Clinical trial NCT02589626
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim
Start date: 2015-10-29; Completion date: 2017-06-02
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomised, double-blind, parallel-group, safety and efficacy study of empagliflozin as add-on to GLP-1 RA in Japanese patients with Type 2 Diabetes Mellitus with insufficient glycaemic control

Detailed description:

Arms: arm 1: empagliflozin 10 mg tablet and placebo matching empagliflozin 25 mg tablet arm 2: empagliflozin 25 mg tablet and placebo matching empagliflozin 10 mg tablet
Interventions: intervention 1: empagliflozin 10mg intervention 2: empagliflozin 25 mg 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:
c03122586-03
BI Trial No.:
1245.106
BI Investigational 
Product:
Jardiance®, Empagliflozin 
Title:
A 52-week randomised, double-blind, parallel group, safety and 
efficacy study of empagliflozin once daily as add-on therapy to 
glucagon-like peptide-1 receptor agonist in Japanese type 2 
diabetes mellitus patients with insufficient glycaemic control
Brief Title:
Empa add-on to GLP-1 RA (Japan)
Clinical Phase:
IV
Trial Clinical 
Monitor:
Phone:
Fax:
Coordinating 
Investigator:
Phone: 
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendments 2)
Version and Date:
Version:
Date:
3.0
20 January 2017
Page 1 of 73
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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance®
Name of active ingredient:
Empagliflozin
Protocol date:
31 AUG 2015
Trial number:
1245.106
Revision date:
20 JAN 2017
Title of trial:
A 52-week randomised, double-blind, parallel group, safety and efficacy study of 
empagliflozin once daily as add-on therapy to glucagon-like peptide-1 receptor 
agonist in Japanese type 2 diabetes mellitus patients with insufficient glycaemic 
control
Coordinating
Investigator:
Trial site(s):
Multi-centre trial in Japan
Clinical phase:
IV
Objective(s):
The objective of the study is to investigate the safety and efficacy of empagliflozin 
(10 mg and 25 mg once daily) given for 52 weeks as add-on therapy to a glucagon-
like peptide 1 (GLP-1) receptor agonist (RA) in Japanese patients with type 2 
diabetes mellitus who have insufficient glycaemic control.
Methodology:
Randomised, double-blind, parallel group 
No. of patients: 
total entered:
64 patients (128 patients enrolled)
each treatment:
Empagliflozin 10 mg : 32 patients
Empagliflozin 25 mg : 32 patients
Diagnosis :
Type 2 diabetes mellitus


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance®
Name of active ingredient:
Empagliflozin
Protocol date:
31 AUG 2015
Trial number:
1245.106
Revision date:
20 JAN 2017
Main criteria
for inclusion:
1.
Diagnosis of type 2 diabetes mellitus prior to informed consent
2.
Male and female patients on diet and exercise regimen who are pre-treated 
with any of the following:
A)
Liraglutide at 0.9 mg/day alone for at least 10 weeks prior to Visit 1
(screening visit). 
-
HbA1c at Visit 1 : ≥7.0% and ≤10.0%
B)
Liraglutide at 0.9 mg/day in combination with one oral antidiabetic 
drug (OAD)i) for at least 10 weeks prior to Visit 1 (screening visit). 
-
HbA1c at Visit 1 : ≥7.0% and ≤9.0%
-
HbA1c at Visit 6 : ≥7.0% and ≤10.0%
C)
One OADi) for at least 10 weeks prior to Visit 1 (screening). The 
patients who are suitable for switching to liraglutide treatmentii) after 
Visit 1 at the investigator’s discretion. 
-
HbA1c at Visit 1 and Visit 6: ≥7.0% and ≤10.0% 
i)
Sulfonylurea is permitted as pre-treatment drug only if the 
dose is equal or less than a half of daily maximum approval 
dose. Any other OADs except thiazolidine dione and SGLT-
2 inhibitor are allowed at any dose.
ii)
Patients should stop their OAD and start switching to 0.3 
mg/day of liraglutide at Visit 2 and the dose titration should 
complete within 2-4 weeks and also should be done in 
accordance with Japanese label (i.e., at least 1 week dosing 
period with 0.3 mg/day and 0.6 mg/day each is required.). 
Patients should be treated with liraglutide at 0.9 mg/day for 
at least 10 weeks (at least 14 weeks of switch period is 
required.) prior to placebo run-in period.
3.
Age ≥20 years at informed consent
4.
Body mass index (BMI) ≤40.0 kg/m2 at Visit 1 (screening)
5.
Signed and dated written informed consent by date of Visit 1 in accordance 
with GCP and Japanese legislation
Test product:
Empagliflozin
dose:
10 mg 
25 mg
mode of 
administration:
Oral
Comparator products:
Not Applicable
dose:
Not Applicable
mode of 
administration:
Not Applicable


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance®
Name of active ingredient:
Empagliflozin
Protocol date:
31 AUG 2015
Trial number:
1245.106
Revision date:
20 JAN 2017
Duration of treatment:
-
Screening: 1 weeks
-
Switch period (including titration and washout periods) : 14 weeksi)
Or
Washout period :10 weeksii)
i)
Patients on one OAD 
ii)
Patients on liraglutide plus one OAD
-
Placebo run-in period (open label): 2 weeks
-
Double-blind treatment period: 52 weeks
-
Follow up period: 1 week
Endpoints
Primary endpoint:
-
Proportion of patients with drug-related adverse events (AE) during 52 
weeks of treatment
Secondary endpoint:
-
Change from baseline in HbA1c after 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:
Safety will be assessed by using frequency tabulations and descriptive statistics by 
treatment group. For efficacy, the change from baseline in HbA1c at Week 52 will 
be analysed by using MMRM including the fixed effects treatment, baseline renal 
function, prior use of antidiabetic agents, visit, treatment-by-visit interaction and the 
covariate baseline HbA1c, baseline HbA1c-by-visit interaction.


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FLOW CHART
Trial Period
Screen
-ing
Switch period6
Placebo run-
in period
Double blind treatment period
Follow up
Titration period
Washout period4
Visit
11
2
37
47
5
625
7
7a24
8
9
10
11
12
13
14
15/EOT20
16(flow-
up)21
Study week
0
na26
na26
na26
na26
na26
0
1
4
8
12
20
28
36
44
52
7 days 
from EOT
Days from Visit 1 or Visit 7
(inclusion criterion 2-A)2
1
>
>
>
>
8
1
7
29
57
85
141
197
253
309
365
EOT+7
Days from Visit 1 or Visit 7
(inclusion criterion 2-B)3
1
>
>
8
43
78
Days from Visit 1 or Visit 7
(inclusion criterion 2-C)5
1
8
22
36
71
106
Visit window (days)
na
na26
na26
na26
na26
na26
na
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+7
Informed Consent
X
Medical 
History/Concomitant 
Diagnoses
X
Demographics
X
In-/Exclusion criteria
X
X8
Physical examination9
X
X
X
Vital signs10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
Diet and exercise 
counselling11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Trial Period
Screen
-ing
Switch period6
Placebo run-
in period
Double blind treatment period
Follow up
Titration period
Washout period4
Visit
11
2
37
47
5
625
7
7a24
8
9
10
11
12
13
14
15/EOT20
16(flow-
up)21
Study week
0
na26
na26
na26
na26
na26
0
1
4
8
12
20
28
36
44
52
7 days 
from EOT
Days from Visit 1 or Visit 7
(inclusion criterion 2-A)2
1
>
>
>
>
8
1
7
29
57
85
141
197
253
309
365
EOT+7
Days from Visit 1 or Visit 7
(inclusion criterion 2-B)3
1
>
>
8
43
78
Days from Visit 1 or Visit 7
(inclusion criterion 2-C)5
1
8
22
36
71
106
Visit window (days)
na
na26
na26
na26
na26
na26
na
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+7
Review Food log, completed 
for 3 days11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead-ECG10,12
X
X
X
X
X
X
Pregnancy Test13
X
X
X
X
X
X
Safety lab Tests 
(Urine and Blood)14
X18,23
X
X
X
X
X
X
X22
X
X22
X
X22
X
X
Fasting Plasma Glucose
X23
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X23
X19
X
X
X
X
X
FFA and Ketone bodies
X
X
X
X
X
X
X
X
X
X
Bone markers
X
X
Insulin & glucagon
X
X
SMBGmeasurement and 
check logs15,16
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
Concomitant Therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense placebo run-in 
medication17
X


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Trial Period
Screen
-ing
Switch period6
Placebo run-
in period
Double blind treatment period
Follow up
Titration period
Washout period4
Visit
11
2
37
47
5
625
7
7a24
8
9
10
11
12
13
14
15/EOT20
16(flow-
up)21
Study week
0
na26
na26
na26
na26
na26
0
1
4
8
12
20
28
36
44
52
7 days 
from EOT
Days from Visit 1 or Visit 7
(inclusion criterion 2-A)2
1
>
>
>
>
8
1
7
29
57
85
141
197
253
309
365
EOT+7
Days from Visit 1 or Visit 7
(inclusion criterion 2-B)3
1
>
>
8
43
78
Days from Visit 1 or Visit 7
(inclusion criterion 2-C)5
1
8
22
36
71
106
Visit window (days)
na
na26
na26
na26
na26
na26
na
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+7
Randomisation (via IRT)
X
Dispense double-blind 
medication17
X
X
X
X
X
X
X
X
Medication compliance 
check
X
X
X
X
X
X
X
X
X
Abbreviations: > = skip, EOT=end of trial, na= not applicable, SMBG= Self Monitoring Blood Glucose


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1.
Patients on Visit 1 do not proceed to the next visit until laboratory results are ascertained by their investigator.
2.
If patients on liraglutide alone, directly start placebo run in period (Visit 6) after screening.
3.
If patients on liraglutide and one OAD, stop their OAD at Visit 4 and start washout after screening. 
4.
Day of randomisation for inclusion criterion is 84 days (12 weeks).
5.
If patients on one OAD, stop their OAD and start switching to liraglutide treatment at Visit 2. The dose titration should be completed within 2-4 weeks and also should be 
done in accordance with Japanese label (i.e., at least 1 week dosing period with 0.3 mg and 0.6 mg each is required.) and liraglutide 0.9 mg/day should be maintained for at 
least 10 weeks prior to placebo run-in period.
6.
14 weeks of switch period should be completed.
7.
At least 1 week interval is necessary between Visit 2 and Visit 3 and also between Visit 3 and Visit 4.
8.
Check inclusion and exclusion criteria before making the IRT call/notification.
9.
Complete physical examination (including cardiac, neurological, dermatological, and pulmological) should be performed by the investigator.
10.
Vital signs and ECG must be done prior to blood sampling.
11.
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). A food log does not need to be provided at Visit 
15/EOT.
12.
In addition to the visits indicated, ECG should be recorded in case of respective cardiac symptoms (indicating rhythm disorders or cardiac ischaemia)
13.
For female patients (local urine pregnancy test in women of child bearing potential) 
14.
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 white blood cells
[WBC]) or nitrites, a midstream urine sample for urine culture (for central lab analysis) should be taken.
15.
Self Monitoring Blood Glucose (SMBG) device to be provided at Visit 2 for one OAD, Visit 4 for liraglutide plus one OAD, and Visit 6 for liraglutide alone. Instruction on 
how the device should be used and the frequency of the measurements should be done when SMBG is provided. Additional instructions and training may be done on other 
visits as per investigator´s discretion and considering patient compliance with protocol-defined measurement and clinical status of the patient.
16.
Throughout the whole trial participation, SMBG testing is recommended to be done daily prior to breakfast but should be performed at least weekly prior to breakfast and at 
any time when the patient is symptomatic, i.e., experiences signs/symptoms of hyper- or hypoglycaemia. 
17.
At all the visits, the respective medication number has to be allocated to the patient via IRT. 
18.
For the screening Visit 1, laboratory only includes liver transaminases (AST and ALT), alkaline phosphatase (ALP), serum creatinine, TSH and urinalysis in addition to 
HbA1c and FPG.
19.
HbA1c at Visit 6 is to be skipped if patients are on liraglutide alone.
20.
In case of early discontinuation from double-blind treatment, Visit 15/EOT visit has to be performed within 7 days of the last dose of the study drugs.


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21.
For patients who completed the trial without any persisting adverse event at Visit 15/EOT, a Visit 16 (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 Visit 15/EOT and
patients who prematurely discontinued the 52-week treatment, a Visit 15/EOT and a Visit 16 (as the follow up-visit, physical examination, vital signs, and safety lab and FPG 
measurement should be performed additionally) should be performed after 7 days of the Visit15/EOT (with +7 days allowance) as clinic visits.
22.
Only blood sampling for haematology and urine dipstick test will be performed.
23.
Blood sample can be taken at any time in non-fasted state.
24.
The investigator or a designated site staff member makes a call to patients to confirm patients’ safety through checking their SMBG results, adverse events and concomitant 
therapies.
25.
14 days (+7 days) interval is necessary between Visit 6 and Visit 7
26.
The visit window (day) prior to randomisation has been shown as follows.


