Conditions: Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 219
Healthy volunteers: no

Brief summary:
This is a study in Chinese adults with type 2 diabetes. The study is open to people who take insulin but still have too high blood sugar levels. Participants may additionally be taking up to 2 other medicines for their diabetes. The purpose of this study is to find out whether empagliflozin taken together with insulin helps people with type 2 diabetes to better control their blood sugar.

The participants are in the study for about 7 months. During this time, they visit the study site about 8 times, 1 additional visit may be either a visit to the study site or a phone call. At the start of the study, participants are put into 3 groups by chance. Participants get either 10 mg empagliflozin tablets, or 25 mg empagliflozin tablets, or placebo tablets once a day. Placebo tablets look like empagliflozin tablets but do not contain any medicine.

The doctors regularly take blood samples from the participants. The changes in blood sugar levels are compared between the groups. The doctors also check the general health of the participants.

Detailed description:

Arms:
arm 1: 1 table of 10 milligrams (mg) of Empagliflozin was administered orally once daily for a treatment period of 24 weeks.

Before the first dose of randomised drug, all participants went through a 2-week open label placebo run-in period, taking Placebo tablets orally once daily. arm 2: 1 table of 25 milligrams (mg) of Empagliflozin was administered orally once daily for a treatment period of 24 weeks.

Before the first dose of randomised drug, all participants went through a 2-week open label placebo run-in period, taking Placebo tablets orally once daily. arm 3: Matching placebo was administered orally once daily for a treatment period of 24 weeks.

Before the first dose of randomised drug, all participants went through a 2-week open label placebo run-in period, taking Placebo tablets orally once daily.

Interventions: intervention 1: Empagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Empagliflozin intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (16.0) / Saved on: 30 Aug 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c26980387-02
BI Trial No.
1245-0191
BI Investigational
Medicinal Product(s)
Jardiance®, Empagliflozin
BI 10773
Title
A phase III, randomised, double-blind, placebo-controlled, 
parallel group study of Empagliflozin (10 mg and 25 mg) 
administered orally once daily in combination with insulin with or 
without up to two oral anti-diabetic agents for 24 weeks in 
Chinese type 2 diabetic patients with insufficient glycemic 
control.
Lay Title
A study to test how well empagliflozin works in Chinese patients 
with type 2 diabetes who already take insulin
Clinical Phase
III
Clinical Trial Leader
Phone: 
Fax: 
Coordinating 
Investigator
Phone: 
Fax: 
Status
A revised protocol based on the first global amendment
Version and Date
Version:
2.0
Date:
20 Apr 2021
Page 1 of 74
Proprietary confidential information.
2021 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
Company name
Boehringer Ingelheim
Protocol date
20 Apr 2021
Revision date
N/A
BI trial number
1245-0191
Title of trial
A phase III, randomised, double-blind, placebo-controlled, parallel group study of 
Empagliflozin (10 mg and 25 mg) administered orally once daily in combination 
with insulin with or without up to two oral anti-diabetic agents for 24 weeks in 
Chinese type 2 diabetic patients with insufficient glycemic control.
Coordinating 
Investigator
Trial site(s)
Multi-center trial conducted in China
Clinical phase
III
Trial rationale
In China, more than 33% of adults with type 2 diabetes receive insulin therapy 
(basal or premixed), but only 26% of those have adequate glycemic control. 
Empagliflozin was approved in China in 2017 for the treatment of T2DM as an 
adjunct to diet and exercise and in combination with various oral anti-diabetic 
therapies. However, using Empagliflozin in combination with insulin has not been 
investigated in Chinese patients with T2DM. The aim of this study is to evaluate 
efficacy and safety over 24 weeks of Empagliflozin therapy in Chinese T2DM
patients whose glycemia is inadequately controlled despite background treatment 
on a stable dose of basal or premixed insulin, with or without other oral 
antihyperglycemic drugs.
Trial objective(s)
To determine the efficacy and safety of Empagliflozin added to insulin-treated 
type 2 diabetes patients.
Trial endpoints
The primary endpoint is:
•
Change from baseline in glycosylated haemoglobin A1c (HbA1c) after 24 
weeks of treatment.
Secondary efficacy endpoints are:
•
Percentage of patients with HbA1c<7.0% after 24 weeks of treatment
•
Change in Body Weight from Baseline to Week 24
•
Change in Systolic Blood Pressure (SBP) from Baseline to Week 24
•
Change in Diastolic Blood Pressure (DBP) from Baseline to Week 24
•
Change in Fasting Plasma Glucose (FPG) from Baseline to Week 24
•
Change in 2-hour Post-prandial Glucose (PPG) from Baseline to Week 24
Secondary safety endpoints are:
•
Occurrence of hypoglycemic events
•
Occurrence of adjudicated diabetic ketoacidosis (DKA) events
Trial design
Randomised, double-blind, multi-center, placebo-controlled, parallel group study 
compares Empagliflozin (10 mg or 25 mg) to placebo as add-on therapy to stable 
insulin with or without up to two oral antidiabetic drugs.
Total number of 
patients randomised 
Approximately 216
Number of patients on 
each treatment
Approximately 72
Diagnosis
The study will be performed in Chinese patients with T2DM who have insufficient 
glycemic control despite diet and exercise and receiving insulin alone or in 
combination with other Oral Antidiabetic Drugs (OADs).


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Main in- and exclusion 
criteria
Inclusion criteria
1.
Age ≥18 years and ≤75 years old at Visit 1;
2.
Chinese patient with diagnosis of Type 2 diabetes prior to Visit 1;
3.
A stable treatment with premixed Insulin (≥ 20IU/day) or basal insulin (≥ 16 
IU/day) for at least 12 weeks prior to enrolment with or without up to two 
OADs
-
With maximum insulin dose of ≤ 1 unit/kg/day. Acceptable basal 
insulins should have duration of action up to 24 h such as insulin 
degludec, insulin glargin, insulin detemir or NPH (neutral protamine 
hagedorn) insulin; Acceptable pre-mixed insulins could be once or 
twice daily posology only.The total insulin dose should not be 
changed by more than 20% of the baseline value within the 12 weeks 
prior to randomisation (Visit 3). Both human insulin and insulin 
analogue are acceptable;
-
If the patient is taking OADs, regimen has to be unchanged for at least 
12 weeks prior to randomization (Visit 3);
-
If the patient is taking metformin, stable dose (at least 1500 mg daily 
or maximum tolerated dose) must be maintained for at least 12 weeks 
without dose adjustments prior to randomization (Visit 3);
4.
HbA1c ≥7.5% and ≤11.0% at Visit 1;
5.
Fasting C-peptide: >0.5 ng/mL (>166pmol/L) at Visit 1;
6.
18.5 kg/m2 ≤ BMI ≤ 45 kg/m2 at Visit 1.
Exclusion criteria
1.
Diagnosis of Type 1 diabetes;
2.
Patients receiving MDI insulin or insulin pump treatment;
3.
eGFR <45ml/min/1.73m2 calculated based on MDRD formula;
4.
Uncontrolled hyperglycemia (glucose level >13.9 mmol/l after an overnight 
fast during placebo run-in);
5.
Severe hypoglycemia episode (event requiring the assistance of another 
person to actively administer carbohydrate, glucagon or other resuscitative 
actions) within 6 months prior to Visit 1; 
6.
History of diabetic ketoacidosis or hyperosmolar non-ketotic coma;
7.
Myocardial infarction, Stroke or transient ischaemic attack within 3 months 
prior to Visit 1;
8.
Bariatric surgery;
9.
SGLT2 inhibitors intake within 12 weeks prior to Visit 1;
10.
Treatment with anti-obesity drugs within 12 weeks prior to Visit 1;
11.
Treatment with Glucagon-Like Peptide-1 (GLP-1) receptor agonists within 
12 weeks prior to Visit 1;
12.
Treatment with Sulphonylurea (SU) if the patient is on premixed insulin
within 12 weeks prior to Visit 1;
13.
Impaired hepatic function (serum alanine aminotransferase, aspartate 
aminotransferase, or alkaline phosphatase >3 times the upper limit of normal)
at V1; 
14.
Contraindication to background anti-diabetes medication according to the 
local label;
15.
Disorders causing hemolysis or unstable red blood cells;
16.
Treatment with systemic steroids at the time of consent; 
17.
Change in dosage of thyroid hormones within 6 weeks prior to Visit 1; 
18.
Alcohol or drug abuse within 12 weeks prior to Visit 1;
19.
History of unstable or rapidly progressing renal disease;
20.
Conditions of congenital renal glucosuria;
21.
Known allergy or hypersensitivity to empagliflozin or other SGLT-2 
inhibitors.
Test product(s)
Empagliflozin


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dose
10 or 25 mg daily
Mode of administration
oral
Comparator product(s)
Placebo
dose
Not applicable
Mode of administration
oral
Duration of treatment
2-week placebo run in
24-week double-blind treatment
1-week follow up
Statistical methods
The primary endpoint in this trial is the change in HbA1c from baseline after 24 
weeks of treatment. The primary analysis is a restricted maximum likelihood 
(REML) based approach using a mixed model for repeated measures (MMRM) 
comparing the mean change in HbA1c from baseline after 24 weeks of treatment. 
The analysis will include treatment, background therapy, and visit as fixed 
classification effects, baseline HbA1c and baseline eGFR as the linear covariates, 
treatment by visit interaction, and baseline HbA1c by visit interaction. The primary 
analysis will be performed on mITT set with patients assigned to the treatment 
they are randomised to and include on-treatment HbA1c values only. The primary 
treatment comparisons will be the contrasts between active treatment 
(Empagliflozin 10 mg and 25 mg, respectively) and placebo at week 24.


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FLOW CHART
Trial Periods
Screening Run-in 
Randomised Treatment 
Follow-up 
Visit
1
2
3
4N
5 N
6 N
7 N
8 
(EoTA)
9
FUP  
Weeks
-3
-2
0
4
8
12
18
24
25
Study Day
-21
-14
1
29
57
85
127
169
176
Time window for visits
±7 days
-7 days
0
±7 
days
±7 
days
±7 
days
±7 
days
+ 7 
days
+ 7 days
Informed consent 
X
DemographicsB
X
X
Medical history
X
In-/Exclusion criteria
X
X
X
Physical examination
X
X
Vital signs
X
X
X
X
X
X
X
X
XM
Height
X
HbA1c
X
X
X
X
X
X
X
Home Blood Glucose 
Monitoring
C
X
X
X
X
X
X
X
X
Dispense placebo run-in kit
D
X
Randomisation (via IRT)
X
Weight
X
X
X
X
X
X
X
Waist circumference
X
X
Diet and exercise
counsellingE
X
X
X
X
X
X
X
12 lead-ECGF
X
X
8-point glucose profileL
X
X
X
Pregnancy testG
X
X
X
X
Glomerular filtration rateH
X
X
X
X
Fasting C-peptide
X
Safety lab tests
I (urine and 
blood)
XI
X
X
X
X
XM
FPG
X
X
X
X
X
X
X
XM
2-hour PPG testJ
X
X
Lipid lab panel
X
X
MTT test (including Insulin 
+ c-peptide)J
X
X
Dispense trial drugsD
X
X
X
X
X
All AEs/SAEs/AESIsK
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
Compliance check 
X
X
X
X
X
X
Completion of patient 
participation 
X
A
Patients who discontinue trial treatment prematurely should undergo the End of Treatment (EOT) visit as soon as 
possible and allow to attend all clinic visits up to the FUP Visit thereafter in order to collect all the data as other 
treatment completed patients. 
B
Only screening relevant demographics (gender, date of birth, race and ethnicity) at Visit 1. Smoking and alcohol status 
could be collected at Visit 2.
C
Instruction and training of the patient to use the device at Visit 2. A full overnight fast (nothing to eat or drink except 
water for at least 10 hours) for all planned tests. Daily measurements during Run-in and Follow-up. During the 
treatment period a weekly test is recommended. During the whole trial participation, additional measurements should 
be done in case of hypo- or hyperglycemia related symptoms without fasting state required.
D
At all visits, the respective kit number has to be allocated to the patient via IRT.


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E
Diligent diet and exercise counselling by a diet specialist or delegated staff member at Visit 2. Counselling is based on 
local diet recommendations. At all visits, patients should be reminded about the importance to follow the 
recommended diet and exercise plan.
F
In addition to the visits indicated, ECG should be recorded in case of respective cardiac symptoms (indicating rhythm 
disorders or cardiac ischaemia).
G
For female patients (local urine pregnancy test in women of child bearing potential).
H
Calculated based on MDRD formula (see Section 5.2.3).
I
Fasting blood samples (full overnight fast (nothing to eat or drink except water for at least 10 hours)). For the 
screening (Visit 1) safety laboratory only includes liver transaminases, alkaline phosphatase, and serum creatinine, for 
which patients do not have to be fasting.
J
At Visit 3, AFTER blood sample of insulin, C-peptide and FPG drawing, patients will have a standardised breakfast 
which should be finished within 15 minutes and intake accepted pre-mixed insulin and/ or OAD (if applicable) 
according to the local insert label, and blood samples for insulin, C-peptide and PPG will be collected at time points 
60 ±10 min and 120 ±10 min after the start of standardised breakfast. Study medication will be taken after blood 
samples drawing.
At Visit 8, 30 min after blood sample of insulin, C-peptide and FPG drawing and administration of study medication
(except the visit is after EOT), patients will have a standardised breakfast which should be finished within 15 min and 
intake accepted pre-mixed insulin and/ or OAD according to the local insert label (if applicable), and blood samples
for insulin, C-peptide and PPG would be collected at time points 60 ±10 minutes and 120 ±10 min after the start of 
standardised breakfast. (All patients at all sites should participate)
K
After the individual patient’s end of the trial the investigator should report only cancers of new histology and 
exacerbations of existing cancer, trial treatment related SAEs and trial treatment related AESIs of which the 
investigator may become aware of and only via the SAE form, please see protocol Section 5.2.6.1.
L 
The 8-point glucose profile must be started in the morning within one week prior to the Visit 3, 6 and 8. 
M
For those patients who have AEs persisting at Visit 8/EOT.
N       For potential modifications of trial conduct in case of restrictions due to COVID-19, please refer to Sections 4.1.4, 
6.1, 8.1, 8.3.2 and 10.2.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................14
1.1
MEDICAL BACKGROUND.............................................................................14
1.2
DRUG PROFILE................................................................................................14
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................16
1.4
BENEFIT - RISK ASSESSMENT.....................................................................16
1.4.1
Benefits.................................................................................................................16
1.4.2
Risks .....................................................................................................................17
1.4.3
Discussion.............................................................................................................20
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................21
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........21
2.1.1
Main objectives....................................................................................................21
2.1.2
Primary endpoint(s)............................................................................................21
2.1.3
Secondary endpoint(s) ........................................................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................23
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................24
3.3
SELECTION OF TRIAL POPULATION .......................................................25
3.3.1
Main diagnosis for trial entry ............................................................................25
3.3.2
Inclusion criteria .................................................................................................26
3.3.3
Exclusion criteria ................................................................................................26
3.3.4
Withdrawal of patients from treatment or assessments..................................27
3.3.4.1
Discontinuation of trial treatment .........................................................................28
3.3.4.2
Withdrawal of consent to trial participation .........................................................29
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................29
4.
TREATMENTS...................................................................................................30
4.1
INVESTIGATIONAL TREATMENTS ...........................................................30
4.1.1
Identity of the Investigational Medicinal Products..........................................30
4.1.2
Selection of doses in the trial and dose modifications......................................31
4.1.3
Method of assigning patients to treatment groups...........................................31
4.1.4
Drug assignment and administration of doses for each patient......................31
4.1.5
Blinding and procedures for unblinding...........................................................32


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4.1.5.1
Blinding.................................................................................................................32
4.1.5.2
Unblinding and breaking the code ........................................................................33
4.1.6
Packaging, labelling, and re-supply...................................................................33
4.1.7
Storage conditions...............................................................................................33
4.1.8
Drug accountability.............................................................................................33
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................34
4.2.1
Other treatments and emergency procedures..................................................34
4.2.2
Restrictions ..........................................................................................................36
4.2.2.1
Restrictions regarding concomitant treatment ......................................................36
4.2.2.2
Restrictions on diet and life style..........................................................................36
4.2.2.3
Contraception requirements..................................................................................36
4.3
TREATMENT COMPLIANCE........................................................................36
5.
ASSESSMENTS..................................................................................................38
5.1
ASSESSMENT OF EFFICACY........................................................................38
5.2
ASSESSMENT OF SAFETY.............................................................................39
5.2.1
Physical examination ..........................................................................................39
5.2.2
Vital signs.............................................................................................................40
5.2.3
Safety laboratory parameters ............................................................................40
5.2.4
Electrocardiogram ..............................................................................................42
5.2.5
Other safety parameters.....................................................................................42
5.2.6
Assessment of adverse events.............................................................................43
5.2.6.1
Definitions of AEs ................................................................................................43
5.2.6.1.1
Adverse event........................................................................................................43
5.2.6.1.2
Serious adverse event............................................................................................43
5.2.6.1.3
AEs considered “Always Serious”........................................................................43
5.2.6.1.4
Adverse events of special interest.........................................................................44
5.2.6.1.5
Intensity (severity) of AEs....................................................................................45
5.2.6.1.6
Causal relationship of AEs....................................................................................45
5.2.6.2
Adverse event collection and reporting ................................................................46
5.2.6.2.1
AE Collection........................................................................................................46
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................46
5.2.6.2.3
Pregnancy..............................................................................................................47
5.2.7
Criteria for hypoglycemic events.......................................................................47
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................48
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................48
5.4.1
Biochemical and cellular biomarkers................................................................48
5.4.2
Pharmacogenomics biomarkers.........................................................................48
5.4.3
Methods of sample collection .............................................................................48
5.5
BIOBANKING ....................................................................................................48
5.6
OTHER ASSESSMENTS...................................................................................49
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................49
6.
INVESTIGATIONAL PLAN.............................................................................50


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6.1
VISIT SCHEDULE.............................................................................................50
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................50
6.2.1
Screening and run-in period(s)..........................................................................51
6.2.2
Treatment period(s)............................................................................................52
6.2.3
Follow-up period and trial completion..............................................................53
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................55
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................55
7.2
PLANNED ANALYSES.....................................................................................55
7.2.1
General considerations .......................................................................................55
7.2.2
Primary endpoint analyses.................................................................................56
7.2.2.1
Primary analysis of the primary endpoint.............................................................56
7.2.2.2
Secondary analyses of the primary endpoint ........................................................57
7.2.2.4
Supplementary analysis......................................................................................58
7.2.3
Secondary endpoint analyses .............................................................................58
7.2.5
Safety analyses.....................................................................................................59
7.2.6
Interim Analyses .................................................................................................59
7.3
HANDLING OF MISSING DATA ...................................................................60
7.4
RANDOMISATION ...........................................................................................60
7.5
DETERMINATION OF SAMPLE SIZE .........................................................60
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........62
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................62
8.2
DATA QUALITY ASSURANCE ......................................................................63
8.3
RECORDS...........................................................................................................63
8.3.1
Source documents ...............................................................................................63
8.3.2
Direct access to source data and documents.....................................................64
8.3.3
Storage period of records ...................................................................................64
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................65
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........65
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................65
8.6
TRIAL MILESTONES.......................................................................................65
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................65
9.
REFERENCES....................................................................................................67
9.1
PUBLISHED REFERENCES............................................................................67
9.2
UNPUBLISHED REFERENCES......................................................................67
10.
APPENDICES.....................................................................................................68
10.1
BLOOD PRESSURE MEASUREMENT PROCEDURE...............................68
10.2
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19.............................................................68


