Clinical trial NCT02589639
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim
Start date: 2015-10-28; Completion date: 2018-01-05
Enrollment: 269 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomised, double-blind, placebo-controlled, parallel-group, efficacy and safety study of empagliflozin as add-on to insulin in Japanese patients with Type 2 Diabetes Mellitus with insufficient glycaemic control

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Empagliflozin intervention 2: Placebo intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: For blinding purposes

Protocol documents:
Prot_000.pdf: 
01-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03122592-02
BI Trial No.:
1245.107
BI Investigational 
Product:
Jardiance®, Empagliflozin 
Title:
A 52-week randomised, double-blind, placebo-controlled, parallel-
group, efficacy and safety study of empagliflozin once daily, as add-
on to insulin in Japanese patients with Type 2 Diabetes Mellitus with 
insufficient glycaemic control
Brief Title:
Empa add-on to Insulin (Japan)
Clinical Phase:
IV
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
 
Phone/Fax: 
Status:
Final Protocol
Version and Date:
Version:
Date:
2.0
13 September 2016
Page 1 of 72
Proprietary confidential information.
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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BI Trial No.: 1245.107
c03122592-02
Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim
Name of finished product:
Jardiance®
Name of active ingredient:
Empagliflozin 
Protocol date:
1 SEP 2015
Trial number:
1245.107
Revision date:
13 SEP 2016
Title of trial:
A 52-week randomised, double-blind, placebo-controlled, parallel-
group, efficacy and safety study of empagliflozin once daily, as add-
on to insulin in Japanese patients with Type 2 Diabetes Mellitus with 
insufficient glycaemic control
Coordinating 
Investigator:
 
Trial site:
Multi-centre trial in Japan
Clinical phase:
IV
Objective:
The objective of the study is to investigate the efficacy and safety of 
empagliflozin (10 mg and 25 mg, once daily) compared to placebo 
given for 16 weeks as add-on therapy to stable insulin treatment and 
the long-term safety and efficacy of empagliflozin (10 mg and 25 mg,
once daily) compared to placebo given for an additional 36 weeks as 
add-on therapy to adjustable-dose insulin treatment in Japanese 
patients with type 2 diabetes mellitus (T2DM) with insufficient 
glycaemic control
Methodology:
Randomised, double-blind, placebo-controlled, parallel group
No. of patients: 
total entered:
267 patients (399 patients enrolled)
each treatment:
3 treatment groups, 1:1:1 ratio of randomisation
Empagliflozin 10 mg : 89 patients
Empagliflozin 25 mg : 89 patients
Placebo : 89 patients
Diagnosis :
Type 2 Diabetes Mellitus


Boehringer Ingelheim
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Name of company:
Boehringer Ingelheim
Name of finished product:
Jardiance®
Name of active ingredient:
Empagliflozin 
Protocol date:
1 SEP 2015
Trial number:
1245.107
Revision date:
13 SEP 2016
Main criteria
for inclusion:
1. Diagnosis of type 2 diabetes mellitus prior to informed consent. 
This diagnosis should be confirmed by clinical judgment and 
negative results of Anti-GAD antibody and Anti-IA-2 antibody at 
Visit 1 (screening).
2. Male and female patients on diet and exercise regimen who are 
pre-treated with any insulin therapya) alone c) or in combination 
with 1 oral antidiabetic drug (OAD) b), c) for at least 12 weeks prior 
to Visit 1 (screening).
a) Any kind of insulin therapy (Basal-Bolus therapy, Bolus 
insulin therapy, Premix insulin therapy and Basal insulin 
therapy) approved in Japan is allowed. The choices of 
insulin product, dosage and usage have to follow
respective insulin product label in Japan at Visit 1
(screening). 
b) Sulfonylurea is permitted as a pre-treatment drug only if 
the dose is not more than a half of daily maximum 
approved dose. Any other OADs except 
thiazolidinedione and SGLT-2 inhibitors are allowed at 
any dose within approved dose.
c) If patients are pre-treated by insulin with 1 OAD at Visit 
1, the OAD should be stopped and washed-out for 10
weeks prior to Visit 4 (placebo run-in). For patients 
receiving insulin alone at Visit 1, no wash-out (of any 
drug) is necessary.
Insulin product and its usage must be unchanged at least from 12 
weeks prior to Visit 1 (screening). Total prescribed insulin dose 
must be 10 U/day, and it has to be within a defined area at least 
12 weeks prior to Visit 5 (randomization) in patients who are pre-
treated by insulin alone and from Visit 1 in patients who are pre-
treated by insulin in combination with 1 OAD.
The defined area is as follows,
In case of the insulin dose at 12 weeks prior to Visit 5 in patients 
who are pre-treated with insulin therapy alone (at Visit 1 in 
patients who are pre-treated with insulin in combination with 1


Boehringer Ingelheim
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BI Trial No.: 1245.107
c03122592-02
Trial Protocol
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01-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Name of company:
Boehringer Ingelheim
Name of finished product:
Jardiance®
Name of active ingredient:
Empagliflozin 
Protocol date:
1 SEP 2015
Trial number:
1245.107
Revision date:
13 SEP 2016
OAD) is 
• 20 U/day: Within +/- 10% change from the dose at Visit 5 is 
allowed.
• 10 U/day and <20 U/day: Within +/- 2 U change from the dose 
at Visit 5 is allowed. (insulin dose <10U is not allowed prior to 
and at Visit 5)
3. Fasting C-peptide: >0.5 ng/mL at Visit 4 in patients who are pre-
treated with insulin alone (at Visit 2 in patients who are pre-
treated with insulin in combination with 1 OAD)
4. Patients who are treated with insulin alone: 
HbA1c at Visit 1: 7.5% and <10.0%
5. Patients who are treated with insulin with 1 OAD: 
HbA1c at Visit 1:  7.0% and <9.5% 
HbA1c at Visit 4:  7.5% and <10.0% 
6. Age at informed consent: 20 years and <75
7. BMI (body mass index) at Visit 1 :  >22 and 40 kg/m2
8. Signed and dated written informed consent by date of Visit 1 in 
accordance with GCP and Japanese legislation
Test product:
Empagliflozin
dose:
10 mg and 25 mg
mode of 
administration:
Oral administration
Comparator products:
Placebo matching for empagliflozin
dose:
Not applicable
mode of 
administration:
Oral administration


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Name of company:
Boehringer Ingelheim
Name of finished product:
Jardiance®
Name of active ingredient:
Empagliflozin 
Protocol date:
1 SEP 2015
Trial number:
1245.107
Revision date:
13 SEP 2016
Duration of treatment:
Screening period: 1 week
Wash-out period (only for patients who are pre-treated by insulin with
1 OAD): 10 weeks
Placebo run-in period (open label): 2 weeks
Double-blind treatment period: 52 weeks
Follow-up period: 1 week
Endpoints
Primary endpoint is the change from baseline in HbA1c after 16
weeks of treatment.
The secondary endpoint is proportion of patients with drug-related 
adverse events during 52 weeks of treatment.
Safety criteria:
Adverse events, serious adverse events, adverse events of special 
interest, adverse events leading to discontinuation, hypoglycaemic 
adverse events, clinical laboratory assessments, vital signs
Statistical methods:
The primary analysis is an analysis of covariance (ANCOVA) 
comparing the change from baseline in HbA1c after 16 weeks of 
treatment. The statistical model includes treatment, renal function and 
type of insulin therapies as fixed effects, and baseline HbA1c as a 
covariate.
The hierarchical testing procedure will be used to evaluate superiority 
of empagliflozin 10 mg against placebo followed by superiority of 
empagliflozin 25mg against placebo, while maintaining the overall 
probability of type I error at 0.05 (two-sided).
Descriptive statistics will be used to analyse the safety endpoints.


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FLOW CHART
Trial period
Screening
Wash-out1
Placebo 
run-in
Double-blind treatment period 1
(fixed dose of insulin)
Double-blind treatment period 2
(adjustment of insulin dose permitted) Double-blind
Follow up
Visit
1
21
3
41
5
5.12
6
7
8
9
10
11
12
13
14
15
16
17
18
19/
EOT12
20/
F-up14
Study week
-3/-13
-12
-8
-2
1
2
4
8
12
16
20
24
28
32
36
40
44
48
52
EOT+1w
Study day
-21/-91
-84
-56
-14
1
8
15
29
57
85
113
141
169
197
225
253
281
309
337
365
EOT+7
Visit window (in 
days)
+/-7
-7
+/-7
-7
na
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+7
Informed Consent
X
Medical history / 
concomitant 
diagnoses
X
Demographics
X
In-/Exclusion 
criteria
X
X
X3
Physical 
Examination
X
X
X
(X)14
Vital Signs4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)14
Height
X
Diet and exercise 
counselling18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Food log, 
completed for 3 
days18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead-ECG4,5
X
X
X
X
X
X
X
Pregnancy testing6
X
X
X
X
X
X
X
Safety Labs4, 7
X10,11
X
X
X16
X16
X
X16
X
X16
X16
X
X16
X16
X
X16
X16
X
(X)14
FFA and Ketone 
bodies
X
X
X
X
X
X
X
X
X
X
Bone markers
X
X
X


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Trial period
Screening
Wash-out1
Placebo 
run-in
Double-blind treatment period 1
(fixed dose of insulin)
Double-blind treatment period 2
(adjustment of insulin dose permitted) Double-blind
Follow up
Visit
1
21
3
41
5
5.12
6
7
8
9
10
11
12
13
14
15
16
17
18
19/
EOT12
20/
F-up14
Study week
-3/-13
-12
-8
-2
1
2
4
8
12
16
20
24
28
32
36
40
44
48
52
EOT+1w
Study day
-21/-91
-84
-56
-14
1
8
15
29
57
85
113
141
169
197
225
253
281
309
337
365
EOT+7
Visit window (in 
days)
+/-7
-7
+/-7
-7
na
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+7
Antibodies (Anti-
GAD, Anti-IA-2)
X11
Fasting C-peptide17
X17
X17
HbA1c
X11
X13
X
X
X
X
X
X
SMBG
measurement and 
log8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IRT transaction
X3
X3
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense placebo 
run-in medication9
X
Medication 
compliance check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomisation (via 
IRT)
X3
Dispense double-
blind medication9
X
X
X
X
X
X
X
X
X
X
X
X
X


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1.
Only patients who are pretreated by insulin with 1 OAD proceed to the wash-out period and are requested to refrain from taking their OAD during the wash-out period.
Patients who are pretreated by insulin therapy alone skip the washout period and proceed to the placebo run-in period.  In either case, the next visit (i.e., Visit 2 or Visit 4) 
should be made after receiving the result of the laboratory tests performed at Visit 1.
2.
The investigator or designated site staff makes a call to patients to confirm patient’s safety through checking patient’s food log, SMBG results, adverse 
events and concomitant therapies.
3.
Inclusion and exclusion criteria should be checked before making the IRT call/notification.
4.
Vital signs and ECG must be measured prior to blood sampling.
5.
In addition to the visits indicated, ECG should be recorded in case of respective cardiac symptoms (indicating rhythm disorders or cardiac ischaemia)
6.
For female patients (local urine pregnancy test in women of child bearing potential) 
7.
Fasting blood samples for central lab testing except for urine dipstick, which is to be done locally; upon positive result at site for leukocyte esterase (for 
WBC) or nitrites a midstream urine sample for urine culture (central lab analysis) should be taken.
8.
Self-Monitoring Blood Glucose (SMBG) device to be provided at Visit 2 to patients who need wash-out of an OAD or at Visit 4 to patients who do not need 
washout. Patients should be instructed to monitor fasting blood glucose at least once daily before breakfast (if possible, it is recommended to monitor 
fasting blood glucose in preprandial state and before bedtime) and at any time the patient is symptomatic related to hypoglicaemia or hyperglicaemia 
through the entire study period (i.e., after providing the SMBG device until the end of follow-up). In addition, in 3 consecutive days in the week before each 
scheduled visit, patients will be requested to monitor fasting blood glucose at preprandial state (i.e., before breakfast, lunch and dinner), before bedtime and 
at any time when the patient is symptomatic. Patients are requested to maintain a diary with daily recordings of glucose values measured by SMBG and of 
insulin dose through the entire study period.
9.
At all the visits which are marked on the flow chart, the respective kit number has to be allocated to the patient via IRT. 
10.
Only includes liver transaminases (i.e. AST and ALT), ALP, serum creatinine, TSH and urinalysis. 
11.
No need to be collected in fasted state.
12.
In case of early discontinuation from treatment, the end of treatment (EOT) visit has to be performed within 7 days of the last dose of the study drugs. And 
the follow up (F-up) visit has to be performed after 7 days of the EOT (with +7 days allowance).
13.
Patients who are pretreated with insulin alone skip the HbA1c measurement at Visit 4.
14.
For patients who completed the trial without any persisting adverse event at EOT, a follow-up visit can be performed as a phone visit (only information on 
SMBG log, adverse events, and concomitant therapies are to be obtained). For patients who completed the trial with persisting adverse event(s) at EOT and 
patients who early discontinued the 52 weeks treatment period, an EOT and a follow-up visit (at the follow up-visit, physical examination, vital signs, and 
safety lab and 
 should be performed additionally) should be performed at clinic visits.
15.
 
16.
Only blood sampling for haematology and urinalysis will be performed.
17.
C-peptide will be measured at Visit 2 in patients who need wash-out of an OAD or Visit 4 in patients who do not need wash-out.
18.
Diligent diet and exercise counselling by a diet specialist or trained staff member. Counselling is based on the diet and exercise recommendations of the 
Japanese Diabetes Society and should include a food log (recording of food intake for 3 consecutive days in the week before the actual visit). 


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................14
MEDICAL BACKGROUND.............................................................................14
1.1
DRUG PROFILE................................................................................................15
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....17
RATIONALE FOR PERFORMING THE TRIAL.........................................17
2.1
TRIAL OBJECTIVES........................................................................................17
2.2
BENEFIT - RISK ASSESSMENT.....................................................................17
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................20
OVERALL TRIAL DESIGN AND PLAN .......................................................20
3.1
3.1.1
Administrative structure of the trial .................................................................21
Data Monitoring Committee.................................................................................22
3.1.1.1
Clinical Event Committee for Diabetic ketoacidosis (DKA)................................22
3.1.1.2
Hepatic external adjudication................................................................................22
3.1.1.3
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................23
SELECTION OF TRIAL POPULATION .......................................................23
3.3
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................26
3.3.4
Removal of patients from therapy or assessments...........................................27
Removal of individual patients .............................................................................27
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................29
3.3.4.2
4.
TREATMENTS...................................................................................................30
TREATMENTS TO BE ADMINISTERED.....................................................30
4.1
4.1.1
Identity of BI investigational products and comparator products.................30
4.1.2
Method of assigning patients to treatment groups...........................................31
4.1.3
Selection of doses in the trial..............................................................................31
4.1.4
Drug assignment and administration of doses for each patient......................31
4.1.5
Blinding and procedures for unblinding...........................................................33
Blinding.................................................................................................................33
4.1.5.1
Unblinding and breaking the code ........................................................................33
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................33


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4.1.7
Storage conditions...............................................................................................34
4.1.8
Drug accountability.............................................................................................34
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional treatments........35
4.2.2
Restrictions ..........................................................................................................36
Restrictions regarding concomitant treatment ......................................................36
4.2.2.1
Restrictions on diet and life style..........................................................................37
4.2.2.2
Restrictions regarding women of childbearing potential ......................................38
4.2.2.3
TREATMENT COMPLIANCE........................................................................38
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................39
TRIAL ENDPOINTS..........................................................................................39
5.1
5.1.1
Primary Endpoint ...............................................................................................39
5.1.2
Secondary Endpoint............................................................................................39
39
ASSESSMENT OF EFFICACY........................................................................40
5.2
ASSESSMENT OF SAFETY.............................................................................41
5.3
5.3.1
Physical examination ..........................................................................................41
5.3.2
Vital Signs............................................................................................................42
5.3.3
Safety laboratory parameters ............................................................................42
5.3.4
Electrocardiogram ..............................................................................................46
5.3.5
Other safety parameters.....................................................................................46
5.3.6
Assessment of adverse events.............................................................................47
Definitions of AEs ................................................................................................47
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................50
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................52
ASSESSMENT OF EXPLORATORY BIOMARKER...................................52
5.5
OTHER ASSESSMENTS...................................................................................52
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................52
5.7
6.
INVESTIGATIONAL PLAN.............................................................................53
VISIT SCHEDULE.............................................................................................53
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................53
6.2
6.2.1
Screening and run-in periods.............................................................................53
6.2.2
Treatment period ................................................................................................55
6.2.3
Follow-up period and trial completion..............................................................56
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................57
STATISTICAL DESIGN - MODEL.................................................................57
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................57
7.2
PLANNED ANALYSES.....................................................................................58
7.3
7.3.1
Primary endpoint analyses.................................................................................58
7.3.2
Secondary endpoint analyses .............................................................................59
59


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7.3.4
Safety analyses.....................................................................................................59
7.3.5
Pharmacokinetic analyses ..................................................................................60
INTERIM ANALYSES ......................................................................................60
7.4
HANDLING OF MISSING DATA ...................................................................60
7.5
RANDOMISATION ...........................................................................................61
7.6
DETERMINATION OF SAMPLE SIZE .........................................................61
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........63
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................63
DATA QUALITY ASSURANCE ......................................................................64
8.2
RECORDS...........................................................................................................64
8.3
8.3.1
Source documents ...............................................................................................64
8.3.2
Direct access to source data and documents.....................................................64
8.3.3
Storage period of records ...................................................................................65
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS65
8.4
8.4.1
Listedness.............................................................................................................65
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................65
STATEMENT OF CONFIDENTIALITY........................................................65
8.5
END OF TRIAL..................................................................................................66
8.6
PROTOCOL VIOLATIONS .............................................................................66
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY..............................................................................66
9.
REFERENCES....................................................................................................67
PUBLISHED REFERENCES............................................................................67
9.1
UNPUBLISHED REFERENCES......................................................................67
9.2
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................70


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ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BI
Boehringer Ingelheim
BMI
body mass index
CEC
clinical event committee
CK
creatinine kinase
CML
local clinical monitor 
CRA
clinical research associate
CRO
contract research organization
CTP
clinical trial protocol
DILI
drug-induced liver injury
DKA
diabetic ketoacidosis
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGRF
estimated glomerula filtration rate
EOT
end of treatment
EudraCT
European Clinical Trials Database
FAS
full analysis set
FFA
free fatty acid
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
GTI
genital tract infection
Hb
haemoglobin
HbA1c
glycosylated haemoglobin A1c
IB
investigator’s brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
interactive response technology
ISF
investigator site file
LDH
lactate dehydrogenase
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
mixed model repeated measures
NBI
Nippon Boehringer Ingelheim
OAD
oral antidiabetic drug


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OC
observed case
PPS
per protocol set
PT
preferred term
RBC
red blood cell
RDC
remote data capture
REP
residual effect period
SAE
serious adverse event
SGLT-2
sodium-glucose co-transporter 2
SMBG
self-monitoring blood glucose
SOC
system organ class
SOP
standard operation procedure
SUSAR
suspected serious unexpected adverse reaction
TCM
trial clinical monitor
TS
treated set
TSAP
trial statistical analysis plan
TSH
thyroid stimulation hormone
T2DM
type 2 diabetes mellitus
ULN
upper limit of normal
UTI
urinary tract infection
WBC
white blood cell


