Clinical trial NCT02580591
Conditions: Diabetes Mellitus, Type 1
Sponsor: Boehringer Ingelheim
Start date: 2015-12-22; Completion date: 2017-09-20
Enrollment: 977 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will investigate the efficacy, safety, tolerability and Pharmacokinetic(PK) of 3 doses of empagliflozin compared with placebo over 26 weeks in 960 patients with type 1 diabetes mellitus as adjunctive therapy to insulin

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Empagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: For blinding purposes

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c02993089-03
EudraCT No.:
2014-005256-26
BI Trial No.:
1245.72
BI Investigational 
Product:
Empagliflozin
Title:
A Phase III, randomised, double blind, placebo-controlled, 
parallel group, efficacy, safety and tolerability trial of once daily,
oral doses of Empagliflozin as Adjunctive to inSulin thErapy over 
26 weeks in patients with Type 1 Diabetes Mellitus (EASE-3)
Brief Title:
Empagliflozin as Adjunctive to InSulin thErapy over 26 weeks in 
patients with Type 1 Diabetes Mellitus (EASE-3)
Clinical Phase:
III
Trial Clinical 
Monitor:
Phone: 
 Fax: 
Coordinating 
Investigator:
Phone:
, Fax: 
Status:
Final Protocol (Revised Protocol based on Global Amendment 1)
Version and Date:
Version: 2.0
Date: 21 Oct 2016
Page 1 of 122
Proprietary confidential information.
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim
Name of finished product:
Name of active ingredient:
Empagliflozin
Protocol date:
14 Jul 2015
Trial number:
1245.72
Revision date:
21 Oct 2016
Title of trial:
A Phase III, randomised, double blind, placebo-controlled, parallel group, efficacy, 
safety and tolerability trial of once daily, oral doses of Empagliflozin as Adjunctive 
to inSulin thErapy over 26 weeks in patients with Type 1 Diabetes Mellitus 
(EASE-3)
Coordinating
Investigator:
Phone: 
Trial sites:
Multi-centre trial planned to be conducted in multiple countries
Clinical phase:
III
Objectives:
The objective of this study is to assess the efficacy, safety, tolerability and 
pharmacokinetics (PK) of once daily oral doses of empagliflozin 2.5 mg, 10 mg 
and 25 mg compared to placebo in patients with Type 1 diabetes mellitus (T1DM) 
as adjunctive to insulin therapy
Methodology:
Randomised, double-blind, placebo-controlled parallel group comparison of 3 oral 
once daily doses (2.5 mg, 10 mg and 25 mg) of empagliflozin to placebo.
Randomisation will be stratified by:

pre-existing insulin therapy (multiple daily injections [MDI] vs continuous 
subcutaneous insulin infusion [CSII])

Visit 5 estimated Glomerular filtration rate (eGFR) as calculated by the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula 
(< 60 mL/min/1.73 m2 vs ≥60 mL/min/1.73 m2)

Visit 5 glycated haemoglobin (HbA1c, < 8.5% vs ≥8.5%)

participation in the CGM substudy (CGM participation versus non-CGM 
participation)
No. of patients:
total entered
(randomised):
960
each treatment:
240 patients per dose group
Empagliflozin 2.5 mg:
240 patients
Empagliflozin 10 mg:
240 patients 
Empagliflozin 25 mg:
240 patients
Placebo:
240 patients
Diagnosis :
T1DM
Main criteria
for inclusion:
Male or female patients ≥ 18 years, with an HbA1c of ≥ 7.5% and ≤10.0% at 
Visit 5 (beginning of the run-in period), and a C-peptide value of < 0.7 ng/mL (< 
0.23 nmol/L) at Visit 2 (beginning of T1DM therapy optimisation period).  
Patients should have been receiving insulin for the treatment of T1DM for at 
least 1 year prior to Visit 1, and be willing to continue this throughout the trial.  


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Name of company:
Boehringer Ingelheim
Name of finished product:
Name of active ingredient:
Empagliflozin
Protocol date:
14 Jul 2015
Trial number:
1245.72
Revision date:
21 Oct 2016
Insulin should be either MDI or CSII with a total daily dose ≥ 0.3 U/kg and ≤1.5 
U/kg at Visit 1
Test products:
Empagliflozin film-coated tablets
dose:
2.5 mg, 10 mg, or 25 mg once daily
mode of 
administration:
Oral
Comparator products:
Placebo to match empagliflozin film-coated tablets 
dose:
Not applicable 
mode of 
administration:
Oral 
Duration of treatment:
1 week screening period
6 week T1DM therapy optimisation period
2 week placebo run-in period
26 week randomised double-blind treatment period
3 week follow-up period after study medication termination 
Endpoints
Primary endpoint is the change from baseline in HbA1c after 26 weeks
Key secondary endpoints are:

incidence rate of symptomatic hypoglycaemic adverse events (AEs) with 
confirmed plasma glucose < 54 mg/dL (< 3.0 mmol/L) and/or severe 
hypoglycaemic AEs per patient-year from Week 5 to Week 26
o
severe hypoglycaemic AEs are defined as events requiring the assistance 
of another person to actively administer carbohydrate, glucagon or other 
corrective actions.  Plasma glucose concentrations may not be available 
during an event, but neurological recovery following the return of plasma 
glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration 

incidence rate of symptomatic hypoglycaemic AEs with confirmed plasma 
glucose < 54 mg/dL (< 3.0 mmol/L) and/or severe hypoglycaemic AEs per 
patient-year from Week 1 to Week 26

change from baseline in body weight (kg) after 26 weeks

change from baseline in total daily insulin dose (TDID), U/kg, after 26 weeks

change from baseline in systolic blood pressure (SBP) after 26 weeks

change from baseline in diastolic blood pressure (DBP) after 26 weeks
Safety criteria:
Incidence rate of symptomatic hypoglycaemic AEs with confirmed plasma glucose 
< 54 mg/dL (< 3.0 mmol/L) and/or severe hypoglycaemic AEs per patient-year 
from Week 1 to Week 4
Frequency of patients with adverse events of special interest (AESIs):

diabetic ketoacidosis (DKA)

hepatic injury

decreased renal function

severe hypoglycaemic episodes
Frequency of patients with hypoglycaemia
Hypoglycaemia rate


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Name of company:
Boehringer Ingelheim
Name of finished product:
Name of active ingredient:
Empagliflozin
Protocol date:
14 Jul 2015
Trial number:
1245.72
Revision date:
21 Oct 2016
Frequency of patients with adjudicated events:

cardiovascular events

severe hypoglycaemia

DKA
Statistical methods:
For the primary endpoint, change from baseline in HbA1c after 26 weeks, restricted 
maximum likelihood estimation based on mixed-effect model for repeated 
measures (MMRM) analysis will be used to obtain adjusted means for the 
treatment effects. This model will include treatment, week and pre-existing insulin 
therapy as discrete fixed effects, baseline eGFR (CKD-EPI) and baseline HbA1c as 
continuous fixed effects, as well as the interaction between week and treatment and 
the interaction between week and baseline HbA1c.  The initial primary treatment 
comparisons will be the Bonferroni adjusted contrast between the doses of 
empagliflozin 10 mg or 25 mg and placebo at Week 26.  The doses of 
empagliflozin 10 mg or 25 mg will therefore be tested at the level of α=0.025 (two-
sided).
The primary analysis will be an efficacy analysis, including on-treatment data only.  
Following the efficacy analysis, an effectiveness analysis (on-and off-treatment 
data) will be performed in a hierarchical manner.  If the null hypothesis is rejected 
for both the efficacy and effectiveness analysis then the primary endpoint (between 
empagliflozin 2.5 mg and placebo, on-treatment data only) and the key secondary 
endpoints will be tested in a confirmatory way using a gatekeeping approach, with 
unequal splitting of the alpha, and sequential testing.
The key secondary endpoints of change from baseline in body weight after 26 
weeks and change from baseline in TDID will be analysed using a similar model to 
the analysis of the primary endpoint, with the addition of baseline and interaction 
between baseline and week for the respective endpoint.
The key secondary endpoint of incidence rate of symptomatic hypoglycaemic AEs 
with confirmed plasma glucose < 54 mg/dL (< 3.0 mmol/L) and/or severe 
hypoglycaemic AEs from Week 5 to Week 26 will be analysed using a negative 
binomial model.  The model will include treatment and pre-existing insulin therapy 
as discrete fixed effects, baseline rate, baseline HbA1c and baseline eGFR as 
continuous fixed effects and logarithm of days of exposure as an offset.  The
primary treatment comparisons will be the rate ratios comparing the incidence rates 
per-patient year from Week 5 to Week 26 on each dose of empagliflozin to 
placebo.  The same analysis strategy will be applied for the key secondary endpoint 
of incidence rate of symptomatic hypoglycaemic AEs with confirmed plasma 
glucose < 54 mg/dL (< 3.0 mmol/L) and/or severe hypoglycaemic events from 
Week 1 to Week 26.
The key secondary endpoints of change from baseline in SBP and DBP after 26 
weeks will be analysed using a similar model to the analysis of the primary 


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Name of company:
Boehringer Ingelheim
Name of finished product:
Name of active ingredient:
Empagliflozin
Protocol date:
14 Jul 2015
Trial number:
1245.72
Revision date:
21 Oct 2016
endpoint, with the addition of terms for baseline and interaction between baseline 
and week for the respective endpoint.


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FLOW CHART
Trial Period
Screen-
ing
T1DM Therapy 
OptimisationB,C
Placebo 
Run-In
Randomised TreatmentF
Follow
-Up
Visit
1
2
3/3TD
4TD
5
6C
7
8
9
10
11 
CGMW
11 
EOTI
eEOT
Early 
Discn. 
OnlyG,I
12G
Study week
-9
-8
-6
-4
-2
1
4
12
18
24
26
29
Study day
-63
-56
-42
-28
-14
-2E
1
8
29
85
127
169
183
204
Visit window (days)A
-7/+4
+/-2
+/-2
+/-2
+/-3
+/-1
n/a
+/-2
+/-7
+/-7
+/-7
+/-3
+/-3
+/-7
Fasting statusH
NF
F
NF
-
NF
-
F
NF
NF
F
NF
NF
F
F
F
Informed consent
x
Demographics
x
Medical history, baseline 
conditions
x
Check of in-/exclusion criteria
x
x
x
x
x
x
Height
x
Weight
x
x
x
x
x
x
x
x
x
Vital signs
x
x
(x)
x
x
x
x
x
x
x
x
x
Physical examination
x
x
x
x
12-lead ECG
x
x
x
Safety laboratory, urinalysisJ
xR
xU
x
xS
x
x
xS
xS
xS
Blood ketone measurement at 
the site with home monitoring 
device, urine ketone 
measurementY
x
(x)
x
x
x
x
x
x
x
x
x
Pregnancy testK
x
x
x
x
x
 
 


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Trial Period
Screen-
ing
T1DM Therapy 
OptimisationB,C
Placebo 
Run-In
Randomised TreatmentF
Follow
-Up
Visit
1
2
3/3TD
4TD
5
6C
7
8
9
10
11 
CGMW
11 
EOTI
eEOT
Early 
Discn. 
OnlyG,I
12G
Study week
-9
-8
-6
-4
-2
1
4
12
18
24
26
29
Study day
-63
-56
-42
-28
-14
-2E
1
8
29
85
127
169
183
204
Visit window (days)A
-7/+4
+/-2
+/-2
+/-2
+/-3
+/-1
n/a
+/-2
+/-7
+/-7
+/-7
+/-3
+/-3
+/-7
Fasting statusH
NF
F
NF
-
NF
-
F
NF
NF
F
NF
NF
F
F
F
HbA1c
x
x
x
x
x
x
x
x
FPG (central lab)
x
x
x
x
x
 
Dispense run-in medication 
(Interactive Response 
Technology, IRT)
x
Randomisation (IRT)
x
Dispense double-blind 
medication (IRT)
x
x
x
x
Compliance/drug 
accountability check
x
x
x
x
x
x
x
Management of diet & 
physical activity, training on 
home monitoring deviceO
Continuous
Home monitoringP
Continuous
 
x
x
 
Training/dispensing of patient 
e-diary
x
Refresher training as required
Check of patient e-diary
x
x
x
x
x
x
x
x
x
x
x


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Trial Period
Screen-
ing
T1DM Therapy 
OptimisationB,C
Placebo 
Run-In
Randomised TreatmentF
Follow
-Up
Visit
1
2
3/3TD
4TD
5
6C
7
8
9
10
11 
CGMW
11 
EOTI
eEOT
Early 
Discn. 
OnlyG,I
12G
Study week
-9
-8
-6
-4
-2
1
4
12
18
24
26
29
Study day
-63
-56
-42
-28
-14
-2E
1
8
29
85
127
169
183
204
Visit window (days)A
-7/+4
+/-2
+/-2
+/-2
+/-3
+/-1
n/a
+/-2
+/-7
+/-7
+/-7
+/-3
+/-3
+/-7
Fasting statusH
NF
F
NF
-
NF
-
F
NF
NF
F
NF
NF
F
F
F
 
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
Termination of trial medication
x
x
Vital status collection
x
A
Permitted visit windows should be strictly adhered to, to ensure laboratory results from a preceding visit are available by the time of the next visit, and to ensure a 
sufficient supply of medication until the next visit.  For patients participating in the CGM substudy, the time span between Visit 5 (Day -14) and Visit 6 (Day 1) should 
ideally be exactly 14 days; the time span between Visit 6 (Day 1) and Visit 8 (Day 29) should ideally be exactly 28 days; the time span between Visit 11 CGM and Visit 
11EOT should ideally be exactly 14 days. For further details see Section 6.1
B
The patient’s therapy for T1DM (e.g. ability to review blood glucose values, skills for carbohydrate estimation and insulin adjustment) should be optimised from Visit 2 
for a period of 6 weeks (i.e. until the patient reaches Visit 5 and the placebo run-in period) to achieve the best standard of care in accordance with local guidelines.  This 
optimal therapy should then be continued from Visit 5 for eligible patients.  For further details see Section 4.2.1
C
During the T1DM therapy optimisation period, and daily for 5 days following clinic Visit 6, data from the electronic (e)-diary should be reviewed remotely by designated 
site personnel, paying particular attention to adjustments in the insulin regimen, glucose values and, if available, ketone measurements.  In addition, the patient should be 
contacted by telephone (e.g. weekly during the T1DM therapy optimisation period) if e-diary data, including glucose data, is not available and/or if the data suggests 
closer monitoring of the patient is required.  Additional clinic visits can also be arranged if necessary.  For further details see Sections 5.2.3 and 6.2.1
D
Visit 4T is a telephone visit. Visit 3 can be a telephone visit (3T), if deemed sufficient based on Investigator judgement, or a clinic visit; if performed as a telephone visit, 
assessments in brackets in the Flow Chart do not have to be performed
E
Visit 5 includes a 9-point plasma glucose profile on Day -2.  No clinic visit is required on this day, as the 9-point plasma glucose profile will be performed by the patient 
at home.  For further details see Footnote N and Section 5.2.6


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F
Following randomisation and prior to the initiation of study medication, Investigators are advised to reduce the patient’s total insulin dose based on need/ by 10% to avoid 
hypoglycaemia; thereafter further insulin adjustments may be implemented as necessary.  For further details see Section 4.2.1
G
An early End of Treatment (eEOT) Visit, as well as a Follow-up Visit 12, should be performed for any patient who discontinues study medication prematurely; the eEOT 
Visit should be completed as soon as possible after study medication is stopped.  
 
the 9-point plasma glucose profile should only be performed if it is feasible for it to be done over a 24 hour period before the eEOT visit 
when study medication is still being taken; otherwise it can be omitted.  Visit 12 should be performed 3 weeks after the eEOT visit, and where possible, patients should 
then be followed up according to the visit schedule.  For further details see Section 6.2.3
H
NF: non-fasting; F: fasting
I
Following the termination of trial medication, and if deemed necessary based on Investigator’s judgement, additional support (e.g. telephone interaction) can be given to 
the patient during the adjustment of T1DM therapy in the Follow-up period  
J
Safety laboratory includes calculation of the eGFR.  Following a positive urine dipstick result (at the site) for leukocyte esterase (for WBC) or nitrite, a midstream urine 
sample for urine culture is triggered.  For further details see Section 5.3.3
K
For female patients of child-bearing potential (local urine pregnancy test)
 
 
 
 
O
Home monitoring device: meter for monitoring of blood (plasma) glucose and ketone levels at home
P
Self-Blood Glucose Monitoring (SBGM) should be performed daily from the beginning of the T1DM therapy optimisation period to the end of the Follow-up period.  
Measurements should be taken 4 times a day as a minimum e.g. at least before breakfast, lunch, dinner and bedtime.  Additional measurements will also be warranted (e.g. 
after clinic Visit 6).  For further details see Section 5.3.2.1.  Ketone measurements should be performed by the patient in case of any symptoms of DKA.  Other conditions 
may also trigger the need for ketone measurement.  For further details see Section 5.3.2.2
Q
 
R
For the screening visit (Visit 1) an abbreviated, safety laboratory and urinalysis will be performed as follows: liver transaminases, alkaline phosphatase, serum creatinine, 
TSH, and urinalysis.  For further details see Section 5.3.3
S
At Visits 6, 11 EOT, eEOT (if applicable) and 12 only, the safety laboratory testing will include lipids.  Samples should be obtained from the patient in a fasting state.  For 
further details see Section 5.3.3
 
U
For Visit 2, an abbreviated safety laboratory (fasting) will be performed as follows: C-peptide, beta-hydroxy-butyrate, bicarbonate and electrolytes only.  For further 
details see Section 5.3.3
 
 


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Y
At visits with safety laboratory, ketone measurements should be done directly before or after the collection of laboratory samples. At visits which require fasting, ketone 
measurements should be done in a fasted state. Regular (e.g. 2-3 times a week) measurements at home before breakfast are recommended throughout the trial as from Visit 
2. More frequent (e.g. once daily) measurements are recommended during the run-in period and during the first 4 weeks of the treatment period.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ......................................................................................................11
ABBREVIATIONS................................................................................................................15
1.
INTRODUCTION...............................................................................................17
MEDICAL BACKGROUND.............................................................................17
1.1
DRUG PROFILE................................................................................................18
1.2
1.2.1
Non-clinical assessment of safety.......................................................................18
1.2.2
Clinical pharmacokinetics..................................................................................18
Clinical pharmacokinetics – Type 2 diabetes mellitus..........................................18
1.2.2.1
1.2.3
Clinical efficacy and safety.................................................................................20
Clinical efficacy and safety – Type 2 diabetes mellitus........................................20
1.2.3.1
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....23
RATIONALE FOR PERFORMING THE TRIAL.........................................23
2.1
TRIAL OBJECTIVES........................................................................................23
2.2
BENEFIT - RISK ASSESSMENT.....................................................................23
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................26
OVERALL TRIAL DESIGN AND PLAN .......................................................26
3.1
3.1.1
Administrative structure of the trial .................................................................27
Data Monitoring Committee.................................................................................28
3.1.1.1
Clinical Event Committee – cardiovascular events ..............................................28
3.1.1.2
Clinical Event Committee – severe hypoglycaemia, DKA...................................28
3.1.1.3
Hepatic external adjudication................................................................................29
3.1.1.4
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................29
SELECTION OF TRIAL POPULATION .......................................................30
3.3
3.3.1
Main diagnosis for trial entry ............................................................................30
3.3.2
Inclusion criteria .................................................................................................30
3.3.3
Exclusion criteria ................................................................................................32
3.3.4
Removal of patients from therapy or assessments...........................................33
Removal of individual patients .............................................................................33
3.3.4.1
Discontinuation of the trial by the Sponsor ..........................................................34
3.3.4.2
4.
TREATMENTS...................................................................................................35
TREATMENTS TO BE ADMINISTERED.....................................................35
4.1


