
 
 
Currently, 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 MOA.  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, which may serve to blunt 
the excursions of glucose values over the course of the day (reduce glycemic variability) 
(Defronzo et al 2013). 
The potential of dapagliflozin as a treatment option for the T1DM population was explored in 
a Phase 2a pilot study (MB102072) which was conducted in US.  The MB102072 study was a 
randomized, double-blind, 5-arm, parallel-group, placebo-controlled exploratory trial to 
evaluate the safety, tolerability, PK and PD of dapagliflozin in subjects with T1DM who had 
inadequate glycemic control on insulin therapy.  Subjects taking insulin monotherapy who met 
the central laboratory enrolment 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 


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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 final 
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. 
In completed clinical studies in subjects with both T2DM and T1DM overseas, dapagliflozin 
was generally 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 adverse events (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). 
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 not only in the overseas but also in Japan. 
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. 
In Clinical Pharmacology studies, dapagliflozin exhibited similar PK and PD properties 
between Japanese and the US-based subjects both who were healthy and with T2DM. Study 
MB102072 conducted in the US studied dapagliflozin PK/PD in patients with T1DM at 1, 2.5, 
5, and 10 mg.  Comparing pooled exposure-response analysis of MB102072 to several T2DM 
studies showed that PK and exposure-response relationship after adjusting baseline parameters 
(fasting plasma glucose (FPG), urine glucose excretions (UGE) and eGFR) were virtually 
identical between patients with T1DM and T2DM in the US.  All of the above results suggest 
that the PK/PD response to dapagliflozin in Japanese T1DM patients are expected to be 
similar to what were observed in T1DM patients in the US.  Therefore, the protocol of Part A 
of this study such as endpoint, treatment period, major inclusion and exclusion criteria were 


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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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designed so that indirect comparison to results of Study MB102072 could be possible.  The 
dose of dapagliflozin 5 and 10 mg were decided corresponding to the international Phase III 
study (MB102230).  The objective of this Part A study of dapagliflozin to evaluate PK and PD 
in Japanese with T1DM then to prove our above hypothesis.  With all of these understandings, 
we propose to conduct the PK/PD study in Japanese T1DM patients to both at 5 and 10 mg 
doses.  In addition, we plan to add the data of this study to the previously pooled PK/PD data 
sets (T1DM and T2DM), in order to compare Japanese T1DM patients with T1DM patients in 
the US and T2DM patients as well.  Furthermore, with the available model, we will be able to 
predict the PK/PD of other dose of dapagliflozin as needed in Japanese T1DM patients using 
all the data we collect.  24-hour urinary glucose excretion will be evaluated as primary 
variable for PD in PK/PD evaluation part of the study. 
Part B study is designed to evaluate the long term safety of dapagliflozin in Japanese with 
T1DM. 
The number of Japanese subjects with T1DM in Part B of this study was decided  to ensure 
that ≥ 100 Japanese subjects in total (Japanese long-term + Global Phase III studies) received 
dapagliflozin for 1 year, whichever candidate is selected, in accordance with the ICH E1 
guideline. 
1.1.3 
Product Development Background 
Dapagliflozin has been designed as a potent and selective inhibitor of the renal sodium-
glucose transporter, SGLT-2.  In the results from Japanese clinical studies for T2DM, it was 
demonstrated that dapagliflozin is associated with a significant reduction of HbA1c from 
baseline compared to placebo and dapagliflozin in combination with another antidiabetic 
agent is generally safe and well tolerated.  Currently, the Phase IV study is ongoing in order to 
evaluate the efficacy and safety of dapagliflozin therapy when added to the therapy of 
Japanese T2DM patients with inadequate glycemic control on insulin. 
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. 
1.2 
Rationale for study design, doses and control groups 
1.2.1 
Research Hypothesis 
In Japanese subjects with T1DM that have inadequate glycemic control with insulin alone, the 
addition of dapagliflozin to adjustable insulin will result in a comparable PK and PD profile 
with non-Japanese patients in Part A, and long term safety of dapagliflozin in Part B. 


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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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1.3 
Benefit/risk and ethical 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 anti-
diabetic medications.  In a recently concluded Phase 2a study (MB102072), the combination 
therapy of dapagliflozin with insulin when used in subjects with T1DM with inadequate 
glycemic control was assessed. In that study, dapagliflozin was found generally 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, 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 (Perkins et al 
2014). 
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 they become 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.  
In case of part A, the subjects would be observed carefully at the Investigator’s site during the 
hospitalization period and communicate with the Investigators by regular telephone (fax or 
email) contact during outpatient following randomization to reduce the risk of hypoglycemia.  
In case of part B, it is recommended that subjects reduce their daily insulin doses by up to 


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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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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 as deemed appropriate to be consistent according to 
SMBG readings, local guidance and individual circumstances. 
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, DKA, urinary tract infections and decreased renal 
function mentioned in the plan (see Section 5.3). 
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. 
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 counselling.  This improvement is expected for subjects in this trial that participate in 
Part A. 
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 in Part B.  Subjects will also receive 
counselling on diet and exercise. 
1.4 
Study Design 
The study is designed to evaluate safety, efficacy, PK and PD of dapagliflozin therapy in 
combination with insulin in Japanese subjects with T1DM who have inadequate glycemic 
control. 
1.4.1 
PK and PD evaluation part (Part A) 
The study design of Part A is a randomized, single-blind, 3 arm, parallel-group, placebo-
controlled design.  Forty-two subjects will be randomized in a 1:1:1 ratio into one of the three 
blinded treatment arms. 
Potential subjects will be assessed for eligibility criteria at the screening visit. On Day 1, 
subjects who meet all the protocol-specific enrolment and randomization inclusion criteria and 
meet none of the exclusion criteria will be randomized into one of the three single-blinded 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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treatment arms (dapagliflozin 5 mg QD, dapagliflozin 10 mg QD, or placebo QD) in a 1:1:1 
ratio. 
Subjects will receive dapagliflozin 5 mg QD, 10 mg QD, or placebo QD for 7 days, and a 1-
week follow-up evaluation. Besides study medications, subjects will be treated with MDI (3 or 
more injections per day of basal and bolus insulin). 
The randomized subject will be observed within 24 hours after first dose of study drug on 
Day 1 at the Investigator’s site in order to adjust their daily insulin doses for both basal and 
bolus insulin to reduce the risk of hypoglycemia.  Subjects will be monitored closely with 
regard to safety parameters, including vital signs, safety laboratory tests, and adverse events. 
Because this is a short-term study, the primary goal for insulin adjustment is to avoid 
significant hyperglycemia or hypoglycemia, rather than strict glycemic control. Insulin 
adjustment is not performed to ‘fine tune’ glycemic control, but rather to ensure patient safety 
in the event that there is a significant change in insulin requirements. Maintaining the majority 
of blood glucose readings between 70 - 220 mg/dL is considered adequate glycemic control 
for subjects during the course of this study. In general, the goal was to maintain FPG between 
70 - 140 mg/dL and postprandial blood glucose below 220 mg/dL, although these goals are 
individualized based upon a specific subject’s personal targets and stability of glycemic 
control at baseline. The two main scenarios in which insulin adjustment was appropriate are 
unexpected events of either hypoglycemia or hyperglycemia. An unexpected event is defined 
as an event that could not be explained by circumstances such as dietary (missed or unusually 
high carbohydrate meal), strenuous exercise, error in insulin dosing, etc. In subjects with one 
or more unexpected events of hypoglycemia or hyperglycemia, insulin dosing is to be adjusted. 
In the event insulin dose adjustment is deemed necessary, the Investigators will guide insulin 
dose changes, based upon review of the insulin and glucose logs, as well as potential 
circumstances that may have contributed to erratic glucose control (eg, insulin dosing errors, 
missed meals, unusual physical activity, etc).  In addition, consultation with the subject and/or 
appropriate representatives of the subject’s diabetes management team is strongly 
recommended 
Subjects should self-monitor their blood glucose at least 7 times per day (generally before and 
after breakfast, lunch, dinner, and bedtime) during the treatment period, and in the occurrence 
of hypoglycemic symptoms, and to contact the Investigators 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 Investigators blood glucose values and/or signs and 
symptoms suggestive of a hypoglycemic episode. 
The study design schematic is presented in Figure 2. 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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Figure 2 
Study Design Schematic (Part A) 
-14
-2
1
E
R
Screening Visit
Treatment period
Follow-up 
period
Day
1
3
Visit
7
4
14
6
Insulin therapy
dapagliflozin 5 mg once daily
dapagliflozin 10 mg once daily
Matching placebo once daily
Screening period
R
2
8
6
Hospitalization
-1
2
5
Telephone (Fax or Email)contact *
 
E: Enrolment, R; Randomization 
* Subjects must report the values on Day 3 to 5 by telephone (fax or email) at least once a day. 


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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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1.4.2 
Long term treatment part (Part B) 
The study design of Part B is a randomized, open-label, 2 arms, and parallel-group design.  
One hundred forty subjects will be randomized in a 1:1 ratio into one of the two treatment 
arms. 
Potential subjects who will join the study from part B will be assessed for eligibility criteria at 
the screening visit.  A wash-out period is applicable only for subjects who received α-GI at 
enrolment or within one month before enrolment.  Eligible subjects who are treated with 
insulin only, will skip the period and directly proceed to the randomization.  On Day 1, 
subjects who meet all the protocol-specific enrolment and randomization inclusion criteria and 
meet none of the exclusion criteria will be randomized into one of the 2 open-label treatment 
arms (dapagliflozin 5 mg QD or dapagliflozin 10 mg QD) in a 1:1 ratio.  Randomization will 
be stratified by the following factors to ensure equal representation across all treatment 
groups: 
x 
HbA1c < 9.0% vs. ≥ 9.0% at screening visit 
Subjects will receive dapagliflozin 5 mg QD or 10 mg QD for 52 weeks, and a 4-week follow-
up evaluation.  Besides study medications, subjects will be treated with MDI (3 or more 
injections per day of basal and bolus 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 (particular basal insulin) in advance of 
study drug administration.  It is at the discretion of the Investigators to determine the extent to 
which to reduce the insulin doses.  Throughout the study during the treatment period, insulin 
dose may be adjusted as deemed appropriate to be consistent 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, and adverse events. 
The study design schematic is presented in Figure 3. 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
37(110) 
Figure 3 
Study Design Schematic (Part B) 
-3
-1
0b
4
8
12
16
40
48
52
56
E
R
Wash-out 
period a
Treatment period
Follow-up 
period
dapagliflozin 5 mg once daily
Week
1
2
3
6
7
8
9
13
14
15
16
Visit
20
10
32
12
Insulin therapy
dapagliflozin 10 mg once daily
R
24
11
1
4
Screening 
Visit
d
2c
(5)
 
E: Enrolment, R; Randomization 
a 
Wash-out period is applicable only for subjects who are on an α-GI at enrolment or within one month before enrolment.  Subjects on insulin only as their 
diabetes treatment will skip the period and directly proceed to the Visit 3. 
b 
Day 1 of Week 0 means the stating day of dapagliflozin. 
c 
Either hospital visit or telephone (fax or email) contact is acceptable for visit at Week 2. 
d 
On Day 2, 4 and 10 patients must contact the Investigators by phone (fax or email) and report the patient’s condition (including glucose and ketone 
values from SMBG).  The investigators must indicate appropriate insulin adjustment.  There is time window ± 1 day for Day 4 and 10. 
 


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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
[Part A] 
To evaluate the PK and PD of 7 days repeated 
doses of dapagliflozin in Japanese patients 
with T1DM with inadequate glycemic control 
under standard insulin therapy. 
PK variables: Cmax, Tmax, AUCτ for dapagliflozin and 
dapagliflozin 3-O-glucuronide, and ratio of 
dapagliflozin 3-O-glucuronide AUCτ to dapagliflozin 
AUCτ. 
PD variables: Change from baseline in 24-hour 
urinary glucose excretion on Day 7. 
[Part B] 
To evaluate safety and tolerability of long-
term treatment (52 weeks) of dapagliflozin in 
Japanese patients with T1DM with inadequate 
glycemic control under standard insulin 
therapy. 
Adverse event (including AEs of hypoglycemia and 
DKA events), physical examination, vital signs 
(blood pressure, heart rate), ECG, and clinical 
laboratory measures, urine test. 
2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure: 
[Part A] 
To evaluate the PD of 7 days repeated doses of 
dapagliflozin in Japanese patients with T1DM 
with inadequate glycemic control under 
standard insulin therapy. 
Change from baseline in FPG on Day 7, daily insulin 
dose, SBP 
[Part A] 
To assess the safety and tolerability of 7 days 
repeated doses of dapagliflozin in Japanese 
patients with T1DM with inadequate glycemic 
control under standard insulin therapy. 
Adverse event (including AEs of hypoglycemia and 
DKA events), physical examination, vital signs 
(blood pressure, heart rate), ECG and clinical 
laboratory measures, urine test. 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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Secondary Objective: 
Outcome Measure: 
[Part B] 
To assess the efficacy of long-term treatment 
(52 weeks) of dapagliflozin 5mg and 10 mg in 
Japanese patients with T1DM inadequately 
controlled on insulin therapy. 
Change from baseline in HbA1c  at Week 24 and 52 
Change from baseline in GA  at Week 24 and 52 
Change from baseline in average glucose values 
measured by 6-point SMBG  at Week 24 and 52 
Change from baseline in postprandial glucose values 
measured by 6-point SMBG  at Week 24 and 52 
Percent change from baseline in total daily insulin 
dose  at Week 24 and 52 
Percent change from baseline in body weight  at 
Week 24 and 52 
Proportion of subjects with HbA1c reduction from 
baseline of at least 0.5% without severe 
hypoglycemia events at Week 24 and 52  
Proportion of subjects with HbA1c reduction from 
baseline of at least 0.5% at Week 24 and 52  
Proportion of subjects with HbA1c < 7.0% at Week 
24 and 52  
Change from baseline to Week 24 and 52 in seated 
SBP among subjects with hypertension at baseline, 
defined as seated SBP ≥ 140 mmHg and/or seated 
DBP ≥ 90 mmHg 
2.3 
Safety objectives 
Safety Objective: 
Outcome Measure: 
Not applicable 
Not applicable 
2.4 
Exploratory objectives 
Exploratory Objective: 
Outcome Measure: 
[Part A]  
Explore relationship between 7-point SMBG 
measurements and other PD variables 
7-point SMBG measurements, 24-hr urinary glucose, 
total daily insulin dose and their changes from 
baseline  
[Part B] 
The efficacy evaluation will be made by 
comparing subgroups BMI <25.0 kg/m2 or 
BMI ≥ 25.0 kg/m2. 
Change from baseline in HbA1c, GA, average/post-
prandial glucose values measured by 6-point SMBG, 
and percent change from baseline in body weight, 
total daily insulin dose by subgroup defined by BMI.  


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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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3. 
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
3.1 
Inclusion criteria 
For inclusion in the study subjects should fulfil the following criteria: 
1. 
Signed Written Informed Consent 
Subjects or their legally responsible representatives must be willing and able to give 
signed and dated written informed consent. In the case of the subject was under the 
age of 20, their legally responsible representatives must be willing and able to give 
signed, relationship and dated written informed consent. 
2. 
Target Population 
(a) 
Diagnosis of T1DM.  In addition, the following criteria also needs to be met; 
Central laboratory test of C-peptide < 0.7 ng/mL 
(b) 
Subject re-enrolment: This study does not permit the re-enrolment of a subject who 
has discontinued the study as a screen failure 
3. 
Insulin use for at least 12 months prior to the enrolment 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 enrolment per subject report or medical records. Subjects 
must be taking a total daily insulin dose of ≥ 0.3 U/kg/day for at least 3 months 
prior to the enrolment.  In Part A, CSII users are excluded. 
(b) 
If on MDI insulin administration subject must be on ≥ 3x injections per day. 
4. 
Gender and reproductive Status 
(a) 
Japanese men and women, 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. 


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Criteria for Part A 
5. 
HbA1c eligibility criteria include: 
(a) 
Screening Visit: Central laboratory HbA1c ≥ 7.0 % and ≤ 10.0 % (One repeat 
HbA1c test for subjects in screening if their initial test result was an HbA1c ± 0.2% 
of the cut off values) 
6. 
BMI ≥ 20.0 kg/m², ≤ 35.0 kg/m² at Visit 1 
7. 
Ages 18 to 65 years, inclusive 
8. 
≥ 18 years old and < 20 years old must have assent forms signed and dated by their 
parents or guardians 
Criteria for Part B 
9. 
HbA1c eligibility criteria include: 
(a) 
Screening Visit: Central laboratory HbA1c ≥ 7.5% and ≤ 10.5% (One repeat HbA1c 
test for subjects in screening if their initial test result was an HbA1c ± 0.2% of the 
cut off values) 
10. 
BMI ≥ 20.0 kg/m² at Visit 1 
11. 
Age 18 to 75 years, inclusive 
12. 
≥ 18 years old and < 20 years old must have assent forms signed and dated by their 
parents or guardians 
3.1.1 
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 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.* 
* Females treated with hormone replacement therapy (HRT), are likely to have artificially 
suppressed FSH levels and may require a wash-out 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 the Investigators should 
use their judgment in checking serum FSH levels.  If the washout period exceeds 4 weeks, 
the subject must have all enrolment procedures and laboratory assessments repeated and all 
of these must meet enrolment 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: 


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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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 
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 wash-out periods as long as 6 months. 
3.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Target Disease Exceptions 
(a) 
History of T2DM 
In cases where the subject has a history of T2DM and has a documented history of 
being auto-antibody positive for GAD65, tyrosine phosphatase IA-2/IA-2β, or Zinc 
Transporter 8 (ZnT8), or fasting c-peptide value below the lower limit of detection 
performed by local or central laboratory, the subject will be eligible for screening 
(b) 
Maturity onset diabetes of young (MODY) 
(c) 
Pancreatic surgery, chronic pancreatitis, or other pancreatic disorders that could 
result in decreased β-cell capacity (eg, pancreatogenous diabetes) 
Criteria for Part A 
(d) 
Any anti-hyperglycemic agent use, other than thiazolidinediones, or insulin, within 
1 month prior to the screening visit. 
(e) 
Use of thiazolidinediones within 6 months prior to the screening visit 
Criteria for Part B 
(f) 
Any anti-hyperglycemic agent use, other than α-GI or insulin, within 1 month prior 
to the enrolment. 
α-GI users at the enrolment or within 1 month prior to the enrolment are permitted 
to enter this study, if subjects can conduct wash-out of the drug. 
(g) 
Use of thiazolidinediones within 6 months prior to the enrolment 
(h) 
History of DKA requiring medical intervention (eg, emergency room visit and/or 
hospitalization) within 1 month prior to the enrolment 
(i) 
History of hospital admission for glycemic control (either hyperglycemia or 
hypoglycemia) within 1 month prior to the enrolment 


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Date 14 December 2016 
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(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 enrolment 
(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 three months prior to the enrolment, or other signs and 
symptoms. 
(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 
enrolment: 
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 
(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 


Clinical Study Protocol  
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Date 14 December 2016 
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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 enrolment 
4) Malignancy within 5 years of the enrolment (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 
(e) 
Unstable pre-proliferative and proliferative retinopathy (untreated or under 
treatment). 
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) > 2.0 mg/dL (34.2 μmol/L) 
(d) 
[Criteria for Part A only] Estimated GFR (eGFR) by the Japanese Society of 
Nephrology formula ≤ 60 mL/min/1.73m2 
[Criteria for Part B only] Estimated GFR (eGFR) by the Japanese Society of 
Nephrology formula ≤ 45 mL/min/1.73m2 
(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 enrolment will be further evaluated for free T4. 
Subjects with abnormal free T4 values will be excluded.   
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 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
45(110) 
(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 taken for > 4 weeks within 3 months prior to the Day 1 visit 
NOTE: Topical or inhaled corticosteroids are allowed 
(f) 
Any unstable endocrine, psychiatric or rheumatic disorders as judged by the 
Investigators 
(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 is, in the judgment of the Investigators, 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. 
(i) 
Subject with any condition which, in the judgment of the Investigators, 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 enrolment. 
(k) 
Subject is a participating Investigators, study coordinator, employee of an 
investigator or immediate family member of any of the aforementioned. 
(l) 
Employee of Bristol-Myers Squibb, AstraZeneca, or their relatives. 
(m) 
Participation in other clinical study within 30 days of the enrolment. 
(n) 
Previous use of SGLT2 inhibitor. 
(o) 
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. 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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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. 
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.4. 
3.3 
Subject enrolment and randomization 
Investigator(s) should keep a record, the subject screening log, of subjects who entered pre-
study screening. 
The Investigator(s) will: 
1. 
Obtain signed informed consent from the potential subject or their guardian/legal 
representative before any study specific procedures are performed. 
2. 
Perform enrolment call in Interactive Web Response System (IWRS). 
3. 
Assign potential subject a unique enrolment number ͆E43XXYYY”, which is 
composed of 4 digits (43XX) of centre number and 3 digits (YYY) of consecutive 
number in order of enrolment registration at each study site. 
4. 
Determine subject eligibility. See Sections 3.1 and 3.2. 
5. 
Perform drug allocation call for randomization at visit 3 in IWRS. 
If a subject withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused. 
Routines for this will be described in the IWRS user manual that will be provided to each 
centre. 
3.4 
Procedures for handling incorrectly enrolled or randomized 
subjects 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Subjects who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment, and must be withdrawn from the study. 
Where a subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigators should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the Investigators regarding whether to continue or discontinue the patient from 
treatment.  The AstraZeneca study physician must ensure all decisions are appropriately 
documented. 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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3.5 
Methods for assigning treatment groups 
3.5.1 
PK and PD evaluation part (Part A) 
Following completion of the screening period, subjects who meet the criteria will be randomly 
assigned by the IWRS at the Day 1 Randomization visit, to one of the following 3 single-blind 
treatment arms in a 1:1:1 ratio using a centralized randomization schedule: 
1. 
Blinded dapagliflozin 5 mg dose group 
2. 
Blinded dapagliflozin 10 mg dose group 
3. 
Blinded placebo dose group 
Randomization schedules for subject treatment will be generated and kept by AstraZeneca. 
3.5.2 
Long term treatment part (Part B) 
Following completion of the screening period or wash-out period, subjects who meet the 
criteria will be randomly assigned by the IWRS at the Day 1 Randomization visit, to one of 
the following 2 open-label treatment arms in a 1:1 ratio using a centralized randomization 
schedule: 
Treatment allocation for patients randomized will be done by following procedure:   
1. 
dapagliflozin 5 mg tablet, once daily 
2. 
dapagliflozin 10 mg tablet, once daily 
Randomization will be stratified by: 
x 
HbA1c < 9.0% vs. ≥ 9.0% at screening visit 
Randomization schedules for subject treatment will be generated and kept by AstraZeneca. 
3.6 
Methods for ensuring blinding (in Part A) 
The Centralized Registration/ Randomization Center will assign the study material to be 
dispensed to each subject.  Each dose will be identical and presented to ensure blinding of the 
medication. 
3.7 
Methods for unblinding (in Part A) 
Since Part A is conducted with single blind, the methods for unblinding for the site is not 
needed. 
For those personnel analysing the PK samples, the randomization code will be provided to 
ensure that only samples from patients who were on active study treatment are analysed.  
Samples from patients not dosed with the relevant active study treatment will only be analysed 