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In case of inclusion criterion 2-A
Patients on Visit 1 can proceed to the Visit 6 after laboratory results are ascertained by their investigator.
Trial Period
Screening 
period
Switch period
Placebo Run-in 
period1
Randomisation
Titration period
Washout period1
Visit
1
2
3
4
5
6
7
Study week
0
>
>
>
>
1
0
Days from Visit 1 (inclusion criterion 
2-A)
1
>
>
>
>
8
1
Visit window (day)
na
>
>
>
>
+/-7
na
1
14 days (+7 days) interval is necessary between Visit 6 and Visit 7
In case of inclusion criterion 2-B
Patients on Visit 1 can proceed to the Visit 4 after laboratory results are ascertained by their investigator.
Trial Period
Screening 
period
Switch period
Placebo Run-in 
period2
Randomisation
Titration period
Washout period1
Visit
1
2
3
4
5
6
7
Study week
0
>
>
1
6
11
0
Days from Visit 1 (inclusion criterion 
2-B)
1
>
>
8
43
78
1
Visit window (day)
na
>
>
+/-7
+/-7
+/-7
na
1
At least 10 weeks of washout period should be completed.
2
14 days (+7 days) interval is necessary between Visit 6 and Visit 7


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In case of inclusion criterion 2-C
Patients on Visit 1 can proceed to the Visit 2 after laboratory results are ascertained by their investigator.
Trial Period
Screening 
period
Switch period1,2
Placebo Run-in 
period4
Randomisation
Titration period
Washout period
Visit
1
2
33
43
5
6
7
Study week
0
1
3
5
10
15
0
Days from Visit 1 (inclusion 
criterion 2-C)
1
8
22
36
71
105
1
Visit window (day)
na
+/-7
+/-7
-14/+7
-14/+7
+/-7
na
1
At least 14 weeks of switch period should be completed.
2
Liraglutide 0.9 mg/day should be maintained for at least 10 weeks prior to placebo run-in period.
3
At least 1 week interval is necessary between Visit 2 and Visit 3 and also between Visit 3 and Visit 4.
4
14 days (+7 days) interval is necessary between Visit 6 and Visit 7


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS................................................................................................................15
1.
INTRODUCTION...............................................................................................17
MEDICAL BACKGROUND.............................................................................17
1.1
DRUG PROFILE................................................................................................18
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....20
RATIONALE FOR PERFORMING THE TRIAL.........................................20
2.1
TRIAL OBJECTIVES........................................................................................20
2.2
BENEFIT - RISK ASSESSMENT.....................................................................20
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................23
OVERALL TRIAL DESIGN AND PLAN .......................................................23
3.1
3.1.1
Administrative structure of the trial .................................................................24
Hepatic external adjudication................................................................................25
3.1.1.1
Clinical Event Committee for Diabetic ketoacidosis (DKA)...........................25
3.1.1.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................25
SELECTION OF TRIAL POPULATION .......................................................26
3.3
3.3.1
Main diagnosis for trial entry ............................................................................27
3.3.2
Inclusion criteria .................................................................................................27
3.3.3
Exclusion criteria ................................................................................................28
3.3.4
Removal of patients from therapy or assessments...........................................30
Removal of individual patients .............................................................................30
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................31
3.3.4.2
4.
TREATMENTS...................................................................................................32
TREATMENTS TO BE ADMINISTERED.....................................................32
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........32
4.1.2
Method of assigning patients to treatment groups...........................................33
4.1.3
Selection of doses in the trial..............................................................................33
4.1.4
Drug assignment and administration of doses for each patient......................33
4.1.5
Blinding and procedures for unblinding...........................................................35
Blinding.................................................................................................................35
4.1.5.1
Unblinding and breaking the code ........................................................................35
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................35
4.1.7
Storage conditions...............................................................................................36


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4.1.8
Drug accountability.............................................................................................36
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................37
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....37
4.2.2
Restrictions ..........................................................................................................38
Restrictions regarding concomitant treatment ......................................................38
4.2.2.1
Restrictions on diet and life style..........................................................................38
4.2.2.2
Restrictions regarding women of childbearing potential......................................39
4.2.2.3
TREATMENT COMPLIANCE........................................................................39
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................40
TRIAL ENDPOINTS..........................................................................................40
5.1
5.1.1
Primary Endpoint(s)...........................................................................................40
5.1.2
Secondary Endpoint(s) .......................................................................................40
....40
ASSESSMENT OF EFFICACY........................................................................41
5.2
ASSESSMENT OF SAFETY.............................................................................42
5.3
5.3.1
Physical examination ..........................................................................................42
5.3.2
Vital Signs............................................................................................................42
5.3.3
Safety laboratory parameters ............................................................................42
5.3.4
Electrocardiogram ..............................................................................................45
5.3.5
Other safety parameters.....................................................................................46
5.3.6
Assessment of adverse events.............................................................................46
Definitions of AEs ................................................................................................46
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................49
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................51
ASSESSMENT OF EXPLORATORY BIOMARKERS.................................51
5.5
OTHER ASSESSMENTS...................................................................................51
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................51
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 period ..............................................................................53
6.2.2
Treatment period ................................................................................................56
6.2.3
Follow Up Period and Trial Completion...........................................................56
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................58
STATISTICAL DESIGN - MODEL.................................................................58
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................58
7.2
PLANNED ANALYSES.....................................................................................58
7.3
7.3.1
Primary endpoint analyses.................................................................................59
7.3.2
Secondary endpoint analyses .............................................................................59
............................................................................60
7.3.4
Safety analyses.....................................................................................................60


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7.3.5
Pharmacokinetic analyses ..................................................................................61
INTERIM ANALYSES ......................................................................................61
7.4
HANDLING OF MISSING DATA ...................................................................61
7.5
RANDOMISATION ...........................................................................................61
7.6
DETERMINATION OF SAMPLE SIZE .........................................................62
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
10.
APPENDICES.....................................................................................................68
BLOOD PRESSURE MEASUREMENT PROCEDURE...............................68
10.1
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................69


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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
DBP
diastolic blood pressure
DILI
drug induced liver injury
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
EOT
end of treatment
EudraCT
European Clinical Trials Database
FAS
full analysis set
FFA
free fatty acid
FPG
fasting plasma glucose
GCP
GLP-1-RA
good clinical practice
glucagon like peptide -1 receptor agonist
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
MedDRA
medical dictionary for drug regulatory activities
MMRM
mixed model repeated measures
NBI
Nippon Boehringer Ingelheim
OAD
oral antidiabetic drug
OPU
operative unit
PMDA
Pharmaceuticals and Medical Devices Agency
PT
preferred term
RBC
red blood cells


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RDC
remote data capture
REP
residual effect period
SAE
serious adverse event
SBP
systolic blood pressure
SGLT-2
sodium-glucose co-transporter 2
SMBG
self-monitoring blood glucose
SOC
system organ class
SOP
standard operation procedure
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 cells


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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 hyperglycemia 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 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 normoglycaemia, 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 glucosuria 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 in 2015, marketing approval has been received in many countries including 
European countries and US. In Japan, empagliflozin received marketing approval 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 a 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 (RA) 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 2 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, 
probenecid and oral contraceptives.
There is no clinical data investigating the interaction between empagliflozin and GLP-1 RA.
Clinical efficacy and safety
The empagliflozin clinical trials are 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) 


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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, thiazolidine dione, 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
In summary, given the safety profile in the preclinical studies, and the safety, tolerability and 
efficacy seen in the adequately designed and conducted clinical studies to date, the available 
clinical and non-clinical data support safe and efficacious use of empagliflozin in humans and 
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 antihyperglycaemic drug for indication of T2DM on 26 
Dec 2014 in Japan. There is no limitation regarding combination with empagliflozin and any 
existing antihyperglycaemic drug. However, no clinical data has been obtained in Japanese 
patients, which demonstrate safety and efficacy results of empagliflozin as add-on therapy to 
glucagon-like peptide-1 (GLP-1) receptor agonist (RA). Therefore, it is planned to conduct a
post marketing clinical trial to investigate the safety and efficacy of empagliflozin given for 
52 weeks as add-on therapy to GLP-1 RA in Japanese patients with T2DM who have 
insufficient glycaemic control.
We will plan to implement this trial 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 safety and efficacy of empagliflozin (10 mg or 
25 mg once daily) given for 52 weeks as add-on therapy to a GLP-1 RA (i.e. liraglutide) in 
Japanese patients with T2DM who have insufficient glycaemic control.
BENEFIT - RISK ASSESSMENT
2.3
The overall safety profile of empagliflozin is outlined in the current IB [c01838761].
All patients with T2DM participating in this trial may derive a direct benefit from being 
treated with an active compound and not a placebo. In addition, 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.
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). If any investigator should have a clinical concern, the safety of the patients 
will be paramount.
Approximately 50% of the patients will receive empagliflozin 25 mg without starting lower 
dose of empagliflozin 10 mg although the Japanese label defines the starting dose as 10 mg. 
Empagliflozin 25 mg as well as 10 mg were used in the phase III trials as for the expected 
therapeutic doses and both empagliflozin doses were well tolerated as initial start dosage. 
Moreover, patient’s safety will be ensured by monitoring the patients for AEs both clinically 
and by laboratory testing. Therefore, the risk of safety related to starting dose of 


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empagliflozin 25 mg is considered to be low. Because of the mechanism of action of 
empagliflozin, the risk of hypoglycaemic episodes is considered to be low. Symptoms 
attributed to not only hypoglycaemia but also hyperglycaemia, or hypo- and hypertension 
will be closely monitored in the trial. In addition, patients who are not adequately controlled, 
as evidenced by a confirmed high glucose value (see Section 3.3.4.1) will be excluded from 
further study participation. 
Diabetic ketoacidosis (DKA) has not been observed in clinical trials of empagliflozin in 
T2DM patients so far in Japan, but special attention will be paid to prevent DKA in this trial 
in accordance with 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 250 mg/dL (14 mmol/L).
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.
Patients who may be at higher risk of DKA while taking SGLT2 inhibitors include patients 
on a very low carbohydrate diet (as the combination may further increase ketone body 
production), severely dehydrated patients, and patients with a history of ketoacidosis or who 
are known to have a low beta-cell function reserve. 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.
The overall frequency of volume depletion is similar between empagliflozin and placebo
[c01838761]. However, the frequency of volume depletion events was increased in patients 
75 years and over of age 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 (e.g., physical 
examination, blood pressure measurements, and laboratory tests including haematocrit) and 
electrolytes is recommended for patients receiving empagliflozin. Also, patients as 
precautionary measure will be requested to drink plenty of fluids. Temporary interruption of 
treatment with empagliflozin should be considered until the fluid loss is corrected.
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.
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 


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follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´ 
safety (see Section 5.3.6.1).
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.
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 to the participating patients will be minimised and 
justified when compared with the potential benefits.
Empagliflozin is market approved as an antihyperglycaemic drug for patients with T2DM in 
many countries including European countries, US and Japan. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a randomised, multi-centre, double-blind, and parallel groups study. The T2DM 
patients with insufficient glycaemic control despite treatment with liraglutide will receive 
either 10 mg or 25 mg of empagliflozin once daily as add-on therapy for 52 weeks.
In total, about 128 patients with T2DM are planned to be screened to ensure that 64 patients 
(32 patients for each treatment) are randamised in the double blind treatment period.
Patients who have signed the informed consent are enrolled in the study. Patients on 
liraglutide alone and suitable for the study after screening (Visit 1) undergo a 2-week open-
label placebo run-in period before randomisation. Patients treated with liraglutide plus one 
OAD and suitable for the study after screening (Visit 1) undergo a 10-weeks OAD washout 
period followed by the placebo run-in period before randomisation. Patients treated with one 
OAD alone and suitable for the study after screening undergo 14-week switch period (from 
OAD to liraglutide, including 2 to 4-week dose titration period) followed by the placebo run-
in period before randomisation.
Patients who successfully complete the placebo run-in period and who still meet the inclusion 
but not meet the exclusion criteria will enter the 52-week double-blind treatment period of the 
study in which they will receive 10 mg or 25 mg of empagliflozin once daily. Randomisation 
of the treatment arms will be double-blinded and assigned at a ratio of 1:1 to one of 2 
treatment arms shown in Figure 3.1: 1. The patient participation is completed when they have 
undergone the last planned visit.
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.