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4.1.1
Identity of BI investigational products and comparator product ..................35
4.1.2
Method of assigning patients to treatment groups...........................................36
4.1.3
Selection of doses in the trial..............................................................................36
4.1.4
Drug assignment and administration of doses for each patient......................37
4.1.5
Blinding and procedures for unblinding...........................................................38
Blinding.................................................................................................................38
4.1.5.1
Unblinding and breaking the code ........................................................................38
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................39
4.1.7
Storage conditions...............................................................................................39
4.1.8
Drug accountability.............................................................................................39
Patient treatment compliance................................................................................40
4.1.8.1
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................40
4.2.1
Rescue medication, emergency procedures, and additional treatments........41
4.2.2
Restrictions ..........................................................................................................43
Restrictions regarding concomitant treatment ......................................................43
4.2.2.1
Restrictions on diet and life style..........................................................................43
4.2.2.2
Restrictions regarding women of childbearing potential......................................44
4.2.2.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................45
TRIAL ENDPOINTS..........................................................................................45
5.1
5.1.1
Primary endpoint................................................................................................45
5.1.2
Secondary endpoints...........................................................................................45
.........................................46
.........................................46
.........................................46
.........................................47
ASSESSMENT OF EFFICACY........................................................................47
5.2
5.2.1
HbA1c and fasting plasma glucose .....................................................................47
5.2.2
Weight ..................................................................................................................47
5.2.3
Electronic diary...................................................................................................48
5.2.4
Systolic/diastolic blood pressure and pulse rate (vital signs)..........................49
ASSESSMENT OF SAFETY.............................................................................51
5.3
5.3.1
Physical examination ..........................................................................................51
5.3.2
Home monitoring ................................................................................................51
Self-blood glucose monitoring..............................................................................51
5.3.2.1
Ketone measurement.............................................................................................52
5.3.2.2
5.3.3
Safety laboratory parameters ............................................................................53
Follow-up on suspicion for urinary tract infections..............................................55
5.3.3.1
5.3.4
Electrocardiogram ..............................................................................................56
5.3.5
Other safety parameters.....................................................................................56
Assessment of hypoglycaemia rate.......................................................................56
5.3.5.1
Criteria for hypoglycaemic events........................................................................56
5.3.5.2
Assessment of cardiovascular events (CEC adjudication)....................................57
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Assessment of severe hypoglycaemia and DKA (CEC adjudication)..................57
5.3.5.4
5.3.6
Assessment of adverse events.............................................................................57
Definitions of AEs ................................................................................................57
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................61
 
APPROPRIATENESS OF MEASUREMENTS..............................................67
5.7
6.
INVESTIGATIONAL PLAN.............................................................................68
VISIT SCHEDULE.............................................................................................68
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................68
6.2
6.2.1
Screening, T1DM therapy optimisation and placebo run-in periods.............68
Screening visit (Visit 1) ........................................................................................68
6.2.1.1
T1DM therapy optimisation period (Visits 2, 3 and 4T) ......................................68
6.2.1.2
Placebo run-in period (Visit 5)..............................................................................69
6.2.1.3
6.2.2
Randomised treatment period ...........................................................................69
Randomisation visit (Visit 6)................................................................................70
6.2.2.1
Interim visits (Visits 7-10)....................................................................................70
6.2.2.2
6.2.3
End of treatment and follow-up period.............................................................71
End of treatment – completers (Visit 11 EOT).....................................................71
6.2.3.1
End of treatment - early discontinuations (eEOT) and withdrawals.....................71
6.2.3.2
Follow-up visit (Visit 12) - completers.................................................................72
6.2.3.3
Follow-up visit (Visit 12) – early discontinuations (eEOT) and withdrawals......72
6.2.3.4
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................74
STATISTICAL DESIGN - MODEL.................................................................74
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................75
7.2
PLANNED ANALYSES.....................................................................................79
7.3
7.3.1
Primary endpoint analyses.................................................................................80
Primary analysis of the primary endpoint.............................................................80
7.3.1.1
7.3.2
Secondary endpoint analyses .............................................................................82


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Key secondary endpoints – confirmatory analyses...............................................82
7.3.2.1
...................................................................
7.3.4
Safety analyses.....................................................................................................85
INTERIM ANALYSES ......................................................................................86
7.4
HANDLING OF MISSING DATA ...................................................................86
7.5
RANDOMISATION ...........................................................................................86
7.6
DETERMINATION OF SAMPLE SIZE .........................................................87
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........88
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................88
DATA QUALITY ASSURANCE ......................................................................88
8.2
RECORDS...........................................................................................................89
8.3
8.3.1
Source documents ...............................................................................................89
8.3.2
Direct access to source data and documents.....................................................89
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS89
8.4
8.4.1
Listedness.............................................................................................................89
8.4.2
Expedited reporting to health authorities and IECs/IRBs..............................89
STATEMENT OF CONFIDENTIALITY........................................................90
8.5
END OF TRIAL..................................................................................................90
8.6
9.
REFERENCES....................................................................................................91
PUBLISHED REFERENCES............................................................................91
9.1
10.
APPENDICES.....................................................................................................94
11.
DESCRIPTION OF GLOBAL AMENDMENTS............................................95


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ANCOVA
Analysis of Covariance
AUC
Area-Under-the-Curve
BP
Blood Pressure
BI
Boehringer Ingelheim
CEC
Clinical Event Committee
CGM
Continuous Glucose Monitoring
CKD-EPI
Chronic Kidney Disease Epidemiology
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRO
Contract Research Organisation
CSII
Continuous Subcutaneous Insulin Infusion
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Coefficient of Variation
DCCT
Diabetes Control and Complications Trial
DEDP
Drug Exposure During Pregnancy
DILI
Drug Induced Liver Injury
DKA
Diabetic Ketoacidosis
DMC
Data Monitoring Committee
DTSQs/c
Diabetes Treatment Satisfaction Questionnaire status/change version
EASE
Empagliflozin as Adjunctive to InSulin thErapy in patients with Type 1 
Diabetes Mellitus
eCRF
Electronic Case Report Form
EDTA
Ethylendiaminetetraacetic acid
eGFR
Estimated Glomerular Filtration Rate
EOT
End of Treatment
e-PRO
Electronic Patient Reported Outcome
EQ-5D-5L
EuroQoL-5Dimension-5Level
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FPG
Fasting Plasma Glucose
GCP
Good Clinical Practice
GLP-1
Glucagon-like-peptide 1
HbA1c
Glycosylated Haemoglobin
HCRU
Health Care Resource Utilisation
HFS-II
Hypoglycaemia Fear Survey II
HFS-W
Hypoglycaemia Fear Survey – Worry sub-scale
HPLC-MS
High performance liquid chromatography – tandem mass spectrometry
HRQoL
Health Related Quality of Life
IB
Investigator’s Brochure
ICU
Intensive Care Unit
IDF
International Diabetes Federation


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IEC
Independent Ethics Committee
IFCC
International Federation of Clinical Chemistry
IPV
Important Protocol Violation
IQR
Inter Quartile Range
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
MAGE
Mean Amplitude of Glycaemic Excursions
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Drug Regulatory Activities
MDG
Mean Daily Glucose
MDI
Multiple Daily Injections
MDRD
Modification of Diet in Renal Disease
mITT
Modified Intention-to-Treat
MMRM
Mixed Model for Repeated Measures
MODY
Maturity Onset Diabetes of the Young
NGSP
National Glycohemoglobin Standardisation Program
PD
Pharmacodynamic
PGx
Pharmacogenomic
PK
Pharmacokinetics
PPS
Per Protocol Set
RDC
Remote Data Capture
REP
Residual Effect Period
RS
Randomised Set
SAE
Serious Adverse Event
SBGM
Self-Blood Glucose Monitoring
SGLT
Sodium-Glucose Co-Transporter
SLC
Sodium-Glucose Co-transport
SOP
Standard Operating Procedure
STEMI
ST Elevation Myocardial Infarction
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1DM
Type 1 Diabetes Mellitus
T2DM
Type 2 Diabetes Mellitus
TCM
Trial Clinical Monitor
TDID
Total Daily Insulin Dose
TDM
Trial Data Manager
TIA
Transient Ischaemic Attack
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TSTAT
Trial Statistician
UACR
Urine Albumin Creatinine Ratio
UGE
Urinary Glucose Excretion
ULN
Upper Limit of Normal
UTI
Urinary Tract Infection
VAS
Visual Analogue Scale
WHO
World Health Organisation


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Type 1 diabetes mellitus (T1DM) accounts for 5 to 10% of all cases of diabetes mellitus.  
This disease is a complex disorder that requires constant attention to diet, exercise, glucose 
monitoring, and insulin therapy to achieve good glycaemic control.  T1DM occurs as a 
consequence of the organ-specific immune destruction of the pancreas’ insulin-producing β-
cells in the islets of Langerhans [R10-6370, R10-6371].
Controlling blood glucose in T1DM leads to improved patient outcomes [R04-2186, R12-
1489].  For this reason, several medical associations have given treatment recommendations 
for T1DM [P13-05979, R12-4773] including glycaemic goals.  Most bodies recommend that 
adult patients with T1DM should obtain glycated haemoglobin (HbA1c) ≤7.0%.  However, 
despite advances in insulin formulation and delivery, such as the development of continuous 
subcutaneous insulin infusion (CSII) systems, refinement of pharmacokinetic (PK) properties 
of rapid- and long-acting insulin analogues, and the use of continuous glucose monitoring 
(CGM) systems, current therapy for patients with diabetes requiring insulin often does not 
lead to satisfactory glycaemic control.  In fact, only a minor portion of patients achieve 
normalisation of HbA1c and restoration of euglycaemia.  Most patients generally achieve 
HbA1c levels no lower than 8.0%.  Hence, with the currently available treatment options, 
patients with T1DM often fail to maintain adequate blood glucose control.  This may not only 
lead to acute conditions such as hyperglycaemia and ketoacidosis, but may also lead to 
debilitating secondary complications including heart disease, blindness and kidney failure 
[R10-6369].  In addition, inadvertent excessive administration of insulin may also contribute 
to acute conditions such as severe hypoglycaemia.
Empagliflozin is a reversible, highly potent (IC50 1.3 nM) and selective competitive inhibitor 
of sodium-glucose co-transporter 2 (SGLT-2), 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 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 glucosuria.  This threshold concentration can be 
decreased by SGLT-2 inhibition [c01678844]; an approximately 5000-fold selectivity over 
human SGLT-1 (IC50 6278 nM), responsible for glucose absorption in the gut, was calculated
for empagliflozin [U06-1742].
It was demonstrated, nearly four decades ago, that in patients with poorly controlled T1DM, 
the maximum tubular reabsorption capacity for glucose was significantly increased, whereas 
one would in fact have suspected that during hyperglycaemia, with increased interstitial and 
intracellular glucose concentrations, the reduced glucose concentration gradient across the 
basolateral membrane of the proximal renal epithelial cell would attenuate glucose efflux 
[R10-6572].  This paradoxically increased glucose reabsorption in T1DM could be explained 
by an up-regulation of glucose transporters, including SGLT-2 which was shown in tubular 
cells cultured from patients with Type 2 diabetes mellitus (T2DM) [R10-0703].  The 
phenomenon of an increased reabsorption of glucose when glucose concentration is elevated 


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could therefore be considered a maladapted response to glucosuria in diabetes, since it would 
rather be desirable for the kidney to excrete the excess filtered glucose load in order to restore 
normoglycaemia [P11-10364].
Based on these pathophysiological considerations, it follows that empagliflozin has the 
potential to provide a novel approach to the treatment of T1DM, as adjunctive therapy to 
insulin.  Empagliflozin lowers both the saturation threshold and the transport maximum of 
SGLT-2 for glucose, resulting in increased glucosuria, insulin-independent reduction of 
plasma glucose levels with potentially low risk of hypoglycaemia, and negative energy 
balance with potential weight reduction in T1DM.
DRUG PROFILE
1.2
Empagliflozin is a novel, orally available, potent, and selective inhibitor of the renal SGLT-2.  
Its selective inhibition reduces renal reabsorption of glucose and promotes increased urinary 
glucose excretion (UGE) resulting in reduction of blood glucose levels.
Empagliflozin has been developed for the treatment of T2DM, and has received marketing 
approval in various regions including the European Union and the USA where it is marketed 
under the brand name Jardiance®.
1.2.1
Non-clinical assessment of safety
For further information regarding pre-clinical evaluation, please refer to the current version 
of the Investigator’s Brochure (IB) for empagliflozin [c01678844].
1.2.2
Clinical pharmacokinetics
Clinical pharmacokinetics – Type 2 diabetes mellitus
1.2.2.1
In humans, empagliflozin predominantly showed linear PK.  Empagliflozin reaches peak 
levels at approximately 1.5 hours and showed a biphasic decline with the terminal elimination 
half-life of 12.4 hours ranging from 10 to 19 hours.
Empagliflozin exposure increases with renal or hepatic impairment; however, no dose 
adjustment is recommended as the observed changes in exposure were not clinically 
meaningful.  The observations from a Phase I study in patients with renal impairment indicate 
a rather low glycaemic efficacy of empagliflozin in patients with severe renal impairment and 
end-stage renal disease, while efficacy is assumed to be unchanged with hepatic impairment.
No clinically relevant PK interactions were observed with other oral antidiabetics, warfarin, 
verapamil, ramipril, simvastatin, digoxin, hydrochlorothiazide, torasemide, gemfibrozil, 
rifampicin, probenecid and oral contraceptives (Microgynon®).
For further details refer to the current version of the IB for empagliflozin [c01678844].


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1.2.3
Clinical efficacy and safety 
Clinical efficacy and safety – Type 2 diabetes mellitus
1.2.3.1
Empagliflozin has been studied as part of a global development program with 15582 patients 
with T2DM treated in clinical studies of which 10004 were treated with empagliflozin, either 
alone or in combination with metformin, a sulfonylurea, a PPARγ agonist, dipeptidyl 
peptidase-4 inhibitors, or insulin.
The Phase III studies in T2DM showed that treatment with empagliflozin 10 mg or 25 mg 
once daily for up to 24 weeks results in a reduction of HbA1c up to 0.85%, body weight up to 
2.2 kg and systolic blood pressure (SBP) up to 4.8 mmHg compared with placebo.  This was 
consistently observed with empagliflozin as monotherapy, add on to metformin, to metformin 
and sulphonylurea, to pioglitazone with or without metformin, and to basal insulin with 
metformin and/or sulphonylurea.  Phase III studies up to 104 weeks in T2DM support the 
sustained effect of empagliflozin.
In clinical studies, empagliflozin was well tolerated in both normal healthy volunteers and 
patients with T2DM up to maximal treatment duration of 104 weeks in completed studies.  
The frequency of overall Adverse Events (AEs), AEs leading to discontinuation and Serious 
AE (SAEs) were comparable to placebo.  There was no significant increase in frequency of 
hypoglycaemia with empagliflozin compared to placebo except when used in combination 
with a sulphonylurea or basal insulin.  In general there was a small increase in frequency of 
urinary tract infection (UTI) compared to placebo.  There was an increase in frequency of 
genital infections with the use of empagliflozin.  There was a small increase in total 
cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) 
cholesterol and no significant changes in triglycerides.  No changes in electrolytes were 
observed with empagliflozin.  There was a reduction in eGFR which gradually returned 
toward baseline values over the treatment period in the trials.  Furthermore, eGFR returned to 
baseline when empagliflozin was discontinued.  In a dedicated study in patients with 
moderate renal impairment (eGFR between 30-60 mL/min/1.73 m2) treatment with 
empagliflozin was well tolerated and led to statistically significant reduction of HbA1c and 
clinically meaningful improvement in FPG (fasting plasma glucose), body weight and BP 
compared to placebo at Week 24.  Similar results were sustained for up to 52 weeks 
[c01678844].
 


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In summary, given the safety profile in the preclinical studies of empagliflozin, and the 
safety, tolerability and efficacy seen in the clinical study programs to date, the available 
clinical and non-clinical data support safe and efficacious use in humans and further 
development of empagliflozin in T1DM and T2DM.
For a more detailed description of the drug profile refer to the current IB which is included in 
the Investigator Site File (ISF).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
In an extensive Phase III program, empagliflozin (10 mg and 25 mg) was shown to be safe 
and efficacious in the treatment of patients with T2DM and has received marketing approval 
in more than 30 countries including the EU and US.  Due to its insulin-independent mode of 
action empagliflozin also has potential for use in the treatment of patients with T1DM.  
 
, this 
Phase III trial is planned to confirm the efficacy and safety of empagliflozin in patients with 
T1DM and to further investigate tolerability and PK.
TRIAL OBJECTIVES
2.2
The objective of this study is to assess the efficacy, safety, tolerability and PK of once daily 
oral doses of empagliflozin 2.5 mg, 10 mg and 25 mg compared to placebo in patients with 
T1DM as adjunctive to insulin therapy.
BENEFIT - RISK ASSESSMENT
2.3
A pharmacologic rationale for the use of empagliflozin in T1DM can be found in Section 1.1.  
The overall tolerability and safety profile outlined in Section 1.2, and the current IB, supports 
chronic administration of empagliflozin 2.5 mg, 10 mg and 25 mg in human studies.
According to the medication assignment planned in this trial, 75% of the patients will receive 
empagliflozin, and 25% of patients will be assigned to placebo.  For those assigned to 
empagliflozin, patients may benefit from positive glycaemic effects.  In addition to achieving 
better glycaemic control, patients receiving empagliflozin are expected to benefit from a 
reduced number and intensity of hypoglycaemic events due to a reduced need for 
insulin/reduced glucose excursions (since when using insulin only, its subcutaneous 
administration often leads to over-insulination ultimately causing hypoglycaemia).  
Nevertheless, patients will be closely monitored for hypoglycaemic episodes throughout the 
trial, and the frequency of this monitoring will be adjusted in accordance with the anticipated 
risk (including night-time glucose measurements during the first days after initiation of the 
study medication).  Patients assigned to both empagliflozin and placebo may also derive 
general medical benefit from careful and close monitoring by medical personnel during the 
study.  Placebo patients may benefit from optimising the therapy for T1DM as part of the 
T1DM therapy optimisation period.
As part of the preparation for entry into the randomised treatment period, therapy for T1DM 
will be optimised (e.g. review of blood glucose values, insulin dose and its adjustment for 
meals, ability to carbohydrate count etc.) over a 6 week period (T1DM therapy optimisation 
period) to ensure that, in the Investigator’s opinion, a patient is achieving the best standard of 
care in accordance with local guidelines before entering the randomised treatment period of 
the trial.  This optimal therapy will then be continued, and at randomisation, Investigators are 


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advised to reduce the patient’s total insulin dose based on need/ by 10% to minimise the risk 
for hypoglycaemia.  Since glomerular filtration is physiologically decreased during episodes 
of severe hypoglycaemia (due to reduced renal blood flow hence leading to lowering of urine 
glucose excretion and therefore efficacy of empagliflozin), hypoglycaemia induced by insulin 
is not expected to be significantly aggravated by empagliflozin [R12-4766].
Special attention will be paid to prevent T1DM-inherent DKA.  Due to the mechanism of 
action, empagliflozin may potentially modify the clinical presentation of DKA.  Patients 
receiving empagliflozin may be at risk to underestimate their need for insulin if blood sugar 
levels are within individual target ranges or only slightly elevated.  Insulin deficiency might 
lead to ketoacidosis which could be life-threatening if not recognised and appropriately 
treated.  All patients will be made aware of this risk and be instructed not to reduce their 
insulin dose below Investigator recommendations.  In addition to blood glucose monitoring, 
the frequency of which will be increased after starting the study medication (for further 
details see Section 5.3.2.1), in the same way as during routine clinical care, patients will be 
reminded how to determine ketones in case of any symptoms of DKA, e.g. nausea, vomiting,
abdominal pain etc.  They will be instructed to do this irrespective of the glucose value in the 
event of DKA symptoms occurring.  More frequent ketone testing (e.g. once daily) will be 
recommended during the run-in period and during the first 4 weeks of the treatment period; 
this will allow patients and Investigators to understand baseline ketosis rates and compare 
them, as appropriate, to the incidence of ketosis following the initiation of study medication.  
A meter will be provided to the patient for this purpose; as an additional safeguard, the meter 
will also be used to check ketone levels at most clinic visits (see Flow Chart).  Patients will 
be reminded of the interpretation of ketone values measured by the meter, and on appropriate 
action to be taken in the event of increased ketone levels (see Section 5.3.2.2). In addition, 
patients will be reminded about insulin adjustment during “sick days” and about the
importance of keeping themselves hydrated.
Investigators should also differentiate deteriorating ketosis/DKA from any mild to moderate 
increase of ketones which may be seen due to the mechanism of action of empagliflozin, 
especially in the fasted state (e.g. in the morning).  See also Section 1.2.3.2.
Patients will be carefully selected for the trial in line with the eligibility criteria, to ensure, in 
the Investigator’s judgement, that they have a good understanding of their disease and how to 
manage it.  They should also be selected in terms of their ability to be compliant with the 
demands of the trial.  This means, for example, that patients should be able to lead the 
optimisation of their T1DM therapy since they are judged to have sound self-management 
skills and approaches to insulin dose adjustment, and are reliable in terms of performing 
frequent home testing of both glucose and ketones when required.
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into 
consideration when empagliflozin is administered.  Other risks to the patients are the risks 
inherent to any investigational medicinal product used in a clinical trial setting, such as 
unexpected adverse clinical or laboratory events.