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1.
INTRODUCTION
Empagliflozin is an orally available inhibitor of the sodium-glucose co-transporter 2 (SGLT-
2), which promotes enhanced glucose excretion in the urine, thereby lowering blood glucose 
concentrations in patients with type 2 diabetes mellitus (T2DM).
MEDICAL BACKGROUND
1.1
Type 2 diabetes mellitus accounts for 90 to 95% of all cases of diabetes and is an increasingly 
prevalent disease with an estimated 387 million affected people worldwide. Its prevalence is 
expected to increase to approximately 592 million people during the next 20 years. 
Complications induced by hyperglycaemia are a common and serious global health problem, 
which have evolved from adult-onset loss of vision, renal failure, and amputation in the 
industrialised world. Diabetes is also associated with macrovascular complications with a 2-
to 4-fold increase in cardiovascular disease risk. The high frequency of complications leads to 
a significant reduction of life expectancy.
Commonly available oral antidiabetic drugs are efficacious for a time, but still fail to achieve 
an optimal blood glucose control in many patients. In Japan, approximately 9.5 million 
people are strongly suspected to be affected by T2DM and approximately 11.0 million people 
are undeniable to be affected by T2DM; total 20.5 million people are suffering from either 
T2DM or pre-diabetic, which is approximately 1 out of 6 of Japanese population (Ministry of 
Health, Labour and Welfare, National Health and Nutrition Examination Survey, 2012)
The Treatment Guide for Diabetes 2014-2015  in Japan recommends to achieve the 
glycaemic goal of glycosylated haemoglobin A1c (HbA1c) to <7.0% in preventing the onset of 
microangiopathy and inhibiting its progress, while it states that suitable current treatment 
aims should be established according to age and complications on a case-by-case basis [R14-
4302]. If good control cannot be achieved with one type of oral antidiabetic agent, 
combination therapy with another drug having a different mode of action should be 
recommended.
SGLT-2 is a member of a larger group of sodium substrate co-transporters, the sodium-
glucose co-transport 5 (SLC5) gene family. [R05-0939]  Under normoglycemia, glucose is 
almost completely reabsorbed by SGLTs in the kidney, whereas the reuptake capacity of the 
kidney is saturated at plasma glucose concentrations higher than approximately 10-11 
mmol/L, resulting in increasing glycosuria typically seen in patients with diabetes mellitus. 
The capacity to reabsorb glucose can be decreased by inhibition of SGLT-2. In humans, 
empagliflozin very highly selectively blockades glucose transport via SGLT-2 (IC50 1.3 
nmol/l), with a 5000-fold selectivity over SGLT-1 (IC50 6278 nM).
In 2014, the Japan Diabetes Society released a recommendation for a proper use of SGLT2 
inhibitors. In the recommendation, it is told that when using SGLT2 inhibitors in combination 
with insulin or sulfonylureas, occurrence of hypoglycaemia should be carefully watched and
the administration of SGLT2 inhibitor should be done carefully for elderly patients; and also


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it is mentioned that the occurrence of dehydration should be paid attention. For further details 
see the recommendation [R15-2908].
DRUG PROFILE
1.2
Empagliflozin received its first worldwide marketing approval in Australia on 17 April 2014. 
As of May 2015, marketing approval has been received in many countries including 
European countries and US. In Japan, empagliflozin was approved for marketing on 26 Dec 
2014.
The efficacy of empagliflozin is expected to be similar to the current oral antidiabetic drugs 
(OADs) and empagliflozin can be administrated in combination with other OADs and may 
show additional efficacy in terms of glucose control when used in combination with insulin 
or glucagon-like peptide-1 (GLP-1) receptor agonist in diabetic patients.
Non-clinical assessment of safety
A comprehensive package of safety pharmacology, genetic toxicology, reproductive 
toxicology and general toxicology studies were conducted in mice, rats, rabbits and dogs to 
support the chronic administration of the two doses of empagliflozin (10 mg/day and 25 
mg/day) to humans. The compound is well tolerated in animals at clinically relevant plasma 
exposures, while adverse effects were observed at higher exposures. 
For further preclinical details see the current version of the empagliflozin Investigator’s 
Brochure (IB) [c01838761].
Clinical pharmacokinetics
Empagliflozin predominantly showed linear pharmacokinetics following single oral doses 
and at steady-state after multiple oral doses in Caucasian and Japanese subjects. 
Empagliflozin was rapidly absorbed reaching peak levels at approximately 1.5 hours in 
Caucasian and 1 to 2.5 hours in Japanese, and showed a biphasic decline with the terminal 
elimination half-life ranging from 10 to 19 hours in Caucasian and from 8 to 12 hours in 
Japanese. 
In Caucasian subjects, following oral administration of [14C]-empagliflozin, approximately 
41.2% and 54.4% of drug-related radioactivity was excreted in faeces and urine, respectively. 
None of the detected metabolites were major. Empagliflozin tablets can be administered with 
or without food.
Empagliflozin exposure increased with hepatic and/or renal impairment; however, no dose 
adjustment is recommended for patients with renal and hepatic impairment as the observed 
changes in empagliflozin exposure in those patients were not clinically meaningful.
No clinically relevant pharmacokinetic interactions were observed
with metformin, glimepiride, pioglitazone, sitagliptin, warfarin, linagliptin, verapamil,
ramipril, simvastatin, digoxin, hydrochlorothiazide, torasemide, gemfibrozil, rifampicin,


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probenecid and oral contraceptives.
Clinical efficacy and safety
The empagliflozin clinical program is expected to include a total of approximately 21,000 
patients by the end of 2015. 
Empagliflozin demonstrated good efficacy with approximately 70 to 90 g/day of urinary 
glucose excretion (UGE), without inducing any increased risk in overall frequency of 
hypoglycaemia. The 12-week global Phase II studies demonstrated an HbA1c reduction of up 
to 0.72 % (placebo subtracted), a fasting plasma glucose (FPG) reduction of up to 33 mg/dL 
and a weight loss of approximately 1.5 kg, in both the monotherapy setting and as an add-on 
to metformin (≥ 1500 mg/day).
In clinical studies, empagliflozin was well tolerated in both healthy subjects and patients with 
T2DM up to maximal treatment duration of 104 weeks in completed studies. Treatment with 
empagliflozin resulted in similar percentage of adverse events (AEs) to that of placebo and 
active comparators. Treatment with empagliflozin showed a higher frequency of genital tract 
infections and symptoms of increased micturition frequency and/or volume, yet was not 
associated with a higher incidence of urinary tract infections or hypoglycaemia. 
In Japan, phase II/III trials were conducted and approximately 2000 patients were 
participated in those trials. Treatment with once daily empagliflozin 10 mg and 25 mg 
showed continuous blood glucose control as shown in improvement/reduction in both HbA1c
and FPG. In addition, reductions in body weight and blood pressure strongly suggest that 
empagliflozin can offer additional benefits.
Based on the Japanese guideline of “Clinical Evaluation Guidelines for Oral 
Antihyperglycemic Drugs [R10-4692]” which was released in July 2010, an add-on therapy 
to an oral antidiabetic drug (sulfonylurea, biguanide, thiazolidinedione, alpha glucosidase 
inhibitor, DPP-IV inhibitor, or glinide) was carried out in Japanese patients (study:1245.52
[U13-1730-01]) and the result showed that empagliflozin 10 mg and 25 mg were well 
tolerated, safe, and efficacious when used in combination with one other oral antidiabetic 
drug.
Although no Japanese were participated in, to evaluate the use of empagliflozin as add-on to 
insulin regimen two clinical studies, Study 1245.33 [U12-3817-01] and Study 1245.49 [U13-
2122-01] were carried out. In the results of these studies, empagliflozin 10 mg and 25 mg
were well tolerated, with overall AE rates being comparable with placebo.
In summary, given the safety profile in the preclinical studies, and the safety, tolerability, and 
efficacy seen in the adequately designed clinical studies to date, the available clinical and 
non-clinical data support safe and efficacious use of empagliflozin in humans and its further 
development in adults and adolescents with type 1 and type 2 diabetes mellitus.
More information about the known and expected benefits, risks, and anticipated AEs can be 
found in the current version of IB [c01838761].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Empagliflozin was approved as an antihyperglycemic drug for indication of Type 2 diabetes
on 26 Dec 2014 in Japan. There is no limitation regarding combination with empagliflozin 
and any existing antihyperglycemic drug. However, no clinical data has been obtained in 
Japanese patients that demonstrate safety and efficacy results of empagliflozin as add-on to 
insulin therapy.
To evaluate the use of empagliflozin once daily as add-on to insulin regimen two clinical 
studies, Study 1245.33 [U12-3817-01] and Study 1245.49 [U13-2122-01] were carried out 
but no Japanese patients were enrolled in the studies. The use experience of empagliflozin
concomitantly with insulin regimen is not enough in Japanese patients with T2DM. 
We carry out this randomised, double-blind, placebo-controlled, and parallel-group study to 
investigate efficacy and safety study of empagliflozin as add-on to insulin, to further establish 
the adverse event profile of empagliflozin, and to assess the long term safety and efficacy
when used with insulin in Japanese patients with T2DM with insufficient glycaemic control.
This trial will be implemented on the risk management plan of empagliflozin submitted to the 
Japanese authorities.
TRIAL OBJECTIVES
2.2
The objective of the study is to investigate the efficacy and safety of empagliflozin (10 mg 
and 25 mg once daily) compared to placebo given for 16 weeks as add-on therapy to stable 
insulin treatment and the long-term safety and efficacy of empagliflozin (10 mg and 25 mg 
once daily) compared to placebo given for an additional 36 weeks as add-on therapy to 
adjustable-dose insulin treatment in Japanese patients with T2DM with insufficient glycaemic 
control.
BENEFIT - RISK ASSESSMENT
2.3
The currently-known safety profile of empagliflozin is outlined in the latest IB [c01838761].
According to the drug assignment planned in this trial, 2/3 (66.6%) of the patients with 
T2DM participating in this trial may derive a direct benefit from being treated with and 
additional active compound and not a placebo. The patients will receive an investigational 
medication empagliflozin that has already demonstrated favorable HbA1c and glucose 
changes at the tested doses. One third (33.3%) of patients will receive placebo and these 
patients thus have a higher probability of treatment failure, i.e., of increase in FPG and 
HbA1c. However, appropriate inclusion/exclusion criteria of HbA1c and FPG value and 


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criteria for rescue therapy and patient discontinuation will ensure an adequate treatment in 
case of any clinical concern.
Because of the mechanism of action of empagliflozin, the risk of hypoglycaemic episodes is 
considered to be low. However, with empagliflozin in combination with insulin, the risk of 
hypoglycemia may be increased compared to the treatment with insulin alone. Symptoms 
attributed to hypoglycemia will be closely monitored in the trial. 
In addition, although, diabetic ketoacidosis (DKA) has not been observed in clinical trials of 
empagliflozin in Type 2 DM patients so far in Japan, special attention will be paid to prevent 
DKA according to the recommendation from “Committee on the proper use of SGLT2 
inhibitors” of the Japanese Diabetes Society that requests physicians to pay attention to DKA
when using an SGLT2 inhibitor [R15-2908]. 
Rare cases of DKA have been reported in patients treated with SGLT2 inhibitors, including 
empagliflozin. In a number of reported cases, the presentation of the condition was atypical 
with only moderately increased blood glucose values, below 14 mmol/L (250 mg/dL).
The risk of DKA must be considered in the event of non-specific symptoms such as nausea, 
vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual 
fatigue or sleepiness. In addition it needs to be taken into account that, due to the insulin 
independent mode of action, there is a possibility that ketoacidosis in patients treated with 
SGLT2 inhibitors is not accompanied by typical hyperglycemia as usually expected for DKA.
Insulin deficiency might lead to ketoacidosis which could be life-threatening if not
recognized and appropriately treated. All patients in this trial will be made aware of this risk 
and be instructed not to reduce their insulin dose below Investigator recommendations.
Furthermore, patients will be reminded of insulin dose adjustment during “sick days” and of
the importance of keeping themselves hydrated. Investigators should also differentiate 
deteriorating ketosis/DKA from any mild to moderate increase of ketones expected from the 
mechanism of action of empagliflozin, especially in the fasted state (e.g., in the morning).
The overall frequency of volume depletion defined in the IB was similar between
empagliflozin and placebo. However, the frequency of volume depletion events was 
increased in patients at the age of 75 years or over treated with empagliflozin compared to 
placebo. Based on the mode of action of SGLT-2 inhibitors, osmotic diuresis may lead to a 
modest decrease in blood pressure and dehydration. Therefore, careful monitoring of volume 
status and electrolytes (e.g. physical examination, blood pressure measurements, and 
laboratory tests including haematocrit) is recommended. Also, patients will be requested to 
drink plenty of fluids as a precautionary measure. Temporary interruption of treatment with 
empagliflozin should be considered until the fluid loss is corrected.
Patients will be carefully selected for the trial in line with the eligibility criteria, to ensure, in 
investigator’s judgement, that patients have a good understanding of their disease and how to 


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manage it. They should also be selected in terms of their ability to be compliant with the 
demands of the trial.
Beneficial effects like body weight reduction and a moderate blood pressure lowering are 
expected based on Phase III studies of empagliflozin and publications of other SGLT-2 
inhibitors.
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into 
consideration when empagliflozin is administered. Other risks to the patients are the risks 
inherent to any treatment such as unexpected adverse clinical or laboratory events.
In the embryo-foetal and fertility studies in rats and rabbits, no effects on early embryonic 
development, mating, male and female fertility, and bearing live young were observed up to a 
dose of 300 mg/kg. Therefore, women who are of child-bearing potential may participate in 
this study provided that they are using adequate contraceptive methods.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´ 
safety. See Section 5.3.6.1 for details.
All patients taking part in the trial may derive general medical benefit from careful and close 
monitoring by medical personnel during the study. Safety will be ensured by monitoring the 
patients for AEs both clinically and by laboratory testing and by the Self-Monitoring Blood 
Glucose (SMBG). Patients who are not adequately controlled, as evidenced by a confirmed 
high glucose value (refer to Section 4.2.1), will receive rescue therapy to ensure their safety 
or will be excluded from further study participation. Special measurements are performed 
like follow-up on genito-urinary tract infections (urine culture) in order to evaluate if possible 
side effects observed for other SGLT-2 inhibitors are also present for empagliflozin.
Given the good safety profile in the toxicity studies of empagliflozin and the good tolerability 
seen in the human studies so far, the careful monitoring to be conducted during the study 
visits, and the blood glucose monitoring to be performed by the patients at home during the 
study, the sponsor considers the risks for the participating patients will be minimised and 
justified when compared with the potential benefits from this trial.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a randomised, double-blind, placebo-controlled, parallel-group study designed to
compare 2 doses of empagliflozin (10 mg and 25 mg once daily) with placebo as add-on 
therapy to insulin in Japanese patients with T2DM.
In total, approximately 400 patients with T2DM are planned to be screened to ensure that 267 
patients are randomised in this trial (89 in each treatment group). The randomised treatment 
will be administered in a double-blinded fashion.
Patients are included in the study once they have signed the informed consent. After 
screening, patients who are pre-treated with insulin in combination with 1 OAD undergo a 
10-week wash-out period. Then patients proceed to a 2-week open-label placebo run-in
period. Patients who are pre-treated with insulin alone skip the wash-out period and proceed 
to an open-label placebo run-in period. Patients who successfully complete the periods and 
who still meet the inclusion but not meet the exclusion criteria will be randomised to the 52-
week double-blind treatment period of the study in which they will receive either 1 of the 2
doses of empagliflozin and/or placebo in addition to insulin.
The double-blind treatment period is divided into 2 periods:

Double-blind treatment period 1 (from Visit 5 to Visit10) - insulin dose should not
be adjusted for reasons other than patient’s safety reasons or unless the patient met 
the criteria for rescue therapy.
Total daily insulin dose should remain within +/-10% of the prescribed insulin 
dose at Visit 5 in patients whose prescribed dose is 20 U/day at Visit 5. Patients 
whose prescribed dose is 10 U/day and <20 U/day at Visit 5, total daily insulin 
dose should remain within +/- 2 U/day from the dose at Visit 5. (For rescue 
therapy, see Section 4.2.1.)

Double-blind treatment period 2 (after Visit 10 to end of treatment [EOT]) - insulin 
dose can be adjusted at the investigators’ discretion.


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R=randomisation
Figure 3.1: 1 Trial design
The first part of the double-blind treatment period (Double-blind treatment period 1) is 
intended to show a superiority of empagliflozin over placebo when added on to insulin 
therapy. The change from baseline in HbA1c after 16 weeks of treatment will be analysed as 
the primary endpoint. It is also intended to investigate the safety of empagliflozin in this 
period.
The second part of the double-blind treatment period (Double-blind treatment period 2) is 
intended to investigate the long-term safety and efficacy of empagliflozin when added on to 
insulin therapy.
The patient participation is completed when they have undergone last planned visit.
The time period, for which adverse events will still be considered on-treatment, is 7 days
following the last intake of trial medication. 
The end of the trial is defined as “last patient out”, i.e., the last visit completed by the last 
patient.
The overall trial design is displayed in Figure 3.1: 1
3.1.1
Administrative structure of the trial
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to 
- manage the trial in accordance with applicable regulations and internal SOPs,
- direct the clinical trial team in the preparation, conduct, and reporting of the trial,
- order the materials as needed for the trial, 
- ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and investigators.


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Data management and statistical evaluation will be done by Boehringer Ingelheim (BI)
according to the BI standard operation procedure (SOP)s.
A list of responsible persons and relevant information as protocol reference can be found in 
the Investigator Site File (ISF).
A coordinating investigator will be nominated and will be responsible to coordinate 
Investigators at different centres participating in this multicentre trial. Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating 
(principal) investigators and other important participants, including their curricula vitae, will 
be filed in the ISF.
Data Monitoring Committee
3.1.1.1
A data monitoring committee (DMC), independent from the sponsor, will be established to 
assess the progress of the trial, including unblinded safety data and the critical efficacy 
endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop 
one or more of the trials covered by the DMC. Measures will be in place to ensure blinding of 
the sponsor and all other trial participants. The tasks and responsibilities of the DMC will be 
specified in a charter. The DMC will maintain written records of all its meetings.
Clinical Event Committee for Diabetic ketoacidosis (DKA)
3.1.1.2
An independent external committee (CEC) will be established to adjudicate centrally and in a
blinded fashion events suspected of DKA (for further details see Section 5.3.3). The CEC 
will evaluate whether pre-specified criteria for adjudication endpoints are met.
For any events that qualify for adjudication, study sites will be asked to provide clinical
documentation such as laboratory values, discharge summaries etc. to support the external
event adjudication.
The tasks and responsibilities of the CEC will be specified in a charter. The CEC will
maintain the adjudication results in writing.
Hepatic external adjudication
3.1.1.3
Certain hepatic events will be adjudicated by external independent experts for severity and
causal relationship with the trial medication in a blinded fashion. The events which will be 
reviewed are defined in a charter for hepatic events. Events may either be defined by 
abnormal laboratory values and/or relevant adverse events or both. For example, assessments 
will be made for hepatic injury events, including liver enzyme elevations.
For qualifying events, relevant source documents generated from any medical evaluations of
these events will be requested including laboratory values, histological analysis, results of


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ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical reports from other
physicians. All evaluations will be performed in a blinded fashion. The assessments will be
analysed based on empagliflozin data combined from multiple trials (i.e. on project level).
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP
The aim of this study is to evaluate the efficacy and safety of empagliflozin 10 mg and 25 mg 
in Japanese patients with T2DM whose glycaemic control is insufficient despite diet/exercise 
and treatment with insulin.
The design of this study is decided according to the draft version of the revised Japanese 
guideline ‘Clinical Evaluation Guidelines for Antihyperglycemic Drugs’ [R15-2907] in 
which 1-year long-term study is required for any antihyperglycemic investigational product 
when used  as added-on therapy to existing antihyperglycemic drugs which are expected to be 
co-administered in clinical practice.
Patients who are pre-treated with insulin in combination with 1 OAD will undergo a 10-week 
wash-out period before a 2-week open-label placebo run-in period. Patients who are pre-
treated with insulin alone will skip the wash-out period and proceed to the placebo run-in
period.
The 10-week wash-out period will minimise the effect of pre-treated OAD on glycaemic
control in patients treated with insulin in combination with the OAD prior to randomisation. 
The 2-week open-label placebo run-in period is set to confirm whether the patients fulfil the 
entry criteria for the double-blind treatment period and to check medical compliance by 
mimicking the dosing in the double-blind treatment period. 
A double-blind and double-dummy design is adopted in order to minimize bias to evaluate 
the efficacy and safety of two doses (i.e. 10 mg and 25 mg) of empagliflozin and in 
comparison with placebo, and the 52 weeks of treatment duration is planned in order to 
investigate the long term efficacy and safety of empagliflozin.
The 1-week follow-up period is considered to be sufficient, as previous studies with 
empagliflozin have shown that the pharmacodynamic effect of empagliflozin only extends to 
about 3 days after the last dose and half-life of empagliflozin in Japanese T2DM after 4 
weeks of treatment was 12 to18 hours.
SELECTION OF TRIAL POPULATION
3.3
It is planned that about 399 patients will be screened for the trial. Approximately 50 trial 
centres will participate in the trial to ensure that 267 patients are randomised to trial 
treatment.