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................70
11.1
GLOBAL AMENDMENT 1 ..............................................................................70


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AGI
α-glucosidase inhibitor
ALT
Alanine Aminotransferase
AMP
Auxiliary Medicinal Products
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BMI
Body Mass Index
BUN
Blood urea nitrogen
CA
Competent Authority
CEC
Clinical Event Committee
CI
Confidence Interval
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT
Computed Tomography
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
DB P
Diastolic blood pressure
DILI
Drug Induced Liver Injury
DKA
Diabetic ketoacidosis
DPP-4I
DPP-4 Dipeptidyl-peptidase IV inhibitior
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoT
End of Treatment
EoTrial
End of Trial
EudraCT
European Clinical Trials Database


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FPG
Fasting plasma glucose
FUP
Follow-up
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GLP-1
Glucagon-Like Peptide-1
GMP
Good Manufacturing Practice
HA
Health Authority
HbA1c
Haemoglobin A1c
HBGM
Home Blood Glucose Monitoring
HDL
High Density Lipoprotein
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
LDL
Low Density Lipoprotein
LPLT
Last Patient Last Treatment
MDI
Multiple daily injections
MDG
Mean Daily Glucose
MedDRA
Medical Dictionary for Drug Regulatory Activities
Met
Metformin
MRI
Magnetic Resonance Imaging
OAD
Oral Antidiabetic Drug
OPU
Operative Unit
p.o.
per os (oral)
PPG
Post-prandial glucose
q.d.
quaque die (once a day)
RA
Regulatory Authority
REP
Residual Effect Period
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
Scr
Serum creatinine


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SGLT-2
Sodium-dependent glucose transporters 2
SOP
Standard Operating Procedure
SU
Sulphonylurea
SUSAR
Suspected Unexpected Serious Adverse Reactions
T2DM
Type 2 Diabetes Mellitus
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
UACR
Urine albumin-to-creatinine ratio
ULN
Upper Level of Normal
UTI
Urinary tract infections
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Type 2 diabetes mellitus (T2DM) is a progressive disease with high morbidity and mortality. 
Recent estimates suggest that the number of people worldwide with T2DM is currently 382 
million and is expected to reach at least 592 million in 2035. In China, it is estimated that 
113.9 million adults 18 years of age or older (11.6% of the adult population) have diabetes. In 
addition, 493.4 million Chinese adults (50.1%) have prediabetes, which is an important risk 
factor for the development of diabetes [R13-5351]. 
According to the Chinese Diabetes Society guideline, insulin therapy should be initiated in 
T2DM patients with insufficient glycemic control despite combination treatment of OADs 
and lifestyle intervention. In addition, patients on background therapy with insulin represent 
an important proportion of the T2DM patient population. A national wide survey showed 
more than 33% [R13-5351] of adults with type 2 diabetes receive insulin therapy, including 
both basal and premixed insulin, but only 26% of those have adequate glycemic control. 
Therefore, it is necessary to combine oral hypoglycemic drugs to control hyperglycemia for 
most patients. However, existing oral hypoglycemic drugs cannot fully meet this demand due 
to their characteristics and mechanism. There remains an unmet need for oral antidiabetes 
agents that can be added to insulin therapy to facilitate further improvements in glycemic 
control without causing hypoglycemia or weight gain. 
SGLT-2 is a member of a larger group of sodium substrate co-transporters, the 
sodium-glucose co-transport 5 (SLC5) gene family [R05-0939]. Under normoglycemia, 
glucose is almost completely reabsorbed by SGLTs in the kidney, whereas the reuptake 
capacity of the kidney is saturated at plasma glucose concentrations higher than 
approximately 10-11 mmol/L, resulting in increasing 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 selectively blocks glucose transport via SGLT-2 
(IC50 1.3 nmol/l), with a 5000-fold selectivity over SGLT-1 (IC50 6278 nM).
In 2017, the guideline of Chinese Diabetes Society recommended SGLT-2 inhibitors as one 
of the second line OADs with special emphasis on its benefits on CV outcome and potential 
renal protection.
1.2
DRUG PROFILE
Empagliflozin (BI 10773) received its first marketing approval in April 2014 in Australia and 
is approved for the treatment of T2DM in more than 107 countries; the preferred trade name 
is Jardiance®. Based on a dedicated cardiovascular outcome trial (EMPA-REG 
OUTCOME®), a separate indication, reduction of the risk of cardiovascular death in patients 
with T2DM and established CV disease, was approved in more than 40 countries including 
the US, Canada and Australia. In over 50 countries including the EU, the indication was 
modified and/or the results included in the clinical trial section acknowledging the positive 
results of the CV outcome study.There have been no marketing withdrawals or suspensions, 
no failures to obtain marketing authorization renewal, no restrictions placed on the 


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distribution of the product and no clinical trial suspensions for any product containing 
empagliflozin.
Mode of action
Empagliflozin (BI 10773), an orally available potent selective SGLT-2 inhibitor, has been
studied as part of a global development program including more than 20000 patients with 
type 2 diabetes treated in clinical studies of which more than 13000 were treated with 
empagliflozin, either alone or in combination with metformin, a sulfonylurea, a PPARγ 
agonist, dipeptidyl peptidase-4 (DPP-) inhibitors, or insulin. This agent lowers both the 
saturation threshold and the transport maximum of SGLT-2 for glucose, resulting in 
increased glucosuria, insulin-independent reduction of plasma glucose levels with a low risk 
of hypoglycemia, and negative energy balance with weight reduction.
Key pharmacokinetic characteristics
Empagliflozin showed mainly linear pharmacokinetics in humans reaching peak levels at 
approximately 1.5 h with a biphasic decline and a terminal elimination half-life of 12.4 h. 
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.
Drug interactions
Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest 
that the primary route of metabolism of empagliflozin in humans is glucuronidation by the 
uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. 
Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. At 
therapeutic doses, the potential for empagliflozin to reversibly inhibit or inactivate the major 
CYP450 isoforms and UGT1 isoforms is remote. Drug-drug interactions involving the major 
CYP450 isoforms and UGT1 isoforms with empagliflozin and concomitantly administered 
substrates of these enzymes are therefore considered unlikely.
No clinically meaningful interactions were observed when empagliflozin was coadministered 
with other commonly used medicinal products. Based on results of pharmacokinetic studies 
no dose adjustment of empagliflozin is recommended when co-administered with commonly 
prescribed medicinal products.
Empagliflozin pharmacokinetics were similar with and without co-administration of 
metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, 
simvastatin, in healthy volunteers and with or without co-administration of torasemide and 
hydrochlorothiazide in patients with T2DM. Increases in overall exposure (AUC) of 
empagliflozin were seen following co-administration with gemfibrozil (59%), rifampicin 
(35%), or probenecid (53%). These changes were not considered to be clinically meaningful.
Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, 
glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, 
hydrochlorothiazide, torasemide and oral contraceptives when co-administered in healthy 
volunteers.


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Residual Effect Period
The Residual Effect Period (REP) of empagliflozin is 7 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
Data from non-clinical studies
A comprehensive package of safety pharmacology, general toxicology, genetic toxicology, 
carcinogenicity, reproductive and developmental toxicology studies were conducted in mice, 
rats, rabbits and dogs to support the chronic administration of empagliflozin to humans. In 
addition, combination studies have been completed in rats with empagliflozin plus metformin 
or empagliflozin plus linagliptin. With the exception of the dose range finding and selected 
safety pharmacology studies, all studies were completed under good laboratory practice 
(GLP) conditions.
Data from clinical studies
Empagliflozin was well tolerated in both healthy subjects and patients with T2DM up to 
maximum treatment duration of 208 weeks in completed T2DM studies Treatment with 
empagliflozin resulted in a similar percentage of overall AEs, severe AEs, and serious AEs 
compared to placebo and/or active comparators.
In the global trial 1245.33 EMPA-REG BASAL™ and 1245.49 EMPA-REG MDI™, 
Empagliflozin was proven to significantly reduce HbA1c in T2DM patients inadequately 
controlled with either basal insulin or MDI insulin [P15-05791, P14-09057]; Furthermore, in 
1245.107, Empagliflozin was proven to be efficacious in Japanese T2DM patients 
inadequately controlled with insulin [c22646053]. Both Caucasian and Japanese patients 
were well tolerated and no new safety problems were found during the treatment period.
For a more detailed description of the Empagliflozin profile, please refer to the current 
Investigator’s Brochure (IB) [c01678844].
1.3
RATIONALE FOR PERFORMING THE TRIAL
In China, more than 33% of adults with type 2 diabetes receive insulin therapy (basal or 
premixed), but only 26% of those have adequate glycemic control. Empagliflozin was 
approved in China in 2017 for the treatment of T2DM as an adjunct to diet and exercise and 
in combination with various oral anti-diabetic therapies. However, using Empagliflozin in 
combination with insulin has not been investigated in Chinese patients with T2DM. The aim 
of this study is to evaluate efficacy and safety over 24 weeks of Empagliflozin therapy in 
Chinese T2DM patients whose glycemia is inadequately controlled during background 
treatment with a stable dose of basal or premixed insulin, with or without oral 
antihyperglycemic drugs.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Potential general benefits for patients in this trial irrespective of the investigational 
medication received are: improvements in glycemic control, regular diet and exercise 
counselling, body weight reduction and a moderate blood pressure lowering, as well as 


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general medical benefit from careful and close monitoring by medical personnel, and Home 
Blood Glucose Monitoring (HBGM) during the trial.
1.4.2
Risks
Empagliflozin is investigational agent. Table 1.4.2: 1 displays the anticipated side effects of 
the study drugs, based on the mechanism of action, observed clinical data from ongoing 
studies, and published clinical data.
Table 1.4.2: 1
Potential risks, their rationale, and mitigation strategy
Potential risks of 
clinical relevance 
for this trial
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product: Empagliflozin
Hypersensitivity 
and allergic 
reactions
Unexpected 
adverse events
As with all drugs, the potential 
for hypersensitivity and allergic 
reactions has to be taken into 
consideration.
Investigators will monitor the 
patients both clinically and by 
laboratory testing
Hyperglycemia
One third (33.3%) of patients 
will receive placebo and these 
patients thus have a higher 
probability of treatment failure, 
i.e., of increase in FPG and 
HbA1c
Appropriate inclusion/exclusion 
criteria of HbA1c and FPG value 
and criteria for rescue therapy 
and patient discontinuation will 
ensure an adequate treatment in 
case of any clinical concern


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Table 1.4.2: 1
Potential risks, their rationale, and mitigation strategy (cont.)
Potential risks of 
clinical relevance 
for this trial
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product: Empagliflozin
DKA
Rare but severe event which can 
be life-threatening and requires 
urgent hospitalization; Insulin 
deficiency might lead to 
ketoacidosis which could be 
life-threatening if not 
recognized and appropriately 
treated. 
DKA is of particular concern for 
prospective safety monitoring 
and safety assessment within 
this trial.
All patients in this trial will be 
made aware of this risk and be 
instructed not to reduce their 
insulin dose below Investigator 
recommendations.
Investigators should also 
differentiate deteriorating 
ketosis/DKA from any mild to 
moderate increase of ketones 
expected from the mechanism of 
action of empagliflozin, 
especially in the fasted state 
(e.g., in the morning).
Volume depletion
Based on the mode of action of 
SGLT-2 inhibitors, osmotic 
diuresis may lead to a modest 
decrease in blood pressure and 
dehydration. 
Carefully monitor the volume 
status and electrolytes (e.g. blood 
pressure measurements, and 
laboratory tests including 
haematocrit);
Patients will be requested to 
drink plenty of fluids as a 
precautionary measure.
Hypoglycemia
Because of the mechanism of 
action of empagliflozin, the risk 
of hypoglycemic episodes is 
considered to be low. However, 
with empagliflozin in 
combination with insulin, the 
risk of hypoglycemia may be 
increased compared to the 
treatment with insulin alone.
Symptoms attributed to 
hypoglycemia as well as glucose 
levels will be closely monitored 
in the trial.


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Table 1.4.2: 1
Potential risks, their rationale, and mitigation strategy (cont.)
Potential risks of 
clinical relevance 
for this trial
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product: Empagliflozin
Urinary tract 
infection (UTI)
Based on the mode of action of 
SGLT-2 inhibitors, the 
incidence of UTI may increase.
The pooled analysis of UTI
showed that, in general, 
empagliflozin
10 and 25 mg had similar 
frequencies of UTIs as placebo. 
Although rare, urosepsis was 
reported for more patients 
treated with empagliflozin than
placebo, but there was no 
increase in frequencies for 
overall complicated urinary tract 
infections, including 
pyelonephritis. The frequency of 
UTIs leading discontinuations of 
studydrug was 0.6% with both 
empagliflozin groups compared 
to 0.3% in the placebo group. 
Symptoms attributed to UTI will 
be closely monitored in the trial.
UTI should be documented as an 
AE and appropriate therapy 
should be initiated.
Drug-induced liver 
injury (DILI)
Rare but severe event, thus 
under constant surveillance by 
sponsors and regulators.
Timely detection, evaluation, and 
follow-up of laboratory 
alterations in selected liver 
laboratory parameters to ensure 
patients' safety.
Trial procedures
Commonly 
experienced in 
association with 
blood sampling
The amount of blood taken 
during the whole course of the 
trial is not believed to be 
excessive and is associated with 
the standard of care for the 
patients.
Risk evaluation in relation with COVID-19 
Patients with serious underlying medical conditions such as T2D are at higher risk for severe 
illness from coronavirus disease 2019 (COVID-19). Therefore, in case of local high risk of 


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COVID-19 infection, on-site visits may not be carried out. In the event of restriction to visit 
the investigator site, a remote visit can be performed. This change is meant to keep the 
integrity of the trial and it will not affect the assessment of benefit-risk of empagliflozin. 
There is no indication that empagliflozin may increase the risk of COVID-19 infection. As 
with any acute illness, empagliflozin use / treatment during COVID-19 infection has the 
potential to increase the risk of diabetic ketoacidosis. The risk of diabetic ketoacidosis in case 
of acute illness is adequately addressed in the IB and in the patient information and consent 
form.
In case of a confirmed COVID-19 infection, trial treatment will be discontinued (see 
Section 3.3.4.1). 
1.4.3
Discussion
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 HBGM. Patients who are 
not adequately controlled, as evidenced by a confirmed high glucose value (refer to 
Section 4.2.1), will receive rescue therapy to ensure their safety or will be excluded from 
further study participation. The patient will continue to receive standard therapy throughout 
and the trial medication will be given in addition to this. Therefore they will continue to 
receive appropriate treatment.
Given the good safety profile in the toxicity studies of empagliflozin and the good tolerability
seen in the human studies so far, the careful monitoring to be conducted during the study
visits, and the blood glucose monitoring to be performed by the patients at home during the
study, the sponsor considers the risks for the participating patients will be minimised and
justified when compared with the potential benefits from this trial.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
The objective of the current study is to investigate the efficacy and safety of Empagliflozin
(10 mg or 25 mg, administered orally, once daily) compared to placebo given for 24 weeks in 
combination with stable insulin with or without up to two oral antidiabetic drugs in Chinese 
patients with T2DM with insufficient glycemic control.
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
To determine the efficacy and safety of Empagliflozin added to stable insulin in Chinese 
patients with type 2 diabetes.
2.1.2
Primary endpoint(s)
The primary endpoint is the change from baseline in glycosylated haemoglobin A1c (HbA1c) 
after 24 weeks of treatment. Throughout the study protocol, the term "baseline" refers to the 
last observed measurement prior to administration of any randomised study drug.
2.1.3
Secondary endpoint(s)
Secondary efficacy endpoints are:
•
Percentage of patients with HbA1c<7.0% after 24 weeks of treatment
•
Change in body weight from Baseline to week 24
•
Change in systolic blood pressure (SBP) from baseline to week 24
•
Change in diastolic blood pressure (DBP) from baseline to week 24
•
Change in Fasting Plasma Glucose (FPG) from baseline to week 24
•
Change in 2-hour Post-prandial Glucose (PPG) from baseline to week 24
Secondary safety endpoints are:
•
Occurrence of hypoglycemic events
•
Occurrence of adjudicated diabetic ketoacidosis (DKA) events


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This randomised, double-blind, multi-center, placebo-controlled, parallel group study 
compares Empagliflozin (10 mg or 25 mg) to placebo as add-on therapy to stable insulin with 
or without up to two oral antidiabetic drugs. The trial design is illustrated in Figure 3.1: 1.
In total, approximately 216 patients with T2DM who meet the entry criteria are planned for 
inclusion in this trial. The randomised treatment will be double-blind between Empagliflozin 
and placebo (i.e.each patient will receive one of two active treatments of Empagliflozin or 
placebo matching Empagliflozin).
Patients already on treatment with insulin with or without other OADs enter a 2-week open-
label placebo run-in period. Patients who successfully complete the run-in period and who 
still meet the inclusion /exclusion criteria will be randomised to the 24-week treatment period 
of the study. 
An independent external Clinical Event Committee (CEC) will be established to adjudicate 
centrally and in a blinded fashion events suspected of DKA (for further details see 
Section 5.2.6.1.4). 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.
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).


