A Randomised, Double-blind, Placebo-controlled, Parallel Group, Efficacy and Safety Study of Empagliflozin (10mg, 25mg) Administered Orally, Once Daily Over 24 Weeks in Hypertensive Black/African American Patients With Type 2 Diabetes Mellitus
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2, Hypertension
Sponsor: Boehringer Ingelheim

Clinical Trial Protocol
Doc. No.: c01945509-06
BI Trial No.:
1245.29   
BI Investigational
Product:
Empagliflozin
Title:
A randomised, double-blind, placebo-controlled, parallel group, 
efficacy and safety study of empagliflozin (10 mg, 25 mg) administered 
orally, once daily over 24 weeks in hypertensive black/African 
American patients with type 2 diabetes mellitus
Clinical Phase:
IIIb
Trial Clinical 
Monitor:
Tel:
Fax:
Co-ordinating 
Investigator:
Phone
Fax: 
Status:
Final Revised Protocol (based on global amendment 4)
Version and Date:
Version: 5.0
Date: 18 July 2016
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TITLE PAGE

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
Empagliflozin
Protocol date:
Trial number:
Revision date:
18 July 2016
15Apr2014 
1245.29
Title of trial:
A randomised, double-blind, placebo-controlled, parallel group, efficacy and safety 
study of empagliflozin (10 mg, 25 mg) administered orally, once daily over 24 weeks
in hypertensive black/African American patients with type 2 diabetes mellitus
Co-ordinating 
Investigator:
Trial sites
Multi-centre trial
Clinical phase:
IIIb
Objectives:
The objective of the current study is to investigate the efficacy and safety of 
empagliflozin (10 mg or 25 mg) compared to placebo on glucose control over 24 
weeks in hypertensive black/African American patients with Type 2 Diabetes Mellitus 
(T2DM).  A second objective of the study is to investigate the efficacy and safety of 
empagliflozin (10 mg or 25 mg) compared to placebo on BP over 12 weeks and on 
weight at 24 weeks in the same patient population. The study is designed to show 
superiority of empagliflozin over placebo.
Methodology:
Randomised, double-blind, placebo-controlled, parallel group comparison
No. of patients: 
total entered:
154 randomised hypertensive black/African American patients with type 2 diabetes 
mellitus (T2DM)
each treatment:
77 patients on empagliflozin 10 mg/25 mg
77 patients on placebo
Diagnosis :
T2DM and hypertension

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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
Empagliflozin
Protocol date:
Trial number:
Revision date:
18 July 2016
15Apr2014 
1245.29
Main criteria
for inclusion:
1. Diagnosis of T2DM prior to informed consent.
Note: Documentation should be available before randomisation at latest.  
Confirmation can be in the form of formal documents or by verbal communication of 
the date of diagnosis from a patient or from their primary care physician (if records 
are not available).  It is up to the medical judgment of the Investigator to deem if the 
information is accurate.
2. Male and female black/African American patients on diet and exercise regimen 
who are EITHER:
drug-naïve (defined as absence of any oral antidiabetic therapy , glucagon like 
peptide-1 (GLP-1) analog or insulin for 12 weeks, 16 weeks for pioglitazone prior to 
randomisation), OR
pre-treated with stable dose of metformin only, or sulfonylurea (SU) only, or DPP-4 
inhibitor only, or metformin plus sulfonylurea, or metformin plus DPP-4 inhibitor.  
Treatment has to be unchanged for a minimum of 12 weeks prior to randomisation
Dose for metformin: maximum tolerated dose 
The maximum daily dose of SU or DPP-4 inhibitor should not exceed that stated in 
the local label .
3. HbA1c of ≥ 7.0% (53 mmol/mol) and ≤ 11.0% (97 mmol/mol) at Visit 1 
(screening)
4. Mean seated SBP 140-180 mmHg  at Visit 1 (screening)
5. Successful completion of baseline ambulatory blood pressure (ABPM) testing with 
a mean systolic blood pressure (SBP) 135-175 mmHg prior to randomisation
6. Treatment with stable doses of at least one but no more than 4 antihypertensive 
medication ≥ 4 weeks prior to randomisation.
7. Age ≥18 years at Visit 1 (screening) 
8. Signed and dated written informed consent by date of Visit 1 in accordance with 
Good Clinical Practice (GCP) and local legislation
Test product:
Empagliflozin
dose:
10 mg / 25 mg, once daily
mode of admin.:
Tablets per os
Comparator product:
Placebo matching empagliflozin
dose:
NA, once daily
mode of admin.:
Tablets per p.o.

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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
Empagliflozin
Protocol date:
Trial number:
Revision date:
18 July 2016
15Apr2014 
1245.29
Duration of treatment:

2 weeks placebo run-in

24 weeks double-blind treatment with either empagliflozin 10 mg or 
empagliflozin 25 mg after dose escalation or placebo followed by two weeks 
follow up post study drug termination

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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
Empagliflozin
Protocol date:
Trial number:
Revision date:
18 July 2016
15Apr2014
1245.29
Criteria for efficacy:
pharmacokinetics:
pharmacodynamics:
The primary endpoint in this study is change from baseline in HbA1c at 24 weeks of 
treatment.
Key secondary endpoints are change from baseline in mean 24-hour ambulatory SBP 
at 12 weeks of treatment, change from baseline in mean trough ambulatory SBP at 12 
weeks, change from baseline in body weight in kilograms (kg) at 24 weeks of 
treatment, and change from baseline in trough seated SBP at 12 weeks of treatment.
Other secondary endpoints are described in Section 5.1.1.
Criteria for safety:
All adverse events including hypoglycaemic events and adverse events of special 
interest (AESI) and clinical laboratory values

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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
Empagliflozin
Protocol date:
Trial number:
Revision date:
18 July 2016
15Apr2014
1245.29
Statistical methods:
For change from baseline in HbA1c up to 24 weeks of treatment a restricted 
maximum likelihood estimation based on a mixed-effect model for repeated measures 
analysis will be used to obtain adjusted means for the treatment effects on the full 
analysis set (FAS). This model will include treatment, visit, and the stratification 
factors renal function at baseline, and pretreatment with Metformin at screening as 
discrete fixed effects, baseline HbA1c as a continuous fixed effect, and interaction 
between visit and treatment, and an interaction between visit and baseline HbA1c. The 
primary treatment comparisons will be the contrast between treatments at the endpoint 
visit at 24 weeks of treatment.
For the change from baseline in trough seated SBP up to 12 weeks of treatment and 
the change from baseline in body weight in kg at 24 weeks as well a restricted
maximum likelihood estimation based on mixed-effect models for repeated measures 
analysis will be used to obtain adjusted means for the treatment effects on the FAS. 
These models will include the same discrete fixed effects as the model for the primary 
endpoint and baseline HbA1c as continuous fixed effect, as well as interaction 
between visit and treatment, and interaction between visit and baseline measurement 
of the key secondary endpoint, as well as the corresponding baseline measurements of 
the key secondary endpoint as continuous effect . The primary treatment comparisons 
will be the contrast between treatments at the 12 week visit for seated SBP and 24 
week visit for body weight.
The key secondary endpoint change from baseline in 24-hour ambulatory SBP and 
change from mean trough ambulatory SBP at 12 weeks will be analyzed by using an 
analysis of covariance (ANCOVA) approach in the FAS with last observation carried 
forward (LOCF) for missing data. The model will include randomised treatment, renal 
function at baseline, pretreatment with Metformin at screening as discrete fixed 
effects and the baseline of the key secondary endpoint and HbA1c at baseline as 
continuous fixed effects. 
The overall type I error across the hypotheses tests in the confirmatory analysis will 
be maintained at a level of α ≤ 0.05 using a hierarchical testing sequence. 
The sample size of 154 patients per group was derived (assuming n=64 per groups 
plus a 20% drop-out rate) based on the requirement that the comparisons of 
empagliflozin versus placebo with respect to the HbA1c, BP and body weight should 
have a power of at least 80% at the two-sided α level of 5%. 
Explorative statistical models and descriptive statistics will be used for the other 
secondary endpoints and safety parameters.

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FLOW CHART
Trial Period
Scree-
ning
Placebo 
run-in 
period
Randomised period
PTD
Premature 
Treatment 
Discontinu
ation only S
Follow
-up 
period
Visit
1A
2.1
2.2 B
3
4
5.1B
5.2
6O
7.1 B
7.2
8
Study week
-3
-2
-1
4
11
12
18
23
24
26
Study day
-21
-14
-7
1
29
78
85
127
162
169
183
Visit window 
(in days)
+/-7
-7
+7
na
-
7/+3
+7
-7/+7
+/-7
+14
+7
+7
Informed 
Consent
X
Medical history 
/ concomitant 
diagnoses
X
Demographics
XH
X
In-/Exclusion 
criteria
X
X
X
Physical 
examination
X
X
X
Vital signs
X
X
X
X
X
X
X
X
 
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Diet and 
exercise 
counselling C
XC
XC
XC
XC
XC
XC
Food intake 
booklet 
completion
XR
X
X
X
X
X
12-lead ECGD
X
Pregnancy test E
X
X
X
X
X
X
Safety lab tests F
(urine and 
blood)
XG
X
X
X
X
X
X
X
FPG sample
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
Lipid lab panel
X
X
X
X
X
 
X
X
X
X
ABPM device 
attachment and 
removal I
X
X
X

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Trial Period
Scree-
ning
Placebo 
run-in 
period
Randomised period
PTD
Premature 
Treatment 
Discontinu
ation only S
Follow
-up 
period
Visit
1A
2.1
2.2 B
3
4
5.1B
5.2
6O
7.1 B
7.2
8
Study week
-3
-2
-1
4
11
12
18
23
24
26
 
X
Home Blood 
Glucose 
Monitoring L
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
Concomitant 
therapy
X
X
X
X
X
X
X
X
X
Dispense 
placebo run-in 
medication M
X
Randomization 
(via an IRT 
system) Q
X
Dispense study 
medication M
X
X
X
Dose escalationN
X
Medication 
compliance 
check
X
X
X
X
X
Study 
medication 
termination
X
X
Trial completion
X
A
The screening procedures can be done on different days within the time window.
B 
Patients will undergo 24-hour ABPM testing. If patients fail the test, this procedure should be repeated.  Each 
patient will be allowed a maximum of two attempts within the visit window to obtained one successful 
measurement starting at each of the ABPM time points (Visit 2.2, 5.1 and 7.1).  If the ABPM testing is successful, 
procedures for the subsequent visit can be conducted on the same day after the ABPM device is removed and 
trough seated blood pressure measurement is taken.  
Visit 2.2 ABPM and any repeat measurements if required should be performed during the run-in period within 7 
days prior to Visit 3 (Day 1).   Day 1 is the day of randomisation, not the day ABPM is applied. 
Visit 5.1 ABPM and any repeat measurements if required should be performed within 7 days prior to Visit 5.2 
(Day 85). 
Visit 7.1 ABPM and any repeat measurements if required should be performed within 7 days prior to Visit 7.2 
(Day 169). dx
  
C
Diligent diet and exercise counselling by a diet specialist or trained staff member at visit 2.1. Counselling is based 
on local diet recommendations and should include a food log (recording of food intake for 3 consecutive days in 
the week before the actual visit). At all visits, patients should be reminded about the importance to follow the 
recommended diet and exercise plan.
D
In addition to the visit indicated, ECG should be recorded in case of respective cardiac symptoms (indicating 
rhythm disorders or cardiac ischemia).

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E 
For female patients (local urine pregnancy test in women of child-bearing potential).
F
Fasting blood and urine samples to be collected, for central labs at each visit indicated (refer to Lab manual). A 
urine dipstick to be done locally,; upon positive result at site for leukocyte esterase (WBC) or nitrites a midstream 
urine sample should be taken and sent for urine culture analysis (central lab).
G
For the screening Visit 1, laboratory tests only include liver transaminases, alkaline phosphatase, serum creatinine, 
TSH and urinalysis. Patients do not have to be fasting.
H
Only screening relevant demographics (gender, date of birth).
I
The ABPM device is attached on the mornings of Visit 2.2, 5.1 and 7.1 before medication intake for measuring 
ABPM.  This also applies to visits for repeat ABPM testing if required.  Patients must have a successful 
completion of V2.2 ABPM prior to randomisation. Do NOT contact IRT system or dispense randomised study 
drug until after a successful 24-hour ABPM  is complete.  If after two attempts a successful reading is not achieved 
at either Visit 5.1 or Visit 7.1, patients should continue with the next scheduled visit (Visit 5.2/Day 85 or Visit 
7.2/Day 169 respectively). 
In case the ABPM must be repeated, the patient should continue taking trial medication. If possible, ABPM should 
take place within the visit window in the Flowchart. If two doses of study medication are taken when the monitor
is attached, then the ABPM should be repeated.
At the conclusion of each attempt, patient should be allowed to rest for at least 15 minutes after removal of the 
ABPM and a trough seated blood pressure measurement should be taken prior to intake of study medication. 
L
Instruction and handover of device at Visit 2.1.  Daily measurements during Run-in and Follow-up should be 
performed. 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.  
M
At all visits the respective kit number has to be allocated to the patient via an interactive response technologies 
(IRT) system. All visit activities must be completed before contacting IRT.
N
At Visit 4 all patients will be dose escalated through an IRT system. 
O
Visit 6 will be conducted as a phone visit.
Q
All visit activities must be completed and continued eligibility for randomisation or dosing confirmed prior to 
using IRT.
R
At Visit 2.1 the food log is dispensed only and to be completed for three consecutive days prior to Visit 3.
S
A Premature Treatment Discontinuation (PTD) Visit, as well as a Follow-up Visit 8, should be performed for any 
patient who discontinues study medication prematurely and are willing to be followed up; the PTD Visit should be 
completed as soon as possible after study medication is stopped. PK sampling can be omitted if the PTD Visit is 
not performed within 24 hours of the last dose of study medication.  Visit 8 should be performed 2 weeks after the 
PTD visit, and where possible, patients should then be followed up according to the visit schedule. For further 
details see Section 6.2.3

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................7
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................17
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 20
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................20
2.2
TRIAL OBJECTIVES.......................................................................................20
2.3
BENEFIT - RISK ASSESSMENT ...................................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 23
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................23
3.1.1
Administrative structure of the trial...................................................24
3.1.1.1
Hepatic External Adjudication.................................................24
3.1.1.2
Clinical Event Committee for Diabetic ketoacidosis (DKA)
25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................25
3.3
SELECTION OF TRIAL POPULATION ......................................................26
3.3.1
Main diagnosis for study entry............................................................27
3.3.2
Inclusion criteria...................................................................................27
3.3.3
Exclusion criteria ..................................................................................28
3.3.4
Removal of patients from therapy or assessments.............................30
3.3.4.1
Removal of individual patients................................................30
3.3.4.2
Discontinuation of the trial by the sponsor..............................31
3.3.5
Re-screening ..........................................................................................31
3.3.6
Repeat test..............................................................................................32
4.
TREATMENTS........................................................................................ 33
4.1
TREATMENTS TO BE ADMINISTERED....................................................33
4.1.1
Identity of BI investigational product and comparator product......33
4.1.2
Method of assigning patients to treatment groups ............................34

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4.1.3
Selection of doses in the trial................................................................34
4.1.4
Drug assignment and administration of doses for each patient .......35
4.1.5
Blinding and procedures for unblinding ............................................36
4.1.5.1
Blinding....................................................................................36
4.1.5.2
Procedures for emergency unblinding .....................................36
4.1.6
Packaging, labelling, and re-supply ....................................................36
4.1.7
Storage conditions.................................................................................37
4.1.8
Drug accountability ..............................................................................37
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE
TREATMENT....................................................................................................38
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................38
4.2.2
Restrictions............................................................................................40
4.2.2.1
Restrictions regarding concomitant treatment .........................40
4.2.2.2
Restrictions on diet and life style.............................................41
4.3
TREATMENT COMPLIANCE.......................................................................41
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 43
5.1
EFFICACY - PHARMACODYNAMICS........................................................43
5.1.1
Endpoints of efficacy.............................................................................43
5.1.2
Assessment of efficacy...........................................................................45
5.2
SAFETY..............................................................................................................48
5.2.1
Endpoints of safety................................................................................48
5.2.2
Assessment of adverse events...............................................................48
5.2.2.1
Definitions of adverse events...................................................48
5.2.2.2
Adverse event and serious adverse event collection and 
reporting...................................................................................52
5.2.3
Assessment of safety laboratory parameters......................................54
5.2.4
Electrocardiogram................................................................................59

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6.
INVESTIGATIONAL PLAN.................................................................. 64
6.1
VISIT SCHEDULE............................................................................................64
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................64
6.2.1
Screening and run-in period ................................................................64
6.2.2
Treatment period ..................................................................................66
6.2.3
End of trial and follow-up period........................................................70
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 73
7.1
STATISTICAL DESIGN - MODEL................................................................73
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................73
7.3
PLANNED ANALYSES....................................................................................74
7.3.1
Primary analyses...................................................................................74
7.3.2
Secondary analyses ...............................................................................76
7.3.3
Safety analyses.......................................................................................77
7.3.4
Interim analyses ....................................................................................77
7.3.5
Pharmacokinetic analyses ....................................................................77
7.3.6
Pharmacodynamic analyses.................................................................77
7.3.7
Pharmacogenomic analyses..................................................................78
7.4
HANDLING OF MISSING DATA ..................................................................78
7.5
RANDOMISATION ..........................................................................................78
7.6
DETERMINATION OF SAMPLE SIZE ........................................................78
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 80
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................80
8.2
DATA QUALITY ASSURANCE .....................................................................81
8.3
RECORDS..........................................................................................................81
8.3.1
Source documents .................................................................................81
8.3.2
Direct access to source data and documents.......................................81
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE
EVENTS..............................................................................................................82

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8.4.1
Listedness...............................................................................................82
8.4.2
Expedited reporting to health authorities...........................................82
8.5
STATEMENT OF CONFIDENTIALITY.......................................................82
9.
REFERENCES......................................................................................... 83
9.1
PUBLISHED REFERENCES...........................................................................83
9.2
UNPUBLISHED REFERENCES.....................................................................83
10. APPENDICES .......................................................................................... 84
10.1
INCLUSION OF ILLITERATE PATIENTS .................................................84
10.1.1 Home blood glucose monitoring ..........................................................84
10.1.2 Patient information and informed consent (including 
pharmacogenetics) ................................................................................84
10.1.3 Food intake diary recording ................................................................85
10.2
BLOOD PRESSURE MEASUREMENT PROCEDURE..............................85
10.3
ORTHOSTATIC BLOOD PRESSURE MEASUREMENT PROCEDURE86
10.4
CLINICAL EVALUATION OF LIVER INJURY .........................................87
10.4.1 Introduction...........................................................................................87
10.4.2 Procedures .............................................................................................87
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 89
11.1
GLOBAL AMENDMENT 1 CHANGES.........................................................89
11.2
GLOBAL AMENDMENT 2 CHANGES.......................................................106
11.3
GLOBAL AMENDMENT 3 CHANGES.......................................................128
11.4
GLOBAL AMENDMENT 4 CHANGES.......................................................139

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ABBREVIATIONS
ABPM
Ambulatory Blood Pressure Monitor
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ANCOVA
Analysis of Covariance
BI
BMI
BNP
BP
BUN
CK
CK-18
Boehringer Ingelheim
Body Mass Index
Brain Natriuretic Peptide 
Blood Pressure
Blood Urea Nitrogen
Creatine Kinase
Cytokeratin-18
CKD-EPI
Cl-
CML
Chronic Kidney Disease Epidemiology Collaboration
Chloride
Local Clinical Monitor 
CO
Competent Authority
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organisation
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBP
Diastolic Blood Pressure
DILI
Drug Induced Liver Injury
DKA
Diabetic Ketoacidosis
dl
decilitres
DNA
Deoxyribonucleic Acid
DPP-4
Dipeptidyl peptidase-4
ECG
eCRF
Electrocardiogram
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
ELF
Enhanced Liver Fibrosis
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
FPG
GCP
Food and Drug Administration
Fasting Plasma Glucose
Good Clinical Practice
GFR
GLP-1
HbA1c
HBGM
HCO3
-
HDL
Glomerular Filtration Rate
Glucagon Like Peptide-1 
Glycated hemoglobin
Home Blood Glucose Monitoring
Bicarbonate
High Density Lipoprotein

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HPLC
hr 
High-performance liquid chromatography
Hour 
IB
Investigator’s Brochure
IC50
half maximal inhibitory concentration
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IPV
Important Protocol Violation
IRB
Institutional Review Board
IRT
Interactive Response Technologies
ISF
Investigator Site File
IUD
Intra Uterine Device
IUS
Intra Uterine System
JNC8
Eighth Report of the Joint National Committee on Prevention, Detection, 
Evaluation, and Treatment of High Blood Pressure
kg
kilogram
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LOCF
Last Observation Carried Forward
m2
Meters squared
MedDRA
mEq/L
mg
Medical Dictionary for Drug Regulatory Activities
milliequivalents per litre
milligrams
mg/dl
milligrams per decilitre
min
minutes
mL
millilitres
mmol/l
Millimoles per litre
MMRM
Mixed Model Repeated Measure
Na+
Sodium
NAFLD
Non-alcoholic Fatty Liver Disease
nM
nmol/L
NOAEL
OPU
nanomoles
nanomoles per litre
No Observed Adverse Effect Level
Operative Unit
p.o.
per os (oral)
PG
PK
Pharmacogenomics
Pharmacokinetics
PPS
PTD
Per Protocol Set
Premature Treatment Discontinuation
RBC
Red Blood Cells
RDC
Remote Data Capture
REP
Residual Effect Period
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SGLT-2
SGOT
SGPT
Sodium-Glucose Co-Transporter-2
Serum Glutamic Oxaloacetic Transaminase
Serum Glutamic Pyruvate Transaminase

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SOP
Standard Operating Procedure
STEMI
ST Wave Elevated Myocardial Infarction
SU
Sulfonylurea
SUSAR
Suspected Unexpected Serious Adverse Reaction
T2DM
TCM
Type 2 Diabetes Mellitus
Trial Clinical Monitor
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
UTI
Urinary Tract Infection
WBC
White Blood Cells

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1.
INTRODUCTION
Empagliflozin is an orally available inhibitor of the sodium-glucose co-transporter 2 (SGLT-
2), that promotes enhanced glucose excretion in the urine, thereby lowering blood glucose 
concentrations in patients with type 2 diabetes mellitus (T2DM).
1.1
MEDICAL BACKGROUND
T2DM accounts for 90 to 95% of all cases of diabetes and is an increasingly prevalent disease 
with an estimated 285 million affected people worldwide. Its incidence is expected to 
increase to approximately 440 million people during the next twenty years. Complications 
induced by hyperglycemia are currently the most frequent cause of adult-onset loss of vision, 
renal failure, and amputation in the industrialized world. Diabetes is also associated with 
macrovascular complications with a 2- to 5-fold increase in cardiovascular disease risk. The 
high frequency of complications leads to a significant reduction of life expectancy. 
SGLT-2 is a member of a larger group of sodium substrate co-transporters, the sodium-
glucose co-transport 5 (SLC5) gene family (R05-0939).  Under normoglycaemia, glucose is 
almost completely reabsorbed by SGLTs in the kidney, whereas the reuptake capacity of the 
kidney is saturated at plasma glucose concentrations higher than approximately 10-11 
mmol/L, resulting in increasing glucosuria typically seen in patients with diabetes mellitus. 
The capacity to reabsorb glucose can be decreased by inhibition of SGLT-2. In humans, 
empagliflozin highly and selectively block glucose transport via SGLT-2 (IC50 1.3 nmol/l), 
with a 5000-fold selectivity over SGLT-1 (IC50 6278 nM).
The efficacy of empagliflozin is similar to the current oral antidiabetic drugs.  It has the 
potential to be combined with other oral antidiabetic drugs and has shown additional efficacy 
in terms of glucose control when used in combination with insulin in diabetic patients. 
Hypertension is four times more common in black/African Americans than in Caucasians.  
One of the risk factors for hypertension is sodium sensitivity and approximately one third of 
the essential hypertensive population is responsive to sodium intake. There is a higher 
association of hypertension with sodium sensitivity in black/African American patients with 
T2DM. This study will investigate the potential of empagliflozin to reduce sodium as well as 
glucose reabsorption by blocking the SGLT2 co-transporters and the possibility of adjustment 
to sodium sensing in the distal segment of the nephron that may affect renin secretion.
1.2
DRUG PROFILE
Non-clinical assessment of safety
A comprehensive package of safety pharmacology, genetic toxicology, reproductive 
toxicology and general toxicology studies were conducted in mice, rats, rabbits and dogs to 
support the chronic administration of empagliflozin to humans. The compound is well 
tolerated in animals at clinically relevant plasma exposures, while adverse effects were 
observed at higher exposures. Noteworthy adverse findings at effect levels above the no 

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observed adverse effect level (NOAEL) in general toxicology studies were body weight loss, 
lower weight gain, dehydration, nephritis and nephropathy. Human clinical exposure at 25 
mg/day is well below the exposure at the NOAEL of 100 mg/kg/day in male rats after 26 
weeks of dosing and the NOAEL of 10 mg/kg/day in the dog after 52 weeks of dosing and 
indicates a 9 to 10 fold therapeutic window to these NOAELs. These toxicology data suggest 
empagliflozin can be safely administered to humans at 50 mg/day in long term-studies.  
Empagliflozin is not known to be carcinogenic.   
Clinical pharmacokinetics
In humans, empagliflozin predominantly shows linear pharmacokinetics. Empagliflozin
reaches peak levels at approximately 1.5 hr and shows a biphasic decline with the 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 feces and 
urine, respectively. None of the detected metabolites were major. Empagliflozin tablets can 
be administered with or without food. Empagliflozin exposure increases with hepatic and 
renal impairment; however, no dose adjustment is recommended for patients with renal and 
hepatic impairment as the observed changes in empagliflozin exposure were not clinically 
meaningful. No clinically relevant pharmacokinetic interactions were observed with 
metformin, glimepiride, pioglitazone, sitagliptin, warfarin, linagliptin, verapamil, ramipril, 
simvastatin, digoxin, hydrochlorothiazide, torasemide, gemfibrozil, rifampicin, probenecid 
and oral contraceptives (Microgynon®).
Clinical efficacy and safety
In clinical studies of over 12000 patients of which 3311 were treated with empagliflozin 10 
mg and 4285 patients treated with 25 mg, empagliflozin was well tolerated in both normal 
healthy volunteers and patients with type 2 diabetes mellitus up to maximal treatment 
duration of 104 weeks in completed studies. The phase III studies have shown that treatment 
with empagliflozin 10 mg or 25 mg once daily for up to 24 weeks results in a reduction of 
glycated haemoglobin (HbA1c) up to 0.85%, body weight up to 2.2 kg and systolic blood 
pressure (SBP) up to 4.8 mmHg compared to placebo. This was consistently observed with
empagliflozin as monotherapy, add on to metformin, to metformin + sulphonylurea, to
pioglitazone with or without metformin, and to basal insulin with metformin and/or
sulphonylurea. Treatment with 10 mg or 25 mg empagliflozin for 12 weeks in a study using 
ABPM to measure changes in blood pressure (BP) (1245.48) resulted in a reduction of 
HbA1c of up to 0.65%, mean 24 hr SBP up to 4.16 mmHg, diastolic blood pressure (DBP) up 
to 1.72 mmHg and body weight up to 1.98 kg.  In this study, the proportion of patients with a 
positive orthostatic BP test after 12 weeks was measured to be 28% in placebo and up to 
39.9% in empagliflozin treatment arms.  These proportions returned to baseline levels 2 
weeks after end of treatment.  None of the patients in the empagliflozin treatment groups 
reported adverse events such as hypotension or orthostatic hypotension that were related to 
changes in orthostatic blood pressure or volume depletion.  African American accounted for 
5.0 % of the total number of patients in the 1245.48 study.  Subgroup analysis by race 
measured a reduction of HbA1c of up to 0.95% in African Americans.  While a reduction in 

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mean 24hr SBP up to -0.65 mmHg was observed in the African American group, there were 
too few patients for reliable blood pressure results.   
Longer-term phase 3 data support sustained and durable effect of empagliflozin. In a double-
blind, controlled independent extensions of the 4 pivotal trials (at least 76 weeks), which 
conducted under a single trial number (1245.31) with one trial protocol and one trial report 
(1245.31). In these trials, patients continued on the randomised trial treatment and the 
background medication they had taken in the initial trials. Sustained empagliflozin efficacy 
compared with placebo was demonstrated for glycaemic control (HbA1c, fasting plasma 
glucose (FPG)), body weight reductions, and lowering of blood pressure. In a head to head 
comparison with glimepride, after 104 week empagliflozin showed greater HbA1c, weight, 
and blood pressure reduction with fewer hypoglycaemic events compared with glimepiride in 
patients with type 2 diabetes mellitus and insufficient glycaemic control despite background 
therapy with metformin.
In addition, empagliflozin 25 mg resulted in a clinically meaningful and significant reduction 
in HbA1c in patients with moderate renal impairment. The frequency of overall adverse 
events (AE)s, AEs leading to discontinuation and serious adverse events (SAE)s were 
comparable to placebo. There was no significant increase in frequency of hypoglycemia with 
empagliflozin compared to placebo except when used in combination with a sulphonylurea or 
basal insulin. In general there was no increase in frequency of urinary tract infection 
compared with placebo, in female patients there was an increase in urinary tract infection 
(UTI) frequency with empagliflozin compared to placebo. No changes in electrolytes were 
observed with empagliflozin. There was a reduction in glomerular filtration rate (GFR) which 
gradually returned toward baseline values over the treatment period in the trials. Furthermore, 
estimated glomerular filtration rate (eGFR) returned to baseline when empagliflozin was 
discontinued.
For further details see the current version of the empagliflozin Investigator’s Brochure [
c01678844].