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Centres which fail to enrol at least one patient in the first 10 weeks of the trial may be 
excluded from further participation. If enrolment of the study is delayed, additional centres 
may be recruited.
Permission to enter more than 25 patients per site must be obtained from the Trial Clinical 
Monitor (TCM) at Nippon Boehringer Ingelheim (NBI). This will only be allowed after a 
careful review of the enrolment status.
Enrolment of patients for this trial is competitive, i.e., enrolment for the trial will stop at all 
centres when it is anticipated that a sufficient number of patients will be randomised to trial 
treatment. Investigators will be notified when the appropriate numbers of patients have been 
enrolled and enrolment is complete, and will not be allowed to recruit additional patients for 
this study. Patients who have signed written informed consent before this notification may 
not participate in the double-blind period after 267 patients are randomised, and patients who 
are in the wash-out or run-in period should be discontinued quickly when the sponsor notify 
to stop the randomisation.
The check for patient eligibility will be based upon a complete medical history including a 
physical examination and clinical laboratory tests. Judgement of the clinical relevance of a 
concomitant disease is at the discretion of the investigator. Conditions under therapy are 
always clinically relevant.
A log of all patients enrolled into the trial (i.e., who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
Re-testing
Re-testing for eligibility criteria is to be performed only for the laboratory result which is 
obviously received beyond stability at the central laboratory or thought to be a spurious result 
based on the previously available laboratory results only for the corresponding laboratory 
test. The re-test should be carried out as soon as possible so that the laboratory test results 
will be received within the next planned visit windows in order to avoid visit violations.
3.3.1
Main diagnosis for trial entry
The study will be performed in Japanese patients with T2DM whose glycaemic control is 
insufficient despite diet/exercise and treatment with insulin alone or in combination with 1 
OAD.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.


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3.3.2
Inclusion criteria
1.
Diagnosis of type 2 diabetes mellitus prior to informed consent. This diagnosis should be 
confirmed by clinical judgment and negative results of Anti-GAD antibody and Anti-IA-
2 antibody at Visit 1 (screening).
2.
Male and female patients on diet and exercise regimen who are pre-treated with any 
insulin therapya) alone c) or in combination with 1 oral antidiabetic drug (OAD) b), c) for at 
least 12 weeks prior to Visit 1 (screening).
a)
Any kind of insulin therapy (Basal-Bolus therapy, Bolus insulin therapy, Premix 
insulin therapy and Basal insulin therapy) approved in Japan is allowed. The 
choices of insulin product, dosage and usage have to follow respective insulin 
product label in Japan at Visit 1 (screening).
b)
Sulfonylurea is permitted as a pre-treatment drug only if the dose is not more than 
a half of daily maximum approved dose. Any other OADs except 
thiazolidinedione and SGLT-2 inhibitors are allowed at any dose within approved 
dose.
c)
If patients are pre-treated by insulin with 1 OAD at Visit 1, the OAD should be 
stopped and washed-out for 10 weeks prior to Visit 4 (placebo run-in). For 
patients receiving insulin alone at Visit 1, no wash-out (of any drug) is necessary.
Insulin product and its usage must be unchanged at least from 12 weeks prior to Visit 1 
(screening). Total prescribed dose must be 10 U/day, and it has to be within a defined 
area at least 12 weeks prior to Visit 5 (randomization) in patients who are pre-treated by 
insulin alone and from Visit 1 in patients who are pre-treated by insulin in combination 
with 1 OAD.
The defined area is as follows, 
In case of the insulin dose at 12 weeks prior to Visit 5 in patients who are pre-treated 
with insulin therapy alone (at Visit 1 in patients who are pre-treated with insulin in 
combination with 1 OAD) is
•
20 U/day: Within +/- 10% change from the dose at Visit 5 is allowed.
•
10 U/day and <20 U/day: Within +/- 2 U change from the dose at Visit 5 is 
allowed. (insulin dose <10 U is not allowed prior to and at Visit 5)
3.
Fasting C-peptide: >0.5 ng/mL at Visit 4 in patients who are pre-treated with insulin 
alone (at Visit 2 in patients who are pre-treated with insulin in combination with 1 OAD)
4.
Patients who are treated with insulin alone: 
•
HbA1c at Visit 1: 7.5% and < 10.0% (HbA1c at Visit 4 is to be skipped)
5.
Patients who are treated with insulin with 1 OAD: 
•
HbA1c at Visit 1:  7.0% and <9.5% 
•
HbA1c at Visit 4:  7.5% and <10.0% 


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6.
Age at informed consent: 20 years and <75
7.
BMI (body mass index) at Visit 1:  >22 and 40 kg/m2
8.
Signed and dated written informed consent by date of Visit 1 in accordance with Good 
Clinical Practice (GCP) and Japanese legislation
3.3.3
Exclusion criteria
1.
Uncontrolled hyperglycaemia with a glucose level >270 mg/dl (>15.0 mmol/L) after an 
overnight fast during wash-out, and placebo run-in period and confirmed by a second 
measurement (not on the same day and one of the measurement should be performed at 
the investigational site after overnight fast).
2.
Patients who are treated with sulfonylurea whose dose is more than a half of daily 
maximum approval dose, glucagon-like peptide 1(GLP-1) analogue, thiazolidinedione
and SGLT-2 inhibitor within 12 weeks prior to informed consent
3.
Acute coronary syndrome (ST elevation myocardial infarction [STEMI], non-STEMI, 
and unstable angina pectoris), stroke or transient ischemic attack (TIA) within 12 weeks 
prior to informed consent
4.
Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), 
or alkaline phosphatase (ALP) above 3 x upper limit of normal (ULN) as determined 
during screening and/or run-in period
5.
Impaired renal function, defined as eGFR<45 mL/min/1.73m2 (Japanese equation) as 
determined during screening and/or run-in phase
6.
Bariatric surgery within the past 2 years and other gastrointestinal surgeries that induce 
chronic malabsorption
7.
Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer 
within the last 5 years 
8.
Blood dyscrasias or any disorders causing hemolysis or unstable red blood cell (e.g.,
malaria, babesiosis, haemolytic anemia)
9.
Contraindications to the background therapy, insulin and empagliflozin according to the 
Japanese label
10. Known allergy or hypersensitivity to insulin or empagliflozin
11. Treatment with anti-obesity drugs (e.g. mazindol) 12 weeks prior to informed consent or 
any other treatment at the time of screening (i.e., surgery, aggressive diet regimen, etc.) 
leading to unstable body weight 


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12. Current treatment with systemic steroids at time of informed consent or change in dosage 
of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled 
endocrine disorder except T2DM
13. Pre-menopausal women (last menstruation 1 year prior to informed consent) who:
- are nursing or pregnant or plan to become pregnant while in the trial
- are of child-bearing potential and are not practicing an acceptable method of birth 
control, or do not plan to continue using this method throughout the study and do not 
agree to submit to periodic pregnancy testing during participation in the trial. 
Acceptable methods of birth control include intra uterine devices/systems (IUDs/IUSs), 
oral contraceptives, barrier method* and vasectomised partner
* Barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/suppository
14. Alcohol or drug abuse within 12 weeks prior to informed consent that would interfere 
with trial participation or any ongoing condition leading to a decreased compliance to 
study procedures or study drug intake 
15. Participation in another trial with an investigational drug within 30 days prior to 
informed consent
16. Any other clinical condition that would jeopardize patients safety while participating in 
this trial by investigator’s judgement 
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for study treatment or study participation, without 
the need to justify the decision.

The patient needs to take concomitant drugs, including herbal/nutritional 
supplements/medication that interfere with the investigational product or other trial
medication (see Section 4.2.2.1).

The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, adverse events, other diseases, or pregnancy)

If a patient becomes pregnant during the trial, the investigational drug will be 
stopped, and the patient will be discontinued from the trial and followed up until 
birth or otherwise termination of the pregnancy. 

Occurrence of hypoglycaemia that may put the patient at risk with continued 
participation (e.g., repeated hypoglycaemic episodes) and are not manageable by 
insulin dose adjustments.

DKA that may put the patient at risk with continued participation. Patients should 
be assessed for ketoacidosis immediately if symptoms occur, regardless of blood 


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glucose level. Discontinuation or temporary interruption of study medication should 
be considered, until the situation is clarified.

Occurrence of hyperglycaemia that meets the following criteria. In this case, the 
reason for study drug discontinuation will be classified as “lack of efficacy”.
During Double-blind treatment period 1 (i.e., from Visit 5 to Visit 10):
Introduction of rescue therapy due to hyperglycemia as described in Section 
4.2.1 does not lead to sufficient treatment efficacy (rescue criteria still met). 
After Double-blind treatment period 1 (i.e., from 1 day after Visit 10 to Follow-up 
visit):
The patient has glucose level >240 mg/dL (>13.3 mmol/l) after an overnight fast
despite the insulin dose adjustment by investigator
The above result should be confirmed, meaning that there is a minimum of two 
measurements, at least one of which should be performed after an overnight fast (at 
the investigational site, if possible), and on a different day from the initial 
measurement.
A patient can be discontinued from the trial after discussion between the sponsor and the 
investigator if the eligibility criteria are being violated, or if the patient fails to comply with
the protocol (e.g., non-attendance at study assessments).
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow-up as outlined in the flow chart and Section 6.2.3.
For all patients the reason for withdrawal (e.g., adverse events) must be recorded in the 
electronic case report forms (eCRFs). These data will be included in the trial database and 
reported.
Patients who drop out before placebo run-in period will be considered a screening failure. 
They have to be recorded as a screening failure in the eCRFs and no further follow-up is 
required (except for AEs, if needed).
Patients who discontinue or withdraw from the study during placebo run-in period and before 
being randomised at Visit 5 will be considered a run-in failure. They have to be recorded as 
run-in failure in eCRFs and no further follow-up is required (except for AEs, if needed).
Patients who are discontinued from the study after randomisation (Visit 5) and before 
completing EOT will be considered as early discontinuations and the reason for the 
discontinuation must be recorded in the eCRFs. The reason will be included in the trial 
database and reported. If determined by the investigator as necessary for the patient’s safety, 
a new antidiabetic medication regimen can be started immediately after discontinuation and 
must be recorded in the eCRFs. In this case, end of treatment (EOT) visit must be performed 
before taking any new antidiabetic drug.


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Patients who are discontinued from the trial after randomisation will not be replaced.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1.
Failure to meet expected enrolment goals overall or at a particular trial site
2.
Emergence of any efficacy/safety information invalidating the earlier positive 
benefit-risk-assessment that could significantly affect the continuation of the trial
3.
Violation of GCP, the Clinical Trial Protocol (CTP), or the contract disturbing the 
appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
The study medication will be provided by Nippon Boehringer Ingelheim.
4.1.1
Identity of BI investigational products and comparator products
The characteristics of test product 1 are below.
Substance:
Empagliflozin
Pharmaceutical form:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit Strength:
10 mg
Route of administration: Per oral (po), once daily
The characteristics of test product 2 are below.
Substance:
Empagliflozin
Pharmaceutical form:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit Strength:
25 mg
Route of administration: po, once daily
The characteristics of the reference product placebo 1 are below.
Substance:
Placebo matching empagliflozin 10 mg
Pharmaceutical form:
Film-coated tablet
Source:
Boehringer Ingelheim 
Unit Strength:
-
Route of administration: po, once daily
The characteristics of the reference product placebo 2 are below.
Substance:
Placebo matching empagliflozin 25 mg
Pharmaceutical form:
Film-coated tablet
Source:
Boehringer Ingelheim 
Unit Strength:
-
Route of administration: po, once daily


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4.1.2
Method of assigning patients to treatment groups
After the patient’s eligibility has been confirmed, the patient will be assigned to placebo at 
Visit 4 and randomly assigned to empagliflozin 10 mg, 25 mg or placebo in a 1:1:1 ratio at 
Visit 5 via Interactive Response Technology (IRT). To facilitate the use of the IRT, the 
Investigator will receive all necessary instructions.
Patient assignment to the treatment groups will be determined by a computer generated 
random sequence. Access to the randomisation code will be controlled and documented – for 
further details please see Sections 4.1.5.1 and 4.1.5.2.
The assigned medication number will be entered in the eCRF, and the corresponding 
medication kit should be given to the patient. Using this procedure, relevant parties who are 
directly concerned with the study conduct will be blinded to the treatment group assignment.
4.1.3
Selection of doses in the trial
The selected doses of empagliflozin are based on the approved and marketed doses for T2DM 
in Japan. Approximately 33% of the patients will receive empagliflozin 25 mg without
starting lower dose of empagliflozin 10 mg although the Japanese label defines the starting 
dose of empagliflozin 10 mg. Empagliflozin 25 mg as well as 10 mg were used in the phase 
III clinical trials as for the expected therapeutic doses and both empagliflozin doses were well 
tolerated as initial dosage.
4.1.4
Drug assignment and administration of doses for each patient
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. Patients who are 
qualified will be randomised to one of the treatment arm schedules described below. 
Medication will be dispensed in a double-blind and double-dummy fashion.
All patients will be assigned to a placebo run-in kit at the beginning of the placebo run-in
period (Visit 4), and dispensing will be done just once. Dispensing of kits for the double-
blind treatment period will begin at Visit 5. Dispensing will be done on 13 occasions over a 
period of 52 weeks (i.e., every 4 weeks in Visit 5 to Visit 18). Patients will receive 
empagliflozin or placebo as trial medication. However, background medication (i.e., insulin) 
will not be dispensed as trial medication. Therefore, background medication will be 
prescribed at each clinical site. For details regarding packaging (e.g., number of tablets per 
container) please see Section 4.1.6.  


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Table 4.1.4: 1
Treatments per dose group
Dose group
Empagliflozin
10 mg
Empagliflozin
25 mg
Total units
per dose
Timing
Placebo run-in period
(open label)
All patients
Matching placebo
Matching placebo
2 tablets
Once daily,
Morning
Double-blind
treatment period
Empagliflozin
10 mg arm
Active drug
Matching placebo
2 tablets
Once daily,
Morning
Empagliflozin
25 mg arm
Matching placebo
Active drug
2 tablets
Once daily,
Morning
Placebo arm
Matching placebo
Matching placebo
2 tablets
Once daily,
Morning
Placebo run-in period (open label):
From the start of the placebo run-in period, patients should be instructed to take their trial 
medication once daily with water. The medication can be taken with or without food but it
should be taken at the same time point every day. If a dose is missed by more than 12 hours, 
this dose should be skipped and the next dose should be taken as scheduled. 
Double-blind treatment period:
During the treatment period, patients should be instructed to take their trial medication once 
daily with water. To ensure a dose interval of about 24 hours, the medication should be taken 
at the same time every day. If a dose is missed but the patient realizes that within 12 hours 
from planned intake, the dose should be taken immediately, and if a dose is missed by more 
than 12 hours, this dose should be skipped and the next dose should be taken as scheduled. 
On days before the next visit, patient should be instructed to take their trial medication 
approximately 22-26 hours before the planned dose at the visit. No double doses should be 
taken at onece. The trial medication can be taken with or without food.
Through the double-blind period (Double-blind treatment period 1and 2), the usage of insulin 
should be unchanged if at all possible. The dosage of insulin should remain unchanged until 
the end of double-blind treatment period 1. After completing the double-blind treatment 
period 1 (i.e. from Visit 10), daily insulin dose can be adjusted at the investigators’
discretion. For further details, see Section 4.2.1.
Patients should be instructed not to take their trial medication in the morning of study visits 
as they will be dosed whilst in the study site. Patients who fail to do so should have the visit 
rescheduled as soon as possible, ideally on the following day. Patients are asked to bring their 


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trial medication to the sites. Visits should be routinely scheduled in the morning, at 
approximately the same time of day for each visit.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Trial medication during run-in period will be open-labelled.
After randomisation at Visit 5, patients, investigators and everyone involved in trial conduct 
or analysis or with any other interest in this double-blind trial will remain blinded with regard 
to the randomised treatment assignments until after database lock. To achieve all dose 
combinations and to ensure blinding, empagliflozin and placebo tablets are combined in 
double-dummy fashion as shown in Table 4.1.4: 1 and patients will have to take two tablets 
for each dose.
However, due to the requirements to report suspected serious unexpected adverse reactions 
(SUSARs), it may be necessary for a representative from BI’s pharmacovigilance department
to access the randomisation code for individual patients during study conduct. In such cases, 
access to the code will be permitted only by authorised pharmacovigilance representatives. 
Access to the code will be done via the IRT.
The randomisation code will be kept secret by Clinical Trial Support until completion of 
database lock. Please see Section 4.1.5.2 for the rules regarding breaking the code for an 
individual or for all patients in emergency situations.
Unblinding and breaking the code
4.1.5.2
In this blinded trial, an emergency code break will be available to the investigator via the IRT 
system. This code break may only be accessed in emergency situations when the identity of 
the trial drug must be known to the investigator in order to provide appropriate medical 
treatment or if required to assure the safety of trial participants. Each site receives a manual 
from the IRT provider that contains instructions on how to unblind the treatment of a patient 
via the IRT (via 24-hour Emergency helpline). If the code break for a patient is accessed, the 
sponsor must be informed immediately. The reason for accessing the code break, together 
with the date, must be documented on the appropriate eCRF page. In case third party needs to 
break the code, however, when the investigator cannot be reached, the code can be opened by 
calling emergency code manager (see Emergency Code Break Manual in the ISF).
4.1.6
Packaging, labelling, and re-supply
Study medications will be provided by Nippon Boehringer Ingelheim.