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Figure 3.1: 1 Trial design
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The aim of this study is to evaluate efficacy and safety over 24 weeks of Empagliflozin 
therapy in Chinese T2DM patients whose glycemia is inadequately controlled during 
background treatment with a stable dose of basal or premixed insulin, with or without oral 
antihyperglycemic drugs.
As the patients entering the study will receive stable insulin as a part of standard of care and 
will receive rescue medication if indicated, a placebo-controlled trial is justified. Since 
patients will continue their baseline treatment, the risk of significant hyperglycemia is low 
during the 24 weeks. Additionally, rescue therapies can be applied during this time frame to 
assure patient safety.
The intention of the run-in period is to ensure central lab data availability for randomization, 
to assess the compliance of the IMP administration, to stabilize glucose related parameters 
other than HbA1c, diet and exercise and background medication and act as a regular 
monitoring of blood glucose with a HBGM device for hyperglycemia assessment at baseline.
A double-blind and double-dummy design is adopted in order to minimize bias to evaluate 
the efficacy and safety of two doses (i.e. 10 mg and 25 mg) of empagliflozin and in 
comparison with placebo.The randomised treatment period is planned for 24 weeks because 
this corresponds to the expected relevant efficacy and safety exposure to support the 
submission of Empagliflozin as a drug for treatment of a chronic disease. 
The one week follow-up period, after treatment, is considered to be sufficient since the 
pharmacodynamic effect of Empagliflozin, with respect to urinary glucose excretion, only 
extends to a maximum of 6-7 days after the last dose.
Placebo
Run-in    
2 weeks
Screening
Visit 
R
1:1:1
Arm 1  Empagliflozin 10mg
Arm 2  Empagliflozin 25mg
Arm 3  Placebo
24-week treatment with stable 
Insulin with or without OAD
EOT   1 week    FU


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3.3
SELECTION OF TRIAL POPULATION
A sufficient number of patients will be enrolled into the trial in China. Approximately 25 trial 
centers will be participating to ensure that approximately 216 patients are randomised to one 
of three treatments (72 to Empagliflozin 10 mg, 72 to Empagliflozin 25 mg, and 72 to 
matched placebo for Empagliflozin).
It is expected that at least 5 patients will be enrolled at each trial center. Investigators who fail 
to enrol at least 1 patient in the first 6 weeks of the trial may be excluded from further 
participation. If enrolment is delayed, additional centers may be recruited.
Permission to randomise more than 30 patients per site must be obtained from the Clinical 
Trial Leader at Boehringer Ingelheim. This will only be allowed after a careful review of the 
enrolment status.
Enrolment of patients for this trial is competitive, i.e., enrolment for the trial will stop at all 
centers when it is anticipated that a sufficient number of patients will be randomised to trial 
treatment. Investigators will be notified when the appropriate numbers of patients have been 
enrolled and enrolment is complete, and will not be allowed to recruit additional patients for 
this study. Patients who have completed Visit 1 procedures prior to notification of the 
termination of recruitment will be allowed to continue in the study, if they meet all entry 
criteria and they are able to follow the visit schedule specified in this protocol.
If the patient’s background treatment type is not balanced as expected, the impact on the 
study conduct will be carefully considered. The sponsor will further monitor the recruitment 
of the trial with regard to the type of patient’s background treatment. The intent is to obtain a 
balanced mix of patients pre-treated with insulin alone or up to two OADs. In the event of an 
imbalance, recruitment will remain open to all patients but investigators may be asked to 
preferentially recruit from a particular subgroup.
The check for patient eligibility will be based upon a complete medical history including a 
physical examination and clinical laboratory tests. Judgement of the clinical relevance of a 
concomitant disease is at the discretion of the investigator. Conditions under therapy are 
always clinically relevant.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
The study will be performed in Chinese patients with T2DM who have insufficient glycemic 
control despite diet and exercise and receiving insulin alone or in combination with other 
OADs.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.


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3.3.2
Inclusion criteria
1.
Age ≥18 years and ≤75 years old at Visit 1;
2.
Chinese patient with diagnosis of Type 2 diabetes prior to Visit 1;
3.
A stable treatment with premixed Insulin (≥ 20IU/day) or basal insulin (≥ 16 IU/day) for 
at least 12 weeks prior to enrolment with or without up to two OADs
-
With maximum insulin dose of ≤ 1 unit/kg/day. Acceptable basal insulins 
should have duration of action up to 24 h such as insulin Degludec, insulin 
glargin, insulin detemir or NPH (neutral protamine hagedorn) insulin; 
Acceptable pre-mixed insulins could be once or twice daily posology only. The 
total insulin dose should not be changed by more than 20% of the baseline value 
within the 12 weeks prior to randomisation (Visit 3). Both human insulin & 
insulin analogue are acceptable;
-
If the patient is taking OADs, regimen has to be unchanged for at least 12 weeks 
prior to randomization (Visit 3);
-
If the patient is taking metformin, stable dose (at least 1500 mg daily or 
maximum tolerated dose) must be maintained for at least 12 weeks without dose 
adjustments prior to randomization (Visit 3);
4.
HbA1c ≥7.5% and ≤11.0% at Visit 1;
5.
Fasting C-peptide: >0.5 ng/mL (>166pmol/L) at Visit 1；
6.
18.5 kg/m2 ≤BMI ≤45 kg/m2 at Visit 1;
7.
Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial;
8.
Male or female patients. Women of childbearing potential (WOCBP)1 must be ready and 
able to use highly effective methods of birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and correctly. A list of 
contraception methods meeting these criteria is provided in the patient information.
3.3.3
Exclusion criteria
1.
Diagnosis of Type 1 diabetes;
2.
Patients receiving MDI insulin or insulin pump treatment;
3.
eGFR <45ml/min/1.73m2 calculated based on MDRD formula;
4.
Uncontrolled hyperglycemia [glucose level >13. 9 mmol/l after an overnight fast 
during placebo run-in];
5.
Severe hypoglycemia episode (event requiring the assistance of another person to 
actively administer carbohydrate, glucagon or other resuscitative actions) within 6 
months prior to Visit 1; 
6.
History of diabetic ketoacidosis or hyperosmolar non-ketotic coma.
7.
Myocardial infarction, stroke or transient ischaemic attack within 3 months prior to 
Visit 1;
8.
Bariatric surgery;
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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9.
SGLT-2 inhibitors intake within 12 weeks prior to Visit 1;
10.
Treatment with anti-obesity drugs within 12 weeks prior to Visit 1;
11.
Treatment with GLP-1 receptor agonists within 12 weeks prior to Visit 1;
12.
Treatment with SU if the patient is on premixed insulin within 12 weeks prior to 
Visit 1;
13.
Impaired hepatic function (serum alanine aminotransferase, aspartate 
aminotransferase, or alkaline phosphatase >3 times the upper limit of normal) at V1; 
14.
Contraindication to background anti-diabetes medication according to the local label;
15.
Disorders causing hemolysis or unstable red blood cells;
16.
Treatment with systemic steroids at the time of consent; 
17.
Change in dosage of thyroid hormones within 6 weeks prior to Visit 1; 
18.
Alcohol or drug abuse within 12 weeks prior to Visit 1;
19.
History of unstable or rapidly progressing renal disease;
20.
Conditions of congenital renal glucosuria;
21.
Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors;
22.
Major surgery (major according to the investigator’s assessment) performed within 12
weeks prior to randomisation or planned within 28 weeks after screening, e.g. hip 
replacement;
23.
Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal cell carcinoma of the skin 
or in situ carcinoma of uterine cervix;
24.
Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g.chronic alcohol or drug abuse or any other 
condition that, in the investigator’s opinion, makes the patient an unreliable trial 
participant);
25.
Previous enrolment in this trial;
26.
Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s), or receiving other 
investigational treatment(s);
27.
Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
28.
Any other clinical condition that would jeopardize patient’s safety while participating 
in this clinical trial (e.g. frequent hypoglycemic events on current therapy) in the 
opinion of the investigator.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Section 5.2.6.2).


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3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future. 

The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment. You may refer to Sections 4.2.1 and 4.2.2.

Introduction of rescue therapy due to hyperglycemia as described in section 4.2.1 does 
not lead to sufficient treatment efficacy (rescue criteria still met). In this case, the reason 
for discontinuation will be classified as “lack of efficacy”.

Occurrence of hypoglycemia that may put the patient at risk with continued participation 
(e.g. repeated hypoglycemic episodes).

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.

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy). In case of a temporary reason, trial 
treatment should be restarted if medically justified.

The patient experiences an infection with SARS-CoV-2. The patient may resume trial 
treatment following recovery from SARS-CoV-2 infection if the patient is expected to
derive clinical benefit, as agreed between the investigator and sponsor.
Patients who discontinue treatment prematurely will be followed up until the end of the trial
as outlined in the Flow Chart and Section 6.2.2.
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 from the trial after discussion between the sponsor and the 
investigator if the eligibility criteria are being violated.
Patients who discontinue or withdraw from the study during placebo run-in period and before 
being randomised at Visit 3 will be considered a run-in failure. They have to be recorded in 
eCRFs and no further follow-up is required (except for AEs, if needed).
Patients who are discontinued from the study after randomisation (Visit 3) and before 
completing 24 weeks of treatment will be considered as early discontinuations and the reason 
for the discontinuation must be recorded in the eCRFs. The reason will be included in the 
trial database and reported. If determined by the investigator as necessary for the patient’s 
safety, a new antidiabetic medication regimen can be started immediately after 
discontinuation and must be recorded in the eCRFs. In this case, end of treatment (EOT) visit 
must be performed before taking any new antidiabetic drug.


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3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, and explain the scientific relevance of their data 
even if he/she discontinue the trial treatment as well as explain the options for continued 
planned visit up to follow-up after trial treatment discontinuation, please see Section 3.3.4.1
above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Deviations from GCP, the trial protocol, or the contract impairing 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
4.1
INVESTIGATIONAL TREATMENTS
The study medication will be provided by Boehringer Ingelheim Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Test product 1: Empagliflozin
Substance:
Empagliflozin
Pharmaceutical formulation:
film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg
Posology:
1 tablet once daily
Mode of administration:
p.o.
Table 4.1.1: 2
Test product 2: Empagliflozin
Substance:
Empagliflozin
Pharmaceutical formulation:
film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
25 mg
Posology:
1 tablet once daily
Mode of administration:
p.o.
Table 4.1.1: 3
Test product 3: Placebo to Empagliflozin
Substance:
Placebo to Empagliflozin 10mg and 25mg
Pharmaceutical formulation:
film-coated tablet


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Table 4.1.1: 3
Test product 3: Placebo to Empagliflozin (cont.)
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
1 tablet once daily
Mode of administration:
p.o.
4.1.2
Selection of doses in the trial and dose modifications
The doses of Empagliflozin chosen for this study are the doses approved in China for the 
treatment of T2DM.
4.1.3
Method of assigning patients to treatment groups
When a patient is confirmed eligible for entry into the randomised double-blind treatment 
period, treatment assignment will be by means of a third-party phone/web-based 
randomisation at Visit 3. This will involve the use of interactive response technology (IRT). 
To facilitate the use of the IRT, the Investigator will receive an IRT manual including all 
necessary instructions for using the IRT. A copy of the manual will be available in the ISF.
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised 
to treatment groups of Empagliflozin film-coated tablet 10 mg, 25 mg or placebo for 
Empagliflozin tablet according to a randomisation plan in a 1:1:1 ratio at Visit 3 via 
Interactive Response Technology (IRT). The randomisation will be stratified by HbA1c (< 
8.5% vs. ≥8.5%) as determined from the blood sample taken at Visit 1 and background 
medication (Insulin alone or Insulin+OAD). For further details please refer to Section 7.5.
Note that the medication number is different from the patient number (the latter is generated 
during screening via the IRT System). 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.
4.1.4
Drug assignment and administration of doses for each patient
Eligible patients will be randomised to Empagliflozin 10 mg, 25 mg or placebo. Medication 
will be dispensed in a double-blind manner. The Empagliflozin dosing is described in the 
Table 4.1.4:1.
Patients will be assigned a placebo run-in kit at the beginning of the placebo run-in period 
(Visit 2), and this kit will contain sufficient medication for the run-in period within visit 
window. Dispensing of kits for the double-blind treatment period will begin at Visit 3 and
occur on 5 occasions over a period of 24 weeks. 


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During the COVID-19 pandemic, there might be situations that would not allow a patient to 
come to the site for Visit 4, 5, 6 or 7. If the investigator judges it as favourable and safe to 
continue trial medication, trial medication might be shipped from the site to the patient.
From the start of the placebo run-in period (Visit 2), patients should be instructed to take their 
trial medication, 2 tablets, once daily with water. To ensure a dose interval of about 24 hours, 
the medication is proposed to 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. No double doses should be taken, and dose reductions are not permitted. 
Empagliflozin can be taken with or without food.
Patients should be instructed not to take their trial medication on the morning of study visits 
as they will be dosed whilst in the trial site. Patients who fail to do so should have the visit 
rescheduled as soon as possible, ideally on the following day. 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.
Patients will continue with their standard insulin with or without concomitant OADs therapy 
throughout the entire study.
Table 4.1.4: 1
Empagliflozin dose administration per dose group
Dose group
Empagliflozin  
10 mg
Empagliflozin 
25 mg
Total units per dose
Timing
Placebo run-in period (open-label)
All patients
matching 
placebo
matching 
placebo
2 tablets
once daily, 
morning
Randomized treatment period (double-blind, double-dummy)
10 mg
active drug
matching 
placebo
2 tablets
once daily, 
morning
25 mg
matching 
placebo
active drug
2 tablets
once daily, 
morning
Placebo
matching 
placebo
matching 
placebo
2 tablets
once daily, 
morning
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomised treatment 
assignments until after database lock.
The access to the randomisation code will be kept restricted until its release for analysis.


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4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP).  Re-
supply to the sites will be managed via an IRT system, which will also monitor expiry dates 
of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
The study medication will consist of packs labelled with the trial identification and 
medication kit number. Each pack will contain an appropriate number of Empagliflozin 
tablets or matching Empagliflozin placebo with some reserve (see below) for dosing until the 
next scheduled visit.
The placebo run-in kit, assigned to all patients successfully completing Visit 2, will contain 
42 tablets (i.e. sufficient supply for 2 weeks, with 1 week in reserve). Each double-blind 
treatment period kit will contain 70 tablets (i.e sufficient supply for 4 weeks, with 1 week in 
reserve). At Visit 3, 4 and 5, the patient will receive 1 treatment kit. At Visit 6 and 7, the 
patient will receive 2 treatment kits. The dose administration for each group and kits please 
refer to Table 4.1.4: 1.
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 Clinical Trial 
Manager (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority


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
Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the Principal Investigator
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee 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 warehouse / 
drug distribution center or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution center will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Throughout the duration of the trial, patients should continue to take insulin alone or in 
combination with acceptable OADs as background therapy.
Acceptable basal insulins should have duration of action up to 24 h such as insulin degludec,
insulin glargin, insulin detemir or NPH (neutral protamine hagedorn) insulin. The 
background medication of OADs should remain unchanged throughout the study. Acceptable 
pre-mixed insulins could be once or twice daily posology only.The total prescribed insulin 
dose should not be changed by more than 10% of the baseline value in the 24 weeks after 
randomisation unless rescue therapy criteria for treatment of hyperglycemia are met or in 
case of hypoglycemia requiring insulin dose reduction beyond the defined limits.The 
background medication will not be provided as part of the clinical trial supplies.
The patients can take their background medication as they are used to and should have the 
same habits of dosing throughout the trial, where it is suggested that basal insulin is always 
given in the evening. Morning dose of OADs/any permitted pre-mixed insulin and study 
medication should be taken after the visits blood sample taken.
Hyperglycemia
If the following FPG criteria in Table 4.2.1: 1 are met and confirmed, investigators may 
increase the insulin dose for the treatment of hyperglycemia according to their discretion and 
the change should be documented in the eCRF [R08-2669].


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The first choice of rescue therapy should be the adjustment of insulin therapy. Its dosage will 
be left to the discretion of the investigator. However the insulin regimen and daily number of 
injections should remain unchanged. In very rare cases, adjustment of background therapy or 
addition of another oral anti-diabetic medication except SGLT-2 inhibitors would be 
appropriate. Such cases should be discussed with the Manager (CTM) or the Clinical Trial 
Leader (CTL). 
Table 4.2.1: 1
FPG criteria for hyperglycemia
Week
Visit
FPG level
Week 1- 4
up to Visit 4  (included)
>270 mg/dl (>15.0 mmol/l) after overnight fast
Week 4-12
up to Visit 6  (included)
>240 mg/dl (>13.3 mmol/l) after overnight fast
Week 12-24
after Visit 6 until Visit 8
>200 mg/dl (>11.1 mmol/l) after overnight fast
To confirm the above results, there should be a minimum of two measurements, at least one 
of which performed after an overnight fast at the investigational site, and on a different day to 
the initial measurement.
A FPG, HbA1c sample should be taken before initiation of rescue therapy and sent to central 
lab for analysis. The HbA1c sample is not required if a sample has been taken and sent to the 
central lab for analysis within the last 4 weeks.
If, in the Investigator’s clinical opinion, no further effect from the rescue medication is 
anticipated, and the patient’s hyperglycemia cannot be controlled, the patient should be 
discontinued from the treatment as specified in section 3.3.4.
Hypoglycemia
If the patient is experiencing hypoglycemia (criteria see section 5.2.7), the investigator should 
review the HBGM log to determine the appropriate approach to reduce occurrences of 
hypoglycemia (e.g., encouraging the patient not to skip meals, increasing carbohydrate intake 
if increasing exercise, decreasing or adjusting the patient’s permitted antidiabetic therapy).
In the case of hypoglycemia that may put patient on risk (e.g. repeated symptomatic 
hypoglycemia or severe hypoglycemia), appropriate adjustment of anti-diabetic therapy such 
as a dose reduction / discontinuation of ongoing rescue medication or existing background 
therapy should be initiated. Reduction or discontinuation of ongoing rescue medication 
should be considered before a reduction in the dose of existing background therapy.
Reduction of insulin dose should be the first choice among the existing background therapy
while the insulin regimen and daily number of injections should remain unchanged.
Any rescue medication will be recorded in the source documents and on the appropriate 
pages of the eCRF.
Rescue medication will not be provided as part of the clinical trial supplies.
Any additional treatment, that does not qualify as a rescue medication, and 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.


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In this trial, the background therapy (i.e. insulin alone or in the combination with OADs) are 
considered as non Auxiliary Medicinal Product (AMP). 
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The following restrictions are applicable during the screening, run-in and treatment period:
•
Treatment with anti-obesity drugs, herbal medications with antidiabetic effects or 
systemic steroids due to their influence on glucose metabolism. However, one off or 
short-term use (i.e. ≤1 week’s duration) of systemic steroids will be permitted as well as 
therapy with non-systemic steroids such as inhaled or local steroids. 
•
For patients taking thyroid hormones, any change in the dose should be avoided. If dose 
changes do occur, then they should be recorded in the source documents and in the 
eCRF.
•
SGLT-2 inhibitors are not allowed even as a rescue therapy. 
Please also refer to section 3.3.3 regarding the permitted use of antidiabetic agents pre-trial.
4.2.2.2
Restrictions on diet and life style
At the beginning of the Run-in period, patients will receive diet and exercise counselling by a 
diet specialist or delegated staff member. The counselling will be based on local diet 
recommendations. The patients will be reminded to follow the agreed diet and exercise plan 
at every visit. To avoid DKA, extreme diets (e.g., ketogenic diets) should be avoided. SGLT-
2 inhibitor has a diuretic action and therefore dehydration may occur. Therefore, the 
investigator should instruct the patients to drink appropriate volume of water every day.
Patients also should not take part in another clinical trial involving an investigational 
medicinal product within 30 days prior to informed consent.
4.2.2.3
Contraception requirements
Women of childbearing potential must use highly effective methods of birth control per ICH 
M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and 
correctly. A list of contraception methods meeting these criteria is provided in the patient 
information.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the CRA authorised by the sponsor.