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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This trial is designed to investigate the efficacy and safety of empagliflozin compared with 
placebo in hypertensive black/African Americans with T2DM.  Since hyperglycemia and 
hypertension are key risk factors for both micro- and macrovascular complications, 
assessment of both glucose and blood pressure lowering effects of empagliflozin in 
hypertensive black/African American patients with T2DM could provide clinically relevant 
information for the use of empagliflozin. 
The treatment duration of this trial (24 weeks) will enable assessment of the clinically 
relevant endpoint of a decrease in HbA1c, a well-accepted measurement of chronic 
glycaemic control, and change in body weight at week 24 whilst the key secondary endpoints 
of decreases in systolic BP (SBP) should be observable by 12 weeks. 
2.2
TRIAL OBJECTIVES
The objective of the current study is to investigate the efficacy and safety of empagliflozin
(10 mg or 25 mg) compared to placebo on glucose control over 24 weeks in hypertensive 
black/African American patients with T2DM. A second objective of the study is to 
investigate the efficacy and safety of empagliflozin (10 mg or 25 mg) compared to placebo 
on weight at 24 weeks and on BP 12 and 24 weeks in the same patient population. The study 
is designed to show superiority of empagliflozin over placebo.
2.3
BENEFIT - RISK ASSESSMENT
Both empagliflozin 10 mg and 25 mg consistently demonstrate sustained clinically
meaningful and statistically significant efficacy in patients with T2DM and eGFR ≥ 45 
mL/min/1.73m2. Since empagliflozin 10 mg provides substantial efficacy with lower 
exposure, 10 mg is recommended as a starting dose. In patients tolerating empagliflozin 10 
mg once daily, the dose can be increased to the maximum once daily dose of 25 mg. In 
general, both doses were well tolerated and there were no meaningful differences between the 
overall safety profiles of both doses. 
In addition, beneficial effects on BP lowering and body weight reduction have been observed 
in a phase III placebo controlled study in 825 patients with T2DM and hypertension 
(1245.48).  In this study, BP was monitored using ABPM devices and empagliflozin 10 and 
25 mg was found to significantly reduce hourly mean SBP and DBP including daytime and 
night time SBP and DBP after 12-weeks of treatment.    Of the patient on 10 mg or 25 mg 
empagliflozin, 4% and 12% respectively had clinically significant reductions in body weight 
relative >5% from baseline [ c01678844].  

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According to the drug assignment planned in this trial, 1/2 (50.0%) of patients participating in 
this trial may derive a direct benefit from being treated with an additional active compound 
and not a placebo. The patients will receive empagliflozin at doses which have demonstrated 
favorable HbA1c, glucose and BP changes multiple phase II and phase III studies [
c01678844]. Patients in the placebo group (50.0%) have a higher probability of not getting an 
additional treatment benefit, i.e. no reduction in FPG or HbA1c values or no reduction in BP 
due to the absence of an additional treatment. However, the placebo arm is required for this 
study and is acceptable up to 31 weeks given that diet and exercise instructions are provided 
to the patients and they are monitored and if necessary rescued properly for significant 
hyperglycemia or high blood pressure.  The patients enter the study in a stable condition with 
regard to glucose control for at least 12 weeks and  BP control for at least 4 weeks before 
randomisation and appropriate criteria for rescue therapy (Section 4.2.1) or patient 
discontinuation (Section 3.3.4) will ensure an adequate treatment in case of any clinical 
concern.
Because of the mechanism of action of empagliflozin, the risk of hypoglycemic episodes is 
low.   The incidence of hypoglycemia was slightly higher for empagliflozin treated patients 
compared with placebo in patients treated on backgrounds of sulfonylurea (SU) or insulin. 
However, the observed difference was not due severe hypoglycemia.  Symptoms attributed to 
hypo- or hyperglycemia, as well as hypo- or hypertension will be closely monitored in the 
trial.
Special attention will be paid to monitor for diabetic ketoacidosis (DKA). A potential risk for 
DKA has been reported by the Food and Drug Administration (FDA) in patients treated with 
SGLT2 inhibitors, including empagliflozin. In a number of reported cases, the presentation of 
the condition was atypical with only moderately increased blood glucose values, below 14 
mmol/L (250 mg/dl).
The risk of DKA must be considered in the event of non-specific symptoms such as nausea, 
vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual 
fatigue or sleepiness. In addition it needs to be taken into account that, due to the insulin 
independent mode of action, there is a possibility that ketoacidosis in patients treated with 
SGLT2 inhibitors is not accompanied by typical hyperglycemia as usually expected for DKA.
Patients who may be at higher risk of DKA while taking SGLT2 inhibitors include patients 
on a very low carbohydrate diet (as the combination may further increase ketone body 
production), severely dehydrated patients, and patients with a history of ketoacidosis or who 
are known to have a low beta-cell function reserve.
As with all drugs, the potential for hypersensitivity and allergic reactions must be taken into 
consideration when empagliflozin is administered. Other risks to the patients are the risks 
inherent to any clinical trial such as unexpected adverse clinical or laboratory events.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients 
safety.

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There are no adequate and well-controlled studies of empagliflozin in pregnant women. 
Empagliflozin is category C for pregnancy. Therefore, women who are of child-bearing 
potential will be included in this study provided that they are using adequate contraceptive 
methods.
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 home blood glucose 
monitoring (HBGM). Patients who are not adequately controlled with regard to
hyperglycemia and hypertension, as evidenced by a confirmed high FPG, HbA1c or BP value 
(refer to Section 4.2.1), will receive rescue therapy to ensure their safety or will be excluded 
from further study participation if no further benefit from the rescue medication  can be 
achieved (refer to Section 3.3.4.1).  Special measurements are performed like follow-up on 
urinary tract infections (urine culture), in order to evaluate if possible side effects observed 
for other SLGT-2 inhibitors are also present for empagliflozin.
The potency, selectivity, and efficacy in patients with T2DM suggest that empagliflozin
would address the significant unmet medical need in hypertensive patients with T2DM. 
Given the good safety profile in the toxicity studies of empagliflozin and the good safety and 
tolerability seen in over 12000 patients with T2DM, the careful monitoring during the study 
visits and the blood glucose monitoring performed by the patients at home, the sponsor feels 
the risks to the participating patients are minimized and justified when compared with the 
potential benefits that a successful clinical development of empagliflozin could provide for 
hypertensive patients with T2DM.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This randomised, double-blind, multi-national, and 2 parallel groups study compares 10 mg 
or 25 mg doses of empagliflozin to placebo in hypertensive black/African American patients 
with T2DM. 
In total, approximately 154 hypertensive black/African American patients with T2DM who 
meet the entry criteria are planned for inclusion in this trial. 
Patients are considered included in the study once they have signed the informed consent. All 
patients suitable after screening undergo a 2-week placebo run-in period before 
randomisation. Patients who successfully complete this period and who still meet the 
inclusion/exclusion criteria will be randomised to the 24-week randomised period of the 
study in which they will receive 10 mg empagliflozin or matching placebo (Figure 3.1:1).  
At Week 4 /Visit 4, patients will be dose escalated to 25 mg empagliflozin or matching 
placebo. 
Current antihypertensive and antidiabetic therapy should be administered during the entire 
trial duration (including placebo run-in and follow-up period) in an unchanged dosage.
The patient’s participation is concluded when they have undergone the last planned visit 
(Visit 8).
For information regarding Adverse event and serious adverse event reporting, please refer to 
Section 5.2.2.2.
The end of the trial is defined as “last patient out”, i.e. last visit completed by last patient.
The overall trial design is displayed in Figure 3.1:1 below.
Figure 3.1:1: 1245.29 Trial design

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3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
BI will appoint a Trial Clinical Monitor (TCM), responsible for coordinating the activities 
required in order to manage the trial in accordance with applicable regulations and internal 
Standard Operating Procedures (SOPs), directing the clinical trial team in the preparation, 
conduct, and reporting of the trial, order the materials as needed for the trial, ensures 
appropriate training and information of local clinical monitors (CML), Clinical Research 
Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical evaluation will be done by BI according to BI SOPs. For 
these activities, a Trial Data Manager and a Trial Statistician will be appointed.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons will be given in the Trial Master 
File (TMF) document.
The organisation of the trial in the participating countries will be done by the respective local 
BI operative unit (OPU) or a by a Contract Research organization (CRO) with which the 
responsibilities and tasks have been agreed and a written contract has been filed before 
initiation of the clinical trial. In each local OPU participating in this study, a CML will be 
appointed responsible for coordinating the activities required in order to manage the trial in 
accordance with applicable regulations and internal SOPs in the countries covered by the 
respective BI OPU.
A Co-ordinating Investigator will be nominated to coordinate investigators at different sites 
participating in this multicenter trial. Tasks and responsibilities for the coordinating 
Investigator will be defined in a contract filed before initiation of the trial.
Documents on participating (Principal) investigators and other important participants, 
especially their curricula vitae, will be filed in the TMF document. 
Details on handling of the trial supplies including responsible institutions are given in Section 
4 of this protocol.
The Investigator Site File (ISF) document will be kept in print-out version at the sites as far 
as required by local regulation and BI SOPs. A copy of the ISF documents will be kept as an 
electronic TMF document according to BI SOPs.
3.1.1.1
Hepatic External Adjudication 
Certain hepatic events will be adjudicated / assessed by external independent experts. The 
events which will be reviewed will be defined in a charter for hepatic events.  Events may be 
defined as abnormal laboratory values and/or relevant adverse events or both.  For example, 
assessments will be made for hepatic injury events, including liver enzyme elevations.  

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For qualifying events, relevant source documents generated from any medical evaluations of 
these events will be requested including lab values, histological analysis, results of 
ultrasound, cat scan (CT), magnetic resonance imaging (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 on project level.   
3.1.1.2
Clinical Event Committee for Diabetic ketoacidosis (DKA)
An independent external committee (CEC) will be established to adjudicate centrally and in a 
blinded fashion events suspected of DKA (for further details see Section 5.2.2.1). 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.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
Empagliflozin used at both 10 mg and 25 mg dose has been shown to reduce seated SBP in 
patients with T2DM (1245.20) and to reduced hourly mean SBP and DBP (ABPM) including 
daytime and night time SBP and DBP in patients with T2DM and hypertension (1245.48) [
c01678844].  Subgroup analysis of the data from the 1245.48 study show clinically 
meaningful changes in HbA1c after 12 weeks of treatment with both doses of empagliflozin 
in the black/African American subgroup; the low percentage of black/African Americans (5% 
of all patients) in that study did not allow for reliable results for SBP and DBP (ABPM).  For 
this study, patients will enter on the basis of insufficient BP and glycemic control despite 
current therapy. 
Metformin therapy represents the drug of choice unless contraindicated in patients newly 
diagnosed with type 2 diabetes mellitus with an HbA1c > 7.0% and should be titrated to a 
maximum tolerated dose which is generally greater than 1500 mg/day. Therefore, patients 
with current metformin treatment represent an important proportion of patient population 
with type 2 diabetes mellitus.
Sulfonylureas (SU) and Dipeptidyl peptidase-4 (DPP-4) inhibitors can be used as 
monotherapy but are frequently added to metformin when patients are not at goal with 
metformin. Sulfonylureas (eg. Glimiperide, glyburide, glipizide) and DPP-4 inhibitors (eg. 
sitagliptin, linagliptin, saxagliptin, alogliptin) are important alternative monotherapies when 
metformin is not used and more importantly when used in combination with metformin.
Therefore patients with current sulfonylurea or DPP-4 inhibitor treatment represent an 
important proportion of the patient population with type 2 diabetes.

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Phase III studies have shown that treatment with empagliflozin 10 mg or 25 mg for up to 24-
weeks results in a reduction of HbA1c up to 0.85%, body weight up to 2.2kg and SBP up to 
4.8 mmHg compared to placebo. This was observed with empagliflozin monotherapy, add on 
to metformin, to metformin plus sulfonylurea, to pioglitazone with or without metformin, and 
to basal insulin with metformin and/or sulfonylurea [c01678844].  Since the observed effect 
on BP is greater with 25 mg compared with 10 mg empagliflozin, the study design will 
include a dose escalation from a starting dose of 10mg to 25 mg empagliflozin 4 weeks after 
the start of treatment.   The placebo-controlled design is considered ethically acceptable on 
the basis of appropriate criteria for patient discontinuation, relatively short study duration and 
criteria for rescue therapy as defined in the relevant guidelines (e.g. FDA Guidance for 
Industry for developing drugs in diabetes) (refer to Section 2.3).
This study will also provide a better understanding of the effect of empagliflozin on the 
circadian patterns of 24-hour BP control in hypertensive black/African American patients 
with T2DM. ABPM is considered a gold standard in BP measurement and a better predictor 
of cardiovascular risk than clinic BP (P13-12437). The use of ABPM has been integrated in 
major hypertension guidelines such as JNC8 (R14-0310) and European Society of 
Hypertension / European Society of Hypertension (P13-12437) and the American Heart 
Association (P08-03352). While slight differences exist among these guidelines there is 
agreement that ABPM provides a more accurate measurement of BP and correlates with 
hypertension related organ damage more closely than office BP, provides a more accurate 
evaluation of “white coat” as well as masked hypertension and a more accurate assessment of 
patients with drug resistance and hypotensive symptoms (P08-03352, P13-12437).  
The randomised period is planned for 24 weeks to reflect both changes in HbA1c (primary 
endpoint) and ABPM and body weight (key secondary endpoints). The two-week follow-up 
period is considered to be sufficient, as previous studies with empagliflozin have shown that 
the pharmacodynamic effect of empagliflozin only extends to about 3 days after the last dose.
The rationale for dose and dose-interval selection is described in Section 4.1.3.
3.3
SELECTION OF TRIAL POPULATION
Approximately 700 patients will be screened for the trial in US. About 85 trial centres will be 
participating to ensure that approximately 154 patients are randomised to trial treatment (77 
to each treatment group).  The intention is that at least 2 patients should be randomised at 
each trial centre.  Investigators who fail to screen at least one patient in the first 6 weeks of 
the trial may be re-evaluated for further participation.  If enrolment is delayed, additional 
centres may be recruited.
Permission to randomise more than 8 patients per site must be obtained from the TCM at 
Boehringer Ingelheim.  This will only be allowed after a careful review of the enrolment 
status.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
centres when such a number of patients has been screened and it is anticipated that a 

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sufficient number of patients will be randomised to trial treatment. Investigators will be 
notified when the appropriate number of patients has been screened and screening 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.
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 included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in black/African American patients (defined as a person having 
origins in any of the black racial groups of Africa as self-identified by the patient) with 
T2DM and hypertension that have insufficient glycaemic and BP control despite diet and 
exercise. 
3.3.2
Inclusion criteria
1. Diagnosis of T2DM prior to informed consent.  
Note: Documentation should be available before randomization at latest.  Confirmation 
can be in the form of formal documents or by verbal communication of the date of 
diagnosis from a patient or from their primary care physician (if records are not 
available).  It is up to the medical judgment of the Investigator to deem if the information 
is accurate.
2. Male and female black/African American patients on diet and exercise regimen                     
who are EITHER
drug-naïve (defined as absence of any oral antidiabetic therapy, glucagon like peptide-
1 (GLP-1) analog or insulin for 12 weeks, 16 weeks for pioglitazone prior to 
randomisation)
OR
pre-treated with stable dose of 

Metformin only, or

Sulfonylurea only, or

DPP-4 inhibitor only, or

metformin plus sulfonylurea, or 

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
metformin plus DPP-4 inhibitor.  
Treatment has to be unchanged for a minimum of 12 weeks prior to randomization.
Dose for metformin: maximum tolerated dose 
The maximum daily dose of SU or DPP-4 inhibitor should not exceed that stated in 
the local label.
3. HbA1c of 7.0% (53 mmol/mol) and ≤11.0% (97 mmol/mol) at Visit 1 (screening).
4. Mean seated SBP 140-180 mmHg at Visit 1 (screening).
5. Successful completion of baseline ABPM testing with a mean SBP 135-175 mmHg prior 
to randomisation.  
6. Treatment with stable doses of at least one but not more than 4 antihypertensive 
medication 4 weeks prior to randomisation.
7. Age 18 years at Visit 1 (screening) 
8. Signed and dated written informed consent by date of Visit 1 in accordance with Good 
Clinical Practice (GCP) and local legislation
3.3.3
Exclusion criteria
1. Uncontrolled hyperglycemia with a glucose level >270 mg/dl (>15.0 mmol/L) after an 
overnight fast during placebo run-in (includes Visit 2.1) and confirmed by a second 
measurement (not on the same day).
2. Exposure to any other antidiabetic medication within 12 weeks prior to randomisation 
other than metformin, sulfonylurea, DPP-4 inhibitor, metformin plus sulfonylurea or 
metformin plus DPP-4 inhibitor.
3. Current hypertension treatment with oral Minoxidil (topical minoxidil for hair growth is 
allowed).
4. Mean seated SBP ≥181 mmHg during placebo run-in visit and confirmed by a second 
measurement (not on the same day) preferably within one day.
5. Upper arm circumference that exceeds the upper circumference level of the cuff size of 
either ABPM and/or BP measurement device used in the study.
6. Night shift workers who routinely sleep during the daytime and/or whose work hours 
include midnight.  
7. Diagnosis of autoimmune diabetes/Type I diabetes mellitus, monogenic (neonatal or 
maturity onset diabetes of the young (MODY)) diabetes or Type I diabetes in adults/ 
latent autoimmune diabetes of adults (LADA) per investigator or patient medical history 
at the time of Visit 1 (screening).
8. Known or suspected secondary hypertension (e.g. renal artery stenosis, 
phaeochromocytoma, Cushing’s disease).

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9. History or evidence of hypertensive retinopathy (Keith-Wagener grade III or IV) and/or
hypertensive encephalopathy.
10. Clinically significant valvular heart disease or severe aortic stenosis in the opinion of the 
investigator.
11. Acute coronary syndrome (non- ST wave elevated myocardial infarction (STEMI), 
STEMI and unstable angina pectoris), stroke or transient ischemic attack within 3 months 
prior to informed consent.
12. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), 
or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during 
screening and/or run-in phase.
13. Impaired renal function, defined as eGFR< 45 ml/min/1.73m2 (moderate renal 
impairment, chronic kidney disease epidemiology collaboration CKD-EPI formula) as 
determined during screening and/or run-in phase.
14. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce 
chronic malabsorption.
15. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer 
within the last 5 years.
16. Blood dyscrasias or any disorders causing hemolysis or unstable Red Blood Cells (e.g. 
malaria, babesiosis, haemolytic anaemia, thalassemia, sickle cell anaemia (sickle cell trait 
is allowed)).
17. Medical history and signs and symptoms of diabetic autonomic neuropathy.  
18. Treatment with anti-obesity drugs 3 months prior to randomisation (i.e. surgery, 
aggressive diet regimen, etc.) leading to unstable body weight.
19. Current treatment with systemic steroids at time of informed consent or change in dosage 
of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled 
endocrine disorder except T2DM in the opinion of the investigator.
20. Pre-menopausal women (last menstruation 1 year prior to informed consent) who:
- are nursing or pregnant or
- are of child-bearing potential and are not practicing an acceptable method of birth 
control, or do not plan to continue using this method throughout the study and do not 
agree to submit to periodic pregnancy testing during participation in the trial. Acceptable 
methods of birth control include tubal ligation, transdermal patch, intra uterine 
devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, complete 
sexual abstinence (if acceptable by local authorities), double barrier method and 
vasectomised partner.
21. Alcohol, drug or confectionary liquorice abuse within the 3 months prior to informed 
consent that would interfere with trial participation or any ongoing condition leading to a 
decreased compliance to study procedures or study drug intake in the investigator’s 
opinion.

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22. Intake of an investigational drug in another trial within 30 days prior to intake of study 
medication in this trial; or participating in another trial (involving an investigational drug
and/or follow-up) after discontinuing medication in that trial.
23. Any other clinical condition that would jeopardize patient’s safety while participating in 
this clinical trial in the opinion of the investigator.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient is to be withdrawn from the trial if:

The patient withdraws consent, without the need to justify the decision.

If a patient becomes pregnant during the trial.  The patient will be followed up until birth 
or otherwise termination of the pregnancy. 
Treatment with study drugs should be discontinued if:

The patient needs to take concomitant drugs that interfere with the investigational product 
or other study medications(s).

The patient is no longer able to participate for other medical reasons (e.g. surgery, AEs, 
or other diseases).

Introduction of rescue therapy due to hyperglycemia, high HbA1c or hypertension as 
described in Section 4.2.1 does not lead to sufficient treatment efficacy (rescue criteria 
still met). In this case, the reason for study drug discontinuation will be classified as “lack 
of efficacy”. 

Occurrence of hypoglycemia (e.g. repeated hypoglycaemic episodes) or DKA that may
put the patient at risk with continued participation.  Patients should be assessed for 
ketoacidosis immediately if symptoms occur, regardless of blood glucose level. 
Discontinuation or temporary interruption of study medication should be considered, until
the situation is clarified.
Patients who discontinue treatment prematurely will be followed up until the end of the study 
(for further details please see Sections 6.2.2 and 6.2.3).
A patient can be discontinued after discussion between sponsor and investigator if eligibility 
criteria are being violated, or if the patient fails to comply with the protocol (e.g. non-
attendance at study assessments).
Patients who drop out during the screening phase prior to randomisation (Visit 3) will be 
considered screening failures. They have to be recorded as screening failure in eCRFs and no 
further follow-up is required.  
Patients who discontinue from treatment or withdraw from the study after randomisation 
(Visit 3) will be considered as “early discontinuations” and the reason for premature 
discontinuation must be recorded in the eCRFs. The data will be included in the trial database 

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and will be reported. If determined by investigator as necessary for patient safety, new 
antidiabetic medication regimen can be started immediately after discontinuation and must be 
recorded in eCRFs.  
For the analysis of this trial it is absolutely crucial that all planned assessments are done as 
planned, even if patients discontinue trial treatment.  All patients who discontinue from 
treatment after randomisation (Visit 3 and beyond) and who do not withdraw consent will be 
followed up for the intended regular treatment period. All assessments related to the primary 
and secondary endpoints must be performed as if the patient would have remained on 
treatment.  Details of procedures to be followed for patients prematurely terminating the trial
treatment can be found in Section 6.2.3). 
If a patient withdraws consent, participation in the study will end, the study medication will 
be stopped and the study staff will try to arrange tests for end of treatment procedures and a 
follow-up visit (Visit 8 procedures) with the patient for the patient’s safety  (For further 
details please see Section 6.2.3). All used medication kit boxes and remaining study 
medication should be returned. Patients who withdraw consent will not be contacted any 
more about the study.
Patients who withdraw or discontinue from the trial after randomisation will not be replaced.
3.3.4.2
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site,
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial and/or invalidate the earlier positive benefit-risk-assessment,
3. Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Re-screening
Re-screening is permitted for the following categories of screen failed patients only:

Patients who were screen failed due to exclusionary background anti-diabetic 
therapies (sulfonylurea, DPP4-inhibitor, metformin + sulfonylurea, metformin 
+DPP4-inhibitor) according to prior versions of the protocol.