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E: enroll, R: randomaised
Figure 3.1: 1 Trial design
3.1.1
Administrative structure of the trial
Boehringer Ingelheim has appointed a trial clinical monitor (TCM), 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 of participating countries.
Data management and statistical evaluation will be done by the BI according to BI SOPs.
A list of responsible persons and relevant local information (as protocol reference, if 
applicable) can be found in the 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 


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(Principal) investigators and other important participants, including their curricula vitae, will 
be filed in the ISF.
Hepatic external adjudication
3.1.1.1
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 
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).
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.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP
The aim of this trial is to evaluate the long-term safety and efficacy of empagliflozin 10 mg 
and 25 mg in Japanese patients with T2DM whose glycaemic control is insufficient despite 
diet/exercise and treatment with liraglutide, which is currently the only approved GLP-1 RA 
in Japan with the monotherapy indication in addition to the combination therapy. 
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 requires for any antihyperglycaemic investigational products
when used as concomitant therapy to existing antihyperglycaemic drugs.


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The 14-week switch period, which consists of 2 to 4 weeks of dose titration period and 10 to 
12 weeks of washout period, indicates that patients currently receiving one OAD at screening 
should stop their OAD treatment and start treatment with liraglutide at Visit 2. The duration 
of the switch period is considered to be appropriate since adequate treatment duration with 
liraglutide monotherapy is provided.
The 10-week OAD washout period indicates that patients currently receiving liraglutide and 
one OAD should stop their OAD for 10 weeks. The duration of the washout period is 
considered to be appropriate to minimise the effect of OAD on glycaemic control of the 
patients pre-treated with liraglutide and one OAD.
The open label 2-weeks placebo run-in period indicates that the patients check medical 
compliance by mimicking the dosing in the double-blind treatment period. The patients who 
have been pre-treated with liraglutide alone at screening (Visit 1) will directly enter into the 
placebo run-in period.
A double-blind and double-dummy design is adopted in order to minimise bias to evaluate 
the safety and efficacy of two doses (i.e. 10 mg and 25 mg) of empagliflozin.
The 52 weeks for treatment period is planned in order to investigate the long term safety of 
empagliflozin 10 mg and 25 mg in accordance with the revised guideline (draft version).
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 patients 
after 4 weeks of treatment ranged from 12 to18 hours.
The rationale for dose selection is described in Section 4.1.3.
SELECTION OF TRIAL POPULATION
3.3
A sufficient number of patients will be screened for the trial to ensure that 64 patients are 
randomised to the trial's double-blind treatment period (32 patients in treatment arm: 
empagliflozin 10 mg plus placebo, 32 patients in treatment arm: empagliflozin 25 mg plus 
placebo). 
The screening failure rate for this trial is expected to be around 10 % for the screening visit 
and approximately 40 % of the patients are not expected to fulfil the criteria for 
randomisation. These rates would give an estimate of the number of patients needed to be 
screened to be 128. 
Screening of patients may be stopped before reaching 128 enrolled or might continue beyond 
these numbers, if the screening failure rate differs from the rates anticipated above.
Enrolment of patients for this trial is competitive, i.e. enrolment for the trial will stop at all 
centres when it has been anticipated that a sufficient number of patients will be randomised to 


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double-blind treatment period. Investigators will be notified when the appropriate number of 
patients has been enrolled and the enrolment is completed, and will not be allowed to recruit 
additional patients for this trial.
Patients who have signed written informed consent before this notification may not 
participate in double-blind treatment period after 68 patients are randomised, and the patients 
who are in switch/washout/placebo run-in period should be discontinued quickly when the 
sponsor notify to stop the randomisation.
Investigators who 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 12 patients per site must be obtained from the TCM at NBI. 
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 singed 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 only to be performed for a laboratory result which is 
obviously received beyond stability at the central laboratory or thought to be a spurious result 
based on previously available laboratory results only for the corresponding laboratory test. 
The re-test should be carried out as soon as possible so the laboratory test results will be 
received within the next planned visit windows in order to avoid protocol visit violations.
3.3.1
Main diagnosis for trial entry
The study will be performed in Japanese patients with T2DM who have insufficient 
glycaemic control despite diet, exercise and receiving liraglutide or one OAD or both.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1.
Diagnosis of type 2 diabetes mellitus prior to informed consent
2.
Male and female patients on diet and exercise regimen who are pre-treated with:
A)
liraglutide at 0.9 mg/day for at least 10 weeks prior to Visit 1 (screening visit). 
HbA1c at Visit 1 : ≥7.0% and ≤10.0%


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B)
liraglutide at 0.9 mg/day in combination with one OADi) for at least 10 weeks prior to 
Visit 1 (screening visit). 
HbA1c at Visit 1 : ≥7.0% and ≤9.0%
HbA1c at Visit 6 : ≥7.0% and ≤10.0%
C)
One OADi) for at least 10 weeks prior to Visit 1 (screening visit). The patients who 
are suitable for switching to liraglutide treatmentii) after Visit 1 at the investigator’s 
discretion . 
HbA1c at Visit 1 and Visit 6: ≥7.0% and ≤10.0% 
i) Sulfonylurea is permitted as pre-treatment drug only if the dose is equal or less than a 
half of daily maximum approval dose. Any other OADs excepting thiazolidine dione 
and SGLT-2 inhibitor are allowed at any dose.
ii) Patients should stop their OAD and start switching to liraglutide treatment at Visit 2 
and the dose titration completed within 2-4 weeks and also should be done in 
accordance with Japanese label (i.e., at least 1 week dosing period with 0.3 mg and 
0.6 mg each is required.). Patients should be treated with liraglutide at 0.9 mg/day for 
at least 10 weeks (14 weeks of switch period is required.) prior to placebo run-in 
period. 
3.
Age ≥20 years at informed consent
4.
Body mass index (BMI) ≤40.0 kg/m2 at Visit 1 (screening visit)
5.
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 values >270 mg/dL (>15.0 mmol/L) 
after an overnight fast during switch/washout/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 drug-naïve at Visit 1 (screening visit) or treat with any of insulin, 
thiazolidine dione, SGLT-2 inhibitor within 10 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 alanine aminotransferase 
(ALT [SGPT]), aspartate aminotransferase (AST [SGOT]), or alkaline phosphatase 
(ALP) above 3 x upper limit of normal (ULN) as determined during screening and/or 
switch/washout/placebo run-in period
5.
Impaired renal function, defined as eGFR <45 mL/min/1.73m2 (Japanese equation) as 
determined during screening and/or switch/washout/placebo run-in period


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6.
Any previous (within 2 years prior to informed consent) bariatric surgery or other 
gastrointestinal surgery that induce chronic malabsorption
7.
Medical history of cancer (except for basal cell carcinoma) and/or treatment for 
cancer within the last 5 years of informed consent
8.
Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells
(RBC) (e.g., malaria, babesiosis, haemolytic anaemia)
9.
Contraindications to liraglutide and empagliflozin according to the Japanese label
10.
Known allergy or hypersensitivity to liraglutide or empagliflozin
11.
The patients who are not able to receive liraglutide 0.9 mg/day for 10 weeks prior to 
placebo run-in period and who do not treat with the same dose during run-in period
12.
Treatment with anti-obesity drugs (e.g. mazindol) within 12 weeks prior to informed 
consent or any other treatment at the time of screening and/or switch/washout/placebo 
run-in period (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body 
weight
13.
Current treatment with systemic steroids(exclude inhaled or local 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
14.
Pre-menopausal women (last menstruation ≤1 year prior to informed consent) who:
a)
are nursing or pregnant or plan to become pregnant while in the trial
b)
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
15.
Alcohol or drug abuse within the 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, in the judgement of the 
investigator
16.
Participation in another trial with an investigational drug within 30 days prior to 
informed consent
17.
Any other clinical condition that would jeopardize patients’ safety while participating 
in this clinical trial by investigator’s judgement


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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 the trial 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 study 
trial medications (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).
•
Occurrence of hyperglycaemia that meets the following criteria. In this case, the 
reason for study drug discontinuation will be classified as “lack of efficacy”.
-
Visit 7 to Visit 10: The patient has glucose values of >270 mg/dL (>15.0
mmol/L) after an overnight fast.
-
Next day after Visit 10 to Visit 15/EOT: The patient has glucose values of >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 if possible, and on a different day to the initial measurement. 
•
Occurrence of hypoglycaemia (e.g. repeated hypoglycaemic episodes) or •
DKA that may put the patient at risk with continued participation. Patients should be 
assessed for ketoacidosis immediately if symptoms occur, regardless of blood glucose 
level. Discontinuation or temporary interruption of study medication should be 
considered, until the situation is clarified.
•
If a patient becomes pregnant during the trial, the investigational drug will be stopped. 
The patient will be discontinued from the trial and the patient will be followed up 
until birth or otherwise termination of the pregnancy. 
A patient can be discontinued 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.


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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 drop out during the screening phase prior to placebo run-in period will be 
considered a screening failure. They have to be recorded as screening failure in 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 in Visit 7 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 discontinue or withdraw from the study after randomisation (Visit 7) and before 
completing Visit 15/EOT will be considered as early discontinuations and the reason for 
premature discontinuation must be recorded in the eCRFs. The reason will be included in the 
trial database and will be 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 eCRFs. In this case, end of treatment (Visit 15/EOT) 
must be performed before taking any new antidiabetic drug.
Patients who are withdrawn or discontinued from the trial after randomisation will not be 
replaced.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim (BI) 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 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 trial medication will be provided from NBI.
4.1.1
Identity of BI investigational product(s) and comparator product(s)
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:
oral, 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:
oral, 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:
oral, 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:
-


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Route of administration:
oral, once daily
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 6 and randomly assigned to either empagliflozin 10 mg plus placebo or empagliflozin 
25 mg plus placebo (1:1 ratio) at Visit 7 via Interactive Response Technology (IRT) (see 
Section 4.1.4). 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 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 in Japan. 
Approximately 50% 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 therapeautic 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 dosage and treatment 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 6), and dispensing will be done just once. Dispensing of kits for the double-
blind treatment period will begin at Visit 7. Dispensing will be done on 8 occasions over a 
period of 52 weeks (i.e. every 4 weeks in Visit 7 to Visit 10; every 8 weeks in Visit 11 to 
Visit 14). Patients will receive empagliflozin as trial medication. However, background 
medication will not be dispensed as trial medication. Therefore, background medication
(liraglutide) 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
Empagliflozin, oral administration per dose group and day
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
Treatment period
Empagliflozin
10 mg
Active drug
Matching placebo
2 tablets
Once daily,
Morning
Empagliflozin
25 mg
Matching placebo
Active drug
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 should be taken at the same time every 
day. If a dose is missed by more than 12 hours, that dose should be skipped and the next dose 
should be taken as scheduled. 
Double-blind 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 is aware of missing the trial 
medication within 12 hours from planned intake, the dose should be taken immediately, and 
if a dose is missed by more than 12 hours, that dose should be skipped and the next dose 
should be taken as scheduled. On days before the next visit, the dose should be taken 22-26 
hours before the planned dose at the visit. No double doses should be taken. Empagliflozin 
can be taken with or without food.
The dosage and usage of background medication should remain unchanged during the 
double-blind treatment period (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 while 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 
trial medication to the sites from. Visits should be routinely scheduled in the morning, at 
approximately the same time of day for each visit. The actual date and time of administration 
of the medication at the trial visit will be recorded in the eCRF.


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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 7, patients, investigators and everyone involved in trial conduct 
or analysis or with any other interest in this double-blind study will remain blinded with 
regard to randomised treatment assignments until 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 drug safety group to access the 
randomisation code for individual patients during study conduct. In such cases, access to the 
code will only be permitted by authorised drug safety representatives. Access to the code will 
be via the IRT.
The randomisation code will be kept secret by Clinical Trial Support up to 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 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 medication will be provided by BI.
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. 