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Treatment compliance (%) =
Number of tablet actually taken 100
     Number of tablet which should have been taken as 
directed by the investigator
If the number of doses taken is not between 80-120%, site staff will explain to the patient the 
importance of treatment compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
HbA1c
Blood samples for the determination of HbA1c at the central laboratory will be taken at all the 
visits except Visit 2, the blood sample can be taken at any time during the visit. For the 
determination of HbA1c, 3 mL of blood will be collected. 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).
Fasting plasma glucose (FPG)
Blood samples for the determination of FPG at the central laboratory will be taken after an 
overnight fast. The samples should be taken before breakfast and before trial drug 
administration. The samples will be measured at a central laboratory using validated assays. 
Further details about sample handling and shipment can be found in the ISF (Lab manual).
Meal Tolerance Test (MTT)
Meal Tolerance Test (MTT) will be performed using a standardised breakfast. MTT at Visit 3 
would be performed before randomisation, i.e. without intake of trial medication during the 
MTT.
At Visit 3, after blood sample of insulin, C-peptide and FPG drawing, patients would have a 
standardised breakfast and intake OADs and/ or accepted pre-mixed insulin (if applicable), 
finished within 15 min, and blood samples for insulin, C-peptide and PPG would be collected 
at time points 60 ±10 min and 120 ±10 min after the start of standardised breakfast. Study 
medication will only be taken after last blood samples drawing, i.e. following randomisation.
At Visit 8, 30 min after blood sample of insulin, C-peptide and FPG drawing and 
administration of study medication (except the visit is after EOT), patients would have a 
standardised breakfast and intake OADs and/ or accepted pre-mixed insulin (if applicable), 
finished within 15 min, and blood samples for insulin, C-peptide and PPG would be collected 
at time points 60 ±10 min and 120 ±10 min after the start of standardised breakfast.
8-Point glucose profile
Eight-point blood glucose profiles are to be collected over a single 24-hour time period 
(approximately) within one week prior to scheduled visits as indicated in the Flow Chart. 
Weighted mean daily glucose (MDG) will be evaluated only on Visits 3, 6 and 8/EOT. 
Mean daily glucose (MDG) will be defined as the area under the curve (calculated using the 
trapezoidal method) divided by the measurement time.
Site should contact patients in advance to remind the conduction of the test. The timing of 
the 8-point blood glucose measurement is proposed as follows:

Fasting before study drug administration, directly (defined as 0-5 minutes) before 
breakfast and fasting for at least 10 hours except for water

120 minutes after study medication administration and end of breakfast 

Directly (0-5 min) before lunch

120 minutes after end of lunch


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
Directly (0-5 min) before dinner

120 minutes after end of dinner 

Directly (0-5 min) before bedtime

Fasting before study drug administration, directly (0-5 min) before breakfast, and fasting 
The 8-point blood glucose measurements will be performed by patients using HBGM
equipment. The 8-point glucose data will be recorded manually on paper HBGM log. At the 
trial centers the 8-point glucose data will be transferred to the eCRF manually at Visits 3, 6
and 8/EOT visit for MDG evaluation. If a measurement is not done exactly at the planned 
time point, the data from the assessments done closest to the planned time point will be used. 
If any additional measurements are done that are not scheduled, the results will not be 
transferred to the eCRF.
Systolic and diastolic blood pressure:
SBP and DBP as well as pulse rate (electronically or by palpation, count for 1 minute) will be 
measured after 5 minutes of rest in the seated position. The blood pressure measurement 
should be performed three times at each time point and each value of these measurements 
will be entered in the eCRF. Further details on the procedure for blood pressure 
measurements are given in Appendix 10.1.
Weight and Waist circumference
Weight measurements should always be done on the same scales for one patient. In order to 
get comparable body weight values, it should be performed in the following way:
•
fasting (except for the screening visit)
•
after the urine sampling (weight after bladder voiding)
•
shoes and coat/jackets should be taken off
•
pockets should be emptied of heavy objects (i.e. keys, coins etc)
Waist circumference measurements should be made around a patient’s bare midriff, after the 
patient exhales while standing without shoes and with both feet touching and arms hanging 
freely. The measuring tape should be made of a material that is not easily stretched, such as 
fibreglass. The tape should be placed perpendicular to the long axis of the body and 
horizontal to the floor and applied with sufficient tension to conform to the measurement 
surface.
Waist circumference should be determined by measuring the midpoint between the lowest rib 
and the iliac crest.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. 
Measurement of height will be performed at the time points specified in the Flow Chart.
The results must be included in the source documents available at the site. 


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5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling.
This includes systolic and diastolic blood pressure (see Appendix 10.1) and pulse rate 
(electronically or by palpation count for 1 minute) in a seated position after 5 minutes of rest. 
The results must be included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1, Table 5.2.3: 2 and 
Table 5.2.3: 3. For the sampling time points please see the Flow Chart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Safety laboratory samples (C-peptide at Visit 1 and all other visits) will be collected after a 
full overnight fast (nothing to eat or drink except water for at least 10 hours) and before 
background antidiabetic therapies and investigational drug as described in the Flow Chart and 
Section 6. The blood sample at Visit 1 (screening visit) except C-peptide can be taken with 
the patient in a fasted or nonfasted state.
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the ISF and EDC
system). The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.
Reduced safety lab panels excluding urinalysis are planned for the following visits:
-
For the screening Visit 1, laboratory only includes liver transaminases, alkaline 
phosphatase, serum creatinine and fasting C-peptide.
-
Lipid fractions will only be determined at baseline (Visit 3) and end of treatment/
Visit 8
The central laboratory will transfer the results of the analysis to the sponsor.


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Table 5.2.3: 1
Safety laboratory tests – Haematology
• Haematocrit
• Haemoglobin
• Red Blood Cells (RBC)/Erythrocytes
• WBC/Leukocytes
• Platelet Count/Thrombocytes
• Differential Automatic (relative and absolute count): Neutrophils, Eosinophils, 
Basophils, Monocytes, Lymphocytes
Table 5.2.3: 2
Safety laboratory parameters – Clinical Chemistry
•
Amylase
•
Lipase
•
AST (aspartate transaminase,SGOT)
•
ALT (alanine transaminase,SGPT)
•
γ-GT (gamma-glutamyltransferase)
•
Alkaline phosphatase
•
Lactic dehydrogenase (LDH)
•
Total bilirubin
•
Direct bilirubin, if total bilirubinis elevated
•
Total Protein
•
Albumin
•
C-peptide (at Visit 1 only)
•
Creatine kinase (CK)Troponin, if CK is 
elevated
•
Potassium
•
Sodium
•
Bicarbonate
•
Creatinine
•
BUN
•
Calcium
•
Inorganic phosphorous
•
Uric acid
•
Cholesterol (total)*
•
HDL cholesterol*
•
LDL cholesterol*
•
Triglycerides*
•
Glucose
*Visits 3, 8, EOT only
Table 5.2.3: 3
Safety laboratory parameters – urine
•
Albumin, Creatinine (spot urine
–quantitative measurement)
•
Protein
•
Ketone
•
Leucocytes
•
Erythrocytes
The urine albumine-to-creatinine ratio (UACR) will be calculated at the central lab. Urine 
sediment will only be done if there is a positive finding on the urinalysis.


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Glomerular filtration rate
The glomerular filtration rate (GFR) will be derived from serum creatinine* values based on 
the standard MDRD formula:
eGFR(ml/min/1.73 m2) = 175 x [Screatinine (umol/L)/88.4]-1.154 x [age]-0.203 x [0.742 if 
patient is female] x [1.212 if patient is of African origin]
*: creatinine methods calibrated to an IDMS reference method
Pregnancy testing (urine) will be performed at site locally in female patients of child bearing 
potential only according to the timepoints indicated in the Flow Chart.
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the flowchart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
5.2.5
Other safety parameters
Home Blood Glucose Monitoring
All patients will be provided with HBGM equipment and supplies for use at home during the 
study period. Instruction on the proper use of the HBGM equipment will be provided by the 
study staff. The patient will be asked to record the results of the HBGM test on a HBGM 
Testing Log that will be included in the patients source document file. Only in the case of 
linked adverse events or of hypoglycemia, the glucose value measured by HBGM will be 
recorded in the eCRF.
During placebo run-in and follow-up period, HBGM testing should be performed once daily 
in the fasted state and at any time the patient is symptomatic related to hypoglicemia or 
hyperglicemia through the entire period. If during placebo run-in period, results of a HBGM 
test reveal blood glucose of >240 mg/dL (13.3 mmol/L) after an overnight fast, the patient 
should contact the site. The investigator should then decide about start of the randomised 
period or further patient participation in the trial based on fasted plasma glucose 
determinations according to the inclusion and exclusion criteria as outlined in Section 3.3.
During the randomised treatment period, HBGM testing is recommended to be done once 
weekly (more frequently if required by local authorities) and at any time the patient is 
symptomatic, i.e., experiences signs/symptoms of hyper- or hypoglycemia. If during this 
period, results of a fasting HBGM test reveal blood glucose levels meeting rescue criteria 
(see Section 4.2.1), the patient should contact the site and the investigator should follow the 
instructions given in section 4.2.1.


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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal 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.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions 
Changes in vital signs, ECG, physical examination, data on HBGM log and laboratory 
test results, if they are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which 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,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
5.2.6.1.3
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 
defined above.


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The latest list of “Always Serious AEs” can be found in the EDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (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. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or

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 in the ISF 
and EDC 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.
Diabetic ketoacidosis (DKA) 
The risk of DKA must be considered in the event of non-specific symptoms such as nausea, 
vomiting, anorexia, abdominal pain, excessive thirst, difficulty in breathing, confusion, 
unusual fatigue or sleepiness.
In case of a suspected DKA, the investigator should ensure that appropriate tests are
performed at the earliest opportunity according to 2017 China T2DM guidelines, such as 
blood tests (glucose, BUN/creatinine, ketone) and blood gas test (pH, bicarbonate, anion 
gap). The results will be collected on the relevant page of the eCRF.
Investigators should also differentiate deteriorating ketosis/DKA from any mild to moderate 
increase of ketones which may be seen due to the mechanism of action of empagliflozin, 
especially in the fasted state (e.g. in the morning). 
Due to its mechanism of action, empagliflozin may potentially modify the clinical


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presentation of KA which may occur at lower plasma glucose levels in patients with DM. The 
diagnosis of KA in these patients can be based on arterial pH ≤7.30, serum bicarbonate 
levels < 15 and measurement of serum betahydroxybutrate levels. Other diagnostic criteria 
which can support the diagnosis of KA are urine ketones and anion gap > 10.
Investigators should note that not all criteria mentioned above need to apply for the diagnosis
of KA, and clinical judgment should also be taken into consideration.
Decreased renal function
Decreased renal function is defined by a creatinine value showing a ≥2 fold increase from 
baseline and is above the ULN.
For the AESI “decreased renal function” the patient needs to be followed-up appropriately 
based on local clinical guidance.
Events leading to lower limb amputation
Any event leading to a lower limb procedure of amputation, auto-amputation or 
disarticulation as defined below is considered as an AESI.
Amputation is a resection of a limb through a bone. Disarticulation is a resection of a limb 
through a joint. Auto-amputation is a 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). (International Working Group of Diabetic Foot, 2015).
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.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, 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. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.


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
A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the 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 new AEs but should only 
report cancers of new histology and exacerbations of existing cancer and trial treatment 
related SAEs and trial treatment related AESIs of which the investigator may become 
aware of by any means of communication, e.g. phone call. Those AEs should be reported 
on the BI SAE form (see section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the 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 (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,


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the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
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. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
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).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.7
Criteria for hypoglycemic events
Every episode of plasma glucose ≤ 70 mg/dl (≤ 3.9 mmol/l) should be documented in the 
eCRF with the respective time and date of occurrence. Such hypoglycemic events should be 
documented in the eCRF according to the following criteria:
-
Asymptomatic hypoglycemia: event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg/dl (3.9 
mmol/l)
-
Documented symptomatic hypoglycemia with glucose concentration ≥54 mg/dl and ≤ 70 
mg/dl (≥3.0 mmol/l and ≤ 3.9 mmol/l): event accompanied by typical symptoms of 
hypoglycemia
-
Documented symptomatic hypoglycemia with glucose concentration < 54 mg/dl (< 3.0 
mmol/l): event accompanied by typical symptoms of hypoglycemia
-
Severe hypoglycemic episode: Event requiring the assistance of another person to 
actively administer carbohydrate, glucagon or other resuscitative actions. 
Note for severe hypoglycemia: If another person hands the carbohydrate or glucagon to the 
patient without having to actively administer the substance because the patient is able to take 
the substance on his or her own, the hypoglycemic episode does not qualify as severe.
Any hypoglycemia with glucose values < 54 mg/dl (< 3.0 mmol/l) and all symptomatic or 
severe hypoglycemia events should be documented as an adverse event of hypoglycemia.


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Further details on documentation of hypoglycemia are provided on the respective eCRF 
pages.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable.
5.4
ASSESSMENT OF BIOMARKER(S)
This section refers to exploratory biomarkers. Established biomarkers of efficacy and safety 
are described and discussed in sections 5.1 and 5.2.
5.4.1
Biochemical and cellular biomarkers
Biomarker assays will be measured in a central laboratory.
1)
C-peptide
2)
Insulin
C-peptide will be tested with the sample collected on Visit 3 and Visit 8 at both fasting and 
postprandial status to assess the beta cell function, which will contribute to a better 
understanding of the influence of Empagliflozin in combination with insulin on the course of 
disease in the patients with T2DM.
Based on the analysis of fasting plasma insulin (FPI) and FPG, the Homeostasis Model 
Assessment (HOMA) indices will be derived in the following way [R07-1029]:
HOMA-Index (to assess insulin resistance (IR))
HOMA-IR = [FPG (mmol/L) × FPI (mU/mL)/22.5]
HOMA-Index (to assess insulin secretion)
HOMA-β = (20 × FPI (mU/mL)) / (FPG (mmol/L)-3.5)
5.4.2
Pharmacogenomics biomarkers
Not applicable.
5.4.3
Methods of sample collection
Additional biomarkers such as C-peptide and insulin will be determined according to the 
Flow Chart. Further details about sample handling and shipment can be found in the ISF (Lab 
manual).
5.5
BIOBANKING
Not applicable.


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5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
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 oral antidiabetic drug, and they are widely used in respective pivotal phase 
III studies.
Measurements of insulin and c-peptide will be conducted in order to characterise endogenous 
insulin production and will contribute to a better understanding of the influence of 
empagliflozin combination with insulin with or without OADs on the pathogenesis and 
possible recovery of diabetes in the patients.
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits should take place in the morning. 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), the 
visit should be rescheduled for another day (except screening) 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. The run-in 
period must be 14-21 days long prior to randomization.
In the event of force majeure or other disruptive circumstances (e.g. pandemic) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient, sponsor and investigator may agree on alternative, back-up or rescue 
methodology which may include but will not be limited to virtual patient visits and 
assessments, and direct-to-patient shipments of trial treatment.
If it is not recommended to conduct Visit 4, 5, 6 or 7 at the trial site, it may be performed 
remotely (via telephone and/or internet- based means of communication). In the event of a 
remote Visit 4, 5, 6 or 7 trial medication may be shipped by courier from site to patient, if 
legally acceptable according to local regulations and considered safe for patient to continue 
treatment. It is important that any remote Visit 4, 5, 6 and 7 is discussed with and approved 
by the sponsor/CRO to ensure delivery of trial medication fulfil the trial specific and country-
specific requirements. All efforts should be made to at least perform two of the four visits 
with the patient visiting the site. The maximum time interval without a face to face contact 
with the patient should not exceed 16 weeks (e.g. the 12 week site visit could only be done 
remote if a face to face contact was performed at the 4 week or 8 week visit). The patient 
must be made aware of any conduct modifications and agreement needs to be obtained prior 
to them being implemented. See Appendix 10.2 on the details of potential modification of 
trial conduct in case of restrictions due to COVID-19.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
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.
Sample collection for C-peptide at screening (Visit 1) and all other visits must be performed 
in fasted state (at least 10 hours with nothing to eat or drink except water).
At the end of every visit from Visit 2 to 8 the patient must be reminded to bring HBGM log, 
and the dispensed medication kit (from Visit 3) 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.


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6.2.1
Screening and run-in period(s)
Screening Period
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 recorded in the eCRF as a screened patient at Visit 1.
Sample collection for C-peptide should be in fasted state, other prodedures at the visit can be 
in fed condition. If the patient comes for screening visit in fed state, all the procedures can be 
performed that day and those for fasting is conducted as soon as possible within the screen
window. Hence all the procedures for Visit 1 may be performed at different days.
All patients on Visit 1 do not proceed to the next visit until laboratory results are reviewed by 
investigator.
Details of any patient who is screened for the study but is found to be ineligible must be 
entered in an enrolment log, registered as a screen failure in the IRT (refer to IRT user 
manual) and documented in the eCRF.
Run-in Period
From this visit on, patients should be fasting (no food or drinks, water only for at least 10
hours) prior to each visit.
Patients who fail the run-in period following Visit 2 procedures should be registered as a
screen failure in the IRT (refer to IRT user manual).
For background treatment details please see section 4.2.1
Monitor adverse events, document in the patients’ file (source data) and eCRF. 
Instruct patients on the correct use of HBGM for glucose testing during the 2 week Run-In
Period
•
Patients should use the HBGM equipment/supplies to test glucose levels in a fasting
state. During the Run-in period patients should test once a day before breakfast (i.e. after 
an overnight fast). Additionally, patients should test their glucose levels if they
experience signs/symptoms of hypo- or hyperglycemia. Test results should be
documented on the HBGM testing log. More frequent HBGM testing is permitted at the 
Investigator’s and/or patient’s discretion.
•
If the HBGM test reveals an overnight fasted blood glucose of >240 mg/dl (>13.3
mmol/l), the patient should contact the study site for a visit at the next day. The
investigator will then draw a new blood sample (overnight fasted samples for FPG
determination) to confirm the hyperglycemia, document the AE if appropriate and decide 
about the possible exclusion from randomisation (screening failure).
The subject will be instructed to perform an 8-point HBGM over a single 24-hour time period 
(approximately) within one week prior to Visit 3. The plasma glucose levels should be 
measured and recorded in the log (including date, time and value) at the defined time points,
details please see section 5.1.
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding T2DM) will be reported on the Baseline Condition eCRF page.