Patients who were screen failed due to exclusionary HbA1c 7.0% (53 mmol/mol) -
7.4% (57 mmol/mol) at Visit 1 according to prior versions of the protocol.  Patients 

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who were screen failed due to exclusionary HbA1c below 7.0% or above 11.0% 
cannot be re-screened.

Patients who were screen failed due to exclusionary mean seated DBP (Visit 1) 
according to prior versions of the protocol.  However, mean seated SBP (Visit 1) must 
have been 140-180 mmHg at the previous screening.

Patients who were screen failed due to taking 4 antihypertensive medications (4 
weeks prior to randomization) according to prior versions of the protocol.

Patients who were screen failed due to out-of-window visits prior to ABPM testing
(Visit 2.2).  If ABPM testing has commenced, no re-screening is permitted.
A patient who was screen failed due to any of the above screen failure reasons is permitted to 
be re-screened once only. A new patient number should be assigned to the re-screened patient
who should be re-consented. Rationale for re-screening must be document in source 
documents.
Re-screening is not permitted for patients who were screen failed due to other reasons. 
3.3.6
Repeat test
HbA1c test (Visit 1) may be repeated once if the test result from the central lab is 
exclusionary but the most recent test result from a local lab (taken before Visit 1 but not older 
than one month), if any, falls within the acceptable range.
ABPM test (Visit 2.2) may be repeated once if the first attempt is unsuccessful. Refer to 
Footnote B and Footnote I of the Flow Chart, as well as Section 5.1.2 and Section 6.2.1 for 
additional details on repeat ABPM.
Rationale for all repeat tests must be documented in source documents.

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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The study medication will be provided by Boehringer Ingelheim.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product one are below.
Substance:
empagliflozin
Pharmaceutical form:
tablet
Source:
Boehringer Ingelheim 
Unit Strength:
10 mg
Route of administration:
p.o., once daily
The characteristics of the test product two are below.
Substance:
empagliflozin
Pharmaceutical form:
tablet
Source:
Boehringer Ingelheim 
Unit Strength:
25 mg
Route of administration:
p.o., once daily
The characteristics of the reference product are below.
Substance:
placebo matching empagliflozin 10 mg
Pharmaceutical form:
tablet
Source:
Boehringer Ingelheim 
Unit Strength:
-
Route of administration:
p.o., once daily

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The characteristics of the reference product are below.
Substance:
placebo matching empagliflozin 25 mg
Pharmaceutical form:
tablet
Source:
Boehringer Ingelheim 
Unit Strength:
-
Route of administration:
p.o., once daily
4.1.2
Method of assigning patients to treatment groups
When a patient is qualified 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 an interactive response technologies (IRT) system.  To 
facilitate the use of the IRT system, the Investigator will receive an IRT system manual 
including all necessary instructions for using the IRT system.  A copy of the manual will be 
available in the ISF.      
Patients will be randomly assigned to empagliflozin 10 mg or placebo in a balanced 1:1 ratio. 
For further details (e.g. stratification) please refer to Section 7.5.    
Patient assignment to the treatment groups will be determined by a computer generated 
random sequence.  Access to the randomisation code will be controlled and documented –
for further details please refer to Sections 4.1.5.1 and 4.1.5.2.  
The assigned medication number will be entered in the eCRF, and the corresponding 
medication kit should be given to the patient. Using this procedure, relevant parties will be 
blinded to the treatment group assignment.  
Kit numbers must be checked carefully before dispensing to patients. Dispensing the
proper medication kit to a patient is important to avoid unintentional switching of
treatments during a patient’s trial participation. If an error in dispensing kits is
discovered, the site must contact the affected patient(s) immediately to have them come
in for a new kit(s). The drug administration pages in remote data capture (RDC) should 
reflect the actual kits taken by the patients.
4.1.3
Selection of doses in the trial
Empagliflozin will be administered in a starting dose of 10 mg once daily.  At Visit 4, 
patients will be dose escalated to a dose of 25 mg once daily.  These doses were selected 
based on the results from previous dose-finding studies (please refer to Section 1.2 and to the 
current version of the IB, c01678844), are currently used in the phase III program and one or 
both doses are expected to be the approved dose(s).

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4.1.4
Drug assignment and administration of doses for each patient
Medication will be dispensed in a double-blind and single-dummy manner.
All patients will be assigned a placebo run-in kit at the beginning of the placebo run-in period 
(Visit 2.1), and dispensing will occur just once.  Dispensing of kits for the double-blind 
treatment period will begin at Visit 3. Dispensing will occur on 3 occasions over a period of 
24 weeks.  For further details regarding packaging (e.g. number of tablets per kit box) please 
refer to Section 4.1.6.  
Patients will be dose escalated at Visit 4/Week 4 to 25 mg empagliflozin.  If it is in the 
investigator’s opinion that the patient cannot tolerate either 10 mg or 25 mg doses, the 
investigator should refer to Section 3.3.4.1 for withdrawal of patient from the study.
Table 4.1.4: 1
empagliflozin, placebo, oral administration per dose group and day 
Dose group
Treatment
total units per dose
timing
Placebo run-in period: 
All patients
placebo
1 tablet
once daily, morning
Treatment period (e.g. double-blind, single-dummy):
10 mg empagliflozin
active drug
1 tablet
once daily, morning
Placebo-matched 10 
mg empagliflozin
matching 
placebo
1 tablet
once daily, morning
Treatment period-Dose escalation (e.g. double-blind, single-dummy):
25 mg empagliflozin
active drug
1 tablet
once daily, morning
Placebo-matched 25 
mg empagliflozin
matching 
placebo
1 tablet
once daily, morning
From the start of the placebo run-in period (Visit 2.1), patients should be instructed to take 
their trial medication once daily with water. To ensure a dose interval of about 24 hours, the 
medication should be taken at approximately 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.  On days before the next visit, the dose should be taken 22-26 hours before the 
planned dose at the visit. No double doses should be taken, and dose reductions are not 
permitted.  Empagliflozin can be taken with or without food.

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Patients should be instructed not to take their trial medication on the morning of study visits 
as they will be dosed whilst in the clinic.  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 (07:00 AM to 11:00 AM) 
for each visit.  The actual date and time of administration of the medication at the trial visit 
will be recorded in the eCRF.  Study medication administration should follow physical and 
laboratory assessments.  
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Placebo for the run-in period from screening to randomization will be open label.
After randomisation at Visit 3, patients, investigators and everyone involved in analysing or 
with an interest in this double-blind study will remain blinded with regard to the randomised 
treatment assignments until after database lock.  However, due to the requirements to report 
Serious Unexpected Suspected Adverse Reactions (SUSARs), it may be necessary for a 
representative from BI’s pharmacovigilance group to access the randomisation code for 
individual patients during study conduct.  In such cases, access to the code will only be 
permitted by authorised pharmacovigilance representatives.  Access to the code will be via an 
IRT system.
The randomisation code will be kept secret by Clinical Trial Support at BI up to database 
lock.  Please refer to Section 4.1.5.2 for the rules regarding breaking the code for an 
individual or for all patients in emergency situations.     
4.1.5.2
Procedures for emergency unblinding
In this blinded trial an emergency unblinding will be available to the Investigator via an IRT 
system. Treatment unblinding may only be allowed in emergency situations when the identity 
of the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or if required to assure safety of trial participants.  If patient treatment is unblinded, 
the Sponsor must be informed immediately. The reason for treatment unblinding, together 
with the date, must be documented on the appropriate eCRF page. 
4.1.6
Packaging, labelling, and re-supply
Study medication (empagliflozin and placebo) will be provided by the Department of 
Pharmaceutical Development of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, 
Germany. 
The study medication will consist of boxes labelled with the trial identification and 
medication kit number.  Each box will contain an appropriate number of empagliflozin tablets 
or matching empagliflozin placebo with some reserve (see below), for dosing until the next 
scheduled visit. 

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Within each kit box, tablets will be packaged in blisters which will contain one tablet in 7 
rows for a 7-day supply (total of seven tablets per blister), according to Table 4.1.4: 1. For 
each dose patients must take one tablet from one row. Blisters will be packaged in medication 
kit boxes labelled with the trial identification and medication kit number. 
The placebo run-in kit, assigned to all patients successfully completing Visit 2.1, will contain 
21 tablets in 3 blisters (i.e. sufficient supply for 2 weeks, with 1-week in reserve). 
Double-blind treatment period kit, dispensed at Visit 3, will contain 35 tablets in 5 blisters 
(i.e. sufficient supply for 4 weeks, with 1-week in reserve).  At Visit 3, one kit will be 
dispensed per patient.  The total number of tablets dispensed to a patient during the treatment 
period will therefore be 35.
Each double-blind treatment period dose escalation kit, dispensed starting at Visits 4 and 5.2, 
will contain 35 tablets in 5 blisters (i.e. sufficient supply for 4 weeks, with 1-week in 
reserve).  Two kits will be dispensed at Visit 4 per patient and three kits will be dispensed at 
Visit 5.2 per patient.  The total number of tablets dispensed to a patient during the treatment 
period will therefore be 175.
Supply and re-supply will be managed by an IRT system.  
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
The trial medication (empagliflozin and placebo) must be kept in its tightly closed original 
packaging under the recommended storage conditions indicated on the label.  The 
minimum/maximum storage temperature must be measured and documented at least weekly 
by the Investigator / pharmacist / investigational drug storage manager in accordance with BI 
(or designated CRO) SOPs.  If storage conditions are found to be outside the specified range, 
site personnel should immediately contact the CML via the list of contacts in the ISF.
4.1.8
Drug accountability
Drug supplies, which will be provided by the sponsor and/or a CRO appointed by the 
sponsor, must be kept in a secure, limited access storage area under the storage conditions 
defined by the sponsor. Where necessary, a temperature log must be maintained to make 
certain that the drug supplies are stored at the correct temperature.
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

approval of the study protocol by the Institutional Review Board (IRB) / ethics 
committee,

availability of a signed and dated clinical trial contract between the sponsor and the 
Centre,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal investigator,

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
availability of a signed and dated clinical trial protocol (CTP) or immediately 
imminent signing of the CTP(in exceptional cases, medication could already be sent 
to the site, before its activation via an IRT system)

if applicable, availability of the proof of a medical licence for the principal 
investigator, 

for USA, availability of the Form 1572.
The investigator / pharmacist / investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the sponsor or alternative disposition of unused product(s). 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational product(s) received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator / pharmacist / investigational drug storage
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the investigator’s possession.
There are no non-investigational medicinal products (NIMPs) defined for this trial.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
Details of all concomitant therapy during the clinical trial will be recorded on the appropriate 
pages of the eCRFs.  Patients who are treated with contraindicated medication should not be 
enrolled into the study.
4.2.1
Rescue medication, emergency procedures, and additional treatments
Throughout the duration of the trial, patients should continue to take their current therapy, the 
dose of which should remain unchanged if at all possible (for further details see below).  This 
medication will not be provided as part of the clinical trial supplies, unless required by local 
laws and regulations. 
Rescue medication, for the treatment of hyperglycemia, can be initiated during the double-
blind treatment period of the trial (i.e. from Visits 3-7.2) and during follow up period but only 
if the criteria below are met:

Week 1 – 12 (i.e. up to and including the result from Visit 5.2): 
The patient has a glucose level > 270 mg/dl (> 15.0 mmol/l) after an 
overnight fast 

Week >12 – 26 (i.e. from the day after Visit 5.2 onwards): 
The patient has a glucose level > 200 mg/dl (> 11.1 mmol/l) after an 
overnight fast

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The above results should be confirmed, meaning that there is a minimum of two 
measurements, at least one of which should be performed after an overnight fast at the 
investigational site, and on a different day to the initial (overnight fast) measurement.  
A FPG and an 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.
Special attention must be paid to monitor for instances of DKA. All patients must be made 
aware of this potential risk and need to be instructed to contact the Investigator or other 
healthcare professional in case of symptoms of DKA. For further details see Section 2.3.
In case of a suspected DKA the Investigator should ensure that appropriate tests are 
performed at the earliest opportunity according to local guidelines, such as a blood gas test 
(i.e. pH, bicarbonate; the results will be collected on the relevant page of the eCRF) and that 
the patient is appropriately treated (i.e. hospitalized or referred to emergency treatment) 
according to local treatment guidelines.
Rescue medication, for the treatment of hypertension, can be initiated during the double-blind 
treatment period of the trial (i.e. from Visits 3-7.2) and during follow up period but only if the 
criteria below are met:

Week 1 – 4 (i.e. up to and including the result from Visit 4.0): 
The patient has a mean seated SBP level ≥180 mm Hg and/or mean seated
DBP level ≥110 mm Hg at the clinic visit

Week 4 – 26 (i.e. from the day after Visit 4.0 onwards): 
The patient has a mean seated SBP level ≥160 mm Hg and/or mean seated
DBP level ≥100 mm Hg at the clinic visit
The above results should be confirmed, meaning that there is a minimum of two seated blood 
pressure measurements (second measurement at the investigational site on a different day to 
the initial measurement).  
If the above criteria are met, the initiation of rescue medication is at the Investigator’s 
discretion, based on the patient’s current clinical condition (e.g. ongoing illness etc.). The 
choice of rescue medication will depend upon the current medication.  Adjustment of the 
current therapy or addition of another antidiabetic and/or antihypertensive medication would 
be appropriate. Rescue medication and its dosage will be left to the discretion of the 
Investigator and the administration of rescue medication is to be conducted according to GCP
with the exception of the following:

Due to their known effect on blood pressure, thiazolidinediones (eg pioglitazone) and 
GLP-1 analogs must not be used as rescue medication for hyperglycemia. 

Any SGLT-2 inhibitor that is or may become available during the conduct of this trial 
must not be used as rescue medication. 

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Regardless of the choice made, rescue medication should be taken in accordance with the 
local prescribing information of that respective medication, taking into account potential 
contraindications. Rescue medication can be used from when it is initiated until the end of the 
trial.
In the case of hypoglycemia and/or hypotension that may put the patient at risk (e.g. repeated 
symptomatic hypoglycemia or severe hypoglycemia, repeated syncope), appropriate 
adjustment of oral antidiabetic and/or antihypertensive therapy such as a dose reduction / 
discontinuation of ongoing rescue medication or existing therapy should be initiated. 
Reduction or discontinuation of ongoing rescue medication should be considered before a 
reduction in the dose of existing therapy.   
If, in the Investigator’s clinical opinion, no further effect from the rescue medication is 
anticipated, and the patient’s hyper- or hypoglycemia, and/or hyper- or hypotension cannot be 
controlled, the patient should discontinue the trial medication as specified in Section 3.3.4.  
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, unless required 
by local laws and regulations.
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.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In any situation other than rescue conditions, the use of other antidiabetic and 
antihypertensive agents will be prohibited during the course of the study except for existing 
current therapy and, if applicable, the ongoing rescue medication.

Pioglitazone and GLP-1 analogs must not be used as rescue medication for 
hyperglycemia. 

Any SGLT-2 inhibitor that is or may become available during the conduct of this trial 
must not be used as rescue medication.
Short-term use of additional prandial/intravenous insulin will be permitted (only in the event 
of an emergency situation and/or hospitalisation) based on clinical judgement of the 
Investigator or treating physician. Prolongation of additional prandial/intravenous insulin 
treatment over more than 2 weeks vs. treatment discontinuation should be discussed on a 

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case-by-case basis between the Investigator and the CML/TCM.  Please also refer to Section 
3.3.3 regarding the permitted use of antidiabetic agents pre-trial.
Additionally, treatment with anti-obesity drugs or systemic steroids will be prohibited due to 
their influence on glucose metabolism.  However, one-off or short-term use (i.e. ≤1 week 
duration) of systemic steroids will be permitted as well as therapy with non-systemic steroids 
such as inhaled or local steroids.  Furthermore, for patients taking thyroid hormones, any 
change in the dose should be avoided.  If dose changes do occur, then they should be 
recorded in the source documents and in the eCRF.  
For patients receiving metformin, in case a vascular administration of iodine containing 
contrast agent is required, metformin should be temporarily discontinued at the time of or 
before the contrast agent is given and resumed not earlier than 48 hours after administration.
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 trained staff member. The counselling will be based on local diet 
recommendations and should include a food log/intake booklet. The patients will be 
reminded to follow the agreed diet and exercise plan at every visit. A food intake booklet will 
be provided as a tool but site specific tools could also be used. Record of the actual food 
intake over a time of three consecutive days before the clinic visit is requested at regular 
intervals as indicated in the Flow chart. The food intake booklet will remain with the patient 
and no data will be transferred to the eCRF. The respective procedure for illiterate patients (if 
included) is described in Appendix 10.1.
Women of child-bearing potential must continue to practice an acceptable method of birth
control (in accordance with the trial exclusion criteria Section 3.3.3) throughout the duration 
of the study.  
Patients should also not take an investigational drug in another trial within 30 days prior to 
intake of study medication in this trial. 
There are no other restrictions on diet and lifestyle.
4.3
TREATMENT COMPLIANCE
Patients will be asked to bring all trial medication containers (with or without any remaining 
tablets) with them to each trial visit.  The tablets will be counted by the Investigator or study 
nurse and compliance will be calculated according to the formula:
%
100
period
same
in the
been taken
have
should
 which 
 tablets
of
Number 
count
t 
last table
since
aken 
actually t
 tablets
of
Number 
(%)
Compliance


Compliance during the placebo run-in period should be between 80% and 120%.  If 
compliance is outside this range, the patient should be carefully interviewed and, if necessary, 

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re-informed about the purpose and the conduct of the trial.  Unreliable patients should not be 
randomised at the discretion of the Investigator.
Compliance during the double-blind treatment period should also be between 80% and 120%. 
Patients who are not compliant according to this definition should be carefully interviewed 
and re-informed about the purpose and the conduct of the trial. 
A comment should be registered in the eCRF (Study medication compliance page) for any 
patient that has taken <80% study medication or who has not taken study medication since 
the last visit. Any time a patient is off study medication for > 7 consecutive days this should 
be also registered in the eCRF on the Study Med Stop page. Starting and stopping study 
medication is allowed in this trial. 
Patients who forget to return trial medication and empty containers should be reminded to 
bring them to their next visit. Compliance for patients who forget to return trial medication in 
two consecutive visits should be calculated per the discretion of the Investigator and this 
should be reflected on the clinical history.

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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - PHARMACODYNAMICS
5.1.1
Endpoints of efficacy
The primary endpoint in this study is change from baseline in HbA1c at 24 weeks of 
treatment. Throughout the study protocol, the term ‘’baseline’’ refers to the last observation 
prior to randomisation of the patient.
Key secondary endpoints:
Change from baseline in mean 24-hour ambulatory SBP at 12 weeks of treatment.
Change from baseline in mean trough ambulatory SBP at 12 weeks of treatment.
Change from baseline in body weight at 24 weeks of treatment
Change from baseline in trough seated SBP at 12 weeks of treatment.
Other secondary endpoints are:
Change from baseline in mean 24-hour ambulatory DBP at 12 weeks of treatment. 
Change from baseline in trough seated SBP at 24 weeks of treatment
Change from baseline in mean 24-hour ambulatory SBP at 24 weeks of treatment.
Change from baseline in mean 24-hour ambulatory DBP at 24 weeks of treatment.
Change from baseline in trough seated DBP at 12 weeks of treatment
Change from baseline in trough seated DBP at 24 weeks of treatment
 
 
 
 

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
 
 
 
 
 

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5.1.2
Assessment of efficacy
HbA1c
Blood samples for the determination of HbA1c at the central laboratory will be taken.
At the screening Visit 1, the blood sample can be taken at any time during the visit. At all 
other Visits, the blood samples should be drawn before breakfast and before trial drug 
administration. The samples will be analysed at a central laboratory or its affiliates having a 
National Glycohaemoglobin Standardisation Program Level I certificate. Further details 
about sample handling, shipment, and assay procedures can be found in the ISF (Lab 
manual).
Fasting plasma glucose
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).
Ambulatory blood pressure monitoring (ABPM)

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ABPM will be performed in parallel using the ABPM device.  A blood pressure monitoring 
device will be provided for ABPM recordings.
On the mornings when the ABPM device will be applied (Visits 2.2, 5.1 and 7.1), patients 
should arrive at approximately half an hour prior to medication intake to allow additional 
time for ABPM procedures, so that dosing of medication occurs as close as possible to patient 
daily dosing time. It is important that the dosing time for the baseline ABPM (Visit 2.2) is the 
same as the dosing time for the 12 and 24 week ABPM (Visits 5.1 and 7.1). In addition, for 
collection of Visit 2.2, 5.1 and 7.1 ABPM, the daytime and night time activities of the patient 
during the 24 hours should be similar. For example, if the baseline ABPM falls on a normal 
workday, then the final ABPM measurement should be scheduled for a normal workday, not 
a weekend or vacation day.  Measurements of BP using the monitor should be taken from the 
same arm that is used to measure seated BP.
The ABPM device will be programmed to measure blood pressure every 20 minutes 
throughout the day and night to measure BP. Patients should be advised not to move the arm 
during each blood pressure measurement and will also be given instructions concerning 
interruption of measurement in case of malfunction of the device or repositioning of the cuff 
if it slips.
At each ABPM visit (Visits 2.2, 5.1 and 7.1), patients are to come to the clinic fasting and the 
following procedure will be performed.   The ABPM device will be attached to the patient 
and test readings will be taken to check if the device is working properly prior to medication 
intake. The first test reading is the Beginning of Test reading. Once it has been confirmed 
that the monitor is properly functioning, study medication will be administered.  Record the 
time the medication was administered and the time the monitor was prompted to take the 
Beginning of Test reading.  The next day when the patient returns to the clinic, the monitor
will be prompted to take a Conclusion of Test reading.  The device will then be removed and 
the time of the Conclusion of Test will be recorded. This should be done within 23:30-24 
hours of starting monitor. 
After each ABPM session, the data from the device is to be downloaded and assessed  to 
determine if the session was  successful.  
At Visit 2.2 only, if the first session does not pass quality criteria or the mean ABPM SBP is
outside the required range , the session should be repeated.  Only one repeat session will be
permitted.  It is important to remember to record the 24-hour mean SBP which is displayed at 
the bottom of the quality compliance (QC) results.  The 24-hour mean SBP at this visit 
together with a  successful session determines eligibility for randomization.  
After the removal of the monitor and prior to study medication intake, the patient will be 
allowed rest for 15 minutes and a seated BP measurement (trough BP) will be taken.  The 
patient will then be given study medication. The time for each of the seated BP 
measurement, medication intake, and the beginning and conclusion of the 24 hours ABPM 
readings must be recorded.  
Further details on the procedure for BP measurement utilizing ABPM device can be found in 
the ISF.

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Blood pressure (seated SBP and DBP)
SBPand DBP as well as pulse rate (electronically or by palpation, count for 1 minute) will be 
measured after 2 minutes of rest in the seated position. The BP measurement should be 
performed three times at each time point and the mean value of these measurements will be 
calculated by RDC. Further details on the procedure for BP measurements are given in 
Appendix 10.2.
Trough mean BP value is the mean of these three measurements on the day of the clinic visit 
before study drug intake.
Weight 
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).

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5.2
SAFETY
5.2.1
Endpoints of safety

Adverse events

Hypoglycaemic events

Adverse events of special interest (AESI)

Changes from baseline in clinical laboratory values

Positive orthostatic blood pressure test after 12 weeks of treatment
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient in a 
clinical investigation who was 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.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off 
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is life-
threatening, results in persistent or significant disability / incapacity, requires inpatient 

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hospitalisation or prolongation of existing hospitalization, is a congenital anomaly / birth 
defect, or is to be deemed serious for any other reason if it is an important medical event 
when based upon appropriate medical judgement which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above.  
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. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
AEs considered “Always Serious” 
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.   The latest list of “Always Serious AEs” can be found in the RDC system.  These 
events should always be reported as SAEs as described in Section 5.2.2.2.
Adverse Events of Special Interest (AESI)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same timeframe 
that applies to SAE, see Section 5.2.2.2. The following events are defined as ‘adverse events of 
special interest (AESI)’:

Hepatic injury defined by the following alterations of liver parameters after 
randomisation at Visit 3: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
bilirubin ≥2-fold ULN measured in the same blood draw sample. 
o
An isolated elevation of AST and /or ALT ≥ 5 fold ULN irrespective of any 
bilirubin elevation

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Patients showing these lab abnormalities need to be followed up according to 
Appendix 10.4.2 of this CTP and the “DILI checklist” provided in RDC/ISF

Decreased renal function: creatinine value shows a ≥2 fold increase from baseline 
and is above the upper limit of normal (ULN)

Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA)
In case of metabolic acidosis, ketoacidosis and DKA further investigations should be 
done according to the medical judgment and the clinical course until a diagnosis is 
made and/or the patient is recovered.
DKA is defined by the diagnostic criteria in Table 5.2.2.1: 1 below, and as defined by 
the American Diabetes Association (ADA) (R14-5435).
Investigators should note that not all criteria in the table below need to apply for the 
diagnosis of DKA, and clinical judgment should also be taken into consideration. Due 
to its mechanism of action, empagliflozin may potentially modify the clinical 
presentation of DKA which may occur at lower plasma glucose levels than stated in 
Table 5.2.2.1: 1 below (see Section 2.3 for further details).
In case of a suspected DKA the Investigator should ensure that appropriate tests are 
performed locally at the earliest opportunity according to local guidelines, such as a 
blood gas test (pH, bicarbonate) and that the patient is appropriately treated (i.e. 
hospitalized or referred to emergency treatment) according to local treatment 
guidelines.
Table 5.2.2.1: 1
Diagnostic criteria for DKA
DKA
Mild
Moderate
Severe
Plasma Glucose (mg/dl)
>250
>250
>250
Arterial pH
7.25-7.30
7.00-7.24
<7.00
Serum bicarbonate (mEg/L)
15-18
10-<15
<10
Urine ketones*
Positive
Positive
Positive
Serum ketones*
Positive
Positive
Positive
Effective serum osmolality (mOsm/kg)**
Variable
Variable
Variable
Anion gap***
>10
>12
>12
Alteration in sensoria or mental 
obtundation
Alert
Alert/drowsy
Stupor/coma
*     Nitroprusside reaction method
**   Calculation: 2[measured Na (mEq/L) + glucose (mg/dl)/18]
*** Calculation: (Na+)-(Cl- + HCO3
-) (mEq/L)

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Patients with AESI need to be followed up appropriately. The investigator should consider 
which, if any, concomitant therapies should not be taken during evaluation. Discontinued 
treatments can be reintroduced per investigator discretion.
These lab findings constitute a hepatic injury alert and the patients showing the above 
alterations in liver parameters or hepatic (S)AEs should be followed up according to Section 
10.4 of this CTP and the “DILI checklist” provided in the ISF.
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.
For any of these AESI adverse events the central lab will alert the investigator and the 
investigator should report the event to the Pharmacovigilance centre immediately (within 24 
hours of being informed, and without waiting for confirmation of the results via a second 
measurement) being documented on an SAE form, even if they do not meet any of the 
seriousness criteria – for details please see Section 5.2.2.2. The investigator shall collect a 
respective trough pharmacokinetics (PK) sample and an unscheduled lab sample for 
creatinine or hepatic enzymes as soon as possible (see Section 5.5.1) and initiate follow-up 
laboratory test of creatinine according to medical judgement and hepatic enzymes according 
to Section 10.5.2.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an adverse event. An adverse
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
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

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• The event is known to be caused by or attributed to the drug class.
• 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. 
preexisting 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 diminished).
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 study drug treatment continues or 
remains unchanged.
5.2.2.2
Adverse event and serious adverse event collection and reporting
AE Collection 
The Investigator shall maintain and keep detailed records of all AEs in their patient files.  The 
following must be collected and documented on the appropriate eCRF by the Investigator:
From signing the informed consent onwards through the Residual Effect Period (REP) until 
trial completion (individual patient’s End of Trial):
all AEs (serious and non-serious), and AESIs. This also applies to patients who 
prematurely discontinue from the study.  
If an individual patient discontinues trial medication prematurely but stays in the trial 
(i.e. if further visits incl. telephone visits, or vital status assessments are planned) 
from then on and until the individual patient’s End of Trial contact, the Investigator 
must report all AEs (serious and non-serious) and AESIs.
After the individual patient’s end of trial:

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
The Investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the Investigator may become 
aware of.
The REP is defined as 7 days following last intake of trial medication. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment please see Section 7.3.3.  Events which occurred after the REP will be considered 
as post treatment events.
AE Reporting to Sponsor and Timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be
provided. For follow-up information the same rules and timeline apply as for initial
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). The Investigator 
should determine the causal relationship to the trial medication and any possible interactions 
between the investigational drug(s).  