Clinical Study Protocol  
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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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on a "for cause" basis, for example if there is suspicion that a patient has been dosed 
incorrectly. 
3.8 
Restrictions 
Subjects who join Part A 
x 
Subjects who join the Part A should enter the hospital from Day -2 to Day 2 and 
Day 6 to Day 8. 
x 
Subjects must abstain alcohol from Day -2 to discharge from hospital on Day 8. 
x 
Subjects must abstain from excessive exercise from Day -2 to discharge from 
hospital on Day 8.  Light work only is recommended. 
x 
Subjects must abstain from sauna from Day -2 to discharge from hospital on Day 8. 
x 
Subjects must be in a fasting state at least 10 hours prior to fasting blood sampling 
(however, drinking water is allowed).  Permitted medications may be taken with 
water only. 
Subjects who join Part A or Part B 
x 
Subjects should not use tobacco/nicotine/alcohol within 8 hours prior to study visit 
with blood pressure and heart rate (HR) measurements. 
x 
Subjects must make every attempt to adhere to the dietary and physical activity 
changes and goals as discussed with the Investigator(s). 
x 
Women of child-bearing potential must immediately contact the Investigators if 
they suspect they might be pregnant and if they have changed, or plan to change 
their birth control method. 
x 
Subjects must comply with their prescribed dosing regimen to preserve study 
integrity and ensure subject safety. 
x 
Subjects should be cautioned that any new prescription medication or over-the-
counter or herbal/nutritional therapies should be discussed thoroughly with the 
Investigators, as concomitant use could result in alterations to their glycemic 
control and may place them at risk for significant hypoglycemic episodes. 
If a subject arrives for a visit without having followed the above instructions, the entire visit 
should be rescheduled (within the allowed visit-window, if possible). 
3.9 
Discontinuation of investigational product 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the Investigators) for any of the following reasons: 
x 
Subject’s request to stop study treatment 
x 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
x 
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness 
which, in the opinion of the Investigators, indicates that continued participation in 
the study is not in the best interest of the subject 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
49(110) 
x 
Unblinding a subject for any reason (emergency or non-emergency) (in Part A) 
x 
Pregnancy 
x 
Termination of the study by the Sponsor 
x 
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness 
x 
Estimated GFR (eGFR) by the Japanese Society of Nephrology formula 
< 30 mL/min/1.73m2 
 
If at any time the subject’s eGFR (based on Japanese Society of Nephrology 
formula) 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 eGFR (based on Japanese Society of Nephrology 
formula) falls below 30 mL/min calculated at local laboratory, a central 
laboratory eGFR should be obtained promptly.  If the eGFR 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. 
x 
Subjects experience at least one protocol-defined on Section 3.9.1.1 hypoglycemia 
episode that leads to a loss of consciousness and/or seizure as determined by the 
Investigators 
x 
Change of insulin administration method (eg, switch from MDI to CSII or vice 
versa) 
x 
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. 
x 
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 D 
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 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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3.9.1 
Procedures for discontinuation of a subject from investigational product  
At any time, subjects are free to discontinue investigational product or withdraw from the 
study (ie, investigational product and assessments – see Section 3.10), without prejudice to 
further treatment.  A subject that decides to discontinue investigational product will always be 
asked about the reason(s) and the presence of any adverse events.  If possible, they will be 
seen and assessed by an Investigator(s).  Adverse events will be followed up (See Section 
4.4); diary cards and all study drugs should be returned by the subject. 
If a subject is withdrawn from study, see Section 3.10. 
3.9.1.1 
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 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: 
x 
At least one hypoglycemia episode that leads to loss of consciousness and/or seizure 
x 
Severe/recurrent hypoglycemia episodes where the possibility of down-titration of 
contributing concomitant medication(s) (other than single-blind study medication), 
and/or contributing factors (eg, excessive physical activity) have been evaluated and 
corrected. 
NOTE: Dose titration is not permitted at any time during the treatment period in part A and 
Part B. 
Section 5.3.1.2 provides additional guidance on management and reporting of hypoglycemia. 
3.10 
Criteria for withdrawal  
3.10.1 
Screen failures  
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomized.  These patients should have the reason for study 
withdrawal recorded as ‘Incorrect Enrolment’ (ie, patient does not meet the required 
inclusion/exclusion criteria).  This reason for study withdrawal is only valid for screen failures 
(not randomized patients). 
3.10.2 
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment. 
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  If possible, they will be seen and assessed by an investigator. AEs 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
51(110) 
will be followed up (See Sections 6.3.2 and 6.4); diary, blood glucose/ketone meters and all 
study drugs should be returned by the subject. 
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn subjects will not be replaced. 
3.11 
Discontinuation of the study 
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that: 
x 
meet individual stopping criteria or are otherwise considered significant  
x 
are assessed as causally related to study drug 
x 
are not considered to be consistent with continuation of the study 
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the eCRF.  All reasons for discontinuation of 
treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
4. 
STUDY PLAN AND TIMING OF PROCEDURES 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
52(110) 
Table 1 
Study schedule for Part A 
Period 
Screening 
Treatment periodb 
Follow-up 
period b, c 
Week (Day) 
Week -2 
(Day -14) 
-1 (Day -1) 
0 (Day 1)a 
0 (Day 3 to 
Day 5) 
1 (Day 7) 
1 (Day 8) 
2 (Day 14) 
Visit 
1 
2 
3 
- 
4 
5 
6 
Visit window (days) 
+7 
- 
0 
- 
+2 
- 
+2 
Eligibility Assessments 
 
 
 
 
 
 
 
Informed Consent 
X d 
 
 
 
 
 
 
Review Inclusion/Exclusion  
X 
X 
X 
 
 
 
 
Review Medical History 
X 
X 
X 
 
 
 
 
General procedures 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
 
 
 
 
 
Brief Physical Examination 
 
X 
X 
 
X 
X 
X 
Vital Signs (BP, HR), Body 
Weight 
X 
X 
X 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X 
X 
Weight (BMI) 
X 
 
X 
 
 
X 
 
Review concomitant 
medications/procedures 
X 
X 
X 
 
X 
X 
X 
Provide Dietary and Exercise 
Counselling 
X 
 
X 
(Day 2) 
 
 
X 
 
Dispense subject diaries, blood 
glucose/ketone meters and provide 
instructions 
X 
 
 
 
 
X 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
53(110) 
Table 1 
Study schedule for Part A 
Period 
Screening 
Treatment periodb 
Follow-up 
period b, c 
Week (Day) 
Week -2 
(Day -14) 
-1 (Day -1) 
0 (Day 1)a 
0 (Day 3 to 
Day 5) 
1 (Day 7) 
1 (Day 8) 
2 (Day 14) 
Visit 
1 
2 
3 
- 
4 
5 
6 
Visit window (days) 
+7 
- 
0 
- 
+2 
- 
+2 
Review subject diaries  
 
X 
X 
(Day 2) 
 
X 
X 
X 
Adjust Insulin Dose, as needed 
 
 
 
 
 
 
 
Hospitalization 
 
 
(From  
Day -2) 
 
(Discharge 
at Day 2) 
 
 
(From  
Day 6) 
 
 
Telephone (fax or email) contact 
 
 
 
X 
(at least 
once a day) 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
Assess Adverse Events  
 
 
 
 
 
 
 
Assess Hypoglycemia Episodes  
 
 
 
 
 
 
 
Assess Diabetic Ketoacidosis 
 
 
 
 
 
 
 
7-point SMBG  
 
 
 
 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
Blood Standard Safety Laboratory 
Test 
X 
 
X 
 
 
X 
X 
Urine Standard Safety Laboratory 
Test 
X 
 
X 
 
 
X 
X 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
54(110) 
Table 1 
Study schedule for Part A 
Period 
Screening 
Treatment periodb 
Follow-up 
period b, c 
Week (Day) 
Week -2 
(Day -14) 
-1 (Day -1) 
0 (Day 1)a 
0 (Day 3 to 
Day 5) 
1 (Day 7) 
1 (Day 8) 
2 (Day 14) 
Visit 
1 
2 
3 
- 
4 
5 
6 
Visit window (days) 
+7 
- 
0 
- 
+2 
- 
+2 
Pregnancy test (serum) WOCBP 
only 
X 
 
 
 
 
 
 
Pregnancy test (urine) WOCBP 
only 
 
 
X 
 
 
X 
X 
Urine (dipstick) 
X 
 
X 
 
 
X 
X 
Microscopic urinalysis 
X 
 
X 
 
 
X 
X 
24-hour urine collection for 
Glucose, Sodium, Uric Acid and 
Creatinine e 
 
X 
X 
 
X 
X 
 
Blood sampling for 
pharmacokinetics e 
 
 
X 
 
X 
X 
 
FPG 
 
 
X 
 
X 
X 
 
C-peptide 
X 
 
 
 
 
 
 
Hepatitis Screen Panel 
X 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
HbA1c 
X 
 
X 
 
 
 
 
Study Drug Supply 
 
 
 
 
 
 
 
Randomize 
 
 
X 
 
 
 
 
Dispense Study Drug 
 
 
X 
 
 
 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
55(110) 
Table 1 
Study schedule for Part A 
Period 
Screening 
Treatment periodb 
Follow-up 
period b, c 
Week (Day) 
Week -2 
(Day -14) 
-1 (Day -1) 
0 (Day 1)a 
0 (Day 3 to 
Day 5) 
1 (Day 7) 
1 (Day 8) 
2 (Day 14) 
Visit 
1 
2 
3 
- 
4 
5 
6 
Visit window (days) 
+7 
- 
0 
- 
+2 
- 
+2 
Contact IWRS 
X 
 
X 
 
 
X 
 
Review study drug dosing  
 
 
X 
X 
X 
 
 
a 
Day 1 of Week 0 means the stating day of dapagliflozin.  The previous day of Day 1 is shown as “Day -1” 
b 
The results of urine glucose (dipstick, spot urine and 24-hour collection urine) at central laboratory are blinded for subjects during the treatment period. 
c 
If a patient meet any study discontinuation criteria, the patient should receive the 1 week follow-up evaluation (Tests and evaluations of Visit 4 are 
unnecessary). 
d 
If a patient performed Informed Consent only, it is to allowed be out of visit window. 
e 
The detail is referred to Table 2. 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
56(110) 
Table 2 
Time schedule of PK and PD sample collection (Part A) 
Date 
Time after administration (hour) 
Blood sampling for PK 
Urine sampling for PD 
Day -1 
 
 
24-hour sampling 
 
Day 1 
Pre dose of dapagliflozin 
X 
 
Day 7 
Pre dose (60 minutes prior to 
dapagliflozin dose, ±5 minutes) 
X 
 
 
0 (dapagliflozin dose) 
 
24-hour sampling 
 
 
0.5 (±5 minutes) 
X 
 
 
1 (±10 minutes) 
X 
 
 
2 (±10 minutes) 
X 
 
 
3 (±10 minutes) 
X 
 
 
4 (±20 minutes) 
X 
 
 
6 (±30 minutes) 
X 
 
 
8 (±40 minutes) 
X 
 
 
12 (±60 minutes) 
X 
 
Day 8 
24 (±60 minutes) 
X 
 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
57(110) 
Table 3 
Study schedule (Part B) 
Period 
Screening 
Wash-
outa 
Treatment period 
Follow-
up 
periodd 
Week 
-3 
-1 
0b 
1 
2c 
4 
8 
12 
16 
20 
24 
32, 40, 48 
52 
56 
Visit 
1 
2 
3 
4 
(5) 
6 
7 
8 
9 
10 
11 
12, 13, 14 
15 
16 
Visit window (days) 
-7 
±3 
0 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
Eligibility 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Review Medical 
History 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
General procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone (fax or 
email) contact (TC) f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Physical 
Examination 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR), 
Body Weight 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Weight (BMI) 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
58(110) 
Table 3 
Study schedule (Part B) 
Period 
Screening 
Wash-
outa 
Treatment period 
Follow-
up 
periodd 
Week 
-3 
-1 
0b 
1 
2c 
4 
8 
12 
16 
20 
24 
32, 40, 48 
52 
56 
Visit 
1 
2 
3 
4 
(5) 
6 
7 
8 
9 
10 
11 
12, 13, 14 
15 
16 
Visit window (days) 
-7 
±3 
0 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
Review concomitant 
medications/ 
procedures 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Provide Dietary and 
Exercise Counselling 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense subject 
diaries, blood 
glucose/ketone meters 
and provide 
instructions 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review subject diaries   
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adjust Insulin Dose, as 
needed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess Adverse Events   
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess Hypoglycemia 
Episodes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess Diabetic 
Ketoacidosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4-point SMBG  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
59(110) 
Table 3 
Study schedule (Part B) 
Period 
Screening 
Wash-
outa 
Treatment period 
Follow-
up 
periodd 
Week 
-3 
-1 
0b 
1 
2c 
4 
8 
12 
16 
20 
24 
32, 40, 48 
52 
56 
Visit 
1 
2 
3 
4 
(5) 
6 
7 
8 
9 
10 
11 
12, 13, 14 
15 
16 
Visit window (days) 
-7 
±3 
0 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
Laboratory 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-peptide 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis Screen Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Standard Safety 
Laboratory Panel 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Standard Safety 
Laboratory Panel 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum) 
WOCBP only 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine) 
WOCBP only 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine (dipstick) 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
Microscopic urinalysis 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
6-point SMBG, Self-
Monitored Blood 
Ketone 
 
 
Xg 
 
 
 
 
Xg 
 
 
Xg 
 
Xg 
 
HbA1c, GA 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug Supply 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
60(110) 
Table 3 
Study schedule (Part B) 
Period 
Screening 
Wash-
outa 
Treatment period 
Follow-
up 
periodd 
Week 
-3 
-1 
0b 
1 
2c 
4 
8 
12 
16 
20 
24 
32, 40, 48 
52 
56 
Visit 
1 
2 
3 
4 
(5) 
6 
7 
8 
9 
10 
11 
12, 13, 14 
15 
16 
Visit window (days) 
-7 
±3 
0 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drug 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Contact IWRS 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Review study drug 
dosing  
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a 
Wash-out period is applicable only for subjects who received α-GI until enrolment.  Subjects not taking other anti-hyperglycemic drugs other than 
insulin skip the period and directly proceed to the Treatment period. 
b 
Day 1 of Week 0 means the stating day of dapagliflozin.  The previous day of Day 1 is shown as “Day -1” 
c 
Either hospital visit or telephone (fax or email) contact is acceptable on Week 2.  
d 
If a patient meet any study discontinuation criteria, the patient should receive the Week 52 and follow-up evaluation. 
e 
If a patient performed Informed Consent only, it is to allowed be out of visit window. 
f 
On Day 2, 4 (± 1 day) and 10 (± 1 day) patients must contact the Investigators by phone (fax or email) and report the patient’s condition (including 
glucose and ketone values from SMBG).  The Investigators must indicate appropriate insulin adjustment. 
g 
It will be performed on any 3 days within a week before each visit. 
 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
61(110) 
4.1 
Enrolment/screening period (2weeks) 
Japanese male and female subjects with T1DM will be enrolled into the study.  Subjects 
should be on insulin for at least 12 months prior to screening per subject report or medical 
records. 
Subjects will be instructed to continue their current insulin and if applicable any ongoing 
therapy during enrolment period. 
Patients for part B on α-GI use currently (see exclusion criteria 1-(f)) of enrolment on top of 
insulin mono-therapy need to undergo a 1-week wash-out period prior to randomization. 
4.1.1 
Retesting During Screening 
Retesting of laboratory parameters and/or other assessments within any single screening will 
be permitted (in addition to any parameters that require a confirmatory value). 
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. 
Retesting is limited to HbA1c as described in Section 3.1. 
4.1.1.1 
Study Materials 
Sponsor will supply the sites with the following materials. 
x 
Blood glucose/ketone meters. One (1) meter will be provided to each study subject 
at screening period and 1 meter will be provided to each investigative site.  SMBG: 
see Section 5.3.1.1. 
x 
Glucose and ketone test strips 
x 
Lancets 
x 
Glucose control solutions 
x 
eCRFs [SAE Forms, Pregnancy Surveillance Forms, Events of Special Interest] 
x 
Subject Alert Cards 
x 
Study Drug inventory control forms 
x 
Site File 
x 
Subject Diary: 
 
Full Diary review by site staff is required for this study 
 
Use of subject diaries are mandatory for the study and will be maintained by 
each study subject for documentation and SMBGs, insulin doses, study 
medication dosing, ketone testing, DKA symptoms, and hypoglycemia 
episodes. 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
62(110) 
 
Subjects are to be instructed to document their insulin dose in their study 
diaries during the protocol defined time period as outlined in Section 5.3.3.  
The eCRF pages will be provided to the sites so they can record the data 
obtained from the diaries in the study database. 
 
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 throughout the study.  Compliance with 
prescribed insulin administration and diary completion should be 
assessed and re-enforced at every visit. 
 
The dates, time, and number of tablets of study medication taken by the subject 
are to be recorded in the study diary.  The eCRF pages will be provided to the 
sites so they can record the data obtained from the diaries in the study database 
(Part A only) 
 
Subjects are to record any hypoglycemic symptoms they may experience and 
SMBG values if they conducted the test when they have symptoms in their 
diaries.  All events recorded in subject diary to be reviewed by site staff 
according to Section 5.3.1. 
 