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Medical History:
Medical history will be collected and reported in the Medical History eCRF page.
Information on clinically significant previous and concomitant illnesses, other than T2DM, or 
any clinically significant signs or symptoms that are present before informed consent, or pre-
existing conditions identified through findings from assessments and examinations done 
during the screening visits will be recorded as medical and surgical history at screening on 
the Baseline Condition page in the eCRF.
6.2.2
Treatment period(s)
Patients must satisfy all inclusion and exclusion criteria prior to randomisation (see 
Section 3.3). In addition, if during the placebo run-in period, there is any indication that a 
patient’s conditions of T2DM are not stable enough for the patient to complete 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 3 and visits should occur 
within the allowed time frame shown in the Flow Chart.
The treatment period is from Visit 3 to Visit 8/EOT. Patients will be dispensed medication at 
each of these visits (except for Visit 8/EOT). Medication number of each occasion will be 
allocated by IRT (refer to IRT user manual).
Patients should not take study medication at home on the morning of trial visits during the
treatment period.
Randomisation visit (Visit 3)
Visits should be performed fasting and as indicated in the Flow Chart and the respective
protocol sections.
•
Collection of urine and blood for laboratory testing must be performed prior to 
administration of study medication
•
ECG is performed and evaluated
•
Blood pressure should always be measured before taking any blood sample, details see 
Appendix 10.1
•
Collect returned run-in medication
•
Collect the HBGM test log
•
Contact IRT to randomize patient and obtain medication kit numbers and dispense the 
medication to the patient
•
After the patient has finished breakfast and last blood sample collected as MTT, 
administer first dose of study medication, which should be the last activity at this visit
•
Patients should be reminded about the importance to follow the agreed diet and exercise 
plan
•
Instruct patient NOT to take study medication and background medications on the 
morning of trial visits as described in Section 4.1.4
Visits 4-8/EOT
Visits should be performed as mentioned in the Flow Chart and the respective protocol
sections.
•
Collection of urine and blood for laboratory testing must be performed prior to 


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administration of study medication according to the Flow Chart
•
All the patients including the treatment discontinued should perform the MTT and follow 
the process described in Section 5.1
•
Blood pressure should always be measured before taking any blood sample, details see 
Appendix 10.1
•
Collect returned medication prior to dispensing new medication
•
Collect the HBGM test log
•
New medication kit must be dispensed according to the Flow Chart, and IRT must be 
contacted at those visits to obtain medication kit numbers to be dispensed
•
Patients should be reminded about the importance to follow the agreed diet and exercise 
plan.
•
Instruct patient NOT to take study medication as well as background medications on the
morning of trial visits as described in section 4.1.4
•
Instruct patients to perform 8-point glucose profile within one week prior to visits as 
indicated in the Flow Chart
•
Visit 8/EOT is the last visit of the treatment period. Study medication will not be 
dispensed at Visit 8/EOT
If a patient prematurely discontinues from the 24-week treatment period, the patient must
return to the trial site for EOT (within 7 days of stopping study treatment) including MTT. 
The reason for premature trial drug discontinuation must be documented in the eCRF. In 
addition patients will be encouraged to attend all subsequent planned onsite visits despite not 
being under treatment anymore and perform all study procedures. If the EOT visit occurs 
within the time window of a planned visit, the EOT visit will replace the planned visit.
The need for coming to future visits in case of premature discontinuation of trial medication 
will be explained to patients prior to their participation in the trial.
The investigator may initiate any additional antidiabetic therapy for the patient, based on his
or her discretion, no sooner than one day after discontinuing study medication or after Visit 8.
Patients who prematurely discontinue the study should be registered as discontinued, and 
patients who complete the full 24-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 protocol or prematurely discontinued 
without persisting AE at Visit 8, a follow-up contact (Visit 9) with the patient (preferably by 
phone) should be done by the investigator at the end of the followup period of 7 days. The 
following should be confirmed and recorded at Visit 9:
• Concomitant therapies
• Any AEs
• HBGM result
For patients completing the study according to the protocol or prematurely discontinued from 
the 24 week treatment period however, agree to return, with persisting AE at Visit 8, the 
following examinations should be performed at Visit 9 additionally:


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• Vital signs
• Collection of blood and urine samples for safety laboratory evaluation
• FPG
Trial completion
The trial completion eCRF page has to be filled-in when the patient has terminated the trial.
The end of the trial is:
•
At the end of the follow-up visit for patients who have completed the trial on 
treatment as planned;
•
After the early end of treatment (EOT) and follow-up visits, if a patient did not 
agree to come to the remaining planned study visits;
•
At the end of Visit 9 for patients who discontinued drug early but agreed to come to 
the remaining planned study visits.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
The superiority of Empagliflozin (10 mg q.d. and 25 mg q.d.) over placebo will be tested 
using the hierarchical hypothesis testing procedure. The following two sets of hypotheses will 
be tested sequentially each at the level of  = 0.05 (two-sided). The second null hypothesis 
(H0,2) for Empagliflozin 10 mg vs. placebo will be tested confirmatively only if the first null 
hypothesis (H0,1) for Empagliflozin 25 mg vs. placebo is rejected. If the first null hypothesis 
(H0,1) is not rejected, the second null hypothesis (H0,2) will be tested in an exploratory 
fashion.
Step 1: The superiority of empagliflozin 25 mg against placebo will be tested for change from 
baseline in HbA1c after 24 weeks of treatment at the level of α=0.05 (two-sided).
H0,1: Mean change from baseline in HbA1c after 24 weeks of treatment with 
Empagliflozin (25 mg q.d.) = Mean change from baseline in HbA1c after 24 weeks of 
treatment with placebo 
H1,1: Mean change from baseline in HbA1c after 24 weeks of treatment with 
Empagliflozin (25 mg q.d.) ≠ Mean change from baseline in HbA1c after 24 weeks of 
treatment with placebo
Step 2: The superiority of empagliflozin 10 mg against placebo will be tested for change from 
baseline in HbA1c after 24 weeks of treatment at the level of α=0.05 (two-sided).
H0,2: Mean change from baseline in HbA1c after 24 weeks of treatment with 
Empagliflozin (10 mg q.d.) = Mean change from baseline in HbA1c after 24 weeks of 
treatment with placebo
H1,2: Mean change from baseline in HbA1c after 24 weeks of treatment with 
Empagliflozin (10 mg q.d.) ≠ Mean change from baseline in HbA1c after 24 weeks of 
treatment with placebo
7.2
PLANNED ANALYSES
7.2.1
General considerations
The statisitical analyses will be performed on the following population.
Treated set (TS)
The TS will consist of all patients who are randomized and treated with at least one dose of 
the study drug. The assignment of patients to treatment groups will be based on the actual 
first study drug intake in the double-blind treatment period.
Modified Intention-to-Treat (mITT) set


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The mITT set will consist of all randomized patients who are treated with at least one dose of 
the study drug and have a baseline HbA1c assessment. The assignment of patients to treatment 
groups will be based on the planned randomised study drug at the time of randomisation.
Per Protocol set (PPS)
The PPS will consist of all patients in mITT set who do not have important protocol deviation 
(iPD) that may have a distorting influence on the assessment of the primary endpoint. The 
definitions of iPDs and the details of the handling of iPDs will be provided in the trial 
statistical analysis plan (TSAP). 
With regard to efficacy and safety endpoints, the term “baseline” refers to the last observed 
measurement prior to administration of any randomised study drug.
7.2.2
Primary endpoint analyses
The primary endpoint in this trial is the change in HbA1c (in unit of %) from baseline after 24 
weeks of treatment. The baseline HbA1c refers to the last HbA1c assessment prior to the 
administration of any randomized study drug and not to the HbA1c assessment used for the 
stratification in the randomisation.
7.2.2.1
Primary analysis of the primary endpoint
The primary analysis is a restricted maximum likelihood (REML) based approach using a 
mixed model for repeated measures (MMRM) comparing the mean change in HbA1c from 
baseline after 24 weeks of treatment. The analysis will include treatment (Empagliflozin 10 
mg, Empagliflozin 25 mg, placebo), background therapy (insulin only, insulin with OAD),
and visit as fixed classification effects, baseline HbA1c and baseline eGFR as the linear 
covariates, treatment by visit interaction, and baseline HbA1c by visit interaction.
The statistical model will be as follows.
HbA1c change from baseline at each on-treatment visit = overall mean 
+ treatment + background therapy
+ baseline HbA1c + baseline eGFR
+ visit + treatment-by-visit interaction 
+ baseline HbA1c-by-visit interaction 
+ random error
Visit will be treated as the repeated measure with an unstructured covariance structure used to 
model the within-patient measurement. 
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom and adjust standard errors. Significance tests will be based on least-squares means 
using a two-sided α=0.05 (two-sided 95% confidence intervals). The residuals are assumed to 


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have a multivariate normal distribution with zero means and covariance matrix as specified 
above. The primary treatment comparisons will be the contrasts between active treatment 
(Empagliflozin 10 mg and 25 mg, respectively) and placebo at week 24.
The primary analysis will be performed on mITT set with patients assigned to the treatment 
they are randomised to and include on-treatment HbA1c values only. If a patient misses a 
visit, the missing data will not be imputed. And all HbA1c values measured after premature 
discontinuation of study drug or after rescue therapy is initiated will be set to missing.  The 
mixed effect model will handle missing data based on a likelihood method under the "missing 
at random” assumption.
7.2.2.2
Secondary analyses of the primary endpoint
Sensitivity analysis
In order to check the sensitivity of the primary analysis results to missing data handling or to 
premature treatment discontinuation, sensitivity analyses will be performed as follows.
Multiple imputation of HbA1c change from baseline after 24 weeks is planned for on- and off-
treatment values for the three treatment groups individually. These analyses will be 
performed based on all randomised patients who have a baseline HbA1c measurement.
Missing on-treatment values will be imputed using Markov Chain Monte Carlo (MCMC) 
simulation and standard techniques. Missing off-treatment data will be imputed based on the 
observed off-treatment data by treatment group, providing at least 6 patients provide off-
treatment data at Week 24 in each treatment group.  If fewer than 6 patients per treatment 
group provide off-treatment data at Week 24, on-treatment information from the placebo 
group will be used as a basis for the imputation. The imputation model will include baseline 
HbA1c and the last on-treatment value.  The analysis model will be an analysis of covariance 
(ANCOVA) model including treatment, background therapy, and continuous baseline HbA1c
and baseline eGFR; a common treatment estimate will be derived based on Rubin’s method.
The number of imputations will be set to 100 in order to ensure adequate efficiency and 
stability of estimation of missing data.  
Analysis on further patient set
The analysis of the primary endpoint will be repeated on the PPS using the same MMRM 
model as for the primary analysis to assess the impact of important protocol deviations.
Analysis of effectiveness
The analysis of the primary endpoint will be repeated on the mITT set but include all on- and 
off-treatment (i.e. measured after premature discontinuation of study drug or after rescue 
therapy is initiated) HbA1c values using the same MMRM model as for the primary analysis 
to assess the effectiveness of the study drug.


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7.2.2.4
Supplementary analysis
To explore the efficacy of pooled Empagliflozin doses (10 mg q.d. and 25 mg q.d.) over 
placebo, additional analysis on the primary endpoint will be repeated on the mITT set using 
the same MMRM model as for the primary analysis. More details will be specified in TSAP.
7.2.3
Secondary endpoint analyses
The percentage of patients with HbA1c <7.0% after 24 weeks of treatment will be 
summarised in a frequency table by treatment groups and analysed using logistic regression. 
Odds ratios and their respective 95% confidence intervals and p-values will be obtained. 
For continuous secondary endpoints of change from baseline in body weight, SBP, DBP and 
FPG at week 24, the similar MMRM approach based on on-treatment values for the primary 
analysis of the primary endpoint will be used. The model will include “baseline value for the 
corresponding endpoint” and its interaction with visit as additional covariates.
For continuous secondary endpoint of change from baseline in 2-hour PPG at week 24, an 
ANCOVA model will be applied since PPG is only measured at baseline and week 24. The 
ANCOVA model will include treatment and background therapy as classification effects, 
baseline PPG and baseline eGFR as the linear covariates.
Number of patients with hypoglycemic events and DKA events will be tabulated in 
frequency tables by treatment groups. Logistic regression will be performed to compare the 
occurrence of hypoglycemic events and DKA events between empagliflorin groups (10 mg 
and 25 mg, respectively) and placebo. Odds ratios and their respective 95% confidence 
intervals and p-values will be obtained.
More details of the analysis of secondary endpoints will be specified in TSAP.


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7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 7 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
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, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
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 MedDRA at 
database lock.
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 summarised. 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, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
Further details of the safety analysis will be specified in TSAP.
7.2.6
Interim Analyses
No interim analysis is planned.


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7.3
HANDLING OF MISSING DATA
For the analysis of the primary endpoint, the handling of missing data is described in section 
7.2.2.
For percentage of patients with HbA1c <7.0% after 24 weeks of treatment, the missing data 
will not be imputed. Patients who prematurely discontinue the treatment or initiate rescue 
therapy will be treated as non-responder (i.e., HbA1c ≥7.0% after 24 weeks of treatment).
No imputation for missing data will be performed for secondary efficacy endpoints of change 
from baseline in body weight, SBP, DBP and FPG. The missing data will be handled by 
MMRM model based on a likelihood method under the "missing at random” assumption. 
Baseline Observation Carried Forward (BOCF) approach will be used for 2-hour PPG in 
ANCOVA analysis. 
Missing or incomplete AE date will be imputed according to BI standards. Other missing 
safety data will not be imputed.
7.4
RANDOMISATION
The trial will be performed as a double-blind design with respect to placebo and the two 
active dose groups of Empagliflozin (10 mg q.d. and 25 mg q.d.). The randomization will be 
stratified by the following factors:

HbA1c value at screening visit (Visit 1) (<8.5%, ≥8.5%)

Background antidiabetic therapy (insulin alone, insulin + OAD)
Block randomization will be used to randomize patients in a ratio of 1:1:1 to placebo or 
Empagliflozin 10 mg or Empagliflozin 25 mg.
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
In the primary MMRM analysis (with excluded off-treatment and post-rescue values), the 
superiority of empagliflozin 25 mg and the superiority of empagliflozin 10 mg compared to 
placebo will be tested separately in a hirachical order at the two-sided alpha level of 0.05. 
The effective sample size is calculated from the assumed treatment effect and the assumed 
covariate-adjusted standard deviation based on a two-sided t-test at alpha-level of 0.05. The 
effective sample size corresponds to the sample size in the absence of treatment drop-out or 
censoring, i.e. when all patients complete the 24 week treatment period without prematurely 


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discontinuing treatment and without initiating rescue therapy. Censored patients still 
contribute some information to the analysis and are accounted for in the actual sample size. 
Censored patients are assumed to contribute to sample size according to the amount of 
information provided as a fraction of a completer. This fraction is referred to as the 
information content. The sample size (SS) is derived from the effective sample size (SSeff), 
the assumed censoring rate (CR) and the assumed information content (IC) using the 
following formula:
		 =
		

1 −(1 −)
Based on the experience in previous studies with Empagliflozin add-on to insulin (e.g. U12-
3817-01, U13-2122-01, P19-10212 ), it is estimated that the difference between 
Empagliflozin (10 mg q.d., 25 mg q.d.) and placebo in the change in HbA1c from baseline at 
week 24 is about 0.62% with standard deviation of 1.1%. Given those assumptions, an 
effective sample size of 68 patients per treatment arm will provide 90% power to detect the 
standardized effect size of 0.564 (0.62/1.1) based on two-sample t-test at two-sided alpha 
level of 0.05 for each dose group. Assuming an 8% censoring rate (including premature 
treatment discontinuation and rescue therapy use) and an information content of 0.4 (based on 
results from previous studies), 72 patients per treatment arm are needed, leading to a total of 
216 patients for three treatment arms.
The sensitivity of the sample size to the different scenarios of the assumptions is shown in 
Table 7.5: 1. Calculations were performed using nQuery Advisor® 7.0 statistical package by 
Statistical Solutions Ltd.
Table 7.5: 1
Power estimates for different scenarios for the MMRM analysis at 
two-sided  = 0.05
Treatment 
effect
(%)
Covariate 
adjusted 
standard 
deviation 
(%)
Censoring 
rate
Information 
content
Effective 
sample 
size per 
treatment 
arm
Sample 
size per 
treatment 
arm
Power
0.62
1.0
0.08
0.4
68
72
94.8
0.62
1.0
0.15
0.4
66
72
94.2
0.62
1.1
0.08
0.4
68
72
90.3
0.62
1.1
0.15
0.4
66
72
89.5
0.62
1.2
0.08
0.4
68
72
84.8
0.62
1.2
0.15
0.4
66
72
83.7


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), and other 
relevant regulations. Investigators and site staff must adhere to these principles. Deviation 
from the protocol, the principles of ICH GCP or applicable regulations as will be treated as 
“protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 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, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and is stored in the 
ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC 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 patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) 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.