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The placebo run-in kit, assigned to all patients successfully completing Visit 6, will contain 
42 tablets in a wallet (i.e., sufficient supply for 2-week administration, with supply for 1-
week administration in reserve). One kit type (wallet) will be used for the double-blind 
treatment either 4 weeks or 8 weeks interval. Wallet will contain 84 tablets (i.e., sufficient 
supply for 4-week administration, with supply for 2-week administration in reserve). When 
patients are in the 4 weeks interval at Visits 7, 8, and 9, they will receive one wallet. When 
patients are in the 8 weeks interval at Visit 10, 11, 12, 13 and 14, they will receive 2 wallets.
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 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 IRB / ethics committee, 
•
Availability of a signed and dated clinical trial contract between the Sponsor and the 
head of the investigational site,
•
Approval/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 
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 and/or appointed 
CRO, the investigational drug storage manager must verify that all unused or partially used 


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drug supplies have been returned by the clinical trial patient and that no remaining supplies
are in the Investigator’s possession.
Back ground medication:
One auxiliary Medicinal Products (AMPs) accountability form will be provided for 
liraglutide to the trial site. This record will include dates, quantities, batch / serial numbers, 
expiry (‘use-by’) dates and unique code numbers to the investigational product and trial 
patients.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
Details of all concomitant therapy during the clinical trial will be recorded on the appropriate 
pages of the eCRFs.
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Throughout the duration of the trial, patients should continue to take background therapy, the 
dose of which should remain unchanged if at all possible (for further details see below). This 
background medication will not be provided as part of the clinical trial supplies. Only the 
liraglutide is allowed to be used as GLP-1 RA background medication.
The use of antidiabetic agents other than liraglutide and the allocated medication after 
randomisation (Visit 7) will be prohibited during the course of the study.
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 
empagliflozin. Temporary interruption of treatment with empagliflozin should be considered 
until the fluid loss is corrected.
In the case of hypoglycaemia that may put the patient at risk (e.g. repeated symptomatic 
hypoglycaemia or severe hypoglycaemia), appropriate dose adjustment of liraglutide, such as 
a dose reduction/discontinuation, should be initiated.
If, in the investigator’s clinical consideration, the patient’s hyper- or hypoglycaemia cannot 
be controlled, the patient should be discontinued from the trial as specified in Section 3.3.4.  
Special attention must be paid to the prevention of DKA. 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. 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 according to guidelines in Japan, such as a blood gas 
test (i.e. pH, bicarbonate anion gap, potassium, blood glucose, etc; the results will be 


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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.
Any additional treatment which is considered necessary for the patient's welfare may be 
given at the discretion of the investigator. Exceptions to this are the restrictions described in 
Section 4.2.2.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
The use of antidiabetic agents other than liraglutide and the allocated study drugs after 
randomisation will be prohibited during the course of the study. 
Short-term use of insulin will be permitted (only in the event of an emergency situation 
and/or hospitalisation) based on clinical judgement of the investigator or treating physician. 
Prolongation of such insulin treatment over more than 2 weeks vs. treatment discontinuation 
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 
duration) 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 dose changes occur, they 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 diuretic had to be avoided if there are 
not sufficient reasons to use these drugs according to the investigators’ clinical judgement.
Restrictions on diet and life style
4.2.2.2
Patients will receive diet and exercise counselling by a diet specialist or trained staff member
throughout the duration of the study. The counselling should be based on the diet and 
exercise recommendation of the Japanese diabetes society. In principle, the contents of diet 
and exercise should not be changed through the study period. Patients keep record (food 
intake diary) of the actual food intake over a time of 3 consecutive days in the week before 
the actual clinic visit and bring the diary at each visit. The patients will be reminded to follow 
the agreed diet and exercise plan at every visit. An 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.


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SGLT-2 inhibitor has a diuretic action and the patients may show signs or symptoms of 
dehydration. Therefore, the investigator should instruct the patients to drink appropriate 
volume of water or other drinks every day.
Patients also should not take any investigational drug in other trials within the last 30 days 
before the date of informed consent for this trial.
There are no other restrictions on diet and lifestyle.
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 duration 
of the study.
TREATMENT COMPLIANCE
4.3
Patients are requested to bring all remaining trial medication including empty package 
material 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(s)
The primary endpoint of the trial is the proportion of patients with drug-related adverse 
events (AE) during 52 weeks of treatment with empagliflozin as add-on to GLP-1 RA (i.e. 
liraglutide).
5.1.2
Secondary Endpoint(s)
The secondary endpoint is a change in HbA1c from baseline after 52 weeks of treatment of 
empagliflozin as add-on to GLP-1 RA (i.e. liraglutide).


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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 at any time in non-fasted state. At all 
other visits, the blood samples should be drawn 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, 
pulmonological) 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.
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 the 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 safety lab panels are planned for the following visits:

For the screening Visit 1, laboratory only includes HbA1c, FPG, liver transaminases (i.e. 
AST and ALT), ALP, serum creatinine, thyroid stimulation hormone (TSH) and 
urinalysis.

FFA and Ketone bodies will be performed as described in the Flow chart.

Bone markers iPTH (intact parathyroid hormone), 25OH Vitamin D, NTx in urine: 
planned as described in the Flow chart.

Only blood sampling for haematology and urine dipstick test will be performed as 
described in the Flow chart.


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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)

RBC/Erythrocytes

WBC/Leukocytes

Platelet count/Thrombocytes

Differential automatic (relative and absolute count): 
Neutrophils, eosinophils, basophils, monocytes,  lymphocytes
Clinical chemistry

Albumin 

ALP

-GT (gamma-glutamyl transferase)
  (reflex test triggered by elevated ALP on two sequential measures)

ALT (alanine aminotransaminase, SGPT)

AST (aspartate aminotransaminase, SGOT) 

Bicarbonate

Bilirubin total, fractionated if increased 

Calcium 

Chloride

Creatinine 

Creatine kinase (CK)

CK-MB, troponin (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)
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/dispsticks 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.
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.


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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 glucose concentrations ≤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 
concentrations <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 concentrations ≤70 mg/dL (3.9 mmol/L)

Documented symptomatic hypoglycaemia with glucose concentrations ≥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 concentrations <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.
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 has 
to be taken and sent to the central lab for confirmation of the diagnosis (including 
antibiogram). 

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 sample has to be taken and sent to the 
central lab for confirmation of the diagnosis (including antibiogram).
5.3.4
Electrocardiogram
Printed paper traces from 12 lead ECGs (I, II, III, aVR, aVL, aVF, V1-V6) will be collected 
as described in flow chart for all patients. In the event of any cardiac symptoms (i.e. 
suspicion of heart rhythm disorders or cardiac ischaemia), an additional ECG will be 


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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 (see Section 5.3.6) 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. BI will not provide ECG 
machine centrally.
5.3.5
Other safety parameters
Self-Monitoring blood Glucose (SMBG)
Patients who are eligible for screening phase (Visit 1) will be provided at the following visit
with SMBG equipment and supplies for use at home during the study periods. Instructions 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 AEs or of hypoglycaemia, the 
single SMBG value will be recorded in the eCRF.
Throughout the whole trial participation, SMBG testing is recommended to be done daily but 
should be performed at least weekly in the fasted state at morning and at any time the patient 
is symptomatic, i.e., experiences signs/symptoms of hyper- or hypoglycaemia. If the results 
of a SMBG test reveal glucose values of >270 mg/dL (15.0 mmol/L) after an overnight fast
up to Visit 10, 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).
After Visit 10 if the results of a SMBG test reveal glucose values of >240 mg/dL (13.3 
mmol/L) after an overnight fast, the patient should contact the site. The investigator should 
follow the instructions given in Section 3.3.4.1.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event


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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 judgement which may jeopardize the patient and may 
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.


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The following are considered as AESIs:
Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA)
In case of metabolic acidosis, ketoacidosis and DKA further investigations should be done 
according to the medical judgement and the clinical course until a diagnosis is made and/or 
the patient is recovered. 
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 judgement 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.
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters at 
randomisation at Visit 7: 

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 
(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 local 
pharmacovigilance centre immediately (within 24 hours of being informed, and without 


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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 sample(s) as soon as 
possible (i.e. lipase, creatinine, or hepatic enzymes). Further follow-up laboratory tests should 
be done according to medical judgement depending on the clinical course.
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.
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 judgement 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 respective IBs 
[c01838761]. In addition to that the Japanese package insert of empagliflozin is used to 
assess local expectedness in Japan.
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


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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 
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 trial procedures outlined under 
Section 6.2, and any possible interactions between the investigational drugs and the AMP.
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.


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Pregnancy
In rare cases that a female patient or a female partner to a male patient participating in this 
clinical trial becomes pregnant after having taken trial medication, the investigator must 
report immediately (within 24 hours) any drug exposure during pregnancy (DEDP) to the 
sponsor pharmacovigilance. Pregnancy Monitoring Form for Clinical Trial (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). 
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/AESI associated with the pregnancy, then the SAE/AESI 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 BIOMARKERS
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 T2DM, 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. 


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Therefore, all measurements applied in this trial are appropriate.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
All trial visits, except for screening (Visit 1), should take place between 7:00 AM and 11:00 
AM. If a patient mistakenly takes trial medication in 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
Trial procedures to be performed at each visit are listed in the Flow chart and the respective 
protocol sections. Explanations of procedures are provided in Section 5. Additional details 
regarding visit procedures are provided below. Please also reference the RDC instructions 
provided in the ISF for clarification on eCRF issues.
All visits, except screening (Visit 1), must be performed in fasted state (at least 10 hours with 
no food but only water).
At the end of every visit from Visit 2 to17 the patient must be reminded to bring SMBG log 
and the dispensed medication kit (from Visit 7) at the next scheduled visit. Preferably, a 
phone call to remind the patient must take place one or two days before the patient's next visit.
6.2.1
Screening and run-in period
Screening Period (Visit 1)
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 and record in the eCRF as a screened patient at Visit 1.
Blood Pressure (BP) and ECG 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 which is requested to 
be completed for three consecutive days in the week prior to the next visit.


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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.
Those patients who are treated with one OAD and qualify after Visit 1 procedures will enter a 
14-week switch period (Visit 2).
Those patients who are treated with liraglutide plus one OAD and qualify after Visit 1 
procedures will enter a 10-week washout period (Visit 4).
Those patients who are treated with liraglutide alone will directly enter the placebo run-in 
period for 2-week (Visit 6).
All patients on Visit 1 do not proceed to the next visit until laboratory results are ascertained 
by investigator.
Switch Period (Visit 2 to Visit 5)
During this period, the patients should stop their OAD and start 0.3 mg/day liraglutide at 
Visit 2.
Following Visit 2 procedures, the patient will return to the clinic at Visit 3 (at least 1 week 
interval is necessary between Visit 2 and Visit 3) and are treated with 0.6 mg/day liraglutide. 
Following Visit 3 procedures, the patients will return to the clinic at Visit 4 (at least 1 week 
interval is necessary between Visit 3 and Visit 4) and are treated with 0.9 mg/day liraglutide. 
Dose titration of liraglutide should complete within 2-4 weeks in accordance with Japanese
label. Following Visit 4 procedures, the patients will return to the clinic for regularly 
scheduled follow up visit, Visit 5 and Visit 6 as specified in the Flow chart. 
Patients will also be given SMBG equipment and all the necessary supplies to use it at Visit 2. 
Instruction on the proper use of 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 the next day. 
For details of handling of SMBG test, see Section 5.3.5.
Blood Pressure 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 each visit, patients will be given a food intake log which is requested to be 
completed for three consecutive days in the week prior to the next visit.
Washout Period (Visit 4 to Visit 5)


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During this period, the patients should stop currently receiving OAD. Following Visit 4
procedures, the patients will return to the clinic for regularly scheduled follow up visit, Visit 
5 and Visit 6 as specified in the Flow Chart.
Patients will also be given SMBG equipment and all the necessary supplies to use it at Visit 4. 
Instruction on the proper use of 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 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 the next day. For 
details of handling of SMBG test, see Section 5.3.5.
Blood Pressure 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 each visit, patients will be given a food intake log which is requested to be 
completed for 3 consecutive days in the week prior to the next visit.
Placebo Run-in Period (Visit 6)
At Visit 6, the patients should be fasting (no food or drinks but water only for at least 10 
hours) prior to each visit.
Those patients who are treated with liraglutide alone will be provided SMBG equipment and 
supplies at Visit 6. 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 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 the next day. For 
details of handling of SMBG test, see Section 5.3.5.
Blood Pressure 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 Visit 6, patients will be given a food intake log which is requested to be 
completed for three consecutive days in the week prior to the next visit (Visit 7).
Following Visit 6 procedures, a run-in kit will be dispensed through the IRT. Trial 
medication for the day of the visit will be administered at the investigational site.
Patients with HbA1c ≥7.0% and ≤10.0% at Visit 6 will be contacted and asked to return to 
the clinic at Visit 7 to complete the eligibility assessments and baseline measurements.
Patients with HbA1c outside the previously mentioned range will also be contacted and will 
be asked to return to the clinic soon.