Any ketone testing performed by the subject, symptoms potentially associated 
with DKA, and relevant events (Section 5.3.2) are to be recorded in the diary. 
All results recorded in subject diary will be reviewed by site staff. 
The central laboratory will provide all laboratory-related materials including home pregnancy 
testing kits for WOCBP to the study sites. 
4.2 
Wash-out period only for part B (1 week, it is applicable exclusively 
for subjects receiving α-GI on top of insulin) 
Subjects, who are previously treated with insulin only but have not been treated with any 
anti-hyperglycemic agent except insulin within 1 month prior to screening visit (see exclusion 
criteria 1-(f)), can skip wash-out period.  Washout means to stop taking anti-hyperglycemic 
agent except insulin. 
Subjects will receive a glucose and ketone meter and a patient diary, testing 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 will be advised to continue self-monitoring their blood glucose as per local guideline, 
and in the occurrence of hypoglycemic symptoms, and to contact the Investigators 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 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
63(110) 
adjustments accordingly and should report to the Investigators blood glucose values and/or 
signs and symptoms suggestive of a hypoglycemic episode. 
Subjects who meet the eligibility criteria at visit 1 and visit 2 are eligible to entry into the 
treatment period at Visit 3. 
4.3 
Treatment period 
4.3.1 
PK and PD evaluation part (Part A) 
Subjects who meet all the protocol-specific enrolment and randomization inclusion criteria 
and meet none of the exclusion criteria will be randomized into one of the three single-blind 
treatment arms (dapagliflozin 5 mg QD, dapagliflozin 10 mg QD, or placebo QD) in a 1:1:1 
ratio. 
Duration of hospitalization:  
x 
First hospitalization: From evening (before dinner, approximately 18:00) on Day -2 
to morning (approximately 10:00) on Day 2 (4 days and 3 nights) and  
x 
Second hospitalization: From evening (before dinner, approximately 18:00) on Day 
6 to morning (approximately 10:00) on Day 8 (3 days and 2 nights) 
Recommendation of calorie control during hospitalization:  
x 
Calculation of adequate calories;  
 
Adequate calorie intake for each patient is calculated by mean of formula as 
followed,  
• 
Calorie intake = (basal metabolic standard [kcal/kg]) x (standard body 
weight [kg]) 
• 
Basal metabolic standard is 20-30 kcal/kg for inpatients. 
• 
Standard body weight (kg) = Height (m) x Height (m) x 22 
 
Total calories and proportion of carbohydrate should be similar between two 
hospitalization periods. 
Recommendation of calorie control during outpatient: 
Patients are recommended to do “light work (desk workers, housewives, etc)” only during 
outpatient (Day 2 to 6).  Total calories and proportion of carbohydrate should be stable as 
much as possible (basal metabolic standard is 25-35 kcal/kg for outpatients).  The 
investigators must instruct the management of excise and diet during the outpatient period 
before discharge from hospital. 
Subjects should self-monitor their blood glucose (see Section 5.3.1.1). 
The randomized subject will be observed within 24 hours after first dose of study drug on 
Day1 at the investigator’s site in order to adjust their daily insulin doses for both basal and 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
64(110) 
bolus insulin to reduce the risk of hypoglycemia.  It is at the discretion of the Investigators 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. 
4.3.2 
Long term treatment part (Part B) 
Subjects who meet all the protocol-specific enrolment and randomization inclusion criteria 
and meet none of the exclusion criteria will be randomized into one of the 2 open-label 
treatment arms (dapagliflozin 5 mg QD or dapagliflozin 10 mg QD) in a 1:1 ratio. 
Subjects should self-monitor their blood glucose (see Section 5.3.1.1).  
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.  
4.4 
Follow-up period 
4.4.1 
PK and PD evaluation part (Part A) 
Subjects will stop taking investigational products at Visit 4 and will be re-evaluated 1 week 
later for AEs and laboratory parameters.  Subjects who discontinue study medication during 
the treatment period will also be re-evaluated 1 week later for AEs and laboratory parameters 
and tests and evaluation of Visit 4 are unnecessary.  Open-label use of anti-diabetic agents are 
permitted during the follow-up period within approved dose range and regimen in Japan. 
4.4.2 
 Long term treatment part (Part B) 
Subjects will stop taking investigational products at Visit 15 (end of treatment period) and will 
be re-evaluated 4 weeks later for AEs and laboratory parameters.  Subjects who discontinue 
study medication during the treatment period will also be re-evaluated 4 weeks later for AEs 
and laboratory parameters.  Open-label use of anti-diabetic agents are permitted during the 
follow-up period within approved dose range and regimen in Japan. 
4.5 
Supplemental Visits 
4.5.1 
Early Treatment Discontinuation Visit 
Subjects discontinued from the treatment period 
Any subject who discontinues study medication during the treatment period in Part B is to 
have the end of treatment visit (Visit 15 in part B) completed.  The ET visit eCRF will also 
need to be completed and the ET visit laboratory kit will need to be used to collect ET Visit 
blood and urine samples.  The IWRS must be called to record the subject status (ie, 
discontinuation status).  In case of ET in part A, the patient would not need tests and 
evaluation of Visit 4. 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
65(110) 
4.5.2 
Other Supplemental (Unscheduled) Visits 
At any time during the trial, the investigator may at his/her discretion arrange for a subject to 
have an unscheduled (supplemental) assessment(s), especially in the case of AEs that require 
follow-up.  If a subject is seen for an unscheduled assessment, the appropriate Supplemental 
Pages of the eCRF must be completed. 
5. 
STUDY ASSESSMENTS   
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The investigator will ensure that data are recorded on the electronic eCRFs as 
specified in the study protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement.  The 
investigator will sign the completed eCRF.  A copy of the completed eCRF will be archived at 
the study site. 
5.1 
Efficacy assessments 
5.1.1 
Efficacy assessments 
The laboratory parameters that will be measured to assess efficacy in Part B are displayed in 
Table 4 by visit.  There is not applicable parameter in part A. 
Table 4 
Efficacy laboratory variables in part B 
Visit 
1 
2 
3 
4 
6 
7 
8 
9 
10 11 12, 13, 14 
15 
16 
Week 
-3 
-1 
0 
1 
4 
8 
12 16 20 24 32, 40, 48 
52/ET 
56/ET+4 
weeks 
6-point SMBG  
 
X 
 
 
 
X 
 
 
X 
 
X 
 
HbA1c, GA 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
5.1.2 
HbA1c and glycoalbumin 
HbA1c is the assessment for the determination of glycemic efficacy accepted referred by The 
Japanese Guideline for Clinical Evaluation of Oral Hypoglycaemic Agents 2010.  HbA1c will 
be analysed by a central laboratory according to the procedures described in the Laboratory 
Manual which will be distributed to each study site during site initiation.  The measurement of 
HbA1c is National Glycohemoglobin Standardization Program (NGSP). 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
66(110) 
Glycoalbumin (GA) will be also analysed by a central laboratory according to the procedures 
described in the Laboratory Manual which will be distributed to each study site during site 
initiation.  GA is a well established measure of glycemic efficacy and considered to be an 
acceptable secondary objective. 
5.1.3 
6-point SMBG profiles 
Subjects will be instructed to perform 6-point SMBG profiles as described below. Subjects 
must use the meter provided by the Sponsor.  
Profiles will be obtained on any 3 days within a week before the Day 1 visit, Week 12 visit, 
and Week 24 visit, week 52 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 (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. 
If a subject fails prior to the randomization, the 6-point SMBG profile will not be required 
within one week prior to Day 1 visit. 
If a randomized subject terminates the study any time prior to the Week 52 visit, the 6-point 
SMBG profile will not be required for the early termination visit. 
5.1.4 
Weight and height 
The subject’s weight will be recorded in kilogram (kg) to one decimal place, with light 
clothing and no shoes.  The subject’s height will be recorded in centimetres, with no shoes.  
All readings should be recorded as accurately as possible and the same scale should be used 
for all assessments for a given subject. 
5.1.5 
Blood pressure 
As BP is both efficacy and safety variable in this study, measurement of BP is described in 
Section 5.3.7. 
5.2 
PD assessment (Part A only)  
5.2.1 
Analysis of 24-hour urinary glucose excretion 
The 24 -hour urinary glucose excretion is an assessment linked to the mechanism of action of 
Dapagliflozin. It is measured based on 24 -hour urine collections. Urine is collected over a 24-
hour period on Days -1 and 7. 
The 24-hour period is defined from morning of one day to morning of the next day. Therefore, 
in the morning, on the day that the 24-h urine collection is started, the first morning void is not 
included in the 24-h collection. The date and time of the first urine should be recorded on the 
urine collection log as the start of the 24-h urine collection. All subsequent urinations 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
67(110) 
throughout the entire day and night and into the following day should be collected. The first 
voided urine of the subsequent day should be included in the 24-hr urine collection. The urine 
collection ends after 24 hrs and the stop time should equal the start time of the previous day. 
The stop date and time should be recorded on the urine collection log. 
5.2.2 
FPG 
FPG is the secondary glycemic parameter. FPG is measured on Days 1, 7 and 8. 
5.3 
Safety assessments 
Safety assessments will include adverse event reporting, as well as marked abnormalities in 
clinical laboratory tests. Please refer to Section 5.5 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 
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. 
5.3.1.1 
Self Monitored Blood Glucose (SMBG) 
Combination glucose and ketone meters will be supplied to each study site. At the screening 
visit, 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. 
In part A, subjects should self-monitor their blood glucose whenever possible at least 7 times 
per day (before and after each meal and before going to bed) from Day -1 to Day 7 and in the 
occurrence of hypoglycemic symptoms, and contact the Investigators in the event of an 
unusually high or low blood glucose value. Study sites will review these diary entries and 
record these data on the eCRF. 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 investigator blood glucose values and/or signs and 
symptoms suggestive of a hypoglycemic episode.  Subjects must report the values to the 
investigator on Day 3 to 5 by telephone (fax or email) at least once a day. 
In part B, subjects should self-monitor their blood glucose whenever possible at least 4 times 
per day (generally before breakfast, lunch, dinner, and bedtime) during the treatment period 
(until Visit 15), and in the occurrence of hypoglycemic symptoms, and contact the 
Investigators in the event of an unusually high or low blood glucose value.  In addition, study 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
68(110) 
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 investigator blood 
glucose values and/or signs and symptoms suggestive of a hypoglycemic episode. 
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. 
5.3.1.2 
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 in their diaries any hypoglycemic symptoms.  They 
should be encouraged to measure, when possible, their blood glucose values when they have 
symptoms of hypoglycemia.  Subjects should carry with them easily ingestible forms of 
carbohydrate at all times in order to treat an event of hypoglycemia should it occur. 
During clinical trials, subjects frequently report symptoms of hypoglycemia when asked, even 
when treated with placebo or medications not otherwise associated with hypoglycemia.  As 
hypoglycemia is an important event associated with diabetes therapy, all episodes which could 
be consistent with the clinical definition of hypoglycemia as assessed by the investigator 
should be documented and reported on the appropriate eCRF page. 
The following definitions of hypoglycemia will be used:  
x 
Severe hypoglycemia: An event requiring assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions.  These episodes 
may be associated with sufficient neuroglycopenia to induce seizure or coma. 
Plasma glucose measurements may not be available during such an event, but 
neurological recovery attributable to the restoration of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma glucose 
concentration. 
x 
Documented symptomatic hypoglycemia: An event during which typical 
symptoms of hypoglycemia are accompanied by a measured plasma glucose 
concentration ≤ 70 mg/dL (3.9 mmol/L). 
x 
Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg/dL 
(3.9 mmol/L). 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
69(110) 
x 
Probable symptomatic hypoglycemia: An event during which symptoms of 
hypoglycemia are not accompanied by a plasma glucose determination (but that was 
presumably caused by a plasma glucose concentration ≤ 70 mg/dL [3.9 mmol/L]). 
Since many people with diabetes choose to treat symptoms with oral carbohydrate 
without a test of plasma glucose, it is important to recognize these events as 
“probable” hypoglycemia.  Such self-reported episodes that are not confirmed by a 
contemporaneous low plasma glucose determination may not be suitable outcome 
measures for clinical studies that are aimed at evaluating therapy, but they should 
be reported. 
x 
Relative hypoglycemia: An event during which the person with diabetes reports 
any of the typical symptoms of hypoglycemia, and interprets those as indicative of 
hypoglycemia, but with a measured plasma glucose concentration > 70 mg/dL 
(3.9 mmol/L).  This category reflects the fact that patients with chronically poor 
glycemic control can experience symptoms of hypoglycemia at plasma glucose 
levels > 70 mg/dL (3.9 mmol/L) as plasma glucose concentrations decline toward 
that level.  Though causing distress and interfering with the patient’s sense of well-
being, and potentially limiting the achievement of optimal glycemic control, such 
episodes probably pose no direct harm and therefore may not be a suitable outcome 
measure for clinical studies that are aimed at evaluating therapy, but they should be 
reported. 
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 episode or discontinuation due to 
hypoglycemia should not be reported on the AE eCRF page, unless the event fulfils protocol 
criteria for a SAE (see Section 6.2), in which case an SAE form must be completed in addition 
to the hypoglycemia eCRF pages for hypoglycemia. 
5.3.2 
Self-Monitored Blood Ketone Testing and Guidance on Management and 
Reporting of Diabetic Ketoacidosis (DKA) Episodes 
DKA 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 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
70(110) 
otherwise not avoid a 20% reduction in total daily insulin dose, their carbohydrate intake 
should be re-valuated and those who have insufficient amount of carbohydrate 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 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 screening period.  Subjects will also be trained in the procedure of 
conducting blood ketone testing according to the manufacture’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.  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. 
In part B, subject will measure their blood ketones using the meter provided by the Sponsor 
when they measure the blood glucose of each before breakfast at 6-point SMBG profiles (see 
Section 5.1.3), and will record the results on the patient diary. The Investigators will review 
these diary entries and record the results on the eCRF. 
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. 
Investigator(s) 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, investigator(s) 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 investigator are 
unsuccessful and if they are in urgent need of medical attention, e.g. sings/symptoms, 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 SGLT2 inhibitor 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 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
71(110) 
from glycemic control assessed by the central laboratory or with clinical symptoms, the 
subject’s glucose and ketone meter should be tested and the procedure for using it reviewed 
with the subject.  Investigators will examine if any of the elevated ketone values from the 
subject’s diary are associated with a DKA event. If yes, investigators will document all DKA 
related symptoms, relevant risk factors, and available laboratory test results (including blood 
ketone values and blood glucose values measured by the glucose/ketone meter) on the DKA 
eCRF pages and report this event to the Sponsor. 
In addition the Sponsor will utilize Standardized Medical Dictionary for Regulatory Activities 
(MedDRA) Queries (SMQs) based on a list of pre-defined terms in MedDRA to identify 
potential DKA events.  The list of these terms is included in the Data Monitoring Committee 
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 in 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, elevated blood/urine ketone values, and a metabolic acidosis characterized by 
low arterial blood pH values and decreased serum bicarbonate with 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 episode or discontinuation due to 
DKA should not be reported on the AE eCRF page, unless the event fulfils protocol criteria 
for a SAE (see Section 6.2), 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. 
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 


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with DKA should be carefully monitored until significant improvement in the symptoms, 
normalization of blood acidity (eg, pH > 7.3), and improvement/absence of ketones in blood 
or urine. 
5.3.3 
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 screening and wash-out period, subjects will be advised to self-monitor their blood 
glucose consistent with local treatment guidelines. The method of documentation for glucose 
results to 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 
according to SMBG readings, local guidance and individual circumstances. 
In part A, the randomized subject will be observed within 24 hours after first dose of study 
drug on Day1 at the investigator’s site in order to adjust their daily insulin doses for both basal 
and bolus insulin to reduce 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.  
In part B, it is recommended that subjects reduce their daily insulin dose by up to 20% for 
both basal and bolus insulin after 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 (particular 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 5.3.2). Subjects are to be instructed to document their daily individual insulin 
doses and at least 4-time self monitored glucose values (before breakfast, lunch, dinner, and 
bedtime) every day during the treatment period in part B and during the treatment period in 
part A.  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. 


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Date 14 December 2016 
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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 two weeks. 
Insulin Dosing Recording in part A 
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. 
x 
Day-3 visit to Day 14 
Insulin Dosing Recording in part B 
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. 
x 
2 weeks prior to randomization 
x 
Day 1 visit after randomization to Day 14 (Week 2) 
x 
Week 10 to Week 12 visit 
x 
Week 22 to Week 24 visit 
x 
Week 50 to Week 52 visit 
The Investigators will review these diary entries and record the total basal, total bolus, and 
total pre-mix (if applicable), 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 Week 2 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: 
x 
Week 2 visit to Week 10 
x 
Week 12 visit to Week 22 
x 
Week 24 visit to Week 50 
x 
Week 52 visit to Week 56 visit 
The Investigators will review these diary entries and record the weekly ranges subject 
received of insulin on the eCRF. 


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Version 3 
Date 14 December 2016 
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5.3.4 
Guidance on Assessment of Urinary Infections & Hematuria 
5.3.4.1 
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 urinary tract infection 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 subject's medical history, related adverse events as defined in Section 6.1. 
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. 
Asymptomatic Bacteriuria 
During enrolment, 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 US nor Europe recommend screening for, or 
treatment of, asymptomatic bacteriuria in non-pregnant diabetic patients (Nicolle et al 2005, 
US Preventative Services Taskforce 2004, European Association of Urology 2008).  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. 
5.3.4.2 
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 an urologist and undergoing evaluation that may 
include abdominal computed tomography (CT), urine cytology, and NMP-22 urine test. The 
subject should continue to be randomized/receive investigational product treatment during 
these investigations (unless otherwise contraindicated). 


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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 6.1. 
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. 
5.3.5 
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: 
x 
AST and/or ALT > 3x ULN and TB > 2x ULN (within 14 days of the AST and/or 
ALT elevation) 
x 
Hepatic events timely related to death (within 30 days before death) 
x 
AST and/or ALT > 10x ULN 
These events should be reported as SAEs. 
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 
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: 
x 
AE assessment 
x 
Physical examination for jaundice and other signs of liver diseases 
x 
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 


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x 
Specialized Liver Laboratory Panel (see Appendix D) 
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 3.9, additional blood sampling must be done 
within 3 days of the confirmed laboratory results (see Appendix D), 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. 
5.3.6 
Physical Examination 
x 
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 
x 
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 law (or 
applicable local law) to perform this procedure. 
Baseline data is collected at Visit 3, and new findings discovered on subsequent physical 
examinations should be recorded as changes from baseline. 
5.3.7 
Blood Pressure and Heart Rate 
Blood pressure (BP) and heart rate (HR) measurements must be taken consistently throughout 
the study.  Only use either the right or the left arm when measuring these parameters. 
Document which arm was used along with the observer’s initials; the same arm should be 
used at each visit. The subject should be in a seated position allowing at least 5 minutes of rest 
before measurement. BP should be measured with the subject’s arm resting on a table, and 
with subject’s back supported and feet flat on the floor. 
BP and HR will be determined from 3 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. 
5.3.8 
Resting 12-Lead ECG 
A 12-Lead ECGs will be performed at noted in Section 5.3.8.  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 


Clinical Study Protocol  
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randomizing the subject. In preparation for the ECG, ensure there is minimal interference 
between the skin surface and the electrode.  Use alcohol 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, spread the electrode with electrode gel.  Place the electrodes 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.  Ensure 
that the subject and the electrodes (including the neutral electrode) are not exposed to 
conducting objects, even if grounded. 
x 
RL: On the right leg (inside calf, midway between knee and ankle) 
x 
LL: On the left leg (inside calf, midway between knee and ankle) 
x 
RA: Right arm (on the inside) 
x 
LA: Left arm (on the inside) 
x 
V1: 4th intercostal space, at right sternal margin 
x 
V2: 4th intercostal space, at left sternal margin 
x 
V3: Midway between V2 and V4 
x 
V4: 5th intercostal space at left midclavicular line 
x 
V5: Same transverse level at V4, at anterior axillary line 
x 
V6: Same transverse level at V4, at left midaxillary line 
Keep one original ECG print-out, assessed, initialled and dated by the investigator, in the 
medical chart.  In addition, ensure a copy is maintained in the source documents for the study 
regarding the print-out such as thermal recording paper that could not be preserved for a long 
time. 
5.3.9 
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. 
5.3.10 
Other safety assessments 
Self-monitored blood glucose, keton, hypoglycemic and DKA events will be collected in a 
subject diary and reviewed by the investigator at each visit. 
5.4 
Other assessments 
5.4.1 
Height and Body Mass Index (BMI) 
x 
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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Study Code D1695C00001 
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Date 14 December 2016 
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x 
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: 
x 
Use actual height and weight. 
x 
To calculate BMI: 
BMI = (weight in kg) / (height in meter) 2 
5.4.2 
Diet and Exercise Counselling 
Starting at entry into the screening visit, subjects will be instructed on a diet and an exercise 
program in accordance with the ADA or similar local guidelines to be followed for the study 
duration. 
A registered dietitian, registered nurse, physician, certified diabetes educator (CDE), 
nutritionist, or other qualified member of the study team who has appropriate documented 
training, will provide this counselling. 
5.5 
Results of Central Laboratory Assessments 
Blood and urine samples will be obtained at specified time points for laboratory evaluations 
(see Table 5 and Table 6).  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. 
Spot urine for glucose, 24-hour collection urine and urine dipstick will be masked for the 
patients during the treatment period in part A. 
The following laboratory variables will be measured. 
Table 5 
Safety laboratory variables (Part A) 
Week (Day) 
-2 
(Day -14) 
-1 
(Day -1) 
0 
(Day 1) 
1 
(Day 7) 
1 
(Day 8) 
2 
(Day 14) 
Visit 
1 
2 
3 
4 
5 
6 
Blood Standard Safety 
Laboratory Test 
X 
 
X 
 
X 
X 
Urine Standard Safety 
Laboratory Test 
X 
 
X 
 
X 
X 
Pregnancy test (serum) WOCBP 
only 
X 
 
 
 
 
 
Pregnancy test (urine) WOCBP 
only 
 
 
X 
 
X 
X 


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Table 5 
Safety laboratory variables (Part A) 
Week (Day) 
-2 
(Day -14) 
-1 
(Day -1) 
0 
(Day 1) 
1 
(Day 7) 
1 
(Day 8) 
2 
(Day 14) 
Visit 
1 
2 
3 
4 
5 
6 
Urine (dipstick) Urine glucose 
X 
 
X 
 
X 
X 
Microscopic urinalysis 
X 
 
X 
 
X 
X 
Hepatitis Screen Panel 
X 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
Table 6 
Safety laboratory variables (Part B) 
Week 
-3 
-1 
0 
1 
4 
8 
12 16 20 24 32, 40, 48 52 
56 
Visit 
1 
2 
3 
4 
6 
7 
8 
9 
10 11 12, 13, 14 15 
16 
Blood Standard Safety 
Laboratory Panel 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Standard Safety 
Laboratory Panel 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum) 
WOCBP only 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine) WOCBP 
only 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine (dipstick) Urine glucose X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
Microscopic urinalysis 
X 
 
X 
 
 
 
 
 
 
X 
 X 
X 
X 
Hepatitis Screen Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Regarding Efficacy and PK/PD laboratory variables (see Section 4) except SMBG and self 
monitoring Blood Ketone variables, the central laboratory for this study will perform the 
analysis of all scheduled laboratory tests and will provide reference ranges for these tests.   
5.5.1 
Blood Standard Safety Laboratory Panels: 
5.5.1.1 
Hematology 
x 
Hemoglobin (g/dL, g/L) 
x 
Hematocrit (%, v/v) 
x 
Red blood cell (RBC) (x106/UL, x1012/L) 


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Study Code D1695C00001 
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Date 14 December 2016 
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RBC count indices: 
x 
Mean Cell Volume (MCV) (fL) 
x 
Mean Cell Hemoglobin (MCH) (pg/cell) 
x 
Mean Cell Hemoglobin Concentration (MCHC) (gHb/dL, gHb/L) 
x 
White blood cell Count and Differential 
x 
Platelet count (x 109/L) 
5.5.1.2 
Serum Chemistry 
x 
AST (IU/L) 
x 
ALT (IU/L) 
x 
ALK-P (IU/L) 
x 
CK/CPK (IU/L) 
x 
Total Bilirubin (mg/dL, μmol/L), Reflex test for direct bilirubin when TB is 
elevated >1.5ULN 
x 
Serum Creatinine (mg/dL, μmol/L). Creatinine Clearance will be calculated by the 
Central Laboratory 
x 
Blood Urea Nitrogen (mg/dL, mmol/L) 
x 
Albumin (g/dl, g/L) 
x 
Bicarbonate (mEq/L, mmol/L) 
x 
Sodium (mEq/L, mmol/L) 
x 
Potassium (mEq/L, mmol/L) 
x 
Chloride (mEq/L, mmol/L) 
x 
Calcium (mg/dL, mmol/L) 
x 
Magnesium (mEq/L, mmol/L) 
x 
Phosphorus (mg/dL, mmol/L) 
x 
Total Protein (g/dL, g/L) 
x 
Uric acid (mg/dL, μmol/L) 
x 
Total ketone (μmol/L), acetoacetic acid (μmol/L), 3-hydroxybutyric acid (μmol/L); 
Part A only 
x 
GA (%); Part B only 
5.5.1.3 
Urine Analyses 
Urine HCG pregnancy test for WOCBP (HCG minimum sensitivity of 25 IU/L; performed at 
site or at home). If a urine HCG test is positive, a blood specimen will be obtained and a 
serum pregnancy test will be performed by the central laboratory for confirmation. 