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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.
To continue the assessment of the long-term safety of empagliflozin, an adjudication of 
certain hepatic events will be performed in this trial.  Furthermore, adjudication of 
cardiovascular events, severe hypoglycaemia and DKA will be performed.  The progress of 
the trial will also be assessed at regular intervals by an independent Data Monitoring 
Committee (DMC).  For further details please refer to Section 3.1.1.1.
Based on the findings in non-clinical studies conducted to date, and in accordance with 
international regulatory guidelines, the inclusion of women of child-bearing potential in this 
trial is justified.  To minimise the risk of unintentional exposure of an embryo or foetus to the 
investigational drug, women of child-bearing potential must agree to the requirements for 
pregnancy testing and contraceptive methods described in this protocol (for further details see 
Section 3.3.3).
Safety will be carefully assessed by monitoring the patients for AEs clinically, by laboratory 
testing and by blood glucose and ketone monitoring.  The Investigator will have the 
discretion to remove patients from the study should there be any safety concerns or if the 
patient’s wellbeing is at jeopardy.
The potency, selectivity, and efficacy in various animal models and the PD data from studies 
in healthy volunteers and patients with diabetes suggest that empagliflozin may be able to 
provide a valuable benefit to patients with T1DM.
Given the positive risk-benefit ratio for empagliflozin to date, the careful selection of patients 
and their monitoring during the study, the blood glucose and ketone monitoring performed by 
the patients at home and the option to adjust a patient’s insulin treatment, the Sponsor 
considers the benefit-risk assessment for the use of empagliflozin in T1DM patients in this 
trial to be favourable.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This multi-national, randomised, placebo-controlled, double-blind, parallel group study 
compares 3 doses of empagliflozin (2.5 mg, 10 mg and 25 mg) to placebo in patients with 
T1DM as adjunctive to insulin therapy.  In total, 960 patients with T1DM who meet the entry 
criteria will be entered (randomised) in the trial.  The randomised treatment will be double-
blind.  A triple-dummy design will be used for masking the treatment assignment, i.e. each 
patient will take 3 tablets a day, receiving 1 active treatment and 2 placebo matching the 
alternative active treatments, or 3 placebos matching the alternative treatments.
Patients will be enrolled (screened) in the trial once they have signed the informed consent. 
All patients who are suitable after screening will undergo a 6 week T1DM therapy 
optimisation period, followed by a 2 week open-label placebo run-in period before 
randomisation.  Patients who successfully complete both of these periods and who still meet 
the inclusion/exclusion criteria will be randomised into the 26 week double-blind treatment 
period in which they will receive either one of the 3 doses of empagliflozin or placebo in 
addition to their regular insulin therapy.
About 30% of the patients will take part in a CGM substudy. In addition to the regular trial 
assessments, these patients will have 4 CGM period of 2 weeks each (Week -2 to Week -1, 
Week 1 to 2, Week 3 to 4 and Week 25 to 26). This substudy will be conducted at selected 
trial sites which are experienced with CGM. Participation in the substudy will be optional for 
patients at these sites.
After the 26 week treatment period, all patients will enter a 3 week follow-up period during 
which they will not be treated with study medication.  During this period all AEs need to be 
collected, documented and reported.  The patient’s participation is concluded when they have 
undergone the last planned visit (i.e. Trial Completion/Visit 12); last-patient-last-visit-
primary-endpoint will occur when all patients have completed 26 weeks of treatment.  The 
end of the trial is defined as “last patient out” (i.e. last Visit 12 completed by the last patient 
in the trial).  For further details regarding the definition of the end of the trial, please see 
Section 8.6.
For a graphical representation of the trial, see Figure 3.1: 1.


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Figure 3.1: 1 Trial Design
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating all required 
activities, in order to:

manage the trial in accordance with applicable regulations and internal Standard 
Operating Procedures (SOPs)

direct the clinical trial team in the preparation, conduct, and reporting of the trial

order the materials as needed for the trial

ensure appropriate training and information of Local Clinical Monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.  For 
these activities, a Trial Data Manager (TDM) and a Trial Statistician (TSTAT) will be 
appointed. Central laboratory services will be provided via
will be provided by 
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 and relevant local information 
can be found in the ISF.
A Coordinating Investigator will be nominated and will be responsible to coordinate 
Investigators at different centres participating in this multicentre trial. Tasks and 


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responsibilities will be defined in a contract. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in the ISF.
Data Monitoring Committee
3.1.1.1
A DMC, independent from the Sponsor, will be established to assess the progress of the trial, 
including unblinded safety data and the critical efficacy endpoints at intervals, and to
recommend to the Sponsor whether to continue, modify, or stop one or more of the trials 
covered by the DMC.  Measures will be in place to ensure blinding of the Sponsor and all 
other trial participants.
The tasks and responsibilities of the DMC will be specified in a charter.  The DMC will 
maintain written records of all its meetings.
Clinical Event Committee – cardiovascular events
3.1.1.2
An independent external committee (Clinical Event Committee, [CEC]) will be established to 
adjudicate centrally and in a blinded fashion events suspect of stroke, myocardial ischaemia 
(including myocardial infarction), cardiovascular death and other relevant events (e.g. 
hospitalisation for unstable angina, hospitalisation for heart failure) 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 electrocardiograms (ECGs), laboratory values, angiography, 
echocardiography reports, CT and/or MRI scans, discharge summaries, and autopsy reports 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.
Clinical Event Committee – severe hypoglycaemia, DKA
3.1.1.3
An independent external committee (CEC) will be established to adjudicate centrally and in a 
blinded fashion events suspect of severe hypoglycaemia (for further details see Section 
5.3.5.2) and DKA (for further details see Section 5.3.6.1).  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.


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Hepatic external adjudication  
3.1.1.4
Certain hepatic events will be adjudicated by external independent experts for severity and 
causal relationship with the trial medication in a blinded fashion.  The events which will be 
reviewed will be defined in a charter.  Events may either be defined by abnormal laboratory 
values and/or relevant adverse events or both.  For example, assessments will be made for 
events of hepatic injury, including liver enzyme elevations.
For qualifying events, relevant source documents generated from any medical evaluations of 
these events will be requested including laboratory values, histological analysis, results of 
ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical reports from other 
physicians.  All evaluations will be performed in a blinded fashion.  The assessments will be 
analysed based on empagliflozin data combined from multiple trials (i.e. on project level).
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP
This trial will investigate the efficacy, safety and tolerability of empagliflozin in patients with 
T1DM, as adjunctive to insulin therapy, and will further characterise the PK.
The trial design was chosen according to the FDA’s “Guidance for Industry, Diabetes 
Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention” [R08-
2669].  According to this guideline, insulin is the essential glucose-lowering therapy for 
patients with T1DM.  All experimental T1DM treatments that are not insulin analogues or 
other insulin receptor ligands should be studied as add-on therapies to insulin.  Consequently, 
in this trial empagliflozin and matching placebo will be administered as add-on to an existing 
insulin therapy.  Treatment with MDI of insulin or CSII (i.e. insulin pump therapy) are held 
as the practical gold standard for the treatment of T1DM [P13-05979].
A 6 week T1DM therapy optimisation period, followed by a 2 week placebo run-in period is 
deemed appropriate to screen out non-compliant patients, and to capture a “true” baseline 
incidence rate of hypoglycaemia, together with optimal insulin use.
HbA1c as the primary endpoint has been demonstrated to be a reflection of the glycaemic 
control over the preceding 12 weeks and maintenance data over a period of approximately 
6 months are requested by the different regulatory agencies.  Therefore the primary endpoint 
is the change from baseline in HbA1c after 26 weeks of randomised treatment.
The 3 week follow-up period is considered to be sufficient, as previous studies with
empagliflozin have shown that its’ PD effect only extends to about three days after the last
dose.  Furthermore, it will allow for the assessment of reversibility of unexpected long-term
side effects.
Use of a placebo group is deemed acceptable since it is expected that the insulin therapy 
requirement of patients receiving placebo will remain unchanged compared to their treatment 
before randomisation.


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The rationale for dose and dose-interval selection is described in Section 4.1.3.
SELECTION OF TRIAL POPULATION
3.3
A sufficient number of male and female patients with T1DM will be screened to ensure the 
randomisation of 960 patients from around 180 trial sites.
It is expected that around 5 patients will be randomised at each trial site.  If enrolment is 
delayed, additional sites may be recruited.  Permission to enrol more than 36 patients per site 
must be obtained from the TCM at BI.  This will only be allowed after a careful review of the 
enrolment status and of the site.
Screening of patients for this trial is competitive across all countries within the trial, i.e. 
screening for the trial will stop at all sites when it is anticipated that a sufficient number of 
patients have been screened to yield the desired number of patients randomised to trial 
treatment.  Investigators will be notified when sufficient patients have been screened and 
when screening is complete, and will not be allowed to recruit additional patients for the 
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 Clinical Trial Protocol 
(CTP).
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Only patients with confirmed, insulin-dependent T1DM for at least a year will be screened 
for suitability for the study.  Inclusion will be based upon a complete medical history, 
including physical examination, vital signs, 12-lead ECG and clinical laboratory tests.
Please refer to section 8.3.1 for the documentation requirements pertaining to the in- and 
exclusion criteria.
3.3.2
Inclusion criteria
1. Signed and dated written informed consent by the date of Visit 1 in accordance with 
Good Clinical Practice (GCP) and local legislation
2. Male or female patient receiving insulin for the treatment of documented diagnosis of 
T1DM for at least 1 year at the time of Visit 1
3. Fasting C-peptide value of < 0.7 ng/mL (0.23 nmol/L) at Visit 2 measured by the central 
laboratory


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4. Use of, and be willing, based on the Investigator’s judgement, to continue throughout the 
duration of the trial, either:

MDI of insulin consisting of at least one basal insulin injection and at least three daily 
bolus injections OR

CSII of any insulin type, with at least 5 months experience of using CSII prior to 
Visit 1
For both MDI and CSII, the total daily insulin dose must be ≥ 0.3 U/kg and ≤1.5 U/kg at 
Visit 1 
5. HbA1c ≥ 7.5% and ≤10.0% at Visit 5 measured by the central laboratory, and provided 
that the patient’s HbA1c does not increase by > 0.5% between Visit 1 and Visit 5
6. Based on the Investigator’s judgement patient must have a good understanding of his/her 
disease and how to manage it, and be willing and capable of performing the following 
study assessments (assessed at Visits 1-5 and just before randomisation):

patient-led management and adjustment of insulin therapy

reliable approach to insulin dose adjustment for meals, such as carbohydrate counting

reliable and regular home-based blood glucose monitoring

recognise the symptoms of DKA, and reliably monitor for ketones

implementation of an established “sick day” management regimen
7. Age ≥18 years at Visit 1
8. Body Mass Index (BMI) of ≥18.5 kg/m2 at Visit 1 
9. eGFR ≥30 mL/min/1.73 m² as calculated by the CKD-EPI formula, based on creatinine 
measured by the central laboratory at Visit 1
10. Women of child-bearing potential* must be ready and able to use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% 
per year when used consistently and correctly.  Such methods should be used throughout 
the study and the patient must agree to periodic pregnancy testing during participation in 
the trial.  A list of contraceptive methods meeting these criteria will be provided in the 
patient information
*Women of child-bearing potential are defined as follows:
Any female who has experienced menarche and is not post-menopausal (defined as at 
least 12 months with no menses without an alternative medical cause) or who is not 
permanently sterilised (e.g. hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy)


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11. Compliance with trial medication administration must be between 80% and 120% during 
the open-label placebo run-in period (see Section 4.1.8.1 for calculation of compliance), 
to be judged before randomisation
12. To participate in the optional CGM substudy: Patient is willing to participate in that 
substudy and eligible based on Investigator’s judgement to perform CGM. CGM substudy 
is conducted at the trial site
13. To participate in the optional CGM substudy: Patient is willing, based on the 
Investigator’s judgement, not to take any paracetamol (acetaminophen) containing drugs 
throughout the CGM monitoring periods, since this may falsely raise CGM glucose 
readings
3.3.3
Exclusion criteria
1. History of T2DM, maturity onset diabetes of the young (MODY), pancreatic surgery or 
chronic pancreatitis
2. Pancreas, pancreatic islet cells or renal transplant recipient
3. T1DM treatment with any other antihyperglycaemic drug (e.g. metformin, alpha-
glucosidase inhibitors, glucagon-like-peptide 1 [GLP-1] analogues, SGLT-2 inhibitors, 
pramlintide, inhaled insulin, pre-mixed insulins etc.) except subcutaneous basal and bolus 
insulin within 3 months prior to Visit 1 or any history of clinically relevant 
hypersensitivity according to Investigator’s judgement
4. Occurrence of severe hypoglycaemia involving coma/unconsciousness and/or seizure that 
required hospitalisation or hypoglycaemia-related treatment by an emergency physician 
or paramedic within 3 months prior to Visit 1 and until randomisation
5. Occurrence of DKA within 3 months prior to Visit 1 and until randomisation at Visit 6
6. Irregular sleep/wake cycle (e.g. patients who habitually sleep during the day and work 
during the night) based on Investigator’s judgement
7. Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or 
transient ischaemic attack (TIA) within 3 months prior to Visit 1 
8. Diagnosis of severe gastroparesis (based on Investigator’s judgement)
9. Diagnosis of brittle diabetes based on Investigator judgement
10. Indication of liver disease, defined by serum levels of either alanine transaminase (ALT), 
aspartate transaminase (AST), or alkaline phosphatase above 3 x upper limit of normal 
(ULN) at Visit 1 or Visit 5 as measured by the central laboratory
11. Eating disorders such as bulimia or anorexia nervosa


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12. Treatment with anti-obesity drugs, weight-loss surgery or aggressive diet regimen leading 
to unstable body weight (based on Investigator’s judgement) 3 months prior to Visit 1 
and until randomisation
13. Treatment with systemic corticosteroids or planned initiation of such therapy at Visit 1
and until randomisation.  Inhaled or topical use of corticosteroids (e.g. for asthma/chronic 
obstructive pulmonary disease) is acceptable
14. Change in dose of thyroid hormones within 6 weeks prior to Visit 1 or planned change or 
initiation of such a therapy at Visit 1 and until randomisation
15. Medical history of cancer or treatment for cancer in the last five years prior to Visit 1. 
Resected basal cell carcinoma considered cured is exempted 
16. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. 
malaria, babesiosis, haemolytic anaemia) at Visit 1
17. Women who are pregnant, nursing, or who plan to become pregnant whilst in the trial
18. Alcohol or drug abuse within the 3 months prior to Visit 1 that would interfere with trial 
participation based on Investigator’s judgement 
19. Intake of an investigational drug in another trial within 30 days prior to Visit 1
20. Patient not able to understand and comply with study requirements, including the use of 
an e-diary, based on Investigator’s judgement
21. Any other clinical condition that, based on Investigator’s judgement, would jeopardise 
patient safety during trial participation or would affect the study outcome (e.g. 
immunocompromised patients who might be at higher risk of developing genital or 
mycotic infections, patients with chronic viral infections etc.)
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for study treatment or study participation, without the need 
to justify the decision.