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The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions

Changes in vital signs, electrocardiogram (ECG), physical examination and laboratory 
test results, if they are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.  
All (S)AEs, including those persisting after individual patient’s end of trial or per last 
protocol contact must be followed up until they have resolved, have been sufficiently 
characterized, or no further information can be obtained.
Pregnancy
In the rare cases, pregnancy might occur in a study.  Once a subject has been enrolled into the 
clinical trial after having taken trial medication, the investigator must report any potential 
drug exposure during pregnancy which occurred in a female subject or in a partner to a male 
subject to the Sponsor immediately (within 24 hours) by means of Part A of the Pregnancy 
Monitoring Form to the Sponsor’s unique entry point (country-specific contact details will be 
provided in the ISF). 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
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. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
All safety laboratory samples (except at Visit 1) will be collected after a full overnight fast 
(nothing to eat or drink except water for at least 10 hours) and before investigational drug as 
described in the Flow Chart and Section 6. The blood sample at Visit 1 (screening visit) can 
be taken with the patient in a fasted or non-fasted state. 
All parameters that will be determined during the trial conduct are listed in Table 5.2.3:1 and 
5.2.3:2. The analysis will be performed by a central laboratory. The respective reference 
range and details about sample handling and shipment will be provided in the ISF (Lab 
Manual). 
Reduced safety lab panels excluding urinalysis are planned for the following visits: 

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
For the screening Visit 1, laboratory only includes liver transaminases, alkaline 
phosphatase, serum creatinine, TSH and urinalysis 

For the first visit after randomisation (4 weeks), only fasting plasma glucose FPG will 
be determined (see Flow Chart).
The following safety lab parameters will only be determined at each of the following study 
visit:

Lipid fractions: planned at V3, V5.2, V7.2 and V8 

TSH: planned at V1 

Albumin (urine) at V3, V5.2, V7.2 and V8

BNP at V3, V5.2 and V7.2
Table 5.2.3: 1
Safety laboratory parameters – whole blood, serum or plasma
Haematology
Haematocrit
Haemoglobin
- Reticulocyte Count (reflex test if Hb outside normal range)
Red Blood Cells (RBC) / Erythrocytes
WBC / Leukocytes
Platelet Count / Thrombocytes
Differential Automatic (relative and absolute count): 
Neutrophils, Eosinophils, Basophils, Monocytes,  Lymphocytes

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Table 5.2.3: 1
Safety laboratory parameters – whole blood, serum or plasma 
(continued)
Clinical chemistry
Albumin 
Alkaline phosphatase
- -GT (gamma-glutamyl transferase) 
  (reflex test triggered by elevated alkaline phosphatase on two sequential measures)
ALT (alanine aminotransaminase, SGPT)
AST (aspartate aminotransaminase, SGOT) 
Bicarbonate
Bilirubin total, fractionated if increased 
Calcium 
Chloride 
Creatinine 
Creatine kinase (CK)
CK-MB, troponin (reflex tests if CK is elevated)
Cystatin C
hsCRP
Lactate dehydrogenase (LDH)
Lipase
Magnesium 
Phosphate 
Potassium 
Protein total 
Sodium
Urea (BUN)
Uric acid
Lipids (only selected visits)
Cholesterol (total)
HDL cholesterol 
Calculated LDL cholesterol 
Triglycerides (reflex test for direct LDL cholesterol triggered if triglycerides are > 400 mg/dl or 4.52 
mmol/l)

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Table 5.2.3: 2
Safety laboratory parameters - urine
Urinalysis 
Semi quantitative (dipstick)
Nitrite* 
Protein
Ketone
Urine pH
Leukocyte Esterase (for WBC)*
Quantitative
Albumin
Creatinine
Microscopic analysis 
-will be performed as reflex test if any of semi-quantitative
tests/dipstick is abnormal:
Urine RBC/Erythrocyte
Urine WBC/Leukocytes*
Urine sediment microscopic examination 
Urine culture:
Reflex test triggered by positive Leucocyte
     Esterase (for WBC) and/or nitrite in the semi
     quantitative test/dipstick
* Nitrite and leucocyte esterase (for WBC) will be determined both locally on site (not recorded in 
CRF) and via central lab. A positive result at site triggers the sampling of mid-stream urine for 
urine culture.
Albumin/creatinine ratio in spot urine will be calculated at the central lab.
The GFR will be derived from serum creatinine values based on the CKD-EPI formula as 
expressed below:
Black Female
If serum creatinine <= 0.7
eGFR = 166 x (serum creatinine /0.7)-0.329 x 0.993Age
If serum creatinine > 0.7
eGFR = 166 x (serum creatinine /0.7)-1.209 x 0.993Age
Black male
If serum creatinine <= 0.9 
eGFR = 163 x (serum creatinine /0.9)-0.411 x 0.993Age
If serum creatinine > 0.9
eGFR = 163 x (serum creatinine /0.9)-1.209 x 0.993Age
where serum creatinine is measured in mg/dl.

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Renal function impairment will be classified in the following way:

eGFR ≥ 120 ml/min/1.73m2;

eGFR 120-60 ml/min/1.73m2;

eGFR ≤60 ml/min/1.73m2
These 3 classes of renal impairment will be the basis for stratification at randomisation 
 
Empagliflozin influences hepatic glucose output and hepatic triglyceride mobilization which 
could theoretically reduce fat stores in the liver.  This may improve liver function and reduce 
the burden of NAFLD.  NAFLD fibrosis score will be used to assess changes in the status of 
NAFLD.  
NAFLD fibrosis score will be calculated in-house:
NAFLD Fibrosis Score = -1.675 + 0.037 x age (yr) + 0.094 x BMI (kg/m2) + 1.13 x 
IFG/diabetes mellitus (yes = 1, no = 0) + 0.99 x AST/ALT ratio - 0.013 x platelet 
(x109/L) - 0.66 x albumin (g/dl)
Pregnancy testing (urine) will be performed in female patients of child-bearing potential only 
according to the time points indicated in the Flow Chart.
Criteria for hypoglycaemic events
Every episode of plasma glucose ≤ 70 mg/dl (3.9 mmol/l) should be documented in the eCRF 
with the respective time and date of occurrence. Any hypoglycemia with glucose values 
< 54 mg/dl (< 3.0 mmol/l) and all symptomatic and severe hypoglycemias should be 
documented as an AE "hypoglycaemic event". 
For the analysis, all hypoglycemias will be classified 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 but no 
need for external assistance

Severe hypoglycaemic episode: Event requiring the assistance of another person to
actively administer carbohydrate, glucagon or other resuscitative actions.

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Follow-up on suspicion for urinary tract infections
Patients having a history of chronic/recurrent UTI or genital infection or an acute episode of 
UTI or genital infection at screening will be identified and this condition has to be 
documented as medical history or baseline condition in the eCRF, respectively. 
For documentation of acute urinary tract infections during trial conduct, the following 
measures have to be taken:

In any case of suspected UTI (symptomatic or asymptomatic) a urine culture sample has 
to be taken and sent to central lab for confirmation of the diagnosis. 

To be able to identify asymptomatic UTIs immediately, a dipstick-test (leucocyte esterase 
[for WBC] and Nitrite) will be performed at the site at each safety visit with urinalysis. In 
case of a positive result at site, a urine culture sample has to be taken and sent to central 
lab for confirmation of the diagnosis. A negative urine dipstick does not require a 
midstream urine culture sample to be sent to central lab, unless UTI is suspected.

If there is negative dipstick at site, but the dipstick performed at the central lab is positive, 
a mid-stream urine sample should be collected from the patient only if the investigator 
has a suspicion of a UTI.
5.2.4
Electrocardiogram
At start of run-in and end of treatment, a complete physical examination will be performed by 
the investigator or qualified designee (see Flow Chart). Documentation of, and findings from 
the physical examination, must be part of the source documents available at the site.
Printed paper traces from 12-lead ECGs (I, II, III ,aVR, aVL, aVF, V1-V6)  will be collected 
at screening. ECG traces on thermopaper should be copied to normal paper to avoid fading. 
In the event of any cardiac symptoms (i.e. suspicion of heart rhythm disorders or cardiac 
ischemia), an additional ECG will be recorded. All ECGs will be evaluated, (signed, dated 
and commented upon) by the treating physician/investigator and stored locally. Any clinically 
relevant changes in the ECG will be reported as AEs and followed up and/or treated locally 
until normal or stable condition.  Any ECG abnormalities will be carefully monitored and if 
necessary the patient will be removed from the trial and medically treated.
5.2.5
Assessment of other safety parameters
All patients will be provided with HBGM equipment and supplies for use at home during the 
2-week Run-In Period. Instruction on the proper use of the HBGM 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 single HBGM values will be recorded in the 
CRF. The respective procedure for illiterate patients (if included) is described in the 
Appendix 10.1.  Even though review of the HBGM log is required, electronic review of the 

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glucometer is not required.  If a patient forgets to return their Log, they should be reminded 
to record HBGM values on the Log and return it at the next visit.
During Run-In and Follow-up, HBGM testing should be performed once daily in the fasted 
state and at any time the patient is symptomatic, i.e., experiences signs/symptoms of hyper-
or hypoglycemia. If during Run-in, results of a HBGM test reveal blood glucose of >270 
mg/dl (>15.0 mmol/L) after an overnight fast the patient should contact the site. Patient 
should also eat or drink something immediately and contact the site in the event that blood 
glucose level drops below 54 mg/dl (3.0 mmol/l). 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 should be performed 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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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits with the exception of ABPM visits should be routinely scheduled in the 
morning, at approximately the same time of day (07:00 AM to 11:00 AM).  For ABPM 
visits, patients should arrive at approximately half an hour prior to medication intake to allow 
additional time for ABPM procedures, so that dosing of medication occurs as close as 
possible to patient daily dosing time.  If a patient mistakenly takes trial medication on the 
morning of a visit before attending the clinic (excluding visits starting before randomisation) 
or comes in non-fasted where a fasting condition is required (all visits except screening), the 
visit should be rescheduled for another day as soon as possible reminding the patient about 
the expected conditions. The rescheduled visit must take place in a short enough time-frame 
so that the patient has sufficient trial medication available.  Fasting visits should take place at 
a minimum of 10 hours after the end of the patient’s last meal.
Patients who are fasting (e.g. for religious or cultural reasons) should be instructed to perform 
HBGM tests regularly and to contact the site in case of signs/symptoms or values suggestive 
hypoglycemia.
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.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart. Additional details 
regarding visit procedures are provided below. All visits, except Visit 1, must be performed 
in fasted state (10 hours without food and only water).
6.2.1
Screening and run-in period
Visit 1 (Screening)

The screening visit is the only visit in this study that does not need to be done fasting.

No trial procedures should be done unless the patient has consented to taking part in the 
trial. Patient identification numbers are available in the RDC system.  If a patient is re-
screened, a new patient identification number should be assigned.  

Once they have consented, the patient is considered to be enrolled in the trial and to have 
started screening. The patient should be recorded on the enrolment log and registered in 
the IRT system as a screened patient.

BP should always be measured before any blood samples are taken. For details regarding 
the correct method for measuring BP, please see Appendix 10.3.

Once Visit 1 procedures are complete and laboratory results are received, 
inclusion/exclusion criteria must be reviewed. If the patient meets inclusion/exclusion 
criteria, the patient should be contacted to schedule next visit. If the patient does not meet 

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inclusion/exclusion criteria the patient must be recorded in CRFs and registered in the 
IRT system as a Screen failure.
Visit 2.1 (Run-in period)

From this visit onwards, patients should be fasting (no food or drinks, water only for at 
least 10 hours) prior to each visit.

Inclusion/exclusion criteria must be reviewed at this visit

BP should always be measured before any blood samples are taken. For details regarding 
the correct method for measuring BP, please see Appendix 10.3.

Collection of urine and blood for laboratory testing must be performed prior to 
administration of study medication.

Provide patient with diet and exercise counseling. Patients should be given a food log to 
be completed for three consecutive days prior to Visit 3 as indicated in the Flow Chart.

Provide HBGM equipment/supplies and instruct patient on the correct use of HBGM.

Instruct patient to perform a HBGM once daily during the run-in period in the fasted state 
and at any time the patient is symptomatic, i.e., experiences signs/symptoms of hyper or
hypoglycemia. Instruct patient to contact site immediately if blood glucose reaches the 
limit described in Section 4.2.1.

Once all visit procedures are conducted, contact the IRT system to obtain run-in 
medication kit number and dispense the medication to the patient.

Administer dose of medication.

Remind the patient to arrive half an hour earlier for the next scheduled visit (Visit 2.2).

Instruct patients NOT to take study medication on the morning of the next trial visit.
Visit 2.2 (Baseline ABPM visit)

ABPM should be done during the run-in period within 7 days prior to Visit 3.

The ABPM device is attached to the patient and proper operation of the device should be 
ensured. 

Record the time the medication was administered and the time the monitor was prompted 
to take the Beginning of Test reading.  

Instruct the patient on the proper use of the ABPM device .  The monitor should remain 
on the patient for at least 24 hours. The patient should be instructed to not remove the 
monitor and schedule a visit for the next day for removal of the monitor if possible. 
Patient should arrive early again for the visit on the next day.

The next day when the patient returns to the clinic (within 23:30-24 hours of the 
beginning of the test), prompt the monitor to take a Conclusion of Test reading.  If an 
invalid reading occurs for the Conclusion of Test reading, continue to trigger a manual 
reading until a valid reading is registered.  The monitor will then be removed and the time 
of the Conclusion of Test will be recorded.  

Once the data from the session is downloaded, review the QC results to determine if the 
session was technically successful.  Remember to record the 24-hour mean SBP displayed 

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at the bottom of the QC results.  The 24-hour mean SBP at this visit together with a  
successful session determines eligibility for randomization.

If the first ABPM attempt was unsuccessful (failed QC and/or the mean ABPM SBP is 
outside the required range), repeat it within 2 days.  Patients having two unsuccessful 
baseline ABPM sessions should not be randomised and must be discontinued. 

If ABPM was successful, the patient is eligible for randomization and procedures for 
Visit 3 can be conducted on the same day after the ABPM device is removed and trough 
seated blood pressure measurement is taken. If conducted on the same day, procedures for 
Visit 3 should be done prior to administrating study medication.

Allow the patient to rest for at least 15 minutes after the monitor is removed.  Then take a 
seated blood pressure measurement.  Record the time of this measurement.  This should 
be done prior to administering study medication.

For further instructions for ABPM measurements, please see Section 5.1.2.

Instruct patients NOT to take study medication on the morning of the next trial visit.
Patients who fail the run-in period following Visit 2 procedures should be registered as a 
screen failure in the IRT system.
6.2.2
Treatment period
The treatment period is from Visit 3 to Visit 7.2.  Patients will be dispensed medication at 
Visits 3, 4, and 5.2.  Patients will receive a new kit number through the IRT system on each 
occasion. Assessments should be performed as mentioned in the Flow Chart and the 
respective protocol sections.  
Throughout the treatment period, BP should always be measured before any blood samples 
are taken.  For details regarding the correct method for measuring BP, please see Appendix 
10.3.
Visit 3 (Randomisation visit)

Inclusion/exclusion criteria must be reviewed prior to randomization

BP measurement and orthostatic blood pressure test should always be done before taking 
any blood sample.

Collection of urine and blood for laboratory testing must be performed prior to 
administration of study medication.

Collect returned run-in medication.

Collect blood sample for PG evaluation after obtaining separate informed consent. PG 
sample should be collected for randomised patients only. 

Patients should be reminded about the importance of following the agreed diet and 
exercise plan. Patients should be given a food log to be completed for three consecutive 
days prior to Visit 4 as indicated in the Flow Chart.

Provide HBGM equipment/supplies and instruct patient on the correct use of HBGM.

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
Instruct patient to perform a HBGM once weekly during the treatment period (more 
frequently if required by local authorities) in the fasted state and at any time the patient is 
symptomatic, i.e., experiences signs/symptoms of hyper or hypoglycemia. Instruct patient 
to contact site immediately if blood glucose reaches the limit described in Section 4.2.1.

Once all visit procedures are conducted, contact the IRT system to randomise the patient 
and obtain medication kit numbers and dispense the medication to the patient. 

Administration first dose of study medication.

Instruct patients NOT to take study medication on the morning of the next trial visit.
Visit 4 

BP should always be measured before taking any blood samples.  

Collection of urine and blood for laboratory testing must be performed prior to 
administration of study medication at each visit.

Collect returned medication. 

New medication kit must be dispensed according to the Flow Chart, and the IRT system 
must be contacted to obtain medication kit numbers to be dispensed.

Patients should be reminded about the importance of following the agreed diet and 
exercise plan. Patients should be given a food log to be completed for three consecutive 
days prior to Visit 5.2 as indicated in the Flow Chart.

Provide HBGM equipment/supplies and instruct patient on the correct use of HBGM.

Instruct patient to perform a HBGM once weekly during the treatment period (more 
frequently if required by local authorities) in the fasted state and at any time the patient is
symptomatic, i.e., experiences signs/symptoms of hyper or hypoglycemia. Instruct patient 
to contact site immediately if blood glucose reaches the limit described in Section 4.2.1..

Once all visit procedures are conducted, contact the IRT system to obtain medication kit 
numbers (Dose escalation kit) and dispense the medication to the patient. Administer dose 
of study medication.

Remind the patient to arrive half an hour earlier for the next scheduled visit (Visit 5.1).

Instruct patients NOT to take study medication on the morning of the next trial visit.
Visit 5.1 (Week 12 ABPM visit)

ABPM should be done within 7 to 2 days prior to Visit 5.2.   

Attach ABPM device to the patient and initiate the test readings to ensure the monitor is 
operating properly. 

Administer study medication on the morning of the study visit after the test readings have 
confirmed that the device is operating properly. Record the time the medication was 
administered and the time the monitor was prompted to take the Beginning of Test 
reading.  

Instruct the patient on the proper use of the monitor. The ABPM device should remain on 
the patient for at least 24 hours.  The patient should be instructed not to remove the 

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monitor and schedule a visit for the next day for removal of the monitor.  Patient should 
arrive early again for the visit on the next day. 

The next day when the patient returns to the clinic (within 23:30-24 hours of the 
beginning of the test), prompt the monitor to take a Conclusion of Test reading.  If an 
invalid reading occurs for the Conclusion of Test reading, continue to trigger a manual 
reading until a valid reading is registered.  The monitor will then be removed and the time 
of the Conclusion of Test will be recorded.  

If ABPM was successful, procedures for Visit 5.2 can be conducted on the same day after 
the ABPM device is removed and trough seated blood pressure measurement is taken.  If 
conducted on the same day, procedures for Visit 5.2 should be done prior to 
administrating study medication.

If the first ABPM attempt was unsuccessful (failed QC), a repeat reading should be taken 
within 2 days.  Patient having two technically unsuccessful ABPM sessions may continue 
with Visit 5.2.  Procedures for Visit 5.2 can be conducted on the same day after the 
ABPM device is removed and trough seated blood pressure measurement is taken.

Allow the patient to rest for at least 15 minutes after the monitor is removed.  Then take a 
seated blood pressure measurement.  Record the time of this measurement.  This should 
be done prior to administering study medication. 

Administer dose of study medication.

For further instructions for ABPM measurements, please see Section 5.1.2.

Instruct patients NOT to take study medication on the morning of the next trial visit.
Visit 5.2

BP and orthostatic blood pressure test should always be done before taking any blood 
samples.  

Collection of urine and blood for laboratory testing must be performed prior to 
administration of study medication at each visit. 

PK trough sample should be collected within 30 minutes prior to intake of study 
medication.

Collect returned medication. 

New medication kit must be dispensed according to the Flow Chart, and the IRT system 
must be contacted to obtain medication kit numbers to be dispensed.

Patients should be reminded about the importance of following the agreed diet and 
exercise plan. Patients should be given a food log to be completed for three consecutive 
days prior to Visit 7.2 as indicated in the Flow Chart.

Provide HBGM equipment/supplies and instruct patient on the correct use of HBGM.

Instruct patient to perform a HBGM once weekly (more frequently if required by local 
authorities) in the fasted state and at any time the patient is symptomatic, i.e., experiences 
signs/symptoms of hyper or hypoglycemia. Instruct patient to contact site immediately if 
blood glucose reaches the limit described in Section 4.2.1.

Once all visit procedures are conducted, contact the IRT system to obtain medication kit 
numbers (Dose escalation kit) and dispense the medication to the patient. Administer dose 
of study medication.

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
Instruct patients NOT to take study medication on the morning of the next trial visit.
Visit 6 (Phone visit)

Remind the patient to arrive half an hour earlier for the next scheduled visit (Visit 7.1).

Instruct patients NOT to take study medication on the morning of the next trial visit.
Visit 7.1 

ABPM should be done within 7 to 2 days prior to visit 7.2. 

Attach ABPM device to the patient and initiate the test readings to ensure the device is 
operating properly. 

Administer study medication on the morning of the study visit after the test readings have 
confirmed that the device is operating properly. Record the time the medication was 
administered and the time the monitor was prompted to take the Beginning of Test 
reading.  

The ABPM device should remain on the patient for at least 24 hours.

Instruct the patient on the proper use of the monitor. The patient should be instructed not 
to remove the monitor and schedule a visit for the next day for it removal. Patient should 
arrive early again for the visit on the next day.

The next day when the patient returns to the clinic (within 23:30-24 hours of the 
beginning of the test), prompt the monitor to take a Conclusion of Test reading.  If an 
invalid reading occurs for the Conclusion of Test reading, continue to trigger a manual 
reading until a valid reading is registered.  The device will then be removed and the time 
of the Conclusion of Test will be recorded. 

If ABPM was successful, procedures for Visit 7.2 can be conducted on the same day after 
the ABPM device is removed and trough seated blood pressure measurement is taken. If 
done on the same day, procedures for Visit 7.2 should be done prior to administrating 
study medication.

If the first ABPM attempt was unsuccessful (failed QC), a repeat reading should be taken 
within 2 days.  Patient having two technically unsuccessful ABPM sessions may continue 
with Visit 7.2.  Procedures for Visit 7.2 can be conducted on the same day after the 
ABPM device is removed and trough seated blood pressure measurement is taken.

Allow the patient to rest for at least 15 minutes after the monitor is removed.  Then take a 
seated blood pressure measurement.  Record the time of this measurement.  This should 
be done prior to administering study medication. 

Administer dose of study medication.

For further instructions for ABPM measurements, please see Section 5.1.2.

Instruct patients NOT to take study medication on the morning of the next trial visit.
Visit 7.2 (end of treatment)

BP measurement and orthostatic blood pressure test should always be done before taking 
any blood samples.  

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
Collection of urine and blood for laboratory testing. 

PK trough sample should be collected. 

Collect returned medication.

Patients should be reminded about the importance of following the agreed diet and 
exercise plan. 

Provide HBGM equipment/supplies and instruct patient on the correct use of HBGM.

Instruct patient to perform a HBGM test at least once daily during the follow up period. 
Instruct patient to immediately perform a blood glucose test if they experience 
signs/symptoms of hypo- or hyperglycemia. Instruct patient to contact site immediately if 
blood glucose reaches limit described in Section 4.2.1.

Visit 7.2 is the last visit of the treatment period after ABPM is done. No study medication 
is administered at this visit.

Instruct patient to continue to take the current therapy as usual. Additional antidiabetic 
medication can be started after the follow-up visit, in case there is no medical need for 
rescue medication before that.
6.2.3
End of trial and follow-up period
For all patients who successfully complete the study according to the protocol a follow-up 
visit (Visit 8) with the patient should be done by the investigator at the end of the follow-up 
period of 14 days.
Visit 8 (follow-up visit)

Vital signs

Body weight measurement

BP measurement and orthostatic blood pressure test should always be done before taking 
any blood samples. 