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Study Code D1695C00001 
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Date 14 December 2016 
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Urine standard safety laboratory panel (without microscopy): 
x 
Spot Urine for glucose, albumin, and creatinine quantification and determination of 
glucose : creatinine and albumin : creatinine ratios 
x 
Calculated Urinary albumin : creatinine ratio (UACR) 
5.5.2 
Screening-Specific Safety Panel 
x 
Thyroid stimulating hormone (TSH) 
 
Reflex Testing: abnormal TSH value at enrolment will be further evaluated by 
free T4. 
 
Hepatitis Screen Panel: 
㸫 
Anti-hepatitis C virus antibody 
x 
Reflex Testing: Low positive results require confirmation. 
x 
Hepatitis B surface antigen 
x 
Serum Pregnancy test for women of childbearing potential 
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.  For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3. 
NB. In case a subject shows an AST or ALT ≥ 3x ULN or total bilirubin ≥ 2x ULN please 
refer to Appendix D, for further instructions. 
5.6 
Pharmacokinetics (PK) in part A 
5.6.1 
Collection of samples 
Blood samples for determination of dapagliflozin and dapagliflozin 3-O-Glucuronide in 
plasma will be taken at the times presented in the study plan Table 1 and Table 2. 
Samples will be collected, labeled stored and shipped as detailed in the Laboratory Manual.  
5.6.2 
Determination of drug concentration 
Samples for determination of drug concentration in plasma will be analysed by a suitable 
bioanalytical laboratory on behalf of AstraZeneca, using an appropriate bioanalytical method.  
Full details of the analytical method used will be described in a separate bioanalytical report. 


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Date 14 December 2016 
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5.7 
Pharmacodynamics (Not Applicable) 
5.8 
Pharmacogenetics (Not Applicable) 
5.9 
Biomarker analysis (Not Applicable) 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
6.1 
Definition of adverse events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
wash-out periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
6.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, treatment, wash-out, 
follow-up) even if no study treatment has been administered, that fulfils one or more of the 
following criteria: 
x 
Results in death 
x 
Is immediately life-threatening 
x 
Requires in-patient hospitalisation or prolongation of existing hospitalisation  
x 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
x 
Is a congenital abnormality or birth defect 
x 
Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol. 


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Date 14 December 2016 
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6.3 
Recording of adverse events 
6.3.1 
Time period for collection of adverse events 
AEs will be collected from the start of the treatment period throughout the treatment period 
(Part A: Visit 3 to 5, Part B: Visit 3 to 15) and including the follow-up period (Part A: Visit 6, 
Part B: Visit 16). 
AEs which occurred and resolved before the randomization will be record only the original 
documents and the data will not be entered into eCRF excluding SAEs. 
SAEs will be recorded from the time of informed consent is obtained until the end of 
follow-up period (Part A: Visit 6, Part B: Visit 16). 
6.3.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigators for as long as medically indicated but without further recording in the eCRF.  
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
6.3.3 
Variables  
The following variables will be collect for each AE; 
x 
AE (verbatim) 
x 
The date when the AE started and stopped 
x 
Maximum intensity 
x 
Whether the AE is serious or not 
x 
Investigator causality rating against the Investigational Product (yes or no) 
x 
Action taken with regard to investigational product 
x 
Outcome. 
In addition, the following variables will be collected for SAEs: 
x 
Date AE met criteria for serious AE 
x 
Date investigator became aware of serious AE 
x 
AE is serious due to 
x 
Date of hospitalisation 
x 
Date of discharge 
x 
Probable cause of death 
x 
Date of death 
x 
Autopsy performed 
x 
Causality assessment in relation to Study procedure(s) 


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Date 14 December 2016 
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x 
Causality assessment in relation to other medication 
x 
Description of AE. 
Maximum intensity will be graded according to the following definitions: 
x 
mild (awareness of sign or symptom, but easily tolerated) 
x 
moderate (discomfort sufficient to cause interference with normal activities) 
x 
severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2. 
6.3.4 
Causality collection 
The investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs causal relationship will also be assessed for other medication and study procedures 
and additional study drug.  Note that for SAEs that could be associated with any study 
procedure the causal relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol. 
6.3.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
6.3.6 
Adverse events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs and other safety variables will only be reported as AEs if they fulfil any of 
the SAE criteria or are the reason for discontinuation of treatment with the investigational 
product, or require the subject to receive specific corrective therapy. 


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If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Any new or aggravated clinically relevant 
abnormal medical finding at a physical examination or ECG evaluation as compared with the 
baseline assessment will be reported as an AE. 
Wherever possible the reporting investigator uses the clinical, rather than the laboratory term 
(eg, anaemia versus low hemoglobin value). In the absence of clinical signs or symptoms, 
clinically relevant deteriorations in non-mandated parameters should be reported as AE(s). 
6.3.7 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiogram, any other potential safety assessment required or not required by protocol 
should also be recorded as a non-serious or serious AE, as appropriate, and reported 
accordingly. 
6.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the CRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigators to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day, ie, immediately but no later than 24 hours of when he or she 
becomes aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the Investigators or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigators/study site personnel how to 
proceed. 


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Version 3 
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6.5 
Overdose 
x 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
x 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days. 
6.6 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
6.6.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study and/or metformin and/or glimepiride may have interfered 
with the effectiveness of a contraceptive medication.  Congenital abnormalities/birth defects 
and spontaneous miscarriages should be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, normal birth or congenital abnormality) must 
be followed up and documented even if the subject was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it. 
The PREGREP module in the eCRF is used to report the pregnancy.  This module in the 
eCRF should be completed by the investigator and the AstraZeneca representative will 
forward the information to the AstraZeneca Patient Safety data entry site using the same 
procedure as for SAE reporting.  An AstraZeneca paper Pregnancy Outcome Report, part 2, is 
used to report the outcome of the pregnancy. 


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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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6.7 
Management of IP related toxicities and dose Reductions- Not 
Applicable 
6.8 
Study governance and oversight 
6.8.1 
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: 
x 
AST and/or ALT > 3 x ULN and TB >2x ULN (within 14 days of the AST and/or 
ALT elevation) 
x 
Hepatic events timely related to death (within 30 days before death) 
x 
AST and/or ALT > 10 x ULN 
A separate Adjudication Charter will define and describe the procedure for the handling, 
reporting, and classification of these events. 
6.8.2 
DKA Adjudication Committee 
A DKA Adjudication Committee, blinded to the treatment of the subjects, will independently 
adjudicate all the DKA events reported by the 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. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
Dapagliflozin (BMS-512148) tablets are packed into high-density polyethylene (HDPE) bottle 
and are supplied by AstraZeneca or their designee.  For details of the identity of the 
investigational product see below. 
Table 7 
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
dapagliflozin 5 mg tablet 
Film coated tablet 5 mg, green, 
plain, diamond shaped 
AstraZeneca 
dapagliflozin 10 mg tablet 
Film coated tablet 10 mg, green, 
plain, diamond shaped 
AstraZeneca 
Matching placebo for 
dapagliflozin 5 mg tablet 
Film coated tablet 5 mg placebo, 
green, plain, diamond shaped 
AstraZeneca 
Matching placebo for 
dapagliflozin 10 mg tablet 
Film coated tablet 10 mg placebo, 
green, plain, diamond shaped 
AstraZeneca 


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7.2 
Dose and treatment regimens 
7.2.1 
PK and PD evaluation part (Part A) 
Dapagliflozin tablet 5 mg, 10 mg or matching placebos administered orally for the 7 days 
single-blind treatment period. 
Each dose will be composed of 2 tablets according to Table 8.  Investigational drug should be 
taken once daily in the morning. 
Table 8 
Composition of dose and number of tablets 
Dose 
Investigational product 
5 mg dose 
5 mg 1 tablet + 10 mg placebo 1 tablet 
10 mg dose 
5 mg placebo 1 tablet + 10 mg 1 tablet 
Placebo dose 
5 mg placebo 1 tablet + 10 mg placebo 1 tablet 
 
7.2.2 
Long term treatment part (Part B) 
Dapagliflozin tablet 5 mg or 10 mg administered orally for the 52-week open-label treatment 
period. 
The investigational product dapagliflozin should be taken once daily in much around the same 
time as directed by the Investigators.   
Table 9 
Drug dispensing scheme 
Visit ID 
1 
2 3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 
Number of bottles to dispense 
dapagliflozin 5 mg or 10 mg 
0 
0 1 
0 
0 
1 
1 
1 
1 
1 
2 
2 
2 
1 
0 
0 
 
7.2.3 
Non-investigational Product 
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. Sponsor(s) will not be supplying other 
medications than dapagliflozin and placebo. 
In this protocol, non-investigational product is insulin 


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7.3 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practise (GMP) and local 
regulatory guidelines.  Label text will be written in local language. 
7.4 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  A 
description of the appropriate storage conditions is specified in the document explaining 
‘Procedures for drug accountability’. 
7.5 
Compliance 
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF. 
Each time study medication is dispensed, compliance will be reinforced.  When study 
medication is returned, compliance will be assessed based upon subject’s interview and a 
count of the tablets returned. Compliance should be between ≥ 80% and ≤ 120%. The 
investigator (or designee) will record the amounts of study medication dispensed and returned 
at each visit, as well as document reasons for non-compliance in the source document. The 
dates of all study medication dosing, including interruptions, missed doses or overdose, must 
be recorded on the eCRF.  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. 
7.6 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
Study drug will not be distributed to the study site until the contract is concluded between the 
study site and AstraZeneca.  The Investigational Product Storage Manager is responsible for 
managing the study drug from receipt by the study site until the return of all unused study 
drug to AstraZeneca.  AstraZeneca will provide the study documents ‘Procedures for drug 
accountability’ and ‘Procedures for drug storage’ which describes the specific requirements.  
The Investigator(s) is responsible for ensuring that the subject has returned all unused study 
drug. 
7.7 
Concomitant and other treatments  
7.7.1 
Prohibited and/or Restricted Treatments 
Once enrolled, subjects must not receive any of the following for the duration of the screening 
(qualification period), wash-out, and treatment periods: 
x 
Anti-hyperglycemic medication (other than protocol required medication) 
x 
Weight loss medication 


Clinical Study Protocol  
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x 
Newly initiated treatment with any systemic corticosteroid therapy that will involve 
≥ 5 days of therapy (inhaled and topical are allowed) 
7.7.2 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
subject’s safety and well being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF. 
7.8 
Post Study Access to Study Treatment 
At the end of the study treatment period, AstraZeneca will not continue to supply study drug 
to subjects/investigators unless AstraZeneca chooses to extend the study.  The Investigators 
should ensure that the subject receives appropriate standard of care to treat the condition under 
study. 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1 
Statistical considerations 
x 
All the analyses for Part A and Part B will be separately conducted. 
x 
Analyses will be performed by AstraZeneca or its representatives. 
x 
Further details will be specified in Statistical Analysis Plan. 
8.2 
Sample size estimate 
8.2.1 
PK and PD evaluation part (Part A) 
Approximately 42 patients are to be randomized to placebo, dapagliflozin 5 mg or 
dapagliflozin 10 mg in ratio 1:1:1. 
Although in view of purpose of Part A being purely exploratory, sample size is not based on 
statistical power calculation, 6 - 8 patients per arm are generally considered sufficient to 
assess the pharmacokinetic profile, as done in Japan Phase I studies. 
In terms of key PD evaluation (mean change in 24-hour urinary glucose [g/24h]), the 
half-width of 95% confidence interval for treatment difference based on 10-14 evaluable 
patients/arm are estimated to be approximately 42-50 [g/24h], assuming the common standard 
deviation of 56 [g/24h]. 
In addition, PK-PD relationships will be evaluated exploratory to compare between those of 
Japanese T1DM patients and those of non-Japanese T1DM patients.  For this evaluation, 10 
patients per arm are considered sufficient. 
Originally, in the initial version of the Clinical Study Protocol issued at 9th July 2015, about 
30 patients were planned to be randomized to the study. However, 12 patients in Part A were 
judged to be unevaluable for PK data due to issue related to sampling tube. It is considered 
that the revised sample size (randomization of about 42 patients) would lead to sufficient 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
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number of patients for evaluating PK profile, as well as exploratory evaluating PK-PD 
relationships, without the 12 patients. 
8.2.2 
Long term treatment part (Part B) 
The number of patients in the Long term treatment part was decided according to the ICH E1 
guideline (1994), “The extent of population exposure to assess clinical safety for drugs 
intended for long-term treatment of non-life-threatening conditions”.  The number of patients 
in the Part B was designed so that approximately 100 Japanese T1DM patients treated by 
dapagliflozin 5 mg and 10 mg for 52 weeks are secured in total, when summed up with 
Japanese T1DM patients randomized in study MB102230, where about 160 Japanese T1DM 
patients are to be randomized to dapagliflozin 5 mg, 10 mg or placebo in ratio 1:1:1.  
With 140 patients randomized to dapagliflozin 5 mg or 10 mg in Part B of this study, 
approximately 59 patients/arm are expected to complete 52-week dapagliflozin treatment in 
this study, assuming drop-out rate of 15%. 
8.3 
Definitions of analysis sets 
Analysis sets for Part A and Part B will be separately determined. 
8.3.1 
PK and PD evaluation part (Part A) 
Pharmacokinetic set -Part A (PK-A): The PK set will consist of all randomized subjects who 
had at least one dose of randomized study medication for Part A and had an evaluable plasma 
concentration data of dapagliflozin and/or its major metabolite dapagliflozin 3-O-glucuronide. 
Pharmacodynamic set -Part A (PD-A): The PD set will be consist of all randomized subjects 
who received at least one dose of randomized study medication for Part A, and who have a 
non-missing baseline value and at least one post-baseline value for at least one 
pharmacodynamic variable. 
Safety set -Part A (SAF-A): The safety analysis set will include all subjects who received at 
least one dose of randomized study medication for Part A and who provide any safety records. 
Subjects will be analysed according to the treatment group for which they received medication. 
8.3.2 
Long term treatment part (Part B) 
Safety set -Part B (SAF-B): The safety analysis set will include all subjects who received at 
least one dose of randomized study medication for Part B and who provide any safety records. 
Subjects will be analysed according to the treatment group for which they received medication.   
Full analysis set -Part B (FAS-B): The full analysis set will include all randomized subject 
who received at least one dose of randomized study medication for Part B, and who have a 
non-missing baseline value and at least one post-baseline efficacy value for at least one 
efficacy variable.  The subjects will be analysed according to the treatment group to which 
they were randomized, regardless of the actual treatment taken.  


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Study Code D1695C00001 
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Date 14 December 2016 
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8.4 
Outcome measures for analyses 
The outcome measures for the primary, secondary and exploratory objectives are as described 
in Sections 2.1 to 2.4. 
8.4.1 
Primary Endpoints 
Part A 
Primary variables for Part A would include following PK/PD variables 
x 
PK variables: Cmax, Tmax, AUCτ for dapagliflozin and dapagliflozin 3-O-
glucuronide, and ratio of dapagliflozin 3-O-glucuronide AUCτ to dapagliflozin 
AUCτ. 
x 
PD variables: Change from baseline in 24-hour urinary glucose excretion on Day 7. 
Part B 
Adverse events (including hypoglycemia / DKA), Serious adverse events (SAEs) and Adverse 
event leading to discontinuation of study drug (DAEs), vital signs (blood pressure, heart rate), 
ECG, and clinical laboratory measures, urine test will be summarized by treatment group 
(dapagliflozin 5 mg or 10 mg). 
8.4.2 
Secondary Endpoints 
Part A  
x 
Secondary PD variables: Change from baseline in FPG on Day 7, daily insulin dose, 
SBP 
x 
Safety variables: Adverse event (including hypoglycemia events and DKA events), 
physical examination, vital signs (blood pressure, heart rate), ECG and clinical 
laboratory measures, urine test. 
Part B 
x 
Change from baseline in HbA1c  at Week 24 and 52 
x 
Change from baseline in GA  at Week 24 and 52 
x 
Change from baseline in average glucose values measured by 6-point SMBG  at 
Week 24 and 52 
x 
Change from baseline in post-prandial glucose values measured by 6-point SMBG  
at Week 24 and 52 
x 
Percent change from baseline in total daily insulin dose  at Week 24 and 52 
x 
Percent change from baseline in body weight  at Week 24 and 52 
x 
Proportion of subjects with HbA1c reduction from baseline of at least 0.5% without 
severe hypoglycemia at Week 24 and 52  
x 
Proportion of subjects with HbA1c reduction from baseline of at least 0.5% at Week 
24 and 52  
x 
Proportion of subjects with HbA1c < 7.0% at Week 24 and 52  


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x 
Change from baseline to Week 24 and 52 in seated SBP among subjects with 
hypertension at baseline, defined as seated SBP ≥ 140 mmHg and/or seated DBP ≥ 
90 mmHg 
8.4.3 
Exploratory Endpoints 
Part A 
The relationship between changes in 7-point SMBG measurements, 24-hr urinary glucose 
excursion and total daily insulin dose will be explored.   
Part B 
The efficacy evaluation will be made by comparing subgroups BMI < 25.0 or BMI ≥ 25.0, as 
measured by the change from baseline in HbA1c, GA, average/post-prandial glucose values 
measured by 6-point SMBG, and percent change from baseline in body weight, total daily 
insulin dose. 
8.4.4 
Baseline value 
For each subject, baseline value of a parameter (eg, efficacy/pharmacodynamic laboratory 
parameter, safety laboratory test, ECG or physical measurement) is defined as the last 
assessment on or prior to the date of the first dose of the randomized study medication. 
8.4.5 
LOCF 
For LOCF, if no measurement is available at a time point, the last post-baseline measurement 
prior to the specific time-point will be used instead for analysis.  
8.4.6 
Calculation of eGFR 
The following Japan guideline recommended equation will be used to calculate eGFR. 
eGFR (mL/min/1.73m2) = 194 x (SCr)-1.094 x (age)-0.287 (x 0.739 if female) 
8.5 
Methods for statistical analyses 
Analyses for Part A and Part B will be separately conducted.  
In both Parts, there will be no confirmatory hypothesis to be tested and hence no multiplicity 
issues occur.  Pharmacodynamic variable in Part A and efficacy variables in Part B will be 
presented mainly descriptively.  Ninety-five percent confidence intervals will be calculated, 
where appropriate, as measures of study precision. 
8.5.1 
Analysis of the primary variable (s) 
Part A 
All PK/PD analysis for Part A will be carried out for PK-A and PD-A. 
PK : summary statistics for Cmax, Tmax, AUCτ for both dapagliflozin and its major metabolite 
dapagliflozin 3-O-glucuronide, and ratio of metabolite to parent AUCτ will be provided by 