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The study medication will consist of containers labelled with the trial identification and 
medication kit number. Each kit will contain an appropriate number of empagliflozin tablets 
or matching placebo tablets with some reserve (see below), for dosing until the next 
scheduled visit. 
The placebo run-in kit will contain 42 tablets in a wallet (i.e., sufficient supply for 2 week 
administration, with 1 week in reserve). 
The double-blind treatment kit, dispensed from Visits 5 to 18 with 4 week interval. It will 
contain 84 tablets in a wallet (i.e., sufficient supply for 4 week administration, with 2 week in 
reserve). The total number of tablets dispensed to a patient during the double-blind treatment 
period will therefore be 1092 at a maximum.
Supply and re-supply will be managed by an IRT.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation 
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigational drug storage manager will receive the investigational drugs delivered by 
the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the Institutional Review Board (IRB), 

Availability of a signed and dated clinical trial contract between the Sponsor and the 
head of the investigational site,

Notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol
The investigational drug storage manager must maintain records of the product’s delivery to 
the trial site, the inventory at the site, the use by each patient, and the return to the Sponsor or 
alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigational drug storage manager will maintain records that document adequately that the 


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patients were provided the doses specified by the CTP and reconcile all investigational 
products received from the Sponsor. At the time of return to the Sponsor or appointed 
contract research organization (CRO), the investigational drug storage manager must verify 
that all unused or partially used drug supplies have been returned by the clinical trial patient 
and that no remaining supplies are in the investigator’s possession.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
Details of all concomitant therapies during the clinical trial will be recorded on the 
appropriate pages of the eCRFs.
4.2.1
Rescue medication, emergency procedures, and additional treatments
Throughout the duration of the trial, patients should continue to use insulin as a background 
therapy. Insulin will not be provided as part of the clinical trial supplies.
During the Week 1 to 16 of the double-blind treatment period (Double-blind treatment period 
1), the dose and usage of insulin must not be changed. (The dose adjustment within +/-10%
[for patients whose prescribed dose is 20 U/day at Visit 5] or +/- 2 U [for patients whose 
prescribed dose is 10 U/day and <20 U/day] of the prescribed insulin dose at Visit 5 is 
allowed. The usage of insulin should be unchanged if at all possible.)
Only for the safety reason mentioned below or when the patient met the criteria for initiating 
rescue therapy, insulin dose can be changed over the above mentioned range, and the dose 
change is treated as rescue therapy. Only dose and usage adjustment of insulin which is used 
as background treatment are allowed as a rescue therapy in this study. All other antidiabetic 
agents are prohibited even as a rescue therapy. The dose of insulin will be left to the 
discretion of the investigator, however, it should follow each Japanese label.
Safety reason for initiating a rescue therapy:

The patient had hypoglycaemia that may put him/her on risk (i.e., repeated 
symptomatic hypoglycaemia or severe hypoglycaemia)
Criteria for initiating a rescue therapy:

Weeks 1 – 12 (i.e., from Visit 5 to Visit 9)
The patient has glucose level >270 mg/dL (>15.0 mmol/L) after an overnight fast

Weeks 12 – 16 (i.e., from the day after Visit 9 up to Visit 10): 
The patient has glucose level >240 mg/dL (>13.3 mmol/L) after an overnight fast
The above result should be confirmed, meaning that there is a minimum of two 
measurements, at least one of which should be performed after an overnight fast at the 
investigational site, and on a different day from the initial measurement.
If the above criteria are met, the initiation of rescue therapy is at the investigator’s discretion, 
based on the patients’ current clinical condition (e.g., ongoing illness etc.).  A fasting glucose 
sample and an HbA1c sample should be taken before initiation of a rescue therapy and sent to 


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the central lab for analysis. The HbA1c sample is not required if a sample has been taken and 
sent to the central lab for analysis within the last 4 weeks.
Patients will continue taking study medication and continue participation in the trial even if 
rescue medication is required, and rescue medication can be used from when it is initiated 
until the end of the trial. 
Short term adjustments of insulin dose for up to 7 days due to disease or hospitalisation, and 
other occasional short term adjustments for up to 7 days as a part of the standard insulin 
therapy, are allowed; this is not considered as a rescue therapy. 
After Week 16 (after Visit 10), daily insulin dose can be adjusted at the investigators’
discretion. The usage of insulin should be unchanged if at all possible.
If, in the investigator’s clinical opinion, the patient’s hyper- or hypoglycaemia cannot be 
controlled, the patient should be discontinued from the trial as specified in Section 3.3.4.1.
Special attention must be paid to the prevention of DKA. Patients receiving empagliflozin are 
at risk to underestimate their need for insulin in case of blood sugar levels within their 
individual target range. Insulin deficiency might lead to ketoacidosis which could be life-
threatening if not recognized, and appropriately treated. All patients must be made aware of 
this risk and need to be instructed to contact the Investigator or other healthcare professional 
in case of symptoms of DKA. In addition patients must be instructed not to reduce their 
insulin intake below Investigator recommendations. For further details see Section 2.3.
In case of a suspected DKA the Investigator should ensure that appropriate tests are 
performed at the earliest opportunity, such as a blood test (i.e. pH, bicarbonate, anion gap, 
potassium, blood glucose, etc.; the results will be collected on the relevant page of the eCRF) 
and that the patient is appropriately treated (i.e. hospitalized or referred to emergency 
treatment) according to treatment guidelines in Japan.
In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful 
monitoring of volume status (e.g. physical examination, blood pressure measurements, 
laboratory tests including haematocrit) and electrolytes is recommended for patients receiving 
IMPs. Temporary interruption of treatment with IMPs should be considered until the fluid 
loss is corrected.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Through the study period, the use of other antidiabetic agents such as GLP-1 analogues, any 
oral antidiabetic drugs, or any insulin product other than background therapy will be 
prohibited. (Background therapy except insulin must be washed out at Visit 2.) In addition, 


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during the Double-blind treatment period 1, the dose and usage of insulin must not be 
changed unless meeting the criteria mentioned in Section 4.2.1.
However, short-term use of other insulin therapy than background therapy will be permitted 
(only in the event of an emergency situation and/or hospitalisation) based on clinical 
judgement of the investigator or treating physician. Whether to prolongation of such insulin 
treatment over more than 2 weeks or to discontinue treatment should be discussed on a case-
by-case basis between the investigator and the TCM.
Additionally, treatment with anti-obesity drugs or systemic steroids will be prohibited due to 
their influence on glucose metabolism. However, one off or short-term use (i.e., ≤2 weeks) of 
systemic steroids will be permitted as well as therapy with non-systemic steroids such as 
inhaled or local steroids. Furthermore, for patients taking thyroid hormones, any change in 
the dose should be avoided. If a change in dose of thyroid hormones changes do occur, this
should be recorded in the source documents and in the eCRF.  
The risk of volume depletion may be increased in a patient treated with diuretic in addition to 
SGLT-2 inhibitor. Therefore, the co-administration of diuretics had to be avoided if there are 
not sufficient reasons to use these drugs according to the investigators’ clinical judgment.
Restrictions on diet and life style
4.2.2.2
At the beginning of the placebo run-in period, patients who are pre-treated with insulin alone
will receive diet and exercise counselling by a diet specialist or a trained staff member, and 
patients who are pre-treated with insulin with 1 OAD will receive the counselling at the 
beginning of the wash-out period. The counselling should be based on the diet and exercise 
recommendation of the Japanese Diabetes Society. To avoid DKA, extreme diets (e.g.,
ketogenic diets) should be avoided. 
In principle, the contents of diet and exercise should not be changed through the study period. 
Patients will keep record (a food intake diary) of the actual food intake over a time of 3 
consecutive days in the week before the clinic visit indicated in the flow chart (these 3 
consecutive days should be the same days that blood glucoses at preprandial state and before 
bedtime are monitored by SMBG) and bring the diary at each visit. The patients will be 
reminded to follow the agreed diet and exercise plan at every visit. The investigator will 
check compliance with the diet and exercise therapy based on the records of the food intake 
diary and also by interview with patients.
SGLT-2 inhibitor has a diuretic action and therefore dehydration may occur. Therefore, the 
investigator should instruct the patients to drink appropriate volume of water or drink every 
day.
Patients also should not participate in other trials within the last 30 days before the date of 
informed consent and throughout the study.
There are no other restrictions on diet and lifestyle.


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Restrictions regarding women of childbearing potential 
4.2.2.3
Women of child-bearing potential must continue to practice an acceptable method of birth 
control (in accordance with the trial exclusion criteria Section 3.3.3) throughout the study.
TREATMENT COMPLIANCE
4.3
Patients are requested to bring all remaining trial medications including empty package 
materials when attending visits.
Based on tablet counts, treatment compliance will be calculated as the number of tablet taken, 
divided by the number of tablet which should have been taken according to the scheduled 
period, multiplied by 100. Compliance will be verified by the on-site monitor authorised by 
the Sponsor.
Treatment compliance (%) =
Number of tablet actually taken 100
Number of tablet which should have been taken
If the treatment compliance is not between 80-120%, site staff will explain the patient the 
importance of treatment compliance.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The primary endpoint is the change from baseline in HbA1c after 16 weeks of treatment.
Throughout the study protocol, the term "baseline" refers to the last observation prior to the 
administration of any randomised study drug.
5.1.2
Secondary Endpoint
The secondary endpoint is proportion of patients with drug-related adverse events during 52 
weeks of treatment.


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ASSESSMENT OF EFFICACY
5.2
HbA1c:
Blood samples for the determination of HbA1c at the central laboratory will be taken.
At the screening visit 1, the blood sample can be taken in non-fasted state. At all other visits, 
the blood samples should be taken before breakfast and before trial drug administration. The 
samples will be analysed at a central laboratory having a National Glycohaemoglobin 
Standardization Program (NGSP) Level I certificate. Further details about sample handling, 
shipment, and assay procedures can be found in the ISF (Lab manual).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
A complete physical examination (including cardiac, neurological, dermatological, 
pulmonary) will be performed by the investigator as described in the flow chart. 
Documentation of, and findings from the physical examination, must be part of the source 
documents available at the site.


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5.3.2
Vital Signs
The seated pulse rate (electronically or by palpation, count for 1 minute) will be measured as 
described in the flow chart. Further details on the procedure for seated pulse rate 
measurements are given in Appendix 10.1. 
5.3.3
Safety laboratory parameters
All safety laboratory samples (except at Visit 1) will be collected after a full overnight fast 
(nothing to eat or drink except water for at least 10 hours) and before investigational drug is 
taken as described in the flow chart and Section 6. The blood sample at Visit 1 (screening 
visit) can be taken with the patient in a fasted or non-fasted state. 
All parameters that will be determined during the trial conduct are listed in Tables 5.3.3: 1
and 5.3.3: 2. The analysis will be performed by a central laboratory. The respective reference 
range and details about sample handling and shipment will be provided in the ISF (Lab 
Manual).
Reduced lab panels are planned for the following visits (For details, see the flow chart):

For the screening Visit 1, laboratory only includes liver transaminases (i.e., AST 
and ALT), alkaline phosphatase, serum creatinine, thyroid stimulation hormone 
(TSH) , anti-GAD antibody, Ant-IA-2 antibody, FPG, HbA1c and urinalysis.

C-peptide will be measured at Visit 2 in patients who need washout an OAD or 
Visit 4 in patients who do not need washout period.

Free fatty acid (FFA) and Blood ketone bodies will be measured at selected visits. 
For the details, see the flow chart. 

Bone markers; iPTH (intact parathyroid hormone), 25OH Vitamin D, NTx in urine: 
planned at Visits 5, 10 and EOT.

Hematology and urinalysis will also be measured at Visit 6, 7, 9 11, 12, 14, 15, 17 
and 18.


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Table 5.3.3: 1
Safety laboratory parameters – whole blood, serum or plasma
Haematology

Haematocrit

Haemoglobin
- Reticulocyte count (reflex test if Hb outside normal range)

Red blood cells (RBC)/Erythrocytes

White blood cell (WBC)/Leukocytes

Platelet count/Thrombocytes

Differential automatic (relative and absolute count): 
Neutrophils, eosinophils, basophils, monocytes,  lymphocytes
Clinical chemistry

Albumin

ALP

-GT (gamma-glutamyl transferase) 

ALT (alanine aminotransaminase, SGPT)

AST (aspartate aminotransaminase, SGOT) 

Bicarbonate

Bilirubin total, fractionated if increased 

C-peptide

Calcium 

Chloride

Creatinine 

Creatinine kinase (CK)

hs troponin T (reflex tests if CK is elevated)

Lactate dehydrogenase (LDH)

Lipase

Magnesium

Phosphate 

Potassium 

Protein total 

Sodium

TSH (only at Visit 1)

Urea (BUN)

Uric acid 

Cholesterol (total)

HDL cholesterol 

Calculated LDL cholesterol 

Triglycerides (reflex test for direct measurement of LDL cholesterol triggered if 
triglycerides are >400 mg/dL or 4.52 mmol/L)


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Table 5.3.3: 1
Safety laboratory parameters – whole blood, serum or plasma 
(continued)
Bone Marker (only at selected visits)

iPTH 

25OH Vitamin D 

  NTx in Urine
FFA and Ketone bodies (only at selected visits) 

Total ketone body

Acetoacetic acid

3-hydroxybutyric acid

Free fatty acid (FFA)
Other

Anti-GAD antibody

Anti-IA-2 antibody
Table 5.3.3: 2
Safety laboratory parameters – urine
Urinalysis
Semi quantitative (dipstick)

Nitrite*

Protein

Ketone

Urine pH

Leukocyte esterase (for WBC)*
Quantitative

Albumin

Creatinine
Microscopic analysis
Will be performed as reflex test if any of the 
semi quantitative tests/dipsticks are abnormal:

Urine RBC/Erythrocyte

Urine WBC/Leukocytes

Urine sediment microscopic examination 

Urine culture (including antibiogram test):
- reflex test triggered by positive leukocyte 
esterase (for WBC) and/or nitrite in the semi-
quantitative test/dipstick
* Nitrite and leukocyte esterase (for WBC) will be determined both locally on site (not 
recorded in eCRF) and via central lab. A positive result at site triggers the sampling of 
mid-stream urine for urine culture.
Albumin/creatinine ratio in spot urine will be calculated at the central lab.


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Glomerular filtration rate:
The eGFR will be derived from serum creatinine values for Japanese equation:
eGFR (mL/min/1.73m2) = 194 x [Screatinine (mg/dL)]-1.094 x [age]-0.287 x [0.739 if 
patient is female]
Renal function impairment will be classified in the following way:

No renal function impairment: eGFR >90 mL/min/1.73m2;

Mild renal function impairment: eGFR 60 to <90 mL/min/1.73m2;

Moderate renal function impairment: eGFR 30 to <60 mL/min/1.73m2;

Severe renal function impairment: eGFR <30 mL/min/1.73m2.
These classes of renal impairment will be the basis for stratification of subgroup analysis.
Pregnancy testing:
Pregnancy testing (urine) will be performed in female patients of child bearing potential only 
according to the time points indicated in the flow chart.
Criteria for hypoglycaemic events:
Every episode of plasma glucose ≤70 mg/dL (3.9 mmol/L) should be documented in the 
eCRF with the respective time and date of occurrence. Any hypoglycaemia with glucose 
values <54 mg/dL (<3.0 mmol/L) and all symptomatic and severe hypoglycaemias should be 
documented as an AE "hypoglycaemic event". 
For the analysis, all hypoglycaemias will be classified according to the following criteria:

Asymptomatic hypoglycaemia: event not accompanied by typical symptoms of 
hypoglycaemia but with a measured glucose concentration ≤70 mg/dL (3.9 
mmol/L)

Documented symptomatic hypoglycaemia with glucose concentration ≥54 mg/dL 
and ≤70 mg/dL (≥3.0 mmol/L and ≤3.9 mmol/L): event accompanied by typical 
symptoms of hypoglycaemia 

Documented symptomatic hypoglycaemia with glucose concentration <54 mg/dL 
(<3.0 mmol/L): event accompanied by typical symptoms of hypoglycaemia but no 
need for external assistance

Severe hypoglycaemic episode: event requiring the assistance of another person to 
actively administer carbohydrate, glucagon or other resuscitative actions
Follow-up on suspicion for urinary tract infections:
Patients having a history of chronic/recurrent urinary tract infections (UTIs) or genital tract 
infections (GTIs) or an acute episode of UTI or GTI at screening will be identified and this 
condition has to be documented as medical history or baseline condition in the eCRF, 
respectively.


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For documentation of acute urinary tract infections during trial conduct, the following 
measures have to be taken:

In any case of suspected UTI (symptomatic or asymptomatic) a urine culture 
sample (including antibiogram) has to be taken and sent to the central lab for 
confirmation of the diagnosis. 

To be able to identify asymptomatic UTIs immediately, a dipstick-test (leukocyte 
esterase [for WBC] and Nitrite) will be performed at the site at each safety visit 
with urinalysis. In case of a positive result at site, a urine culture (including 
antibiogram) sample has to be taken and sent to the central lab for confirmation of 
the diagnosis.
5.3.4
Electrocardiogram
Printed paper traces from 12 lead electrocardiogram (ECG)s (I, II, III,aVR,aVL,aVF,V1-V6) 
will be collected at Visit 1, 5, 8, 10, 13, 16 and EOT for all patients. In the event of any 
cardiac symptoms (i.e., suspicion of heart rhythm disorders or cardiac ischemia), an 
additional ECG will be recorded. All ECGs will be evaluated, (signed, dated and commented 
upon) by the investigator and stored locally. Any clinically relevant changes in the ECG will 
be reported as AEs and followed up and/or treated locally until normal or stable condition.
Any ECG abnormalities will be carefully monitored and if necessary the patient will be 
removed from the trial and medically treated.
Investigators will use the ECG machine available at the site. NBI will not provide ECG 
machine centrally.
5.3.5
Other safety parameters
Self-Monitoring blood Glucose (SMBG)
All patients will be provided with Self-Monitoring Blood Glucose (SMBG) equipment and 
supplies for use at home during the study period. Instruction on the proper use of the SMBG
equipment will be provided by the study staff. The patient will be asked to record the results 
of the SMBG test on a SMBG Testing Log that will be included in the patients source 
document file. Only in the case of linked adverse events or of hypoglycaemia, the glucose 
value measured by SMBG will be recorded in the eCRF.
During wash-out, placebo run-in, double-blind treatment and follow-up period, SMBG
testing is recommended to be performed at least once daily before breakfast (if possible, it is 
recommended to monitor fasting blood glucose in preprandial state and before bedtime) and 
at any time the patient is symptomatic related to hypoglicaemia or hyperglicaemia through
the entire study period. In addition, in 3 consecutive days in the week before each scheduled 
visit, patients will be requested to monitor fasting blood glucose at preprandial state (i.e., 


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before breakfast, lunch and dinner), before bedtime and at any time when the patient is 
symptomatic. Patients are requested to maintain a diary with daily recordings of glucose 
values measured by SMBG and of insulin dose through the entire study period.
If during wash-out and placebo run-in period, results of a SMBG test reveal blood glucose of 
>270 mg/dL (15.0 mmol/L) after an overnight fast, the patient should contact the site. 
The investigator should ask the patient to visit the site for FPG determination as soon as 
possible, preferably on the next day. The investigator will take two blood samples, one for 
local determination of FPG for acute patient management, and one for central laboratory 
determination for trial analysis. If two consecutive measurements at either the local or central 
laboratory, or SMBG on different days (at least one measurement has to be done at the local 
or central lab) reveal overnight fasted blood glucose of >270 mg/dL (15.0 mmol/L), then the 
patient should be withdrawn from the trial (see Section 3.3.3).
Until Visit 9 after randomization, results of a SMBG test reveal blood glucose of >270 mg/dL 
(15.0 mmol/L), or until the completion of trial from one day after Visit 9, results of a SMBG
test reveal blood glucose of >240 mg/dL (13.3 mmol/L) after an overnight fast the patient 
should contact the site, and the investigator should follow procedure described in the 
Sections 4.2.1 and 3.3.4.1.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:
results in death,
is life-threatening,
requires inpatient hospitalisation or prolongation of existing hospitalisation,
results in persistent or significant disability or incapacity,
is a congenital anomaly/birth defect,
or
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 


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require medical or surgical intervention to prevent one of the other outcomes listed 
in the above definitions.
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
Every new occurrence of cancer must be reported as a serious event regardless of the duration 
between discontinuation of the drug and the occurrence of the cancer.
The following events will be handled as “deemed serious for any other reason”. An AE which 
possibly leads to disability will be reported as an SAE.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the remote data capture (RDC)
system. 
These events should always be reported as SAEs as described in Section 5.3.7.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters after 
randomisation at Visit 5: 
An elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or
Marked peak aminotransferase (ALT, and/or AST) elevations ≥5 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided via the 
RDC-system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 


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(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Decreased renal function
A decreased renal function is defined by the following alterations of renal laboratory 
parameters:

Creatinine value shows a ≥2 fold increase from baseline and is above the upper 
limit of normal (ULN)
The patient with any of the events is mentioned above need to be followed up appropriately. 
The investigator should consider which, if any, concomitant therapies should not be taken 
during evaluation. Discontinued treatments can be reintroduced per investigator discretion.
For any of these AESI, the investigator should report the event to the pharmacovigilance 
centre immediately (within 24 hours of being informed, and without waiting for confirmation 
of the result via a second measurement) on the SAE form, even if they do not meet any of the 
seriousness criteria. 
The investigator should collect the relevant unscheduled laboratory samples as soon as 
possible (i.e., lipase, creatinine, or hepatic enzymes). Further follow-up laboratory tests 
should be done according to medical judgment depending on the clinical course.
Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA)
In case of metabolic acidosis, ketoacidosis and DKA further investigations should be done 
according to the medical judgment and the clinical course until a diagnosis is made and/or the 
patient is recovered.
Diabetic ketoacidosis (DKA) is defined as a state in which a severe shortage of insulin and an 
increase in counter regulatory hormones combine to induce hyperglycemia (≥250 mg/dL), 
hyperketonemia (increased β-hydroxybutyric acid), and acidosis (pH<7.30; bicarbonate 
concentration<18 mEq/L), and as defined by the Japanese guideline, Evidence-based Practice 
Guideline for the Treatment for Diabetes in Japan 2013 [R13-3738].
Investigators should note that not all criteria in the described above need to apply for the 
diagnosis of DKA, and clinical judgment should also be taken into consideration.
Due to its mechanism of action, empagliflozin may potentially modify the clinical 
presentation of DKA which may occur at lower plasma glucose levels than stated above.
Medical history of DKA prior to the informed consent will be reported in the eCRF.
Events involving lower limb amputation
This definition includes amputation (i.e. resection of a limb through a bone), disarticulation 
(i.e. resection of a limb through a joint) and auto-amputations (i.e. spontaneous separation of 
non-viable portion of the lower limb).