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6.2.2
Treatment period
The treatment period is from Visit 7 to Visit 15/EOT. Patients will be dispensed medication 
at each of these visits (except Visit 7a and Visit15/EOT) and will receive a new kit number 
through the IRT on each occasion.
Patients must satisfy all inclusion and exclusion criteria prior to randomisation (see Section 
3.3). In addition, if 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 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 visit should be determined based on the date of Visit 7 and visits should occur 
within the allowed time frame shown in the Flow chart. 
At Visit 7a, the investigator or a designated site staff member makes a call to patients to 
confirm patient’s safety through checking patient’s 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.
Assessments should be performed as mentioned in the Flow chart and the respective protocol 
sections. Randomisation/treatment allocation and dispensing of study medication should be 
the last activity at each visit. 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.
At the end of each visit, patients will be given a food intake log which is requested to be 
completed for three consecutive days in the week prior to the next visit.
Visit 15/EOT will need to be performed for any patients who complete/discontinue the study, 
i.e. both for patients who complete the full 52-week double-blind treatment period and for 
patients who prematurely discontinue the study. 
Patients who prematurely discontinue the study should be registered as withdrawn, 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 Visit 
15/EOT, a follow-up visit (Visit 16) can be performed as a phone visit by the investigator at 
the end of the follow-up period of 7 days. Visit 16 should occur 7 days after Visit 15/EOT
within the timeframe (+7 days).


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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 Visit 16 via telephone:
•
Concomitant therapies
•
Any AEs
•
SMBG result
Patients completing the study according to the protocol with persisting AE at Visit 15/EOT
and patients who prematurely discontinue the study, the patient should return to follow up 
visit (Visit 16, 7 days after Visit 15/EOT). The following examinations should be performed 
at Visit 16 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 52-week, randomised, multi-centre, parallel group study to investigate the safety and 
efficacy of empagliflozin (10 mg or 25 mg administered orally once daily) as add-on therapy 
to GLP-1 RA (i.e., liraglutide) in patients with T2DM with insufficient glycaemic control.
Patients to be enrolled in this study are those with T2DM who have insufficient glycaemic 
control despite background monotherapy with liraglutide. Empagliflozin 10 mg or 25 mg is 
administrated with liraglutide over 52 weeks. Patients will be randomly assigned to 
empagliflozin 10 mg or 25 mg.
The primary endpoint in this trial is frequency of patients with drug-related adverse events 
(AE) during 52 weeks of treatment. The secondary endpoint in this study is the change from 
baseline in HbA1c after 52 weeks of treatment.
Based upon these design considerations, the trial will be analysed using descriptive statistics
for the primary endpoint. For the secondary endpoint, the HbA1c changes from baseline is 
considered as normally distributed based on experiences with similar endpoints in other trials 
and literature data. Therefore, the statistical model used for the secondary endpoint is a 
restricted maximum likelihood (REML)-based mixed model with repeated measures 
(MMRM) including the fixed effects treatment, baseline renal function, prior use of 
antidiabetic agents, visit, treatment-by-visit interaction and the covariate baseline HbA1c, 
baseline HbA1c-by-visit interaction.
NULL AND ALTERNATIVE HYPOTHESES
7.2
There will be no confirmatory statistical testing in this study.
PLANNED ANALYSES
7.3
No confirmatory statistical analysis is planned. The statistical analysis will be based on the 
following populations. With regard to each efficacy and safety endpoint during the 
randomised 52-week treatment period, the term "baseline" refers to the last observed 
measurement prior to the administration of any randomised trial medication.
Treated set
The treated set (TS) will consist of all patients who were randomised and treated with at least 
one dose of the study drug. The assignment of patients to treatment group will be based on 
the first study drug intake in the double-blind treatment period.
Full analysis set


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The full analysis set (FAS) will consist of all patients in TS who were treated with at least 
one dose of the randomised study drug and had a baseline HbA1c assessment. The 
assignment of patients to treatment groups will be based on the randomised study drug at 
time of randomisation.
7.3.1
Primary endpoint analyses
The primary endpoint in this trial is frequency of patients with drug-related adverse events 
(AE) during 52 weeks of treatment, which will be analysed in the same way as other safety 
analysis. More details are given in Section 7.3.4.
7.3.2
Secondary endpoint analyses
HbA1c
The change from baseline in HbA1c after 52 weeks of treatment will be calculated on FAS by 
treatment using MMRM. The statistical model is as follows:
HbA1c change from baseline = overall mean + treatment + baseline HbA1c + baseline renal 
function + prior use of antidiabetic agents + visit + treatment-by-visit + baseline HbA1c-by-
visit + error
Analyses will include “treatment”, “baseline renal function”, “prior use of antidiabetic 
agents”, “visit” and “treatment-by-visit” interaction as fixed effects, “baseline HbA1c”, and 
“baseline HbA1c-by-visit” interaction as covariates. The term “baseline HbA1c” refers to the 
last HbA1c assessment prior to the administration of any randomised medication (HbA1c 
values at Visit 7) and not to the HbA1c measurement used for the stratification in the 
randomisation. “Baseline renal function” will be a classification effect derived from the 
categorisation of eGFR at baseline. Regarding “prior use of antidiabetic agents”, patients will 
be classified as liraglutide only, OAD only or liraglutide plus OAD. An unstructured 
covariance structure will be used to model the within-patient measurements. If the analysis 
fails to converge, the following covariance structure 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. This model will 
also be used to evaluate the change from baseline in HbA1c overtime during the 52-week 
treatment period.
Only the available data which were observed whilst patients were on treatment will be 
included in the analysis. Missing data are handled implicitly by the above statistical model, 
rather than by using any imputation. This approach will also additionally set to missing all 
values measured after the restricted antidiabetic medication during the trial (See Section 
4.2.2)
 


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The last available on-treatment HbA1c value is defined as the last available HbA1c value 
measured up to a period of seven days after the last dose of the randomised study medication 
or the last available HbA1c value prior to the restricted antidiabetic medication during the 
trial (See Section 4.2.2).
7.3.4
Safety analyses
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned. 
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. For this, all AEs occurring between start of study treatment and end of the 
residual effect period (REP) will be considered “treatment-emergent”. The REP is defined as 
a period of 7 days after the last dose of double-blind trial medication. Adverse events that 
start before first study drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’. 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 7 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’.


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Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Number of patients with hypoglycaemia episodes, intensity, the presence of typical 
hypoglycaemia symptoms and the need for assistance due to hypoglycaemia will be
displayed.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs observed, during the course of the trial and at the end-of-trial evaluation will be 
compared to findings before the start of double-blind treatment.
7.3.5
Pharmacokinetic analyses
Not applicable
INTERIM ANALYSES
7.4
No interim analysis is planned for this study.
HANDLING OF MISSING DATA
7.5
As defined for the MMRM, missing data are handled implicitly by the statistical model, 
rather than by using any imputation (see Section 7.3.2). In case of ANCOVA analyses, 
missing data will be imputed using the LOCF approach. If no value after first intake of trial 
medication is available, the baseline value will be used for HbA1c. Further details will be 
provided in the TSAP.
With respect to safety evaluations, it is not planned to impute missing values.
RANDOMISATION
7.6
The trial will be performed as a double-blind design with respect to the two active dose 
groups of empagliflozin. Eligible patients assessed by investigator will be randomised in 
blocks to the two study treatments in a 1:1 ratio. The randomisation will be stratified by the 
following factors:


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
Pre-randomisation HbA1c value (<8.0%, ≥8.0%) using the Visit 1 HbA1c values for 
patients pre-treated with liraglutide alone and Visit 6 HbA1c values for other patients

Pre-randomisation eGFR value (≥90 mL/min/1.73m2, 60 to <90 mL/min/1.73m2, 45 to 
<60 mL/min/1.73m2) calculated based on Visit 6 creatinine values.
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
The draft version of Japanese guideline ‘Clinical Evaluation Guidelines for 
Antihyperglycemic Drugs’ [R15-2907] requires one year long-term study on background 
therapies with several approved antidiabetic drugs. The guideline requires observing 50 to 
100 patients during one year for each background therapy. The sample size for this trial was 
determined according to the outcome of the PMDA consultation on December 2014. At least 
50 patients as 52-week completers including two doses were necessary for the background 
therapy with GLP-1 RA for safety evaluation. 
Based on the above, and allowing for a discontinuation/dropout rate of approximately 20% 
during the trial, the sample size for empagliflozin 10 mg and 25 mg were determined at 32 
per arm in the GLP-1 RA background group.


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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 Harmonised Tripartite Guideline 
for Good Clinical Practice (GCP), 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 patients 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 / the trial site and of the sponsor with regard to publication of 
the results of this trial are described in the investigator contract/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 the insurance cover is made available to the investigator and the patients, 
and is stored in the ISF.
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) and competent authority (CA) 
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, the 
sponsor’s designees, or by IRBs 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
eCRFs 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 eCRF 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 eCRF, all data must be derived from source documents. 
Additionally, the following source documents must be collected and filed at the investigator’s 
trial site:
•
ECG results (original or copies of printouts)
•
Physical examinations (original documentation)
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. eCRFs 
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 trial monitor, auditor 
and inspection by health authorities (e.g. FDA). The CRA/on site monitor and auditor may 


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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.
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 the IB [c01838761]. In addition to that the 
Japanese package insert of empagliflozin is used to assess local expectedness in Japan. For 
liraglutide, the reference document is the EPAR product information. The current versions of 
these reference documents are to be provided in the ISF. No AEs are classified as listed for 
matching placebo, study design, or invasive procedures.
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 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB and the regulatory authorities.


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END OF TRIAL
8.6
The end of the trial is defined as 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 
patients 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
R14-5435
American Diabetes Association Hyperglycemic crises in diabetes. Diabetes 
Care 27 (Suppl. 1), S94 - S102, 2004
R14-4302
The Japan Diabetes Society. Treatment Guide for Diabetes 2014-2015. Tokyo, 
Bunkodo; 2014.
R15-2907
MHLW draft revised guideline - Clinical Evaluation Guidelines for 
Antihyperglycemic Drugs
R15-2908
The Japan Diabetes Society. Recommendation from “Committee on the proper 
use of SGLT2” inhibitors
R13-3738
Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 
2013
R14-5435
American Diabetes Association Hyperglycemic crises in diabetes. Diabetes 
Care 27 (Suppl. 1), S94 - S102, 2004
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
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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10.
APPENDICES
BLOOD PRESSURE MEASUREMENT PROCEDURE
10.1
The preferred method for blood pressure measurement is electronic sphygmomanometer 
provided by NBI. If, for some reason, the electronic sphygmomanometer cannot be used for 
the measurement of blood pressure, a standard mercury sphygmomanometer may be used as 
an alternate method.
Initially, blood pressure should be taken 3 times in both arms. If the pressures differ by more 
than 10 mmHg (as in the presence of a subclavian steal syndrome), the arm with the higher 
pressure (systolic or – if needed to decide- diastolic) should be used for subsequent 
measurements.
Blood pressure measurements should be performed on the same arm and, if possible, by the 
same person. The same method must be used throughout the trial, for a given patient, i.e. if a 
patient receives the first blood pressure measurement for example with an electronic device, 
the same method and device should be used throughout the study for this patient (without 
switching to manual blood pressure measurement). On the other hand, inter-patients 
variability is acceptable, i.e. a study site is allowed to consistently use an electronic device to 
measure the blood pressure in a given patient throughout the study and a manual technique in 
another patient.
After patients have rested quietly, in the seated position for 5 minutes, 3 times of blood 
pressure measurements will be taken approximately 2 minutes apart. The seated pulse rate at 
the second measurement will be used as the study data when an electronic device is used for 
the blood pressure measurement. In case of the measurement by using standard mercury 
sphygmomanometer, the seated pulse rate will be taken during the 2-minute interval between 
the second and third blood pressure reading.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
13 October 2016
EudraCT number
BI Trial number
1245.106
BI Investigational Product(s)
Jardiance®, Empagliflozin
Title of protocol
A 52-week randomised, double-blind, parallel 
group, safety and efficacy study of empagliflozin 
once daily as add-on therapy to glucagon-like 
peptide-1 receptor agonist in Japanese type 2 
diabetes mellitus patients with insufficient 
glycaemic control
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
x
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed 
1
Throughout the whole protocol
Description of change
Randomization 
To be changed to:
Randomisation
Rationale for change
Typographical error
Section to be changed 
2
Abbreviations
Description of change
european clinical trials database
To be changed to:
European Clinical Trials Database
Rationale for change
Typographical error
Section to be changed 
3
Section 1.1
Description of change
normoglycemia


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To be changed to:
normoglycaemia
Rationale for change
Typographical error
Section to be changed 
4
Throughout the whole protocol
Description of change
antihyperglycemic
To be changed to:
antihyperglycaemic
Rationale for change
Typographical error
Section to be changed 
5
Throughout the whole protocol
Description of change
therapeutic
To be changed to:
therapeautic
Rationale for change
Typographical error
Section to be changed 
6
Section 2.3
Description of change
Labolatory
To be changed to:
laboratory
Rationale for change
Typographical error
Section to be changed 
7
Section 2.3
Description of change
250 mg/dl (14 mmol/l)
To be changed to:
250 mg/dL (14 mmol/L)
Rationale for change
Typographical error
Section to be changed 
8
Section 3.1.1
Description of change
co-ordinating investigator
To be changed to:
coordinating investigator
Rationale for change
Typographical error
Section to be changed 
9
Section 3.2
Description of change
Lilraglutide
To be changed to:
liraglutide
Rationale for change
Typographical error