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If study conduct may need to be adjusted (see Sections 6.1 and 10.2) during the COVID-19
pandemic, the patient must be made aware of any modifications and agreement needs to be
obtained prior to them being implemented.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC 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.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. 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
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Copies of source documents necessary for adjudication will be provided to CRO responsible 
for adjudication . Before sending or uploading those copies, the investigator must ensure that 
all patient identifiers (e.g. patient’s name, initials, address, phone number, social security 
number) have properly been removed or redacted from any copy of the patients’ source 
documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:


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
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, see Section 
6.1), site access may be restricted thus limiting the ability to perform standard site monitoring 
activities such as on-site source data review and source data verification. Therefore, some of 
these activities may be performed remotely or replaced by centralized monitoring to the 
extent possible, based on a documented risk assessment and in alignment with local 
regulations.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised 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 at the site
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 / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Not applicable.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely). Individual investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site. Early 
termination of the trial is defined as the premature termination of the trial due to any reason 
before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 


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BI has appointed a Clinical Trial Leader (CT Leader), 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,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
The organisation of the trial in China will be performed by the local or regional BI-
organisation (Operating Unit, OPU) in accordance with applicable regulations and BI SOPs, 
or by a Contract Research Organisation (CRO) with which the responsibilities and tasks will 
have been agreed and a written contract filed before initiation of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT Manual and Central Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R05-0939
Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pfluegers 
Archiv - European Journal of Physiology 2004; 447 (5), 510 - 518.
R07-1029 
Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling.
Diabetes Care 2004. 27(6):1487-1495.
R08-2669 
Guidance for industry: diabetes mellitus: developing drugs and therapeutic 
biologics for treatment and prevention (draft guidance, February 2008). 
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2008.
R13-5351
Xu Y, et al, China Noncommunicable Disease Surveillance Group. Prevalence 
and control of diabetes in Chinese adults. JAMA. 2013 Sep 4; 310(9):948-959.
P14-09057
Rosenstock J, Jelaska A, Salsali A, Kim G, Woerle HJ, Broedl UC, EMPA-
REG MDI Trial Investigators Improvedglucose control with weight loss, lower 
insulin doses, and no increased hypoglycemia with empagliflozin added to 
titrated multiple daily injections of insulin in obese inadequately controlled 
type 2 diabetes. Diabetes Care 37, 1815–1823 (2014)
P15-05791
Rosenstock J, Jelaska A, Zeller C, Kim G, Broedl UC, Woerle HJ, EMPA-
REG BASAL Trial Investigators Impact of empagliflozin added on to basal 
insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week 
randomized, double-blind, placebo-controlled trial.  Diabetes Obes Metab 
17(10), 936–948 (2015)
P19-10212
Sone H, Kaneko T, Shiki K, Tachibana Y, Pfarr E, Lee J, et al. Efficacy and 
safety of empagliflozin as add-on to insulin in Japanese patients with type 2 
diabetes: a randomised, double-blind, placebo-controlled trial. Diabetes 
Obesity and Metabolism, Accepted Article, First Published: 06 November 
2019, doi: 10.1111/dom.13909; 2020. p. 417-426.
9.2
UNPUBLISHED REFERENCES
c01678844
Investigator's Brochure BI 10773 in type 2 diabetes mellitus, CHF, CKD, 
paediatric diabetes, and type 1 diabetes mellitus, Current Version
c22646053
Clinical Trial Report of 1245.0107,


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10.
APPENDICES
10.1
BLOOD PRESSURE MEASUREMENT PROCEDURE
The preferred method for blood pressure measurement is electronic sphygmomanometer. 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 the same model of 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 five minutes, three blood pressure 
measurements will be taken approximately two minutes apart. The seated pulse rate of 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 two-minute interval 
between the second and third blood pressure reading.
10.2
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19 
As mentioned in section 6.1, in case of any restrictions during the COVID-19 pandemic, 
study conduct may need to be adjusted. The following contingency measures have been 
introduced to ensure patient safety and appropriate trial continuation based on a thorough 
benefit risk assessment (see Protocol Section 1.4.2).
In exceptional cases, when it is impossible to conduct the visits at the trial site, visits may be 
performed remotely (via telephone and/or internet based means of communication). Based on 
a thorough benefit-risk assessment (see Protocol Section 1.4.2), the visit procedures may be 
adjusted for the purpose of particular visits, whereby critical safety measures will remain in 
place. All remote visits need to be discussed with and approved by the sponsor`s trial team. 
Local regulatory and legal requirements of the participating country need to be respected for 
all modifications.
Under these circumstances, the below modifications can be considered. Patients need to be 
informed about the modifications and agree to them before implementation:
Remote visit


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If a patient is not able to come to the site for an outpatient visit, a remote visit (by phone) 
should be performed instead and all assessments that can be done by phone performed.
Assessments that should be performed during a remote visit are:
Adverse Events, concomitant therapy, Diet and exercise counselling,
Safety lab, other laboratory tests
If taking blood samples for central lab is not possible, blood analysis for safety lab can be 
done in a local lab for remote visit 6. The results of the lab tests are to be reported and 
transferred to the investigator, who has to ensure medical review and proper documentation.
Minimum required safety lab parameters are eGFR, liver enzymes and urine pregnancy test in 
women of child bearing potential which will be captured in the eCRF. A urine analysis 
should not be performed locally. On top of this the home blood glucose monitoring by the 
patient needs to be reported to the investigator at each remote visit 4, 5, 6 and 7 anyway.
COVID-19 PCR testing at remote visits is not part of trial procedures and may only be 
performed based on investigator judgement about the needs.
Dispensation of Trial medication (IMP)
If a patient is not able to come to visit 4, 5, 6 or 7 as planned but the investigator considers it 
favourable and safe for patient to continue with IMP, IMP can be shipped from site directly 
to the patient (if legally acceptable according to the local regulations). Temperature 
monitoring will be considered, and the documentation should be filed in ISF


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
20Apr2021
BI Trial number
1245-0191
BI Investigational Medicinal 
Product(s)
Jardiance®, Empagliflozin
BI 10773
Title of protocol
A phase III, randomised, double-blind, placebo-
controlled, parallel group study of Empagliflozin 
(10 mg and 25 mg) administered orally once daily 
in combination with insulin with or without up to 
two oral anti-diabetic agents for 24 weeks in 
Chinese type 2 diabetic patients with insufficient 
glycemic control.
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Title page
Description of change
CTL information changed
Rationale for change
Team member hand over
Section to be changed
Synopsis
Description of change
Trial design, number of patients, inclusion criteria 
and statistical methods
Rationale for change
To be consistent with the sections 3.1, in the 
protocol.
Section to be changed
section 3.1
Description of change
Added Empagliflozin pooled doses in design and 
updated the total patient number
Rationale for change
To reflect the update in 7.2 planned analysis and 
7.5 sample size calculation.
Section to be changed
section 3.3
Description of change
updated the total patient number and each 
treatment number
Rationale for change
To reflect the update in section 7.5 sample size 
calculation.
Section to be changed
section 3.3.2, section 4.2.1
Description of change
Inclusion criteria #3 is updaed “Acceptable basal 
insulins should have duration of action up to 24 h 
such as Insulin Degludec, insulin glargin, insulin 
detemir or NPH (neutral protamine hagedorn) 
insulin;”


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Inclusion criteria #5, the SI unit for Fasting C-
peptide is added
Rationale for change
To clarify better the acceptable basal insulins 
definition
To be consistant with the unit in the lab report;
Section to be changed
section 3.3.4.1
Description of change
Added one more criteria of treatment 
discontinuation:
The patient experiences an infection with SARS-
CoV-2. The patient may resume trial treatment 
following recovery from SARS-CoV-2 infection 
if the patient is expected to derive clinical benefit, 
as agreed between the investigator and sponsor.
Removed “as run-in falure” from “They have to 
be recorded in eCRFs and no further follow-up is 
required (except for AEs, if needed).”
Rationale for change
COVID-19 pandemic; 
To consistent with eCRF form.
Section to be changed
section 4.1.4
Description of change
To ensure a dose interval of about 24 hours, the 
medication is proposed to be taken at the same 
time every day.
Rationale for change
To clarify the medication taken time requirement 
which is not at the exact same time every day for 
actual practise.
Section to be changed
section 4.2.1
Description of change
added the adverbial clause in “The total 
prescribed insulin dose should not be changed by 
more than 10% of the baseline value in the 24 
weeks after randomisation unless rescue therapy 
criteria for treatment hyperglycemia are met 
or in case of hypoglycemia requiring insulin 
dose reduction beyond the defined limits.”
Rationale for change
To clarify the insulin dose is allowed to change 
under the specific condition as described in the 
same section.
Section to be changed
section 5.1
Description of change
Site should contact patients in advance to remind 
the conduction of the test. The timing of the 8-
point blood glucose measurement is proposed 
as follows


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Rationale for change
To clarify better the requirement for the 8-point 
glucose measurement.
Section to be changed
section 6.2.1
Description of change
If the HBGM test reveals an overnight fasted 
blood glucose of >240 mg/dl (>13.3 mmol/l), the 
patient should contact the study site for a visit at 
the next day.
Rationale for change
To correct typo in the unit
Section to be changed
Section 7.2.2.1
Description of change
In MMRM, the response variable HbA1c change 
from baseline at week 24 were changed HbA1c 
change from baseline to at each on-treatment 
visit.
Rationale for change
To correct the typo in the response variable.
Section to be changed
Section 7.2.2.4
Description of change
Added supplementary analysis to explore the 
efficacy of empagliflozin pooled doses (10 mg + 
25 mg) against placebo.
Rationale for change
To better address the scientific question whether 
Empagliflozin is efficacious as add-on to insulin 
in Chinese patients with T2DM.
Section to be changed
Section 7.5
Description of change
The estimated difference between Empagliflozin 
(10 mg q.d., 25 mg q.d.) and placebo in the 
change in HbA1c from baseline at week 24 is 
updated to 0.62% and 72 (instead of 91) patients 
per treatment arm and a total of 216 patients are 
needed.
Rationale for change
A study of Empagliflozin as add-on to insulin in 
Japanese patients with T2DM has shown a more 
pronounced effect.
Section to be changed
section 8.3.2 
Description of change
Added the extra access to source data and 
documents:
In the event of force majeure or other disrupting 
circumstances (e.g. pandemic, war, please see 
section 6.1), site access may be restricted thus 
limiting the ability to perform standard site 
monitoring activities on site such as on-site
source data review and source data verification. 
Therefore, some of these activities may be 


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performed remotely or replaced by centralized 
monitoring to the extent possible, based on a 
documented risk assessment and in alignment 
with local regulations.
Rationale for change
COVID-19 pandemic
Section to be changed
Section 9.1
Description of change
Published reference P19-10212 is added.
Rationale for change
As reference for the updated estimated treatmnent 
difference.
Section to be changed
Section 1.4.2
Description of change
Risk evaluation in relation with COVID-19 
added:
Patients with serious underlying medical 
conditions such as T2D are at higher risk for 
severe illness from coronavirus disease 2019 
(COVID-19). Therefore, in case of local high risk 
of COVID-19 infection, on-site visits may not be
carried out. In the event of restriction to visit the 
investigator site, a remote visit can be performed. 
This change is meant to keep the integrity of the 
trial and it will not affect the assessment of 
benefit-risk of empagliflozin. 
There is no indication that empagliflozin may 
increase the risk of COVID-19 infection. As with 
any acute illness, empagliflozin during COVID-
19 infection has the potential to increase the risk 
of diabetic ketoacidosis. The risk of diabetic 
ketoacidosis in case of acute illness is adequately 
addressed in the IB and in the patient information
and consent form.
In case of a confirmed COVID-19 infection, trial 
treatment will be discontinued.
Rationale for change
COVID-19 pandemic
Section to be changed
Flow Chart, Section 4.1.4, 6.1, 8.1 and 10.2; 
Description of change
Contingency measures have been introduced to 
ensure patient safety and appropriate trial 
continuation based on a thorough benefit risk 
assessment (see Section 1.4.2) and above.
Introduce flexibility for trial visits: to allow in 
exceptional cases visits to be done as remote 
visits; to allow for IMP shipment from site to 


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patient in this case. Patients need to agree to 
changes prior to them being implemented.
Comment added below the Flow Chart to refer to 
the contingency measures if they are needed.
Rationale for change
COVID-19 pandemic


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26980387
2.0
clinical-trial-protocol
A phase III, randomised, double-blind, placebo-controlled, parallel group study of
Empagliflozin (10 mg and 25 mg) administered orally once daily in combination with
insulin with or without up to two oral anti-diabetic agents for 24 weeks in Chinese
type 2 diabetic patients with insufficient glycemic control.
Approval-Team Member Medicine
06 May 2021 13:33 CEST
Author-Trial Statistician
07 May 2021 03:48 CEST
Approval-Clinical Trial Leader
07 May 2021 05:58 CEST
Approval
07 May 2021 07:57 CEST
Verification-Paper Signature
Completion
07 May 2021 10:14 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26980387
2.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c31811315-01
BI Trial No.:
1245-0191
Title:
A phase III, randomised, double-blind, placebo-controlled, parallel
group study of Empagliflozin (10 mg and 25 mg) administered
orally once daily in combination with insulin with or without up to
two oral anti-diabetic agents for 24 weeks in Chinese type 2
diabetic patients with insufficient glycemic control.
Investigational 
Product(s):
Empagliflozin (BI 10773)
Responsible trial 
statistician(s):
Phone:
Date of statistical 
analysis plan:
12 November 2021 SIGNED
Version:
Final
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim                                                                                         c31811315-01
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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..................................................................................8
4
CHANGES IN THE PLANNED ANALYSIS OF THE 
STUDY ....................................................................................................9
5
ENDPOINTS ........................................................................................10
5.1
PRIMARY ENDPOINT ....................................................................................10
5.2
SECONDARY ENDPOINTS............................................................................10
5.2.1
Key secondary endpoints..............................................................................10
5.2.2
Other secondary endpoints...........................................................................10
6
GENERAL ANALYSIS DEFINITIONS...........................................12
6.1
TREATMENTS..................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS...................................................13
6.3
SUBJECT SETS ANALYSED..........................................................................15
6.5
POOLING OF CENTERS ................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................19
6.6.1
Definition of rescue therapy for censoring..................................................20
6.6.2
Methods of data selection..............................................................................20
6.6.3
Safety and other variables ............................................................................20
6.6.4
Missing dates and times ................................................................................21
6.6.5
Values below/above limits of quantification ...............................................22
6.6.6
HOMA-β.........................................................................................................22
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS .................22
7
PLANNED ANALYSES......................................................................26
7.1
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS......26
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................27
7.3
TREATMENT COMPLIANCE .......................................................................27
7.4
PRIMARY ENDPOINT ....................................................................................27
7.4.1
Primary analysis of the primary endpoint..................................................27
7.4.4
Supplementary analysis ................................................................................30
7.5
SECONDARY ENDPOINTS............................................................................30
7.5.1
Key secondary endpoints..............................................................................30
7.5.2
Other secondary endpoints...........................................................................30


Boehringer Ingelheim                                                                                         c31811315-01
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7.5.2.1
Responder analysis .....................................................................................30
7.5.2.2
Change from baseline in body weight, SBP, DBP and FPG ......................30
7.5.2.3
Change from baseline in 2-hour PPG.........................................................31
7.5.2.4
Occurrence of hypoglycemic events and adjudicated DKA 
events..........................................................................................................31
7.7
EXTENT OF EXPOSURE................................................................................33
7.8
SAFETY ANALYSIS.........................................................................................34
7.8.1
Adverse events ...............................................................................................34
7.8.1.1
Assignment of AEs to treatment.................................................................34
7.8.1.2
Analysis of other significant AEs...............................................................35
7.8.1.3
AE summaries.............................................................................................35
7.8.1.5
AEs of special interest (AESIs)..................................................................35
7.8.1.6
Events qualifying for external adjudication by the Clinical 
Event Committee (CEC).............................................................................37
7.8.1.7
AEs while patients taking wrong medication.............................................37
7.8.2
Laboratory data.............................................................................................37
7.8.2.1
Elevated liver enzymes...............................................................................37
7.8.2.2
Renal laboratory parameters.......................................................................38
7.8.3
Vital signs.......................................................................................................38
7.8.4
ECG ................................................................................................................38
7.8.5
Creatinine and eGFR time curve analysis ..................................................38
8
REFERENCES.....................................................................................39
10
HISTORY TABLE...............................................................................43


Boehringer Ingelheim                                                                                         c31811315-01
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LIST OF TABLES
Table 6.1:1
Treatment regimens / study intervals ..............................................................12
Table 6.2:1
Important protocol deviations .........................................................................14
Table 6.3:1
Summary of which data sets will be used for which class of endpoints .........17
Table 6.7:1
Endpoint specific follow-up period for the assignment to treatment phase....23
Table 6.7:2
Time windows for on-treatment efficacy measurement scheduled for each on 
treatment visit..................................................................................................24
Table 10:1 
History table ....................................................................................................43


Boehringer Ingelheim                                                                                         c31811315-01
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2
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
ALQ
Above Limit of Quantification
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ASA
Acetylsalicylic acid
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical classification
BI
Boehringer Ingelheim
BIcMQ
BI-customised MedDRA query
BLQ
Below Limit of Quantification
BMI
Body mass index
CEC
Clinical event committee
CRF
Case report form
CT
Concomitant therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBP
Diastolic blood pressure
DKA
Diabetic Ketoacidosis
ECG
Electrocardiogram
eCCr
Estimate creatinine clearance
eGFR
Estimated glomerular filtration rate
EoT
End of treatment
FPG
Fasting plasma glucose
FPI
Fasting plasma insulin
HbA1c
Glycated haemoglobin
HOMA-IR
Homeostatic model assessment - insulin resistance
HOMA-β
Homeostatic model assessment - β
ICH
International Conference on Harmonisation
IPD
Important protocol deviation
IRT
Interactive Response Technology


Boehringer Ingelheim                                                                                         c31811315-01
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Term
Definition / description
LOCF
Last observation carried forward
LQ
Limit of Quantification
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
mITT
Modified intention to treat
MMRM
Mixed-effect Model Repeated Measures
MQRM
Medical Quality Review Meeting
MTT
Meal tolerance test
NCF
Non-completers considered failure
OAD
Oral antidiabetic drug
OC
Observed case
OC-AD
Observed cases – all data
OR
Original results
PK
Pharmacokinetics
PPG
Post parandial glucose
PPS
Per protocol set
PT
Preferred term
PD
Protocol deviation
Q1
Lower quartile
Q3
Upper quartile
REML
Restricted maximum likelihood
RPM
Report planning meeting
SBP
Systolic blood pressure
SCR
Screened set
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
SMQ
Standardised MedDRA query
SOC
System Organ Class
TOC
Table of contents
TSAP
Trial statistical analysis plan


Boehringer Ingelheim                                                                                         c31811315-01
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Term
Definition / description
UACR
Urine albumin-to-creatinine ratio
ULN
Upper limit of normal
UTI
Urinary tract infection


Boehringer Ingelheim                                                                                         c31811315-01
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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 trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomization.
SAS® Version 9.4 or later version will be used for all analyses.


Boehringer Ingelheim                                                                                         c31811315-01
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4
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
There are no changes in this TSAP compared to the statistical methods described in the CTP. 


Boehringer Ingelheim                                                                                         c31811315-01
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5
ENDPOINTS
5.1
PRIMARY ENDPOINT
The endpoint will be used as defined in CTP Section 2.1.2.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Since there are no key secondary endpoints specified in the CTP, this section is not 
applicable.
5.2.2
Other secondary endpoints
The endpoints will be used as defined in CTP Section 2.1.3.


Boehringer Ingelheim                                                                                         c31811315-01
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Boehringer Ingelheim                                                                                         c31811315-01
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6
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
There will be five treatment study phases in this trial: screening, placebo run-in, double-blind 
study treatment phase (with empagliflozin and matching placebo), post-treatment and post-
study.
Table 6.1:1
Treatment regimens / study intervals
Label
Interval
Start date 
Start time
Screening
Screening
Date of informed 
consent
00:00
Run-in
Run-in
Date of first 
administration of run-in
medication
Time of first 
administration of 
run-in 
medication,
12:00 if missing
Placebo/
Empagliflozin 10mg/
Empagliflozin 25mg
Treatment
Date of first 
administration of 
double-blind study 
medication
Time of first 
administration of 
double-blind  
study medication,
12:00 if missing
Post-treatment 
Post-treatment
Date of last intake of 
study medication +X+1 
(see definition of X 
below)
00:00
Post-study
Post-study
Start date= Last contact 
date, defined as the
maximum of (Trial
completion date, last
study medication intake 
+ X) +1
00:00 
The purpose of the definitions above is to describe all the different study/treatment intervals, 
to which a patient can be assigned during the course of the trial. Note that the term “treatment 
regimen” can also cover time periods with no active treatment.
In general, for safety analyses, data up to 7 days after last study medication intake will be 
considered as on-treatment for AEs, 3 days for laboratory values and 1 day for pulse rate: To 
clarify:

Pre-treatment: before the first intake of any study medication.

On treatment: begins from the date of first administration of the initial randomised 
study medication to last intake of study medication + X days (inclusive), where X=1, 
3 or 7 days for pulse rate, safety laboratory, and AE respectively.


Boehringer Ingelheim                                                                                         c31811315-01
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
Post-treatment: begins from the last intake of study medication + X days + 1 day up to 
the last contact date (inclusive). Last contact date is defined in Table 6.1:1. Post 
treatment period is not applicable for patients with last contact equal to ‘last intake + 
X + 1 days’ where X is 1, 3, or 7 days as previously specified.