Collection of urine and blood for laboratory testing. 

Home blood glucose monitoring 

Documentation of any adverse events. 

Documentation of concomitant therapies
Patients discontinuing trial medication early from the trial
In general patients should be encouraged to re-start study medication in case of temporary 
treatment interruptions.  If the duration of interruption is more than 7 days, this should be 
recorded in the “Study Medication Temporary Discontinued/re-started" eCRF.  
For the analysis of this trial it is absolutely crucial that all planned assessments are done as 
planned, even if patients discontinue trial treatment. Patients who discontinue treatment 
prematurely and who do not withdraw their informed consent must therefore be followed up 
for the intended regular treatment period. All assessments related to the primary and 
secondary endpoints must be performed as if the patient would have remained on treatment.

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For patients who stop study medication permanently prior to completion of 24 weeks of 
treatment and who are willing to be followed up, the following should be performed 
whenever possible: 

Premature treatment discontinuation (PTD) visit should be performed within 7 days of 
last intake of study drug or as soon as possible including all examinations and
assessments that are part of the Visit 7.2. If the PTD visit occurs within the time 
window of a scheduled visit, the PTD visit will replace the scheduled visit.

Subsequently, a follow-up visit (Visit 8 procedures) should be conducted within 14
days of the PTD visit that replaces the next visit according to the visit schedule.

Thereafter, patients would be followed up according to the visit schedule. 

Visit 7.2 will be the last visit for these patients. Follow-up Visit 8 does not need to be 
performed.
The last per study contact should be at Visit 7.2.  If determined by investigator as necessary 
for patient safety, new antidiabetic medication regimen can be started immediately after 
discontinuation and must be recorded in eCRFs. 
If a patient is not able to attend a study visit, the study staff should contact him/her (or 
someone designated – e.g. family member or personal physician) to inquire about medical 
information pertaining to adverse events, particularly primary and key secondary outcome 
events, and/or mortality, until the end of the study.  Alternatively, data should be collected 
from medical records. 
For patients who discontinue treatment prematurely but do not wish to follow the visit 
schedule, the following should be performed whenever possible:

Visit 7.2 should be performed within 7 days of last intake of study drug. 

Subsequently, a follow-up visit (Visit 8 procedures) should be conducted within 14 
days of the premature discontinuation visit.  
If this patient withdraws consent, then the last per study contact will be Visit 8.  
Patients who withdraw consent
Patients who withdraw consent during the trial should perform Visit 7.2 within 7 days of last 
intake of study drug.  A follow-up visit (Visit 8 procedures) should be conducted within 14 
days of the premature discontinuation for their safety.  
The following procedures should be performed at Visit 8.

Vital signs

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
Body weight measurement

BP measurement and orthostatic blood pressure test should always be done before taking 
any blood samples. 

Collection of blood and urine samples for safety laboratory evaluation.

Documentation of any adverse events. 

Documentation of concomitant therapies
A patient who reverses the decision to withdraw consent should be re-consented with the 
latest version and will continue the visit schedule according to the date of randomisation.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a multi-centre, multi-national, randomised, parallel-group, double-blind, placebo-
controlled trial to investigate the effect of (10 mg/25 mg) of empagliflozin and placebo after 
24 weeks treatment on glucose control, BP and body weight in hypertensive black/African 
American patients with T2DM. The randomisation will be performed stratified by screening 
HbA1c values (<8.5%, ≥8.5%), renal function at screening (eGFR ≥120 
ml/min/1.73m2,eGFR 120-60ml/min/1.73m2, eGFR ≤60 ml/min/1.73m2) and pretreatment 
with Metformin at screening (yes/no). 
Based on experiences with the primary endpoints in other trials and based on literature data, 
the HbA1c change from baseline, and change from baseline in BP are regarded as normally 
distributed. Therefore, a restricted maximum likelihood estimation based on mixed-effect 
model for repeated measures analysis or an analysis of covariance (ANCOVA) approach can 
be used. 
With regard to efficacy and safety endpoints, the term "baseline" refers to the last observed 
measurement prior to administration of any randomised study medication.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Primary Hypotheses
The confirmatory analyses will compare empagliflozin to placebo. The following hierarchical 
multiple testing procedure will be used to evaluate superiority for the primary endpoint 
followed by the evaluation of superiority of the key secondary endpoints, while maintaining 
the overall probability of a type I error at 0.05. The primary endpoint of change from baseline 
to 24 weeks in HbA1c along with the key secondary endpoints change from baseline in mean 
24-hour ambulatory SBP at 12 weeks of treatment, change from baseline in mean trough 
ambulatory SBP at 12 weeks of treatment, change from baseline in body weight in kg at week 
24 of treatment, and change from baseline in trough seated SBP at 12 weeks of treatment, 
will be tested in the following pre-specified hierarchical sequence, to address issues of 
multiplicity. Proceeding onto the next step in the sequence relies upon rejecting H0 in the 
previous step, a ‘success’. Each step will only be considered confirmatory if all previous 
steps were ‘successful’. If any of the previous steps were not successful, the tests of the 
subsequent steps have to be interpreted in an exploratory sense. This procedure allows testing 
each step at the two-sided alpha-level of 5%:
1. change from baseline in HbA1c at 24 weeks of treatment
2. change from baseline in mean 24-hour ambulatory SBP at 12 weeks of treatment
3. change from baseline in mean trough ambulatory SBP at 12 weeks of treatment
4. change from baseline in body weight in kg at week 24 of treatment 
5. change from baseline in trough seated SBP at 12 weeks of treatment

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At each of the 5 stages of the hierarchical sequence the hypotheses will be tested as described 
below:
H0,1:
No difference in mean endpoint between empagliflozin and placebo
H1,1:
A difference in mean endpoint between empagliflozin and placebo
7.3
PLANNED ANALYSES
The statistical analysis will be based on the following populations.
Treated Set
The treated set will consist of all patients who were randomised and treated with at least one 
dose of trial medication.
Full Analysis Set
The full analysis set (FAS) will consist of all randomised patients who were treated with at 
least one dose of study drug and had a baseline and at least one on-treatment HbA1c 
measurement
Per Protocol Set
The per-protocol set (PPS) will consist of all randomised patients who are part of the FAS but 
who do not have any important protocol violations (IPV) leading to exclusion. Further details 
on the definition of the PPS and the definition of IPVs will be provided in the TSAP.
7.3.1
Primary analyses
Mean changes from baseline for HbA1c up to 24 weeks of treatment will be analyzed using a 
restricted maximum likelihood (REML)-based repeated measures approach on the FAS data 
set. Patients will be analysed according to the treatment group they are randomised to.  
Analyses will include the fixed, categorical effects of treatment, pre-treatment with 
Metformin at screening, renal function at baseline, visit, and treatment-by-visit interaction, as 
well as the continuous, fixed covariates of baseline HbA1c and baseline HbA1c -by-visit 
interaction. An unstructured (co)variance structure will be used to model the within patient 
measurements. If the model first fails to converge using an unstructured (co)variance 
structure, then a hierarchical approach is applied until a (co)variance structure is obtained 
where the model converges. Therefore the following (co)variance structures are tested 
according to the pre-specified order: (1) unstructured, (2) Toeplitz, (3) variance components, 
(4) compound symmetry. As soon as one model converges this will be the final model used, 
therefore no further testing of subsequent (co)variance structures is required. The Kenward-
Roger approximation will be used to estimate denominator degrees of freedom. Significance 
tests will be based on least-squares means using a two-sided α = 0.05 (two-sided 95% 

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confidence intervals). The primary treatment comparisons will be the contrast between 
treatments at the endpoint visit at 24 weeks of treatment.
For the key secondary endpoint change from baseline in mean 24-hour ambulatory SBP at 12 
weeks of treatment an ANCOVA comparing the change from baseline in mean 24-hour 
ambulatory SBP at 12 weeks of treatment will be used as primary analysis on the FAS using 
last observation carried forward (LOCF) for missing ABPM assessments.
The statistical model will be the following:
change from baseline in 24-hour ambulatory SBP at 12 weeks =
overall mean + baseline 24-hour ambulatory SBP + treatment + pre-treatment with 
Metformin + renal function + HbA1c + random error
‘Treatment’, ‘pre-treatment with Metformin’, and ‘renal function’ are fixed 
classification effects and ‘baseline 24-hour ambulatory SBP’ and ‘ HbA1c’   are fixed 
covariates. The random error is assumed to be normally distributed with mean 0 and 
unknown variance σ². 
A similar ANCOVA models on the FAS using LOCF for missing ABPM assessments will be 
performed for the change from baseline in mean trough ambulatory SBP at 12 weeks of 
treatment just replacing the relevant key secondary endpoint’s baseline and 12 week 
assessments in the model.
For the key secondary endpoints change from baseline in body weight in kg at week 24 of 
treatment and change from baseline in trough seated SBP at 12 weeks of treatment a 
restricted maximum likelihood estimation based on mixed-effect model for repeated 
measures for mean changes from baseline will be used on the FAS observed case 
analysis set to obtain adjusted means for the treatment effects. These models will include the 
same discrete fixed effects as the model for the primary endpoint and baseline HbA1c as a 
continuous fixed effect. Furthermore these models will include the interaction between visit 
and treatment, and an interaction between visit and baseline measurement of the key 
secondary endpoint as well as the corresponding baseline measurements of the key secondary 
endpoint as continuous fixed effect. The covariance approach for this model will be the same 
as for the primary endpoint. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. The primary treatment comparisons will be the contrast 
between treatments at the 12 week visit for trough seated SBP and 24 week visit for the body 
weight and significance tests will be based on least-squares means using a two-sided α = 0.05 
(two-sided 95% confidence intervals).
All analyses will be implemented using SAS®.

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7.3.2
Secondary analyses
The primary endpoint analysis method as detailed in Section 7.3.1 will be repeated for the 
PPS.
The primary endpoint will as well be analysed using an ANCOVA model in the FAS. The 
model will include randomised treatment, pre-treatment with Metformin, and renal function 
at baseline as categorical fixed effects, and baseline HbA1c as continuous covariate. Missing 
HbA1c data will be imputed using the LOCF approach. 
The term "baseline HbA1c" refers to the last assessment prior to the administration of any 
randomised study medication. 
The model for the primary endpoint is as follows: 
HbA1c change from baseline at week 24 =
overall mean
+ HbA1c at baseline
+ treatment
+ renal function
+ pretreatment with Metformin
+ random error
This model includes effects accounting for the following sources of variation: ‘HbA1c at 
baseline’, ‘renal function’ at baseline, ‘pretreatment with Metformin’ at screening, and 
‘treatment’.  ‘Treatment’, ‘renal function’, and ‘pretreatment with Metformin’ are fixed 
classification effects and ‘HbA1c baseline’ is a linear covariate. The random error is assumed 
to be normally distributed with mean 0 and variance σ². This secondary analysis will be 
performed on the FAS with treatment assignment as randomised. Missing data will be 
imputed using the LOCF approach.
For the key secondary endpoints change from baseline in body weight in kg at week 24 of 
treatment and change from baseline in trough seated SBP at 12 weeks as well an ANCOVA 
model will be calculated on the FAS. The model for the change from baseline includes
‘treatment’, ‘renal function’ at baseline, ‘pretreatment with Metformin’ at screening as fixed 
categorical effects, and HbA1c at baseline, and baseline trough seated SBP or baseline body 
weight in kg respectively, as linear covariate.  Missing data will be imputed using the LOCF 
approach. 
The other continuous secondary endpoints as listed in Section 5.1.1 will be analysed on the 
FAS as follows: 

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The continuous secondary endpoints will be analysed using similar models as used for the 
primary analyses for the key secondary endpoints.
 
 
7.3.3
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 7 days after the last dose of trial medication, will be assigned to the 
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. To this end, all adverse events occurring between start of treatment and end 
of the REP will be considered ‘treatment-emergent’.  The REP is defined as 7 days 
following last intake of trial medication. 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 the MedDRA.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values. Vital signs, 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.
7.3.4
Interim analyses
No interim analyses are planned. 
7.3.6
Pharmacodynamic analyses
Not applicable.

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7.3.7
Pharmacogenomic analyses
Not applicable.
7.4
HANDLING OF MISSING DATA
Mixed Model Repeated Measures (MMRM) models and ANCOVA models including a 
LOCF imputation of missing data are used like discussed above in Section 7.3.1 and Section 
7.3.2. The mixed effect model
will handle missing data based on a likelihood method under the "missing at random
assumption". Efficacy data will be censored at the date of first intake of antidiabetic rescue 
medication for all analyses, i.e., will be set to missing, if not explicitly stated otherwise.
Blood pressure data will additionally be censored from the day of change in antihypertensive 
therapy. 
With respect to safety evaluations, it is not planned to impute missing values. 
Further details will be provided in the TSAP.
7.5
RANDOMISATION
The trial will be performed as a double-blind design with respect to study medication. 
Patients will be randomised to the two study treatments in a 1:1 ratio. The randomisation will 
be performed in blocks. The block size will be reported in the Clinical Trial Report (CTR). 
The randomisation will be stratified by the following factors:

screening HbA1c value (<8.5%,  ≥8.5%)

renal function at screening (eGFR ≥120 ml/min/1.73m2,eGFR 120-60ml/min/1.73m2,
eGFR≤60 ml/min/1.73m2)

pretreatment with Metformin at screening (yes/no)
The randomisation of patients to the treatment groups will be performed via an IRT system. 
BI will arrange for the randomisation as well as packaging and labelling of study medication. 
The randomisation list will be generated using a validated system, which involves a 
pseudorandom number generator and a supplied seed number so that the resulting allocation 
of medication numbers to treatment is both reproducible and non-predictable.
7.6
DETERMINATION OF SAMPLE SIZE
In order to ensure that each comparisons of empagliflozin and placebo with respect to 
HbA1c, mean systolic ABPM blood pressure and body weight have a power of at least 80%,
64 patients plus an additional 20%  drop-out rate, resulting in 77 patients per arm are required 
per treatment group. This is derived from the assumption that the difference in change from 
baseline compared to placebo in 24-hour SBP is  5 mmHg with a standard deviation of 10

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mmHg (resulting in a power of 80%), and the difference in body weight is 2 kg with a 
standard deviation of 2.3kg (resulting in a power of 99%). With this sample size the power to 
detect a 0.6% difference in HbA1c with a standard deviation of 1.1% will be >85%. 
The planned treatment group sizes are considered as sufficient for the confirmatory 
evaluation of efficacy and the descriptive assessment for safety, tolerability and PK.

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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
GCP and relevant BI SOPs. Standard medical care (prophylactic, diagnostic and therapeutic 
procedures) remains in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
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 general rule, no trial results should be 
published prior to finalisation of the CTR.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective 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 respective procedure for illiterate patients (if included) is described in the Appendix 
10.1.
The patient must be informed that his/her personal trial-related data will be used by BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by BI, by appropriate 
IRB / IEC members, and by inspectors from regulatory authorities.

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8.2
DATA QUALITY ASSURANCE
In order to achieve a high level of standardised processes, data collection of efficacy and 
safety endpoints is coordinated centrally:

central lab analysis of efficacy endpoints, biomarkers and safety lab

central IRT system for stratification, randomisation and kit allocation at each visit

Central hepatic adjudication assessment
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan available in TMF.
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs 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
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on 
paper or via RDC. See Section 4.1.5.2 for rules about emergency code breaks. For drug 
accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The CRA/ on site monitor 
and auditor may review all CRFs/eCRFs, and written informed consents. The accuracy of the 
data will be verified by reviewing the documents described in Section 8.3.1.

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8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For the empagliflozin this is: the current version of the IB c01678844. The current version of 
this reference document is to be provided in the ISF. No AEs are classified as listed for 
matching placebo.
8.4.2
Expedited reporting to health authorities
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities (for European Union), i.e. the 
CA.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P08-03352
Chavanu K, Merkel J, Quan AM. Role of ambulatory blood pressure 
monitoring in the management of hypertension. Am J Health Syst Pharm 
2008. 65(3):209-218.
P13-12437
Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, 
Christeaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee 
DE, Jaarsma T, Kirchhof P, Kjeldsen S, Laurent S, Manolis AJ, Nilsson PM, 
Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B and 
Zannad F. 2013 ESH/ESC Guidelines for the management of arterial 
hypertension: the Task Force for the management of arterial hypertension of 
the European Society of Hypertension (ESH) and of the European Society of 
Cardiology (ESC).  J Hypertens. 2013 Jul;31(7):1281-357.
R01-0055
Consensus statement on the definition of orthostatic hypotension, pure 
autonomic failure, and multiple system atrophy. Neurology. 1996; 46: 1470
R05-0939 
Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pfluegers 
Arch 447 (5), 510 - 518 (2004).
R14-0310
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, 
Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith 
SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E.  
2014 Evidence-Based Guideline for the Management of High Blood Pressure 
in Adults.  Report From the Panel Members Appointed to the Eighth Joint 
National Committee (JNC 8).  JAMA. 2014 Feb 5;311(5):507-20
R14-5435
American Diabetes Association.  Hyperglycemic crises in diabetes. Diabetes 
Care 27 (Suppl 1), S94 - S102 (2004)
9.2
UNPUBLISHED REFERENCES
c01678844
BI 10773 Investigator’s Brochure.

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10.
APPENDICES
10.1
INCLUSION OF ILLITERATE PATIENTS
10.1.1
Home blood glucose monitoring
In the event of recruiting an illiterate patient, the following process should be followed with 
respect to HBGM and documenting the results:
-
At Visit 2.1, the person assisting the patient with this process (e.g. the patient’s caregiver 
or relative) will attend the clinic together with the patient.
-
The site staff should confirm that this individual will be present with the patient, 
whenever he/she is likely to need to perform HBGM.
-
The site staff should then train both the patient and above-mentioned individual with 
respect to the correct use of the HBGM equipment during each period of the trial.  This 
will include the use of the glucose meter itself and the test strips, lancet device and 
control solution(s).
-
The site staff should also train both the patient and the above-mentioned individual with
respect to the completion of the HBGM testing log.  As for all other patients, the results 
of all per-protocol HBGM that is performed by/on illiterate patients should be 
documented on a HBGM testing log that will be included in the patients source document 
file.  In the event of hyper or hypoglycemia, the person assisting the patient should record 
symptoms on the HBGM testing log in accordance with the patient’s description.  
HGBM tests can be performed either by the patient him/herself, or by the person assisting the 
patient with this aspect of the trial. 
10.1.2
Patient information and informed consent (including pharmacogenetics)
In the event of recruiting an illiterate patient, the following process should be followed with 
respect to patient information and informed consent: 
-
The designated site personnel performing the informed consent process will read the trial-
approved patient information sheet and informed consent form to the patient, and explain 
the details of the trial, all in the presence of an impartial witness. 
-
This impartial witness must be literate, and can be the patient’s relative or caregiver, or a 
member of staff employed by the clinic but not part of the immediate trial team. In 
addition, if there are any further local regulations with respect to the consent of illiterate 
patients, these should also be followed. 
-
The requirements of the trial will be explained thoroughly and the patient will be given 
ample time to ask questions and consider his/her participation.  If he/she wishes, the 
patient can take the patient information sheet and informed consent form home for further 
consideration.

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-
If patient agrees to take part in the trial, he/she would then return to the clinic for the 
consent process to be completed.  The site designated personnel responsible for this 
process will confirm that the patient has no further questions in the presence of the same 
impartial witness (if the patient returns on another day).  If a different impartial witness is 
present, the entire informed consent process must be repeated.
-
Participating patients will provide a thumb impression or make a mark (or signature if the 
patient is able to sign him/herself) on the signature section of the informed consent form.
-
The date of the patient’s signature will be left blank as the patient is illiterate.  However, 
if the patient is able, he/she will date the mark/signature personally.
-
The impartial witness or the site designated personnel may write the name of the patient 
on the informed consent form.
-
The impartial witness should enter his/her name, sign and personally date the witness 
section of the informed consent form.  In countries where local data protection regulation 
permits it, the address or identification number of the impartial witness should also be 
entered.  The signature then attests that the content of the patient information sheet and 
informed consent form was accurately explained to the patient, who apparently 
understood and freely gave consent to participate in the trial.
-
The designated site personnel also signs and personally dates the informed consent form.
-
The same process as outlined above will be followed for obtaining consent for the 
optional pharmacogenetic aspect of the trial.
10.1.3
Food intake diary recording
For illiterate patients, the recording in the food intake diary will be assisted by the person 
who attended the clinic with the patient and who was also briefed by the site staff on how to 
complete the food intake diary.
10.2
BLOOD PRESSURE MEASUREMENT PROCEDURE
Blood pressure measurements are to be made per the Flow Chart.
The preferred method for blood pressure measurement is standard mercury 
sphygmomanometry.  If a standard mercury sphygmomanometer is not available, it is 
suggested that the investigator use http://www.dableducational.org to determine if the device 
is recommended.
Initially, blood pressure should be taken 3 times in both arms. If the mean pressures differ by 
more than 10 mmHg, the arm with the higher pressure (systolic or – if needed, diastolic) 

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should be used for subsequent measurements.  If the pressures are <≤10mmHg, the non-
dominant arm 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 and type of device should be used throughout the trial, for a 
given patient.   All blood pressure measurements should be performed approximately at the 
same time, i.e. in the morning prior to any blood being drawn or any study medication being 
taken.
After patients have rested quietly, in the seated position for two minutes, three blood pressure 
measurements will be taken approximately two minutes apart.  The seated pulse rate will be 
taken during the two-minute interval between the second and third blood pressure reading.
Blood pressure measurements should be recorded to the nearest 2 mmHg only when 
measured with a manual sphygmomanometer; when digital devices are used the value from 
the device should be recorded to the nearest 1 mmHg and the pulse rate from the second 
measurement should be used.
For calculation of mean values, decimal places should be rounded to integers (e.g. a DBP of 
94.5 would be rounded to 95 mmHg and a DBP of 109.4 would be rounded to 109 mmHg).
10.3
ORTHOSTATIC BLOOD PRESSURE MEASUREMENT PROCEDURE
Orthostatic blood pressure measurements should be performed on the same arm as BP and 
ABPM and, if possible, by the same person. The same method and device must be used 
throughout the trial, for a given patient. All blood pressure measurements should be 
performed approximately at the same time, i.e. in the morning prior to any blood being drawn 
or any study medication being taken.
Procedure for Orthostatic Blood pressure:
1. Obtain the patient’s pulse rate and BP while supine for 5 minutes
2. Record the readings
3. Have the patient stand.
4. Obtain the patient’s pulse  rate and BP every minute during the first 3 minutes while 
standing  (1, 2 and 3 minutes)
5. Record the readings
If any one of the three pulse rates has increased by 20 BPM from the supine pulse rate or any 
one of the three systolic blood pressures has decreased by 20 mmHg from supine SBP, or any 
one of the three DBPs has decreased by 10 mmHg from supine DBP, orthostatic BP test is 
considered positive.

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If the patient is unable to stand, orthostatic BP test may be taken while the patient is sitting 
with feet dangling. If positive orthostatic BP test changes occur while sitting, DO NOT 
continue in the standing position. 
Document the time and vital signs for supine and standing positions after 1, 2 and 3 minutes.
10.4
CLINICAL EVALUATION OF LIVER INJURY
10.4.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 , AESI, and hepatic 
SAEs are to be further evaluated using the following procedures: 
10.4.2
Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 
to 72 hours and provide additional blood sample to the central laboratory for automatic reflex 
testing of the below listed laboratory parameters. Only in case whereby the central laboratory 
is not immediately available (e.g. if the logistics are such that the patient´s repeat specimen 
would not reach the central laboratory in a reasonable timeframe), ALT, AST, and bilirubin 
(total and direct) will be evaluated by local laboratory and results are made available to the 
investigator and to BI as soon as possible. If in such a case ALT and/or AST >3 fold ULN 
combined with an elevation of total bilirubin >2 fold ULN or an isolated elevation of AST 
and/or ALT ≥ 5 fold ULN (without an elevation of total bilirubin ≥ 2 fold ULN) are 
confirmed, results of the laboratory parameters described below must be made available to 
the investigator and to BI as soon as possible.
In addition, 
o
obtain a detailed history of current symptoms and concurrent diagnoses and 
medical history according to the “DILI checklist” provided in the ISF 
o
obtain history of concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets according to the “DILI checklist” 
provided in the ISF;
o
obtain a history of exposure to environmental chemical agents (consider home 
and work place exposure) according to the “DILI checklist” provided in the 
ISF;
and report these via the CRF and/or the “DILI checklist”.
The following laboratory tests should be performed:

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Clinical chemistry
alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferrin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Hep A total), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C 
(Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Hep D Antibody), Hepatitis E (Anti-
HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody (titer), Anti-
nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-mitochondrial 
antibody
Hormones, tumor marker
TSH
Haematology
Thrombocytes, eosinophils
o
Provide abdominal ultrasound to rule out biliary tract, pancreatic or 
intrahepatic pathology, e.g. bile duct stones or neoplasm.
o
Initiate close observation of subjects by repeat testing of ALT, AST, and total 
bilirubin (with fractionation by total and direct) at least weekly until the 
laboratory ALT and / or AST abnormalities stabilize or return to normal, then 
according to the protocol. Depending on further laboratory changes, additional 
parameters identified e.g. by reflex testing will be followed up based on 
medical judgement and GCP.

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11.
DESCRIPTION OF GLOBAL AMENDMENTS
11.1
GLOBAL AMENDMENT 1 CHANGES
Number of global 
amendment
1.0
Date of CTP 
revision
16Dec2014
EudraCT number
N/A
BI Trial number
1245.29
BI Investigational 
Product(s)
empagliflozin
Title of protocol
A randomised, double-blind, placebo-controlled, parallel group, 
efficacy and safety study of empagliflozin (10 mg, 25 mg) 
administered orally, once daily over 24 weeks in hypertensive 
black/African American patients with type 2 diabetes mellitus
To be implemented 
only after approval 
of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in 
order to eliminate 
hazard –
IRB / IEC / 
Competent 
Authority to be 
notified of change 
with request for 
approval
Can be implemented 
without IRB/IEC/ 
Competent 
Authority approval 
as changes involve 
logistical or 
administrative 
aspects only
Section to be 
changed
1
Synopsis; Main criteria for inclusion and 3.3.2 Inclusion criteria
Description of 
change
1. Diagnosis of T2DM prior to informed consent.