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Section to be changed 
10
Section 3.3
Description of change
pateints
To be changed to:
patients
Rationale for change
Typographical error
Section to be changed 
11
Throughout the whole protocol
Description of change
judgment
To be changed to:
judgement
Rationale for change
Typographical error
Section to be changed
12
Section 5.3.6.1 
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 
13
Section 7.3.2
Description of change
Categorization


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To be changed to:
categorisation
Rationale for change
Typographical error
Section to be changed 
14
Section 7.4
Description of change
interm
To be changed to:
interim
Rationale for change
Typographical error
Section to be changed 
15
Section 7.6
Description of change
labeling
To be changed to:
labelling
Rationale for change
Typographical error
Number of global amendment
2
Date of CTP revision
20 January 2017
EudraCT number
BI Trial number
1245.106
BI Investigational Product(s)
Jardiance®, Empagliflozin
Title of protocol
A 52-week randomised, double-blind, parallel 
group, safety and efficacy study of empagliflozin 
once daily as add-on therapy to glucagon-like 
peptide-1 receptor agonist in Japanese type 2 
diabetes mellitus patients with insufficient 
glycaemic control
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed 
1
Section 3.1.1.2


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Description of change
The following section for “Clinical Event 
Committee for Diabetic ketoacidosis (DKA)” is 
added,
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.
Rationale for change
To newly align with the DKA adjudication of 
empagliflozin project.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03122586
3.0
clinical-trial-protocol-version-03
A 52-week randomised, double-blind, parallel group, safety and efficacy study of
empagliflozin once daily as add-on therapy to glucagon-like peptide-1 receptor
agonist in Japanese type 2 diabetes mellitus patients with insufficient glycaemic
control
Author-Trial Clinical Monitor
23 Jan 2017 03:35 CET
Author-Trial Statistician
23 Jan 2017 04:20 CET
Approval-Team Member Medicine
23 Jan 2017 08:32 CET
Approval-Clinical
26 Jan 2017 14:29 CET
Verification-Paper Signature
Completion
02 Feb 2017 07:34 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03122586
3.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c18322796-01
BI Trial No.:
1245.106
Title:
A 52-week randomised, double-blind, parallel group, safety and 
efficacy study of empagliflozin once daily as add-on therapy to 
glucagon-like peptide-1 receptor agonist in Japanese type 2 
diabetes mellitus patients with insufficient glycaemic control
Including Protocol Amendment 1 [c03122586-02]
Including Protocol Amendment 2 [c03122586-03]
Investigational
Product(s):
Jardiance®, Empagliflozin
Responsible trial 
statistician(s):
Phone:
Fax:
Date of statistical 
analysis plan:
29 JUN 2017, SIGNED
Version:
FINAL
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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 ..........................................................................................9
5.1
PRIMARY ENDPOINT ......................................................................................9
5.2
SECONDARY ENDPOINT ................................................................................9
...........................................9
.........................................10
.........................................10
.........................................11
.........................................11
6.
GENERAL ANALYSIS DEFINITIONS...........................................12
6.1
TREATMENTS..................................................................................................12
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................13
6.3
PATIENT SETS ANALYSED..........................................................................16
................................................................................16
6.5
POOLING OF CENTRES ................................................................................17
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................20
7.
PLANNED ANALYSIS.......................................................................23
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........23
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................23
7.3
TREATMENT COMPLIANCE .......................................................................23
7.4
PRIMARY ENDPOINT ....................................................................................24
7.5
SECONDARY ENDPOINTS............................................................................24
7.5.1
Key secondary endpoint................................................................................24
7.5.2
Secondary endpoint.......................................................................................24
........................................................26
7.8
SAFETY ANALYSIS.........................................................................................26
7.8.1
Adverse events ...............................................................................................26
7.8.1.1
Assignment of AEs to treatment.................................................................27
7.8.1.2
Analysis of other significant AEs...............................................................27
7.8.1.3
AE summaries.............................................................................................28
7.8.1.4
Analysis of hypoglycaemic events .............................................................28
7.8.1.5
Adverse event of special interest (AESI) ...................................................29
7.8.1.6
Analysis of urinary tract infections (UTI) / genital infections ...................30
7.8.1.7 Analysis of complicated UTI......................................................................30
7.8.1.8  Analysis of volume depletion.....................................................................30
7.8.1.9  Analysis of adjudicated events ...................................................................30


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7.8.2
Laboratory data.............................................................................................31
7.8.3
Vital signs.......................................................................................................34
7.8.4
ECG ................................................................................................................34
8.
REFERENCES.....................................................................................35
..........................................................36
10.
HISTORY TABLE...............................................................................37


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LIST OF TABLES
Table 6.1: 1
Treatment regimens / study intervals ..............................................................12
Table 6.2: 1
Important PVs..................................................................................................13
Table 6.3: 1
Patient sets analysed........................................................................................16
....................................................................17
Table 6.7: 1
Endpoint specific follow-up period for the assignment to active treatment....21
Table 6.7: 2
Time windows for on-treatment HbA1c, body weight, and waist 
circumference measurements scheduled for each on-treatment visit ..............................21
Table 6.7: 3
Time windows for on-treatment FPG, vital sign, and safety lab measurements
scheduled for each on-treatment visit ..............................................................................22
Table 6.7: 4
Time windows for on-treatment biomarkers measurement and bone markers
scheduled for each on-treatments visit.............................................................................22
Table 7.8.2: 1
Japanese equation eGFR staging ................................................................32
Table 7.8.2: 2
Cockcroft-Gault eCcr staging.....................................................................33
Table 10: 1
History table ....................................................................................................37


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis data set
AE
Adverse event
AESI
Adverse event of special interest
AIC
Akaike information criterion
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ASA
Acetylsalicylic acid
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical classification
BI
Boehringer Ingelheim
BIcMQ
BI-customised MedDRA query
BLQ
Below the limit of quantification
BMI
Body mass index
BRPM
Blinded report planning meeting
CT
Concomitant therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Data base lock
DBP
Diastolic blood pressure
DKA
Diabetic ketoacidosis
eCcr
Estimated creatinine clearance rate
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EoT
End of treatment
FAS
Full analysis set
FFA
Free fatty acid
FPG
Fasting plasma glucose
HbA1c
Glycated haemoglobin
HDL
High density lipoprotein


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Term
Definition / description
ICH
International Conference on Harmonisation
ITT
Intention-to-treat
IRT
Interactive response tool
LDL
Low density lipoprotein
LOCF
Last observation carried forward
LOCF-IR
Last observation carried forward including values after rescue
LLQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model repeated measures
NCF
Non-completers considered failure
OAD
Oral antidiabetic drug
OC
Observed cases
OC-IR
Observed case including values after rescue
OR
Original results
PPS
Per protocol set
PT
Preferred term
PV
Protocol violation
Q1
First quartile
Q3
Third quartile
SBP
Systolic blood pressure
SCR
Screened patients set
SD
Standard deviation
SMQ
Standardised MedDRA query
SOC
System organ class
TBILI
Total bilirubin
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
ULQ
Upper limit of quantification
UTI
Urinary tract infection


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3.
INTRODUCTION
As per 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 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, randomization.”
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
No changes in the planned analysis.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint of the trial is the proportion of patients with drug-related adverse 
events (AE) during 52 weeks of treatment with empagliflozin as add-on to GLP-1 RA (i.e. 
liraglutide).
5.2
SECONDARY ENDPOINT
The secondary endpoint is the change in HbA1c from baseline after 52 weeks of treatment of 
empagliflozin as add-on to GLP-1 RA (i.e liraglutide).


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For efficacy analyses, data up to 7 days after last treatment intake will be considered as on-
treatment for HbA1c and waist circumference, and 1 day for all other efficacy endpoints. For 
safety analyses, data up to 7 days after last treatment intake will be considered as on-
treatment for AEs, 3 days for safety lab measurements and 1 day for pulse rate. For further 
details see Table 6.7: 1. For this purpose, the following treatment regimens and study 
intervals will be defined in Table 6.1: 1. More detailed information is provided in the trial 
Analysis Data Set plan.
Table 6.1: 1
Treatment regimens / study intervals
Label
Interval
Start date 
Start time
Screening
Screening period
Date of informed consent
00:00
Run-in*
Placebo Run-in 
period
Date of first administration 
of  placebo medication
Time of first administration 
of placebo medication, 
12:00 if missing

Empa10 mg/
Placebo for 
Empa25 mg

Empa25 mg/ 
Placebo for 
Empa10 mg
Double-blind 
treatment period
Date of first administration 
of 52-week double-blind 
study medication
Time of first administration 
of 52-week double-blind 
study medication,
12:00 if missing
Post-treatment
Post-treatment
Date of last intake of study 
drug + X** +1 day
00:00
Post-study
Post-study
Last contact date +1 day
00:00 
* There is switch period which consists of titration period and washout period between screening 
period and placebo run-in period. After screening period, patients of inclusion criterion 2-A proceed 
to placebo run-in period, patients of inclusion criterion 2-B proceed to washout period prior to 
placebo run-in period, patients of inclusion criterion 2-C proceed to titration period then washout 
period prior to placebo run-in period.
** The endpoint specific follow-up periods for the assignment to active treatment are presented in 
detail in Section 6.7. 
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.


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Additionally, the AEs with an onset during the time of the incorrect study treatment will also 
be tabulated and listed separately.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Violations that lead to exclusion from analysis populations are indicated as such in Table 6.2: 
1.
The final decision about which patients will be excluded from analysis sets will be taken 
during the course of the study and finalised at the medical quality review meeting or last 
blinded report planning meeting (BRPM).
Table 6.2: 1
Important PVs
Category / 
Code
Description
Comment/Example
Exclude 
from
Program/ 
manual?*
A
Entrance criteria not met
A1
Target indication not met
A1.01
No type 2 diabetes
IN1
None
Program
A1.02
Antidiabetic background therapy 
not as required
IN2
detect manually for cleaning
None
Program
A2
Inclusion criteria not met
A2.01
HbA1c out of range
HbA1c out of range for 
IN2(A), IN2(B), or IN2(C)
by >0.2%
None
Program
A2.02
Age out of range
IN3
None
Program
A2.03
BMI out of range
IN4
None
Program
A3
Exclusion criteria violated
A3.01
Uncontrolled FPG level
EX1
detect manually for cleaning
None
Program
A3.02
Additional background therapy
EX2
detect manually for cleaning
None
Program
A3.03
Relevant concomitant diagnoses
EX3, 7
None
Program
A3.04
Bariatric or other relevant 
gastrointestinal surgery within the 
past two years
EX6
None
Program
A3.05
Blood dyscrasias or any disorders 
causing hemolysis or unstable red 
blood cell count 
EX8
None
Program
A3.06
Indication of liver disease
EX4
None
Program
A3.07
Contraindication to liraglutide or 
empagliflozin
EX9, 10
None
Program
A3.08
Treatment with protocol excluded 
anti-obesity drugs
EX12
Forbidden CTs list will be 
reviewed for cleaning
None
Program + 
CT list
A3.09
Renal insufficiency or renal 
impairment (assessed by eGFR)
EX5
None
Program
A3.10
Treatment with protocol excluded 
systemic steroids or recent change 
in thyroid hormone dose
EX13
Forbidden CTs list will be
reviewed for cleaning
None
Program + 
CT list
*For “Program”, ADS will be created by program. For “manual”, ADS will be created by important excel spread sheet. 
CT: Concomitant therapy, IRT: Interactive response tool, DBL: Data base lock, FAS: Full analysis set, TS: Treated set, 
eCRF: electronic case report form