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Drug Substance dapagliflozin (BMS-512148)  
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arm.  Geometric mean and CV (coefficient of variation) will be presented for Cmax, AUCτ and 
ratio of metabolite to parent AUCτ.  Medians and ranges will be presented for Tmax.  
PD: change from baseline to Day 7 in 24-hour urinary glucose will be summarized by arm. 
Also difference of dapagliflozin vs. placebo and 95%CIs will be summarized if appropriate.  
No formal statistical testing will be performed. 
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, 
hypoglycemia) will be explored as needed.  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 exposure-response relationship.  Listings and summary statistics will be reported 
for the sampled pharmacokinetic measurements.  The PPK and exposure-response analyses 
will be specified in Statistical Analysis Plan in details, and described in a separate report. 
Part B 
All safety analysis for Part B will be carried out for SAF-B. 
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 event 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 SAEs or DAEs 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 examinations, vital signs and ECG data will be summarized 
by treatment group. 
8.5.2 
Analysis of the secondary variable(s) 
Part A 
All the pharmacodynamic (PD) evaluation will be conducted on PD-A.  
For secondary PD parameters to be assessed by change from baseline (ie, FPG and SBP), 
similar analysis like primary PD variable of 24-hour urinary glucose will be carried out.  For 


Clinical Study Protocol  
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Version 3 
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PD parameters to be assessed by percent change from baseline (ie, daily basal insulin dose, 
daily bolus insulin dose, total daily dose of insulin), similar analysis will be carried out with 
exception that mean percent change from baseline will be calculated from the exponentiated 
values of estimates obtained on the natural logarithmic scale. 
All safety analysis for Part A will be carried out for SAF-A.  
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 SAEs or DAEs 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 examinations, vital signs and ECG data will be summarized 
by treatment group. 
Part B 
All efficacy analyses for Part B will be carried out for FAS-B.  
Unless otherwise specified, all available efficacy data obtained up to Week 52 or premature 
discontinuation of study drug (regardless of insulin uptitiration) will be included in the 
analysis. For the selected efficacy variables (eg, Change from baseline in HbA1c, Percent 
change from baseline in body weight), analyses excluding data after insulin up-titration may 
also be performed supportively.  
x 
Change from baseline in HbA1c  at Week 24 and 52 
x 
Change from baseline in GA  at Week 24 and 52 
x 
Change from baseline in average glucose values measured by 6-point SMBG  at 
Week 24 and 52 
x 
Change from baseline in post-prandial glucose values measured by 6-point SMBG  
at Week 24 and 52 
x 
Percent change from baseline in total daily insulin dose  at Week 24 and 52 
x 
Percent change from baseline in body weight  at Week 24 and 52 
x 
Change from baseline to Week 24 and 52 in seated SBP among subjects with 
hypertension at baseline, defined as seated SBP ≥ 140 mmHg and/or seated DBP ≥ 
90 mmHg 


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Version 3 
Date 14 December 2016 
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Efficacy analyses on change from baseline in HbA1c, GA, average glucose values measured 
by 6-point SMBG, post-prandial glucose values measured by 6-point SMBG and SBP are to 
be analysed by Mixed Model with Repeated Measures (MMRM).  Point estimate an 95%CI 
for each treatment by time point will be presented from the model.  For analysis for change 
from baseline, model will include the change from baseline as a response variable and 
treatment, stratification factor, visit as a fixed categorical effects and baseline value as a fixed 
continuous covariate and interactions for treatment x visit and baseline x visit.  For within 
subject correlation, unstructured covariance matrix (UN) will be assumed.  
Efficacy analyses on percent change from baseline in total daily insulin dose, and body weight 
are to be analysed by the similar model using the log transformed values.  Point estimate an 
95%CI for percentage change from baseline will be calculated by exponentiating the estimates 
obtained from the model and will be presented by treatment and time point. 
x 
Proportion of subjects with HbA1c reduction from baseline of at least 0.5% without 
severe hypoglycemia at Week 24 and 52  
x 
Proportion of subjects with HbA1c reduction from baseline of at least 0.5% at Week 
24 and 52  
x 
Proportion of subjects with HbA1c < 7.0% at Week 24 and 52  
Number and proportion of subjects meeting each criterion will be summarized descriptively.  
95%CIs will also be provided if appropriate.  
8.5.3 
Exploratory analyses 
Detail will be documented in the separate statistical analysis plan.  
8.5.4 
Interim Analyses 
Interim database locks/analysis occurs once after completion of Part A 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1 
Training of study site personnel 
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC 
system(s) utilized. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a training record of all individuals involved in the 
study (medical, nursing and other staff). 


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9.2 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
x 
Provide information and support to the Investigator(s) 
x 
Confirm that facilities remain acceptable 
x 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed 
x 
Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating subjects. This 
will require direct access to all original records for each subject (eg, clinic charts) 
x 
Ensure withdrawal of informed consent to the use of the subject’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the subject. 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
9.2.1 
Source data 
Refer to the Clinical Study Agreement for location of source data. 
9.2.2 
Direct access to source data in Japan 
The Head of the study site and the Principal Investigator/ Investigator will cooperate for 
monitoring and audit by AstraZeneca, and accept inspection by the IRB or regulatory 
authorities. All study documents such as raw data will be open for direct access to source data 
at the request of the monitor and the auditor of AstraZeneca, the IRB, or regulatory authorities. 
9.2.3 
Study agreements 
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled. 
9.2.4 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Study Agreement. 


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9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The study is expected to start in October, 2015 and to end by October, 2017.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with dapagliflozin.
9.4
Data management by AstraZeneca
Data management will be performed
according to the Data Management Plan.
Data will be entered into the WBDC system Rave at the study site. Trained site staff will be
entering the data as specified in the protocol and according to the eCRF instructions. Data
entered into the WBDC system will be immediately saved to a central database and changes
tracked to provide an audit trail. The data will then be Source Data Verified, reviewed,
queried and updated as needed.
AEs and medical/surgical history will be classified according to the terminology of the latest
version the Medical Dictionary for Regulatory Activities (MedDRA). Medications will be 
classified according to the AstraZeneca Drug Dictionary. All coding will be performed by the 
Medical Coding Team at the Data Management Centre.
The Principal Investigator is responsible for signing the eCRF and this may be delegated to a 
trained Investigator.
The data will be validated as defined in the Data Management Plan. Quality control
procedures will be applied to each stage of data handling to ensure that all data are reliable
and have been processed correctly. The Data Management Plan will also clarify the roles and
responsibilities of the various functions and personnel involved in the data management
process.
When all data have been coded, validated, signed and locked, clean file will be declared. Any
treatment revealing data may thereafter be added and the final database will be locked. A
copy of the eCRF will be archived at the study site when the study is completed.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.
Data Management of genotype data
Not applicable in this study.
Redacted


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Data associated with human biological samples 
Not applicable in this study. 
Management of external data 
Data Management determines the format of the data to be received from external vendors.  
External data reconciliation will be done with the clinical database as applicable. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples. 
10.2 
Subject data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
10.3 
Ethics and regulatory review 
An IRB should approve the final study protocol, including the final version of the Informed 
Consent Form and any other written information and/or materials to be provided to the 
subjects.  The head of the study site will ensure the distribution of these documents to the 
applicable IRB, and the Principal Investigator to the Investigator and study site staff. 
The opinion of the IRB should be given in writing.  The head of the study site should submit a 
notification of direction/determination as well as the IRB written approval to AstraZeneca and 
the Principal Investigator before enrolment of any subject should into the study. 
The IRB should approve all advertising used to recruit subjects for the study. 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 
The head of the study site should seek the opinion of the IRB with respect to the 
appropriateness of continuing the study at the study site at least once a year when the duration 
of the study exceeds one year. The Principal Investigator should submit progress reports to the 
IRB via the head of the study site at the time of the protocol re-approval. 
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority with notification 


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provided, according to local regulations.  AstraZeneca will handle the distribution of any of 
these documents to the national regulatory authorities. 
AstraZeneca will provide Regulatory Authorities, IRB, the head of the study site and the 
Principal Investigator with safety updates/reports according to local requirements. 
The head of the study site should submit a written report to the IRB providing the details of all 
safety relative information reported by AstraZeneca. 
10.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
x 
Ensure each subject is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 
x 
Ensure each subject is notified that they are free to discontinue from the study at 
any time 
x 
Ensure that each subject is given the opportunity to ask questions and allowed time 
to consider the information provided 
x 
Ensure each subject provides signed and dated informed consent before conducting 
any procedure specifically for the study 
x 
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
x 
Ensure a copy of the signed Informed Consent Form is given to the subject 
x 
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are 
described in the informed consent form that is approved by an IRB. 
10.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.  If it is necessary for the Clinical Study Protocol to be amended, 
the amended Clinical Study Protocol should be submitted to the Head of the Study Site.  If the 
changes are of an administrative nature, it is submitted to the IRB.  If the changes have a 
significant impact on the safety of the subjects, the scientific value of the study, the conduct 
and management of the study, and the quality of any investigational product used in the study, 
it should be approved by the IRB.  If applicable, AstraZeneca should submit a notification to 
the regulatory authority before it is implemented.  If the amended Clinical Study Protocol 
requires a change to a particular centre's Informed Consent Form, then AstraZeneca and the 
centre's IRB should be notified by the Principal Investigator.  Approval of the revised 
Informed Consent Form by AstraZeneca and by the IRB is required before the revised form is 
used. 


Clinical Study Protocol  
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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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10.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements (see Section 10.1).  The Investigator will contact 
AstraZeneca immediately if contacted by a regulatory agency about an inspection at the centre. 
11. 
LIST OF REFERENCES 
Beck et al 2012 
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. 
Cleland et al 2013 
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. 
Cryer 2002 
Cryer PE. Hypoglycaemia: The limiting factor in the glycaemic management of Type 1 and 
Type II Diabetes. Diabetologia 2002;45:937-48. 
Daneman 2006 
Daneman D. Type 1 Diabetes. Lancet 2006;367:847-58. 
Defronzo et al 2013 
Defronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, et al. 
Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects 
and subjects with type 2 diabetes. Diabetes Care 2013;36:3169-76. 
European Association of Urology 2008 
European Association of Urology. Guidelines on the management of urinary and male 
genitaltract infections 2008. Available from: URL: http://www.uroweb.org/ 
Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013 
Development Committee of “Evidence-based Practice Guideline for the Treatment for 
Diabetes in Japan 2013”. Evidence-based Practice Guideline for the Treatment for Diabetes in 
Japan 2013. Available from: URL: 
http://www.jds.or.jp/modules/publication/index.php?content_id=4 


Clinical Study Protocol  
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
102(110) 
Ferriss et al 2006 
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. 
Kilpatrick et al 2007a 
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. 
Kilpatrick et al 2007b 
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 
Nicolle et al 2005 
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 in 
adults. Clin Infect Dis 2005;40:643-54. 
Perkins et al 2014 
Perkins BA, Cherney DZ, Partridge H, Soleymanlou N, Tschirhart H, Zinman B, et al. 
Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of 
an 8-week open-label proof-of-concept trial. Diabetes Care 2014;37:1480-3. 
Soedamah-Muthu et al 2008 
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. 
Tajima N, Morimoto A 2012 
Tajima N, Morimoto A. Epidemiology of childhood diabetes mellitus in Japan. Pediatr 
Endocrinol Rev. 2012 Oct;10 Suppl 1:44-50 
The Diabetes Control and Complications Trial Research Group 1993 
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;329:977–86. 
The Japanese Guideline for Clinical Evaluation of Oral Hypoglycaemic Agents 2010 
The Japanese Guideline for Clinical Evaluation of Oral Hypoglycaemic Agents 2010. 
Available from: URL: http://www.pmda.go.jp/files/000157329.pdf 


Clinical Study Protocol  
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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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US Preventative Services Taskforce 2004 
US Preventative Services Taskforce. Recommendation Statement Screening or Asymptomatic 
Bacteriuria. Revised 2004. Available from: URL: 
http://www.ahrq.gov/clinic/uspstf/uspsbact.htm 
Weinstock et al 2013 
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. 


Clinical Study Protocol Appendix A 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
104(110) 
Appendix A 
Additional Safety Information 
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS ADVERSE EVENT 
(SAE) 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
x 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
x 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 
x 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
x 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation 
x 
Development of drug dependency or drug abuse 
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 


Clinical Study Protocol Appendix A 
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Study Code D1695C00001 
Version 3 
Date 14 December 2016 
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x 
Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
x 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
x 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug? 
x 
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors. 
x 
Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge. 
x 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship. 
In difficult cases, other factors could be considered such as: 
x 
Is this a recognized feature of overdose of the drug? 
x 
Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgement.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 


Clinical Study Protocol Appendix B 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
106(110) 
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B or Exempt.  There 
is no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus: 
x 
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 
x 
UN 3373 – Biological Substance, Category B 
x 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
x 
Clinical trial samples will fall into Category B or exempt under IATA regulations 
x 
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging  
x 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
x 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable 
x 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used. 


Clinical Study Protocol Appendix C 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
107(110) 
Appendix C 
New York Heart Association (NYHA) Classification 
NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION 
The NYHA classification will be based on the following definitions: 
Class I 
No limitation: 
Ordinary physical exercise does not cause undue fatigue, dyspnoea or 
palpitations. 
Class II 
Slight limitation of physical activity: 
Comfortable at rest but ordinary activity results in fatigue, palpitations, 
dyspnoea. 
Class III 
Marked limitation of physical activity: 
Comfortable at rest but less than ordinary activity results in symptoms. 
Class IV 
Unable to carry out any physical activity without discomfort: 
Symptoms of congestive heart failure are present even at rest with increased 
discomfort with any physical activity. 
 
 


Clinical Study Protocol Appendix D 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
108(110) 
Appendix D 
Sustained Elevated Liver Safety Abnormalities Flow Chart 
Figure 4 
Sustained elevated liver safety abnormalities flow chart 
 
a 
In subjects with repeat ALT or AST > 3X ULN but ≤ 10X ULN, only patient with TB ≤ 2.0X ULN at Step 1 should be followed according to Step 2b. 
 
Subjects with an initial TB and confirmatory repeat TB > 2.0X ULN should be followed according to Step 2d. 
b 
Refer to next page for details on additional assessments to be performed (AE assessment, review of current medical history including focused review of 
risk factors for liver diseases and collection of blood samples [specialized liver panel or liver discontinuation panel]) 
c 
Confirmatory repeat AST, ALT, ALK-P and TB should be obtained every 3 days following receipt of prior laboratory results, until the ALT and AST 
are ≤ 2X ULN or until ALT and AST are at or below baseline levels.  The frequency of retesting can decrease to once a week or less if abnormalities 
stabilize and the subject is asymptomatic. 


Clinical Study Protocol Appendix D 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
109(110) 
Specialized Liver Panel: 
For subjects who are being monitored frequently as a result of confirmed AST and/or ALT > 
3X ULN, additional central laboratory tests will be performed within 3 days of receipt of 
confirmatory results.  These laboratory tests will study the possible causes of the increased 
ALT and/or AST and/or TB, and may include, but are not limited to, the following tests: 
x 
Hepatitis A IgM 
x 
Hepatitis BsAg 
x 
Hepatitis B Core Ab IgM 
x 
Hepatitis C virus RNA or RIBA 
x 
Hepatitis C Ab 
x 
Hepatitis E IgM 
x 
Epstein-Barr Virus (EBV) IgM Ab 
x 
Lactate Dehydrogenase (LDH) 
x 
Gamma-glutamyl-transpeptidase (GGT) 
x 
Carbohydrate deficient transferrin (CDT) 
x 
Prothrombin time (PT/INR) 
x 
Iron Panel - iron, ferritin, total iron binding capacity (TIBC) 
x 
Immunology Panel including Antinuclear Antibody (ANA), Anti-Smooth Muscle 
Antibody (SMA) and Anti-Liver/Kidney Microsomal Antibody (Anti-LKM) 
x 
Anti-tissue Transglutaminase Antibody 
Liver Discontinuation Panel: 
For subjects who are discontinued from the study as a result of sustained elevated liver safety 
abnormalities, additional central laboratory tests will be performed at the time of Early 
Termination (End-of-Treatment) visit. Similar to the Specialized Liver Panel, these laboratory 
tests will study the possible causes of the increased ALT and/or AST and/or TB, and may 
include, but are not limited to, the following tests: 
x 
Cytomegalovirus (CMV) IgM Ab 
x 
Herpes Simplex Virus (HSV) 1 and 2 


Clinical Study Protocol Appendix D 
Drug Substance dapagliflozin (BMS-512148)  
Study Code D1695C00001 
Version 3 
Date 14 December 2016 
110(110) 
x 
Ceruloplasmin 
x 
Toxoplasmosis 
x 
Alpha-1 antitrypsin 
 
For specific details regarding the Specialized Liver Panel and the Liver Discontinuation Panel 
laboratory tests, refer to the Central Laboratory Manual for this study. 
 
 

SAP_000.pdf: 
Statistical Analysis Plan
Study Code
D1695C00001(Part B)
Edition Number
2.0
Date
16 March 2017
A clinical pharmacology and long term study to evaluate the safety,
efficacy, pharmacokinetics and pharmacodynamics of dapagliflozin therapy 
in combination with insulin in Japanese subjects with type 1 diabetes who 
have inadequate glycemic control






Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
4
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
SIGNATURE OF STUDY STATISTICIAN ..........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN....................................3
TABLE OF CONTENTS.........................................................................................4
LIST OF ABBREVIATIONS..................................................................................8
AMENDMENT HISTORY ...................................................................................10
1.
STUDY DETAILS.................................................................................................12
1.1
Study objectives.....................................................................................................12
1.2
Study design...........................................................................................................13
1.3
Number of subjects ................................................................................................19
2.
ANALYSIS SETS .................................................................................................19
2.1
Definition of analysis sets......................................................................................19
2.1.1
Enrolled set – Part B ..............................................................................................19
2.1.2
Randomized set – Part B........................................................................................19
2.1.3
Safety analysis set – Part B (SAF-B).....................................................................19
2.1.4
Full analysis set – Part B (FAS-B).........................................................................19
2.2
Violations and deviations.......................................................................................20
3.
PRIMARY AND SECONDARY VARIABLES...................................................20
3.1
Primary variables (Safety) .....................................................................................20
3.2
Secondary variables (Efficacy)..............................................................................20
4.
ANALYSIS METHODS .......................................................................................21
4.1
General principles ..................................................................................................21
4.1.1
Objectives and hypotheses.....................................................................................21
4.1.2
Definitions..............................................................................................................21
4.1.2.1
Baseline value ........................................................................................................21
4.1.2.2
Change and percent change from baseline.............................................................21
4.1.2.3
Insulin up-titration more than 25% than baseline..................................................23
4.1.2.4
Last Observation Carried Forward (LOCF)...........................................................23
4.1.2.5
Mean daily glucose of 6-point self monitored blood glucose (SMBG).................24
4.1.2.6
Post-prandial glucose values of self monitored blood glucose (SMBG)...............24
4.1.3
Descriptive summary of continuous variables.......................................................24
4.1.4
Descriptive summary of categorical variables.......................................................24


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
5
4.1.5
Mixed Model for Repeated Measures (MMRM) for outcomes with single 
measurement per week t.........................................................................................25
4.1.6
Mixed Model with Repeated Measures (MMRM) for outcomes with 
multiple measurements per week t.........................................................................25
4.1.7
Kaplan-Meier curve and estimates for time-to-event analysis...............................26
4.1.8
Analysis of proportions..........................................................................................26
4.2
Analysis methods...................................................................................................26
4.2.1
Study population ....................................................................................................26
4.2.1.1
Subject disposition.................................................................................................26
4.2.1.2
Demographic and other baseline characteristics....................................................26
4.2.1.3
Specific and general disease histories....................................................................28
4.2.2
Extent of exposure .................................................................................................28
4.2.2.1
Study medication ...................................................................................................28
4.2.2.2
Interruption of Study Medication...........................................................................29
4.2.2.3
Current and concomitant medications....................................................................29
4.2.2.4
Measurement of Treatment Compliance................................................................29
4.2.3
Efficacy..................................................................................................................30
4.2.3.1
Change from baseline in HbA1c (including/excluding data after insulin 
up-titration) at Week 24 and 52 .............................................................................30
4.2.3.2
Change from baseline in GA (including data after insulin up-titration) at 
Week 24 and 52 .....................................................................................................31
4.2.3.3
Change from baseline in average glucose values measured by 6-point 
SMBG (including data after insulin up-titration) at Week 24 and 52....................31
4.2.3.4
Change from baseline in post-prandial glucose values measured by 6-point 
SMBG (including data after insulin up-titration) at Week 24 and 52....................31
4.2.3.5
Percent change from baseline in total daily insulin dose (including data 
after insulin up-titration) at Week 24 and 52.........................................................32
4.2.3.6
Percent change from baseline in body weight (including/excluding data 
after insulin up-titration) at Week 24 and 52.........................................................32
4.2.3.7
Proportion of subjects with HbA1c reduction from baseline of at least 
0.5% without severe hypoglycemia at Week 24 and 52 (including data 
after insulin up-titration)........................................................................................33
4.2.3.8
Proportion of subjects with HbA1c reduction from baseline of at least 
0.5% at Week 24 and 52 (including data after insulin up-titration).......................33
4.2.3.9
Proportion of subjects with HbA1c < 7.0% at Week 24 and 52 (including 
data after insulin up-titration) ................................................................................33
4.2.3.10
Change from baseline to Week 24 and 52 in seated SBP (including data 
after insulin up-titration) among subjects with hypertension at baseline, 
defined as seated SBP ≥ 140 mmHg and/or seated DBP ≥ 90 mmHg...................33
4.2.3.11
Time to Insulin up-titration by more than 25% .....................................................34
4.2.4
Safety .....................................................................................................................34
4.2.4.1
Adverse Events ......................................................................................................35
4.2.4.2
Adverse Events of Special Interest ........................................................................37
4.2.4.3
Laboratory Evaluation ...........................................................................................42