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Number of global 
amendment
1.0
Note: Documentation should be available before randomization 
at latest.  Confirmation can be in the form of formal documents 
or by verbal communication of the date of diagnosis from a 
patient or from their primary care physician (if records are not 
available).  It is up to the medical judgment of the Investigator 
to deem if the information is accurate.
Rationale for 
change
Clarification of this inclusion criteria
Section to be 
changed
2
Synopsis; Main criteria for inclusion and 3.3.2 Inclusion criteria
Description of 
change
2. Male and female black/African American patients on diet and 
exercise regimen alone or who are:
drug-naïve (defined as absence of any oral antidiabetic therapy , 
GLP-1 analog or insulin for 12 weeks, 16 weeks for pioglitazone 
prior to randomisation) 
or  
pre-treated with stable dose of metformin at a minimum dose of  
1500 mg/day or maximum tolerated dose unchanged for 12 
weeks prior to randomisation.
Rationale for 
change
Some patients are not on or able to tolerate a Metformin dose of 
1500mg/day.  This change will allow entry of patients who are on a 
lower or maximum tolerate stable dose of Metformin into the study.
Section to be 
changed
3
Synopsis; Main criteria for inclusion and 3.3.2 Inclusion criteria
Description of 
change
6. Treatment with stable doses of at least one but not more than 3
≤ 3 antihypertensive medication 4 weeks prior to 
randomisation.
Rationale for 
change
Clarification on number of stable anti-hypertensive medication.  
Section to be 
changed
4
Synopsis: Criteria for safety
Description of 
change
All adverse events including hypoglycaemic events and protocol 
specified adverse events of special interest (AESI) cardiovascular 
events (Clinical Event Committee adjudication results), changes from 
baseline in electrocardiogram (ECG) and clinical laboratory values
Rationale for 
change
Removed reference to CEC and ECG

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Number of global 
amendment
1.0
Section to be 
changed
5
Synopsis: Statistical methods; 7.1 Statistical Design-model; 7.3.1 
Primary analysis; 7.3.2 Secondary analysis; 7.5 Randomisation
Description of 
change
background medication of pretreatment with Metformin
Rationale for 
change
Correcting reference to metformin as pretreatment.
Section to be 
changed
6
Flowchart 
Description of 
change
1. Visit window for visit 2.2 adjusted from -6 to +6.
2. Visit window for visit 5.2 adjusted from -2/+7 to -1/+7.
3. Added check for food log completion.
4. Foot note “N” combined with “B”; Foot note “N” removed. 
Added: ABPM visits should not overlap with subsequent 
visits.
5. Fasting blood and urine samples to be collected, for central 
labs at each visit indicated (refer to Lab manual). except: 
uA urine dipstick to be done locally,; upon positive result at 
site for leukocyte esterase (WBC) or nitrites a midstream 
urine sample for urine culture (central lab analysis) should be 
taken and sent for urine culture analysis (central lab).
6. At the conclusion of each attempt, patient should be 
allowed to rest for at least 15 minutes after removal of the 
ABPM and a trough seated blood pressure measurement 
should be taken prior to intake of study medication.
7. /PWA
8. At these visits samples for liver fibrosis, inflammation and/or 
steatosis will be collected.
Rationale for 
change
1. Correction of window
2. Correction of window to avoid overlap of visits
3. Correction.
4. Clarification
5. Clarification of safety labs to be collected at each visit
6. Adjustment of footnotes
7. Clarification
8. Clarification to specify PWA measurements
9. Clerical correction
Section to be 
changed
7
Abbreviations
Description of 
change
DEDP      Drug Exposure During Pregnancy
DMC        Data Monitoring Committee
Rationale for
change
Added new term
Removed reference to DMC

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Number of global 
amendment
1.0
Section to be 
changed
8
3.1 Overall Trial Design and Plan
Description of 
change
The Residual Effect Period (REP), that is, the time period, for which 
adverse events will still be considered “on-treatment” is  7 days
following last intake of trial medication. Events which occurred 
after the REP will be considered as post treatment events. All 
AEs, including those persisting after trial completion must be tracked
followed up until they have resolved ution, have been sufficiency 
characterized,  or until the site confirms that no further information 
can be obtained.
Rationale for 
change
Clarification on the definition of adverse events occurring within the 
REP and follow up activities.
Section to be 
changed
9
3.1.1 Administrative structure of the trial
Description of 
change
Clinical Event Committee
An independent external committee (Clinical Event Committee 
(CEC)) will be established to adjudicate centrally and in a blinded 
fashion events suspect of stroke, myocardial ischemia (incl. 
myocardial infarction), cardiovascular death and other relevant 
events based on the FDA guideline [R09-2151]. 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 ECGs, laboratory values, 
angiography, echocardiography reports, CAT scan (CT) and or 
Magnetic Resonance Imaging (MRI) scans, discharge summaries, 
and autopsy reports to support the external event adjudication. 
The tasks and responsibilities of the CEC will be filed in a contract 
before initiation of the trial and will contain written operating 
procedures. The CEC will maintain the adjudication results in 
writing. Details will be described in a specific charter. 
Rationale for 
change
Data from this study will not be adjudicated for cardiac events.
Section to be 
changed
10
3.3.3 Exclusion criteria
Description of 
change
18. Systolic blood pressure difference of >10 mmHg between the 
arms at screening.  
Rationale for 
change
Not required for safety reasons per consultation with co-ordinating 
investigator.  This exclusion criteria was also in conflict with 

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instructions for measuring BP in Appendix. 
Section to be 
changed
11
3.3.4 Removal of patients from therapy or assessment
Description of 
change
All patients who discontinue from treatment after randomisation 
(Visit 3 and beyond) will be followed up until the end of the study. It 
is very important that patients who discontinue treatment after 
randomisation conduct a premature discontinuation visit (Visit 7.2 
procedures) and also a follow-up visit (Visit 8 procedures).  After 
these procedures, the patient should return to complete the 
remainder of the scheduled visits are followed up using the same 
visit schedule until the end of the trial (For further details please see 
Section 6.2.2).  The last per study contact for these patients 
should be at Visit 7.2; Visit 8 will not need to be done at this 
point.   If a patient is not able to attend a study visit, the study staff 
should contact him/her (or someone designated – e.g. family member 
or personal physician) to inquire about medical information 
pertaining to adverse events, particularly primary and key secondary 
outcome events, and/or mortality, until the end of the study.  
Alternatively, data should be collected from medical records. 
Additionally the investigator will ask patients who discontinued the 
study drug to actively contact the site in case of a cardiovascular 
outcome event that may qualify as a primary or key secondary 
endpoint (i.e. Non-fatal MI, non-fatal stroke, hospitalization for 
unstable angina).
If a patient withdraws consent, participation in the study will end, the 
study medication will be stopped and the study staff will try to 
arrange the End of Study tests and procedures tests for premature 
discontinuation procedures and a follow-up visit (Visit 8 
procedures) with the patient for the patient’s safety. All used 
medication kit boxes and remaining study medication should be 
returned. Patients who withdraw consent will not be contacted any 
more about the study.
Rationale for 
change
Clarification of study procedures and visits for patients who 
prematurely discontinue study medication.
Section to be 
changed
12
4.2.1 Rescue medication, emergency procedures and additional 
treatments; 
Description of 
change
Adjustment of the background current therapy or addition of another 
antidiabetic and/or antihypertensive medication would be 
appropriate.
Rationale for 
change
Clarified reference to background medication as current therapy.

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Section to be 
changed
13
4.2.2.1 Restrictions regarding concomitant treatment
Description of 
change
In any situation other than rescue conditions, the use of other 
antidiabetic and antihypertensive agents will be prohibited during the 
course of the study except for background existing current therapy 
and, if applicable, the ongoing rescue medication.
Rationale for 
change
Clarified reference to background medication as existing current 
therapy.
Section to be 
14
5.1.1 Endpoints of efficacy

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change
clarification.  

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Change from baseline 
 
Section to be 
changed
19
5.1.2 Assessment of efficacy
Description of 
change
At each ABPM/PWA visit (Visits 2.2, 5.1 and 7.1), patients are to 
come to the clinic fasting and the following procedure will be 
performed.   The ABPM/PWA monitor will be attached to the patient 
and test readings will be taken to checked to see if the device it is 
working properly prior to medication intake.  The first test reading 
is the Beginning of Test reading. Once it has been confirmed that 
the monitor is properly functioning, study medication will be 
administered followed by prompting of the monitor to take the 
Beginning of Test reading.  Record the time the medication was 
administered and the time the monitor was prompted to take the 
Beginning of Test reading.  The next day when the patient returns to 
the clinic, the monitor will be prompted to take a Conclusion of Test 
reading.  The device will then be removed and the time of the 
Conclusion of Test will be recorded.  This should be done within 22
23:30-24 hours of starting monitor. 
Rationale for 
change
Clarification on the Beginning of Test ABPM reading and time frame 
for Conclusion of Test.
Section to be 
20

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Section to be 
changed
21
5.2.1 Endpoints of safety
Description of 
change

Protocol-specified aAdverse events of special interest (AESI)
Rationale for 
change
Updating name for adverse events of special interest
Section to be 
changed
22
5.2.2.1 Definitions of adverse events (Adverse event)
Description of 
change
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.
Rationale for 
change
Clarification of AE definition
Section to be 
changed
23
5.2.2.1 Definitions of adverse events (Serious adverse event)
Description of 
change
A serious adverse event (SAE) is defined as any AE which results in 
death, is immediately life-threatening, results in persistent or 
significant disability / incapacity, requires or prolongs inpatient 
hospitalisation or prolongation of existing hospitalization, is a 
congenital anomaly / birth defect, or is to be deemed serious for any 
other reason if it is an important medical event when based upon 
appropriate medical judgement which may jeopardise the patient and 
may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definitions.
Life-threatening in this context refers to an event in which the 
patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if 
more severe.
Every new occurrence of cancer will be reported as a SAE 

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regardless of the duration between discontinuation of the drug and 
the occurrence of the cancer.
Cancers with new histology or exacerbation of an existing cancer are 
always considered serious.
Rationale for 
change
Updated definition of SAE.
Section to be 
changed
24
5.2.2.1 Definitions of adverse events (Causal relationship of adverse 
event)
Description of 
change
Medical judgment should be used to determine the relationship, 
considering all relevant factors, including pattern of reaction, 
temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and 
relevant history. Assessment of causal relationship should be 
recorded in the case report forms. 
Yes:
There is a reasonable causal relationship between the 
investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the 
investigational product 
administered and the AE. 
If a SAE is reported from a still blinded trial, tThe causal relationship 
must be provided by the investigator for all potential trial drugs, i.e. 
the BI trial drug and for all other trial drugs (i.e. such as any active 
comparator or placebo and for according to the trial 
proceduredesign).
The reason for the decision on causal relationship needs to be 
provided on the SAE form (if applicable).
Rationale for 
change
Updating language for causality of AEs.
Section to be 
changed
25
5.2.2.1 Definitions of adverse events
Description of 
change
AEs considered “Always Serious” 
In accordance with the European Medicines Agency initiative on 
Important Medical Events, Boehringer Ingelheim has set up a list 
of AEs, which by their nature, can always be considered to be 
“serious” even though they may not have met the criteria of an 
SAE as given above.   In order to support the investigator with 
the identification of these “always serious adverse events”, if a 

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non-serious AE is identified to be serious per BI definition, a 
query will be raised. The investigator must verify the description 
and seriousness of the event.  If the event description is correct, 
the item “serious” needs to be ticked.  These events should always 
be reported as SAEs as described in section 5.2.2.2.
The latest list of “Always Serious AEs” can be found in the RDC 
system.  
Rationale for 
change
Updated description of how to manage BI always serious adverse 
events. 
Section to be 
changed
26
5.2.2.1 Definitions of adverse events
Description of 
change
Protocol Specified Adverse Events of Special Interest (AESI)

The term AESI relates to any specific AE that has been 
identified at the project level as being of particular 
concern for prospective safety monitoring and safety 
assessment within this trial, e.g. the potential for AEs 
based on knowledge from other compounds in the same 
class. AESI need to be reported to the Sponsor’s 
Pharmacovigilance Department within the same timeframe 
that applies to SAE. The term AESI are events of medical 
concern requiring monitoring and rapid communication and 
can be classified as either serious or non-serious.  

In addition These lab findings constitute a hepatic injury 
alert and the patients showing the above alterations in liver 
parameters or hepatic (S)AEs should be followed up 
according to Section 10.5.2 of this CTP  and the “DILI 
checklist” provided in the ISF.
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.
Rationale for 
Clarification of definition and instructions for AESI with updated 

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change
language.  
Section to be 
changed
27
5.2.2.2 Adverse event and serious adverse event reporting
Description of 
change
All AEs, serious and non-serious, occurring during the course of the 
clinical trial (i.e., from signing the informed consent onwards through 
the Follow-up period) will be collected, documented and reported to 
the sponsor by the investigator on the appropriate CRF(s) / eCRFs / 
SAE reporting forms. Reporting will be done according to the 
specific definitions and instructions detailed in the ‘Adverse Event 
Reporting’ section of the ISF. 
AE Collection 
The following must be collected and documented on the appropriate 
eCRF by the Investigator:
From signing the informed consent onwards until trial 
completion (End of Trial) or last per protocol contact, all AEs 
(serious and non-serious), and AESIs.  This also applies to 
patients who prematurely discontinue from the study.
For each adverse event, the investigator will provide the onset date, 
end date, intensity, treatment required, outcome, seriousness, and 
action taken with the investigational drug. The investigator will 
determine the relationship of the investigational drug to all AEs as 
defined in Section 5.2.2.1. 
The Residual Effect Period (REP), that is, the time period, for which 
adverse events will still be considered “on-treatment” is  7 days
following last intake of trial medication. Events which occurred after 
the REP will be considered as post treatment events.
Post Study:  After the last per protocol contact, Tthe investigator 
does not need to actively monitor patients for AEs adverse events 
once the clinical trial has ended. However, if the investigator 

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becomes aware of an SAE(s) or AESI that occurred after the last per 
protocol contact patient has completed the clinical trial (including 
any protocol required REP and / or follow-up), it should be reported 
by the investigator to the sponsor if considered relevant by the 
investigator.  Reporting will be done according to the specific 
definitions and instructions detailed in the ‘Adverse Event Reporting’ 
section of the ISF. 
BI has set up a list of AEs which are defined to be always serious. In 
order to support the investigator with the identification of these 
“always serious adverse events”, if a non-serious AE is identified to 
be serious per BI definition, a query will be raised. The investigator 
must verify the description and seriousness of the event.  If the event 
description is correct, the item “serious” needs to be ticked and an 
SAE has to be reported in expedited fashion following the same 
procedure as above.
The list of these adverse events can be found via the RDC-system.
With receipt of any further information to these events, a follow-up 
SAE report has to be provided. SAEs, AESI and non-serious AEs 
must include a causal relationship assessment made by the 
investigator.
The SAE form is to be forwarded immediately (within 24 hours of 
awareness) to the defined unique entry point identified for the BI 
OPU (country-specific contact details will be provided in the ISF) or 
by using the electronic submission process. This immediate report is 
required irrespective of whether the investigational product has been 
administered or not and irrespective of causal relationship. In 
specific occasions the Investigator could inform the Sponsor 
upfront via telephone; however, this does not replace the 
requirement to complete and submit the BI SAE form.  It also 
applies if new information to existing SAEs, AESI or non-serious 
AEs relevant to the SAE or AESI becomes available. 
Pregnancy
In the rare case that a female subject participating in this clinical 
trial becomes pregnant s, pregnancy might occur in clinical trials. 
Once a female subject has been enrolled into the clinical trial, after 
having taken study medication, the investigator must report 
immediately (within 24 hours) any the drug exposure during 
pregnancy (DEDP) to the sponsor’s. Drug exposure during 
pregnancy has to be reported immediately (within 24 hours of 
awareness to the defined unique entry point for SAE forms of the 

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Number of global 
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respective BI OPU (country-specific contact details will be provided 
in the ISF). The Pregnancy Monitoring Form for Clinical Trials 
(Part A) should be used.
The outcome of the pregnancy associated with the drug exposure 
during pregnancy must be followed up and reported to the 
Sponsor’s unique entry point on the Pregnancy Monitoring Form 
for Clinical Trials (Part B).
In the absence of an (S)AE, only the Pregnancy Monitoring Form for 
Clinical Trials and not the SAE form is to be completed. If there is 
an SAE associated with the pregnancy then the SAE has to be 
reported on the SAE form in addition.
Rationale for 
change
Clarification on the instructions for reporting AEs and SAE with 
updated language.  
Section to be 
changed
28
5.2.4 Electrocardiogram
Description of 
change
At start of run-in and end of treatment, a complete physical 
examination will be performed by the investigator or qualified 
designee (see Flow Chart). Documentation of, and findings from the 
physical examination, must be part of the source documents available 
at the site.
Rationale for 
change
Added allowance for qualified designee to perform physical exams
Section to be 
changed
29
6.2.1 Screening and run-in period;  Visit 2.2 (Baseline ABPM visit)
Description of 
change

The next day when the patient returns to the clinic (within 22
23:30-24 hours of the beginning of the test), prompt the monitor 
to take a Conclusion of Test reading.  The monitor will then be 
removed and the time of the Conclusion of Test will be 
recorded. 

Allow the patient to rest for at least 15 minutes after the monitor 
is removed.  Then take a seated blood pressure measurement.  
Record the time of this measurement.  This should be done 
prior to administering study medication. 
Rationale for 
change
Clarification on the time frame for Conclusion of Test and rest time 
after removal of monitor at Visit 2.2. and 
Section to be 
changed
30
6.2.2 Treatment period; Visit 5.1 (Week 12 ABPM visit) and Visit 

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7.1 
Description of 
change

Attach ABPM/PWA monitor to the patient and initiate the test 
readings to ensure the monitor is operating properly. 

Administer study medication on the morning of the study visit 
after the test readings have confirmed that the device is 
operating properly prior to starting the monitor. Record the 
time the medication was administered and the time the 
monitor was prompted to take the Beginning of Test reading.

The next day when the patient returns to the clinic (within 22
23:30-24 hours of the beginning of the test), prompt the monitor 
to take a Conclusion of Test reading.  The monitor will then be 
removed and the time of the Conclusion of Test will be 
recorded.  

Allow the patient to rest for at least 15 minutes after the monitor
is removed.  Then take a seated blood pressure measurement.  
Record the time of this measurement.  This should be done 
prior to administering study medication.
Rationale for 
change
Clarification on timing and procedure for staring ABPM readings, the 
time frame for Conclusion of Test and rest time after removal of the 
monitor at Visits 5.1 and 7.1. 
Section to be 
changed
31
6.2.3 End of trial and follow-up period
Description of 
change
Patients discontinuing trial medication early from the trial
Patients who stop study medication for more than 7 consecutive days 
during the trial should have the discontinuation recorded in the 
eCRFs. In general patients should be encouraged to re-start study 
medication in case of temporary treatment interruptions.  If the 
duration of interruption is more than 7 days, this should be 
recorded in the “Study Medication Temporary Discontinued/re-
started" eCRF.  
For patients who stop study medication permanently, a 
premature discontinuation visit (Visit 7.2 procedures) and also a 
follow-up visit (Visit 8 procedures) should be conducted.  The 
patient should then continue with to follow the study visit schedule 
per the Flow Chart with the exception of the follow up visit which 
will not be required.  The last per study contact should be at Visit 
7.2.  If determined by investigator as necessary for patient safety, 
new antidiabetic medication regimen can be started immediately after 

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discontinuation and must be recorded in eCRFs. 
Patients who withdraw consent
Patients who withdraw consent during the trial will be asked to 
complete premature discontinuation procedures and a follow-up 
visit (Visit 8 procedures) Final Visit and Follow up procedures, for 
their safety.  A patient who reverses the decision to withdraw consent 
should be re-consented with the latest version and will continue the 
visit schedule according to the date of randomization. 
In case of premature discontinuation from the 24 week treatment 
period, a Visit 7.2 procedures should be performed and the patient 
should return to Visit 8 (14 days after Visit 7.2). The following 
procedures should be performed at Visit 8.
Rationale for 
change
Provide clarification on procedures and study visit to be conducted 
for patients who prematurely discontinue treatment or withdraw 
consent.
Section to be 
changed
32
7.3 PLANNED ANALYSIS
Description of 
change
Full Analysis Set
The full analysis set (FAS) will consist of all randomised patients 
who were treated with at least one dose of study drug and had a 
baseline and at least one follow-up on-treatment HbA1c 
measurement
Rationale for 
change
Correction on definition of full analysis set to clearly state that the 
HbA1c measurement after baseline needs to be an on-treatment 
measurement.
Section to be 
changed
33
7.3 PLANNED ANALYSIS
Description of 
change
Per Protocol Set
Further details on the definition of the PPS will be provided in the 
Trial Statistical Analysis Plan (TSAP).
Rationale for 
change
Corrected for document formatting.
Section to be 
changed
34
7.3.3 Safety analyses

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Description of 
change
Adverse events will be coded using the Medical Dictionary for Drug 
Regulatory Affairs (MedDRA). Adverse events occurring prior to the 
first drug administration will be assigned to the screening period 
while all other adverse events, if within 7 days of the last study 
medication intake, will be assigned to the treatment period for 
evaluation.  Events which occurred after the REP will be considered 
as post treatment events.
Rationale for 
change
Clarification on AEs after the REP.
Section to be 
changed
35
8.2 Data Quality Assurance
Description of 
change
In order to achieve a high level of standardised processes, data 
collection of efficacy and safety endpoints is coordinated centrally:

central lab analysis of efficacy endpoints, biomarkers and 
safety lab

central ECG collection (for clinically relevant ECG changes 
documented as an AE or suspected clinically relevant ECG 
changes)

central IRT system for stratification, randomisation and kit 
allocation at each visit

Central hepatic adjudication and malignancy assessment
Rationale for 
change
Removed reference to ECG collection and adjudication.
Section to be 
changed
36
9.1 Published References
Description of 
change
R09-2151
FDA Guidance for Industry - Diabetes Mellitus -
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to 
Treat Type 2 Diabetes
Rationale for 
change
CEC will not be utilized in the study.  Removed reference.
Section to be 
changed
37
10.3 Blood pressure measurement procedures
Description of 
change
The preferred method for blood pressure measurement is standard 
mercury sphygmomanometry.  If a standard mercury 
sphygmomanometer is not available, it.  It is suggested that the 
investigator use http://www.dableducational.org/
www.dsbleducational.org to determine if the device is recommended.