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Table 6.2: 1 (cont’d)
Important PVs
Category / 
Code
Description
Comment/Example
Exclude 
from
Program/ 
manual?*
A3.11
Intake of an investigational drug 
in another trial within 30 days 
prior to intake of study 
medication in this trial
EX16
(Medical judgement), 
depending on the type of 
drug given in the prior trial 
(only if investigational drug 
interferes with glucose 
metabolism).
None
Program
A3.12
Specific exclusion criterion for 
pre-menopausal women violated
EX14
None
Program
A3.13
Relevant alcohol or drug abuse 
and other conditions affecting 
study compliance 
EX15
None
Program
A3.14
Any other clinical condition 
unsafe for participation that 
would jeopardise patient safety 
while participating in this clinical 
trial
EX17
None
Program
A3.15
Liraglutide dose prior to or during 
placebo run-in period not as 
required
EX11
None
Program
B
Informed Consent
B1
Informed consent not given
Date of informed consent 
missing, 
or
No signature on patient’s 
“Declaration of Informed 
Consent”
Patient’s data will not be 
used at all.
All
Program
B2
Informed consent too late
Date of informed consent 
not obtained prior to any 
study related procedure.
None
Program
C
Trial medication and 
randomisation
C1
Incorrect trial medication taken
C1.01
No study medication taken
Patient randomised but no 
study medication taken.
TS
Program
C1.02
Incorrect trial medication taken
Wrong medication taken for 
more than 20% of the 
overall treatment duration.
Can only be finally judged 
after DBL since unblinding 
information is required.
None
Manual
C2
Randomisation not followed
C2.01
Treated without randomisation
Patient was treated, but not 
randomised according to 
IRT.
None
Program
*For “Program”, ADS will be created by program. For “manual”, ADS will be created by important excel spread sheet. 
CT: Concomitant therapy, IRT: Interactive response tool, DBL: Data base lock, FAS: Full analysis set, TS: Treated set, 
eCRF: electronic case report form


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Table 6.2: 1 (cont’d)
Important PVs
Category / 
Code
Description
Comment/Example
Exclude 
from
Program/ 
manual?*
C3
Non-compliance
C3.01
Non-compliance with study drug 
intake
Overall study treatment 
compliance outside 80% and 
120% (exclusive) or study 
treatment compliance below 
80% in the last visit interval.
None
Program
C3.03
Last treatment more than 7 days 
prior to next visit
Last treatment more than 7 
days prior to next visit.
None
Manual
C4
Medication code broken
C4.01
Medication code broken without 
just cause
Medication code was broken 
for no valid reason.
None
Manual
D
Concomitant medication
D2
Prohibited medication use
D2.01
Use of prohibited medication
during treatment period
Review of eCRF for 
prohibited medication.
Forbidden CTs list will be 
reviewed
None
Manual + CT 
list
E
Missing data
E1.01
No baseline HbA1c value
No valid baseline HbA1c
value
FAS
Program
G
Trial specific
G3
Other trial specific violation
G3.13
Prohibited antidiabetic medication
More than 14 days of insulin 
treatment or any duration of 
other antidiabetics
None
Program
G3.17
Change of background 
antidiabetic therapy
Increase with/without AE or 
decrease with reason 
“Other” during double blind 
treatment period
None
Program
I
Other safety related violations
I1
Violations regarding ECG
I1.01
First ECG after drug intake and 
ECG-related adverse event at 
baseline
None
Manual
I1.02
ECG Missing at a visit where 
ECG was planned
None
Manual
I2
Pregnancy monitoring
I2.01
Pregnancy
None
Program
I2.02
Pregnancy test not done for 
woman of child bearing potential 
for at least one visit before 
treatment discontinuation
None
Program
I4
Misuse of study drug
I4.02
Administration of unsealed 
medication kit
None
Manual
*For “Program”, ADS will be created by program. For “manual”, ADS will be created by important excel spread sheet. 
CT: Concomitant therapy, IRT: Interactive response tool, DBL: Data base lock, FAS: Full analysis set, TS: Treated set, 
eCRF: electronic case report form


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6.3
PATIENT SETS ANALYSED
The following analysis sets will be defined for this trial.
Screened set
The screened set (SCR) will consist of all patients who were screened for the trial with 
informed consent given and completed at least one screening procedure at visit 1.
Randomised set
The randomised set (RS) will consist of all patients in the screened set who were randomised 
to study drug, regardless of whether any study drug was taken.
Treated set
The treated set (TS) will consist of all patients who were randomised and treated with at least 
one dose of the study drug. The assignment of patients to treatment group will be based on 
the first study drug intake in the double-blind treatment period.
Full analysis set
The full analysis set (FAS) will consist of all patients in TS who were treated with at least 
one dose of the randomised study drug and had a baseline HbA1c assessment. The 
assignment of patients to treatment groups will be based on the randomised study drug at 
time of randomisation.
Table 6.3: 1
Patient sets analysed
Class of endpoint
SCR
TS
FAS
Secondary efficacy endpoints 
OC, OC-IR, LOCF
Other continuous efficacy 
endpoints
OC, LOCF
Other binary efficacy endpoints
NCF
Primary safety endpoints
OR
Other safety endpoints 
OR, OC-IR, LOCF-IR
Disposition
OR
Demographic
OR
Baseline endpoints
OC
OR: Original results, LOCF-IR: Last observation carried forward including values after rescue, OC-IR: Observed case
including values after rescue, NCF: Non-completers considered failure


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6.5
POOLING OF CENTRES
This section is not applicable because centre is not included in the statistical model.
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 efficacy endpoints of this trial, 
depending upon the type of the endpoint (see Table 6.3: 1).
Original result (OR) analysis
OR 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 (see Section 5.4.2) or if it is not meaningful to
apply any imputation rule on them for replacing the missing values.
Observed cases (OC) analysis
For all efficacy endpoints, it is planned to analyse only the available data that are observed
while patients are on treatment. In other words, missing data will not be replaced in the OC 
analysis. The time window as described in Section 6.7 is to be considered in the OC 
approach. For all efficacy endpoints, this OC-technique will set to missing for all values 
measured after the first day of taking rescue medication (see Section 5.4.2).
For lipid parameters, it is planned to analyse by using OC- technique but including the 
original observed values after taking rescue medication. That is called OC including
values on rescue medication (OC-IR).


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Last observation carried forward (LOCF)
For quantitative endpoints, missing values will be replaced by the last observed measurement 
on treatment. If the patient has no on-treatment value, baseline value will be carried forward. 
This method tends to result in more conservative estimates than an OC-analysis. The values 
measured after taking rescue medication during the treatment period will be set to missing, 
and these missing values will be imputed by LOCF approach.
The last observation on-treatment need not necessarily to be a value selected as a visit value
if multiple measurements are performed within a time window for a visit. In this case the last 
on-treatment value within time window will be carried forward, while the visit value can be 
the value that is observed closest to the planned visit date or the first value observed in the 
time window. See Section 6.7.
Missing values within a course of measurements on treatment 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 a missing 
endpoint;
D-1 = date of the previous-visit (with end-point value non-missing) before the visit with a 
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)).
For lipid parameters, it is planned to analyse by using LOCF- technique but including the 
original observed values after taking rescue medication. That called LOCF including values 
on rescue medication (LOCF-IR).
Non-completes considered failure (NCF)
For binary endpoints, 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. The values measured after taking rescue medication will be replaced as 
“failure”.


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For binary endpoints that are derived from quantitative endpoints, 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.
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
Missing or partial date information for AEs will be replaced according to general
Boehringer Ingelheim (BI) rules described in the BI guidance for “Handling of missing and
incomplete AE dates” (1).
If the date of first drug administration is missing but the patient has been 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 is in the same month. If randomisation is 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 in
the morning.
As a general rule, a missing drug stop date will be imputed according to the
following principles.
• If an End of treatment (EoT) visit is documented, it should be the date of the EoT visit.
• If the date is incomplete with only month and year and the EoT visit is missing, 
it should be the first day of the following month.
• If the patient is lost to follow-up, it should be the date of the last visit + 1 or the 
longest treatment duration based on drug supply + 1 day.
• If the patient dies 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 takes 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.
If only the year of birth is known, 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.
For partial start and stop dates for concomitant therapies 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 end date is set to last day of the month.


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• 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 then 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 team on an individual basis, using the above
points as guidance.
Values below/above limits of quantifications
For biomarkers (insulin, glucagon) we will replace the values which are below the lower limit
of quantification (LLQ) with 2/3 times LLQ. This is approximately the median of the
expected “true” value if the biomarker follows a normal distribution. We will replace the
values which are above the upper limit of quantification (ULQ) with 3/2 times ULQ. With
this approach even a change of the method with different limit of quantifications can be 
handled within a trial. The number of below the LLQ will be included in the biomarker table.
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 medication will be 
considered pre-treatment values. These pre-treatment values will be assigned to a visit 
according to the nominal visit number as record on the eCRF or 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
FPG
1
Body weight
1
Blood pressure
1
Insulin and glucagon
1
Waist circumference
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 7).
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 (see Table 6.7: 1).
Table 6.7: 2
Time windows for on-treatment HbA1c, body weight, and waist 
circumference measurements scheduled for each on-treatment visit
Time window (actual days on treatment)
Visit number
Visit label
Planned days
Start
EndA
7
Baseline
0
NA
1 B
9
Week 8
56
2
98
11
Week 20
140
99
196
13
Week 36
252
197
308
15
Week 52/EoT
364
309
Study drug stop 
date + X days
A
In case of premature discontinuation of the study drug a Visit 15 has to be performed. If such a Visit 15 falls into 
the time window of a previous visit, measurements will be assigned to this previous visit and the visit value will be 
determined as described below. In this case the time window for the visit that includes Visit 15 will end X days 
after the study drug stop date, including Day X. The definition of X is endpoint specific, cf. Table 6.7: 1. As visit 
16 is optional, no time window for this visit is planned.
B
Only values taken prior to the start of treatment with randomised study drug can be considered baseline values. 
Time windows will be used for assignment of measurements to scheduled visits. 


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Table 6.7: 3
Time windows for on-treatment FPG, vital sign, and safety lab 
measurements scheduled for each on-treatment visit
Time window (actual days on treatment)
Visit number
Visit label
Planned days
Start
EndA
7
Baseline
0
NA
1B
8
Week 4
28
2
42
9
Week 8
56
43
70
10
Week 12
84
71
112
11
Week 20
140
113
168
12
Week 28
196
169
224
13
Week 36
252
225
280
14
Week 44
308
281
336
15
Week 52/EoT
364
337
Study drug stop 
date + X days
A
In case of premature discontinuation of the study drug a Visit 15 has to be performed. If such a Visit 15 falls into 
the time window of a previous visit, measurements will be assigned to this previous visit and the visit value will be 
determined as described below. In this case the time window for the visit that includes Visit 15 will end X days 
after the study drug stop date, including Day X. The definition of X is endpoint specific, cf. Table 6.7: 1. As visit 
16 is optional, no time window for this visit is planned.
B
Only values taken prior to the start of treatment with randomised study drug can be considered baseline values. 
Time windows will be used for assignment of measurements to scheduled visits. 
Table 6.7: 4
Time windows for on-treatment biomarkers measurement and bone 
markers scheduled for each on-treatments visit
Time window (actual days on treatment)
Visit number
Visit label
Planned days
Start
EndA
7
Baseline
0
NA
1B
15
Week 52/EoT
364
2
Study drug stop 
date + X days
A
In case of premature discontinuation of the study drug a Visit 15 has to be performed. If such a Visit 15 falls into 
the time window of a previous visit, measurements will be assigned to this previous visit and the visit value will be 
determined as described below. In this case the time window for the visit that includes Visit 15 will end X days 
after the study drug stop date, including Day X. The definition of X is endpoint specific, cf. Table 6.7: 1. As visit 
16 is optional, no time window for this visit is planned.
B
Only values taken prior to the start of treatment with randomised study drug can be considered baseline values. 
Time windows will be used for assignment of measurements to scheduled visits. 
Repeated and unscheduled efficacy and safety measurements will be assigned to the nominal 
visits and listed in the Clinical Trial Report (CTR) Appendix 16.2 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 the closest to the 
protocol-planned visit day. If there are two observations that 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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7.
PLANNED ANALYSIS
For End-of-Text tables, the set of summary statistics is: N (number of patients with
nonmissing values) / Mean / SD / Min / Q1 / Median / Q3 / Max.
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.
Disposition of the patient population participating in the trial will be analysed by treatment
groups on the SCR and presented in the CTR as a frequency-distribution. Reason for not
randomising screened patients will be tabulated on the SCR. 
The frequency of patients in different analysis sets will also be analysed for each treatment 
group.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive analysis of the demographic variables and baseline characteristics described in
Section 5.4.1 will be presented on the FAS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the CTR using the FAS.
CT will be summarised by Anatomical-Therapeutic-Chemical classification level 3 (ATC3) 
and preferred name at baseline and on-treatment on the FAS. Separate summaries of use of 
antihypertensives, acetylsalicylic acid (ASA), or lipid lowering drugs at baseline by preferred 
name will be presented on the FAS.
Antidiabetic medication introduced on treatment will be summarised on the FAS.
Concomitant diseases will be summarised by MedDRA system organ class (SOC) and 
preferred term (PT) on the FAS. Relevant diabetic medical history will also be presented on 
the FAS.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the CTR. The number and
percentage of patients with overall compliance for the study drug will be summarised on the 
FAS. The overall compliance will be calculated as a weighted average of reported 


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compliance. 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). 
7.4
PRIMARY ENDPOINT
The primary endpoint of this trial is the frequency of patients with drug-related AE during 52 
weeks of treatment. Frequency tabulation and descriptive statistics will be used to assess the 
safety by summarizing drug-related AE during 52 weeks of treatment by treatment group 
(Empagliflozin 10 mg or 25 mg) based on TS. More details are given in Section 7.8.
  