The patient needs to start a restricted concomitant therapy (as listed in Section 4.2) that, 
in the Investigator’s opinion, poses a safety risk if taken as add-on to the trial medication

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, AEs, other diseases, or pregnancy)


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
The patient experiences severe hypoglycaemia (for further details see Section 5.3.5.2) or 
repeated hypoglycaemic episodes or DKA that, in the Investigator’s opinion, may put the 
patient at risk with continued participation
If a patient becomes pregnant during the trial the study medication will be stopped, the 
patient will be discontinued from the trial and the patient will be followed up until birth or 
otherwise termination of the pregnancy.
A patient can be discontinued after discussion between 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, T1DM therapy optimisation, or run-in periods 
prior to randomisation will be considered screening failures.  They will be recorded as 
screening failures in the Electronic Case Report Form (eCRF) and no further follow-up is 
required.  The data will be included in the trial database and will be reported.
Patients who discontinue the trial treatment or withdraw from the study after randomisation 
will be considered as “early discontinuations” and the reason for this premature 
discontinuation of trial treatment or withdrawal from the study must be recorded in the eCRF.  
The data will be included in the trial database and will be reported.
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.  
Details of procedures to be followed for patients prematurely terminating the trial treatment 
can be found in Section 6.2.3.
Patients who discontinue or withdraw from the study after randomisation will not be 
replaced.
Discontinuation of the trial by the Sponsor
3.3.4.2
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site

Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial

Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
The study medication will be provided by BI.
Existing insulin therapy is not considered part of the clinical trial supplies, and therefore will 
not be provided.
4.1.1
Identity of BI investigational products and comparator product
The characteristics of the test products are as shown below.
Substance:
empagliflozin
Pharmaceutical formulation: film-coated tablet
Source:
Boehringer Ingelheim
Unit Strength:
2.5 mg
Posology:
once daily
Route of administration:
oral
Substance:
empagliflozin
Pharmaceutical formulation: film-coated tablet
Source:
Boehringer Ingelheim 
Unit Strength:
10 mg
Posology:
once daily
Route of administration:
oral
Substance:
empagliflozin
Pharmaceutical formulation: film-coated tablet
Source:
Boehringer Ingelheim
Unit Strength:
25 mg
Posology:
once daily
Route of administration:
oral
The characteristics of the reference products are as shown below.
Substance:
placebo matching empagliflozin 2.5 mg
Pharmaceutical formulation: film-coated tablet
Source:
Boehringer Ingelheim
Unit Strength:
-
Posology:
once daily
Route of administration:
oral


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Substance:
placebo matching empagliflozin 10 mg
Pharmaceutical formulation: film-coated tablet
Source:
Boehringer Ingelheim
Unit Strength:
-
Posology:
once daily
Route of administration:
oral
Substance:
placebo matching empagliflozin 25 mg
Pharmaceutical formulation: film-coated tablet
Source:
Boehringer Ingelheim
Unit Strength:
-
Posology:
once daily
Route of administration:
oral
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 randomisation system at Visit 6, 
Day 1.  This will involve the use of IRT, which will take into consideration the relevant 
stratification factors.  To facilitate the use of IRT, the Investigator will receive all necessary 
instructions and/or documents for using the IRT.
Patients will be randomly assigned, in a 1:1:1:1 ratio, to either:
(i)
empagliflozin 2.5 mg
(ii)
empagliflozin 10 mg 
(iii) empagliflozin 25 mg 
(iv) placebo  
For further details refer to Section 7.6.
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 kit(s) corresponding to the assigned medication number(s) should be given to the patient 
and the number of the kit(s) that was/were dispensed will be entered in the eCRF.  Using this 
procedure, relevant parties will be blinded to the treatment group assignment.
4.1.3
Selection of doses in the trial
The exposure response relationship between empagliflozin and UGE was evaluated for 
patients with T1DM (for further details please refer to Section 1.2.2).  Results indicate that 
near maximal effects are achieved with empagliflozin 10 mg and 25 mg once daily; these 
findings are comparable to those observed in patients with T2DM.  It is concluded that there 
are no clinically relevant differences in PK/PD between the T1DM and T2DM populations 
and that the approved doses for T2DM patients are appropriate for use in studies assessing 


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the safety and efficacy of empagliflozin in adult patients with T1DM.  A detailed comparison 
of empagliflozin PK/PD in patients with T1DM versus T2DM is provided in Section 1.2.2.3.
In addition, an empagliflozin 2.5 mg dose group is included into this trial to establish a 
minimal safe and effective dose for the treatment of patients with T1DM.
For further details with respect to T2DM PK/PD, please refer to Section 1.2.2.1 and to the 
current version of the IB for empagliflozin [c01678844].
4.1.4
Drug assignment and administration of doses for each patient
The treatments to be evaluated are outlined in Table 4.1.4: 1 below.  Patients who qualify will 
be randomised to one of the dosage and treatment schedules described.  Except for the open-
label run-in period, trial medication will be dispensed in a double-blind manner.
All patients will be assigned placebo at the beginning of the placebo run-in period (Visit 5) 
and dispensing will occur once within this period.  Dispensing of kits for the double-blind 
treatment will begin at Visit 6.  Dispensing will occur on 4 occasions as indicated in the Flow 
Chart, covering a period of 26 weeks.  For further details regarding packaging please refer to 
Section 4.1.6.
The dose of empagliflozin is fixed as shown in Table 4.1.4: 1 below.  Double doses and dose 
reductions are not permitted.  On the other hand, adjustment of a patients’ existing insulin 
therapy is permitted (for further details see Section 4.2.1).
From the start of the run-in period, patients will be instructed to take their trial medication 
once daily in the morning with a glass of water.  To ensure a dose interval of about 24 hours, 
the medication should be taken each day at approximately the same time in the morning.
Table 4.1.4: 1 Empagliflozin and matching placebo, daily oral administration per dose group 
Empagliflozin 
2.5 mg
Empagliflozin 
10 mg
Empagliflozin 
25 mg
Total # 
units per 
dose
Timing
Placebo run-in period (open-label):
All patients
Matching 
placebo
Matching 
placebo
Matching 
placebo
3 tablets
Once daily, 
morning
Treatment period (double-blind):
Dose group
2.5 mg
Empagliflozin 
2.5 mg
Matching 
placebo
Matching 
placebo
3 tablets
Once daily, 
morning
10 mg
Matching 
placebo
Empagliflozin 
10 mg
Matching 
placebo
3 tablets
Once daily, 
morning
25 mg
Matching 
placebo
Matching 
placebo
Empagliflozin 
25 mg
3 tablets
Once daily, 
morning
Placebo
Matching 
placebo
Matching 
placebo
Matching 
placebo
3 tablets
Once daily, 
morning


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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 prior to a visit, the dose should be taken approximate-
ly 24 hours before the planned dose at the visit.  Empagliflozin can be taken with or without 
food.
Patients should be instructed not to take their trial medication in the morning before visits as 
they will be dosed at the site.  Patients who fail to do so should have the visit rescheduled as 
soon as possible, ideally on the following day.  Insulin administration (basal and/or bolus) on 
the morning of clinic visits will be left to the discretion of the patient and/or Investigator and 
may be dependent on planned meal intake etc.  Visits should be routinely scheduled in the 
morning, at approximately the same time of day (e.g. 7am to 11am) for each visit.  The actual 
date and time of administration of the medication at the trial visit will be recorded in the 
eCRF.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
After randomisation at Visit 6, 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 
Suspected Unexpected Serious Adverse Reactions (SUSARs), it may be necessary for a 
representative from BI’s drug safety group to access the randomisation code for individual 
patients during study conduct.  In such cases, access to the code will only be permitted by 
authorised drug safety representatives.  Access to the code will be via the IRT 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.
The randomisation codes will be provided to bioanalytics prior to last patient out to allow 
them to exclude PK samples taken from placebo-treated patients from the bioanalytical 
analyses.  Bioanalytics will not disclose the randomisation code or the results of their 
measurements until the study is officially unblinded.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator /Pharmacist /investigational drug 
storage manager via IRT.  It must only be used in an emergency situation when the identity of 
the trial medication must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants.  The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page along with the date of 
unblinding.


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4.1.6
Packaging, labelling, and re-supply
Trial medication will be labelled with the trial identification and medication code number.  It 
will be dispensed as indicated in the Flow Chart.  At each dispensing, an appropriate number 
of tablets (empagliflozin and/or placebo-to-match empagliflozin) plus some reserve will be 
given to the patient.
Supply and re-supply will be managed by the IRT.  
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
The trial medication must be kept in its tightly closed original packaging under the 
recommended storage conditions indicated on the label.  A temperature log must be 
maintained by the Investigator/Pharmacist/investigational drug storage manager to make 
certain that the medication is stored at the correct temperature.  If storage conditions are 
found to be outside the specified range, the process outlined in the ISF should be followed.
Trial medication must be stored securely at the study sites, out of reach of children and be 
protected from moisture and direct sunlight, e.g. in a locked cupboard or at a Pharmacy.  It 
may only be dispensed to trial patients fulfilling the inclusion and exclusion criteria by 
authorised study personnel as documented in the ISF.  Receipt, usage and return of the trial 
medication must also be documented on the respective forms in the ISF.
All unused medication including all packaging, empty or filled, must be either returned to the 
Sponsor, or, following written authorisation from the Sponsor, may be destroyed at site.  
Receipt, usage and return must be documented on the respective forms.  Account must be 
given for any discrepancies.
4.1.8
Drug accountability
The Investigator and/or Pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the Sponsor when the following requirements are 
fulfilled:

approval of the CTP by the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) 

availability of a signed and dated clinical trial contract between the Sponsor and the Head 
of Trial Centre

approval/notification of the regulatory authority, e.g. Competent Authority

availability of the curriculum vitae of the Principal Investigator

availability of a signed and dated CTP

availability of the proof of a medical licence for the Principal Investigator (if applicable) 

for USA: availability of the Form 1572


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The Investigator and/or Pharmacist and/or 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 (see Section 4.1.8.1 below), 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 products 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 products received from the Sponsor.  At the time of return to the 
Sponsor and/or appointed CRO (Contract Research Organisation), 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.
Patient treatment compliance
4.1.8.1
Patients will be asked to bring all trial medication kits (with or without any remaining tablets) 
with them to each trial visit.  The tablets will be counted by the Investigator or a qualified 
designee and compliance will be calculated according to the following formula unless there
are reasons to use a different calculation (e.g. to account for periods during which a patient 
was genuinely unable to take any trial medication):
%
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 open-label placebo run-in period must be between 80% and 120%.  If 
compliance is outside this range, the patient should not be randomised.
Compliance during the randomised period should also be between 80% and 120%.  Patients 
who are non-compliant according to this definition will be treated as protocol violators.  The 
significance of protocol violations will be determined individually for the purposes of the 
per-protocol analysis.
Patients who are not compliant with their medication should again be carefully interviewed 
and again informed about the purpose and the conduct of the trial.  This discussion should be 
documented.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
Details of all concomitant therapy used during the trial will be recorded on the appropriate 
pages of the eCRF.  Where appropriate, dedicated eCRF pages may also be developed to 
record information and any changes relating to certain classes of concomitant therapy (e.g. 
anti-hypertensive concomitant therapy).


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4.2.1
Rescue medication, emergency procedures, and additional treatments
There are no rescue medications in this trial.
All patients will be required to keep their existing insulin therapy as stable as possible from 
screening at Visit 1 until the beginning of the T1DM therapy optimisation period at Visit 2.  
From Visit 2, therapy for T1DM should be optimised (e.g. review of blood glucose values 
and insulin dose and its adjustment for meals, improve the patients’ ability to carbohydrate 
count etc.) over a 6 week period to ensure that, in the Investigator’s opinion, a patient is 
achieving the best standard of care in accordance with local guidelines.  In CSII patients, and 
where considered appropriate, adjustments in T1DM therapy might be supported by basal 
rate testing.
Optimisation of the T1DM therapy should be complete by the end of the 6 week T1DM 
therapy optimisation period (i.e. by Visit 5), so that a patient’s insulin regimen is as stable as 
possible as they enter the placebo run-in period and for 2 weeks prior to randomisation at 
Visit 6.
During periods of stability, in case of hypoglycaemia (e.g. with measured glucose 
concentration ≤70 mg/dL [≤3.9 mmol/L]), patients should preferably ingest additional 
carbohydrates according to standard practice in the management of T1DM.  However, a 
patient’s existing insulin regimen should be adjusted any time for safety reasons if deemed 
necessary by the Investigator, e.g. in case of persisting hyperglycaemia or hypoglycaemia 
despite adequate carbohydrate intake.
Based on the mode of action of empagliflozin and the results of previous trials in T1DM (for 
further details see Section 1), at randomisation on Day 1 (Visit 6) and the initiation of 
randomised study medication, for patients with an HbA1c of 7.5 to < 8% at Visit 5,
Investigators are advised to reduce the patient’s total insulin dose by 10% to avoid 
hypoglycaemia.  For patients with an HbA1c of ≥8% at Visit 5, Investigators are advised to 
adjust the patient’s total insulin dose based on need as assessed by frequent SBGM and close 
patient follow-up upon initiation of randomised study medication.  In all cases, the actual 
reduction will be dependent upon individual glucose values.  Thereafter and until the end of 
the trial (Visit 12), further adjustments to insulin therapy (both basal and bolus insulin) may 
be implemented as necessary to avoid hypoglycaemia and also hyperglycaemia to keep 
ensuring that, in the Investigator’s opinion, the patient is achieving the best standard of care 
in accordance with local guidelines.
Apart from the recommendation for an initial insulin reduction as mentioned above at the 
start of randomised treatment, there will be no protocol-defined algorithm towards insulin 
adjustment in this trial. However, the Sponsor will provide additional support to the 
Investigator with respect to insulin adjustment via training documentation that will be 
presented at Investigator Meetings and made available in the ISF.  Throughout the trial, 
adjustment needs to balance a patient’s individual risk for hypoglycaemia on the one hand 
and the risk for hyperglycaemia and DKA on the other hand with special caution at the 
beginning of the treatment period, and in the Follow-up period, when empagliflozin treatment 


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is started and stopped respectively.  Any insulin dose change or adjustment must be based on 
laboratory tests or SBGM.  However, there are no blood glucose targets defined throughout 
this trial to allow Investigators to follow their local standard of care guidelines for the 
management of blood glucose.  Whenever possible, patients should keep to the same 
trademark and application device for their existing insulin with no intention to change this 
during the trial; for medical/safety reasons however (e.g. malfunction of a pump in a CSII 
patient), switches in mode of insulin delivery are permitted.  There should also be no planned 
major changes of the injection sites/areas.
In accordance with Section 3.3.2, Investigator’s must ensure that patients selected for the trial 
are capable of leading the management and adjustment of their insulin therapy when at home, 
including a “sick day” management plan, and at the same time, can be relied upon to contact 
the Investigator for advice at the appropriate point in time, as this is an outpatient trial.  
Investigator oversight will also be an important element of the insulin adjustment process.
Special attention must be paid to the prevention of DKA.  Due to the mechanism of action, 
patients receiving empagliflozin are at risk to underestimate their need for insulin in case of 
blood sugar levels within their individual target range.  Insulin deficiency might lead to 
ketoacidosis which could be life-threatening if not recognised and appropriately treated.  All 
patients must be made aware of this risk and be instructed not to reduce their insulin intake 
below Investigator recommendations.  For further details see Section 2.3.
In addition to performing glucose monitoring, the frequency of which will be increased after 
starting the study medication (for further details see Section 5.3.2.1), in the same way as 
during routine clinical care, patients will be reminded to determine ketones in case of any 
symptoms of DKA, e.g. nausea, vomiting, abdominal pain etc (see Section 5.3.2.2).  They 
will be instructed to do this irrespective of the glucose value in the event of DKA symptoms 
occurring.  A meter will be provided to the patient for this purpose.  Patients will also be 
reminded about the interpretation of ketone values measured via the meter, and on 
appropriate action to take in the event of increased ketone levels (see Section 5.3.2.2).  
Ketones should also be determined in case of repeatedly elevated blood glucose levels (e.g. 
> 200 - 240 mg/dL [> 11.1 - 13.3 mmol/L]) which cannot be explained.  Regular (e.g. 2-3 
times a week) measurements before breakfast are recommended throughout the trial as from 
Visit 2. More frequent (e.g. once daily) measurements before breakfast are recommended 
during the run-in period and during the first 4 weeks of the treatment period and might also 
be agreed upon with the patient afterwards if deemed necessary by the Investigator.  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.
Other concomitant therapies should be kept as stable as possible over the course of the trial 
but might be changed in case of medical need.  New anti-diabetic therapy should not be 
initiated during the randomised treatment period and the Follow-up period.


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Insulin will not be provided as part of the clinical trial supplies.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Treatment with anti-obesity drugs or systemic corticosteroids will be prohibited due to their 
influence on glucose metabolism.  There are no restrictions on treatment with non-systemic 
corticosteroids such as inhaled or local corticosteroids.
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.
Patients participating in the CGM substudy must not take any paracetamol (acetaminophen) 
containing drugs – provided there is no medical necessity – throughout the CGM monitoring 
periods, since this may falsely raise CGM glucose readings.
Restrictions on diet and life style
4.2.2.2
Throughout the trial, patients must follow a reliable approach to insulin dose adjustment for 
meals, such as carbohydrate counting, and based on Investigator recommendations.  This 
method will be discussed with the patient at Visit 1 as part of the eligibility checks.
Patients who participate in the CGM substudy and who already use real-time CGM as part of 
their therapy for T1DM may continue their own CGM but would also need to wear the 
(blinded) trial CGM in addition during the trial CGM periods.
At the beginning of the T1DM therapy optimisation period (Visit 2), patients will be 
reminded about the appropriate management of their diet and physical activity by the 
Investigator or qualified site personnel.  This must include a reminder to maintain adequate 
daily fluid intake to avoid dehydration.  They will also be reminded about the importance of 
following a “sick day” management plan and corresponding insulin adjustments, should they 
become unwell during the trial.  This discussion will be based on local recommendations for 
individuals with T1DM and should be evident from source documents (see Section 8.3.1).  
Site-specific tools may be used where necessary.  Patients will be reminded to follow the 
recommended dietary and physical activity plan during the study. Extreme diets (e.g. 
ketogenic diets such as the Atkins diet) should be avoided.
Patients must not take any other investigational drug within 30 days before Visit 1 until the 
last visit (Visit 12) of this trial.


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Restrictions regarding women of childbearing potential
4.2.2.3
Women of child-bearing potential must continue to practice a highly effective method of 
birth control (in accordance with the trial inclusion criteria Section 3.3.2) throughout the 
duration of the study including the Follow-up period.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary endpoint
In this trial, the primary endpoint to assess efficacy is the change from baseline in HbA1c (%) 
after 26 weeks.  Throughout this CTP, the term “baseline” for HbA1c refers to the last 
observation prior to the first intake of randomised trial medication.
5.1.2
Secondary endpoints
The key secondary endpoints to assess efficacy are as shown below.  Throughout this CTP, 
the term “baseline” refers to the 4 week period prior to randomisation for the rate of 
symptomatic hypoglycaemic AEs with confirmed plasma glucose < 54 mg/dL (< 3.0 
mmol/L) and/or severe hypoglycaemic AEs and the 2 week placebo run-in period for the 
mean daily insulin requirement.

Incidence rate of symptomatic hypoglycaemic AEs with confirmed plasma glucose 
< 54 mg/dL (< 3.0 mmol/L) and/or severe hypoglycaemic AEs per patient-year from 
Week 5 to Week 26
o
severe hypoglycaemia is defined as an event requiring the assistance of another 
person to actively administer carbohydrate, glucagon or other corrective actions.  
Plasma glucose concentrations may not be available during an event, but 
neurological recovery following the return of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma glucose 
concentration (see Section 5.3.5.2)
o
The rate will be calculated from Day 29 (start of Week 5) up to Day 183 (end of 
Week 26 + 1 day) or date of last study medication intake + 1 day inclusive, 
whichever occurs first

Incidence rate of symptomatic hypoglycaemic AEs with confirmed plasma glucose 
< 54 mg/dL (< 3.0 mmol/L) and/or severe hypoglycaemic AEs (see Section 5.3.5.2) per 
patient-year from Week 1 to Week 26
o
the rate will be calculated from the date of first study medication  intake up to Day 
183 (end of Week 26 + 1 day) or date of last study medication intake + 1 day 
inclusive, whichever occurs first

Change from baseline in body weight (kg) after 26 weeks

Change from baseline in total daily insulin dose (TDID), U/kg, after 26 weeks

Change from baseline in systolic blood pressure (SBP) after 26 weeks

Change from baseline in diastolic blood pressure (DBP) after 26 weeks


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ASSESSMENT OF EFFICACY
5.2
5.2.1
HbA1c and fasting plasma glucose
FPG and HbA1c will be analysed by the central laboratory at the timepoints indicated in the 
Flow Chart.
The samples will be analysed at a central laboratory or its affiliates having a National 
Glycohemoglobin Standardisation Program (NGSP) Level I certificate.  HbA1c results will be 
reported in both NGSP (%) and International Federation of Clinical Chemistry, IFCC 
(mmol/mol) units.  The relationship between HbA1c results from the NGSP network (% 
HbA1c) and the IFCC network (mmol/mol) has been evaluated and a master equation has 
been developed (NGSP = [0.09148*IFCC] + 2.152).  This relationship is continuously 
monitored and any changes are investigated.  The NGSP certification process and test results 
for NGSP-certified methods do not change as a result of the IFCC standardisation of HbA1c, 
and will continue to be directly traceable to the Diabetes Control and Complications Trial 
(DCCT) reference and now also the IFCC reference.
Further details about HbA1c sample handling, shipment, and assay procedures can be found in 
the laboratory manual in the ISF.
Blood samples for the determination of FPG at the central laboratory will be taken after an 
overnight fast (no food or drinks except for water for at least 10 hours).  The samples should 
be taken before trial medication administration.  The samples will be measured at a central 
laboratory using validated assays.  Further details about FPG sample handling and shipment 
can be found in the laboratory manual in the ISF.
5.2.2
Weight
Weight measurements should always be done on the same approved scales for an individual 
patient at the timepoints indicated in the Flow Chart.