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Not included in this definition are debridement (removal of callus or dead tissue), procedures 
on a stump (like stump revision, drainage of an abscess, wound revision etc.) and other 
procedures (e.g., nail resection or removal) without a concomitant resection of a limb 
(amputation or disarticulation).
Each lower limb amputation, disarticulation, or auto-amputation should be reported 
separately. The SAE report should include the date of the procedure, the level of amputation 
or disarticulation, the medical condition(s) leading to the procedure and if the patient had 
some of the known risk factor(s) for lower limb amputation.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild: Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate: Enough discomfort to cause interference with usual activity
Severe: Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the eCRFs. The reason for 
the decision on causal relationship other than the related listed AEs in the IB [c01838761] 
and respective Japanese package insert needs to be provided in the eCRF.
Yes: There is a reasonable causal relationship between the investigational product 
administered and the AE.
No: There is no reasonable causal relationship between the investigational product 
administered and the AE.
5.3.7
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF by the 
Investigator:
-
From signing the informed consent onwards through the residual effect period (REP), 
until individual patient’s end of trial: 
-all AEs (serious and non-serious) and all AESIs.
-
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the investigator may become aware 
of.
The REP is defined as a period of 7 days after the last trial medication application. All AEs
which occurred through the treatment phase and throughout the REP will be considered as on 


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treatment (see Section 7.3.4). Events which occurred after the REP will be considered as post 
treatment events.
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (contact details will be provided in the ISF). The same timeline 
applies if follow-up information becomes available. In specific occasions the investigator 
could inform the sponsor upfront via telephone. This does not replace the requirement to 
complete and fax the BI SAE form.
All SAEs and AESIs must be reported immediately to the head of the trial site.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, outcome, 
seriousness, and action taken with the investigational drugs. The investigator should 
determine the causal relationship to the trial medication.
The following should also be recorded as an (S)AE in the eCRF and SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions

Changes in vital signs, ECG, physical examination and laboratory test results, if 
they are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In the rare case that a female subject or a female partner to a male subject participating in this 
clinical trial becomes pregnant after having taken trial medication, the Investigator must 
report immediately (within 24 hours) the drug exposure during pregnancy (DEDP) to the
pharmacovigilance centre. The Pregnancy Monitoring Form for Clinical Trials (Part A) 
should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 


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As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
Not Applicable
ASSESSMENT OF EXPLORATORY BIOMARKER
5.5
Not Applicable
OTHER ASSESSMENTS
5.6
No other assessment such as pharmacogenomics samples will be performed in this study.
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects in an appropriate way. 
The scheduled measurements are appropriate to see drug induced changes in vital signs, 
standard laboratory values, biomarkers specific to efficacy of treatment of type 2 diabetes 
mellitus, and ECG. The primary and secondary endpoints are standard and accepted for 
evaluation of safety and tolerability of an OAD, and they are widely used in this kind of 
study.
Therefore, all measurements applied in this trial are appropriate.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
All trial visits (except Visit 1, 5.1 and phone contact for Follow up visit) should take place in 
the morning. If a patient mistakenly takes trial medication on the morning of a visit before 
attending the clinic (excluding visits starting before randomisation) or comes in fed condition
where a fasting condition is required (all visits except screening), the visit should be 
rescheduled for another day as soon as possible reminding the patient of the expected 
conditions. The rescheduled visit must take place in a short enough time-frame so that the 
patient has sufficient trial medication available.
All patients are to adhere to the visit schedule as specified in the flow chart. If any visit has to 
be rescheduled, subsequent visits should follow the original visit date schedule. The trial 
medication packs contain sufficient medication to allow for these time windows.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening and run-in periods
Screening Period
The screening visit is the only visit in this study that does not need to be done in fasting.
No trial procedures should be done unless the patient has consented to taking part in the trial.
Once they have consented, the patient is considered to be enrolled in the trial and should then 
be recorded in the enrolment log, and screening will be started. The patient should be 
registered in the IRT as a screened patient at Visit 1.
ECG and BP should always be measured before any blood samples are taken. For details 
regarding the correct method for measuring BP, see Appendix 10.1.
At the end of the screening visit, patients will be given a food intake log/booklet which is 
requested to be completed for three consecutive days in the week prior to the next visit.
Details of any patient who is screened for the study but is found to be ineligible must be 
entered in an enrolment log and documented in the eCRF.
Patients who are treated with insulin alone and qualify at Visit 1 will undergo a 2-week 
placebo run-in period. And patients who are treated with insulin in combination with one 
OAD and qualify at Visit 1 will undergo a 10-week wash-out period.
Wash-out Period
Only the patients who are treated with insulin in combination with one OAD as the previous 
treatments will undergo this period. These patients will be requested to wash-out the OAD at 
Visit 2. Patients who are treated with insulin alone will skip this period.


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From Visit 2, the patients should be fasting (no food or drinks, water only for at least 10 
hours) prior to each visit. And at Visit 2, patients will be requested not to take OAD on the 
morning of a visit before attending the clinic.
The patients will be provided Self-Monitoring Blood Glucose (SMBG) equipment and 
supplies at Visit 2. Instruction on the proper use of the SMBG equipment will be provided by 
site staff. Please refer to Section 5.3.5 (Self-Monitoring blood Glucose) for the details of 
measurement frequency and the record.
If the SMBG test reveals an overnight fasted blood glucose of >270 mg/dL (15.0 mmol/L), 
the patient should contact the study site for a visit as soon as possible, on ideally the next day 
 See Section 5.3.5.
 
At the end of the each visit in this period, patients will be given a food intake log/booklet 
which is requested to be completed for three consecutive days in the week prior to the next 
visit. These 3 consecutive days should be the same days that blood glucoses at preprandial 
state and before bedtime are monitored by SMBG. 
Investigators will ask the patients to visit the site 4 weeks after Visit 2 to check the patient’s 
safety after wash-out of the OAD. After completing the wash-out period, the patients will 
proceed to a 2-week placebo run-in period.
Placebo Run-in Period
From Visit 4, patients who are pre-treated with insulin alone should be fasting (no food or 
drinks, water only for at least 10 hours) prior to each visit.
And these patients will be provided SMBG equipment and supplies at Visit 4. Instruction on 
the proper use of the SMBG equipment will be provided by site staff. Please refer to Section 
5.3.5 (Self-Monitoring blood Glucose) for the details of measurement frequency and the 
record.
If the SMBG test reveals an overnight fasted blood glucose of >270 mg/dL (15.0 mmol/L), 
the patient should contact the study site for a visit as soon as possible, ideally on the next day 
 See Section 5.3.5.
 
At the end of Visit 4, patients will be given a food intake log/booklet which is requested to be 
completed for 3 consecutive days in the week prior to the next visit (Visit 5). These 3 
consecutive days should be the same days that blood glucoses at preprandial state and before 
bedtime are monitored by SMBG.


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6.2.2
Treatment period
The double-blind treatment period is from Visit 5 to EOT. Patients will be dispensed 
medication at each of these visits (except Visit 5.1, 6 and EOT) and will receive a new kit 
number through the IRT on each occasion.
Patients must satisfy all inclusion but not meet the exclusion criteria prior to randomisation 
(see Section 3.3). In addition, if during the placebo run-in period there is any indication that a 
patient’s conditions of T2DM are not stable enough for the patient to complete safely the 
study or that the patient will not be compliant with the study medication or restrictions, the 
patient should not be randomised to the treatment.
The date of each visit after Visit 5 should be determined based on the date of Visit 5 and 
visits should occur within the allowed time frame shown in the flow chart.
Throughout the double treatment period, the usage of insulin should be unchanged if at all 
possible. And during the Double-blind treatment period 1, the insulin dose must not be 
changed unless patient meets the rescue criteria, but the insulin dose can be adjusted within 
+/- 10% from the dose at Visit 5 in patients whose insulin dose is 20 U/day at Visit 5, and 
within +/- 2 U/day from the dose at Visit 5 in patients whose insulin dose is <20 U/day at 
Visit 5.
After completing the double-blind treatment period 1 (i.e., from Visit 10), daily insulin dose 
can be adjusted at the investigators’ discretion. For further details, see Section 4.2.1.
Throughout the double-blind treatment period, ECG and BP should always be measured 
before any blood samples are taken. 
 
Visit 5.1 will be done via phone by investigator or designated site staff to confirm patient’s 
safety through checking SMBG results, adverse events and concomitant therapies. The 
investigator should ask the patient to visit the clinic, if determined by the investigator as 
concerning the patient’s safety.
Randomisation/treatment allocation and dispensing of study medication should be the last 
activity at each visit. And trial medication for the day of the visit will be administered at the 
investigational site after all necessary procedures are completed. The time patients visit the 
investigational site should be arranged to allow patients to take the trial medication at the 
same time as usual. 
Until Visit 9 after randomization, results of a SMBG test reveal blood glucose of >270 mg/dL 
(15.0 mmol/L), or until the end of the double blind period from one day after Visit 9, results 
of a SMBG test reveal blood glucose of >240 mg/dL (13.3 mmol/L) after an overnight fast 
the patient should contact the site, and the investigator should follow procedure described in 
the Sections 4.2.1 and 3.3.4.1.


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At the end of each visit, patients will be given a food intake log/booklet which is requested to 
be completed for 3 consecutive days in the week prior to the next visit. These 3 consecutive 
days should be the same days that blood glucoses at preprandial state and before bedtime are 
monitored by SMBG.
EOT visit will need to be performed for any patients who are administered study medication, 
i.e. both for patients who complete the full 52-week double-blind treatment period and for 
patients who discontinue study medication early. Patients who discontinue study medication 
early should be registered as discontinued, and patients who complete the full 52-week 
double-blind treatment period should be registered as “completed” in the IRT. 
6.2.3
Follow-up period and trial completion
For all patients completing the study according to the protocol without persisting AE at EOT, 
a follow-up visit can be performed as a phone visit by the investigator at the end of the 
follow-up period of 7 days. Follow-up visit should occur 7 days after EOT (+7 days visit 
allowance).
During the follow-up period, results of a SMBG test reveal blood glucose of >240 mg/dL 
(13.3 mmol/L) after an overnight fast the patient should contact the site, and the investigator 
should follow procedure described in the Sections 4.2.1 and 3.3.4.1.
The following should be confirmed and recorded at follow-up visit via telephone:

concomitant therapies

any AEs

SMBG log
Patients completing the study according to the protocol with persisting AE at EOT or in case 
of early discontinuation from the 52-week double-blind treatment period, however, EOT 
should be performed and the patient should return to follow-up visit (7 days after EOT). The 
following examinations should be performed at follow-up visit in addition to the above 
mentioned items:

Physical examination

Vital signs

Collection of blood (include FPG sample) and urine samples for safety laboratory 
evaluation


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a randomised, double-blind, placebo-controlled, parallel-group study designed to 
compare 2 doses of empagliflozin (10 mg and 25 mg once daily) to placebo as add-on therapy 
to insulin in Japanese patients with T2DM.
The primary analysis is an analysis of covariance (ANCOVA) comparing the change from 
baseline in HbA1c after 16 weeks of treatment. The statistical model includes treatment, renal 
function and type of insulin therapies as fixed effects, and baseline HbA1c as a covariate.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The following hierarchical testing procedure will be used to evaluate superiority of 
empagliflozin 10 mg against placebo followed by superiority of empagliflozin 25mg against 
placebo, while maintaining the overall probability of type I error at 0.05 (two-sided).
Step 1: The superiority of empagliflozin 10 mg against placebo will be tested for change from 
baseline in HbA1c after 16 weeks of treatment at the level of α=0.05 (two-sided).

H0, 1: Mean change from baseline in HbA1c after 16 weeks of treatment with 
empagliflozin 10 mg = Mean change from baseline in HbA1c after 16 weeks of 
treatment with placebo

H1, 1: Mean change from baseline in HbA1c after 16 weeks of treatment with 
empagliflozin 10 mg ≠Mean change from baseline in HbA1c after 16 weeks of 
treatment with placebo
If the null hypothesis for the superiority of empagliflozin 10 mg against placebo is rejected at 
the 5% level, then the following Step 2 will be performed. If the null hypothesis for the 
superiority of empagliflozin 10 mg against placebo cannot be rejected, then the testing of the 
superiority of the empagliflozin 25mg against placebo will be done in an exploratory manner 
only.
Step 2: The superiority of empagliflozin 25 mg against placebo will be tested for change from 
baseline in HbA1c after 16 weeks of treatment at the level of α=0.05 (two-sided).

H0, 1: Mean change from baseline in HbA1c after 16 weeks of treatment with 
empagliflozin 25 mg = Mean change from baseline in HbA1c after 16 weeks of 
treatment with placebo

H1, 1: Mean change from baseline in HbA1c after 16 weeks of treatment with 
empagliflozin 25 mg ≠Mean change from baseline in HbA1c after 16 weeks of 
treatment with placebo


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PLANNED ANALYSES
7.3
The assignment of patients to treatment groups will be based on the first study drug taken in 
the study for safety evaluation, and as randomised for efficacy evaluation. The statistical 
analysis will be based on the following populations.
[Treated set]
The treated set (TS) will consist of all randomised patients who were treated with at least one 
dose of the study drug.
[Full analysis set]
The full analysis set (FAS) will consist of all patients in TS who had a baseline measurement 
of the primary endpoint.
[Per protocol set]
The per protocol set (PPS) will consist of all patients in FAS who have no important protocol 
violations which may affect the efficacy evaluation. The important protocol violations will be 
specified in the trial statistical analysis plan (TSAP).
Baseline for any parameter is defined as the last measurement prior to the administration of 
any randomised study drug.
7.3.1
Primary endpoint analyses
The primary analysis will be performed on the FAS with missing data imputed using a last 
observation carried forward (LOCF) approach as described in Section 7.4.
The primary endpoint will be analysed using an ANCOVA. The model includes ‘treatment’, 
‘baseline renal function’ and ‘type of insulin therapies’ as a fixed effect, and baseline HbA1c
as a covariate as follows:
Change from baseline in HbA1c after 16 weeks = overall mean + baseline HbA1c + treatment 
+ baseline renal function + type of insulin therapies + random error
The random error is assumed to be normally distributed with mean 0 and variance σ².
[Sensitivity analysis]
Sensitivity analyses of the primary endpoint will be performed as follows:

The primary analysis as specified in Section 7.3.1 will be repeated on the PPS 
(LOCF).

The primary endpoint will be analysed on the FAS (observed case, OC) using a 
restricted maximum likelihood (REML)-based mixed model repeated measures 
(MMRM). The model includes ‘treatment’, ‘baseline renal function’, ‘type of 
insulin therapies’, ‘visit’, ‘treatment by visit interaction’ and ‘baseline HbA1c by 
visit interaction’ as a fixed effect, and baseline HbA1c as a covariate as follows:


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Change from baseline in HbA1c at each on-treatment visit = overall mean + baseline HbA1c + 
treatment + baseline renal function + type of insulin therapies + visit + treatment by visit 
interaction + baseline HbA1c by visit interaction + random error
For each patient, the error terms from the on-treatment visits represent the within-patient 
variability, and are assumed to follow a multivariate normal distribution with an unstructured 
covariance matrix.
If this unstructured covariance structure fails to converge, the following structures will be 
tested: compound symmetry, variance components and Toeplitz. The covariance structure 
converging to the best fit, as determined by Akaike’s information criterion, will be used.
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom.
Additional sensitivity analyses on the primary endpoint may be performed. Such sensitivity 
analyses will be specified in the TSAP.
7.3.2
Secondary endpoint analyses
Refer to Section 7.3.4 for the analysis of secondary endpoint.
7.3.4
Safety analyses
Standard safety analyses will be performed on the TS.
Safety analyses will be descriptive in nature and will be based on BI standards. No formal 
inferential analysis is planned.


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Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). AEs occurring one day before the first intake of the double-blind treatment will 
be assigned to the ‘screening period’. AEs occurring between the first intake of the double-
blind treatment and seven days after the last intake of double-blind treatment will be assigned 
to ‘double-blind treatment period’ for evaluation. AEs occurring thereafter will be assigned to 
‘post-treatment period’.
Frequency of patients with AEs will be summarised by system organ class (SOC) and 
preferred term (PT). In addition, AEs by intensity, drug-related AEs, serious AEs, AESIs and
hypoglycaemic events will also be summarised.
Descriptive statistics of laboratory values for the change from baseline will be provided. 
Frequency tables of changes with respect to the reference range between baseline and last 
value on treatment will also be presented.
Change from baseline will be summarised for vital signs.
Further details on the safety analysis will be specified in the TSAP.
7.3.5
Pharmacokinetic analyses
Not specified in this protocol.
INTERIM ANALYSES
7.4
No interim analysis is planned in this trial.
HANDLING OF MISSING DATA
7.5
Censoring rules for the efficacy data will be defined in the TSAP. Censored efficacy data will 
be set as missing, and different methods for handling missing data will be used as below.
Missing data for the primary analysis will be imputed using the last observation carried 
forward (LOCF) approach. The baseline value will be carried forward if no post-baseline
value is available.
The impact of all methods of handling missing data on the primary endpoint will also be 
investigated using sensitivity analyses.
MMRM will be applied in order to handle missing data in the sensitivity analysis. Only the 
available data will be included in the analysis (observed case, OC). Missing data are handled 
implicitly by MMRM model, rather than using any imputation.
With respect to safety evaluations, it is not planned to impute missing values.