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Number of global 
amendment
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Rationale for 
change
Corrected link to webpage.
11.2
GLOBAL AMENDMENT 2 CHANGES
Number of global 
amendment
2.0
Date of CTP 
revision
12Aug2015
EudraCT number
N/A
BI Trial number
1245.29
BI Investigational 
Product(s)
empagliflozin
Title of protocol
A randomised, double-blind, placebo-controlled, parallel group, 
efficacy and safety study of empagliflozin (10 mg, 25 mg) 
administered orally, once daily over 24 weeks in hypertensive 
black/African American patients with type 2 diabetes mellitus
To be implemented 
only after approval 
of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in 
order to eliminate 
hazard –
IRB / IEC / 
Competent 
Authority to be 
notified of change 
with request for 
approval
Can be implemented 
without IRB/IEC/ 
Competent 
Authority approval 
as changes involve 
logistical or 
administrative 
aspects only
Section to be 
1
Synopsis: No. of patients; 3.1 Overall trial design and plan; 3.3 

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Number of global 
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2.0
changed
Selection of trial population 
Description of 
change
Total no. of sites: 70 85
Total no. of patients screened: 560 385
Total no/ of patients entered: 280 154
No. of patients in each treatment group: 140 77
No. of patients at each site: 4 2
Rationale for 
change
Patient numbers adjusted according to a decrease in statistical 
power determined for the study.
Section to be 
changed
2
Synopsis; Main criteria for inclusion and 3.3.2 Inclusion criteria
Description of 
change
2. Male and female black/African American patients on diet and 
exercise regimen who are:
drug-naïve (defined as absence of any oral antidiabetic therapy , 
glucagon like peptide-1 (GLP-1) analog or insulin for 12 weeks, 
16 weeks for pioglitazone prior to randomisation) 
or  
pre-treated with stable dose of metformin, sulfonylurea (SU), 
DPP-4 inhibitor, metformin plus sulfonylurea or metformin 
plus DPP-4 inhibitor.  
Treatment has to be unchanged for a minimum of 12 weeks 
prior to randomisation
Minimum dose for metformin:
- 1500 mg/day or 
- maximum tolerated dose 
The maximum daily dose of SU or DPP-4 inhibitor should not 
exceed that stated in the local label 
at a minimum dose of  ≥ 1500 mg/day or maximum tolerated 
dose unchanged for 12 weeks prior to randomization.
note:  Patients who were screen failed due to exclusionary 
anti-diabetic background medication according to versions of 
the protocol prior to Version 3 (SU, SU+Met, DPP-4
inhibitor, DPP-4 inhibitor +Met) are allowed to be re-
screened.
Rationale for 
change
Allow inclusion of patients currently treated with sulfonylurea, 
DPP-4 inhibitor.
Section to be 
changed
3
Synopsis: Criteria for efficacy; 2.1 Rational for performing the 
trial; 2.2 Trial Objectives; 5.1.1 Endpoints of efficacy; 7.2 Null 
and alternative hypothesis
Description of 
Added to key secondary endpoint: change from baseline in body 

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change
weight in kilograms (kg) at 24 weeks of treatment
Removed from key secondary endpoint:  change from baseline in 
mean 24-hr ambulatory diastolic blood pressure (DBP) at 12 
weeks.
Rationale for 
change
Readjustment of key secondary endpoints to include body weight. 
Mean 24-hr DBP at 12 weeks moved from key secondary 
endpoint to secondary endpoint section.
Section to be 
changed
4
Synopsis: Statistical methods
Description of 
change
For the change from baseline in trough seated SBP up to 12 
weeks of treatment and the change from baseline in body 
weight in kg at 24 weeks as well a restricted maximum 
likelihood estimation based on mixed-effect models for repeated 
measures analysis will be used to obtain adjusted means for the 
treatment effects on the full analysis set (FAS). Theseis models
will include the same discrete fixed effects as the model for the 
primary endpoint and baseline HbA1c as continuous fixed effect, 
as well as interaction between visit and treatment, and interaction 
between visit and baseline measurement of the key secondary 
endpoint, as well as the corresponding baseline measurements of 
the key secondary endpoint as continuous effect . The primary 
treatment comparisons will be the contrast between treatments at 
the 12 week visit for seated SBP and 24 week visit for body 
weight.
The key secondary endpoint change from baseline in 24-hour 
ambulatory SBP and DBP at 12 weeks, and change from mean 
trough ambulatory SBP at 12 weeks will be analyzed by using an 
analysis of covariance (ANCOVA) approach in the FAS with last 
observation carried forward (LOCF) for missing data. The model 
will include randomised treatment, renal function at baseline, 
pretreatment with Metformin at screening as discrete fixed 
effects and the baseline of the key secondary endpoint and 
HbA1c at baseline as continuous fixed effects. 
The overall type I error across the hypotheses tests in the 
confirmatory analysis will be maintained at a level of α ≤ 0.05 
using a hierarchical testing sequence. 
The sample size of 140 154 patients per group was derived 
(assuming n=64 per groups plus a 20% drop-out rate) based 
on the requirement that the comparisons of empagliflozin versus 
placebo with respect to the HbA1c. and BP and body weight 

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should have a power of at least 980% at the two-sided α level of 
5%.  
Rationale for 
change
Inclusion of body weight as a key secondary endpoints; sample 
size reduced according to recalculation of statistical power for the
study.  
Section to be 
changed
5
Flowchart
Description of 
change
1. Added column for PTD visit and footnote S added
2. Visit window for visit 2.2 adjusted from +6 to +7.
3. Visit window for visit 5.1 adjusted from -5 to +7.
4. Visit window for visit 5.2 adjusted from -1/+7 to -7/+7.
5. Visit window for visit 7.1 adjusted from +5 to +14.
6. Footnote R added
7. Footnote “B”; Removed: sentences stating that ABPM 
visits should not overlap with subsequent visits and added 
If the ABPM testing is successful, procedures for the 
subsequent visit can be conducted on the same day 
after the ABPM device is removed and trough seated 
blood pressure measurement is taken.  
8. Footnote “J”; added: At Visit 7.2 patients should not 
intake study medication after collection of PK sample.  
Rationale for 
change
1. Clarify PTD visit procedures and timing.
2. Allow following visit procedures to be conducted after 
successful completion of ABPM session.
3. Allow following visit procedures to be conducted after 
successful completion of ABPM session.
4. Allow following visit procedures to be conducted after 
successful completion of ABPM session.
5. Allow following visit procedures to be conducted after 
successful completion of ABPM session.
6. Clarification
7. Allow following visit procedures to be conducted after 
successful completion of ABPM session.
8. Clarification
Section to be 
changed
6
Entire Document
Description of 
change
References to pulse wave assessment (PWA) removed from body 
of document.
Rationale for 
change
PWA will be removed as a study procedure and data will no 
longer be collected.
Section to be 
7
Abbreviations

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changed
Description of 
change
Cl-            Chloride
DKA        Diabetic Ketoacidosis
HCO3
-      Bicarbonate
mEq/L      milliequivalents per litre
mg/dl      milligrams per decilitre
PWA        Pulse Wave Analysis
Rationale for 
change
Added new terms and removed reference to PWA
Section to be 
changed
8
2.3
Benefit - Risk Assessment
Description of 
change
Special attention will be paid to monitor for diabetic 
ketoacidosis (DKA). A potential risk for DKA has been 
reported by the FDA in patients treated with SGLT2 
inhibitors, including empagliflozin. In a number of reported 
cases, the presentation of the condition was atypical with only 
moderately increased blood glucose values, below 14 mmol/L 
(250 mg/dl).
The risk of DKA must be considered in the event of non-
specific symptoms such as nausea, vomiting, anorexia, 
abdominal pain, excessive thirst, difficulty breathing, 
confusion, unusual fatigue or sleepiness. In addition it needs 
to be taken into account that, due to the insulin independent 
mode of action, there is a possibility that ketoacidosis in 
patients treated with SGLT2 inhibitors is not accompanied by 
typical hyperglycemia as usually expected for DKA.
Patients who may be at higher risk of DKA while taking 
SGLT2 inhibitors include patients on a very low 
carbohydrate diet (as the combination may further increase 
ketone body production), severely dehydrated patients, and 
patients with a history of ketoacidosis or who are known to 
have a low beta-cell function reserve.
Rationale for 
change
Added information on DKA class effect and risks of DKA with 
empagliflozin.
Section to be 
changed
9
3.1.1 Administrative structure of the trial and 8.2 Data Quality 
assurance
Description of 
change
Section 3.1.1. 
Hepatic External Adjudication and Cancer Assessments

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Certain events of cancer and certain hepatic events will be 
adjudicated / assessed by external independent experts. The 
events which will be reviewed will be defined in two a charters, 
one for hepatic events and one for malignancies.  Events may be 
defined as abnormal laboratory values and/or relevant adverse 
events or both.  For example, assessments will be made for events 
of malignancies and hepatic injury events, including liver enzyme 
elevations.
Section 8.2.  
Central hepatic adjudication and malignancy assessment
Rationale for 
change
Within the huge clinical trial program there is no evidence that 
empagliflozin treatment is associated with an increased risk of 
cancer.  Therefore no further cancer assessments are deemed 
necessary.
Section to be 
changed
10
3.2
Discussion of trial design, including the choice of control 
group
Description of 
change
Sulfonylureas and DPP-4 inhibitors can be used as 
monotherapy but are frequently added to metformin when 
patients are not at goal with metformin. Sulfonylureas (eg. 
Glimiperide, glyburide, glipizide) and DPP-4 inhibitors (eg. 
sitagliptin, linagliptin, saxagliptin, alogliptin) are important 
alternative monotherapies when metformin is not used and 
more importantly when used in combination with metformin. 
Therefore patients with current sulfonylurea or DPP-4 
inhibitor treatment represent an important proportion of the 
patient population with type 2 diabetes.
Rationale for 
change
Added information on patients treated with SU and DPP-4 
inhibitor; these patients are eligible for the study.
Section to be 
changed
11
3.3.3 Exclusion criteria
Description of 
change
Exposure to aAny other antidiabetic medication within 12 weeks 
prior to randomisation other than metformin, sulfonylurea, DPP-
4 inhibitor, metformin plus sulfonylurea or metformin plus 
DPP-4 inhibitor.
Rationale for 
change
Adjusted to permit entry of patient treated with monotherapy SU 
or DPP-4 inhibitor or in combination with metformin.
Section to be 
changed
12
3.3.3 Exclusion criteria

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Description of 
change
11. Acute coronary syndrome (non- ST wave elevated 
myocardial infarction (STEMI), STEMI and unstable 
angina pectoris), stroke or transient ischemic attack 
within 3 months prior to informed consent.
22. Intake of an investigational drug in another trial within 30 
days prior to intake of study medication in this trial; or 
participating in another trial (involving an investigational 
drug and/or follow-up) after discontinuing medication in 
that this trial.
Rationale for 
change
Correction of clerical errors.
Section to be 
changed
13
3.3.4 Removal of patients from therapy or assessment
Description of 
change
1) Occurrence of hypoglycemia (e.g. repeated 
hypoglycaemic episodes) or DKA that may put the 
patient at risk with continued participation. (e.g. repeated 
hypoglycaemic episodes) as assessed by the investigator. 
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.
2) Patients who drop out during the screening phase prior to 
randomisation (Visit 3) will be considered screening 
failures. They have to be recorded as screening failure in 
eCRFs and no further follow-up is required.  SAEs 
occurring in patients after having discontinued in the 
study due to screening failures and who did not receive 
any study medication, should be reported if the 
investigator considers the SAE to be related to the 
screening procedure.
3) For the analysis of this trial it is absolutely crucial that 
all planned assessments are done as planned, even if 
patients discontinue trial treatment.  All patients who 
discontinue from treatment after randomisation (Visit 3 
and beyond) and who do not withdraw consent will be 
followed up for the intended regular treatment period
until the end of the study. All assessments related to the 
primary and secondary endpoints must be performed 
as if the patient would have remained on treatment.  It 
is very important that patients who discontinue treatment 
after randomization conduct a premature discontinuation 

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visit (Visit 7.2 procedures) and also a follow-up visit 
(Visit 8 procedures). After these procedures, the patient 
should return to complete the remainder of the scheduled 
visits (For further details please see Details of 
procedures to be followed for patients prematurely 
terminating the trial treatment can be found in Section 
6.2.3).  The last per study contact for these patients should 
be at Visit 7.2; Visit 8 will not need to be done at this 
point.   If a patient is not able to attend a study visit, the 
study staff should contact him/her (or someone designated 
– e.g. family member or personal physician) to inquire 
about medical information pertaining to adverse events, 
particularly primary and key secondary outcome events, 
and/or mortality, until the end of the study.  Alternatively, 
data should be collected from medical records. 
Additionally the investigator will ask patients who 
discontinued the study drug to actively contact the site in 
case of a cardiovascular outcome event that may qualify 
as a primary or key secondary endpoint (i.e. Non-fatal MI, 
non-fatal stroke, hospitalization for unstable angina).
If a patient withdraws consent, participation in the study 
will end, the study medication will be stopped and the 
study staff will try to arrange tests for end of treatment
premature discontinuation procedures and a follow-up 
visit (Visit 8 procedures) with the patient for the patient’s 
safety  (For further details please see Section 6.2.3). All 
used medication kit boxes and remaining study 
medication should be returned. Patients who withdraw 
consent will not be contacted any more about the study.
Rationale for 
change
1) Included guidance for cases of DKA.
2) Removed reference to SAE reporting; detailed in section 
5.2.2
3) Clarification of follow up procedures for patients who 
prematurely discontinue from the study.
Section to be 
changed
14
4.2
Concomitant therapy, restrictions, and rescue treatment
Description of 
change
Patients who are treated with contraindicated medication 
should not be enrolled into the study.
Rationale for 
change
Added as a reminder to not enrol patients on contra-indicated 
medication.
Section to be 
changed
15
4.2.1
Rescue medication, emergency procedures, and additional 
treatments
Description of 
Special attention must be paid to monitor for instances of 

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change
DKA. All patients must be made aware of this risk and need 
to be instructed to contact the Investigator or other 
healthcare professional in case of symptoms of DKA. For 
further details see Section 2.3.
In case of a suspected DKA the Investigator should ensure 
that appropriate tests are performed at the earliest 
opportunity according to local guidelines, such as a blood gas 
test (i.e. pH, bicarbonate; the results will be collected on the 
relevant page of the eCRF) and that the patient is 
appropriately treated (i.e. hospitalized or referred to 
emergency treatment) according to local treatment 
guidelines.
Rationale for 
change
To provide guidance on managing cases of DKA.

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Number of global 
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Section to be 
changed
18
5.2.2 Assessment of adverse events
Description of 
change
1) Adjusted language for definitions of adverse events, 
residual effect period, AE reporting, and pregnancy and 
restructured section.
2) Metabolic acidosis, ketoacidosis and diabetic 
ketoacidosis (DKA)
In case of metabolic acidosis, ketoacidosis and DKA 
further investigations should be done according to the 
medical judgment and the clinical course until a 
diagnosis is made and/or the patient is recovered.
DKA is defined by the diagnostic criteria in Table 
5.2.2.1: 1 below, and as defined by the American 
Diabetes Association (ADA) [R14-5435].
Investigators should note that not all criteria in the 
table below need to apply for the diagnosis of DKA, 
and clinical judgment should also be taken into 
consideration. Due to its mechanism of action, 
empagliflozin may potentially modify the clinical 
presentation of DKA which may occur at lower plasma 
glucose levels than stated in Table 5.2.2.1: 1 below (see 
Section 2.3 for further details).
In case of a suspected DKA the Investigator should 
ensure that appropriate tests are performed locally at 
the earliest opportunity according to local guidelines, 
such as a blood gas test (pH, bicarbonate) and that the 
patient is appropriately treated (i.e. hospitalized or 
referred to emergency treatment) according to local 

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Number of global 
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treatment guidelines.
Table 5.2.2.1: 1
Diagnostic criteria for DKA
DKA
Mild
Moderat
e
Severe
Plasma Glucose (mg/dl)
>250
>250
>250
Arterial pH
7.25-
7.30
7.00-7.24
<7.00
Serum bicarbonate 
(mEg/L)
15-18
10-<15
<10
Urine ketones*
Positive
Positive
Positive
Serum ketones*
Positive
Positive
Positive
Effective serum osmolality 
(mOsm/kg)**
Variabl
e
Variable
Variabl
e
Anion gap***
>10
>12
>12
Alteration in sensoria or 
mental obtundation
Alert
Alert/dr
owsy
Stupor/
coma
*     Nitroprusside reaction method
**   Calculation: 2[measured Na (mEq/L) + glucose 
(mg/dl)/18]
*** Calculation: (Na+)-(Cl- + HCO3
-) (mEq/L)
Rationale for 
change
1) Update based on new template
2) Inclusion of DKA as AESI
Section to be 
changed
19
5.2.3
Assessment of safety laboratory parameters
Description of 
change
1) For the first visit after randomisation (4 weeks), only 
fasting plasma glucose and lipid status will be determined 
(see Flow Chart).
2) NAFLD fibrosis score will be calculated in-house at the 
central labs based on the following formula:
Rationale for 
change
1) Lipids will not be assessed at this visit, correction
2) Clarification on where scores will be calculated
Section to be 
changed
20

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Number of global 
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Section to be 
changed
21
6.2.1 Screening and run-in period (Visit 2.2); 6.2.2 Treatment 
period (Visit 5.1 and 7.1) 
Description of 
change
1. Added, “If an invalid reading occurs for the 
Conclusion of Test reading, continue to trigger a 
manual reading until a valid reading is registered.”
2. (Visit 2.2 only) added word to, “Patients having two 
technically unsuccessful baseline ABPM/PWA sessions 
should not be randomized and must be discontinued.”
3. Updated and added language to allow for procedures for 
next visits to be done on the same day as the return 
ABPM session if the ABPM reading is successful.
Rationale for 
change
1. Added procedure to ensure that the accurate conclusion of 
test (COT) is recorded on the device.  Only a valid 
reading will trigger the COT; otherwise the last valid 
reading will be used as the COT.
2. To emphasize that patients cannot be randomised if they 
do not achieve a successful baseline ABPM read.
3. Allowance provided for those patients who cannot take 
multiple days off in close succession. 
Section to be 
changed
22
6.2.3
End of trial and follow-up period
Description of 
change
For all patients who successfully completeing the study 
according to the protocol a follow-up visit (Visit 8) with the 
patient should be done by the investigator at the end of the 
follow-up period of 14 days.
Visit 8 (follow-up visit)

Vital signs

Body weight measurement

BP measurement and orthostatic blood pressure test should 
always be done before taking any blood samples. 

Collection of urine and blood for laboratory testing. 

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Number of global 
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
Documentation of any adverse events. 

Documentation of concomitant therapies
Rationale for 
change
Administrative change to clarify Visit 8 procedures and to 
include body weight data since this is now a key secondary 
endpoint.
Section to be 
changed
23
6.2.3
End of trial and follow-up period
Description of 
change
Patients discontinuing trial medication early from the trial
In general patients should be encouraged to re-start study 
medication in case of temporary treatment interruptions.  If the 
duration of interruption is more than 7 days, this should be 
recorded in the “Study Medication Temporary Discontinued/re-
started" eCRF.  
For the analysis of this trial it is absolutely crucial that all 
planned assessments are done as planned, even if patients 
discontinue trial treatment. Patients who discontinue 
treatment prematurely and who do not withdraw their 
informed consent must therefore be followed up for the 
intended regular treatment period. All assessments related to 
the primary and secondary endpoints must be performed as if 
the patient would have remained on treatment.
For patients who stop study medication permanently prior to 
completion of 24 weeks of treatment and who are willing to be 
followed up, the following should be performed whenever 
possible: 

Premature treatment discontinuation (PTD) visit
should be performed within 7 days of last intake of 
study drug or as soon as possible including all 
examinations and assessments that are part of the Visit 
7.2. If the PTD visit occurs within the time window of 
a scheduled visit, the PTD visit will replace the 
scheduled visit.

Subsequently, a follow-up visit (Visit 8 procedures) 
should be conducted within 14 days of the PTD on visit 
that replaces the next visit according to the visit 
schedule.

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
Thereafter, patients would be followed up according to 
the visit schedule. 

Visit 7.2 will be the last visit for these patients. Follow-
up Visit 8 does not need to be performed.
, a premature discontinuation visit (Visit 7.2 procedures) and also 
a follow-up visit (Visit 8 procedures) should be conducted.  The 
patient should then continue with the study visit schedule per the 
Flow Chart with the exception of the follow up visit which will 
not be required.  The last per study contact should be at Visit 7.2.  
If determined by investigator as necessary for patient safety, new 
antidiabetic medication regimen can be started immediately after
discontinuation and must be recorded in eCRFs. 
If a patient is not able to attend a study visit, the study staff 
should contact him/her (or someone designated – e.g. family 
member or personal physician) to inquire about medical 
information pertaining to adverse events, particularly 
primary and key secondary outcome events, and/or mortality, 
until the end of the study.  Alternatively, data should be 
collected from medical records. 
For patients who discontinue treatment prematurely but do 
not wish to follow the visit schedule, the following should be 
performed whenever possible:

Visit 7.2 should be performed within 7 days of last 
intake of study drug. 

Subsequently, a follow-up visit (Visit 8 procedures) 
should be conducted within 14 days of the premature 
discontinuation visit.  
If this patient withdraws consent, then the last per study 
contact will be Visit 8.  
Patients who withdraw consent
Patients who withdraw consent during the trial they should 
perform will be asked to complete premature discontinuation 
Visit 7.2 procedures within 7 days of last intake of study drug.  
and a A follow-up visit (Visit 8 procedures) should be 

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Number of global 
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conducted within 14 days of the premature discontinuation
for their safety.  
The following procedures should be performed at Visit 8.

Vital signs

Body weight measurement

BP measurement and orthostatic blood pressure test 
should always be done before taking any blood samples. 

Collection of blood and urine samples for safety 
laboratory evaluation.

Documentation of any adverse events. 

Documentation of concomitant therapies
A patient who reverses the decision to withdraw consent should 
be re-consented with the latest version and will continue the visit 
schedule according to the date of randomisation. 
In case of premature discontinuation from the 24 week treatment 
period, Visit 7.2 procedures should be performed and the patient 
should return to Visit 8 (14 days after Visit 7.2). The following 
procedures should be performed at Visit 8.

Vital signs

Collection of blood and urine samples for safety laboratory 
evaluation.

Documentation of any adverse events. 
Documentation of concomitant therapies
Rationale for 
change
To clarify and distinguish the expectations for follow up of 
patients that prematurely discontinue treatment who agree to be
followed up, who do not want to be followed up, and who 
withdraw consent.  
Section to be 
changed
24
7.1
Statistical design - model
Description of 
change
This is a multi-centre, multi-national, randomised, parallel-group, 
double-blind, placebo-controlled trial to investigate the effect of 
(10 mg/25 mg) of empagliflozin and placebo after 24 weeks 
treatment on glucose control, and  BP and body weight in 

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Number of global 
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hypertensive black/African American patients with T2DM.
Rationale for 
change
Changed to include body weight.
Section to be 
changed
25
7.3
Planned analyses
Description of 
change
Per Protocol Set
The per-protocol set (PPS) will consist of all randomised patients 
who are part of the FAS but who do not have any important 
protocol violations (IPV) leading to exclusion.
o
Were treated for 24 weeks with the study medication
o
Had an overall study treatment compliance between 80% 
and 120% (inclusive)
o
Received only the study treatment that they were 
randomised to
o
Had a week 24 HbA1c assessment within 161 to 175 days 
(inclusive) from Study Day1.
o
Had stable on-study antihypertensive and antidiabetic 
background therapy
o
Were NOT prematurely unblinded by the investigator.
Further details on the definition of the PPS and the definition of 
IPVs will be provided in the TSAP.
Rationale for 
change
FAS definition changed to be in line with current internal project 
standard. Detailed FAS definition will be found in TSAP where 
IPVs are defined as well.
Section to be 
changed
26
7.3.1
Primary analyses
Description of 
change
1. Mean changes from baseline for HbA1c up to 24 weeks of 
treatment will be analyzed using a restricted maximum 
likelihood (REML)-based repeated measures approach on 
the FAS data set. Patients will be analysed according to 
the treatment group they are randomized to.  Analyses 
will include the fixed, categorical effects of treatment, 
pretreatment with Metformin at screening, renal function 
at baseline, visit, and treatment-by-visit interaction, as 

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well as the continuous, fixed covariates of baseline 
HbA1c and baseline HbA1c -by-visit interaction. An 
unstructured (co)variance structure will be used to model 
the within patient measurements. If this analysis fails to 
converge, the following covariance structures will be 
tested: AR (1), Toeplitz and compound symmetry. If the 
model first fails to converge using an unstructured 
(co)variance structure, then a hierarchical approach is 
applied until a (co)variance structure is obtained 
where the model converges. Therefore the following 
(co)variance structures are tested according to the pre-
specified order: (1) unstructured, (2) Toeplitz, (3) 
variance components, (4) compound symmetry. As 
soon as one model converges this will be the final 
model used, therefore no further testing of subsequent 
(co)variance structures is required. If the analysis with 
unstructured (co)variance structure fails, the covariance 
structures AR (1), Toeplitz and compound symmetry are 
tested and the covariance structure converging to the best 
fit, as determined by Akaike’s information criterion, will 
be used as the primary analysis.
2. A sSimilar ANCOVA models on the FAS using LOCF for 
missing ABPM assessments will be performed for the 
change from baseline in mean trough ambulatory SBP at 
12 weeks of treatment and for change from baseline in 
mean 24-hour ambulatory DBP at 12 weeks of treatment
just replacing the relevant key secondary endpoint’s
baseline and 12 week assessments in the model.
3. For the key secondary endpoints change from baseline in 
body weight in kg at week 24 of treatment and change 
from baseline in trough seated SBP at 12 weeks of 
treatment a restricted maximum likelihood estimation 
based on mixed-effect model for repeated measures for 
mean changes from baseline in trough seated SBP up to 
week 12 will be used on the FAS observed case (OC) 
analysis set to obtain adjusted means for the treatment 
effects. Theseis models will include the same discrete 
fixed effects as the model for the primary endpoint and 
baseline HbA1c as a continuous fixed effect. 
Furthermore Tthese models will include the interaction 
between visit and treatment, and an interaction between 
visit and baseline measurement of the key secondary 

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Number of global 
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endpoint as well as the corresponding baseline 
measurements of the key secondary endpoint as 
continuous fixed effect. The covariance approach for this 
model will be the same as for the primary endpoint. The 
Kenward-Roger approximation will be used to estimate 
the denominator degrees of freedom. The primary 
treatment comparisons will be the contrast between 
treatments at the 12 week visit for trough seated SBP 
and 24 week visit for the body weight and significance 
tests will be based on least-squares means using a two-
sided α = 0.05 (two-sided 95% confidence intervals).
Rationale for 
change
1. Covariance structure in combination with model selection 
for MMRM model was changed to ensure type I error 
control for model selection using a hierarchical model 
selection approach.
2. & 3. Analysis section adjusted for new key secondary 
endpoint change from baseline in body weight in kg at 
week 24 of treatment and deletion of parts on old key 
secondary endpoint change from baseline in mean 24-
hour ambulatory DBP at 12 weeks
Further editorial changes were performed in this Section, 
e.g. medication of Metformin was replaced by pre-
treatment with Metformin as this was missed to be 
updated in the last protocol amendment. 
Section to be 
changed
27
7.3.2
Secondary analyses
Description of 
change
1. The primary endpoint will as well be analysed using an 
analysis of covariance model (ANCOVA) in the FAS. 
The model will include randomised treatment, pre-
treatment with Metformin, and renal function at baseline 
as categorical fixed effects, and baseline HbA1c as 
continuous covariate. Missing HbA1c data will be 
imputed using the LOCF approach.
The term "baseline HbA1c" refers to the last assessment 
prior to the administration of any randomised study 
medication. 
2. For the key secondary endpoints change from baseline 
in body weight in kg at week 24 of treatment and

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Number of global 
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change from baseline in trough seated SBP at 12 weeks as 
well an ANCOVA model will be calculated on the FAS. 
The model for the change from baseline includes 
‘treatment’, ‘renal function’ at baseline, ‘pretreatment 
with Metformin’ at screening as fixed categorical effects, 
and HbA1c at baseline, and baseline trough seated SBP or 
baseline body weight in kg respectively, as linear 
covariate.  Missing data will be imputed using the LOCF 
approach.
Rationale for 
change
Paragraph adjusted for new key secondary endpoint and reference 
to metformin as pre-treatment was corrected.
Section to be 
changed
28
7.3.3
Safety analyses
Description of 
change
Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) coding dictionary. Standard 
BI summary tables and listings will be produced. All adverse 
events with an onset between start of treatment and end of 
the residual effect period (REP), a period of 7 days after the 
last dose of trial medication, will be assigned to the 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. To this 
end, all adverse events occurring between start of treatment 
and end of the residual effect period will be considered 
‘treatment-emergent’.  The residual effect period is defined as 
7 days following last intake of trial medication. 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 the Medical Dictionary for Drug Regulatory Activities 
(MedDRA).
Laboratory data will be analysed both quantitatively as well 
as qualitatively. The latter will be done via comparison of 
laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant 
will be highlighted in the listings. Treatment groups will be 
compared descriptively with regard to distribution 
parameters as well as with regard to frequency and 

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Number of global 
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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.
Standard safety analyses will be performed on the TS.
The empagliflozin treatment group will be compared with the 
placebo group in a descriptive way.  Tabulations of 
frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive 
statistics will be used to summarise continuous (quantitative) 
data.
Adverse events will be coded using the Medical Dictionary for 
Drug Regulatory Affairs (MedDRA). Adverse events occurring 
prior to the first drug administration will be assigned to the 
screening period while all other adverse events, if within 7 days 
of the last study medication intake, will be assigned to the 
treatment period for evaluation.  Events which occurred after the 
REP will be considered as post treatment events.
Independent of this rule, the relationship of an adverse event to 
the study drug will be assessed by the investigator. The 
evaluation of adverse events will comprise various frequency 
tabulations.
Descriptive statistics will be presented for the tolerability 
parameters.
Descriptive statistics of laboratory values over time and for the 
difference from baseline will be provided. Frequency tables of 
changes with respect to the reference range between baseline and 
last value on treatment will also be presented.
Reasons for discontinuation and use of post-baseline concomitant 
medications will be tabulated.
The details of the analysis will be specified in the TSAP.
Rationale for 
change
This section was changed to reflect new project standard for 
safety analyses.  Analysis details will be described in TSAP.
Section to be 
changed
29
7.6
Determination of sample size

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Number of global 
amendment
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Description of 
change
In order to ensure that each comparisons of empagliflozin and 
placebo with respect to HbA1c, and mean systolic ABPM blood 
pressure and body weight have a power of at least 9080%, 140
are required per treatment group 64 patients plus an additional 
20%  drop-out rate, resulting in 77 patients per arm are 
required per treatment group. This is derived from the 
assumption that the difference in change from baseline compared 
to placebo in 24-hour SBP is 4 5 mmHg with a standard 
deviation of 10 mmHg (resulting in a power of 80%), and the 
difference in DBP body weight is 2 kgmmHg with a standard 
deviation of 5 mmHg 2.3kg (resulting in a power of 99%).  
With this sample size the power to detect a 0.65% difference in 
HbA1c with a standard deviation of 1.1% will be >8595%. 
The planned treatment group sizes are considered as sufficient for 
the confirmatory evaluation of efficacy and the descriptive 
assessment for safety, tolerability and pharmacokinetics.
For blood pressure scenarios see sample size calculations in table 
below.
Scena
rio 
1
2
3
4
5
6
7
8
9
10
SBP/
DBP
S
B
P
SB
P
SB
P
SB
P
S
B
P
D
BP
D
BP
D
BP
DB
P
DB
P
Mean 
chang
e from 
baseli
ne
4
4
4
3.7
3.
4
2
2
2
1.9
1.8

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Number of global 
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Stand
ard 
deviat
ion
10
10
10
11
1
0
5
5
5
5.6
5.3
Sampl
e size 
(both 
group
s)
28
0
252 
(10
% 
off 
fro
m 
280
)
26
6 
(5
% 
off 
fro
m 
28
0)
28
0
2
8
0
28
0
25
2 
(10
% 
off 
fro
m 
28
0)
26
6 
(5
% 
off 
fro
m 
28
0)
28
0
28
0
Power
92
89
90
80
8
1
92
89
90
81
81
Rationale for 
change
Power and patient numbers adjusted due to new underlying 
assumptions made to reflect realistic assumptions for this specific 
trial population, to avoid overpowering and to be able to finalize 
this trial in a reasonable time period with low recruitment rates 
occurring. 
Section to be 
changed
20
9.
References
Description of 
change

R14-5435
American Diabetes Association.  
Hyperglycemic crises in diabetes. Diabetes Care 27 
(Suppl 1), S94 - S102 (2004)

U06-1897-08 c01838761
 BI 10773 
Investigator’s Brochure BI 10773 in type 2 diabetes 
mellitus, current version 12. 15 July 2015.
Rationale for 
change
1. Added new reference for DKA management
2. Update to Investigator Brochure version.