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In order to get comparable body weight values, it should ideally be performed in the 
following way:

fasting (at visits to which a patient has to come fasted, see Flowchart)

after bladder voiding

shoes and coat/jackets should be taken off

pockets should be emptied of heavy objects (i.e. keys, coins etc.)
5.2.3
Electronic diary 
From the beginning of the T1DM therapy optimisation period (Visit 2) until the end of the 
Follow-up period (Visit 12), all patients will be provided with an electronic (e)-diary for daily 
use during these periods of the study.  Prior to its first use, instructions on the proper use of 
the e-diary will be provided by the site staff.  Refresher training should be provided at 
subsequent timepoints as deemed appropriate by the Investigator or designated site-
personnel.
Daily entries into the e-diary will include at least: 

glucose values from SBGM (see Section 5.3.2.1)

any hypoglycaemic events that have occurred
o
for criteria for hypoglycaemic events, see Section 5.3.5.2

insulin requirement
Any ketone measurements performed should also be entered into the e-diary if and when any 
data becomes available (see Section 5.3.2.2).
During the T1DM therapy optimisation period, and daily for 5 days following clinic Visit 6, 
data from the e-diary should be reviewed remotely by designated site personnel, paying 
particular attention to adjustments in the insulin regimen, glucose values, and if available, 
ketone measurements.  In addition, the patient should be contacted by telephone (e.g. weekly 
during the T1DM therapy optimisation period) if e-diary data, including glucose data, is not 
available and/or if the data suggest closer monitoring of the patient is required.  Additional 
clinic visits can also be arranged if necessary (for further details see Section 6.2.2); 
assessments at such visits would be defined according to Investigator judgement.
Throughout the trial, the Investigator and/or designated site personnel should review the 
patient’s glucose and e-diary results to determine if treatment adjustments need to be 
implemented.  As a minimum, this review must take place at the timepoints indicated in the 
Flow Chart.
The e-diary data will be transferred to a vendor server for data collection and transfer to the 
Sponsor.


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5.2.4
Systolic/diastolic blood pressure and pulse rate (vital signs)
SBP and DBP as well as pulse rate (electronically or by palpation, count for 1 minute) will be 
measured at the timepoints indicated in the Flow Chart with a calibrated electronic 
sphygmomanometer.  The BP measurement should be performed three times at each 
timepoint and the mean value of the measurements will be analysed.
Initially, BP should be taken 3 times in both arms.  The arm with the higher average pressure 
(systolic or – if equal – diastolic) should be used for subsequent measurements; if 
measurements for both arms are equal, the non-dominant arm should be chosen.
BP measurements should always be performed on the same arm and, if possible, by the same 
person and using the same device.  The same method must be used throughout the trial for a 
given patient i.e. if a patient receives the first BP measurement for example with an electronic 
device, the same method and device should be used throughout the study for this patient.
After patients have rested quietly, in the seated position for at least 5 minutes, 3 BP 
measurements will be taken approximately 2 minutes apart.  The seated pulse rate should be 
from the second BP reading.
BP measurements should be recorded to the nearest 1 mmHg.
BP should always be measured before any blood samples are taken.
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
Physical examinations will be performed by the Investigator or designated site-personnel at 
the timepoints indicated in the Flow Chart.  Documentation of, and findings from the physical 
examination, must be part of the source documents available at the site.
5.3.2
Home monitoring
Self-blood glucose monitoring
5.3.2.1
From the beginning of the T1DM therapy optimisation period (Visit 2) until the end of the 
Follow-up period (Visit 12), all patients will be provided with SBGM equipment (i.e. a 
glucose monitoring device/meter) and supplies for use at home during the study for self-
measurement of blood glucose.  Instructions on the proper use of the SBGM equipment will 
be provided by the site staff.  The patient will be asked to enter data from the glucose meter 
to the e-diary on a daily basis.
Routinely, SBGM testing should be performed 4 times a day as a minimum (e.g. at least 
before breakfast, lunch, dinner and at bedtime); furthermore, for 5 days from the day of 
randomisation (i.e. Days 1-5), SBGM testing frequency should be increased to 8-10 times a 


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day and include at least one overnight measurement (i.e. a measurement taken at night, 
between the patient going to bed and getting up).  On one of these 5 days, the daytime 
timepoints of the SBGM testing should mirror the timepoints for a 9-point plasma glucose 
profile (for further details see Section 5.2.5).  Additional tests should be done as 
recommended by the Investigator (e.g. up to 7 days post randomisation) or at any time the 
patient is symptomatic, i.e. experiences signs/symptoms of hyper- or hypoglycaemia.  In 
patients prone to nocturnal hypoglycaemic events, a bedtime snack consisting of long-acting 
carbohydrates should be considered.  Alternatively, minimum glucose levels of e.g.  > 110-
130 mg/dL (> 6.1-7.2 mmol/L) should be targeted at bedtime to avoid nocturnal 
hypoglycaemia.  The Sponsor will also provide guidance on this topic via documentation in 
the ISF.
If, after an overnight fast, an SBGM test result reveals blood glucose of > 200 – 240 mg/dL 
(> 11.1 – 13.3 mmol/L) or ≤70 mg/dL (≤3.9 mmol/L), the patient should be asked to contact 
the site for advice.  The Investigator should then instruct the patient on appropriate measures 
in order to adequately control their hyperglycaemia or hypoglycaemia.  All insulin treatment 
decisions should be based on blood glucose values measured using SBGM or based on 
laboratory values obtained through the central laboratory (or, if applicable, the local 
laboratory).
A comparable SBGM system will be supplied to all patients and must be used by them 
throughout the study.  In accordance with Section 3.3.2, Investigator’s should carefully select 
patients for the study in terms of their ability to comply with the SBGM requirements.  
Patients not adhering to the SBGM instructions given by the Investigator should be retrained 
at the earliest possible opportunity.
Ketone measurement
5.3.2.2
Patients will be equipped with an electronic device to determine their ketone concentration 
(i.e. a blood glucose monitoring device/meter that is also capable of measuring blood 
ketones).
Patients should be reminded to test their ketones in case of any symptoms of DKA, e.g. 
nausea, vomiting, abdominal pain, etc., irrespective of the glucose value.  Patients must be 
reminded about the signs and symptoms of DKA, on the interpretation of ketone values 
measured via the meter, and on appropriate action to take in the event of increased ketone 
levels (see below).  In the same way as during routine clinical care, patients should also be 
reminded to test for ketones in case of repeatedly elevated blood glucose levels (e.g. > 200 -
240 mg/dL [> 11.1 - 13.3 mmol/L]) which cannot be explained.  Regular (e.g. 2-3 times a 
week) measurements before breakfast are recommended throughout the trial as from Visit 2. 
More frequent (e.g. once daily) measurements before breakfast are recommended during the 
run-in period and during the first 4 weeks of the treatment period and might also be agreed 
upon with the patient afterwards if deemed necessary by the Investigator.
In the event of increased ketones, patients should either follow the rules given by their 
Investigator (e.g. increased fluid intake and/or insulin bolus; food intake and insulin bolus in 
case of near-normal blood glucose) or contact their trial site.  In case of deteriorating ketosis, 


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blood glucose and ketone levels should be checked every 1-2 hours until they are back in a 
range considered to be normal for the patient.  Patients should be instructed to immediately 
refer themselves to hospital and/or the Investigator, or to contact an emergency physician in 
case of a blood ketone concentration > 1.5 mmol/L (as indicated in the meter manual).  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 (pH, 
bicarbonate).  The results will be collected on the relevant page of the eCRF.
Investigators should also differentiate deteriorating ketosis/DKA from any mild to moderate 
increase of ketones which may be seen due to the mechanism of action of empagliflozin, 
especially in the fasted state (e.g. in the morning).  For further details, see also Sections 
1.2.3.2 and 2.3.
In accordance with Section 3.3.2, Investigator’s should carefully select patients for the study 
in terms of their ability to comply with ketone measurement requirements.  Patients not 
adhering to the instructions given by the Investigator should be retrained at the earliest 
possible opportunity.
5.3.3
Safety laboratory parameters
At the following visits, laboratory samples will be collected from the patient after a full 
overnight fast (i.e. nothing to eat or drink except water for at least 10 hours): Visits 2, 6, 9, 11
EOT, eEOT (if applicable), and 12.  At all other visits, the patient does not have to be in a 
fasted state when laboratory samples are taken.
When applicable, laboratory samples, as described in the Flow Chart, should be collected 
before trial medication is taken.
All parameters that will be determined during the trial conduct are listed in Table 5.3.3: 1 and 
Table 5.3.3: 2.  The analysis will be performed by a central laboratory.  The respective 
reference ranges and details about sample handling and shipment will be provided in the 
laboratory manual in the ISF.
UACR in spot urine will be calculated at the central laboratory.
The central laboratory will derive the eGFR from (and report it together with) serum 
creatinine values based on the CKD-EPI formula which is considered more accurate in the 
normal range than the Modification of Diet in Renal Disease (MDRD) formula.  The CKD-
EPI formula will be defined in central laboratory documentation due to regional/racial 
variations in the formula that is applied.
The eGFR (cystatin C, serum) will also be derived, at the visits where cystatin C levels are 
measured.


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Table 5.3.3: 1
Safety laboratory parameters – blood, serum or plasma
Haematology

Haematocrit

Haemoglobin
o
reticulocyte count (reflex test if 
haemoglobin is outside normal 
range)

Red blood cells (RBC)/erythrocytes

White blood cells (WBC)/leukocytes

Platelet count/thrombocytes

Differential automatic (relative and 
absolute count):
o
neutrophils, eosinophils, baso-
phils, monocytes, lymphocytes
Clinical chemistry

Albumin

Alkaline phosphatase1
o
gamma-glutamyl transferase (-
GT, reflex test triggered by 
elevated alkaline phosphatase on 
two sequential measures)

ALT (alanine aminotransferase, SGPT)1

AST (aspartate aminotransferase, SGOT)1

Beta-hydroxy-butyrate

Bicarbonate

Bilirubin total, fractionated if elevated

Creatine kinase (CK)
o
troponin I (reflex test if CK is 
elevated) 

Cystatin C3

Lactate dehydrogenase

Lipase

Magnesium 

Phosphate 

Potassium 

Protein total

iPTH (intact parathyroid hormone)4

Calcium

Chloride

C-peptide2

Creatinine1

Sodium

TSH1,5

Blood urea nitrogen (BUN)

Uric acid
Lipids6

Cholesterol (total)

HDL cholesterol 

LDL cholesterol (calculated)

Free fatty acids

Apo A-1

Apo B 

Triglycerides
o
direct measurement of LDL cho-
lesterol (reflex test if triglycerides 
are > 400 mg/dL or 4.52 mmol/L)
1
At the screening visit (Visit 1), only the following parameters are part of the profile: liver 
transaminases, alkaline phosphatase, creatinine, and TSH
2
C-peptide will only be assessed at Visit 2
3
Cystatin C will only be assessed at Visits 6, 11 EOT, eEOT (if applicable) and 12
4
iPTH will be only be assessed at Visits 6, 8, 11 EOT and eEOT (if applicable)
5
TSH will only be assessed at Visit 1
6
Lipids will only be assessed at Visits 6, 11 EOT, eEOT (if applicable), and 12


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Table 5.3.3: 2
Laboratory parameters – urine
Semi-quantitative (dipstick) urinalysis

Nitrite1

Protein

Ketones3

Urine pH

Leukocyte esterase (for WBC)1
Quantitative urinalysis

Albumin

Creatinine

Human chorionic gonadotrophin 
(hCG)2
Microscopic urinalysis
Microscopic analysis will be performed as a reflex test if any of the above semi-
quantitative (dipstick) tests except for ketones are abnormal:

Urine RBC/erythrocyte

Urine WBC/leukocytes1

Urine sediment microscopic examination
Urine culture
Urine culture will be triggered by positive leukocyte esterase (for WBC) and/or nitrite in 
the semi-quantitative test/dipstick.  The culture will include an antibiogram
1
Nitrite and leukocyte esterase (for WBC) will be determined both locally on site (not 
recorded in eCRF) and via the central laboratory.  A positive result at site triggers the 
sampling of mid-stream urine for urine culture
2
Urine pregnancy testing will be performed locally in female patients of child-bearing 
potential only according to the timepoints indicated in the Flow Chart
3
At clinic visits where centralized safety laboratory tests are not planned, urine ketones 
will be determined only locally at the site.
Follow-up on suspicion for urinary tract infections 
5.3.3.1
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 must be documented 
as medical history or as a baseline condition in the eCRF, respectively.
Throughout the trial, patients should be closely observed for symptoms of UTI or genital 
infection.  In case these symptoms occur, symptomatic relief and anti-infectives should be 
provided as appropriate [c01678844].
For documentation of acute UTI during trial conduct, the following measures have to be 
taken:


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
In any case of suspected UTI (symptomatic or asymptomatic) a urine culture sample has 
to be taken and sent to the central laboratory for confirmation of the diagnosis and to 
obtain an antibiogram 

To be able to identify asymptomatic UTIs immediately, a dipstick test (leukocyte esterase 
[for WBC] and nitrite) will be performed at the site at the timepoints indicated in the 
Flow Chart.  In case of a positive result at site, a urine culture sample must be obtained 
and sent to the central laboratory for confirmation of the diagnosis and to obtain an 
antibiogram
5.3.4
Electrocardiogram
Printed paper traces from 12-lead ECGs (I, II, III, aVR, aVL, aVF, V1-V6) will be collected 
at the timepoints indicated in the Flow Chart.  In the event of any cardiac symptoms (i.e. 
suspicion of heart rhythm disorders or cardiac ischaemia), 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.
5.3.5
Other safety parameters
Assessment of hypoglycaemia rate
5.3.5.1
Hypoglycaemia rates will be assessed based on AE data, which in turn rely on the criteria for 
hypoglycaemic events (see Section 5.3.5.2 below).  Glucose values used within the criteria 
for hypoglycaemic events will originate in the SBGM device and from central laboratory 
measurements.  All glucose values originating in the SGBM device will subsequently be 
entered into the e-diary (for further details please see Sections 5.2.3 and 5.3.2.1).
Criteria for hypoglycaemic events
5.3.5.2
Every episode of blood/plasma glucose ≤70 mg/dL (≤3.9 mmol/L) should be documented 
with the respective time and date of occurrence.  This includes hypoglycaemia with glucose 
values < 54 mg/dL (< 3.0 mmol/L) and all symptomatic and all severe hypoglycaemic events.
For the analysis, all hypoglycaemias will be classified according to the following criteria:

Asymptomatic hypoglycaemia: event not accompanied by typical symptoms of 
hypoglycaemia but with a measured glucose concentration ≤70 mg/dL (≤3.9 mmol/L)

Documented symptomatic hypoglycaemia with glucose concentration ≥54 mg/dL and 
≤70 mg/dL (≥3.0 mmol/L and ≤3.9 mmol/L): event accompanied by typical symptoms 
of hypoglycaemia

Documented symptomatic hypoglycaemia with glucose concentration < 54 mg/dL 
(< 3.0 mmol/L): event accompanied by typical symptoms of hypoglycaemia but no need 
for external assistance

Severe hypoglycaemia: event requiring the assistance of another person to actively 
administer carbohydrates, glucagon or take other corrective actions.  Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 


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the return of plasma glucose to normal is considered sufficient evidence that the event 
was induced by a low plasma glucose concentration [R14-0982]
If a patient is provided with an emergency glucagon injection device as part of their local, 
routine T1DM care, it is advisable for the patient to carry this throughout the trial.
Assessment of cardiovascular events (CEC adjudication)
5.3.5.3
Please refer to Section 3.1.1.2.
Assessment of severe hypoglycaemia and DKA (CEC adjudication)
5.3.5.4
Please refer to Sections 3.1.1.3 and 5.3.5.2.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a 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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death

is life-threatening

requires inpatient hospitalisation or prolongation of existing hospitalisation

results in persistent or significant disability or incapacity

is a congenital anomaly/birth defect
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgement which may 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.


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AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of AEs, which by their nature, can always be considered to be “serious” 
even though they may not have met the criteria of an SAE as given above.
The latest list of “Always Serious AEs” can be found in the Remote Data Capture (RDC)
system.  These events should always be reported as SAEs as described in Section 5.3.6.1
Adverse events of Special Interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class.  
AESIs need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
Patients with AESIs need to be followed up appropriately, regardless of the origin of the 
laboratory data (e.g. central, local etc.). The Investigator should consider which, if any, 
concomitant therapies should not be taken during evaluation.  Discontinued treatments can be 
reintroduced per Investigator discretion.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters after 
randomisation (Visit 6): 

an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN measured in the same blood sample

an isolated elevation of ALT and/or AST ≥5 fold ULN
These laboratory findings constitute a hepatic injury alert and the patients showing these 
abnormalities need to be followed up according to the “DILI checklist” provided via the 
RDC-system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, unex-
plained coagulopathy, right upper quadrant abdominal pain, etc.) without laboratory 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.


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Decreased renal function
Decreased renal function is defined by a creatinine value showing a ≥2 fold increase from 
baseline and is above the ULN.
For the AESI “decreased renal function” the Investigator shall collect an unscheduled 
laboratory sample for creatinine as soon as possible and initiate follow-up laboratory tests of 
creatinine according to medical judgement.
Diabetic ketoacidosis (DKA)
DKA is defined by the diagnostic criteria in Table 5.3.6.1: 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 judgement should also be taken into consideration. Due to its 
mechanism of action, empagliflozin may potentially modify the clinical presentation of DKA 
which may occur at lower plasma glucose levels than stated in Table 5.3.6.1: 1 below (see 
Sections 1.2.3.2 and 2.3 for further details).
Table 5.3.6.1: 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 (mEq/L)
15-18
10 to <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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Severe hypoglycaemic episodes 
Severe hypoglycaemic episodes are events requiring the assistance of another person to 
actively administer carbohydrate, glucagon or other corrective actions.  Plasma glucose 
concentrations may not be available during an event, but neurological recovery following the 
return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.
This includes fatal hypoglycaemic events.
Events involving lower limb amputation
This definition includes amputation (i.e. resection of a limb through a bone), disarticulation 
(i.e. resection of a limb through a joint) and auto-amputations (i.e. spontaneous separation of 
non-viable portion of the lower limb).
Not included in this definition are debridement (removal of callus or dead tissue), procedures 
on a stump (like stump revision, drainage of an abscess, wound revision etc.) and other 
procedures (e.g., nail resection or removal) without a concomitant resection of a limb 
(amputation or disarticulation).
Each lower limb amputation, disarticulation, or auto-amputation should be reported 
separately. The SAE report should include the date of the procedure, the level of amputation 
or disarticulation, the medical condition(s) leading to the procedure and if the patient had 
some of the known risk factor(s) for lower limb amputation.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
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.