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
6
4.2.4.4
Vital Signs..............................................................................................................44
4.2.4.5
Electrocardiograms ................................................................................................45
4.2.4.6
Pregnancy Test Results..........................................................................................45
4.2.5
Figures and Graphs ................................................................................................45
5.
INTERIM ANALYSES – NOT APPLICABLE....................................................46
 
 


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
7
LIST OF TABLES
Table 1
Study schedule (Part B)............................................................................15
Table 2
Formulae Used to Transform Back the Results onto the Original 
Scale .........................................................................................................22
Table 3
Demographic and Baseline Characteristics..............................................27
Table 4
Diabetes-Related Baseline Characteristics...............................................27
Table 5
Baseline Renal Function...........................................................................28
Table 6
Subgroup factors for descriptive summary of HbA1c..............................30
 
LIST OF FIGURES
Figure 1
Study Design Schematic (Part B).............................................................14


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
8
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ACE-I
Angiotensin-converting-enzyme inhibitor
ADA
American Diabetes Association
AE
Adverse event
ALT
Alanine aminotransferase
ARB
Angiotensin receptor blocker
AST
Aspartate aminotransferase
AT
Amniotransferase ; short for ALT or AST
AZDD
AZ Drug Dictionary
BMI
Body mass index
CRF
Case Report Form (electronic/paper)
CSII
Continuous subcutaneous insulin infusion
DAE
Discontinuation of study drug
DBP
Diastolic blood pressrue
DKA
Diabetic ketoacidosis
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate
FAS-b
Full analysis set –Part B
GA
Glycoalbumin
HABA1C
Hemoglobin A1c (glycated hemoglobin)
IWRS
Interactive Web Response System
LOCF
Last Observation Carried Forward
MA
Marked Abnormality
MDG
Mean Daily Glucose
MDI
Multiple daily injection
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model with Repeated Measures
MPDG
Mean postprandial daily glucose
PT
Preferred term
QD
qd quaque die, once daily
SAE
Serious adverse events


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
9
Abbreviation or 
special term
Explanation
SAF-B
Safety set –Part B
SD
Standard deviation
SMBG
Self monitored blood glucose
SMQ
Standardized MedDRA Queries
SOC
System organ class
T1DM
Type 1 diabetes mellitus
TSH
Thyroid Stimulating Hormone
UACR
Urinary albumin creatinin ratio
ULN
Upper limit of normal
WOCBP
Women of Childbearing Potential






Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
12
1.
STUDY DETAILS
The present Statistical Analysis Plan (SAP) refers to the Part B of the study D1695C00001. 
1.1
Study objectives
Objectives for Part B this study are as follows:
Primary Objective:
Outcome Measure:
[Part B]
To evaluate safety and tolerability of long-
term treatment (52 weeks) of dapagliflozin 
5mg and 10 mg in Japanese patients with 
T1DM with inadequate glycemic control 
under standard insulin therapy.
Adverse event (including AEs of hypoglycemia and 
diabetic ketoacidosis (DKA) events), physical 
examination, vital signs (blood pressure, heart rate), 
ECG, and clinical laboratory measures, urine test.
Secondary Objective:
Outcome Measure:
[Part B]
To assess the efficacy of long-term treatment 
(52 weeks) of dapagliflozin 5mg and 10 mg in 
Japanese patients with T1DM inadequately 
controlled on insulin therapy.
Change from baseline in HbA1c at Week 24 and 52
Change from baseline in glycoalbumin (GA) at Week 
24 and 52
Change from baseline in average glucose values 
measured by 6-point self-monitored blood glucose 
(SMBG) at Week 24 and 52
Change from baseline in postprandial glucose values 
measured by 6-point SMBG at Week 24 and 52
Percent change from baseline in total daily insulin 
dose at Week 24 and 52
Percent change from baseline in body weight  at 
Week 24 and 52
Proportion of subjects with HbA1c reduction from 
baseline of at least 0.5% without severe 
hypoglycaemia at Week 24 and 52 
Proportion of subjects with HbA1c reduction from 
baseline of at least 0.5% at Week 24 and 52 
Proportion of subjects with HbA1c < 7.0% at Week 
24 and 52 
Change from baseline to Week 24 and 52 in seated 
SBP among subjects with hypertension at baseline, 
defined as seated SBP ≥ 140 mmHg and/or seated 
DBP ≥ 90 mmHg


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
13
Exploratory Objective:
Outcome Measure:
[Part B]
The efficacy evaluation will be made by 
comparing subgroups BMI <25.0 kg/m2 or 
BMI ≥25.0 kg/m2.
Change from baseline in HbA1c, GA, average/post-
prandial glucose values measured by 6-point SMBG, 
and percent change from baseline in body weight, 
total daily insulin dose by subgroup defined by BMI.
1.2
Study design
The study design of Part B is a randomized, open-label, 2 arm, parallel-group design.  One 
hundred forty Japanese subjects in total will be randomized in a 1:1 ratio into one of the two 
treatment arms; dapagliflozin 5 mg or dapagliflozin 10 mg.
Potential subjects who will join the study from part B will be assessed for eligibility criteria at 
the screening visit. A wash-out period is applicable only for subjects who received α-GI at
enrolment or within one month before enrolment.  Eligible subjects who are treated with 
insulin only, will skip the period and directly proceed to the randomization.  On Day 1, 
subjects who meet all the protocol-specific enrolment and randomization inclusion criteria and 
meet none of the exclusion criteria will be randomized into one of the 2 open-label treatment 
arms (dapagliflozin 5 mg QD or dapagliflozin 10 mg QD) in a 1:1 ratio. Randomization will 
be stratified by the following factor to ensure equal representation across all treatment groups:
!
HbA1c < 9.0% vs. ≥ 9.0% at screening visit
Subjects will receive dapagliflozin 5 mg QD or 10 mg QD for 52 weeks, and a 4-week follow-
up evaluation. Besides study medications, subjects will be treated with MDI (3 or more 
injections per day of basal and bolus insulin) or CSII.
The study design schematic is presented in Figure 1. Study assessment schedule is presented 
in Table 1. 


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
14
Figure 1
Study Design Schematic (Part B)
-3
-1
0b
4
8
12
16
40
48
52
56
E
R
Wash-out 
period a
Treatment period
Follow-up 
period
dapagliflozin 5 mg once daily
Week
1
2
3
6
7
8
9
13
14
15
16
Visit
20
10
32
12
Insulin therapy
dapagliflozin 10 mg once daily
R
24
11
1
4
Screening 
Visit
d
2c
(5)
E: Enrolment, R; Randomization
a
Wash-out period is applicable only for subjects who are on an α-GI at enrolment or within one month before enrolment.  Subjects on insulin only as their 
diabetes treatment will skip the period and directly proceed to the Visit 3.
B
Day 1 of Week 0 means the stating day of dapagliflozin.
C
Either hospital visit or telephone contact is acceptable for visit at Week 2.
D
On Day 2, 4 and 10 patients must contact the Investigators by phone and report the patient’s condition (including glucose and ketone values from 
SMBG). The investigators must indicate appropriate insulin adjustment.  There is time window ± 1 day for Day 4 and 10.


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
15
Table 1
Study schedule (Part B)
Period
Screening
Wash-
outa
Treatment period
Follow-up 
periodd
Week
-3
-1
0b
1
2c
4
8
12
16
20
24
32, 40, 48
52
56
Visit
1
2
3
4
(5)
6
7
8
9
10
11
12, 13, 14
15
16
Visit window (days)
-7
±3
0
0
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
Eligibility Assessments
Informed Consent e
X
Review 
Inclusion/Exclusion 
X
X
X
Review Medical History
X
X
X
General procedures
Telephone contact (TC) f
Complete Physical 
Examination
X
Brief Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (BP, HR), 
Body Weight
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
12-lead ECG
X
X
X
X
Weight (BMI)
X
X
X
X
X
X
X
X
X
X
X
X
X
Review concomitant 
medications/ procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Provide Dietary and 
Exercise Counselling
X
X
X
X
X
X
X
X
X
X
X


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
16
Table 1
Study schedule (Part B)
Period
Screening
Wash-
outa
Treatment period
Follow-up 
periodd
Week
-3
-1
0b
1
2c
4
8
12
16
20
24
32, 40, 48
52
56
Visit
1
2
3
4
(5)
6
7
8
9
10
11
12, 13, 14
15
16
Visit window (days)
-7
±3
0
0
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
Dispense subject diaries, 
blood glucose/ketone 
meters and provide 
instructions
X
X
X
X
X
X
X
X
X
X
Review subject diaries 
X
X
X
X
X
X
X
X
X
X
X
Adjust Insulin Dose, as 
needed
Safety Assessments
Assess Adverse Events 
Assess Hypoglycemia 
Episodes 
Assess Diabetic 
Ketoacidosis
SMBG 4 point
Laboratory Assessments
C-peptide
X
Hepatitis Screen Panel
X
TSH
X
Blood Standard Safety 
Laboratory Panel
X
X
X
X
X
X
X
X
X
X
X


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
17
Table 1
Study schedule (Part B)
Period
Screening
Wash-
outa
Treatment period
Follow-up 
periodd
Week
-3
-1
0b
1
2c
4
8
12
16
20
24
32, 40, 48
52
56
Visit
1
2
3
4
(5)
6
7
8
9
10
11
12, 13, 14
15
16
Visit window (days)
-7
±3
0
0
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
Urine Standard Safety 
Laboratory Panel
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test (serum) 
WOCBP only
X
Pregnancy test (urine) 
WOCBP only
X
X
X
X
X
X
X
X
X
X
Urine (dipstick)
X
X
X
X
X
X
X
X
X
Microscopic urinalysis
X
X
X
X
X
X
6point SMBG, Self-
Monitored Blood Ketone
X g
X g
X g
X g
HbA1c, GA
X
X
X
X
X
X
X
X
X
X
Study Drug Supply
Randomization
X
Dispense Study Drug
X
X
X
X
X
X
X
X
Contact IWRS
X
X
Review study drug 
dosing 
X
X
X
X
X
X
X
X
X
X
a
Wash-out period is applicable only for subjects who received α-GI until enrolment.  Subjects not taking other anti-hyperglycemic drugs other than 
insulin skip the period and directly proceed to the Treatment period.
B
Day 1 of Week 0 means the stating day of dapagliflozin.  The previous day of Day 1 is shown as “Day -1”
c
Either hospital visit or telephone contact is acceptable on Week 2. 


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
18
D
If a patient meet any study discontinuation criteria, the patient should receive the Week 52 and follow-up evaluation.
E
If a patient performed Informed Consent only, it is to allowed be out of visit window.
F
On Day 2, 4 (± 1 day) and 10 (± 1 day) patients must contact the Investigators by phone and report the patient’s condition (including glucose and ketone 
values from SMBG). The Investigators must indicate appropriate insulin adjustment.
G
It will be performed on any 3 days within a week before each visit


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
19
1.3
Number of subjects
The number of patients in the Long term treatment part was decided according to the ICH E1 
guideline (1994), “The extent of population exposure to assess clinical safety for drugs 
intended for long-term treatment of non-life-threatening conditions”.  The number of patients 
in the Part B was designed so that approximately 100 Japanese T1DM patients treated by 
dapagliflozin 5 mg and 10 mg for 52 weeks are secured in total, when summed up with 
Japanese T1DM patients randomized in study MB102230, where about 160 Japanese T1DM 
patients are to be randomized to dapagliflozin 5 mg, 10 mg or placebo in ratio 1:1:1. 
With 140 patients randomized to dapagliflozin 5 mg or 10 mg in Part B of this study,
approximately 59 patients/arm are expected to complete 52-week dapagliflozin treatment in 
this study, assuming drop-out rate of 15%.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Enrolled set – Part B
The enrolled set includes data collected from all subjects who signed informed consent.
2.1.2
Randomized set – Part B 
The randomized set includes data collected from all subjects who received a randomization 
number. 
2.1.3
Safety analysis set – Part B (SAF-B)
The safety analysis set will include all subjects who received at least one dose of study 
medication for Part B and who provide any safety records. Subjects will be analysed 
according to the treatment group for the study medication which they received. 
In case a subject did not receive the treatment as assigned by randomization (or received study
medication but were not randomized), then the safety data for that subject will be presented by 
the first study medication administered.
2.1.4
Full analysis set – Part B (FAS-B)
The full analysis set will include all randomized subject who received at least one dose of 
randomized study medication for Part B, and who have a non-missing baseline value and at 
least one post-baseline efficacy value for at least one efficacy variable.  The subjects will be 
analysed according to the treatment group to which they were randomized, regardless of the 
actual treatment administered. 


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
20
2.2
Violations and deviations
Protocol deviations will be reviewed by the study team prior to database lock. Subjects who 
deviate from important protocol conditions (e.g., selected inclusion/exclusion criteria) will be 
reported as having major (or significant) protocol deviations.
There will be no data exclusion associated with major protocol deviations in Part B of this 
study. Subjects having major protocol deviations will be presented by treatment group. Major 
protocol deviations are given in (but not limited to) Appendix 9.3.
In the unlikely case that a subject did not provide signed and dated written informed consent 
this subject will be excluded from all summaries.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Primary variables (Safety) 
Safety of long-term dapagliflozin (5mg or 10 mg) treatment when coadministered with 
flexible insulin regimen in T1DM subjects in Part B of this study will be evaluated by the 
following safety measures:   
!
Adverse events (including hypoglycemia / DKA)
!
Serious adverse events (SAEs) 
!
Adverse event leading to discontinuation of study drug (DAEs)
!
Vital signs 
!
ECG
!
Clinical laboratory measures(including  urine test) 
3.2
Secondary variables (Efficacy) 
Efficacy of long-term dapagliflozin (5mg or 10 mg) treatment when co-administered with 
flexible insulin regimen in T1DM subjects in Part B of this study will be evaluated by the 
following efficacy measures:
!
Change from baseline in  HbA1c at Week 24 and 52
!
Change from baseline in GA at Week 24 and 52
!
Change from baseline in average glucose values measured by 6-point SMBG at 
Week 24 and 52
!
Change from baseline in post-prandial glucose values measured by 6-point SMBG  
at Week 24 and 52


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
21
!
Percent change from baseline in total daily insulin dose at Week 24 and 52
!
Percent change from baseline in body weight at Week 24 and 52
!
Proportion of subjects with HbA1c reduction from baseline of at least 0.5% without
severe hypoglycemia at Week 24 and 52
!
Proportion of subjects with HbA1c reduction from baseline of at least 0.5% at Week 
24 and 52
!
Proportion of subjects with HbA1c < 7.0% at Week 24 and 52
!
Change from baseline to Week 24 and 52 in seated SBP among subjects with 
hypertension at baseline, defined as seated SBP ≥ 140 mmHg and/or seated DBP ≥ 
90 mmHg
4.
ANALYSIS METHODS
4.1
General principles
4.1.1
Objectives and hypotheses
Objectives of this study are assessing the safety, tolerability, and efficacy of long-term 
dapagliflozin (5mg or 10 mg) treatment up to 52 weeks when co-administered with adjustable
insulin regimen.  No formal hypothesis testing will be performed. 
4.1.2
Definitions
4.1.2.1
Baseline value
For each subject, baseline value of a parameter is defined as the last assessment of that 
parameter on or prior to the date of the first dose of study medication.  
For measurements referring to multiple data collections during a day (i.e. 6-point 
measurement parameters) or to 24-hour collection periods (i.e. daily insulin dose), baseline 
values are considered as the available assessments of that parameter prior to the date of the 
first dose of the study medication.
For measurements collected over several days during the same visit window (i.e. 6-point
measurement parameters, daily insulin dose), please refer to the algorithm outlined in Section 
6.3 in order to define the baseline value.
4.1.2.2
Change and percent change from baseline
Change from baseline to any Week t in treatment period is defined as follows:
CWeek t = MWeek t – Mbaseline ,
where:


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
22
!
CWeek t is the change from baseline at Week t,
!
MWeek t is the measurement at Week t,
!
Mbaseline is the measurement at baseline.
Percent change from baseline to any Week t in treatment period is defined as follows:
PWeek t =100×(MWeek t – Mbaseline) / Mbaseline .
Where PWeek t is the percent change from baseline at Week t, and MWeek t and Mbaseline are 
defined as above.
For analyses of parameters in terms of percent change from baseline at Week t, values will 
first be transformed to natural logarithms (Ln) and the results will be expressed as geometric 
mean percent changes from baseline. Analysis will be performed using the logarithms of the 
post-baseline to baseline ratios. Subsequently, the estimates from the analysis will be back 
transformed to original values for reporting in the tables using the formulae detailed in Table 2.
Table 2
Formulae Used to Transform Back the Results onto the Original Scale
Quantity 
Computation method
Mean percent change from baseline
100 ∀[exp(mean change from baseline in 
natural logarithm) – 1]
Standard error of mean percent change from 
baseline
100 ∀exp(mean change from baseline in 
natural logarithm) ∀standard error of mean 
change from baseline in natural logarithm 
– or, equivalently –
100 ∀Geometric mean of the Week t to 
baseline ratio ∀standard error of mean change 
from baseline in natural logarithm
Lower confidence limit for mean percent 
change from baseline
100 ∀[exp(lower confidence limit for mean 
change from baseline in natural logarithm) – 1]
Upper confidence limit for mean percent 
change from baseline
100 ∀[exp(upper confidence limit for mean 
change from baseline in natural logarithm) – 1]
Adjusted mean percent change from baseline
100 ∀[exp(Adjusted mean change from 
baseline in natural logarithm) – 1]


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
23
Quantity 
Computation method
Standard error of adjusted mean percent change 
from baseline
100 ∀exp(Adjusted mean change from baseline 
in natural logarithm) ∀standard error of mean 
change from baseline in natural logarithm
– or, equivalently –
100 ∀adjusted geometric mean of the Week t to 
baseline ratio ∀standard error of mean change 
from baseline in natural logarithm
Lower confidence limit for adjusted mean 
percent change from baseline
100 ∀[exp(lower confidence limit for adjusted 
mean change from baseline in natural 
logarithm) – 1]
Upper confidence limit for adjusted mean 
percent change from baseline
100 ∀[exp(upper confidence limit for adjusted 
mean change from baseline in natural 
logarithm) – 1]
4.1.2.3
Insulin up-titration more than 25% than baseline
Insulin dose for bolus and basal quantities will be collected as weekly ranges (minimum and 
maximum value of total daily dose over a weekly interval) during the study duration and total 
daily quantities (total daily basal, total daily bolus and pre-mixed separately) for limited 
number of days that will be used for analysis. For those days that the total daily bolus and total 
basal quantities are reported separately, the total daily insulin dose will be calculated by 
summing up the bolus and basal quantity for the same day. If either bolus or basal for the 
same day are missing, then the total daily will not be calculated for that day. 
The minimum and maximum value for each week will be calculated by combining the non-
missing information from the weekly data collection intervals together with the information 
from the daily data collection intervals. The midpoint (= (maximum+ minimum)/2) of the 
range for each week will be calculated. If for two consecutive weeks the midpoint value is 
25% higher than the baseline value, then this would qualify as up-titration more than 25%. 
The starting time point of the up-titration is considered to be the first day of the first of the two 
consecutive weeks. The baseline value for this calculation will be defined as the midpoint of 
the last week (defined as the last 7 days) prior to randomization date or first dose date of study 
medication, whichever is earlier. During this interval, insulin is collected daily. The 
calculation will follow the algorithm specified above in order to derive that value that will be 
used to compare on study values to define insulin up-titration more than 25%.
4.1.2.4
Last Observation Carried Forward (LOCF)
In analysis of change (or percent change) from baseline as well as response endpoint at Week 
t LOCF, the measurement assigned as the Week t measurement will be used. If no Week t
measurement is available (subject has discontinued before Week t, or measurement not taken 
at Week t though subject was not discontinued), the last available earlier post-baseline
measurement will be used. Unless specified otherwise, all data regardless of insulin up-


Statistical Analysis Plan 
Study Code D1695C00001(Part B)
Edition Number 2.0
Date 16 March 2017
24
titration will be used for the calculation of LOCF values. In the case that analysis would 
exclude data from subjects after insulin up-titration more than 25% from baseline, their last 
post-baseline measurement taken prior to or on the date of up-titration will be used.
4.1.2.5
Mean daily glucose of 6-point self monitored blood glucose (SMBG)
Prior to Day 1 visit, Week 12, Week 24 and Week 52/Study Termination or Early Treatment 
Termination, subjects must perform 6-point finger stick blood glucose monitoring (before 
meals, 2 hours post meal) at home for 3 days within the week of the visit. Meals are 
considered to be breakfast, lunch and dinner. Preprandial and postprandial measurements will 
be considered eligible for analysis if they occur prior to the start time of each meal and 
between 1.5 and 2.5 hours after the start of the meal time, respectively. The pre- and post-
prandial meal glucose measurements obtained outside the time windows (prior to the meal, 1.5 
to 2.5 hours after the start time of the meal) will be excluded from the summaries and analyses.
Glucose concentrations at each of the 6 time points will be averaged over the 3 days to derive 
the mean glucose concentrations at each of the 6 time points. The mean daily glucose (MDG) 
will then be calculated as the average over the average glucose concentrations at the 6 time 
points. The daily average data will be calculated only if at least one pair of average pre-
prandial and post-prandial blood glucose values is available. Only complete pairs of the 
average pre-prandial and post-prandial blood glucose values will be used for the calculation. 
For example, if the available average time point data for a subject at a visit are pre-breakfast, 
post-breakfast, and pre-dinner, then the daily average will be calculated as (pre-breakfast + 
post-breakfast)/2.  
4.1.2.6
Post-prandial glucose values of self monitored blood glucose (SMBG) 
The post-prandial glucose values of SMBG readings will be those values that occur 2 hours 
after the start time of breakfast, lunch and dinner. Postprandial measurements will be 
considered eligible for analysis if they occur between 1.5 and 2.5 hours after the start of the 
meal time. The post-prandial measurements obtained outside the time windows (1.5 to 2.5 
hours after the start time of the meal) will be excluded in the summaries and analyses. For 
SMBG parameters, glucose concentrations at each of the 3 post-prandial time points will be 
averaged, over the days of data collection, to derive the mean glucose concentrations at each 
of the 3 time points. The mean post-prandial daily glucose (MPDG) will then be calculated as 
the average over the average glucose concentrations at the 3 time points. The average of all 
post-prandial glucose values during a day will be used for the analysis of change in post-
prandial glucose values independently of whether there is a corresponding preprandial value 
available.
4.1.3
Descriptive summary of continuous variables
Descriptive summaries of continuous variables in terms of change or percent change from
baseline values will be provided by treatment group and overall, if applicable.
4.1.4
Descriptive summary of categorical variables
Descriptive summaries of categorical variables will consist of frequencies and percentages for