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11.3
GLOBAL AMENDMENT 3 CHANGES
Number of global 
amendment
3.0
Date of CTP 
revision
14April2015
EudraCT number
N/A
BI Trial number
1245.29
BI Investigational 
Product(s)
empagliflozin
Title of protocol
A randomised, double-blind, placebo-controlled, parallel group, 
efficacy and safety study of empagliflozin (10 mg, 25 mg) 
administered orally, once daily over 24 weeks in hypertensive 
black/African American patients with type 2 diabetes mellitus
To be implemented 
only after approval 
of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in 
order to eliminate 
hazard –
IRB / IEC / 
Competent 
Authority to be 
notified of change 
with request for 
approval
Can be implemented 
without IRB/IEC/ 
Competent 
Authority approval 
as changes involve 
logistical or 
administrative
aspects only
Section to be 
changed
1
Synopsis; Main criteria for inclusion and 3.3.2 Inclusion criteria
Description of 
change
2. Male and female black/African American patients on diet and 
exercise regimen who are:
drug-naïve (defined as absence of any oral antidiabetic therapy , 
glucagon like peptide-1 (GLP-1) analog or insulin for 12 weeks, 
16 weeks for pioglitazone prior to randomisation) 

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Number of global 
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or  
pre-treated with stable dose of metformin, sulfonylurea (SU), 
DPP-4 inhibitor, metformin plus sulfonylurea or metformin plus 
DPP-4 inhibitor.  
Treatment has to be unchanged for a minimum of 12 weeks prior 
to randomisation
Minimum dDose for metformin:
- 1500 mg/day or
                                                            - maximum tolerated dose 
The maximum daily dose of SU or DPP-4 inhibitor should not 
exceed that stated in the local label 
note:  Patients who were screen failed due to exclusionary anti-
diabetic background medication according to versions of the 
protocol prior to Version 3 (SU, SU+Met, DPP-4 inhibitor, DPP-
4 inhibitor +Met) are allowed to be re-screened.
Rationale for 
change
Clarification on the dose for metformin
Section to be 
changed
2
Synopsis; Main criteria for inclusion and 3.3.2 Inclusion criteria
Description of 
change
3. HbA1c of ≥ 7.05% (538 mmol/mol) and ≤ 11.0% (97 
mmol/mol) at Visit 1 (screening)
Rationale for 
change
Adjustment of lower limit for HbA1c to allow for entry of 
patients with HbA1c between 7.0% and 7.4%.
Section to be 
changed
3
Synopsis; Main criteria for inclusion and 3.3.2 Inclusion criteria
Description of 
change
4. Mean seated SBP 140-180 mmHg and DBP 90-110 mmHg at 
Visit 1 (screening)
Rationale for 
change
Removed mean seated DBP criteria to allow for entry of patients 
with isolated systolic hypertension.
Section to be 
changed
4
Synopsis; Main criteria for inclusion and 3.3.2 Inclusion criteria
Description of 
change
6. Treatment with stable doses of at least one but no more than 34
antihypertensive medication ≥ 4 weeks prior to randomisation.
Rationale for 
change
Increased number of permitted background antihypertensive 
medications to permit entry of patients on 4 antihypertensive 
therapy.  Patients with severe hypertension will still be excluded 
by upper limit for mean seated SBP in inclusion criteria 4.  
Section to be 
5
Flowchart- Footnote B

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Number of global 
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changed
Description of 
change
Patients will undergo 24-hour ABPM testing. If patients fail the 
test testing is unsuccessful, this procedure should be repeated.  
Rationale for 
change
Administrative clarification on ABPM testing outcome.
Section to be 
changed
6
Abbreviations and Entire Document 
Description of 
change
Updated list of abbreviations and corrected text in document 
accordingly.
Rationale for 
change
Administrative change.
Section to be 
changed
7
Entire Document and Section 9.2 Unpublished References 
Description of 
change
1. c01838761 c01678844
2. c01838761 c01678844
BI 10773 
Investigator’s Brochure BI 10773 in type 2 diabetes 
mellitus, current version 13. 11 Feb 2016.
3. R09-1164
Nathan, et al. Medical Management of 
Hyperglycemia in Type 2 Diabetes: 
A Consensus Algorithm for the Initiation and Adjustment 
of Therapy. A consensus statement of the American 
Diabetes Association and the European Association for 
the Study of Diabetes. Diabetes Care 39(1)193] (2009).       
Rationale for 
change
Replace link to reference and undated reference to Investigator 
Brochure. Removed reference.
Section to be 
changed
8
3.1
OVERALL TRIAL DESIGN AND PLAN
Description of 
change
For information regarding Adverse event and serious adverse 
event reporting, please refer to Section 5.2.2.2
The Residual Effect Period (REP), that is, the time period, for 
which adverse events will still be considered “on-treatment” is  
7 days following last intake of trial medication. Events which 
occurred after the REP will be considered as post treatment 
events. All AEs, including those persisting after trial completion 
must be followed up until they have resolved, have been 
sufficiency characterized, or no further information can be 
obtained.  The investigator does not need to actively monitor 
patients for adverse events once the clinical trial has ended. 
However, if the investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the clinical trial 

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Number of global 
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(including any protocol required REP and / or follow-up), it 
should be reported by the investigator to the sponsor if considered 
relevant by the investigator. Such reports should contain an 
assessment of causality with regard to the trial treatment
Rationale for 
change
Administrative change
Section to be 
changed
9
3.1.1.2 Clinical Event Committee for Diabetic ketoacidosis 
(DKA) 
Description of 
change
An independent external committee (CEC) will be established 
to adjudicate centrally and in a blinded fashion events 
suspected of DKA (for further details see Section 5.2.2.1). The 
CEC will evaluate whether pre-specified criteria for 
adjudication endpoints are met.  For any events that qualify 
for adjudication, study sites will be asked to provide clinical 
documentation such as laboratory values, discharge 
summaries etc. to support the external event adjudication.
The tasks and responsibilities of the CEC will be specified in
a charter. The CEC will maintain the adjudication results in 
writing.
Rationale for 
change
New adjudication process for diabetic ketoacidosis was added to 
trial.
Section to be 
changed
10
3.3 Selection of Trial Population
Description of 
change
Approximately up to 385 620 patients will be screened for the 
trial in US. About 85 trial centres will be participating to ensure 
that approximately 154 patients are randomised to trial treatment 
(77 to each treatment group).  
Rationale for 
change
Increased number of patients expected to be screened to reflect a 
higher screen failure rate.
Section to be 
changed
11
3.3.3
Exclusion criteria
Description of 
change
4. Mean seated SBP ≥181 mmHg and/or mean seated DBP≥111 
mmHg during placebo run-in visit and confirmed by a second 
measurement (not on the same day) preferably within one 
day.
Rationale for 
change
Removed mean seated DBP to align with changes to inclusion 
criteria 4.

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Number of global 
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Section to be 
changed
12
5.1.2
Assessment of efficacy- Ambulatory blood pressure 
monitoring (ABPM) 
Description of 
change
After each ABPM session, the data from the device is to be 
downloaded and assessed for quality to determine if the 
session was technically successful.  If the first session does not 
pass quality criteria or the mean ABPM SBP is below the 
required threshold, the session should be repeated.  Only one 
repeat session will be permitted.  At Visit 2.2 only, it is 
important to remember to record the 24-hour mean systolic 
blood pressure which is displayed at the bottom of the QC 
results.  The mean systolic BP at this visit together with a 
technically successful session determines eligibility for 
randomization.  
Rationale for 
change
To provide clarification on ABPM testing process.
Section to be 
changed
13
5.2.2.1 Definitions of adverse events-Adverse reaction
Description of 
change
Adverse reaction
An adverse reaction is defined as a response to a medicinal 
product which is noxious and unintended. Response in this 
context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable 
possibility. Adverse reactions may arise from use of the 
product within or outside the terms of the marketing 
authorisation or from occupational exposure. Conditions of 
use outside the marketing authorization include off label use, 
overdose, misuse, abuse and medication errors.
Rationale for 
change
Addition of new definition of Adverse Reaction
Section to be 
changed
14
5.2.2.1 Definitions of adverse events- Serious adverse events
Description of 
change
Medical and scientific judgement should be exercised in 
deciding whether other situations should be considered 
serious reactions, such as important medical events that 
might not be immediately life threatening or result in death 
or hospitalisation but might jeopardise the patient or might 
require intervention to prevent one of the other outcomes 
listed above.  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. Any 

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Number of global 
amendment
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suspected transmission via a medicinal product of an 
infectious agent is also considered a serious adverse reaction.
Rationale for 
change
Administrative addition to provide further guidance on 
assessment of serious adverse events or adverse reactions.
Section to be 
changed
15
5.2.2.1 Definitions of adverse events- Causal relationship of 
adverse event
Description of 
change
The definition of an adverse reaction implies at least a 
reasonable possibility of a causal
relationship between a suspected medicinal product and an 
adverse event. An adverse
reaction, in contrast to an adverse event, is characterised by 
the fact that a causal relationship between a medicinal 
product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, 
considering all relevant factors, including pattern of reaction, 
temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and 
relevant history. 
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.
• 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. preexisting 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 
diminished).
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 

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Number of global 
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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 study 
drug treatment continues or remains unchanged.
Yes:
There is a reasonable causal relationship between the 
investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the 
investigational product 
administered and the AE. 
Rationale for 
change
Administrative changes to provide guidance on causality 
assessment.
Section to be 
changed
16
5.2.2.2 Adverse event and serious adverse event reporting-AE 
collection
Description of 
change
1. From signing the informed consent onwards through the 
Residual Effect Period (REP) until trial completion 
(individual patient’s End of Trial) or last per protocol 
contact,:
all AEs (serious and non-serious), and AESIs.  This also 
applies to patients who prematurely discontinue from the 
study.  
If an individual patient discontinues trial medication 
prematurely but stays in the trial (i.e. if further visits 
incl. telephone visits, or vital status assessments are 
planned) from then on and until the individual 
patient’s End of Trial contact, the Investigator must 
report all AEs (serious and non-serious) and AESIs.

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Number of global 
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            After the individual patient’s end of trial:

The Investigator does not need to actively monitor the 
patient for AEs but should only report relevant SAEs 
and relevant AESIs of which the Investigator may 
become aware of.
2. Post Study:  After the last per protocol contact, the 
investigator does not need to actively monitor patients for 
AEs.  However, if the investigator becomes aware of an 
SAE(s) or AESI that occurred after the last per protocol 
contact (including any protocol required REP and / or 
follow-up), it should be reported by the investigator to the 
sponsor if considered relevant by the investigator.  
Reporting will be done according to the specific 
definitions and instructions detailed in the ‘Adverse Event 
Reporting’ section of the ISF.
Rationale for 
change
Administrative changes to provide clarification on expectations 
for adverse event report at specific time points.
Section to be 
changed
17
5.2.3
Assessment of safety laboratory parameters
Description of 
change
The following safety lab parameters will only be not be 
determined at each of the following study visit:

Lipid fractions: planned at V3, V5.2, V7.2 and V8 

TSH: planned at V1 

Albumin (urine) at V3, V5.2, V7.2 and V8

Brain natriuretic peptide (BNP) at V3, V5.2 and V7.2
Rationale for 
change
Administrative change to clarify tests that will only be collected 
at specific visits.  
Section to be 
changed
18
5.6.1

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Number of global 
amendment
Section to be 
changed
19
6.2.1 Visit 2.1 (Run-in period); 6.2.2 Visit 3 (Randomisation 
visit)
Description of 
change
Inclusion/exclusion criteria must be reviewed prior to 
randomization
Rationale for 
change
Administrative change to clarify that patient eligibility must be 
reviewed at these visits.
Section to be 
changed
20
6.2.1 Visit 2.2 (Run-in period)
Description of 
change

Once the data from the session is downloaded, review the 
QC results to determine if the session was technically 
successful.  Remember to record the 24-hour mean 
systolic BP displayed at the bottom of the QC results.  The 
mean systolic BP at this visit together with a technically 
successful session determines eligibility for randomization.

If the first ABPM attempt was technically unsuccessful 
(failed QC and/or the mean ABPM SBP is below the 
required threshold), repeat it within 2 days.  Patients having 
two technically unsuccessful baseline ABPM sessions should 

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Number of global 
amendment
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not be randomised and must be discontinued. 

If ABPM was technically successful, the patient is eligible 
for randomization and procedures for Visit 3 can be 
conducted on the same day after the ABPM device is 
removed and trough seated blood pressure measurement is 
taken. If conducted on the same day, procedures for Visit 3 
should be done prior to administrating study medication.
Rationale for 
change
To provide clarification on ABPM testing process and 
determination of eligibility for randomization.
Section to be 
changed
21
6.2.2 Visit 5.1 (Week 12 ABPM visit); Visit 7.1
Description of 
change

Removed the word technically from these sections.

If the first ABPM attempt was technically unsuccessful 
(failed QC), a repeat reading should be taken within 2 days.  
Rationale for 
change
To provide clarification on ABPM testing process and 
determination of eligibility for randomization.
Section to be 
changed
22
6.2.3 End of trial and follow-up period
Description of 
change
Visit 8 (follow-up visit)
•
Vital signs
•
Body weight measurement
•
BP measurement and orthostatic blood pressure test 
should always be done before taking any blood samples. 
•
Collection of urine and blood for laboratory testing. 
•
Home blood glucose monitoring
•
Documentation of any adverse events. 
•
Documentation of concomitant therapies
Rationale for 
change
To correct omission of home blood glucose monitoring at this 
visit to align with flow chart.  
Section to be 
changed
23
8.4.1
Listedness
Description of 
change
To fulfil the regulatory requirements for expedited safety 
reporting, the sponsor evaluates whether a particular adverse 
event is "listed", i.e. is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of 
listedness needs to be provided. For the empagliflozin this is: the 
current version of the IB (c01838761 c01678844). The current 
version of this reference document is to be provided in the ISF. 
No AEs are classified as listed for matching placebo, study 

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Number of global 
amendment
3.0
design, or invasive procedures.
Rationale for 
change
Administrative correction
Section to be 
24
Rationale for 
change
Removed 
  This information is in Section 
5.3.3.1.
Section to be 
changed
25
10.3
Blood Pressure Measurement Procedure
Description of 
change
Initially, blood pressure should be taken 3 times in both arms. If 
the mean pressures differ by more than 10 mmHg, the arm with 
the higher pressure (systolic or – if needed, diastolic) should be 
used for subsequent measurements.  If the pressures are 
<≤10mmHg, the non-dominant arm should be used for 
Rationale for 
change
Administrative clarification.
Section to be 
changed
26
10.4

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Number of global 
11.4
GLOBAL AMENDMENT 4 CHANGES
Number of global 
amendment
4.0
Date of CTP 
revision
18 July 2016
EudraCT number
N/A
BI Trial number
1245.29
BI Investigational 
Product(s)
empagliflozin
Title of protocol
A randomised, double-blind, placebo-controlled, parallel group, 
efficacy and safety study of empagliflozin (10 mg, 25 mg) 
administered orally, once daily over 24 weeks in hypertensive 
black/African American patients with type 2 diabetes mellitus
To be implemented 
only after approval 
of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in 
order to eliminate 
hazard –
IRB / IEC / 
Competent 
Authority to be 
notified of change 
with request for 
approval
Can be implemented 
without IRB/IEC/ 
Competent 
Authority approval 
as changes involve 
logistical or 
administrative 
aspects only

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Number of global 
amendment
4.0
Section to be 
changed
1
Synopsis; Main criteria for inclusion and 3.3.2 Inclusion criteria
Description of 
change
Male and female black/African American patients on diet and 
exercise regimen alone,  or who are EITHER
drug-naïve (defined as absence of any oral antidiabetic therapy, 
glucagon like peptide-1 (GLP-1) analog or insulin for 12 weeks, 
16 weeks for pioglitazone prior to randomisation) OR
pre-treated with stable dose of 

Metformin only, or

Sulfonylurea only, or

DPP-4 inhibitor only, or

metformin plus sulfonylurea, or 

metformin plus DPP-4 inhibitor.  
Treatment has to be unchanged for a minimum of 12 weeks 
prior to randomization.
Dose for metformin:  maximum tolerated dose 
The maximum daily dose of SU or DPP-4 inhibitor should not 
exceed that stated in the local label 
note:  Patients who were screen failed due to exclusionary anti-
diabetic background medication according to versions of the 
protocol prior to Version 3 (SU, SU+Met, DPP-4 inhibitor, DPP-
4 inhibitor+Met) are allowed to be re-screened.
Rationale for 
change
Administrative clarification, and to maintain consistency of 
information within the document. Screen failure instructions
moved to new section (3.3.5)
Section to be 
changed
2
3.3 Selection of Trial Population
Description of 
change
Approximately up to 620 700 patients will be screened for the 
trial in US.
Rationale for 
change
Increased number of patients expected to be screened to reflect a 
higher screen failure rate.
Section to be 
changed
3
3.3.5 Re-screening
Description of
change
Re-screening is permitted for the following categories of 
screen failed patients only:

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
Patients who were screen failed due to exclusionary 
background anti-diabetic therapies (sulfonylurea, 
DPP4-inhibitor, metformin + sulfonylurea, metformin 
+DPP4-inhibitor) according to prior versions of the 
protocol.

Patients who were screen failed due to exclusionary 
HbA1c 7.0% (53 mmol/mol) -7.4% (57 mmol/mol) at 
Visit 1 according to prior versions of the protocol.  
Patients who were screen failed due to exclusionary 
HbA1c below 7.0% or above 11.0% cannot be re-
screened.

Patients who were screen failed due to exclusionary 
mean seated DBP (Visit 1) according to prior versions 
of the protocol.  However, mean seated SBP (Visit 1) 
must have been 140-180 mmHg at the previous 
screening. 

Patients who were screen failed due to taking 4 
antihypertensive medications (4 weeks prior to 
randomization) according to prior versions of the 
protocol.

Patients who were screen failed due to out-of-window 
visits prior to ABPM testing (Visit 2.2).  If ABPM 
testing has commenced, no re-screening is permitted.
A patient who was screen failed due to any of the above 
screen failure reasons is permitted to be re-screened once 
only. A new patient number should be assigned to the re-
screened patient who should be re-consented.   Rationale for 
re-screening must be document in source documents.
Re-screening is not permitted for patients who were screen
failed due to other reasons.
Rationale for 
change
Added subsection to allow re-screen of patients who were screen 
failed based on the earlier versions of the protocol but would be 
eligible based on the revised inclusion/exclusion criteria in the 
subsequent protocol versions.
Section to be 
changed
4
3.3.6
Repeat test
Description of 
change
HbA1c test (Visit 1) may be repeated once if the test result 
from the central lab is exclusionary but the most recent test 
result from a local lab (taken before Visit 1 but not older than 

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one month), if any, falls within the acceptable range.
ABPM test (Visit 2.2) may be repeated once if the first 
attempt is unsuccessful. Refer to Footnote B and Footnote I of 
the Flow Chart, as well as Section 5.1.2 and Section 6.2.1 for 
additional details on repeat ABPM.
Rationale for all repeat tests must be documented in source 
documents.
Rationale for 
change
To allow confirmatory testing of HbA1c if there is a discrepancy 
of values between central and  local lab results.
ABPM re-test is not new. It is repeated in this section for 
completeness of information.
Section to be 
changed
5
5.1.1 Endpoints of efficacy
Description of 
change
Change from baseline in mean seated trough heart rate at 12 
weeks of treatment
Rationale for 
change
Administrative clarification.
Section to be 
changed
6
5.1.2 Assessment of efficacy
Description of 
change
After each ABPM session, the data from the device is to be 
downloaded and assessed for quality to determine if the session 
was technically successful. 
At Visit 2,2 only, Iif the first session does not pass quality 
criteria or the mean ABPM SBP is below outside the required 
range threshold, the session should be repeated.  Only one repeat 
session will be permitted.  At Visit 2.2 only, iIt is important to 
remember to record the 24-hour mean SBP which is displayed at 
the bottom of the quality compliance (QC) results.  The 24-hour 
mean SBP at this visit together with a technically successful 
session determines eligibility for randomization
Rationale for 
change
Administrative clarification and to maintain consistency of 
information within the document.
Section to be 
changed
7
5.2.2.2 Adverse event and serious adverse event collection and 
reporting
Description of 
change
Added the words “collection and” to the sub title.
Rationale for 
change
Administrative clarification.

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Section to be 
8
Section to be 
changed
9
6.2.1 Screening and run-in period
Description of 
change
Visit 1 (Screening)

The screening visit is the only visit in this study that does not 
need to be done fasting.

No trial procedures should be done unless the patient has 
consented to taking part in the trial.  Patient identification 
numbers are available in the RDC system.  If a patient is 
re-screened, a new patient identification number should 
be assigned.  
Rationale for 
Added information on patient identification numbers.

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change
Section to be 
changed
10
6.2.1 Screening and run-in period
Description of 
change
Visit 2.2 (Baseline ABPM visit)

Once the data from the session is downloaded, review the QC 
results to determine if the session was technically successful.  
Remember to record the 24-hour mean SBP displayed at the 
bottom of the QC results.  The 24-hour mean SBP at this visit 
together with a technically successful session determines 
eligibility for randomization.
If the first ABPM attempt was unsuccessful (failed QC and/or the 
mean ABPM SBP is below outside the required range 
threshold), repeat it within 2 days.  Patients having two 
unsuccessful baseline ABPM sessions should not be randomised 
and must be discontinued. 
Rationale for 
change
Administrative clarification on ABPM repeat, and to maintain 
consistency of information within the document.
Section to be 
changed
11
8.4.2
Description of 
change
Expedited reporting to health authorities and IECs/IRBs
BI is responsible to fulfil their legal regulatory reporting 
obligation and in accordance to the requirements defined in 
this CTP. Expedited reporting of serious adverse events, e.g. 
SUSARs to health authorities and IECs/IRBs, will be done 
according to local regulatory requirements. Further details 
regarding this reporting procedure are provided in the ISF
Rationale for 
change
To fulfil both global and local regulatory reporting obligations.
Section to be 
changed
12
10 Appendices
Description of 
change
Re-numbring of the following appendices
10.3 re-numbered to 10.2
10.4 re-numbered to 10.3
10.5 re-numbered to 10.4
Rationale for 
change
Administrative corrections.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01945509
7.0
clinical-trial-protocol
A randomised, double-blind, placebo-controlled, parallel group, efficacy and safety
study of empagliflozin (10 mg, 25 mg) administered orally, once daily over 24 weeks
in hypertensive black/African American patients with type 2 diabetes mellitus
Author-Trial Clinical Monitor
19 Jul 2016 21:54 CEST
Approval-Medical 
20 Jul 2016 04:20 CEST
Author-Trial Statistician
20 Jul 2016 08:52 CEST
Approval-Team Member Medicine
20 Jul 2016 09:23 CEST
Approval-Clinical Pharmacokinetics
20 Jul 2016 13:13 CEST
Approval-Therapeutic Area 
22 Jul 2016 14:52 CEST
Verification-Paper Signature
Completion
22 Jul 2016 15:44 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01945509
7.0