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoint
 
 
Mixed model repeated measures (MMRM)
Restricted maximum likelihood-based MMRM will be performed on FAS (OC) with the 
following model.
HbA1c change from baseline
= overall mean + treatment + baseline HbA1c + baseline renal function +
visit + treatment-by-visit interaction + baseline HbA1c-by-visit interaction + 
error
In the above MMRM model, “treatment”, “baseline renal function”,  “visit” and “treatment-
by-visit” interaction are fixed classification effects, “baseline HbA1c” and “baseline HbA1c-
by-visit” interaction are covariates. 
The term “baseline HbA1c” refers to the last HbA1c assessment prior to the administration of 
any randomised medication (HbA1c values at Visit 7) and not to the HbA1c measurement 
used for the stratification in the randomisation. 
“Baseline renal function” is a classification variable derived from the categorization of eGFR 
at baseline as specified in Section 5.4.1 and Table 6.4: 1. For modeling purpose, eGFR 
categories <90 and ≥90 are used in the model.
Unstructured covariance structure will be used to model the within-patient correlation due to 
repeated measurements. If the model fails to converge, the following covariance structure 


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will be tested: compound symmetry, variance components and Toeplitz. The covariance 
structure, with which the model converges and provides the best fit as determined by Akaike 
information criterion (AIC), will be used for final analysis. The Kenward-Roger
approximation will be used to estimate the denominator degrees of freedom.
Because the change in HbA1c from baseline at each on-treatment visit is used as the outcome 
variable in the MMRM model, the above model is also used to evaluate the HbA1c change 
from baseline overtime.
Only the available data which are observed whilst patients are on treatment will be included 
in the analysis. Missing data are handled implicitly by the above statistical model, rather than 
by using any imputation. This approach will also additionally set to missing all values
measured after the use of restricted antidiabetic medication during the trial (see Section 4.2.2 
in CTP).
 
 
 
 
 
 
 
 
 
 


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse events
AEs will be coded using the most recent version of the Medical dictionary for regulatory 
Activities (MedDRA) coding dictionary.


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The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and not on the number of AEs. For this purpose, AE data will be 
combined in a 2-step procedure into AE records.
In a first step, multiple AE occurrence data on the eCRF will be collapsed into AE episodes 
provided that all of the following applies:

The same MedDRA lowest level terms are reported for the occurrences

The occurrences are 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 the collapsing 
will begin.)

Treatment is not changed between the onset of the occurrences or treatment is changed 
between the onset of the occurrences, but no deterioration is observed for the later 
occurrence
In a second step, AE episodes will be condensed into AE records provided that the episodes 
have been reported with the same term on the respective MedDRA level and that the episodes 
are assigned to the same treatment. For further details on summarisation of AE data, please 
refer to the guideline “Handling and summarisation of AE data for CTRs and integrated 
summaries” (2).
7.8.1.1
Assignment of AEs to treatment
The analysis of AEs will be based on the concept of treatment emergent AEs. That means
that all AEs occurring between first drug intake till last drug intake + residual effect period (7 
days for this trial) will be assigned to the randomised treatment. All AEs occurring before 
first drug intake will be assigned to ‘screening’ and all AEs occurring after the residual effect 
period will 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 (3).AEs 
classified as “other significant” will include those non-serious AEs with:

“action taken = discontinuation” or “action taken = reduced”, or

Marked haematological and other lab abnormalities or lead to significant CT as 
identified by the Clinical Monitor/Investigator at a medical quality review meeting or 
BRPM. 


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7.8.1.3
AE summaries
An overall summary of AEs will be presented.
The frequency of patients with AEs will be summarised by treatment, primary SOC and PT.
AEs will also be reported by intensity. Separate tables will be provided for patients with 
drug-related AEs, for patients with AEs leading to discontinuation, for patients with serious 
AEs, for patients with other significant AEs and for patients with AESI.
The SOCs will be sorted according to the standard sort order specified by European
medicines agency, PTs will be sorted by frequency (within SOC).
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 as 
described in CTP, Section 5.3.3. 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
The frequency of patients with hypoglycaemia according to investigator’s judgement will be 
summarised by primary SOC and PT.
Confirmed hypoglycaemic AE is defined as hypoglycaemic AE with glucose value available 
and below 70 mg/dL or where assistance is required.
Summaries of confirmed hypoglycaemic AEs will include total number of hypoglycaemic
AEs (asymptomatic and symptomatic), severity and intensity of the worst episode, action 
taken, minimum glucose level of worst episode, time to onset of first episode, and number of 
episodes per patient (asymptomatic and symptomatic).


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Subgroup analyses of hypoglycaemic AEs with respect to age category, rescue therapy and 
renal function will be performed.
Summary table will include rate of confirmed hypoglycaemic AEs by severity, by age 
categories, and by renal function. For subgroup of age categories and renal function, time at 
risk for each group will be used.
Time to the onset of the first hypoglycaemia will be analysed by Kaplan-Meier estimates. 
The Kaplan-Meier analysis will be performed based on confirmed AEs.
Different summaries will be shown for the number of patients with hypoglycaemia 
(symptomatic, asymptomatic reported as AE, or asymptomatic reported as non-AE), severity 
of the worst episode, minimum glucose level of worst episode, time to onset of first episode, 
and number of episodes per patient in the CTR, Appendix 16.1.9.2.
7.8.1.5
Adverse event of special interest (AESI)
Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA)
The frequency of patients with metabolic acidosis will be summarized by type and treatment 
group. Patients with DKA will be retrieved based on narrow BI-customised MedDRA query
(BIcMQ) for DKA. 
Decreased renal function/Hepatic injury
The frequency of patients with the protocol defined renal and hepatic events (See CTP, 
Section 5.3.6.1) will be summarised by primary SOC and PT as AESIs. The renal and hepatic 
events are identified through the AE being flagged as AESI on the eCRF.
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
Events involving lower limb amputation
The frequency of patients with events leading to lower limb amputation will be summarized 
by type and treatment group. 


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7.8.1.6
Analysis of urinary tract infections (UTI) / genital infections
UTIs / genital infection will be tabulated based on the official BIcMQ. 
The frequency of patients with UTIs / genital infections based on BIcMQ will be summarised 
by primary SOC and PT. The frequency tables by sex will also be provided for the UTIs / 
genital infections.
UTIs / genital infections will be summarised by intensity (mild, moderate, severe), age group, 
time of occurrence (in the first 3 months of treatment or after), time to onset of first event (0 
to ≤3 months, >3 months), duration (<7 days, 7-14 days, >14 days), treatment for the event 
(no treatment, therapy assigned, hospitalisation), whether leading to discontinuation of 
treatment, and the number of episodes per patient.
Subgroup analyses of UTIs / genital infections with respect to age group, sex, baseline 
HbA1c, and history of UTI / genital infections will be performed.
In the analysis of the number of episodes of UTI and genital infection, AEs will be collapsed 
within each BIcMQ regardless of PT 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.
Kaplan-Meier time to event analyses will also be presented for the UTIs and genital
infections.
7.8.1.7 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.
7.8.1.8  Analysis of volume depletion
Volume depletion will be tabulated on the basis of the BIcMQ for overall summary and by 
age group and renal function based on baseline eGFR.
7.8.1.9  Analysis of adjudicated events
Hepatic events will be adjudicated by an external expert committee. The patients with 
adjudicated hepatic events will be summarized by treatment and relationship with the trial 
medication.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (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. 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 is described in the BI 
guideline (4). All analyses considering multiple of times upper limit of normal (ULN) will be 
based on original and not normalised data.
General laboratory evaluation
Descriptive statistics with normalised values will be provided by treatment group for baseline, 
on-treatment values and for changes from baseline. 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. Frequency 
tables for categorical laboratory values categorised by value at baseline and last value on 
treatment will be shown. Frequency tables will summarise the number of patients with 
potentially clinically significant abnormalities. In addition, descriptive statistics with 
normalised values and frequency for categorical laboratory values will be provided for 
overtime in the CTR, Appendix 16.1.9.2.
General laboratory evaluation will also be provided for bone markers.
Hepatic laboratory parameters
To support analyses of liver related adverse drug effects, patients with following alterations 
of hepatic laboratory parameters at randomisation at Visit 7 are of special interest:

An elevation of AST and/or ALT ≥3xULN combined with concomitant or subsequent 
total bilirubin ≥2xULN in a 30 day period after AST/ALT elevation and/or

Marked peak aminotransferase (ALT, and/or AST) elevations ≥5xULN
The start of the 30 day time span is triggered by each liver enzyme elevation above the 
defined thresholds. Patients who fulfil one or two of the criteria for ALT/AST or total 
bilirubin(TBILI) but 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 TBILI ≥2xULN” or “ALT and/or AST ≥5xULN”.
Summaries will be presented for patients with elevated liver enzymes. Details on patients 
with elevated liver enzymes will also be listed.


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Renal laboratory parameters
All calculations for the grading of renal function will be based on the originally measured 
laboratory values and the ULNs given by the laboratory, not on normalised values with BI 
standard reference ranges. 
The creatinine clearance (Ccr) and glomerular filtration rate (GFR) will be estimated 
according to the two formulas:

Cockcroft-Gault formula [mL/min]: 
eCcr = (140 – age) x (weight [kg]) x (0.85 if female) / (72 x serum creatinine [mg/dL])

Japanese equation [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 the age will be 
from the same visit as the other variables. The weight used in the calculations will be that 
from the same visit, if available. If a value is not available, an interpolated value from the 
previous and subsequent visits will be used. If no subsequent value is available an LOCF 
approach will be used. Baseline values will not be interpolated.
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 PVs based on renal function, the central laboratory values will be used.
Staging of the eGFR will be categorized according to the following staging:
Table 7.8.2: 1
Japanese equation eGFR staging
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 categorized according to the following staging:


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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)
Descriptive statistics will be created for creatinine and eGFR values over time. Descriptive 
statistics for eCcr will be presented in the CTR, Appendix 16.1.9.2. These data will be used 
to create plots of the parameters over time. Subgroups tables of these descriptive statistics at 
Week 52 will also be presented for age subgroups.
A summary will also be created representing the number of patients with creatinine on 
treatment ≥2 x baseline and greater than the upper limit of normal.
A shift table from baseline to last value on treatment for eGFR (Japanese equation) will be 
provided in the CTR, Section 15 and eCcr (Cockcroft-Gault) will be provided in the CTR, 
Appendix 16.1.9.2.
In addition, urine albumin and urine albumin / creatinine ratio will be summarised in the CTR. 
Urine creatinine does not have a reference range and it 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 
below the quantification limits (e.g. <3 mg/L), the albumin / creatinine ratio is determined as 
missing and will not be replaced by estimated values. 
Four 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)), descriptive statistics of urine albumin by baseline value 
(<20mg/L, 20-<200mg/L and ≥200mg/L) and frequency of transitions from baseline based on 
the before mentioned categories.
Serum lipid parameters/free fatty acid (FFA)
Lipid parameters (Total cholesterol, HDL, LDL, LDL/HDL ratio, Non-HDL, and 
Triglycerides) and FFA will be analysed using descriptive statistics and MMRM modelling. 
Descriptive statistics will be shown over time for the TS (LOCF-IR and OC-IR) including 
change from baseline and percent change from baseline. For each lipid parameter, separate 
MMRM models will be fitted on the TS (OC-IR) for both change from baseline and 
percentage change from baseline. The MMRM models will include “baseline lipid” and 
“baseline HbA1c” as continuous covariates and “treatment”, “baseline renal function”, “visit”
and “treatment-by-visit” interaction as fixed effects.
Blood ketone body


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Descriptive statistics will be created for blood ketone bodies (total ketone bodies, acetoacetic 
acid, 3-hydroxybutyric acid) over time. 
7.8.3
Vital signs
Only descriptive statistics of pulse rate are planned for this section of the CTR.
7.8.4
ECG
No analysis will be conducted. Any clinically significant new findings in the ECG
measurement after the first screening ECG will be considered as AEs.


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
2
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", version 5.0; IDEA for CON.
3
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
4
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
29-JUN-17
None
This is the final TSAP without any 
modification