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The 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 (such as any active comparator or placebo and for 
trial procedure).
5.3.7
Adverse event collection and reporting
AE collection
The following must be collected and documented on the appropriate eCRF and/or other 
designated data collection repository by the Investigator (see also Figure 5.3.7: 1 below):

From signing the informed consent onwards through the Residual Effect period (REP), 
until trial completion, all AEs (serious and non-serious), and AESIs

If in an individual patient only vital status information is collected from a certain time 
point on, no further AEs or AESIs will be reported for this patient
Figure 5.3.7: 1
Trial periods for collection of AEs
The REP is defined as 7 days after the last trial medication application, except for 
hypoglycaemia, where the REP is 1 day.  All AEs which occurred through the treatment 
period and throughout the REP will be considered as on treatment (please see Section 7.3.4). 
Events which occurred after the REP will be considered as post-treatment events.
After the last per protocol contact the Investigator does not need to actively monitor patients 
for AEs.  However, if the Investigator becomes aware of SAEs or AESIs that occurred after 
the last per protocol contact, the SAEs and AESIs should be reported by the Investigator to 
the Sponsor if considered relevant by the Investigator.
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).  


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The same timeline applies if follow-up information becomes available.  On 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 
eCRF pages and/or other designated data collection repository 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 the trial procedures outlined under Section 6.2.
The following should also be recorded as an (S)AE in the eCRF and/or other designated data 
collection repository and SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after trial completion must be followed up until they 
have resolved, have been sufficiently characterised, or no further information can be obtained.
Screening failures
SAEs occurring in patients after having discontinued in the trial due to screening failures, i.e. 
after the screening period and who did not receive any trial medication, are to be reported if 
the Investigator considered the SAE related to the screening procedure.  SAEs which 
occurred during the screening period are to be reported according to standard procedures.
Pregnancy
In the rare case that a female patient participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (country-
specific contact details will be provided in the ISF).  The Pregnancy Monitoring Form for 
Clinical Trials (Part A) should be used.


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The outcome of the pregnancy associated with the DEDP must be followed up and reported 
to the Sponsor’s unique entry point on the Pregnancy Monitoring Form for Clinical Trials 
(Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed.  If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition.
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).


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APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements performed during this trial are considered standard measurements in the 
clinical development of a non-insulin product such as empagliflozin, and/or standard as part 
of routine care for T1DM [R08-2669, R14-0344].  All defined measurements will be 
performed in order to monitor safety and tolerability aspects and to determine efficacy and 
PK in an appropriate way.
A surrogate endpoint (i.e. the laboratory parameter HbA1c) is used as the primary efficacy 
endpoint, since for the purposes of drug approval and labeling, which will support an 
indication of glycaemic control, regulatory authorities state that this endpoint, albeit 
surrogate, is the primary endpoint of choice [R08-2669].
 
 
 
 
 
 


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
All trial visits should take place in the morning (e.g. between 7am and 11am).  All patients 
must adhere to the visit schedule as specified in the Flow Chart.
 
 
If any visit has to be re-scheduled, subsequent visits should follow the original visit schedule.  
The trial medication kits will contain sufficient medication to allow for the protocol-
permitted visit windows.
If a patient mistakenly takes trial medication on the morning of a visit before attending the 
clinic (excluding visits prior to randomisation) or comes in non-fasted where a fasting 
condition is required, the visit should be re-scheduled to the next day reminding the patient 
about the expected conditions.
 
 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
At each visit, assessments should be performed as indicated in the Flow Chart and as detailed 
in the respective protocol sections.
6.2.1
Screening, T1DM therapy optimisation and placebo run-in periods
Screening visit (Visit 1)
6.2.1.1

The screening visit does not need to be done with the patient in a fasted state (see Section
5.3.3)

No trial procedures should be done unless the patient has consented to taking part in the 
trial.  Once they have consented, the patient is considered to be enrolled in the trial and to 
have started screening.  The patient should be recorded on the enrolment log and be 
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, see Section 5.2.4

Patients who are not eligible to proceed to Visit 2 should be registered as a screen failure 
in the IRT system and the eCRF and no further follow-up is required
T1DM therapy optimisation period (Visits 2, 3 and 4T)
6.2.1.2

Visit 2 should be done with the patient in a fasted state (i.e. no food or drink except water 
for 10 hours) (see Section 5.3.3)


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
 

Visit 3T, if performed as a telephone visit, does not require attendance at the clinic.  If 
performed as a clinic visit, Visit 3 does not need to be done with the patient in a fasted 
state (see Section 5.3.3)

Visit 4T is a telephone visit and does not require attendance at the clinic

Each visit should only be performed once it has been confirmed that the patient is eligible 
to progress to the next visit; ineligible patients should be registered in the IRT system and 
the eCRF as a screen failure and no further follow-up is required

BP should always be measured before any blood samples are taken (relevant for Visit 2 
only).  For details regarding the correct method for measuring BP, see Section 5.2.4

At the end of each visit, patients should be reminded about the importance of entering 
data into their e-diary on a daily basis, including data from the glucose/ketone meter, so 
that optimisation of the T1DM therapy can be monitored remotely by designated site-
personnel, and an assessment made of the need for weekly telephone discussions and/or 
additional visits  
Placebo run-in period (Visit 5)
6.2.1.3

Visit 5 does not need to be done with the patient in a fasted state (see Section 5.3.3)

Visit 5 should only be performed once it has been confirmed that the patient is eligible to 
progress to this visit, based on an assessment of results from Visits 2 to 4T

As for Visit 1, BP should always be measured before any blood samples are taken.  For 
details regarding the correct method for measuring BP, see Section 5.2.4

Following completion of the Visit 5 procedures, eligible patients will be dispensed a 
placebo run-in kit for the 2 week run-in period which will be assigned via the IRT system.  
Ineligible patients should be registered in the IRT system and the eCRF as a screen failure 
and no further follow-up is required

 
 
 
 
 
 
 
 
 
6.2.2
Randomised treatment period
The randomised treatment period is from Visit 6 to Visit 11 EOT.


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Throughout the treatment period, BP should always be measured before any blood samples 
are taken.  For details regarding the correct method for measuring BP, see Section 5.2.4.
Laboratory samples should also be taken prior to the intake of trial medication at clinic visits 
throughout the treatment period.
All patients, including those who discontinue treatment early, must be followed up until the 
end of the study.  Patients must continue to be followed up according to the visit schedule 
(unless they withdraw consent for further follow-up) in order to collect data at the end of the 
planned observation period.  For further details see Section 6.2.3.
Randomisation visit (Visit 6)
6.2.2.1

Visit 6 should be done with the patient in a fasted state (i.e. no food or drink except water 
for 10 hours), and only once it has been confirmed that the patient is eligible to progress 
to randomisation.  This includes a check of the data from the patient e-diary, and 
 

Eligible patients will be randomised on Day 1 by using the IRT system; all visit 
assessments should have been completed prior to this, and before the first intake of study 
medication

At Visit 6 (Day 1) the patient should also be reminded to contact the site without delay if 
he/she has any questions or concerns with respect to insulin adjustments.  The patient 
should also be reminded to increase the frequency of SBGM testing for 5 days from the 
day of randomisation (i.e. on Days 1-5), 
 
 
  
Where considered necessary, the patient should be called daily for 5 days following 
Day 1 to discuss further adjustment of their insulin therapy; additional clinic visits should 
be scheduled if closer monitoring of the patient is warranted
Interim visits (Visits 7-10)
6.2.2.2

Visit 9 should be done with the patient in a fasted state (i.e. no food or drink except water 
for 10 hours); Visits 7, 8 and 10 do not require fasting

 

Prior to each clinic visit, patients should be reminded to attend without having taken their 
trial medication in the morning, and to bring all used/unused medication with them to the 
visit 

 
using their SBGM device, 
starting directly before a dose of study medication is administered, and to continue this 
until directly before administering study medication on the following day

 


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6.2.3
End of treatment and follow-up period
End of treatment – completers (Visit 11 EOT)
6.2.3.1
Patients who successfully complete the 26 week treatment period should have the 
assessments for Visit 11 EOT performed, as indicated in the Flow Chart.  Patients who 
complete the full 26 week treatment period should be registered as completed in the IRT 
system.

Visit 11 EOT should be done with the patient in a fasted state (i.e. no food or drink except 
water for 10 hours), and patients should be reminded to attend without having taken their 
trial medication in the morning as they will take the last dose at the site, and to bring all 
used/unused medication with them to the visit.  The patient should be reminded not to 
start any new anti-diabetic therapy until after Visit 12

 

Patients should be reminded to continue with e-diary entries, checks of glucose and 
ketones using the glucose and ketone monitoring device for another 3 weeks until Visit 12
End of treatment - early discontinuations (eEOT) and withdrawals
6.2.3.2
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.
Patients who discontinue study medication early should have the assessments for eEOT 
(Early Discontinuations Only) performed, as indicated in the Flow Chart.  For such patients, 
the eEOT Visit should be done as soon as possible after the decision to discontinue has been 
made.  If the eEOT Visit occurs within the time window of a scheduled visit and the patient 
continues to be followed up, the eEOT Visit will replace that scheduled visit.  For example:

if a patient discontinues study medication 16 weeks after randomisation (i.e. between 
Visits 9 and 10), the eEOT Visit could be scheduled one week later, and it would occur 
within the time window of the next scheduled visit (i.e. Visit 10 at Week 18 +/-7 days).  
When returning to the visit schedule, after completing the 3 week Follow-up Visit (see 
Section 6.2.3.3 below), the patient would return for Visit 11 EOT at Week 26
If a patient intends to immediately discontinue (withdraw) from the study, an eEOT Visit 
should be performed as soon as possible after the decision to withdraw has been made.


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Patients who discontinue treatment prematurely (prior to 26 weeks) but continue to be 
followed up should be registered as “withdrawn from treatment” in the IRT system, whereas 
patients who withdraw from the trial should be registered as “withdrawn from study”.

eEOT should be done with the patient in a fasted state (i.e. no food or drink except water 
for 10 hours), and patients should be reminded to bring all used/unused medication with 
them to the visit.  The patient should be reminded not to start any new anti-diabetic 
therapy until after Visit 12

 

Patients should be reminded to continue with e-diary entries, checks of glucose and 
ketones using the glucose and ketone monitoring device for the remainder of the 
observation period
Follow-up visit (Visit 12) - completers
6.2.3.3
Patients who successfully complete the 26 week treatment period should have the 
assessments for Visit 12 performed, as indicated in the Flow Chart. For these patients: 

Visit 12 should be done with the patient in a fasted state (i.e. no food or drink except 
water for 10 hours) 

The patient e-diary will be checked after which it should be removed from the patient, 
together with all other study-related devices and equipment, once Visit 12 is complete
Follow-up visit (Visit 12) – early discontinuations (eEOT) and withdrawals
6.2.3.4
For patients who discontinue treatment prematurely prior to completion of 26 weeks the 
following should be performed whenever possible once an eEOT Visit has been completed 
(see Section 6.2.3.2):

3 weeks after the date of the eEOT Visit, patients should complete Visit 12.  Visit 12
should be done with the patient in a fasted state (i.e. no food or drink except water for 10 
hours), and all assessments indicated in the Flow Chart for Visit 12 should be performed 

Thereafter, patients should be followed up according to the visit schedule (e.g. a patient 
who discontinued study medication a week after Visit 8 (Week 4) – i.e. at Week 5 -
would next be followed up for Visit 9 (Week 12) after having completed an eEOT visit as 
soon as possible after Week 5, and a Visit 12 at Week 8.

The Investigator may negotiate a revised visit schedule should the patient be unwilling or 
unable to adhere to the regular schedule according to the Flow Chart.  These follow-up 
visits may occur by telephone or in the clinic but Visit 11 EOT (Week 26) must be 
performed as a clinic visit in order to complete all scheduled assessments

When being followed up according to the visit schedule, only assessments relating to the 
primary and secondary endpoints and general safety have to be completed (i.e. weight, 
vital signs, physical examination, ECG, safety laboratory, pregnancy test, HbA1c, e-diary 
completion, 
 and the 


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collection of AEs and changes in concomitant therapy).  All other assessments 
 
are optional

Visit 11 EOT at 26 weeks will be the last visit for these patients, since Visit 12 will 
already have been completed 3 weeks after the eEOT Visit as explained above.  At Visit 
11 EOT therefore, the patient e-diary will be checked after which it should be removed 
from the patient, together with all other study-related devices and equipment, once the 
visit is completed
For patients who discontinue treatment prematurely and do not wish to follow the visit 
schedule, at least a contact should be planned, at the timepoint of the primary endpoint at 26
weeks to collect data about the vital status as a minimum.
If study treatment is stopped prior to completion of 26 weeks and the patient intends to 
immediately discontinue (withdraw) from the study, an eEOT Visit should be performed as 
soon as possible after the decision to withdraw has been made.  The patient should return for 
a Visit 12 (3 weeks after the eEOT).  At this visit all assessments should be performed 
according to the Flow Chart.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a randomised, double blind, multi-centre, placebo-controlled, parallel group, 26 week 
study to assess the efficacy, safety, tolerability, and PK of once daily oral doses of 
empagliflozin 2.5 mg, 10 mg and 25 mg compared to placebo in patients with T1DM as 
adjunctive to insulin therapy.
The superiority of the 3 doses of empagliflozin will be tested against placebo. A Bonferroni 
adjustment will first correct for the parallel testing of the 2 higher doses (empagliflozin 25 
mg and 10 mg) in order to maintain a type I error rate of 0.05.  Each of these 2 doses will 
therefore be tested at the level of α=0.025 (two-sided).
Following the efficacy analysis (on-treatment data only) of the primary endpoint, change 
from baseline in HbA1c after 26 weeks, for the 2 higher doses, an effectiveness analysis (on-
and off-treatment data) will be performed in a hierarchical manner.  If the null hypothesis is 
rejected for both the efficacy and effectiveness analysis the error rate will be unequally split 
and transferred between the testing of the lowest dose empagliflozin 2.5 mg (with an 
allocated alpha weight of 1/5) and the testing of key secondary endpoints (with an allocated 
alpha weight of 4/5) in a gatekeeping strategy.  If the null-hypothesis of “equal HbA1c change 
after 26 weeks between placebo and empagliflozin 2.5 mg” can be rejected using on-
treatment data only, alpha of this test will be equally split and added to the alpha level for the 
test of the key secondary endpoints of the two higher doses.
Superiority of empagliflozin 10 mg versus placebo in key secondary endpoints will be 
sequentially tested with an unequal alpha split.  The same approach will be followed to test 
superiority of empagliflozin 25 mg versus placebo on these endpoints.
See Section 7.2 for further details on the endpoint testing strategy.
With regard to efficacy and safety endpoints, the term “baseline” refers to the last observed 
measurement prior to administration of any randomised study medication, the 4 week period
prior to randomisation for the rate of hypoglycaemia and the run-in period from Visit 5 to 
Visit 6 for the mean daily insulin requirement.
Patients who prematurely discontinue trial medication will continue to attend all visits and be 
followed up until the end of the trial when possible.
The randomisation will be stratified by the Visit 5 eGFR value (< 60 mL/min/1.73 m2 versus 
≥60 mL/min/1.73 m2), the Visit 5 HbA1c value (< 8.5% versus ≥8.5%), by the patients’ pre-
existing insulin therapy (MDI versus CSII), and by the patient’s participation in the CGM 
substudy (CGM participation versus non-CGM participation).  If necessary, and depending 
upon global distribution, entry of patients into a particular HbA1c stratum may be capped.


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NULL AND ALTERNATIVE HYPOTHESES
7.2
The following testing procedure will be used to evaluate the superiority for the primary
endpoint for empagliflozin 25 and 10 mg doses against placebo at the level of α=0.025.  The 
overall probability of type I error is therefore maintained at α=0.05 (two-sided).
The superiority of treatment with empagliflozin to placebo will be tested for HbA1c change 
from baseline at Week 26, via the pairwise comparison of the two higher empagliflozin doses
against placebo, at α=0.025 level.  Both doses will be tested in parallel on the Full Analysis 
Set (FAS) for the efficacy analysis and on the modified Intention-to-Treat (mITT) set for the 
effectiveness analysis; see Section 7.3 for the analysis set definitions.  Both analyses will test 
the same null hypothesis:
H0,0,1: Mean change from baseline in HbA1c (%) after 26 weeks in the empagliflozin 10 mg 
group = Mean change from baseline in HbA1c (%) after 26 weeks in the placebo group
H0,0,2: Mean change from baseline in HbA1c (%) after 26 weeks in the empagliflozin 25 mg 
group = Mean change from baseline in HbA1c (%) after 26 weeks in the placebo group
Following testing of the null hypotheses H0,0,1 and H0,0,2 for both efficacy and effectiveness 
for HbA1c, within each dose group (empagliflozin 10 and 25 mg) the remaining alpha will be 
unequally split for testing the superiority of empagliflozin 2.5 mg to placebo on the primary 
endpoint and for testing the superiority of the key secondary endpoints for the higher doses as 
detailed below.

One-fifth of the remaining alpha will be used for testing the superiority of 
empagliflozin 2.5 mg to placebo on the primary endpoint.  The test will be done two-
sided.  The null hypothesis is as follows: 
H0,0,3: Mean change from baseline in HbA1c (%) after 26 weeks in the empagliflozin 2.5 mg 
group= Mean change from baseline in HbA1c (%) after 26 weeks in the placebo group
Depending on the success of the testing of H0,0,1 and H0,0,2, H0,0,3 will be tested at the following 
alpha level α0,3:

If either H0,0,1 or H0,0,2 is rejected at 0.025 level, then 
o α0,3 = 1/5×0.025=0.005.

If H0,0,1 and H0,0,2 are both rejected at 0.025 level, then
o α0,3 = 1/5×0.025+ 1/5×0.025= 0.01.

Four-fifth of the remaining alpha will be transferred for testing the superiority of the 
key secondary endpoints for empagliflozin 10 and 25 mg.  Additionally, if H0,0,3 is 
rejected,  the alpha α0,3 of the testing of H0,0,3 will be equally split and added to the 
alpha level for testing the superiority of the key secondary endpoints.  For further 
details, see Step 2 in Table 7.2: 1.  The null hypotheses for the key secondary 
endpoints are as follows:


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H0,1,1: Mean change from baseline in body weight (kg) after 26 weeks in the empagliflozin 
10 mg group = Mean change from baseline in body weight (kg) after 26 weeks in the placebo 
group
H0,2,1: Mean change from baseline in TDID (U/kg) after 26 weeks in the empagliflozin 10 mg 
group = Mean change from baseline in TDID (U/kg) after 26 weeks in the placebo group
H0,3,1: Incidence rate of hypoglycaemia from Week 5 to Week 26 in the empagliflozin 10 mg 
group = Incidence rate of hypoglycaemia from Week 5 to Week 26 in the placebo group
H0,4,1: Incidence rate of hypoglycaemia from Week 1 to Week 26 in the empagliflozin 10 mg 
group = Incidence rate of hypoglycaemia from Week 1 to Week 26 in the placebo group
H0,5,1: Mean change from baseline in SBP after 26 weeks in the empagliflozin 10 mg group = 
Mean change from baseline in SBP after 26 weeks in the placebo group
H0,6,1: Mean change from baseline in DBP after 26 weeks in the empagliflozin 10 mg group = 
Mean change from baseline in DBP after 26 weeks in the placebo group
All tests will be done two-sided.
Similarly, we note H0,1,2 to H0,6,2  the null hypotheses for the test of superiority of 
empagliflozin 25 mg versus placebo on the key secondary endpoints.
Within each dose group (empagliflozin 10 mg and 25 mg), the key secondary endpoints will 
be tested sequentially with an unequal alpha split.  One-tenth of the alpha level for the key 
secondary endpoints will be used to sequentially test H0,1,1 and H0,2,1.  Nine-tenths of the 
alpha level for the key secondary endpoints will be used to sequentially test H0,3,1 and H0,4,1 as 
follows.
Depending on the success of the testing of H0,0,1 and H0,0,2 and H0,0,3, H0,1,1 will be tested at 
the following alpha level α1,1:

If H0,0,1 is rejected at 0.025 level, but H0,0,3 is not rejected then 
o α1,1 = 1/10 ×(4/5× 0.025)=0.002

If H0,0,1 is rejected at 0.025 level, as well as H0,0,3, then
o α1,1 = 1/10 ×[4/5× (0.025) + 1/2×(0.005)]=0.00225, if H0,0,2 is not rejected
o α1,1 = 1/10 ×[4/5× (0.025) + 1/2×(0.01)]=0.0025, if H0,0,2 is rejected at 0.025

If H0,0,2 is rejected at 0.025 level, as well as H0,0,3, but H0,0,1 is not rejected then
o α1,1 = 1/10 ×[4/5× (0) + 1/2×(0.005)]=0.00025

Otherwise H0,1,1 will not be tested
The same will apply for H0,2,1, provided H0,1,1 is rejected.