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each treatment group and overall, if applicable.
4.1.5
Mixed Model for Repeated Measures (MMRM) for outcomes with single 
measurement per week t
A longitudinal repeated measures analysis using ‘direct likelihood’ will be performed. The 
SAS procedure PROC MIXED will be used. The dependent variable will be the change from 
baseline to each week t included in the model for efficacy endpoints examining changes from 
baseline. For analyses of parameters in terms of percent change from baseline at Week t, 
values will first be transformed to logarithms and the results will be expressed as geometric 
mean percent changes from baseline. The dependent variable will be the natural logarithms 
(Ln) of the post-baseline to baseline ratios. The model estimates will be back transformed to 
original values using the formulae detailed in Table 2.  
The preferred model will include the fixed categorical effects of treatment, week, 
randomization stratification factor and treatment-by-week interaction as well as the 
continuous fixed covariates of baseline measurement and baseline measurement-by-week 
interaction. Model results will only be reported if at least 10 subjects have both baseline and 
Week t measurements in all treatment groups. Otherwise, just mean (SD) and mean change 
from baseline (SD) will be displayed for Week t in the table. For parameters analyzed as
percent change from baseline, the natural logarithm of the baseline values will be used in the
above model specification. 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.
In case of non-convergence of the preferred model or memory space issues the following 
backup models are defined:
1) The first backup model is the same as the preferred model but the Kenward-Roger method
will be replaced by Satterthwaite approximation.
2) The second backup model is the same as the preferred model but without the term for
baseline measurement-by-week interaction. The second back-up model will only be provided 
if the first back-up model does not converge or has memory issues.
The model will provide least-squares mean estimates, standard errors and 2-sided 95%
confidence intervals for mean change at all time points within treatments. 
4.1.6
Mixed Model with Repeated Measures (MMRM) for outcomes with multiple 
measurements per week t
Some efficacy parameters (i.e. parameters from 6-point SMBG or daily insulin dose) are 
measured daily during a visit window.  Within each visit window (including baseline and 
post-baseline visit windows as outlined in section 6.2) the average for all available data points 
will be calculated and this will constitute the baseline or Week t value (as applicable).
Analysis will be performed with a longitudinal repeated measurements model as outlined in
Section 4.1.5.


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4.1.7
Kaplan-Meier curve and estimates for time-to-event analysis
Kaplan-Meier plots of time to event variables will be displayed by treatment group. Unless
otherwise specified, the plot will be presented only when there are at least 5 events in one
treatment group. Additionally, a table will accompany the plot and will display the Kaplan-
Meier estimates of the cumulative proportion (with 95% CI calculated based on Greenwood’s 
method when applicable) of subjects with event at specific time points by treatment group. If 
the estimated lower bound of 95% CI is below 0 or the estimated upper bound of 95% CI is 
over 1, then it will be restricted to 0 or 1 respectively.
4.1.8
Analysis of proportions
For proportions of responders (e.g. meeting A1C criteria) percentage (100*n/N) and 95% 
confidence intervals will be provided by the Clopper-Pearson method. 
4.2
Analysis methods
4.2.1
Study population 
4.2.1.1
Subject disposition
The disposition of subjects for the pre-randomization period, the study treatment period and 
safety follow-up period (where applicable) will be summarized. 
The summary of status in the pre-randomization will include all subjects enrolled (who signed 
informed consent). The summary of status in the study treatment period will include all 
subjects in Randomized set, and be presented by randomized treatment group. This summary 
will include subjects completing and discontinuing the study treatment period with reasons for 
discontinuation. 
Reasons for discontinuation for subjects who discontinued from the pre-randomization period 
and from the randomized study treatment period will be tabulated and listed. 
Subjects enrolled, randomized, included in the Full analysis set and included in the Safety set
will be summarized by study site.
4.2.1.2
Demographic and other baseline characteristics
Demographic and other baseline characteristics, including diabetes-related characteristics and
renal function characteristics will be summarized by treatment group and overall, using the
Randomized set.
Demographic and baseline characteristics are listed in Table 3. Diabetes related baseline 
characteristics are listed in Table 4. Renal function baseline characteristics are listed in Table 
5.
All summaries of continuous characteristics will be based on non-missing observations. For
categorical characteristics, percentages will be calculated out of the total number of subjects in


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the data set, overall and by treatment group (i.e., each denominator includes the number of 
subjects with missing/unknown values for the characteristic).
Table 3
Demographic and Baseline Characteristics
Characteristic
Summarized as
Categories
Gender
Categorical
Male, Female
Age
Categorical and Continuous 
< 65 yrs 
≥ 65 – < 75 yrs
# 75 yrs
< 35 yrs
≥35 - < 50 yrs
≥50 yrs
Female Age
Categorical
∃50 yrs
>50 yrs
Body Weight
Continuous
-
Body Mass Index
Categorical and Continuous
< 25 kg/m2
# 25 kg/m2
# 27  kg/m2
# 30 kg/m2
Table 4
Diabetes-Related Baseline Characteristics
Characteristic
Summarized as
Categories
Duration of Type 1 Diabetes
Categorical and Continuous
< 10 yrs
# 10 and ∃20 yrs
> 20 yrs
HbA1c
Categorical and Continuous 
< 8%
≥ 8 and < 9%
# 9%
< 9%
≥9%
C-peptide*
Categorical and Continuous
< 0.1 ng/mL
≥0.1 ng/mL
Method of insulin administration Categorical
Multiple Daily Injections
Continuous Subcutaneous 
Insulin Infusion


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Characteristic
Summarized as
Categories
Total daily insulin, basal insulin, 
bolus insulin
Continuous
Stratum HbA1c**
Categorical
< 9%
≥ 9%
* For C-peptide values (see appendix 9.2) that will be received with an operator sign as a part of the result (below 
detection limit <0.1 ng/mL), a process to strip the operator sign will be applied and the resulting numeric values 
will be used for data analysis. The raw value with operator remained as such in the database.
** Will be used from IWRS randomization stratum
Table 5
Baseline Renal Function
Characteristic
Summarized as
Categories
eGFR
(Japanese formula)
Categorical and Continues
< 30 mL/min/1.73 m2
# 30 and < 45 mL/min/1.73 m2
# 45 and < 60 mL/min/1.73 m2
# 60 and < 90 mL/min/1.73 m2
# 90 mL/min/1.73 m2
4.2.1.3
Specific and general disease histories
The number (percent) of subjects with diabetes, diabetes-related disease histories will be
summarized by treatment group and overall using the Randomized set. 
The number (percent) of subjects with general medical history findings will also be
summarized by treatment group and overall using the Randomized set.
4.2.2
Extent of exposure
4.2.2.1
Study medication
The extent of exposure to study medication during the treatment period is defined as the 
difference between the last and the first dose of study medication of the treatment period plus 
1 day. The extent of exposure to study medication will be summarized using the Safety set for 
the treatment period, where the number and percent of subjects with an extent of exposure 
within pre-specified day ranges will be presented by treatment group. The categorization for 
the treatment period is 1-7, 8-30, 31-60, 61-90, 91-120, 121-180, 181-270, 271-360, >360
days. The mean (SD), median and range of the number of days of exposure will also be 
presented.
A listing of subjects by batch number of study medication will also be generated.


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In addition, the exposure in terms of total patient-years will be calculated by treatment group 
using the sum of the exposure to study medication of all subjects (in years) in a treatment 
group.
4.2.2.2
Interruption of Study Medication
Interruption of study drug is indicated by missing intervals in drug administration on the CRF.
4.2.2.3
Current and concomitant medications
Concomitant medications will be summarized using the Safety analysis set by drug class and 
(generic) drug name. A by-subject listing of current medications will be provided. A summary 
table by drug class and generic drug name will be generated for each of the following:
!
all concomitant medication
!
all concomitant diuretic medication
!
all concomitant loop diuretic medication
!
all concomitant ARB and/or ACE-I medication
!
all concomitant anti-hypertensive medication
Current medications are defined as medications with a start date prior to the first day of 
treatment period and without a stop date prior to the consent date, i.e. current medication will 
be any medication with at least 1 dose taken on or after the day of consent date up to the day 
prior to the first dose of study medication.
Concomitant medication is defined a medication with either
!
a recorded medication start date falling within the treatment period, or
!
a recorded medication start date prior to the first day of study medication during the 
treatment period without any recorded medication stop date prior to the start of the 
treatment period.
This means that concomitant medications will be any medication taken from start of the 
treatment period up to the end of the treatment period. 
Missing and partial date handling of start and stop dates of previous, current and concomitant 
medications, is described in Section 6.6. The AZ Drug Dictionary (AZDD) is used to code the 
non-study medication.
4.2.2.4
Measurement of Treatment Compliance
Percent treatment compliance is calculated treatment period for study medication. For each
subject, percent compliance is defined as the number of tablets taken divided by the number of 


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tablets that should have been taken.  A subject is considered compliant if percent compliance 
is ≥ 80% and ≤ 120%.  The number and percent of subjects compliant during the treatment 
period will be displayed for the Safety set (SAF-B). 
Details in calculating percent compliance are specified in Section 6.9.
4.2.3
Efficacy
This section describes the efficacy analyses as defined in secondary/exploratory objectives. 
The Full analysis set (FAS-B) will be used for all efficacy analyses. No formal statistical 
testing will be made. Estimates and two-sided 95% confidence intervals by treatment group 
will be provided as necessary. Unless otherwise specified, all available efficacy data obtained 
up to Week 52 or premature discontinuation of study drug (regardless of insulin uptitiration) 
will be included in the analysis. For the selected efficacy variables (change from baseline in 
HbA1c and percent change from baseline in body weight, analyses excluding data after insulin 
up-titration will be performed.
4.2.3.1
Change from baseline in HbA1c (including/excluding data after insulin 
up-titration) at Week 24 and 52
The analysis of change from baseline in HbA1C from baseline to Week 24/52 will be based 
on an MMRM using ‘direct likelihood’ (see Section 4.1.5) and point estimates and 95% CI for 
the mean change within each treatment group at Week 24/52 will be calculated. 
The model will be restricted to data from subjects in the Full Analysis Set who have at least 
one baseline assessment and any post-baseline treatment period assessment.
The above mentioned analyses will be performed regardless of insulin up-titration and 
excluding data after insulin up-tiration (subjects whose post-randomization insulin dose is up-
titrated by more than 25% relative to baseline, measurements obtained after the first instance 
the 25% up-titration criteria is met will correspond to rescue and be excluded).
Descriptive summary (as specified in Section 4.1.3) of change from baseline in HbA1c over 
time (including/excluding data after insulin up-titration) will be also provided.  
Further descriptive summary of change from baseline in HbA1c over time (including data 
after insulin up-titration) will be provided by subgroup as defined in Table 6.
Table 6
Subgroup factors for descriptive summary of HbA1c
Group variables
Subgroups
Gender
Female
Male
Baseline A1c
< 9, >= 9 %
Age
< 65, 65-<75, >= 75 years 
Female Age
Female <= 50 years, Female > 50 years


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Table 6
Subgroup factors for descriptive summary of HbA1c
Group variables
Subgroups
Method of insulin administration
Multiple Daily Injections
Continuous Subcutaneous Insulin Infusion
Baseline BMI
< 25, >= 25 kg/m2
4.2.3.2
Change from baseline in GA (including data after insulin up-titration) at Week 
24 and 52
The analysis of change from baseline in GA from baseline to Week 24/52 will be based on an 
MMRM using ‘direct likelihood’ (see Section 4.1.5) and point estimates and 95% CI for the 
mean change within each treatment group at Week 24/52 will be calculated.
Descriptive summary (as specified in Section 4.1.3) of change from baseline over time 
(including data after insulin up-titration) will be also provided.  
4.2.3.3
Change from baseline in average glucose values measured by 6-point SMBG
(including data after insulin up-titration) at Week 24 and 52
See Section 4.1.2.5 for the calculation of average glucose values of 6-point SMBG.
The analysis of change from baseline in average glucose values measured by 6-point SMBG 
from baseline to Week 24/52 will be based on an MMRM using ‘direct likelihood’ (see 
Section 4.1.6) and point estimates and 95% CI for the mean change within each treatment 
group at Week 24/52 will be calculated.
Descriptive summary (as specified in Section 4.1.3) of change from baseline over time 
(including data after insulin up-titration) will be also provided. 
Similar descriptive summary will be repeated for each of 6 time points.  
4.2.3.4
Change from baseline in post-prandial glucose values measured by 6-point 
SMBG (including data after insulin up-titration) at Week 24 and 52
See Section 4.1.2.6 for the postprandial glucose values of 6-point SMBG. 
The 6-point SMBG parameters should include capillary blood glucose values. In case that 
there are capillary plasma values reported, they will be converted to capillary blood equivalent 
values as described in Section 6.10. 
The analysis of change from baseline in average glucose values measured by 6-point SMBG 
from baseline to Week 24/52 will be based on an MMRM using ‘direct likelihood’ (see 
Section 4.1.6) and point estimates and 95% CI for the mean change within each treatment 
group at Week 24/52 will be calculated.


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Descriptive summary (as specified in Section 4.1.3) of change from baseline over time 
(including data after insulin up-titration) will be also provided.  
4.2.3.5
Percent change from baseline in total daily insulin dose (including data after 
insulin up-titration) at Week 24 and 52
Insulin data are collected on a daily basis over 2-week periods corresponding to distinct study 
visits/weeks. Each data collection corresponds to insulin doses over a 24-hour period (see 
implications for baseline and study week definitions in Section 4.1.2.1 and Section 6.3).
Information is entered on CRF regarding the total daily bolus and basal insulin administered. 
The total daily insulin dose is the sum of the total daily bolus, total daily basal insulin and pre-
mixed doses. If information is not available on basal or bolus insulin dose on a specific day, 
then the total will not be calculated for that day and it will be considered as missing to
analysis.
In between those 2-week periods of total daily insulin dose data collection, insulin is reported 
as minimum and maximum values of total daily insulin administration over weekly intervals. 
The data from these weekly intervals will not be used for the analysis of secondary efficacy 
endpoint described in this section.
The analysis of the percent change (using logarithmic transformation for the endpoint in the 
model) in total daily insulin from baseline to Week 24/52 will be based on a MMRM analysis 
using ‘direct likelihood’ (see Section 4.1.5) and point estimates and 95% CI for the mean 
change within each treatment group at Week 24/52 will be calculated.
The same analyses will be repeated for the total daily basal and total daily bolus insulin doses. 
In cases that either of this information is missing on a specific day, then this information will 
be considered as missing for these two analyses.
Descriptive summary (as specified in Section 4.1.3) of percent change from baseline over time 
will be also provided.  
4.2.3.6
Percent change from baseline in body weight (including/excluding data after 
insulin up-titration) at Week 24 and 52
Body weight is collected at selected visits during the long-term period with a single value at
each visit.
The analysis of the percent change (using logarithmic transformation for the endpoint in the 
model) in body weight from baseline to Week 24/52 will be based on a MMRM analysis using 
‘direct likelihood’ (see Section 4.1.5) and point estimates and 95% CI for the mean change 
within each treatment group at Week 24/52 will be calculated.
The above mentioned analysis of the percent change in body weight from baseline to Week 
24/52 will be performed excluding data from subjects whose post-randomization insulin dose 


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is up-titrated by more than 25% of insulin relative to baseline and including data after insulin 
up-tiration.
Descriptive summary (as specified in Section 4.1.3) of percent change from baseline over time 
for body weight (including/excluding data after insulin up-titration) will be also provided.  
4.2.3.7
Proportion of subjects with HbA1c reduction from baseline of at least 0.5%
without severe hypoglycemia at Week 24 and 52 (including data after insulin 
up-titration)
Point estimates and 2-sided 95% confidence intervals for the proportion within each treatment 
group will be provided by treatment group.  This analysis will be performed including data
after insulin up-tiration. For missing HbA1c at Week 24/52, LOCF will be applied. 
4.2.3.8
Proportion of subjects with HbA1c reduction from baseline of at least 0.5% at 
Week 24 and 52 (including data after insulin up-titration)
Point estimates and 2-sided 95% confidence intervals for the proportion within each treatment 
group will be provided by treatment group.  This analysis will be performed including data
after insulin up-tiration.  For missing HbA1c at Week 24/52, LOCF will be applied.
4.2.3.9
Proportion of subjects with HbA1c < 7.0% at Week 24 and 52 (including data 
after insulin up-titration)
Point estimates and 2-sided 95% confidence intervals for the proportion within each treatment 
group will be provided by treatment group. This analysis will be performed including data
after insulin up-tiration.  For missing HbA1c at Week 24/52, LOCF will be applied.
4.2.3.10
Change from baseline to Week 24 and 52 in seated SBP (including data after 
insulin up-titration) among subjects with hypertension at baseline, defined as 
seated SBP ≥ 140 mmHg and/or seated DBP ≥ 90 mmHg
Seated systolic blood pressure is collected at selected visits with a single value at each visit.
The analysis of change from baseline in seated SBP from baseline to Week 24/52 will be 
based on an MMRM using ‘direct likelihood’ (see Section 4.1.6) and point estimates and 95% 
CI for the mean change within each treatment group at Week 24/52 will be calculated.
The model will be restricted to data from subjects in the Full Analysis Set who have at least 
one baseline assessment and any post-baseline treatment period assessment and who have 
hypertension at baseline (defined as seated SBP >= 140mmHg and/or seated DBP >=
90mmHg).
The above mentioned analyses will be performed including data after insulin up-tiration. 
Descriptive summary (as specified in Section 4.1.3) of change from baseline over time 
(including data after insulin up-titration) will be also provided.  


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4.2.3.11
Time to Insulin up-titration by more than 25% 
Time to the first post-randomization insulin up-titration by more than 25% relative to the
baseline insulin dose will be presented by treatment group using a Kaplan-Meier curve using
methodology described in Section 4.1.7. A plot will be presented only when there are at least 
5 subjects meeting the criteria in one treatment group. An accompanying table of the 
cumulative proportion of subjects whose insulin was up-titrated by more than 25% from 
baseline at specific time points will be produced.
4.2.3.12
Descriptive summary of efficacy variables by BMI subgroup 
Also, descriptive summary on various efficacy variables by baseline BMI (< 25, >= 25 kg/m2) 
will be provided as an exploratory analysis for following efficacy variables. 
!
Change from baseline in HbA1c at Week 24/52 (including data after insulin up-
titration) by baseline BMI (as already mentioned in Table 6) 
!
Change from baseline in GA at Week 24/52 (including data after insulin up-
titration) by baseline BMI
!
Change from baseline in average glucose values measured by 6-point SMBG at 
Week 24/52 (including data after insulin up-titration) by baseline BMI  
!
Change from baseline in postprandial glucose values measured by 6-point SMBG at 
Week 24/52 (including data after insulin up-titration) by baseline BMI
!
Percent change from baseline in mean total daily insulin dose (including data after 
insulin up-titration) at Week 24/52 by baseline BMI 
!
Percent change from baseline in mean daily basal insulin dose (including data after 
insulin up-titration) at Week 24/52 by baseline BMI
!
Percent change from baseline in mean daily bolus insulin dose (including data after 
insulin up-titration) at Week 24/52 by baseline BMI
!
Percent change from baseline in body weight (including data after insulin up-
titration) at Week 24/52 by baseline BMI
4.2.4
Safety
This section describes the safety analyses as defined in primary objective. The Safety set will 
be used for all safety analyses. No formal statistical testing will be made and data will be 
presented with descriptive summary by treatment group.   
Unless otherwise specified, safety analyses will include any data regardless of 25% insulin up-
titration after randomization.   