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Further details will be provided in the TSAP.
RANDOMISATION
7.6
The trial will be performed as a double-blind design with respect to placebo and 2 active 
treatment groups of empagliflozin (10 mg and 25 mg). Patients who meet the inclusion 
criteria but not meet the exclusion criteria will be randomised in 1:1:1 ratio to each treatment 
group at Visit 5.
The randomisation will be stratified by the following factors:

Baseline HbA1c (at Visit 1 for insulin alone, Visit 4 for insulin with one OAD)
(<8.5% or <69.4 mmol/mol, ≥8.5% or ≥69.4 mmol/mol)

Baseline Renal function (at Visit 4) (eGFR <60 mL/min/1.73 m2, eGFR ≥60 
mL/min/1.73 m2)

Type of insulin therapies (basal insulin therapy, other insulin therapy)
The randomisation of patients to the treatment groups will be performed via an IRT. BI will 
arrange for the randomisation as well as packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a 
pseudorandom number generator and a supplied seed number so that the resulting allocation 
of medication numbers to treatment is both reproducible and non-predictable. The access to 
the randomisation codes will be controlled and documented.
DETERMINATION OF SAMPLE SIZE
7.7
Based upon previous experience with empagliflozin [U12-3817-01], it is estimated that the 
difference of change from baseline in HbA1c after 16 weeks of treatment between 
empagliflozin (10 mg or 25 mg) and placebo add-on to insulin is 0.5% and that the standard 
deviation of this difference is 1.0%. The Type I error for each hierarchical testing procedure 
to evaluate superiority of empagliflozin 10 mg against placebo followed by superiority of 
empagliflozin 25 mg against placebo, is assumed to be 5% (two-sided), while maintaining the 
overall probability of type I error at 0.05.
The number of analysed patients should be 86 per treatment arm to have 90% power to test 
the primary endpoint of each empagliflozin 10 mg and 25 mg, leading to 81% overall power. 
Assuming that approximately 3% of patients will not be eligible for inclusion into the FAS, 3
additional patients should be randomised per arm. As such sample size will be 89 per arm. 
Calculations were performed using nQuery Advisor® 7.0.
Meanwhile, the draft version of the revised Japanese guideline “Clinical Evaluation 
Guidelines for Antihyperglycemic Drugs” [R15-2907] requires at least 100 patients who are 
treated for 1 year with oral antihyperglycemic drug. Therefore, assuming a 20 % loss of 


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randomised patients during the 52 weeks of treatment, at least 63 patients should be 
randomised per arm (126 patients from both empagliflozin 10 mg and 25 mg arms).
On the basis of the above, a total of 267 patients (89 per arm) need to be randomised.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs) and 
the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 
1997) and the Japanese GPSP regulations (Ministry of Health, Labour and Welfare 
Ordinance No. 171, December 20, 2004).
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP and the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997).
The rights of the investigator / trial site and of the sponsor with regard to publication of the 
results of this trial are described in the trial site’s contract. As a general rule, no trial results 
should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is 
stored in the ISF (Investigator Site File).”
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) according to national and 
international regulations. The same applies for the implementation of changes introduced by 
amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The Investigator must give a full explanation to trial patients by using the patient information 
form, which is prepared avoiding the use of technical terms and expressions. The patient is 
given sufficient time to consider participation in the trial. The Investigator obtains written 
consent of the patient’s own free will with the informed consent form after confirming that 


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the patient understands the contents. The Investigator must sign and date the informed 
consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the Investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
RECORDS
8.3
eCRF for individual patients will be provided by the Sponsor via remote data capture. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB review and 
regulatory inspection, providing direct access to all related source data / documents. eCRF 
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the Sponsor’s clinical monitor, auditor and 
inspection by health authorities (e.g. FDA). The CRA and auditor may review all eCRFs, and 
written informed consents. The accuracy of the data will be verified by reviewing the 
documents described in Section 8.3.1.
An adaptive approach to clinical trial monitoring will be utilised. This is initiated by an 
assessment of the risk associated with the trial combined with identification of critical data 


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and process. An Integrated Quality and Risk Management Plan documents the strategies 
involved with the implementation of onsite, offsite and central monitoring activities in order 
to direct focus to the areas of greatest risk which have the most potential impact to subject 
safety and data quality. Trial oversight is achieved by regular review of a report of risk which 
then influences any monitoring adaptations.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source documents and essential documents for a period defined 
by the Japanese GCP regulation and trial site’s contract with the sponsor.
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e., is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For empagliflozin this is the current version of IB [c01838761]. In addition to that the 
Japanese package insert of empagliflozin is used to assess local expectedness in Japan.
The current versions of these reference documents are provided in the ISF. No AE are 
classified as listed for matching placebo, trial design.
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IRBs, will be done according to local regulatory 
requirements. Further details regarding this reporting procedure are provided in the ISF.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 


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need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB and the regulatory authorities.
END OF TRIAL
8.6
The end of the trial is defined as the last patient out. 
When the trial is completed, the Investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
Sponsor of the completion in writing.
PROTOCOL VIOLATIONS
8.7
The investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the Sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
R05-0939
Wright EM, Turk E. The sodium/glucose cotransport family SLC5. 
Pfluegers Archiv - European Journal of Physiology 2004; 447 (5), 510 -
518.
R10-4692
MHLW Guideline - Clinical Evaluation Guidelines for Oral 
Antihyperglycaemic Drugs
R13-3738
Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 
2013
R14-4302
The Japan Diabetes Society. Treatment Guide for Diabetes 2014-2015. 
Tokyo, Bunkodo; 2014.
R15-2907
MHLW draft revised guideline (draft) - Clinical Evaluation Guidelines for 
Antihyperglycemic Drugs
R15-2908
The Japan Diabetes Society. Recommendation from “Committee on the 
proper use of SGLT2 inhibitors”
UNPUBLISHED REFERENCES
9.2
c01838761
Investigator’s Brochure: empagliflozin and empagliflozin/linagliptin FDC, 
Indication: type 2 diabetes mellitus,  Project No. 1275.P1, 1245.P1, Current 
Version
U12-3817-01
 
 
 
 
. A phase IIb, 
randomised, double-blind, placebo-controlled, parallel group, safety and 
efficacy study of BI 10773 (10 mg and 25 mg) administered orally, once 
daily over 78 weeks in type 2 diabetic patients receiving treatment with 
basal insulin (glargine, detemir, or NPH insulin only) with or without 
concomitant metformin and/or sulfonylurea therapy and insufficient 
glycaemic control. BI Trial No. 1245.33. 11 Jan 2013.
U13-1730-01
 
 
 
 A 52-week, randomised, 
multi-centre, parallel group study to investigate the safety and efficacy of 
BI 10773 (10 mg or 25 mg administered orally once daily) as add-on 
therapy to an oral antidiabetic drug (sulfonylurea, biguanide, 
thiazolidinedione, alpha glucosidase inhibitor, DPP-IV inhibitor, or glinide) 
in patients with type 2 diabetes mellitus with insufficient glycaemic control. 
BI Trial No. 1245.52. 26 September 2013.


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U13-2122-01
, 
 
, 
 A phase III, randomised, 
double-blind, placebo-controlled, parallel group safety and efficacy study of 
BI 10773 (10 mg and 25 mg administered orally once daily) during 52 
weeks in patients with type 2 diabetes mellitus and insufficient glycemic
control on MDI insulin regimen alone or with metformin. BI Trial 
No.1245.49. 20 Sep 2013.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
13 September 2016
EudraCT number
BI Trial number
1245.107
BI Investigational Product
Jardiance®, Empagliflozin
Title of protocol
A 52-week randomised, double-blind, placebo-
controlled, parallel-group, efficacy and safety study 
of empagliflozin once daily, as add-on to insulin in 
Japanese patients with Type 2 Diabetes Mellitus 
with insufficient glycaemic control
To be implemented only after 
approval of the IRB
To be implemented immediately 
in order to eliminate hazard –
IRB to be notified of change 
with request for approval
Can be implemented without 
IRB approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
3.3.2 and synopsis (Change 1)
Description of change
Text in inclusion criteria 2 is reformulated to:
Insulin product and its usage must be unchanged at 
least from 12 weeks prior to Visit 1 (screening).
Total prescribed dose must be 10 U/day and 
0.2U/kg/day, and it has to be within a defined area
at least 12 weeks prior to Visit 5 (randomization) in 
patients who are pre-treated by insulin alone and 
from Visit 1 in patients who are pre-treated by
insulin in combination with 1 OAD.
Rationale for change
To carry out the study in common clinical setting 
in Japan, the criterion of the dose of insulin is 
updated. (It is estimated that there are many T2DM 
patients who are treated with insulin which doses 
are more than or equal to 10U/day but below
0.2U/kg/day in common clinical setting in Japan)
Section to be changed
3.3.2 and synopsis (Chang 2)
Description of change
Inclusion criteria 3 is reformulated to:
Fasting C-peptide: 0.6 >0.5 ng/mL at Visit 4 in 
patients who are pre-treated with insulin alone (at 


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Visit 2 in patients who are pre-treated with insulin 
in combination with 1 OAD)
Rationale for change
The criterion was set up to remove the patients who 
are in insulin-dependent state. The treatment Guide 
for Diabetes 2014-2015 says that C-peptide ≤0.5 is 
insulin-depedent state. To match with the treatment 
guide, this is updated.
Section to be changed
5.3.6.1 (Chang 3)
Description of change
The following description for “events involving 
lower limb amputation” is added,
Events involving lower limb amputation
This definition includes amputation (i.e. 
resection of a limb through a bone), 
disarticulation (i.e. resection of a limb through a 
joint) and auto-amputations (i.e. spontaneous 
separation of non-viable portion of the lower 
limb).
Not included in this definition are debridement 
(removal of callus or dead tissue), procedures on 
a stump (like stump revision, drainage of an 
abscess, wound revision etc.) and other 
procedures (e.g., nail resection or removal) 
without a concomitant resection of a limb 
(amputation or disarticulation).
Each lower limb amputation, disarticulation, or 
auto-amputation should be reported separately. 
The SAE report should include the date of the 
procedure, the level of amputation or 
disarticulation, the medical condition(s) leading 
to the procedure and if the patient had some of 
the known risk factor(s) for lower limb 
amputation.
Rationale for change
To align with the updated AESI definition of 
empagliflozin project.
Section to be changed
6.1 (Chang 4)
Description of change
Text reformulated to:
All trial visits (except Visit 1, 5.1 and phone 
contact for Follow up visit) should take place 
between 7:00 AM and 11:00 Am in the morning.
Rationale for change
Clarification (phone visit can be done not in the 
morning) / It is difficult to complete visits’
procedures by 11:00 AM


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Section to be changed
10.1 (Chang 5)
Description of change
Text reformulated to:
 
 
 
 
Rationale for change
Clarification


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03122592
2.0
clinical-trial-protocol-version-02
A 52-week randomised, double-blind, placebo-controlled, parallel-group, efficacy
and safety study of empagliflozin once daily, as add-on to insulin in Japanese patients
with Type 2 Diabetes Mellitus with insufficient glycaemic control
Approval-Team Member Medicine
13 Sep 2016 12:12 CEST
Author-Trial Clinical Monitor
13 Sep 2016 12:31 CEST
Author-Trial Statistician
15 Sep 2016 09:47 CEST
Approval-Clinical VP
19 Sep 2016 20:17 CEST
Verification-Paper Signature
Completion
28 Sep 2016 03:51 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03122592
2.0

SAP_001.pdf: 
TITLE PAGE
ABCD
Trial Statistical Analysis Plan
c08863148-01
BI Trial No.:
1245.107
Title:
A 52-week randomised, double-blind, placebo-controlled, parallel-
group, efficacy and safety study of empagliflozin once daily, as add-
on to insulin in Japanese patients with Type 2 Diabetes Mellitus 
with insufficient glycaemic control
Including Protocol Amendment [c03122592-02]
Investigational 
Product:
Jardiance®, Empagliflozin
Responsible trial 
statistician:
Phone: 
, Fax: 
Date of statistical 
analysis plan:
26 SEP 2017 SIGNED
Version:
Final
Page 1 of 40
Proprietary confidential information
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATIONS ...............................................................5
3.
INTRODUCTION..................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......8
5.
ENDPOINTS ..........................................................................................8
5.1
PRIMARY ENDPOINT ......................................................................................8
5.2
SECONDARY ENDPOINT ................................................................................8
.8
.8
.9
10
10
11
11
11
11
6.
GENERAL ANALYSIS DEFINITIONS...........................................11
6.1
TREATMENTS..................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................12
6.3
PATIENT SETS ANALYSED..........................................................................15
.17
6.5
POOLING OF CENTRES ................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................18
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................23
7.
PLANNED ANALYSIS.......................................................................26
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........26
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................27
7.3
TREATMENT COMPLIANCE .......................................................................27
7.4
PRIMARY ENDPOINT ....................................................................................27
7.4.1
Primary efficacy analysis..............................................................................28
7.5
SECONDARY ENDPOINT ..............................................................................29
30
30
7.7
EXTENT OF EXPOSURE................................................................................31
7.8
SAFETY ANALYSIS.........................................................................................31
7.8.1
Adverse events ...............................................................................................31
7.8.1.1
Assignment of AEs to treatment.................................................................32
7.8.1.2
Analysis of other significant AEs...............................................................32


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7.8.1.3
AE summaries.............................................................................................32
7.8.1.4
Analysis of hypoglycaemic events .............................................................33
7.8.1.5
AEs of special interest (AESI)....................................................................34
7.8.1.6
Events qualifying for external adjudication by the Clinical Event 
Committee (CEC).......................................................................................35
7.8.1.7 Analysis of adjudicated events ......................................................................35
7.8.1.8
AEs while patients taking wrong medication.............................................35
7.8.2
Laboratory data.............................................................................................35
7.8.3
Vital signs.......................................................................................................38
7.8.4
ECG ................................................................................................................38
7.8.5
Creatinine and eGFR time curve analysis ..................................................38
7.8.6
Lipid parameter and FFA analyses .............................................................38
7.8.7
Ketone bodies analyses..................................................................................38
8.
REFERENCES.....................................................................................39
40
10.
HISTORY TABLE...............................................................................40


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LIST OF TABLES
Table 6.1: 1
Treatment regimens / study intervals ..............................................................12
Table 6.2: 1
Important Protocol Violations.........................................................................13
Table 6.3: 1
Summary of which data sets will be used for which class of endpoints .........16
17
Table 6.7: 1
Endpoint specific follow-up period for the assignment to active treatment....24
Table 6.7: 2
Time windows for on-treatment efficacy measurement scheduled for each on-
treatment visit 25
Table 7.8.2: 1
eGFR staging (by Japanese formula)..........................................................36
Table 7.8.2: 2
Cockcroft-Gault eCcr staging.....................................................................37


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
ALQ
Above Limit of Quantification
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical classification
BC
Body composition (set)
BI
Boehringer Ingelheim
BICMQ
BI-customized MedDRA query
BLQ
Below the limit of quantification
BMI
Body mass index
BRPM
Blinded report planning meeting
CEC
Clinical event committee
CRF
Case report form
CT
Concomitant therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DBP
Diastolic blood prressure
DI
Disposition index
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
eCcr
Estimated creatinine clearance rate
ECG
Electrocardiogram
eCCr
Estimated creatinine clearance
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate
EMA
European medicines agency
EoT
End of treatment
FAS
Full analysis set


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Term
Definition / description
FPI
Fasting plasma insulin
gCV
Geometric coefficient of variation
gMean
Geometric mean
HbA1c
Glycated haemoglobin
HCRU
Health care resource utilisation
HOMA-IR
Homeostatic model assessment - insulin resistance
HOMA-IS
Homeostatic model assessment - insulin secretion
ICH
International Conference on Harmonisation
INN
International non-proprietary names
IPV
Important protocol violation
IRC
Independent Review Committee
ITT
Intention to treat
IVRS
Interactive Voice Randomisation System
IWRS
Interactive Web Randomisation System
LOCF
Last observation carried forward
LQ
Limit of quantification
MDRD
Modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effect Model Repeated Measures
MQRM
Medical Quality Review Meeting
NCF
Non-completers considered failure
O*C
Oracle Clinical
OC
Observed case
OC-IR
Observed cases, including values after rescue
OLS
Open label set
OR
Original results
PK
Pharmacokinetics
PPG
Postprandial glucose
PPS
Per protocol set


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Term
Definition / description
PT
Preferred term
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
RS
Randomised set
SBP
Systolic blood pressure
SCR
Screened set
SD
Standard deviation
SDL
Subject data listing
SMQ
Standardised MedDRA query
SOC
System Organ Class
SSC
Special search category
SUB
Sub-searches
TBL
Total bilirubin
TOC
Table of contents
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
UTI
Urinary tract infection
WHO
World Health Organisation
3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9, the purpose of this document is 
to provide a more technical and detailed elaboration of the principal features of the analysis 
described in the protocol, and to include detailed procedures for executing the statistical 
analysis of the primary and secondary variables and other data.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
SAS® Version 9.2 or later version will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP have already been outlined in the CTP. There are no 
changes compared to the planned analysis of the study.
5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint in this study is the change from baseline in HbA1c after 16 weeks of 
treatment. Throughout the study protocol, the term "baseline" refers to the last observation 
prior to the administration of any randomised study medication.
5.2
SECONDARY ENDPOINT
The secondary endpoint is proportion of patients with drug-related adverse events during 52 
weeks of treatment.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
There will be four treatment phases in this trial: screening, study treatment phase (with 10 mg 
or 25 mg empagliflozin or matching placebo), post-treatment and post-study. 


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The purpose of the definitions below is to describe all the different study/treatment intervals, 
in which a patient can lie during the course of the trial. Note that the term "treatment 
regimen" can also cover time periods with no active treatment.
Table 6.1: 1
Treatment regimens / study intervals
Label
Interval
Start date
Start time
Screening
Screening
Date of informed consent
00:00
Placebo/ 
Empagliflozin 10mg/
Empagliflozin 25mg
Treatment
Date of first 
administration of study 
medication
Time of first 
administration 
of study 
medication
12:00 if missing
Post-treatment
Post-treatment
Date of last intake of 
study drug +1 day
00:00 
Post-study
Post-study
Date of trial completion 
(in termination page of 
eCRF) + 1 day
00:00 
For efficacy and safety analyses, measurements will still be considered on-treatment during a 
follow-up period specific to each parameter. These follow-up periods are defined in Table 
6.7: 1.
The efficacy analyses will follow the intention-to-treat (ITT) principle in assigning patients to 
treatment groups, i.e. patients will be analysed as randomised. 
Safety analyses will assign patients to the treatment group as treated. If a patient erroneously 
receives the wrong trial drug, the patient will be analysed as per the first treatment received. 
The only exception will be drug-related adverse events (AE) which will be analysed based on 
the actual treatment taken at the time of the AE onset. Additionally, the AEs with an onset 
during the time of the incorrect study treatment will also be listed separately.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Not all important protocol violations (IPV) will generate exclusion from the per protocol 
population. Violations that lead to exclusion from analysis populations are indicated as such 
in Table 6.2.1
The decision about which IPV could generate exclusion from analysis sets will be taken 
during the course of the study and finalised at the last blinded report planning meeting 
(BRPM).