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Depending on the success of the testing of H0,0,1 and H0,0,2 and H0,0,3, H0,3,1 will be tested at 
the following alpha level α3,1:

If H0,0,1 is rejected at 0.025 level, but H0,0,3 is not rejected then 
o α3,1 = 9/10 ×(4/5× 0.025)=0.018

If H0,0,1 is rejected at 0.025 level, as well as H0,0,3, then
o α3,1 = 9/10 ×[4/5× (0.025) + 1/2×(0.005)]=0.02025,  if H0,0,2 is not rejected
o α3,1 = 9/10 ×[4/5× (0.025) + 1/2×(0.01)]=0.0225, if H0,0,2 is rejected at 0.025

If H0,0,2 is rejected at 0.025 level, as well as H0,0,3, but H0,0,1 is not rejected then
o α3,1 = 9/10 ×[4/5× (0) + 1/2×(0.005)]=0.00225

Otherwise H0,3,1 will not be tested
The same will apply for H0,4,1, provided H0,3,1 is rejected.
Depending on the success of each sequential testing, the alpha will contribute towards the 
significance level for the sequential testing of H0,5,1 and H0,6,1.

If H0,1,1 and H0,1,2  are rejected, but H0,3,1 or H0,4,1 are not rejected then α= α1,1 will 
contribute towards the testing of H0,5,1, and H0,6,1.

If H0,3,1 and H0,4,1 are both rejected, but H0,1,1, or H0,1,2  are not rejected then α= α3,1 
will contribute towards the testing of H0,5,1, and H0,6,1.

If all null hypotheses (H0,1,1 to H0,4,1) are rejected, H0,5,1 and H0,6,1 will be tested at the 
level α = α1,1 + α3,1
The same approach will apply for the testing of key secondary endpoints for Empagliflozin 
25 mg.
If at any stage a null hypothesis cannot be rejected, all subsequent tests in the same branch 
according to the diagram in Table 7.2: 1 will be performed in an exploratory manner only.


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Table 7.2: 1 
Summary of endpoint testing strategy
Empagliflozin 10 mg
Empagliflozin 2.5 mg
Empagliflozin 25 mg
Step 1:
Primary
endpoint
(efficacy)
Bonferroni,
two-sided 
(alpha=0.025)
If H0,0,1 for primary 
endpoint is rejected at 
alpha=0.025 level
using on-treatment 
data only then go to 
step 2, otherwise 
procedure is stopped 
and subsequent tests 
will be done only for 
exploratory purposes.
If H0,0,2 for primary 
endpoint is rejected at 
alpha=0.025 level 
using on-treatment 
data only then go to 
step 2, otherwise 
procedure is stopped 
and subsequent tests 
will be done only for 
exploratory purposes.
Step 2:
Primary 
endpoint
(effectiveness)
If H0,0,1 is rejected at 
alpha=0.025 level 
using all on- and off-
treatment data then 
go to step 3, 
otherwise procedure 
is stopped and 
subsequent tests will 
be done only for 
exploratory purposes
If H0,02 is rejected at 
alpha=0.025 level 
using all on- and off-
treatment data then go 
to step 3, otherwise 
procedure is stopped 
and subsequent tests 
will be done only for 
exploratory purposes
Step 3: 
Primary 
endpoint 
Gatekeeping


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Table 7.2: 1 
Summary of endpoint testing strategy (continued)
Step 4: 
Key
secondary 
endpoints 
Sequential 
testing, 
Gatekeeping 
with alpha 
based on the 
outcome of 
primary 
endpoint 
testing
PLANNED ANALYSES
7.3
To account for the testing of 2 doses of empagliflozin 25 and 10 mg, a Bonferroni adjustment 
will be applied to the type I error rate and tests for the primary endpoint (efficacy and 
effectiveness sequentially) will be conducted at the level of α=0.025 (two-sided).  A 
gatekeeping strategy will then be employed for the test of the primary endpoint for 
empagliflozin 2.5 mg against placebo.  Gatekeeping and sequential testing strategy will 
follow for tests of the key secondary endpoints for empagliflozin 25 and 10 mg to maintain 
the type I error rate at the level of α=0.025 (two-sided) within each dose (see Section 7.2 for 
details).
Safety analyses will be performed on the treated set (TS).  The TS is defined as all patients 
treated with at least one dose of study medication.
The primary efficacy analysis for all empagliflozin doses will be performed on the FAS.  The 
FAS is defined as all randomised patients who are treated with at least one dose of study 
medication, have a baseline HbA1c and at least one on-treatment HbA1c measurement.  The 
effectiveness analysis of the primary endpoint for empagliflozin 10 mg and 25 mg will be 
performed on the mITT set.  The mITT set is defined as all randomised patients who have a 
baseline HbA1c and at least one post randomisation HbA1c measurement.
A per protocol set (PPS) of patients following the trial protocol in essential criteria will be 
created for sensitivity analyses.  Patients included in the FAS who have important protocol 
violations (IPVs) that can be expected to have a distorting influence on the assessment of the 


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primary endpoint will be excluded from the PPS.  Details regarding the definitions of IPVs 
will be provided in the Trial Statistical Analysis Plan (TSAP).
Further sensitivity analyses will be based on the randomised set (RS).  The RS includes all 
randomised patients regardless of treatment with study medication.
All analyses will be conducted in SAS® version 9.2 or later.
7.3.1
Primary endpoint analyses
Primary analysis of the primary endpoint
7.3.1.1
The primary endpoint in this trial is the change from baseline in HbA1c (%) after 26 weeks.
The primary efficacy analysis will be performed on the FAS; patients will be assigned to the 
treatment they were randomised to and analysed according to the stratum to which they 
belong (regardless of any mis-assignment based on identification of the wrong stratum).  
Only on-treatment HbA1c values will be included in the primary analysis for efficacy.
Mean changes from baseline in HbA1c after 26 weeks will be analysed using a restricted 
maximum likelihood-based repeated measures approach (MMRM analysis).  Analyses will 
include the fixed categorical effects of treatment, pre-existing insulin therapy, week and 
treatment by week interaction, as well as the continuous, fixed covariates of baseline HbA1c, 
baseline eGFR and baseline HbA1c by week 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: 
compound symmetry, variance components and Toeplitz.  The (co)variance structure 
converging to the best fit, as determined by Akaike’s information criterion, will be used as 
the primary analysis.
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 = 0.025 (two-
sided 97.5% confidence intervals).  The residuals are assumed to have a multivariate normal 
distribution with zero means and covariance matrix as specified above.  The primary 
treatment comparisons will be the contrast between treatments at Week 26.
The statistical model will be:
HbA1c change from baseline = overall mean + continuous baseline HbA1c + pre-existing 
insulin therapy + continuous baseline eGFR + treatment + 
week + baseline HbA1c by week interaction + treatment by 
week interaction + random error
For empagliflozin 10 mg and 25 mg, following the analysis of the efficacy estimand, an 
effectiveness analysis will be performed on the mITT set.  This will use the same model as 
described for the efficacy analysis, but include all available on- and off- treatment values.


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7.3.2
Secondary endpoint analyses
For empagliflozin 10 and 25 mg the key secondary endpoints will be tested in a confirmatory 
way.
Key secondary endpoints – confirmatory analyses
7.3.2.1
The analysis of change from baseline in body weight after 26 weeks will follow the strategy 
for the primary endpoint, MMRM, with the addition of terms for baseline body weight and 
baseline body weight by week interaction into the model.  This analysis will be performed on 
the FAS, including all available on-treatment data.


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The analysis of change from baseline in TDID after 26 weeks will follow the strategy for the 
primary endpoint MMRM, with the addition of terms for baseline TDID and baseline TDID 
by week interaction into the model.  This analysis will be performed on the FAS, including
all available on-treatment data.  The baseline TDID will be calculated based on the mean 
daily insulin requirement during the 2 week run-in period.  The TDID after 26 weeks will be 
calculated based on the mean daily insulin requirement over the previous 7 days (i.e. during 
Week 26).
The analysis of the incidence rate of symptomatic hypoglycaemic AEs with confirmed 
plasma glucose < 54 mg/dL (<3.0 mmol/L) and/or severe hypoglycaemic AEs per patient-
year from Week 5 to Week 26 will utilise a negative binomial model, with terms for 
treatment, baseline rate, baseline HbA1c, baseline eGFR and pre-existing insulin therapy as 
fixed effects, and log(days of follow-up) as an offset.  This analysis will include patients from 
the FAS, including all available on-treatment events from the start of Week 5 (Day 29) up to 
one day after treatment stop.  The baseline rate of symptomatic hypoglycaemic AEs with 
confirmed plasma glucose < 54 mg/dL (<3.0 mmol/L) and/or severe hypoglycaemic AEs will 
be calculated based on the event rate during the 4 weeks prior to randomisation.
The analysis of the incidence rate of symptomatic hypoglycaemic AEs with confirmed 
plasma glucose < 54 mg/dL (<3.0 mmol/L) and/or severe hypoglycaemic AEs per patient-
year from Week 1 to Week 26 will follow the same strategy as the analysis from Week 5 to 
Week 26.  This analysis will include all patients from the FAS, including all available on-
treatment events from date of first study medication intake up to one day after treatment stop.
The analysis of change from baseline in SBP after 26 weeks will follow the strategy for the 
primary endpoint MMRM, with the addition of terms for baseline SBP and baseline SBP by 
week interaction into the model.  This analysis will be performed on the FAS, including all 
available on-treatment data.
The analysis of change from baseline in DBP after 26 weeks will follow the strategy for the 
primary endpoint MMRM, with the addition of terms for baseline DBP and baseline DBP by 
week interaction into the model.  This analysis will be performed on the FAS, including all 
available on-treatment data.
 
 
 


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7.3.4
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.1.3.2. All treated patients will be 
included in the safety evaluation (i.e. in the TS).  Safety analyses will assign patients to the 
treatment group as randomised. Safety analyses will be mostly descriptive in nature and will 
be based on BI standards.  In addition, statistical analysis for selected endpoints (to be 
defined in the TSAP) may be performed, if appropriate.  No hypothesis testing is planned.
The active empagliflozin treatment groups 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).  The analysis of AEs will be based on the concept of treatment emergent adverse 
events.  That means that all AEs occurring from first study medication intake until 7 days 
after last study medication intake will be assigned to the randomised treatment.  This includes 
AEs that start before first study medication intake and deteriorate under treatment.  All AEs 
occurring before first study medication intake will be assigned to ‘pre-treatment’ and all AEs 
occurring after last study medication intake + 7 days will be assigned to ‘post-treatment’.  
Additional listings based on actual treatment at onset of AE will be produced for patients who 
receive incorrect treatment at any point during the trial.  Specific analyses of hypoglycaemia 
will assign events only up to the end of the last study medication intake + 1 day to the 
randomised treatment, later hypoglycaemia events will be assigned to ‘post-treatment’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of the MedDRA.
Independent of this rule, the relationship of an AE to the study medication will be assessed by 
the Investigator.
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.
 
 


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INTERIM ANALYSES
7.4
There is no interim analysis planned for this trial but the conduct of the trial will be 
monitored by a DMC. For further details please refer to Section 3.1.1.1.
HANDLING OF MISSING DATA
7.5
For the primary analysis of the primary endpoint, if a patient misses a visit, the missing data 
will not be imputed and only on-treatment data will be included.  The mixed effect model 
will handle missing data based on a likelihood method under the "missing at random 
assumption".  Every randomised patient with at least baseline and one on-treatment 
measurement will be included in the analysis.  This approach will also be used for the 
confirmatory analysis of the key secondary endpoints investigating change from baseline in 
body weight, TDID, SBP and DBP.
An analysis including off-treatment data and multiple imputation will be used as a sensitivity 
analysis for the primary endpoint to handle missing data.  A detailed description of multiple 
imputation will be included in the TSAP.  This approach will also be applied to the key 
secondary endpoints of change from baseline in body weight, TDID, SBP and DBP.
For the key secondary endpoint of incidence rate of symptomatic hypoglycaemic AEs with 
confirmed plasma glucose < 54 mg/dL (<3.0 mmol/L) and/or severe hypoglycaemia, 
available on-treatment data will be analysed and no imputation performed.  A sensitivity 
analysis including post treatment events will also be performed.
Details regarding the imputation rule for further endpoints will be specified in the TSAP.  No 
imputation is planned for any analysis of AEs, laboratory data, and vital signs.
RANDOMISATION
7.6
The trial will be performed as a double-blind design with respect to placebo and the 3 active 
dose groups of empagliflozin.  Patients will be randomised in blocks to the 4 study treatments 
in a 1:1:1:1 ratio at Visit 6.  The randomisation will be stratified by the baseline eGFR value 
as calculated by the CKD-EPI formula (< 60 mL/min/1.73 m2 versus ≥60 mL/min/1.73 m2), 
baseline HbA1c (< 8.5% versus ≥8.5%), the patients’ pre-existing insulin therapy (MDI 


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versus CSII), and by the patient’s participation in the CGM substudy (CGM participation 
versus non-CGM participation). If necessary, and depending upon global distribution, entry 
of patients into a particular HbA1c stratum may be capped.
The randomisation of patients to the treatment groups will be performed via IRT.  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.  The block size 
will be documented in the CTR.  Access to the codes will be controlled and documented.
DETERMINATION OF SAMPLE SIZE
7.7
Based on previous experience with empagliflozin 
 it is 
estimated that the change in HbA1c from baseline after 26 weeks of treatment is 0.3% in 
empagliflozin (2.5 mg, 10 mg and 25 mg) and 0% in placebo and that the standard deviation 
of this difference is 0.9%.
As this trial investigates primarily the 2 higher dose levels of empagliflozin, 10 mg and 25 
mg, the alpha (Type I error) is assumed to be 2.5%.  Assuming that the change from baseline 
in HbA1c follows a normal distribution (Student’s t-test) and that a two-sided test will be 
employed, with equal standard deviations, then a sample size of 225 patients per arm will 
show superiority with a power of 90%.
Based on the results of these 2 tests (see Section 7.2 for further details), when comparing 
empagliflozin 2.5 mg (n=225) to placebo (n=225) on the primary endpoint, there is 82%
power, respectively 76%, to detect a significant difference (alpha=1%, respectively 
alpha=0.5%) of 0.3% with a common standard deviation of 0.9%.
Software package nQuery version 7.0 was used to derive the sample size.
Given that there are 4 treatment groups, a total sample size of 960 patients (240 per group) 
will be randomised to allow for an estimated 6% of patients who do not qualify for the FAS.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline 
for GCP,relevant BI SOPs and relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract.  As a rule, no trial results should be 
published prior to finalisation of the CTR.
As applicable locally, the certificate of insurance cover will be made available to the 
Investigator and the patients, and will be stored in the ISF.
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB /IEC and 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.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the Sponsor’s instructions.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor 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.


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RECORDS
8.3
eCRFs for individual patients will be provided by the Sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks.  For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the Investigator’s site.
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.  The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For 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.  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 eCRFs, and written informed consents.  The accuracy of the data will 
be verified by reviewing the documents described in Section 8.3.1.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.  
Therefore, a unique reference document for the evaluation of listedness needs to be provided.  
For empagliflozin this is the current version of the Investigator’s Brochure [c01678844], 
which will be provided in the ISF.
No AEs are classified as listed for matching placebo, trial design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements.