Post-study: From day after last contact defined in Table 6.1:1. If period starts at end
of on-treatment period, then post-treatment period is not applicable.
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 
further details, see Table 6.7:1.
The efficacy analyses will follow the intention-to-treat (ITT) principle in assigning patients to 
treatment groups, i.e. patients will be analysed in the treatment group they were randomized 
to. 
Safety analyses will assign patients to the treatment group as initially treated.
In addition, AEs with an onset during the time of the incorrect study treatment will be listed 
separately.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Not all important protocol deviations (IPDs) will generate exclusion from the per protocol 
population. Deviations that lead to exclusion from analysis populations are indicated as such 
in Table 6.2:1. 
IPD definitions will include consideration of, among others, important deviations of entry 
criteria, treatment non-compliance, treatment dispensing errors, prohibited concomitant 
medication and premature unblinding. 
The decision about which protocol deviation (PD) could generate exclusion from analysis 
sets will be taken during the course of the study and finalised at the last report planning 
meeting (RPM), i.e. before unblinding.
The following table defines the different categories of IPDs. The final column describes 
which analysis set will the patients be excluded from.


Boehringer Ingelheim                                                                                         c31811315-01
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Table 6.2:1
Important protocol deviations
IPD 
Code
IPD Category & brief 
description
Example/Comment
Exclude 
from which 
analysis set
A
Entrance criteria not met
A1
Target indication not met
A1.01
No type 2 diabetes
Inclusion criterion #2 not met
PPS
A1.02
Antidiabetic background therapy 
not as required
Inclusion criterion #3 not met
PPS
A2
Inclusion criteria not met
A2.01
HbA1c out of range 
Inclusion criterion #4 not met
PPS
A2.02
Age out of range
Inclusion criterion #1 not met
None
A2.03
Body mass index out of range
Inclusion criterion #6 not met
None
A2.04
Fasting C-peptide out of range
Inclusion criterion #5 not met
None
A3
Exclusion criteria met
A3.01
Uncontrolled FPG level
Exclusion criterion #4 met
None
A3.02
Additional background therapy
Exclusion criterion #2, #9, #11, #12, #14
met
PPS
A3.03
Relevant concomitant diagnoses
Exclusion criterion #1, #6, #7, #20, #23 met
None
A3.04
Bariatric or other relevant 
gastrointestinal surgery within the 
past two years  
Exclusion criterion #8 met
PPS
A3.05
Blood dyscrasias or any disorders 
causing hemolysis or unstable red 
blood cell count
Exclusion criterion #15 met
PPS
A3.06
Indication of liver disease
Exclusion criterion #13 met:
ALT or AST or alkaline phosphatase > 
3xULN at V1
None
A3.08
Treatment with protocol excluded 
anti-obesity drugs
Exclusion criterion #10 met
PPS
A3.09
Renal insufficiency or renal 
impairment (assessed by eGFR)
Exclusion criterion #3 met
PPS
A3.10
Treatment with protocol excluded 
systemic steroids or recent change 
in thyroid hormone dose
Exclusion criterion #16, #17 met
PPS
A3.11
Relevant alcohol or drug abuse 
and other conditions affecting 
study compliance 
Exclusion criterion #18 met
PPS
A3.12
Any other clinical condition 
unsafe for participation that would 
jeopardise patient safety while 
participating in this clinical trial
Exclusion criterion #5, #22, #24, #25, #26
met
None
A3.13
Renal insufficiency or renal 
impairment (assessed by eCcR)
Exclusion criterion #19 met
PPS
A3.14
Known allergy or hypersensitivity 
to empagliflozin or other SGLT-2 
inhibitors
Exclusion criterion #21 met
None


Boehringer Ingelheim                                                                                         c31811315-01
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Table 6.2 :1
Important protocol deviations (cont.)
IPD 
Code
IPD Category & brief 
description
Example/Comment
Exclude 
from which 
analysis set
A3.15
Women who are pregnant, 
nursing, or who plan to become 
pregnant while in the trial.
Exclusion criterion #27 met
None
B
Informed Consent
B1 
Informed consent not available/not 
done
Inclusion criterion #7 not met
All
B2 
Informed consent too late
Date of informed consent not obtained prior 
to any study related procedure.
Minimum requirement <= date of Visit
1/date of any study procedure
None
C
Trial medication and 
randomisation
C1.01
No study medication taken
Patient randomised according to IRT system 
but no medication taken according to 
eCRF/IVRS
TS, mITT, 
PPS
C1.02
Incorrect trial medication taken
Wrong medication taken, i.e. eCRF kit 
number does not match kit number assigned 
by IVRS*
[Needs unblinding to determine if kit was 
same medication as assigned or not – so, 
will be finally judged after DBL]
PPS
C2.01
Treated without randomisation
Patient treated according to eCRF, but not 
randomised according to IVRS
mITT, PPS
C3.01
Non-compliance with study drug 
intake
Overall study compliance outside 80% and
120% (exclusive) or study treatment 
compliance below 80% in the last visit 
interval before primary endpoint assessment.
[Final decision at the DBL meeting based on 
medical judgement.]
PPS
C4.01
Medication code broken at site 
without just cause
Medication code was broken for no valid 
reason.
PPS
D
Concomitant medication
D2.01
Background antidiabetic therapy 
not taken as specified in the 
protocol
Review of eCRF for prohibited medication 
and check whether other than protocol 
defined rescue medication was taken*
[Final decision at the DBL meeting based on 
medical judgment]
PPS
E
Missing data
E1.01
No baseline HbA1c value
No valid baseline HbA1c value
mITT, PPS
6.3
SUBJECT SETS ANALYSED
The following analysis sets will be defined for this trial.

Screened patients set (SCR):


Boehringer Ingelheim                                                                                         c31811315-01
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This patient set includes all patients screened for the trial, with informed consent 
given and who completed at least one screening procedure at Visit 1.

Treated set (TS): 
This patient set includes all patients who are randomized and treated with at least one 
dose of study medication. The assignment of patients to treatment groups will be 
based on the actual first study medication intake in the double-blind treatment period.
The TS is the basis for safety analyses.

Modified Intention-to-Treat (mITT) set:
This patient set includes all randomized patients who are treated with at least one dose 
of the study medication and have a baseline HbA1c assessment and at least one on
treatment HbA1c value. The assignment of patients to treatment groups will be based 
on the planned randomised study medication at the time of randomisation. The 
primary efficacy analysis will be performed on mITT set with patients who have a 
baseline HbA1c and at least one on treatment HbA1c measurement during 
randomized period.

Per-protocol set (PPS):
This patient set includes all patients in the mITT set who do not have any important 
protocol deviations (iPDs) which can be expected to have a distorting influence on the 
assessment of the primary endpoint. iPDs are detailed in Table 6.2:1.
In Table 6.3:1 the data sets which are to be used for each category class of endpoint are 
illustrated.


Boehringer Ingelheim                                                                                         c31811315-01
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Table 6.3:1
Summary of which data sets will be used for which class of endpoints
Class of endpoint 
Subject sets
SCR
TS
mITT
PPS
Disposition
OR
Demographics
OR
Baseline variables
OR
Background 
total daily insulin 
dose/concomitant 
medications
OR
Concomitant 
diagnoses/relevant 
medical history
OR
Exposure/
compliance
OR
Primary endpoints
Primary analysis
(OC)
&
Secondary analyses
(MI, OC-AD)
OC
Secondary and 
further efficacy 
endpoints-
continuous
OC,
OR#
Secondary and 
further efficacy 
endpoints-binary
NCF
Subgroup 
analyses
OC
Safety endpoints
OR
SCR=screened set, mITT set=modified intention-to-treat set, PPS=per protocol set, TS=treated set; patient sets are defined in 
Section 6.3
OR=original results, OC=observed cases on treatment, OC-AD=observed cases-after discontinuation and rescue therapy,
NCF=Non-completers considered failures. Handling of missing data is described in Section 6.6
#OR results will only be presented for time to first rescue medication and number of patients with rescue.


Boehringer Ingelheim                                                                                         c31811315-01
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Boehringer Ingelheim                                                                                         c31811315-01
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6.5
POOLING OF CENTERS
This section is not applicable because center 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 the efficacy endpoints of this 
trial, depending upon the type of the endpoint (see Table 6.3:1).


Boehringer Ingelheim                                                                                         c31811315-01
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6.6.1
Definition of rescue therapy for censoring
For some of the imputation methods defined below, values after first rescue medication will 
be set to missing. In this context, the following three situations are defined as use of rescue 
medication: 

Additional antidiabetic medication used for ≥7 consecutive days

For insulin, a change of >10% (increase/decrease) from the last dose recorded prior to 
the baseline visit (Visit 3) taken for ≥7 days

For OADs, a change in dose (increase/decrease) compared with the baseline dose for 
≥7 consecutive days
This approach will be used when considering which data to exclude from the OC analyses.
6.6.2
Methods of data selection
Original result (OR) analysis
Original result analysis implies the analysis of data exactly as observed. OR analysis will be 
performed on endpoints that are either not affected by patients’ antidiabetic rescue 
medication use 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 were observed 
while patients were on treatment, i.e., excluding the missing data. In other words, OC 
analysis will be performed and missing data in this analysis will not be replaced. 
For all efficacy endpoints, this OC-technique will set all values measured after antidiabetic 
rescue medication taken to missing (antidiabetic rescue medication as defined in section 
6.6.1).
Observed cases analysis including data after treatment discontinuation and rescue therapy 
(OC-AD)
To mimic an intent-to-treat (ITT) analysis, post-treatment as well as post-rescue 
measurements may also be included. This will be done as a secondary analysis of the primary 
endpoint with OC as the imputation rule.
Non-completers considered failure (NCF)
For binary endpoints, like a treat to target response of HbA1c <7.0%, a conservative method 
to replace missing values is to consider them as "failures". Missing data due to early 
discontinuation per the completer definition will be replaced as "failure" (i.e. HbA1c ≥7.0%) 
up to the planned final visit to be reached by all patients. Values obtained after rescue 
medication was started are also replaced as "failure".
A multiple imputation (MI) approach will also be used as a sensitivity analysis for the 
primary endpoint. Further details can be found in Section 7.4.2.
6.6.3
Safety and other variables
Missing safety data will not be replaced.


Boehringer Ingelheim                                                                                         c31811315-01
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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.
6.6.4
Missing dates and times
Missing or partial date information for AEs will be replaced according to general BI rules 
described in the BI guidance for handling of missing and incomplete AE dates (1). 
If the date of first drug administration is missing but the patient was randomised, the date of 
the first drug administration will be set to the date of randomisation. If the date of first 
administration is partially missing with the month and year present, the day will be set to the 
date of randomisation if randomisation was in the same month. If randomisation was in the 
month prior to the first drug administration the missing day will be imputed as the first day of 
the month.  
A missing time of first drug administration will be imputed as 12:00 o'clock noon, missing 
administration times at on-treatment visits will be imputed by 08:00 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, visit 8, 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 + the longest 
treatment duration based on drug supply + 1 day. 

If a patient died during the course of the trial and no additional information about 
drug stop date are available, the date of death will be used as drug stop date assuming 
that the patient took the medication until the day of death.

All other cases need to be assessed by the trial team on an individual basis, trying to 
use the points above as guidance. 
For partial start and stop dates for concomitant therapies (CT) and additional antidiabetic 
drugs, the following derivations will be used to impute 'worst case' values. 

If the day of the end date is missing then the end date is set to last day of the month.

If the day and month of the end date are missing then end date is set to 31st December 
of the year

If the day of the start date is missing the start date is set to first day of the month

If the day and month of the start date are missing then the start date is set to 1st 
January of the year.
All other cases need to be assessed by the trial team on an individual basis, using the above 
points as guidance.
In case of missing visit date for a compliance record, the following hierarchy will be used to 
select a date to impute the missing visit date: 

The visit date registered in the IRT system

The date of the vital sign measurement for the same visit


Boehringer Ingelheim                                                                                         c31811315-01
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
The date of the safety laboratory sampling for the same visit
All other cases need to be assessed by the trial team on an individual basis, using the above 
points as guidance.
6.6.5
Values below/above limits of quantification
For biomarkers (C-peptide, insulin) reported values below the limit of quantification (BLQ) 
will be replaced with 2/3 times lower LQ. This is approximately the median of the expected 
‘true’ value if the biomarker follows a normal distribution. The inverse of the factor 2/3 will 
be used to replace values above the upper LQ, resulting in 1.5 times upper LQ. The analysis 
dataset will contain flags to indicate that the value was BLQ and a variable for the value of 
the LQ. With this approach, even a change of the method with different LQs can be handled 
within a trial. The number of samples above and below the limit of quantification will be 
included in the biomarker tables.
6.6.6
HOMA-β
Please refer to CTP Section 5.4.1 for the definition of HOMA-β. For FPG values <3.5 
mmol/L, HOMA-β assumes extreme negative values for FPG values only slightly smaller 
than 3.5. For FPG=3.5 mmol/L, the ratio is not defined. Therefore, HOMA- β will only be 
calculated for FPG>3.5 mmol/L and set to missing for lower values.
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. Pre-treatment values will be assigned to a visit according to 
the nominal visit number as recorded on the eCRF or as provided by the laboratory. 
In general, 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 medication 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 medication for efficacy analyses and to the first 
study medication taken for safety analyses. 


Boehringer Ingelheim                                                                                         c31811315-01
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Table 6.7:1
Endpoint specific follow-up period for the assignment to treatment 
phase
Endpoint
Last day of assignment to treatment phase
(days after study medication stop date)
Efficacy
HbA1c
7
FPG
1
Body weight
1
Blood pressure (systolic, diastolic)
1
PPG
1
MDG
1
C-peptide
1
Biomarkers of insulin resistance 
and secretion
1
Waist circumference
7
Safety
Adverse events
7
Safety laboratory measurements
3
Pulse rate
1
Measurements taken after the end of the endpoint specific follow-up period and after the last 
intake of study medication will be considered post-treatment values. 
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 medication (see Table 
6.7:2). 


Boehringer Ingelheim                                                                                         c31811315-01
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Table 6.7:2
Time windows for on-treatment efficacy measurement scheduled for 
each on treatment visit
Time window (actual days on 
treatment)
Visit number
Visit label
Planned days
Start
EndA
3
Baseline
0
NA
1B
4
Week 4
28
2
42
5
Week 8
56
43
70
6
Week 12
84
71
105
7
Week 18
126
106
147
8
Week 24/EOT
168
148
Study 
medication stop 
date + X days
A  In case of premature discontinuation of the study medication an early EoT visit has to be performed. If such 
an EoT Visit 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 the early EoT visit will end X days after the study medication stop date, including Day X. The 
definition of X is endpoint specific, cf. Table 6.7:1. Patients will then be asked to continue in the study 
according to the visit schedule. Off-treatment measurements will be assigned to visits in the same manner. 
No time window for optional visit is planned.   
B     Only values taken prior to the start of treatment with randomised study medication can be considered 
baseline values. Time windows will be used for assignment of measurements to scheduled visits.
Reasons to base the time windows on the actual treatment start date rather than the 
randomisation date are:

If first intake of study medication shows a large delay by e.g. more than one week 
after the date of randomisation, a measurement taken four weeks after randomisation
rather reflects the drug effect after three weeks than after four weeks and thus may 
underestimate the treatment effect at this visit.

With large delays of the introduction of study medication after the randomisation, the 
time window for the first on-treatment visit could include times the patient was not 
yet on study medication.
The time window for the first visit after randomisation starts on the day after the first intake 
of study medication. This maximises the number of measurements used in by visit analyses 
may lead to an underestimation of the treatment effect at the first visit for parameters that 
react slowly on treatment.
The midpoint between two on-treatment visits defines the end of a time window, with the 
midpoint being included in the time window of the preceding visit. The end of the time 
window of the last on-treatment visit (end of treatment (EoT)) is endpoint dependent (Table 
6.7:1). 
Repeated and unscheduled efficacy and safety measurements will be assigned to the nominal 
visits and listed in the SDL according to the time windows described above. Only one 
observation per time window will be selected for analysis at an on-treatment visit - the value 


Boehringer Ingelheim                                                                                         c31811315-01
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will be selected which is closest to the protocol planned visit day. If there are two 
observations which have the same difference in days to the planned day or if there are two 
observations on the same day, the first value will be used. If an observation is available on 
the last day of treatment, this observation will be preferably selected over any later 
observation that is still within the time window (not applicable for standard laboratory 
summaries). If there are multiple values within the time window of the last visit, including a 
value on the last day of drug intake, the value on the last day of drug intake is used as the 
value of the last visit.
Data prior to randomisation will be based on nominal visits and time windowing will not be 
applied. For these time points, data from the scheduled visit will always be selected if they 
are collected correctly. Unscheduled visits will only be considered if no correct data from the 
scheduled visit is available. If no correct data from a scheduled visit is available and multiple 
unscheduled correct values are available for a visit, the first correct value will be selected. 


Boehringer Ingelheim                                                                                         c31811315-01
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7
PLANNED ANALYSES
Disposition of the patient population participating in the trial will be analysed by treatment 
groups and presented in the clinical trial report as a frequency-distribution. The number of
patients participating in the study will also be analysed by treatment group and presented as a 
frequency distribution.
A frequency of patients with iPDs, also summarised by whether the iPD led to exclusion from 
the PPS, will be presented by treatment group for treated set. The frequency of patients in 
different analysis sets will also be presented for each treatment group. 
For in-text tables presenting descriptive analysis of the endpoints and other variables 
(analysed in original scale), the set of summary statistics is: N (number of patients with non-
missing values), mean, standard deviation (SD).
For end-of-text tables, the set of summary statistics is: N (number of patients with non-
missing values) / Mean / SD / Min / Q1 (lower quartile) / Median / Q3 (upper quartile) / Max.
For the in-text, end-of-text and appendix tables presenting descriptive analysis of the 
endpoints and other variables (analysed on logarithmic scale), the respective summary 
statistics (e.g., gMean, gCV, etc.) will be used.
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline "Reporting of Clinical Trials and Project Summaries" (2). Patient level 
results for the calculated endpoints HOMA-IR will be presented to one decimal place. 
HOMA-β will be presented as full integers. The summary statistics of these parameters will 
follow the aforementioned guideline.
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 actual missing values. Percentages will be 
based on all patients in the respective patient set whether they have non-missing values or 
not.
In all specified statistical analyses, treatment comparisons will be made between each 
randomised empagliflozin group (10mg and 25mg) and placebo.
7.1
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Descriptive analysis of the following demographic variables measured at baseline will be 
presented:
Sex, age (years) (continuous and categories), race, ethnicity, BMI (kg/m2) (continuous and 
categories), height (cm), smoking history and alcohol status, time since diagnosis of diabetes 
(years) (continuous and categories), background medication, background insulin type, eGFR 
MDRD (mL/min/1.73 m²) (continuous and categories) and UACR (mg/g) (continuous and 
categories).Categories for baseline characteristics are defined in Table 6.4:1.
Descriptive analysis of the following variables measured at baseline will be presented:
HbA1c (%) (continuous and categories), FPG (mg/dL)(continuous and categories), weight 
(kg) (continuous and categories) , waist circumference (cm), blood pressure (mmHg) 
(categories), fasting serum C-peptide, HOMA-IR and HOMA-β.