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4.2.4.1
Adverse Events
Adverse Events (AEs) will be classified by Primary System Organ Class (SOC) and Preferred
Term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA).
Summaries of AEs will use the version of MedDRA that is current at the time of database lock
for each study. No statistical test will be performed to compare adverse event rates between 
treatment groups. Counting rules for adverse events are described in Section 6.7.
In summaries by SOC and PT, AEs will be sorted by decreasing frequency within each SOC 
and PT according to the highest Dapagliflozin dose group. In summaries by PT, AEs will be 
sorted by decreasing frequency within PT according to the highest dapagliflozin dose group.
Separate pages to capture events of hypoglycemia are contained within the CRF.
Hypoglycemia or discontinuation due to hypoglycemia would not be reported on an AE CRF 
page unless the event fulfilled criteria for a Serious AE (SAE) in which case an SAE form 
would be completed.  Hypoglycemia events that are reported as SAEs will be included in all 
summaries of AEs or SAEs. Separate summaries will be provided including hypoglycemia 
events reported on that special CRF pages.
All Adverse Events
All adverse events (serious and non-serious, excluding hypoglycemic events/DKA events that 
are not reported as SAEs) with onset during the treatment period will be summarized by SOC, 
PT, and treatment group. In addition, a subject listing of all reported adverse events will be 
produced, displaying all events (including pre-treatment events). All adverse events (serious 
and non-serious) including all hypoglycemic events/DKA events will also be summarized by 
treatment group.
AEs and SAEs with an onset from Day 1 of the treatment period up to and including 4 days 
and 30 days respectively, after the last dose date in the treatment period will be considered as 
occurring during the treatment period.
In addition, number of subjects reporting any of the following during the treatment period will 
be summarized for all treated subjects:
!
at least one adverse event
!
at least one hypoglycemia event
!
at least one DKA event 
!
at least one AE or hypoglycemia event or DKA event
!
at least one related adverse event
!
deaths
!
at least one SAE


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!
at least one related SAE
!
SAE leading to discontinuation of study medication
!
AE leading to discontinuation of study medication
!
hypoglycemia leading to discontinuation of study medication
!
DKA leading to discontinuation of study medication
In addition, the following summaries will be provided for treatment period (excluding 
hypoglycemic events/DKA events that are not reported as SAEs):
!
Proportion of subjects with adverse events in subgroups of subjects defined by age 
category (< 65 and ≥ 65yrs), by gender, by female age category (≤ 50 and > 50yrs)
and by baseline BMI (<25, >= 25 kg/m2).
!
Most common adverse events by PT and treatment group (i.e., reported by ≥2% of 
subjects in any treatment group),
!
Non-serious adverse events by preferred term (i.e., reported by ≥5% of subjects in 
any treatment group)
!
Adverse events by SOC, PT, intensity and treatment group,
!
Adverse events related to study medication by SOC, PT, and treatment group.
In addition to analyses of event incidence at the subject level, recurrence analyses will be
performed at the event level. In order to prepare these summaries, the CRF data will be
processed according to standard sponsor algorithms to categorize each line of patient data as a
new occurrence or a continuation of an existing event. This determination will be based upon
onset and resolution dates. Each line of patient data will represent the maximum severity
observed as well as the last known assessed relationship to study medication by the
investigator.
The following summary information will be provided:
Total number and rate (exposure adjusted) of occurrences for all AEs occurring in at least 5%
of the subjects treated. This data will be presented as the rate per 100 years of patient exposure. 
Exposure to study medication will be calculated according to approved standard sponsor 
algorithms as well. As an example, if 5 patients report 7 unique episodes of headache and had 
a combined cumulative exposure of 20 years to study medication, the incidence rate is 
reported as 7 / 20 * (100) or 35 cases per 100 patient years of exposure.
In addition, a subject listing of all reported adverse events will be produced, displaying all 
events (including pre-treatment events) that occurred prior to the start date of treatment


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period, if any, or in subjects who dropped-out during the treatment period. The listing will flag 
AE not counted as a unique AE.
For the purpose of clinical trial transparency, listing of most common non-serious AEs (≥5 % 
of subjects in any treatment group) will be produced for posting at public websites (e.g., 
NIH’s www.ClinialTrials.gov).
Deaths
All deaths recorded on the status page, the AE page, or SAE page (with a death date, cause of
death, outcome or SAE categorization present) of the CRF will be considered a death in the
analyses. Any deaths that occur during the study will be described in depth as narrative in the
CSR. A summary table by treatment group of all deaths that occurred during the treatment 
period will be produced. Deaths with an onset from day 1 of treatment period up to and 
including 30 days after the last dose date in the treatment period will be considered as 
occurring during the treatment period.
Additionally a listing of all deaths that occurred occur prior to the start date of treatment
period will be produced for enrolled subjects.
Serious Adverse Events
All SAEs (including hypoglycemic events) will be described in narratives, regardless of
investigator assessment of causality. SAEs with an onset from Day 1 of the treatment period 
up to and including 30 days after the last dose date in the treatment period will be considered 
as occurring during the treatment period.
SAEs occurring during the treatment period will be summarized by SOC, PT, and treatment 
group. In addition, the proportion of subjects with related SAEs will be presented by SOC, PT, 
and treatment group. A listing of all SAEs will be produced, displaying all SAEs (including 
pre-treatment events).
Adverse Events Leading to Discontinuation of Study Medication
AEs with an onset during the treatment period reported with an action taken of discontinuation 
of study medication will be summarized by SOC, PT, and treatment group . This summary 
will include hypoglycemia events that are reported as SAEs. When summarizing AEs leading 
to discontinuation, no upper cutoff day windows (i.e. 4 days and 30 days from last dosing date 
treatment period for AEs and SAEs respectively) are applied. 
In addition, a subject listing of discontinuation due to AEs will be provided, displaying all 
events that led to discontinuation.
4.2.4.2
Adverse Events of Special Interest
Separate summaries will be provided for the following AEs of special interest. To identify 
each type of AE of special interest in this section, a list of PTs will be selected before database 
lock. Unless otherwise specified, AEs and SAEs of special interest with an onset from Day 1 


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of the treatment period up to and including 4 days and 30 days respectively, after the last dose 
date in treatment period will be considered as occurring during the treatment period.
Hepatic adverse events
To facilitate monitoring of liver safety in subjects treated with dapagliflozin, a list of PTs were
selected before database lock of the study to form the Standard MedDRA Query (SMQ) for
events of hepatic disorders. The number and percentage of subjects with events of hepatic
disorders will be summarized by PT and treatment group. 
Genital infection
The definition of events of genital infection is based on the dapagliflozin predefined list of
events.
The number and percentage of subjects with events of genital infections will be summarized 
by PT and treatment group in the treatment period. The number and percentage of subjects 
with events of genital infections will also be summarized by gender and treatment group.
The number and percentage of subjects with events of genital infection will be summarized 
for the subgroups defined on the basis of categorized variables including the frequency of 
events per subject (recurrence; 1, 2, 3 or > 3) and additional treatment (yes, no or unknown).
The number and percentage of subjects with events of genital infections qualifying as an SAE
will be summarized by PT and treatment group in the treatment period.
The number and percentage of subjects with events of genital infections leading to
discontinuation of study medication will be summarized by PT and treatment group.
Urinary-tract Infection 
The definitions of events of urinary-tract infection and its subset of kidney infections are 
based on the dapagliflozin predefined list of events.
The number and percentage of subjects with events of urinary-tract infection and with kidney
infections will be summarized by PT and treatment group in the treatment period. The number 
and percentage of subjects with urinary-tract infection will also be summarized by gender and 
treatment group in the treatment period.
The number and percentage of subjects with events of urinary-tract infection will be 
summarized for the subgroups defined on the basis of categorized variables including the
frequency of events per subject ( recurrence; 1, 2, 3 or > 3) and additional treatment (yes, no, 
or unknown).
The number and percentage of subjects with events of urinary-tract infection qualifying as an
SAE will be summarized by preferred term and treatment group in the treatment period.


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The number and percentage of subjects with events of urinary-tract infection leading to
discontinuation of study medication will be summarized by PT and treatment group in the 
treatment period.
Diabetic ketoacidosis (DKA)
A DKA Adjudication Committee will independently adjudicate all the DKA events reported 
by the investigators and those identified based on predefined algorithm during the study 
period. A separate Adjudication Manual will define and describe the procedure for the 
handling, reporting, and classification of these cases.
DKA events with an onset from Day 1 of the treatment period up to and including 4 days after 
the last dose date will be considered as occurring during the treatment period. The proportion 
of subjects with DKA events will be tabulated both by type assigned at adjudication and 
overall by treatment group in the treatment period.
DKA events with an onset during the treatment period and leading to discontinuation of study 
medication will be summarized by treatment group. When summarizing DKA events leading 
to discontinuation, no upper cutoff day windows are applied.
The number and percentage of subjects with DKA events, both overall and adjudicated as 
definite, will be summarized by frequency of events per subject (recurrence; 1, 2, 3, > 3). The 
total number of events by treatment group will be summarized for the treatment period. The 
exposure adjusted incidence rate of DKA events (including recurrences) will be summarized
by monthly intervals in order to assess any over time changes in the incidence rate.
Time to first DKA event adjudicated as definite will be presented by treatment group using a 
Kaplan-Meier curve using methodology described in Section 4.1.7. A plot will be presented 
only when there are at least 5 events in one treatment group. An accompanying table of the 
cumulative proportion of subjects with time to first DKA event adjudicated as definite at 
specific time points will be produced.
A listing of subjects will be produced and it will display all confirmed adjudicated DKA 
events with an onset date/time from the start date/time of study treatment. 
Hypoglycemia
Separate pages to capture events of hypoglycemia are contained within the CRF.
Hypoglycemic events with an onset from Day 1 of study treatment up to and including 4 days 
after the last dose date in treatment period will be considered as occurring during the treatment 
period.
Hypoglycemic events will be categorized using the following classes following ADA
recommendation :
1.
Severe hypoglycemia. “An event requiring assistance of another person to actively
administer carbohydrate, glucagons, or other resuscitative actions. These episodes 


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may be associated with sufficient neuroglycopenia to induce seizure or coma. 
Plasma glucose measurements may not be available during such an event, but 
neurological recovery attributable to the restoration of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.”
2.
Documented symptomatic hypoglycemia. “An event during which typical 
symptoms of hypoglycemia are accompanied by a measured plasma glucose 
concentration <=70mg/dl (3.9mmol/l).”
3.
Asymptomatic hypoglycemia. “An event not accompanied by typical symptoms of
hypoglycemia but with a measured plasma glucose concentration ≤ 70mg/dl 
(3.9mmol/l). Since the glycemic threshold for activation of glucagon and 
epinephrine secretion as glucose levels decline is normally 65–70mg/dl (3.6–
3.9mmol/l)  and since antecedent plasma glucose concentrations of ≤ 70mg/dl 
(3.9mmol/l) reduce sympathoadrenal responses to subsequent hypoglycemia , this 
criterion sets the lower limit for the variation in plasma glucose in nondiabetic, 
nonpregnant individuals as the conservative lower limit for individuals with 
diabetes.”
4.
Probable symptomatic hypoglycemia. “An event during which symptoms of 
hypoglycemia are not accompanied by a plasma glucose determination (but that was 
presumably caused by a plasma glucose concentration ≤ 70mg/dl [3.9mmol/l]). 
Since many people with diabetes choose to treat symptoms with oral carbohydrate 
without a test of plasma glucose, it is important to recognize these events as 
“probable” hypoglycemia. Such self-reported episodes that are not confirmed by a 
contemporaneous low plasma glucose determination may not be suitable outcome 
measures for clinical studies that are aimed at evaluating therapy, but they should be 
reported.”
5.
Relative hypoglycemia. “An event during which the person with diabetes reports 
any of the typical symptoms of hypoglycemia, and interprets those as indicative of 
hypoglycemia, but with a measured plasma glucose concentration > 70mg/dl 
(3.9mmol/l). This category reflects the fact that patients with chronically poor 
glycemic control can experience symptoms of hypoglycemia at plasma glucose 
levels > 70mg/dl (3.9mmol/l) as plasma glucose concentrations decline toward that 
level. Though causing distress and interfering with the patient’s sense of well-being, 
and potentially limiting the achievement of optimal glycemic control, such episodes 
probably pose no direct harm and therefore may not be a suitable outcome measure 
for clinical studies that are aimed at evaluating therapy, but they should be 
reported.”
The above mentioned classification refers to plasma glucose measurements. In cases where
whole blood glucose measurements are reported, they will be converted to plasma equivalent 
as described in section 6.10.


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All analyses of hypoglycemic events will be performed both overall and by class of events as 
per ADA categorization presented above.
Hypoglycemic events with an onset during the treatment period and those leading to
discontinuation of study medication will be summarized by treatment group. When
summarizing hypoglycemic events leading to discontinuation no upper cutoff day windows 
are applied. 
Time to hypoglycemic events leading to discontinuation of study medication will be presented
by treatment group using a Kaplan-Meier curve using methodology described in Section 4.1.7. 
A plot will be presented only when there are at least 5 events in one treatment group. An
accompanying table of the cumulative proportion of subjects with time to hypoglycemic
events leading to discontinuation of study medication at specific time points during the
treatment period will be produced.
The number and percentage of subjects with hypoglycemic events will be summarized by
frequency of events (recurrence; for severe hypoglycemia: 1, 2, >=3 ; for documented
symptomatic hypoglycemia: 1-3, 4-6, or >=7, for asymptomatic, probable symptomatic, 
relative hypoglycemia and all hypoglycemic events independently of ADA categorization: 1-5, 
6-9, or >=10). The total number of events by treatment group will be summarized for the 
treatment period. The exposure-adjusted incidence rate of hypoglycemic events (including 
recurrences) will be summarized by monthly intervals in order to assess any over time
changes in the incidence rate.
Volume Depletion (Hypotension/Dehydration/Hypovolemia)
The definitions of volume depletion events are based on the dapagliflozin predefined list of 
events. The number and percentage of subjects with hypotension/dehydration/hypovolemia 
events will be summarized by PT and treatment group in the treatment period.
Renal Impairment/Failure
The definitions of renal impairment/failure events are based on the dapagliflozin predefined 
list of events. The number and percentage of subjects with renal impairment/failure events 
will be summarized by PT and treatment group in the treatment period.
Fractures
The definitions of events of fracture are based on the dapagliflozin predefined list of events.
The number and percentage of subjects with events of fracture will be summarized by PT and
treatment group in the treatment period.
Breast Cancers
The definitions of breast cancer are based on the SMQ of such events. The number and 
percentage of subjects with breast cancers will be summarized by PT and treatment group in 
the treatment period and a corresponding listing of subjects will be provided.


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Bladder Cancers
The definitions of bladder cancer are based on the SMQ of such events. The number and 
percentage of subjects with bladder cancers will be summarized by PT and treatment group in 
the treatment period and a corresponding listing of subjects will be provided.
Hypersensitivity
The definition of hypersensitivity is based on the SMQ of hypersensitivity narrow list. The 
number and percentage of subjects with hypersensitivity will be summarized by PT and
treatment group in the treatment period and a corresponding listing of subjects will be 
provided.
4.2.4.3
Laboratory Evaluation
Unless otherwise specified, laboratory data obtained after the start of study medication dosing 
up to and including 4 days (30 days for liver function laboratory tests) after the last dosing 
date will be considered as obtained during the treatment period. Laboratory data obtained 
from the day after the last study medication + 4 days (30 days for liver function laboratory 
tests) up to the last visit date of the follow-up period will be considered as obtained during the 
follow-up period.  For liver safety, a summary of proportion of subjects with elevated liver 
test including elevated aminotransferases (AT; alanine aminotransferase [ALT] and/or 
aspartate aminotransferase [AST]) and total bilirubin (see Section 9.1 for definition) will be 
provided. In addition, a summary of proportion of subjects with elevated liver tests and/or 
reported AE of hepatic disorder will also be provided. For those summaries, liver test data 
obtained after the start of study medication dosing up to and including 30 days after the last 
dosing date will be considered as obtained during the treatment period. Further, a listing 
presenting sustained elevated liver safety abnormalities will be provided.
Listings of individual laboratory measurements by subject (including pre-treatment values and 
values measured during the follow-up period) will be provided upon request.
Marked Laboratory Abnormalities
Laboratory abnormalities will be evaluated based on marked abnormality (MA) values. The 
predefined criteria for marked abnormalities are detailed in Section 9.1. If both the baseline 
and on-treatment values of a parameter are beyond the same MA limit for the parameter, then 
the on-treatment value will be considered a MA only if it is more extreme (farther from the 
limit) than was the baseline value. If the baseline value is beyond the low MA limit, and the 
post-baseline value is beyond the high MA limit (or vice-versa), then the post-baseline value 
will be considered a MA.
Laboratory abnormalities occurring during the treatment period will be summarized by 
treatment group. In the treatment period the summaries will be presented. The direction of 
change (high or low) in MA will be indicated in the tables.  
Additionally, for each subject with a MA for a parameter, all the subject’s values of that
parameter over the treatment period and the follow-up period, where applicable, will be listed.


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Change from Baseline in Selected Laboratory Parameters Over Time
All analyses of laboratory data will use observed data regardless of insulin up-titration that
occurs post-randomization. Visit windows are provided in Section 6.3 in order to link each
laboratory test to a scheduled visit. Change from baseline during the treatment period for 
selected laboratory parameters will be summarized by treatment group using descriptive 
statistics:
!
hematocrit
!
hemoglobin
!
red blood cell (RBC) count
!
platelet count
!
mean cell volume (MCV)
!
mean cell hemoglobin (MCH)
!
mean cell hemoglobin concentraction (MCHC)
!
white blood cell (WBC) count
!
total bilirubin
!
alanine aminotransferase (ALT)
!
alkaline phosphatase
!
aspartate aminotransferase (AST)
!
blood urea nitrogen (BUN)
!
estimated GFR using Japan guideline equation:
eGFR (mL/min/1.73m2) = 194 x (Scr)-1.094 x (Age)-0.287 x (0.739 if female) 
!
creatine kinase (creatine phosphokinase) (CK)
!
creatinine, serum (Scr)
!
creatinine clearance (change and percent change from baseline)
!
electrolytes - sodium, potassium, bicarbonate, chloride, magnesium and calcium
!
total protein, serum
!
uric acid


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!
albumin
!
inorganic phosphorus
!
uric acid
!
urinary albumin to creatinine ratio (UACR) 
!
urinary glucose to creatinine ratio
!
urinary glucose
!
urinary albumin
Additional Laboratory Data Summaries
For the treatment period, the following summaries will be provided.
Shift Tables for Electrolytes (Sodium, Potassium, Calcium, Phosphate, and Magnesium)
Categories
Shift tables of Safety Set subjects with electrolytes values in categories of low, normal, and 
high (based on normal range of central laboratory) will be summarized by treatment group 
using the highest (for sodium, calcium, phosphate, and magnesium) and lowest (for sodium, 
potassium, and calcium) values (regardless of post-randomization insulin up-titration)
obtained during the treatment period.
Shift Tables for Urine Albumin Excretion Categories
Shift tables of Safety Set subjects with urine albumin to creatinine ratios in 0 - < 30mg/g 
(normoalbuminuria), 30 - < 300mg/g (microalbuminuria), and # 300mg/g (macroalbuminuria) 
will be summarized by treatment group using the Week 24/52 values (the last observation 
regardless of post-randomization insulin up-titration prior to Week 24/52 will be used if no 
Week 24/52 measurement is available).
Self Monitored Blood Ketone
Self monitored blood ketone (measured before breakfast meal) will be recorded on the same 
days as SMBG (section 4.1.2.5). Valid measurements (taken before start of breakfast meal) 
were averaged over 3 days for each visit before analysis. Change from baseline over time will 
be summarized for self monitored blood ketone values.
4.2.4.4
Vital Signs
Vital signs data obtained after the start of study medication dosing up to and including 4 days
after the last dose will be considered as obtained during the treatment period.
Visit windows are provided in Section 6.3 in order to link each vital sign measurement to a
scheduled visit. Measured values and changes from baseline in vital sign measurements will 


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be summarized by treatment group at each scheduled visit using descriptive statistics (using
available data regardless of insulin up-titration for subjects in Safety Set).
4.2.4.5
Electrocardiograms
The normality/abnormality of the ECG tracing, as determined by the investigator, will be
summarized using frequency tables on number of subjects who have a normal/abnormal ECG
tracing at Week 24/52 of the treatment period, overall and by the ECG tracing at baseline. 
When the data at Week 24/52 is not available for a discontinued subject, then the last 
observation before discontinuation of that subject (regardless of insulin up-titration) will be
used for summary.
4.2.4.6
Pregnancy Test Results
By-subject listing of pregnancy test results will be provided using Safety Set.
4.2.5
Figures and Graphs
The graphs given below will be provided (by treatment group).
Longitudinal plots:
!
HbA1c adjusted mean change from baseline over time (including/excluding data after 
insulin up-titration)
!
GA adjusted mean change from baseline over time (including data after insulin up-
titration)
!
Mean daily 6-point SMBG glucose (including data after insulin up-titration)
!
Means daily 6-point SMBG post-prandial glucose (including data after insulin up-
titration)
!
Total daily insulin dose adjusted mean change from baseline over time (including data 
after insulin up-titration)
!
Body weight adjusted mean change from baseline over time (including/excluding data 
after insulin up-titration)
!
Mean 6-point SMBG glucose concentration by time points (before and after 
breakfeast, lunch, dinner)
Kaplan-Meier curve:
!
Time to first insulin up-titration due to inappropriate glycemic control
!
Time to discontinuation of study medication due to hypoglycemia


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!
Time to first event of DKA adjudicated as definite
Kaplan-Meier plots will be provided only when there are at least 5 events in one treatment 
group.
5.
INTERIM ANALYSES – NOT APPLICABLE