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Table 6.2: 1
Important Protocol Violations
Category / 
Code
Description
Comment/Example
Excluded 
from 
A
Entrance Criteria Not Met
A1
Target indication not met
A1.01
No type 2 diabetes
INC1 checked
PPS
A1.02
Antidiabetic background therapy not 
as required
INC2 checked
PPS 
A2
Inclusion criteria violated
A2.01
HbA1c out of range 
HbA1c out of range for inclusion by 
more than 0.2%
for insulin alone:
[7.5%, 10%] at Visit 1
for insulin with 1 OAD: 
[7.0%, 9.5%] at Visit 1
[7.5%, 10%] at Visit 4
PPS
A2.02
Age out of range 
INC6 checked and calculated date 
checked
None
A2.03
BMI out of range 
INC7 checked
None
A2.06
Fasting serum C-peptide levels out of 
range
INC3 checked
None
A3
Exclusion criteria violated
A3.01
Uncontrolled FPG level
EXC1 checked
None
A3.02
Additional background therapy 
EXC2 checked
PPS
A3.03
Relevant concomitant diagnoses 
EXC3, EXC7 checked
None
A3.04
Bariatric or other relevant 
gastrointestinal surgery within the 
past two years
EXC6 checked.
PPS
A3.05
Blood dyscrasias or any disorders 
causing hemolysis or unstable red 
blood cell
EXC8 checked
PPS
A3.06
Indication of liver disease 
EXC4 checkedParameters above 3 
ULN at screening or during run-in 
period
None
A3.07
Contraindication to any of the drugs 
in the study regimen
EXC9 checked
None
A3.08
Treatment with protocol excluded 
anti-obesity drugs
EXC11 checked
PPS
A3.09
Renal insufficiency or renal 
impairment (assessed by eGFR) 
EXC5 checked:
eGFR < 45mL/min/1.73m2 during 
screening or run-in period
PPS
A3.10
Treatment with protocol excluded 
systemic steroids or change in thyroid 
hormone dose
EXC12 checked
PPS
A3.11
Intake of an investigational drug in 
another trial within 30 days prior to 
intake of study medication in this trial 
EXC15 checked, review at 
MQRM/BRPM to determine 
efficacy impact
(Medical judgement), depending 
on the type of drug given in the 
prior trial (only if investigational 
drug interferes with glucose 
metabolism).
PPS
Final 
decision at 
the DBL 
meeting
A3.12
Specific exclusion criterion for pre-
menopausal women violated
EXC13 checked
None


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Category / 
Code
Description
Comment/Example
Excluded 
from 
A3.13
Relevant alcohol or drug abuse and 
other conditions affecting study 
compliance
EXC14 checked 
None
A3.14
Any other clinical condition unsafe 
for participation that would 
jeopardize patient safety while 
participating in this clinical trial 
EXC16 checked.
None
A3.26
Known allergy or hypersensitivity to 
insulin or empagliflozin
EXC10 checked
None
B
Informed Consent
B1
Informed consent not available
INC8 checked, 
No signature, or Inform consent 
date missing
Patient’s data will not be used at 
all
All
B2
Informed consent too late
INC8 checked
Inform consent date > Visit 1 
date/date of any study procedure
None
C
Trial medication and randomisation
C1
Incorrect Trial Medication Taken
C1.01
No study medication taken
Patient randomised according to 
IRT but no medication taken 
according to eCRF or IRT
TS
C1.02
Incorrect trial medication taken
Wrong medication taken for more 
than 20% of the treatment duration 
up to Visit 10 or for more than 
20% of the last visit interval before 
the primary endpoint assessment 
(different medication than the 
patient was randomised to taken 
i.e. drug kit recorded in eCRF from 
different treatment group than drug 
kit assigned by IRT)
Can only be judged after DBL 
since unblinding information is 
required
PPS
C2
Randomisation not followed
C2.01
Treated without randomisation
Patient treated according to eCRF 
but not randomised according to 
IRT. 
PPS
C3
Non-compliance
C3.01
Non-compliance with drug intake
During the treatment period, 
overall study treatment compliance
up to Visit 10 outside 80% and 
120% (exclusive) or study 
treatment compliance below 80% 
in the last visit interval up to Visit 
10.
PPS
C3.03
Last treatment more than 7 days prior 
to next visit
Last treatment prior to Visit 10 was 
more than 7 days prior to next 
visit.
PPS


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Category / 
Code
Description
Comment/Example
Excluded 
from 
C4.01
Medication code broken without just 
cause
Medication code was broken prior 
to Visit 10 for no valid reason.
[manual check. Final decision at 
the DBL meeting based on medical 
judgement. This decision will 
overwrite the programmed result.]
PPS
Final 
decision at 
the DBL 
meeting
Concomitant Medication
D2
Prohibited medication use 
D2.01
Use of prohibited medication 
Review of eCRF for prohibited 
medication.  If first prohibited 
medication was taken prior to Visit 
10 then exclude from PPS. If first 
prohibited medication was taken 
between Visit 10 and end of 
treatment then do not exclude from 
PPS. 
[manual check. Final decision at 
the DBL meeting based on medical 
judgement. This decision will 
overwrite the programmed result.]
PPS/None
D3
Mandatory medication not taken
D3.01
Background antidiabetic therapy not 
taken as specified in the protocol
- Changes in insulin total daily 
dose outside +/-10% or +/-2U
range from baseline prescribed 
dose before Visit 10 for more than 
7 consecutive days and not for 
rescue (exclude from PPS). If the 
change in insulin consists of 
several records of consecutive 
changes, it will be considered "not 
for rescue" only if none of the 
records are checked at “Yes” for 
“Rescue medication” in eCRF.
PPS
E
Missing data
E1.01
No baseline HbA1c value
No valid baseline HbA1c value
FAS
I2
Pregnancy monitoring
I2.01
Pregnancy
Positive pregnancy test or manual 
iPV
None
I2.02
Pregnancy test not done for woman
of child bearing potential for at least 
one visit before treatment 
discontinuation
None
6.3
PATIENT SETS ANALYSED
The following analysis sets will be defined for this trial.

SCR – Screened patients set
All patients screened for the trial, with informed consent given and who completed at 
least one screening procedure at Visit 1. 


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
RS – Randomised set
All patients from the screened set who were randomised to study drug, regardless of 
whether any study drug was taken. 

TS – Treated set
All patients randomised and treated with at least one dose of study drug. The TS is the 
basis for safety analyses.

FAS – Full analysis set
All patients randomised, treated with at least one dose of study drug, and with a 
baseline HbA1c value. The FAS is the basis for the ITT analysis. 

PPS – Per-protocol set
All patients in the FAS without IPV leading to exclusion. See Table 6.2:1.
In Table 6.3: 1 the data sets which are to be used for each category class of endpoint are 
illustrated.
Table 6.3: 1
Summary of which data sets will be used for which class of endpoints
Class of endpoint 
SCR
TS
FAS
PPS
Primary endpoint (at 
week 16)
LOCF-16,
OC-16
LOCF-16
 
 
 
 
 
 
Safety endpoints
OR,
OC-IR^
Disposition
OR
Demographics
OR
Baseline efficacy
OC-16
#OR results will only be presented for time to first rescue medication and number of patients with rescue.
^ OC-IR will only be used for lipids.
 
 
Similarly, note that patient set PPS is only applicable to analysis performed at week 16.
Note that the number of patients with available data for an endpoint may differ. For details, 
see Section 6.6 “Handling of missing data”.


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6.5
POOLING OF CENTRES
Centres will not be pooled.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Based on the different reasons of patients’ data missing for different endpoints, various 
methods will be used to assess the impact of missing data on the efficacy endpoints of this 
trial, depending upon the type of the endpoint (see Table 6.3.1).
 
 
 


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Original result (OR) analysis
Original result analysis implies the analysis of data exactly as observed, no time-windowing 
as described in Section 6.7. OR analysis will be performed on endpoints that are either not 
affected by patients’ rescue medication use or if it is not meaningful to apply any imputation 
rule on them for replacing the missing values. 
Observed cases analysis at week 16 (OC-16)
For efficacy endpoints at week 16, it is planned to analyse only the available data that were 
observed while patients were on treatment, i.e., excluding the missing data. In other words, 
OC-16 analysis will be performed and missing data in this analysis will not be replaced. 
This OC-16 technique will set all values measured after rescue medication taken to missing. 
The criterion for rescue medication for this analysis types is based on the definition of rescue 
medication for the analysis of efficacy endpoints at week 16, as described in Section 5.3.3.1. 
It includes changes in insulin above and/or below the range +/- 10% or +/- 2U from the 
baseline prescribed dose for 8 consecutive days or more.
As insulin dose can be adjusted after Visit 10, values collected after visit 10 will also be set to 
missing for the OC-16 technique.  
Observed cases analysis at week 52 (OC-52)
For efficacy endpoints at week 52, a similar OC technique will be used but considering a 
different criteria for setting values measured after rescue medication to missing.
The criterion for rescue medication for OC-52 is based on the definition of rescue medication 
for the analysis of efficacy endpoints at week 52, as described in Section 5.3.3.1. As insulin 
adjustments are allowed between visit 10 and visit 19, changes in insulin use will not be 
considered rescue therapy. This applies to data recorded in all parts of the study (including 
visits 5-10).
Observed cases analysis including values on rescue medication (OC-IR)
In addition, for lipids, the OC-technique will also be adapted without setting the values 
measured after any rescue medication taken to missing (whether this is change in insulin use 
or not), and using the original observed values instead.
For analyses at week 16, the OC-IR technique will set values to missing after the visit 10
date.
Last observation carried forward (LOCF-16, LOCF-52 and LOCF-IR)
An alternative method for quantitative endpoints is to replace missing values due to early 
discontinuation of a patient by her/his last observed measurement. This method tends to result 
in more conservative estimates than an OC-analysis. 


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The last observation need not necessarily be a value selected as a visit value if multiple 
measurements were performed within a time window for a visit. In this case the last on-
treatment value within the time window will be carried forward, while the visit value can be 
the value that was observed closest to the planned visit date or the first value observed in the 
time window. See Table 6.7: 2 for further details.
If a patient is on rescue medication after Visit 5 and before Visit 6, then all the on-treatment 
visits will be set to missing and the baseline HbA1c value will be carried forward to populate 
the missing on-treatment values in HbA1c. 
Missing values within a course of measurements will be interpolated based on the last 
observed value before the missing visit and the first observed value after the missing visit. 
This is independent from the selection of a value as the picked visit value to be used in the 
descriptive analysis by visit.
Let: 
D0 =  date of a visit with a missing endpoint value;
D1 = date of the next-visit (with end-point value non-missing) after the visit with missing 
endpoint;
D-1 = date of a previous-visit (with end-point value non-missing) before the visit with missing 
endpoint;
Ei = endpoint values for visits D-1,D0,D1 for i= -1, 0 and 1.
Then the missing endpoint value can be interpolated as:
E0 = E-1 + ((E1 – E-1) x (D0 – D-1) / (D1 – D-1)).
In general, the values measured after rescue medication was taken during the active treatment 
period by the patients will be set to missing; and these missing values will be imputed by 
LOCF technique. 
As for the OC techniques, two approaches will be used for the criteria of rescue medication, 
whether we are analysing efficacy endpoints at week 16 or at week 52 (see Section 5.3.3.1 for 
more details):

LOCF-16 will be based on the definition of rescue medication for the analysis of 
efficacy endpoints at week 16

LOCF-52 will be based on the definition of rescue medication for the analysis of 
efficacy endpoints at week 52
For the LOCF-16 technique, as insulin dose can be adjusted after Visit 10, values collected 
after visit 10 will also be set to missing, and the missing values will be imputed by LOCF.


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Another technique, LOCF including values on rescue medication (LOCF-IR), will be used, 
when values measured after initiation of rescue medication are not set to missing. For 
analyses at week 16, the values after the visit 10 date will be set to missing prior to LOCF-IR 
imputation.
Missing data will only be imputed up to the planned visit to be reached by all randomised 
patients (week 16 for LOCF-16, week 52 for LOCF-52). 
Non-completers considered failure (NCF-16 and NCF-52)
For binary endpoints, like a treat to target response of HbA1c<7.0%, a conservative method to 
replace missing values is to consider them as “failures”. Missing data due to early 
discontinuation will be replaced as “failure” up to the planned final visit to be reached by all 
patients. 
For binary endpoints that are derived from quantitative endpoints (e.g. HbA1c), missing 
values within a course of measurements on treatment will be replaced on the basis of the 
corresponding imputed value of the underlying quantitative endpoint (e.g. interpolation for 
HbA1c). 
The values measured after rescue medication was taken during the active treatment period by 
the patients will be set to "failures". Two approaches will be used for the criteria of rescue 
medication, whether we are analysing endpoints at week 16 or at week 52 (see Section 
5.3.3.1 for more details):

NCF-16 will be based on the definition of rescue medication for the analysis of 
efficacy endpoints at week 16. For the NCF-16 technique, as insulin dose can be 
adjusted after Visit 10, values collected after visit 10 will be set to missing.

NCF-52 will be based on the definition of rescue medication for the analysis of 
efficacy endpoints at week 52
Safety and other variables
Missing safety data will not be replaced, but an analysis of the changes from baseline to the 
last available value under treatment and the minimum and maximum post baseline will be 
determined for quantitative safety laboratory variables. 
Missing dates and times
a) Missing AE dates
Missing or partial date information for AEs will be replaced according to general BI rules 
described in the BI guidance for handling of missing and incomplete AE dates [1]. 
b) Missing drug administration dates


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If the date of first drug administration is missing but the patient was randomised, the date of 
the first drug administration will be set to the date of randomisation. If the date of first 
administration is partially missing with the month and year present, the day will be set to the 
date of randomisation if randomisation was in the same month. If randomisation was in the 
month prior to the first drug administration the missing day will be imputed as the first day of 
the month. A missing time of first drug administration will be imputed as 12:00 o’clock noon, 
missing administration times at on-treatment visits will be imputed by 8:00 o’clock in the 
morning.
As a general rule, a missing drug stop date will be imputed according to the following 
principles:

If the date is completely missing and an end of treatment (EoT) visit or a Visit 19 is 
documented, it should be the minimum of these two dates.

If the date is incomplete with only month and year, it should be the first day of the 
following month, or the minimum between end of treatment (EoT) visit and Visit 19
(if they are documented).

If the patient is lost to follow-up it should be the date of the last visit + the longest 
treatment duration based on drug supply + 1 day. 

If a patient died during the course of the trial and no additional information about 
drug stop date are available, the date of death will be used as drug stop date assuming 
that the patient took the medication until the day of death.

All other cases need to be assessed by the trial team on an individual basis, trying to 
use the points above as guidance.  
c) Missing dates for concomitant and other antidiabetic therapies
For partial start and stop dates for concomitant therapies (CT) and additional antidiabetic 
drugs the following derivations will be used to impute 'worst case' values. 

If the day of the end date is missing then the end date is set to last day of the month.

If the day and month of the end date are missing then end date is set to 31st December 
of the year

If the day of the start date is missing the start date is set to first day of the month

If the day and month of the start date are missing then the start date is set to 1st
January of the year.

All other cases need to be assessed by the trial team on an individual basis, using the 
above points as guidance
d) Missing Visit 10 date


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The visit 10 date is used as a cut-off date in several situations:

for the definition of several iPVs, in order to identify violations leading to exclusion 
from PPS

for the definition of OC-16 and LOCF-16 imputation techniques, where values 
collected after visit 10 date are set to missing

for summaries of AEs at week 16
For these analyses, if a patient skipped visit 10 (e.g. attended visit 11 or visit 12 as the next 
visit) and visit 10 date is missing as a result, then the planned visit 10 date will be used 
instead, i.e. 112 days from start of study drug.
e) Other dates
Only the year of birth will be collected in the eCRF, and the day and month of birth will be 
imputed as 01 January. For other incomplete date information always the midpoint of the 
possible interval will be used. If only the year is present the day and month will be imputed 
as 01 July, if year and month is present the day will be imputed as 15. If the year is missing, 
the date will be considered missing.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
With regard to efficacy and safety endpoints, the term "baseline" refers to the last observed 
measurement prior to administration of any randomised study medication.
Measurements taken prior to the first intake of randomised study drug will be considered pre-
treatment values. These pre-treatment values will be assigned to a visit according to the 
nominal visit number as recorded on the electronic case report form (eCRF) or as provided by 
the laboratory. 
The date and clock time of the first drug administration will be used to separate pre-treatment 
from on-treatment values. Measurements taken after the first intake of randomised study drug 
will be considered on-treatment values if they have been obtained up to end of the parameter 
specific follow-up period as defined in Table 6.7: 1 below and will be assigned to the 
randomised study drug for efficacy analyses, and to the first study drug taken for safety 
analyses.
Measurements taken after the end of the endpoint specific follow-up period and after the last 
intake of study drug will be considered post-treatment values.


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Table 6.7: 1
Endpoint specific follow-up period for the assignment to active 
treatment 
Endpoint
Last day of assignment to treatment phase
(days after study drug stop date)
Efficacy
HbA1c
7
 
Safety
Adverse events
7
Safety laboratory measurements
3
Pulse rate
1
On-treatment efficacy and safety measurements will be assigned to visits based on time 
windows around the planned visit dates. These time windows are defined based on the 
planned number of days after the date of first administration of study drug (usually this is at 
Visit 5). Reasons to base the time windows on the actual treatment start date rather than the 
randomisation date are:

If first intake of study drug shows a large delay by e.g. more than one week after the date 
of randomisation, a measurement taken four weeks after randomisation rather reflects the 
drug effect after three weeks than after four weeks and thus may underestimate the 
treatment effect at this visit.

With large delays of the introduction of study drug after the randomisation, the time 
window for the first on-treatment visit could include times the patient was not yet on 
study drug.
The time window for the first visit after randomisation starts on the day after the first intake 
of study drug. This maximises the number of measurements used in by visit analyses and 
provides consistency with the LOCF approach, but may lead to an underestimation of the 
treatment effect at the first visit for parameters that react slowly on treatment. 
The midpoint between two on-treatment visits defines the end of a time window, with the 
midpoint being included in the time window of the preceding visit.
The end of the time window of the last on-treatment visit is endpoint dependent (cf. Table 
6.7: 1). 


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Table 6.7: 2
Time windows for on-treatment efficacy measurement scheduled for 
each on-treatment visit 
Time window (actual days on 
treatment)
Visit number
Visit label
Planned days 
Start
End
5
Baseline
0
NA
1A
6
Week 2
14
2
21
7
Week 4
28
22
42
8
Week 8
56
43
70
9
Week 12
84
71
98
10
Week 16
112
99
126
11
Week 20
140
127
154
12
Week 24
168
155
182
13
Week 28
196
183
210
14
Week 32
224
211
238
15
Week 36
252
239
266
16
Week 40
280
267
294
17
Week 44
308
295
322
18
Week 48
336
323
350
19
Week 52
364
351
Study drug stop 
date + XB days
End of 
treatment 
(EoT) visit
For patients who prematurely discontinue treatment, the end of treatment 
(EoT) visit should be the last on-treatment visit. That visit will be assigned 
to a scheduled visit (above) according to the time window it falls into. The 
time window will end XB days after the study drug stop date.
A: only values taken prior to the start of treatment with randomised study drug can be 
considered baseline values.
B: the definition of X is endpoint specific, cf. Table 6.7: 1. 
For examinations that are not planned at every on-treatment visit, the time windows will be 
defined according to the same algorithm, based on the midpoint between the planned visit 
days of such an examination. 
Repeated and unscheduled efficacy and safety measurements will be assigned to the nominal 
visits and listed in the SDL according to the time windows described above. Only one 
observation per time window will be selected for analysis at an on-treatment visit – the value 
will be selected which is closest to the protocol planned visit day. If there are two 
observations which have the same difference in days to the planned day or if there are two 
observations on the same day, the first value will be used. If an observation is available on 
the last day of treatment, this observation will be preferably selected over any later 
observation that is still within the time window (not applicable for standard laboratory 
summaries). If there are multiple values within the time window of the last visit, including a 
value on the last day of drug intake, the value on the last day of drug intake is used as the 
value of the last visit.