Boehringer Ingelheim                                                                                         c31811315-01
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Both demographic and baseline characteristics tables will be presented on treated set by 
treatment groups.
A summary of the number of patients in each randomisation stratum per treatment will also
be shown. This will be based upon the data received from the IRT provider. Analyses will be 
based on actual information collected via the CRF / central laboratory, not via IRT.
7.2
CONCOMITANT DISEASES AND MEDICATION
Descriptive statistics are planned for this section of the report using the treated set. 
Concomitant medication use will be summarised by Anatomical-Therapeutic-Chemical 
classification level 3 (ATC3) and preferred name. Summaries will be presented for 
concomitant therapies taken during screening, taken during randomised treatment and those 
taken at baseline. Separate summaries of antidiabetic treatment at enrolment, use of 
antihypertensives, acetylsalicylic acid (ASA) or lipid lowering drugs at enrolment by 
preferred name will be presented. The display categories and defining ATC levels and ATC 
code are shown in Section 9.1.
Concomitant diseases will be summarised by Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class (SOC) and preferred term (PT). Relevant diabetic medical 
history by treatment group will also be presented. Both summaries will be presented using the 
treated set.
7.3
TREATMENT COMPLIANCE
Descriptive statistics are planned for this section of the report. The number and percentage of 
patients with overall compliance will be reported. Overall compliance will be calculated as a 
weighted average of reported 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).  The treated set will be considered. Refer to Section 6.6.4 for how to 
handle a single missing visit date for a compliance record, in the overall compliance 
calculation.
If compliance is missing at more than one on-treatment visit (>1), the overall compliance will 
be set to missing.
If a patient prematurely discontinues from treatment, compliance will be calculated until last 
study medication intake. Missing compliance values for off-treatment visits will not be 
considered in the calculation for overall compliance.
7.4
PRIMARY ENDPOINT
The primary endpoint in this trial is the change in HbA1c (%) from baseline after 24 weeks of 
treatment.
7.4.1
Primary analysis of the primary endpoint
The primary analysis is a restricted maximum likelihood (REML)based mixed model 
repeated measures (MMRM) approach comparing the change from baseline in HbA1c after 
24 weeks of treatment. The analysis will be performed on the mITT set (OC) with treatment 
assignment as randomized and include on-treatment HbA1C only. If a patient misses a visit, 


Boehringer Ingelheim                                                                                         c31811315-01
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the missing data will not be imputed. The mixed effect model will handle missing data based 
on a likelihood method under the “missing at random” assumption.
The statistical model will be:
Change in HbA1c (%) from baseline to the end of 24 weeks
= overall mean + treatment + background therapy + baseline HbA1c + 
baseline eGFR + visit + treatment-by-visit interaction + baseline HbA1c-by-
visit interaction + random error.
The analysis will include treatment (Empagliflozin 10 mg, Empagliflozin 25 mg, placebo), 
background therapy (insulin only, insulin with OADs), and visit as fixed classification 
effects, baseline HbA1c and baseline eGFR as the linear covariates, treatment by visit 
interaction, and baseline HbA1c by visit interaction. 
For each patient, the error terms from all the visits represent the within-patient variability and
are assumed to follow a multivariate normal distribution with an unstructured covariance 
matrix. The random error is assumed to be normally distributed with mean 0 and unknown 
variance σj². If an unstructured (co)variance structure fails to converge, the following 
structures will be tested in order: compound symmetry, variance components and Toeplitz. 
The (co)variance 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 and adjust standard errors.
A hierarchical testing sequence will be used as defined in the protocol. Superiority will be 
tested using the p-value of the treatment effect (least-squares means) and a two-sided 95% 
confidence interval for the treatment difference.


Boehringer Ingelheim                                                                                         c31811315-01
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Boehringer Ingelheim                                                                                         c31811315-01
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7.4.4
Supplementary analysis
The same MMRM analysis method as described in Section 7.4.1 will be applied on the mITT
set (OC) to compare the change from baseline in HbA1c after 24 weeks of treatment between 
pooled Empagliflozin doses (10 mg q.d. and 25 mg q.d.) and placebo. The model includes 
treatment (Empagliflozin, placebo), background therapy (insulin only, insulin with OADs), 
and visit as fixed classification effects, baseline HbA1c and baseline eGFR as the linear 
covariates, treatment by visit interaction, and baseline HbA1c by visit interaction. 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been specified in the CTP.
7.5.2
Other secondary endpoints
The secondary endpoints for this study are described in CTP Section 2.1.3.
7.5.2.1
Responder analysis
The HbA1c responder analyses will be performed on mITT (NCF) by determining the 
percentage of patients that fulfil responder criteria (for the definition of treat to target and 
relative efficacy response, see Section 5.2.2) by treatment. Non-completers considered 
failures (NCF) imputation-technique will be used to impute the missing data for this analysis 
strategy. 
Each analysis will consist of a tabulation by treatment of the percentage of patients meeting 
the response criteria along with 95% exact confidence intervals for the percentage.
Additionally, a logistic regression model with treatment, background therapy, baseline eGFR
and continuous HbA1c will be fitted on the binary response variable to calculate the estimate 
of the odds ratio of each dose to placebo. Estimate of odds ratios and 95% confidence 
intervals (Wald) will be presented along with the p-values for each comparison.
7.5.2.2
Change from baseline in body weight, SBP, DBP and FPG
The MMRM models constructed for the primary endpoint will also be conducted for 
continuous secondary endpoints of change from baseline in body weight, SBP, DBP and FPG 
at week 24. Analyses will be performed on the mITT set (OC). The model will include the 
baseline value of the corresponding endpoint and its interaction with visit as covariates.


Boehringer Ingelheim                                                                                         c31811315-01
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7.5.2.3
Change from baseline in 2-hour PPG 
A valid 2-hour PPG sample has to be taken between 1:50 and 2:10 h after the start of the 
meal in the MTT . To be eligible for use as baseline, the 2-hour PPG sample has to be taken 
prior to the intake of the first dose of the randomised study medication. 
For continuous secondary endpoint of change from baseline in 2-hour PPG at week 24,
ANCOVA will be performed based on the mITT (OC) set. The respective model will include 
treatment and background therapy as classification effects, baseline HbA1c, baseline PPG 
and baseline eGFR as the linear covariates. 
7.5.2.4
Occurrence of hypoglycemic events and adjudicated DKA events
Number of patients with confirmed hypoglycemic events and adjudicated DKA events will be 
tabulated in frequency tables by treatment groups. Logistic regression will be performed to 
compare the occurrence of confirmed hypoglycemic events and adjudicated DKA events 
between empagliflorin groups (10 mg and 25 mg, respectively) and placebo. Odds ratios and 
their respective 95% confidence intervals and p-values will be obtained. Baseline HbA1c 
value and treatment will be included in the model. Time to the onset of the first event will be 
analysed by Kaplan-Meier estimates.
Summaries of hypoglycemic events will include total number of hypoglycemic events, 
descriptive hypoglycemic event rate, number of episodes per patient, severity and intensity of 
the worst episode, action taken, minimum glucose level of worst episode, and time to onset of 
first episode. Hypoglycemic events will also be summarised by background medication, type 
of insulin, age group and use of rescue medication.
Different tables will be shown for (i) patients with investigator defined asymptomatic or
symptomatic hypoglycemia reported as AE or non-AE, and (ii) patients with confirmed
hypoglycemic adverse events, i.e. hypoglycemic adverse events that had a plasma glucose
concentration ≤ 70 mg/dL or required assistance.


Boehringer Ingelheim                                                                                         c31811315-01
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Boehringer Ingelheim                                                                                         c31811315-01
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7.7
EXTENT OF EXPOSURE
A descriptive statistics table with mean, SD, median and range of the number of days a 
patient was on treatment will be provided for the treated set. The tables will also provide the 
sum total of the time (in years) that all patients pooled together were on treatment. A separate 
listing will be created of any patients that switched treatment at any time indicating exposure 
to each treatment. 
A frequency table of number and percent of patients belonging to each categorical range of 
exposure weeks will be provided as well. The following are the categories of exposure-ranges 
(in weeks):
>0 to 4 weeks, >4 to 8 weeks, >8 to 12 weeks, >12 to 18 weeks, >18 to 24 weeks, >24 weeks. 


Boehringer Ingelheim                                                                                         c31811315-01
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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse events
AEs will be coded using the latest version of the MedDRA coding dictionary at database 
lock. 
Definitions of Boehringer Ingelheim customized MedDRA Queries (BIcMQs) for new
MedDRA versions are maintained by the BI dictionary maintenance group.
Any clinically significant new finding in the physical examination, vital signs (blood pressure 
and pulse symptoms) and in the 12-lead ECG starting after visit 3 (randomisation visit) will 
be considered as an AE and will be reported as such.
The analyses of adverse events will be descriptive in nature. All analyses of AEs will be 
based on the number of patients with AEs (not the number of AEs). For this purpose, AE data 
will be combined in a 2-step procedure into AE records.
In the first step, AE occurrences, i.e. AE entries on the CRF, will be collapsed into AE 
episodes
provided that all of the following applies:

The same MedDRA lowest level term was reported for the occurrences

The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence. Exceptions: (i) Hypoglycemic events are only 
collapsed if they occur within 12 hours of each other. The 12-hour period will begin 
with the first hypoglycemia onset time. If another event occurs outside this initial 12-
hour window a new period for collapsing will begin. (ii) Genital infection events will 
not be collapsed if they are representative of different types (i.e. fungal balanitis or 
vulvovaginitis versus other than fungal balanitis or vulvovaginitis). (iii) Sepsis events 
will not be collapsed if they are representative of different sources of infection (i.e. 
urinary tract (urosepsis) versus other than urinary tract)

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence.
In a second step, AE episodes will be condensed into AE records provided that the episodes
were reported with the same term on the respective MedDRA level and that the episodes are
assigned to the same treatment. For further details on summarization of AE data, please refer
to the guideline ‘Handling and summarization of adverse event data for clinical trial reports
and integrated summaries’.
7.8.1.1
Assignment of AEs to treatment
In general, the analysis of adverse events will be based on the concept of treatment emergent 
adverse events.  That means that all adverse events occurring between first drug intake until 7 
days after last drug intake will be assigned to the on treatment. All adverse events occurring 
before first drug intake will be assigned to 'pre-treatment' and all adverse events occurring 


Boehringer Ingelheim                                                                                         c31811315-01
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after last drug intake + 7 days will be assigned to 'post-treatment' (for listings only). For 
details on the treatment definition, see Section 6.1.
In general, in-text AE tables will only present AEs assigned to the first treatment taken except 
drug-related AEs which will be presented as actual treatment taken at each given timepoint.  
End-of-text tables will display in addition AEs observed 'pre-treatment' (including AEs 
observed during screening and placebo run-in regardless of treatment group). AEs and 
serious adverse events (SAEs) are assigned to the following phases: Screening, placebo run-
in, each treatment group, post-treatment for each treatment group will be listed.
7.8.1.2
Analysis of other significant AEs
Other significant AEs will be reported and summarised according to ICH E3 criterion (3). 
Thus, AEs classified as 'other significant' will include those non-serious adverse events with:

‘action taken = discontinuation’ or ‘action taken = reduced’, or

Marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality 
Review meeting or Blinded Report Planning Meeting.
7.8.1.3
AE summaries
An overall summary of adverse events will be presented.
The frequency of patients with adverse events will be summarised by treatment, primary SOC
and PT. AEs will also be reported by intensity. Separate tables will be provided for patients 
with other significant AEs according to ICH E3 (3), for patients with adverse events of 
special interest (AESI), for patients with serious adverse events, for patients with AEs leading 
to discontinuation, and for patients with drug-related AEs.
The SOC will be sorted alphabetically, preferred terms will be sorted by frequency (within 
SOC). Customized sorting orders may also be used based on trial needs, e.g. SOC sorted by 
frequency.
7.8.1.5
AEs of special interest (AESIs)
The protocol defines the following adverse events that for analysis purposes will be 
considered as AESIs:

Hepatic injury 

Decreased renal function

Diabetic ketoacidosis (DKA)

Events leading to lower limb amputation


Boehringer Ingelheim                                                                                         c31811315-01
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Events of these AESIs are identified through the AE being flagged by the investigator as an 
AESI on the case report form (CRF) and based on SMQs/BIsMQ.
Hepatic injury
Adverse events reported as AESIs relating to hepatic injury as specified in the protocol will 
be summarised.
Additionally, hepatic injury AEs will be summarized based on an SMQ based definition. 
From SMQ Drug related hepatic disorders (20000006) the following narrow sub-SMQs will 
be used:

Liver related investigations, signs and symptoms: 20000008 (narrow SMQ)

Cholestasis and jaundice of hepatic origin: 20000009 (narrow SMQ)

Hepatitis, non-infectious: 20000010 (narrow SMQ)

Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions: 
20000013 (narrow SMQ)
A table with frequencies of patients with these AEs by treatment, primary SOC and PT will 
be provided. Hepatic injury SAEs and hepatic injury AEs leading to discontinuation based on 
the above SMQ definition will be presented.
Patients with hepatic injury will be listed.
Decreased renal function
Adverse events reported as AESIs relating to decreased renal function as specified in the 
protocol will be summarised, i.e. patients with elevated creatinine ≥2 x baseline and above 
upper limit of normal (ULN)
A frequency table of patients with AEs of acute renal failure by treatment, primary SOC and 
PT will additionally be provided based on the narrow standardized MedDRA query (SMQ) 
Acute renal failure (20000003).
SAEs and AEs leading to discontinuation based on the SMQ Acute renal failure (20000003) 
will be presented.
Patients with decreased renal function will be listed.
Events leading to lower limb amputation
A frequency table of patients with AEs leading to lower limb amputation as identified by the 
investigator by treatment, primary SOC and PT will be provided.


Boehringer Ingelheim                                                                                         c31811315-01
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A separate table for AEs leading to lower limb amputation which lead to discontinuation will 
be presented.
SAEs will also be presented.
Patients with lower limb amputation will be listed.
7.8.1.6
Events qualifying for external adjudication by the Clinical Event Committee (CEC)
An independent external CEC regularly reviews events suspected of DKA and evaluates 
whether pre-specified criteria for these adjudication endpoints are met. Details on 
composition of the CEC, responsibilities and clinical event definitions are provided in a 
separate CEC Charter.
The CEC will be provided with additional, specified background material on the patients with 
these events and perform an assessment of the events.
Adjudication assessments will be incorporated to the database. Frequency tables will be 
provided for the preferred terms in the specified SMQs of events and for the adjudication 
endpoints. Tables will be provided for events qualifying for adjudication and then separately 
the events that were confirmed or non-assessable.
7.8.1.7
AEs while patients taking wrong medication
A listing using the TS will be provided for AEs that occurred while a patient was taking the 
wrong medication.
7.8.2
Laboratory data
For continuous safety laboratory parameters standardized and normalized values will be 
derived as well as the differences to baseline.  The process of standardization and 
normalisation as well as standard analyses for safety laboratory data are described in the BI 
guidance for the Display and Analysis of Laboratory Data (4). All analyses considering 
multiple of times upper limit of normal (ULN) will be based on original and not normalized
data.
Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomised or re-randomised study medication. In general, laboratory measurements 
taken up to 3 days after the last administration of randomised study medication will be 
considered as on-treatment. The exception will be for the liver enzyme elevation analysis (see
Section 7.8.2.1).
Only patients with at least one available on-treatment value will be included in the analysis of 
an individual laboratory parameter. All individual data will be presented in listings.
7.8.2.1
Elevated liver enzymes
The frequency of the number of patients with AST/ALT elevations >= 3xULN, >= 5xULN, 
>= 10xULN, and >= 20xULN will be displayed.
To support analyses of liver related adverse drug effects, patients with AST and/or ALT 
≥3xULN with concomitant or subsequent TBILI≥2xULN in a 30-day period after AST/ALT 
elevation are of special interest. 


Boehringer Ingelheim                                                                                         c31811315-01
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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 elevations above and has no information available for the remaining parameter(s) at 
the same time-point or within the 30 day time window will not be listed under “ALT and/or 
AST ≥ 3xULN with Total Bilirubin ≥ 2xULN”. An additional presentation including all 
events up to 30 days after the last dose of study treatment will also be included.
In a similar manner, patients with AST and/or ALT ≥5xULN with no concomitant or 
subsequent TBILI≥2xULN in a 30-day period after AST/ALT elevation will also be 
displayed. If no TBILI measurement is available in the 30-day period then the patient will not 
be listed.
7.8.2.2
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 normalized values with BI 
standard reference ranges.  The creatinine clearance and glomerular filtration rate will be 
estimated according to the formula and stored in the trial databases:

Cockcroft-Gault formula (mL/min): eCcr = (140 – age) x (weight in kg) x (0.85 if 
female) / (72 x creatinine (mg/dL))

MDRD formula (mL/min/1.73m²): eGFR = 175 x (creatinine (umol/L) / 88.4)-1.154 x 
[age]-0.203 x (0.742 if female)
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 PDs based on renal function the central laboratory values will be used.
7.8.3
Vital signs
In addition to the analysis of SBP and DBP as secondary endpoints. Only descriptive 
statistics are planned for the summary of pulse rate (bpm), change from baseline in pulse rate 
after 24 weeks of treatment.
7.8.4
ECG
12-lead ECG measurements will be taken at baseline (Visit 3) and at EoT (Visit 8). Any 
clinically significant new findings in the ECG measurement after the first ECG will be 
considered as AEs and analyzed as planned in Section 7.8.1.
7.8.5
Creatinine and eGFR time curve analysis
Descriptive statistics will be created for creatinine and eGFR values over time by treatment
and presented in tables. Descriptive statistics for eCcr will be presented. These data will be 
used to create plots of the parameters over time.


Boehringer Ingelheim                                                                                         c31811315-01
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8
REFERENCES
1
BI-KMED-BDS-HTG-0035: “Handling of missing and incomplete AE dates”, current 
version; KMED.
2
Corp Guideline, “Reporting of Clinical Trials and Project Summaries”, current
version, in: DMSM; BI Intranet: rdmnet.
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.


Boehringer Ingelheim                                                                                         c31811315-01
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Boehringer Ingelheim                                                                                         c31811315-01
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Boehringer Ingelheim                                                                                         c31811315-01
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Boehringer Ingelheim                                                                                         c31811315-01
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10 HISTORY TABLE
Table 10:1
History table
Version
Date 
(DDMMMYY)
Author
Sections
changed
Brief description 
of change
Final
12-Nov-21
None
This is the final 
TSAP without 
any
modification