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Note: for LOCF imputation, the last observed on-treatment value will be carried forward, 
whether or not it was selected in the previous time window. For interpolation only selected 
values are to be used. For more details on LOCF refer to Section 6.6.
7.
PLANNED ANALYSIS
Disposition of the patient population participating in the trial will be analysed by treatment 
groups and presented in the clinical trial report as a frequency-distribution.
A frequency of patients with IPVs, also summarised by whether the IPV led to exclusion 
from the PPS, will be presented by treatment group for the randomised set. The frequency of 
patients in different analysis sets will also be analysed for each treatment group.
For in-text tables presenting descriptive analysis of the endpoints and other variables 
(analysed in original scale), the set of summary statistics is: N (number of patients with non-
missing values), mean, standard deviation (SD).
For end-of-text tables, the set of summary statistics is: N (number of patients with non-
missing values) / Mean / SD / Min / Q1 (lower quartile) / Median / Q3 (upper quartile) / Max.
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline “Reporting of Clinical Trials and Project Summaries” [5].
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there are actually missing values. Percentages will be 
based on all patients in the respective patient set whether they have non-missing values or 
not.
Treatment comparisons:
In all specified statistical analyses, treatment comparisons will be made between each 
randomised empagliflozin group (10 and 25 mg) and placebo.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive analysis of the following demographic variables measured at baseline will be 
presented:
Sex, age (in years), age groups, BMI (kg/m2), BMI categories, history of hypertension, height
(cm), smoking history and alcohol status, duration of diabetes (categories based on years), 
renal impairment (eGFR and eCCr) and type of insulin therapies. Categories for baseline 
characteristics are defined in Section 6.4.
Descriptive analysis of the following variables measured at baseline will also be presented:


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HbA1c (%), HbA1c categories, fasting plasma glucose (mg/dL), weight (kg), weight 
categories, waist circumference (cm), blood pressure, blood pressure categories and mean
daily glucose.
Both demographic and baseline characteristics tables will be presented for the FAS.
A summary of the number of patients in each randomisation strata per treatment will also be 
shown. This will be based upon the data received from the IRT provider.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report using the FAS. 
Concomitant medication use will be summarised by WHO Anatomical-Therapeutic-Chemical 
classification level 3 (ATC3) and preferred name. Summaries will be presented for 
concomitant therapies taken during randomised treatment and those taken at baseline. 
Separate summaries of use of antihypertensives, ASA or lipid lowering drugs at baseline by 
preferred name will be presented.
Prescribed background medication daily dose at baseline will be presented for total daily 
insulin.
Concomitant diseases will be summarised by MedDRA system organ class and preferred 
term. Relevant diabetic medical history by treatment group will also be presented. Both
summaries will be presented using the FAS.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. The number and 
percentage of patients with overall compliance outside 80% and 120% (exclusive) will be 
reported. The sum of all reported compliance over the planned visits (disregarding run-in) 
will be divided by the total duration (until last visit where medication is returned) to derive 
the overall compliance. The FAS will be considered.
7.4
PRIMARY ENDPOINT
The primary analysis is at 16 weeks and will be performed on the full analysis set (FAS) with 
LOCF-16 being the implemented imputation rule. 
For further information on the imputation rule see Section 6.6.
In all modelling, the variable ‘baseline renal function’ will be defined as last eGFR value 
before first intake of study treatment categorised according to the CKD staging (as explained 
in Section 7.8.2).


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7.4.1
Primary efficacy analysis
The primary analysis is an analysis of covariance (ANCOVA) comparing the change from 
baseline in HbA1c after 16 weeks of treatment. All randomised treatment groups will be 
included in the same analysis. The statistical model will be:
Change from baseline in HbA1c after 16 weeks = overall mean + baseline HbA1c + treatment 
+ baseline renal function + type of insulin therapies + random error
This model includes effects accounting for the following sources of variation: ‘baseline
HbA1c’, ‘baseline renal function’, ‘type of insulin therapies’ and ‘treatment’. ‘Treatment’, 
‘baseline renal function’, and ‘type of insulin therapies’ are fixed classification effects and 
‘baseline HbA1c’ is a linear covariate. Note that baseline renal function refers to the eGFR 
categorization (>=60 mL/min/1.73 m2, <60 mL/min/1.73 m2). Such categorization is 
applicable to the analysis of other endpoints as well.
The random error is assumed to be normally distributed with mean 0 and unknown variance. 
The primary analysis will be performed on the FAS with treatment assignment as 
randomised. 
A hierarchical testing sequence will be used as defined in the protocol. 


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7.5
SECONDARY ENDPOINT
Refer to Section 7.8 for the analysis of secondary endpoint.


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7.7
EXTENT OF EXPOSURE
A descriptive statistics table of the extent of exposure with mean, SD, median and range of 
the number of days a patient was on treatment will be provided for the treated set. 
This table will also provide the sum total of the time (in years) that all patients pooled 
together were on treatment. A separate listing will be created of any patients that switched 
treatment at any time indicating exposure to each treatment. This will also be defined as a 
protocol violation. 
Frequencies of number and percent of patients belonging to each categorical range of 
exposure weeks will be provided as well. The following are the categories of exposure-ranges 
(in weeks):
>0 to 4 weeks, >4 to 10 weeks, >10 to 16weeks, >16 to 24 weeks, >24 to 32 weeks, >32 to 42
weeks, >42 to 52 weeks, >52 weeks
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
7.8.1
Adverse events
AEs will be coded using the most recent version of the MedDRA coding dictionary. 
The analyses of adverse events will be descriptive in nature. All analyses of AEs will be 
based on the number of patients with AEs (not the number of AEs). For this purpose, AE data 
will be combined in a 2-step procedure into AE records.
In a first step, AE occurrences, i.e. AE entries on the CRF, will be collapsed into AE episodes 
provided that all of the following applies:

The same MedDRA lowest level term was reported for the occurrences

The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence. Hypoglycaemic events are only collapsed if they 
occur within 12 hours of each other. The 12 hour period will begin with the first 
hypoglycaemia onset time. If another event occurs outside this initial 12 hour window 
a new period for collapsing will begin.)


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
Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence
In a second step, AE episodes will be condensed into AE records provided that the episodes 
were reported with the same term on the respective MedDRA level and that the episodes are 
assigned to the same treatment. For further details on summarization of AE data, please refer 
to the guideline ‘Handling and summarization of adverse event data for clinical trial reports 
and integrated summaries’ [2].
7.8.1.1
Assignment of AEs to treatment
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till 7 days after 
last drug intake will be assigned to the randomised treatment. All adverse events occurring 
before first drug intake will be assigned to ‘pre-treatment’ and all adverse events occurring 
after last drug intake + 7 days with be assigned to ‘post-treatment’. 
7.8.1.2
Analysis of other significant AEs
Other significant AEs will be reported and summarised according to ICH E3 criterion [3]. 
Thus, AEs classified as ‘other significant’ will include those non-serious and non-significant 
adverse events with:
(i)
‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii)
Marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality 
Review meeting (MQRM) or BRPM.
7.8.1.3
AE summaries
An overall summary of adverse events will be presented. 
The frequency of patients with adverse events will be summarised by treatment, primary 
system organ class and preferred term. AEs will also be reported by intensity. Separate tables
will be provided for patients with other significant adverse events, for patients with adverse 
events of special interest (AESI), for patients with serious adverse events, for patients with 
AEs leading to discontinuation, and for patients with drug-related AEs.
The system organ classes will be sorted according to the standard sort order specified by 
EMA, preferred terms will be sorted by frequency (within system organ class).
The following AE summaries will also be provided at week 16, including data up to visit 10
date only: AE overall summary, the frequency of patients with AEs summarised by treatment, 
primary system organ class and preferred term, frequency of patients with AEs reported by 
intensity, patients with other significant adverse events, patients with adverse events of 
special interest (AESI), patients with serious adverse events, patients with AEs leading to 


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discontinuation, patients with drug-related AEs, and analyses of hypoglycaemic events (as 
described in Section 7.8.1.4).
7.8.1.4
Analysis of hypoglycaemic events
The investigator will record for each AE whether it represents a hypoglycaemic event and, if 
so, record additional information to assess the intensity of the hypoglycaemic event. On the 
basis of this information the hypoglycaemic event will be classified as:

asymptomatic hypoglycaemia: event not accompanied by typical symptoms of 
hypoglycaemia but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 
mg/dL), 

documented symptomatic hypoglycaemia with a measured plasma glucose concentration 
≥ 3.0 mmol/L and ≤ 3.9 mmol/L (≥ 54 mg/dL and ≤ 70 mg/dL): event accompanied by 
typical symptoms of hypoglycaemia, 

documented symptomatic hypoglycaemia with a measured plasma glucose concentration 
< 3.0 mmol/L (< 54 mg/dL): event accompanied by typical symptoms of hypoglycaemia 
but no need for external assistance, 

severe hypoglycaemic episode: event requiring the assistance of another person to 
actively administer carbohydrate, glucagon or other resuscitative actions. 

symptomatic hypoglycaemia and plasma glucose concentration > 3.9 mmol/L (70 mg/dL) 

symptomatic hypoglycaemia and plasma glucose concentration not measured
Different tables will be shown for (i) patients with investigator defined asymptomatic or 
symptomatic hypoglycaemia reported as AE or non-AE, and (ii) patients with confirmed 
hypoglycaemic adverse events, i.e. hypoglycaemic adverse events that had a plasma glucose 
concentration ≤ 70 mg/dL or required assistance.
The number of patients with hypoglycaemia according to investigator’s judgement will be 
tabulated by treatment group. A subgroup analysis of confirmed events with respect to age 
category, rescue therapy and renal function will be performed and the impact of treatment on 
the occurrence of hypoglycaemia will be explored using logistic regression with model 
involving treatment and continuous baseline HbA1c. Time to the onset of the first 
hypoglycaemia will be analysed by Kaplan-Meier estimates. The logistic regression and 
Kaplan-Meier analysis will be performed on confirmed events.
Summaries of hypoglycaemic events will include total number of hypoglycaemic events, 
descriptive hypoglycaemic event rate, number of episodes per patient, severity and intensity 
of the worst episode, action taken, minimum glucose level of worst episode, and time to onset
of first episode. Hypoglycaemic events will also be summarised by baseline eGFR category 
(CKD staging), background medication and age group.
In the number of episodes analysis, hypoglycaemic events will be collapsed with the 
collapsing following the description at the start of Section 7.8.1 but the condensing will not 
be conducted in order to maintain multiple episodes per patient.


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7.8.1.5
AEs of special interest (AESI)
The protocol defines the following adverse events that for analysis purposes will be 
considered as AESIs:

Decreased renal function

Hepatic injury 

Metabolic acidosis, ketoacidosis and DKA

Events involving lower limb amputation
Events of these AESIs are identified through the AE being flagged by the investigator as an 
AESI on the case report form (CRF).
AE frequency tables will also be created for renal and hepatic events based on narrow SMQs.
Renal:
20000003 Acute renal failure
Hepatic:
20000008 Liver related investigations, signs and symptoms (SMQ)
20000009 Cholestasis and jaundice of hepatic origin (SMQ)
20000010 Hepatitis, non-infectious (SMQ)
20000013 Hepatic failure, fibrosis and cirrhosis and other liver damage-related
conditions
Metabolic acidosis, ketoacidosis and DKA
The frequency of patients with DKA will be summarised based on the applicable BICMQ at 
the time of the analysis.
Events involving lower limb amputation
The frequency of patients with events involving lower limb amputation will be summarised.
The following specific adverse events will be tabulated by treatment group.

Genital infections (the applicable BICMQ at the time of the analysis)

Urinary tract infections (the applicable BICMQ at the time of the analysis)
Specific adverse events of UTIs and genital infections will additionally be summarised by 
age group, baseline HbA1c, intensity (mild, moderate or severe), whether leading to 
discontinuation of treatment, time of occurrence (in the first 3 months of treatment or after), 
duration (<7 days, 7-14 days and >14 days), sex, by how the event was treated (no treatment, 
therapy assigned, hospitalisation) and the number of episodes per patient. In the number of 
episodes analysis of UTI and genital infection AEs will be collapsed within each BIcMQ
regardless of preferred term with the collapsing following the description at the start of 


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Section 7.8.1 but the condensing will not be conducted in order to maintain multiple episodes 
per patient.
Kaplan-Meier time to event analyses will also be presented for the UTI and genital infections 
specific adverse events.
Analysis of complicated UTI
Complicated UTI includes serious AEs of narrow BIcMQ UTI, all events of sub-BIcMQ 
pyelonephritis and all events of preferred term Urosepsis. Frequency of patients with 
complicated UTI will be summarized.
An additional specific adverse events of volume depletion will be tabulated.
Volume depletion: the applicable BICMQ at the time of the analysis
7.8.1.6
Events qualifying for external adjudication by the Clinical Event Committee (CEC)
An independent external CEC regularly reviews events and evaluates whether pre-specified 
criteria for these adjudication endpoints are met. Details on composition of the CEC, 
responsibilities and clinical event definitions are provided in a separate CEC Charter
The CEC will be provided with additional, specified background material on the patients with 
these events and perform an assessment of the events.
Adjudication assessments will be incorporated to the database. Frequency tables will be 
provided.
7.8.1.7 Analysis of adjudicated events
Hepatic events will be adjudicated by an external expert committee. The patients with 
adjudicated hepatic events will be summarized.
7.8.1.8
AEs while patients taking wrong medication
A listing will be provided for AEs that had onset while a patient was taking the wrong 
medication.
7.8.2
Laboratory data
For continuous safety laboratory parameters standardised and normalised values will be 
derived as well as the differences from baseline. The process of standardisation and 
normalisation as well as standard analyses for safety laboratory data are described in the BI 
guidance for the Display and Analysis of Laboratory Data [4]. All analyses considering 
multiple of times upper limit of normal (ULN) will be based on original and not normalised 
data.
The frequency of the number of patients with AST/ALT elevations >= 3xULN, >= 5xULN, 
>= 10xULN, and >= 20xULN will be displayed.


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To support analyses of liver related adverse drug effects, analysis of patients with AST and/or 
ALT≥3xULN with concomitant or subsequent TBILI≥2xULN in a 30 day period after 
AST/ALT elevation will also be performed.
The start of the 30 day time span is triggered by either liver enzyme elevation above the 
defined thresholds. Patients who fulfil one of the criteria for ALT/AST or total bilirubin 
elevations above and have no information available for the remaining parameter(s) at the 
same time-point or within the 30 day time window will not be listed under "ALT and/or 
AST≥3xULN with Total Bilirubin ≥ 2xULN". 
Patients with elevations as described will be summarised and stratified by Alkaline 
phosphatase < 2xULN and >=2xULN. 
All calculations for the grading of renal function will be based on the originally measured 
laboratory values given by the laboratory, not on normalised values with BI standard 
reference ranges.  The creatinine clearance and glomerular filtration rate will be estimated 
according to the two formulas and stored in the trial databases:

Cockcroft-Gault formula (mL/min): 
eCcr = (140 – age) x (weight in kg) x (0.85 if female) / (72 x creatinine (mg/dL))

Japanese formula (mL/min/1.73m2): 
eGFR (mL/min/1.73m2) = 194 x [Serum creatinine (mg/dL)]-1.094 x [age]-0.287 x [0.739 if 
patient is female]
Age will be considered as a discrete variable for the above calculations, and from the same 
visit.
For the analysis of eGFR and for the covariates in the statistical modelling the values 
calculated from the above formula using the serum creatinine values from the central 
laboratory will be used, not the eGFR values provided by the central laboratory. For the 
assignment of IPVs based on renal function the central laboratory values will be used.
To support analysis of renal function, eGFR throughout the trial will be categorised according 
to the following eGFR staging.
Table 7.8.2: 1
eGFR staging (by Japanese formula)
Stage
eGFR [mL/min/1.73m²]
Description
1
≥90
Normal renal function 
2
60 to <90
Mild renal impairment
3
30 to <60 
Moderate renal impairment
4
<30
Severe to end-stage renal impairment
Staging of the eCcr will be prepared with respect to the following categorisation and a shift 
table will be supplied for eCcr as well.


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Table 7.8.2: 2
Cockcroft-Gault eCcr staging
Stage
eCcr [mL/min]
Description
1
≥90
Normal renal function 
2
60 to <90
Mild renal impairment
3
30 to <60
Moderate renal impairment
4
<30
Severe renal impairment and beyond
(e.g., End-stage renal disease)
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (see DM&SM: Display and Analysis of Laboratory Data) [4]
Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomised study drug. Laboratory measurements taken up to 3 days after the last 
administration of randomised study drug will be considered as on-treatment.
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of patients within and outside the reference range at baseline and the 
last measurement on treatment. Descriptive statistics will be provided by treatment group for 
baseline, on-treatment values and for changes from baseline. Frequency tables will 
summarise the number of patients with potentially clinically significant abnormalities as 
defined for the new XLAB macro. Summaries will also be presented for patients with 
elevated liver enzymes. A summary will also be created representing the number of patients 
per treatment group that experienced a doubling in creatinine on treatment compared to 
baseline that was out of the normal range.
Only patients with at least one available on-treatment value will be included in the analysis of 
an individual laboratory parameter. All individual data will be presented in listings. 
Urine creatinine does not have a reference range and is determined to calculate the albumin / 
creatinine ratio. Only the albumin / creatinine ratio will be analysed as for urine creatinine no 
normalised values can be derived. In cases where urine albumin values are reported to be 
BLQ (e.g. <3 mg/L) the albumin / creatinine ratio is determined as missing and will not be 
replaced by estimated values. Four additional summaries will be presented for the descriptive 
statistics of urine albumin/creatinine ratio by baseline value (normal <30mg/g, 
microalbuminurea 30-<300 mg/g and macroalbuminurea ≥300 mg/g) and transitions from 
baseline based on the aforementioned categories. Similar analyses will be provided for urin 
albumin with the following categories (<20mg/L; 20-<200mg/L; ≥200mg/L).
A shift table from baseline to last value on treatment for eGFR (Japanese formula) will be 
provided in Section 15 and a shift table from baseline to last value on treatment for eCcr 
(Cockcroft-Gault) will be provided in Section 16.1.9.2.
General laboratory evaluation will also be provided for bone markers.


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7.8.3
Vital signs
Other than the analysis of SBP and DBP as efficacy endpoints only descriptive statistics are 
planned for the summary of pulse rate (bpm), change from baseline in pulse rate over time up 
to week 52. 
7.8.4
ECG
12-lead ECG measurements will be taken at baseline (visit 5), visit 8, visit 10, visit 13, visit 
16 and visit 19. ECG-findings before first intake of trial drug will be considered as baseline 
condition. Any clinically significant new findings in the ECG measurement after the first 
screening ECG were to be reported by the investigator as AEs and will be analysed as 
planned in Section 7.8.1.
7.8.5
Creatinine and eGFR time curve analysis
Descriptive statistics will be created for creatinine and eGFR values over time by treatment 
and presented in tables. Descriptive statistics for eCcr will be presented in Section 16.1.9.2. 
These data will be used to create plots of the parameters over time. Subgroups tables of these 
descriptive statistics over time will also be presented for age subgroups.
7.8.6
Lipid parameter and FFA analyses
Lipid parameters and FFA will be analysed using descriptive statistics and MMRM
modelling. Descriptive statistics will be shown over time for the treated set (LOCF-IR and 
OC-IR) including change from baseline and percent change from baseline. For each lipid 
parameter and FFA, separate MMRM models will be fitted on the treated set (OC-IR) for 
both change from baseline at week 52 and percentage change from baseline at week 52 as 
dependent variables. The MMRM models will include ‘baseline lipid’ (only for lipid 
parameters), ‘baseline FFA’ (only for FFA) and ‘baseline HbA1c’ as continuous covariates 
and ‘baseline eGFR (Japanese formula)’, ‘type of insulin therapies’, ‘treatment’, ‘visit’ and 
‘treatment by visit interaction’ as fixed effects.
7.8.7
Ketone bodies analyses
Descriptive statistics will be created for blood ketone bodies (total ketone body, acetoacetic 
acid, 3-hydroxybutyric acid) over time.


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", version
2.0; IDEA for CON.
2
001-MCG-156:  "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON 
3
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
guideline topic E3, current version; Note For Guidance on Structure and Content of 
Clinical Study Reports 
4
001-MCG-157: "Display and Analysis of Laboratory Data", current version, in: 
IDEA for CON.  
5
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current 
version, in: IDEA for CON.  


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date 
(DD-MMM-
YYYY)
Author
Section 
changed
Brief description of change
Final
26-SEP-2017
 
None
This is the final TSAP without 
any modification