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STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below.  
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare.  Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities.
END OF TRIAL
8.6
The end of the trial is defined as defined in Section 6.2.3.
The IEC/CA in each participating EU member state will be notified about the end (i.e. last 
patient last trial visit) or early termination of the trial.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
R10-6370
Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical 
interventions in type 1 diabetes. Nature 2010;464:1293-1300
R10-6371
Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, 
Joyce C, Peoples T, Perkins BA, Welsh JB, Willi SM, Wood MA, STAR 3 
Study Group. Effectiveness of sensor-augmented insulin-pump therapy in type 
1 diabetes. N Engl J Med 2010;363(4):311-320
R04-2186
The Diabetes Control and Complications, Trial Research Group. The Effect of 
Intensive Treatment of Diabetes on the Development and Progression of Long-
Term Complications in Insulin-Dependent Diabetes Mellitus. N Engl J Med. 
1993, 329, pp. 977-986
R12-1489
Nathan, DM et al. Intensive diabetes treatment and cardiovascular disease in 
patients with type 1 diabetes. N Engl J Med. 2005, 353, pp. 2643-2653, R12-
1489
P13-05979
American Diabetes Association. Standards of Medical Care in Diabetes –
2013. Diabetes Care. 2013, 36 (Suppl. 1), pp. S11 -S66
R12-4773
Rewers M, Pihoker C, Donaghue K, Hanas R, Swift P, Klingensmith GJ. 
Assessment and monitoring of glycemic control in children and adolescents 
with diabetes. Pediatric Diabetes. 2009, 10 (Suppl. 12), pp. 71-81
R10-6369
Fatourechi MM, Kudva YC, Murad MH, Elamin MB, Tabini CC, Montori 
VM. Hypoglycemia with intensive insulin therapy: a systematic review and 
meta-analyses of randomized trials of continuous subcutaneous insulin 
infusion versus multiple daily injections. J Clin Endocrinol Metab 
2009;94(3):729-740
R05-0939
Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pfluegers 
Arch 2004, 447 (5), pp. 510-518
R10-6572
Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal 
hemodynamics during rapid hypertonic glucose infusion in normal and 
diabetic subjects. Scand J Clin Lab Invest 1971;28(1):101-109
R10-0703
Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. 
Glucose transporters in human renal proximal tubular cells isolated from the 
urine of patients with non-insulin-dependent diabetes. Diabetes 2005, 54(12), 
pp. 3427-3434


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P11-10364
Salvatore T, Carbonara O, Cozzolino D, Torella R, Nasti R, Lascar N, Sasso 
FC. Kidney in diabetes: from organ damage target to therapeutic target. Curr 
Drug Metab. 2011, 12 (7), pp. 658-666
R12-4766
Patrick AW, Hepburna DA, Swainsonb CP, Frier BM.  Changes in Renal 
Function During Acute Insulin-induced Hypoglycaemia in Patients with Type 
1 Diabetes. Diabet Med. 1992, 9, pp. 150-155
R08-2669
U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER). Guidance 
for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention. Draft guidance, February 2008
R09-2151 
Guidance for industry: diabetes mellitus - evaluating cardiovascular risk in 
new antidiabetic therapies to treat type 2 diabetes (December 2008). Silver 
Spring: U.S.Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER). (2008)
R14-0344
American Diabetes Association. Standards of Medical Care in Diabetes –
2014. Diabetes Care 37 (Suppl. 1), pp. S14 –S80
R14-5435
American Diabetes Association.  Hyperglycemic Crises in diabetes. Diabetes 
Care 27 (Suppl. 1), pp. S94 – S102.  
R14-0982
Sequist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller S, 
Rodriguez H, Rosenzweig J, Vigersky R.  Hypoglycemia and diabetes: a 
report of a workgroup of the American Diabetes Association and The 
Endocrine Society.  Diabetes Care 36(5), pp 1384-1395 (2013)
R12-5607
Guidance for industry: patient-reported outcome measures: use in medical 
product development to support labelling claims (December 2009, 
clinical/medical).  
http://www/fda/gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/Guida nces/UCM193282.pdf (access date: 14 December 2012); U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), Center for Biologics 
Evaluation and Research (CBER), Center for Devices and Radiological Health 
(CDRH) (2009)
 


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
21-Oct-2016
EudraCT number
2014-005256-26
BI Trial number
1245.72
BI Investigational Product(s)
Empagliflozin
Title of protocol
A Phase III, randomised, double blind, placebo-
controlled, parallel group, efficacy, safety and 
tolerability trial of once daily, oral doses of 
Empagliflozin as Adjunctive to inSulin thErapy over 
26 weeks in patients with Type 1 Diabetes Mellitus
(EASE-3)
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
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Endpoints:
“Secondary endpoints which will be assessed in an 
exploratory fashion in a subset of about 30% of the 
patients are:

Change from baseline in the percentage of 
time spent in target glucose range of 70-180 
mg/dL (3.9-10.0 mmol/L) as determined by 
CGM in Week 25 to 26

Change from baseline in interstitial glucose 
variability (inter quartile range, IQR) as 
determined by CGM in Week 25 to 26

Change from baseline in AUC for interstitial 
glucose (mmol/24 hour, average from 
evaluable data from CGM period, minimum 


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of 1 week required) in Week 25 to 26”
Has been removed
Rationale for change
Exploratory secondary endpoints were moved from 
secondary endpoints to further endpoints to align 
with project standards
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Safety criteria:
“Incidence rate of symptomatic hypoglycaemic AEs 
with confirmed plasma glucose < 54 mg/dL (< 3.0 
mmol/L) and/or severe hypoglycaemic AEs per 
patient-year from Week 1 to Week 4
Frequency of patients with adverse events of special 
interest (AESIs):

diabetic ketoacidosis (DKA)

hepatic injury

decreased renal function

severe hypoglycaemic episodes
Frequency of patients with hypoglycaemia
Frequency of patients with adjudicated events:

cardiovascular events

severe hypoglycaemia

DKA”
Has been changed to:
“Incidence rate of symptomatic hypoglycaemic AEs 
with confirmed plasma glucose < 54 mg/dL (< 3.0 
mmol/L) and/or severe hypoglycaemic AEs per 
patient-year from Week 1 to Week 4
Frequency of patients with adverse events of special 
interest (AESIs):

diabetic ketoacidosis (DKA)

hepatic injury

decreased renal function

severe hypoglycaemic episodes
Frequency of patients with hypoglycaemia
Hypoglycaemia rate
Frequency of patients with adjudicated events:

cardiovascular events

severe hypoglycaemia

DKA”
Rationale for change
Addition of “Hypoglycaemia rate” to correct omitted 
text in the original protocol


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Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Statistical methods:
“The subsequent test will be the confirmatory testing 
of the primary endpoint between empagliflozin 2.5 
mg and placebo and will follow a gatekeeping 
strategy.
For empagliflozin 10 mg and 25 mg the key 
secondary endpoints will be tested in a confirmatory 
way, following the test of the primary endpoint.  The 
key secondary endpoints will be analysed using a 
gatekeeping approach, with unequal splitting of the 
alpha, and sequential testing.”
Has been changed to:
“The primary analysis will be an efficacy 
analysis, including on-treatment data only.  
Following the efficacy analysis, an effectiveness 
analysis (on-and off-treatment data) of 
empagliflozin 10 mg and 25 mg versus placebo 
will be performed in a hierarchical manner.  If 
the null hypothesis is rejected for both the 
efficacy and effectiveness analysis then the 
primary endpoint (between empagliflozin 2.5 mg 
and placebo, on-treatment data only) and the key 
secondary endpoints will be tested in a 
confirmatory way using a gatekeeping approach, 
with unequal splitting of the alpha, and sequential 
testing.”
Rationale for change
Adjustments of the primary analysis based on 
regulatory feedback
Section to be changed
FLOW CHART
Description of change
“Visit 3”
Has been changed to:
“Visit 3/3TD”
Rationale for change
To increase flexibility for visit scheduling
Section to be changed
FLOW CHART
Description of change
Rows “Vital signs” and “Blood ketone measurement 
at the site with home monitoring device, urine
ketone measurement”:


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Brackets have been added around the assessment at 
Visit 3/3T
Rationale for change
If Visit 3 is performed as a telephone visit these 
assessments are not required
Section to be changed
FLOW CHART
Description of change
Footnote B:
“The patient’s therapy for T1DM (e.g. skills for 
carbohydrate estimation and insulin adjustment) 
should be optimised from Visit 2 for a period of 6 
weeks (i.e. until the patient reaches Visit 5 and the 
placebo run-in period) to achieve the best standard
of care in accordance with local guidelines.”
Has been changed to:
“The patient’s therapy for T1DM (e.g. ability to 
review blood glucose values, skills for carbohydrate 
estimation and insulin adjustment) should be 
optimised from Visit 2 for a period of 6 weeks (i.e. 
until the patient reaches Visit 5 and the placebo run-
in period) to achieve the best standard of care in 
accordance with local guidelines.”
Rationale for change
To align with section 4.2.1
Section to be changed
FLOW CHART
Description of change
Footnote D:
“Visit 4T is a telephone visit”
Has been changed to:
“Visit 4T is a telephone visit. Visit 3 can be a 
telephone visit (3T), if deemed sufficient based on 
Investigator judgement, or a clinic visit; if 
performed as a telephone visit, assessments in 
brackets in the Flow Chart do not have to be 
performed”
Rationale for change
To increase flexibility for visit scheduling
Section to be changed
FLOW CHART
Description of change
Footnote F:
“Following randomisation and prior to the initiation 
of study medication, Investigators are advised to 
reduce the patient’s total insulin dose by 10% to 
avoid hypoglycaemia; thereafter further insulin 
adjustments may be implemented as necessary.”


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Has been changed to:
“Following randomisation and prior to the initiation 
of study medication, Investigators are advised to 
reduce the patient’s total insulin dose based on 
need/ by 10% to avoid hypoglycaemia; thereafter 
further insulin adjustments may be implemented as 
necessary.”
Rationale for change
Clarification and optimisation of suggested insulin
titration
Section to be changed
FLOW CHART
Description of change
Footnote Y:
“At visits with safety laboratory, ketone 
measurements should be done directly before or after 
the collection of laboratory samples and also in a 
fasted state.  At visits without safety laboratory, 
ketones could be measured in a non-fasted state. 
Regular (e.g. 2-3 weekly) measurements at home 
before breakfast are recommended throughout the 
trial as from Visit 2.  More frequent (e.g. once daily) 
measurements are recommended during the run-in 
phase and during the first 4 weeks of the treatment 
phase.”
Has been changed to:
“At visits with safety laboratory, ketone 
measurements should be done directly before or after 
the collection of laboratory samples. At visits which 
require fasting, ketone measurements should be 
done in a fasted state. Regular (e.g. 2-3 times a 
week) measurements at home before breakfast are 
recommended throughout the trial as from Visit 2.  
More frequent (e.g. once daily) measurements are 
recommended during the run-in period and during 
the first 4 weeks of the treatment period.”
Rationale for change
Clarification
Section to be changed
ABBREVIATIONS
Description of change
The following abbreviations have been added:
CV
Coefficient of Variation
MAGE
Mean Amplitude of Glycaemic Excursions
mITT
Modified Intention-to-Treat
Rationale for change
New abbreviation required due to modified text in


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the revised protocol
Section to be changed
Multiple Sections
Description of change
1.1 MEDICAL BACKGROUND
1.2.1 Non-clinical assessment of safety
1.2.2.1 Clinical pharmacokinetics – Type 2 diabetes 
mellitus
1.2.3.1 Clinical efficacy and safety – Type 2 diabetes 
mellitus
4.1.3 Selection of doses in the trial
5.3.3.1 Follow-up on suspicion for urinary tract
infections
8.4.1 Listedness
9.2 UNPUBLISHED REFERENCES
In all of the above sections reference “c01838761”
has been changed to “c01678844”
Rationale for change
Administrative change. The referenced document, 
“Investigator Brochure, Empagliflozin (BI 10773)” 
has remained the same
Section to be changed
1.2.3.1 Clinical efficacy and safety – Type 2 diabetes 
mellitus
Description of change
“Approximately 550 healthy volunteers were 
exposed to empagliflozin (up to 800 mg single dose 
and up to 50 mg multiple dosing).  In addition, 
approximately 250 patients with T2DM included in 
Phase I trials received multiple dosing with 
empagliflozin up to 100 mg. Approximately 8500 
patients with T2DM have been treated with 
empagliflozin in research studies, of which 
approximately 4400 have been treated for more than 
52 weeks.  As of May 2014 approximately 8000 
patients are still participating in ongoing long-term 
studies with empagliflozin.”
Has been changed to:
“Empagliflozin has been studied as part of a 
global development program with 15582 patients 
with T2DM treated in clinical studies of which 
10004 were treated with empagliflozin, either 
alone or in combination with metformin, a 
sulfonylurea, a PPARγ agonist, dipeptidyl 
peptidase-4 inhibitors, or insulin.”
Rationale for change
Alignment of protocol with latest edition of


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Investigator’s brochure for empagliflozin
Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change
“As part of the preparation for entry into the 
randomised treatment period, therapy for T1DM will 
be optimised (e.g. review of insulin dose and its 
adjustment for meals, ability to carbohydrate count 
etc.) over a 6 week period (T1DM therapy 
optimisation period) to ensure that, in the 
Investigator’s opinion, a patient is achieving the best 
standard of care in accordance with local guidelines 
before entering the randomised treatment period of 
the trial. This optimal therapy will then be 
continued, and at randomisation, Investigators are 
advised to reduce the patient’s total insulin dose by 
10% to minimise the risk for hypoglycaemia.  Since 
glomerular filtration is physiologically decreased 
during episodes of severe hypoglycaemia (due to 
reduced renal blood flow hence leading to lowering 
of urine glucose excretion and therefore efficacy of 
empagliflozin), hypoglycaemia induced by insulin is 
not expected to be significantly aggravated by 
empagliflozin [R12-4766].”
And
“In addition to blood glucose monitoring, the 
frequency of which will be increased after starting 
the study medication (for further details see Section 
5.3.2.1), in the same way as during routine clinical 
care, patients will be reminded how to determine 
ketones in case of any symptoms of DKA, e.g. 
nausea, vomiting, abdominal pain etc.  They will be 
instructed to do this irrespective of the glucose value 
in the event of DKA symptoms occurring.  A meter 
will be provided to the patient for this purpose. ”
Has been changed to:
“As part of the preparation for entry into the 
randomised treatment period, therapy for T1DM will 
be optimised (e.g. review of blood glucose values, 
insulin dose and its adjustment for meals, ability to 
carbohydrate count etc.) over a 6 week period 
(T1DM therapy optimisation period) to ensure that, 
in the Investigator’s opinion, a patient is achieving 


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the best standard of care in accordance with local 
guidelines before entering the randomised treatment 
period of the trial. This optimal therapy will then be 
continued, and at randomisation, Investigators are 
advised to reduce the patient’s total insulin dose 
based on need/ by 10% to minimise the risk for 
hypoglycaemia.  Since glomerular filtration is 
physiologically decreased during episodes of severe 
hypoglycaemia (due to reduced renal blood flow 
hence leading to lowering of urine glucose excretion 
and therefore efficacy of empagliflozin), 
hypoglycaemia induced by insulin is not expected to 
be significantly aggravated by empagliflozin [R12-
4766].”
And
“In addition to blood glucose monitoring, the 
frequency of which will be increased after starting 
the study medication (for further details see Section 
5.3.2.1), in the same way as during routine clinical 
care, patients will be reminded how to determine 
ketones in case of any symptoms of DKA, e.g. 
nausea, vomiting, abdominal pain etc.  They will be 
instructed to do this irrespective of the glucose value 
in the event of DKA symptoms occurring.  More 
frequent ketone testing (e.g. once daily) will be 
recommended during the run-in period and 
during the first 4 weeks of the treatment period; 
this will allow patients and Investigators to 
understand baseline ketosis rates and compare 
them, as appropriate, to the incidence of ketosis 
following the initiation of study medication.  A 
meter will be provided to the patient for this 
purpose; as an additional safeguard, the meter 
will also be used to check ketone levels at most 
clinic visits (see Flow Chart).”
Rationale for change
Clarification and optimisation of suggested insulin
titration; clarification of additional safety monitoring
Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change
“To continue the assessment of the long-term safety 
of empagliflozin, an adjudication of certain hepatic 
events, and an external assessment of cancer events 
will be performed in this trial.”


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Has been changed to:
“To continue the assessment of the long-term safety 
of empagliflozin, an adjudication of certain hepatic 
events will be performed in this trial.”
Rationale for change
Removal of the requirement for external
assessment of cancer events based on cumulative
safety data obtained to date
Section to be changed
3.1 OVERALL TRIAL DESIGN AND PLAN
Description of change
“The patient’s participation is concluded when they 
have undergone the last planned visit (i.e. Trial 
Completion/Visit 11 EOT); last-patient-last-visit-
primary-endpoint will occur when all patients have 
completed 26 weeks of treatment.”
Has been changed to:
“The patient’s participation is concluded when they 
have undergone the last planned visit (i.e. Trial 
Completion/Visit 12); last-patient-last-visit-primary-
endpoint will occur when all patients have 
completed 26 weeks of treatment.”
Rationale for change
Correction of a typo
Section to be changed
3.1.1.4 Hepatic external adjudication and cancer
assessments
Description of change
Section title has been changed to: “Hepatic external 
adjudication”
And
“Certain events of cancer will be assessed for causal 
relationship with the trial medication, and certain 
hepatic events will be adjudicated by external 
independent experts for severity and causal 
relationship with the trial medication; both in a 
blinded fashion.  The events which will be reviewed 
will be defined in two charters, one for hepatic 
events and one for malignancies.  Events may either 
be defined by 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.”


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Has been changed to:
“Certain hepatic events will be adjudicated by 
external independent experts for severity and causal 
relationship with the trial medication in a blinded 
fashion.  The events which will be reviewed will be 
defined in a charter.  Events may either be defined 
by abnormal laboratory values and/or relevant 
adverse events or both.  For example, assessments 
will be made for events of hepatic injury, including 
liver enzyme elevations.”
Rationale for change
Removal of the requirement for external
assessment of cancer events based on cumulative
safety data obtained to date
Section to be changed
3.3 SELECTION OF TRIAL POPULATION
Description of change
“A sufficient number of male and female patients 
with T1DM will be screened to ensure the 
randomisation of 960 patients from around 170 trial 
sites.”
Has been changed to:
“A sufficient number of male and female patients 
with T1DM will be screened to ensure the 
randomisation of 960 patients from around 180 trial 
sites.”
Rationale for change
Adjustment
Section to be changed
3.3.2 Inclusion criteria
Description of change
“Women of child-bearing potential are defined as 
follows:
Any female who has experienced menarche and is 
not post-menopausal (defined as at least 12 months 
with no menses without an alternative medical 
cause) or who is not permanently sterilised (e.g. 
tubal occlusion, hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy)”
Has been changed to:
“Women of child-bearing potential are defined as 
follows:
Any female who has experienced menarche and is 


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not post-menopausal (defined as at least 12 months 
with no menses without an alternative medical 
cause) or who is not permanently sterilised (e.g. 
hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy)”
Rationale for change
Tubal occlusion is not accepted as a method of 
permanent sterilisation any longer. (Though it is 
considered as a method of highly effective birth 
control)   
Section to be changed
3.3.3 Exclusion criteria
Description of change
“4. Occurrence of severe hypoglycaemia involving 
coma and/or seizure that required hospitalisation or 
hypoglycaemia-related treatment by an emergency 
physician or paramedic within 3 months prior to 
Visit 1”
And
“13. Treatment with systemic corticosteroids or 
planned initiation of such therapy at Visit 1.  Inhaled 
or topical use of corticosteroids (e.g. for 
asthma/chronic obstructive pulmonary disease) is 
acceptable”
And
“14. Change in dose of thyroid hormones within 6 
weeks prior to Visit 1 or planned change or initiation 
of such a therapy at Visit 1”
Has been changed to:
“4. Occurrence of severe hypoglycaemia involving 
coma/unconsciousness and/or seizure that required 
hospitalisation or hypoglycaemia-related treatment 
by an emergency physician or paramedic within 3 
months prior to Visit 1 and until randomisation”
And
“13. Treatment with systemic corticosteroids or 
planned initiation of such therapy at Visit 1 and 
until randomisation.  Inhaled or topical use of 
corticosteroids (e.g. for asthma/chronic obstructive 
pulmonary disease) is acceptable”


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And
“14. Change in dose of thyroid hormones within 6 
weeks prior to Visit 1 or planned change or initiation 
of such a therapy at Visit 1 and until 
randomisation“
Rationale for change
Adjustment of eligibility for safety reasons, and
clarification
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
“An individual patient is to be withdrawn from trial 
treatment if:
[…]

The patient needs to take forbidden 
concomitant therapy (as listed in Section 
3.3.3 and Section 4.2)”
Has been changed to:
“An individual patient is to be withdrawn from trial 
treatment if:
[…]

The patient needs to start a restricted
concomitant therapy (as listed in Section 4.2)
that, in the Investigator’s opinion, poses a 
safety risk if taken as add-on to the trial 
medication”
Rationale for change
Concomitant therapies that require to screen-fail a 
patient might not always pose a safety risk. It should 
therefore be left to investigator’s discretion if a 
patient should discontinue the trial medication if 
such concomitant therapies need to be initiated after 
randomization 
Section to be changed
4.1.8.1 Patient treatment compliance
Description of change
“The tablets will be counted by the Investigator or a 
qualified designee and compliance will be calculated 
according to the formula: […] Compliance during the 
open-label placebo run-in period must be between 
80% and 120%.  If compliance is outside this range, 
the patient should be carefully interviewed and, if 
necessary, re-informed about the purpose and the 
conduct of the trial.  Unreliable patients should not 
be randomised at the discretion of the Investigator.”


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And
“The tablets will be counted by the Investigator or a 
qualified designee and compliance will be calculated 
according to the following formula unless there are 
reasons to use a different calculation (e.g. to 
account for periods during which a patient was 
genuinely unable to take any trial medication):
[…] Compliance during the open-label placebo run-
in period must be between 80% and 120%.  If 
compliance is outside this range, the patient should 
not be randomised.”
Rationale for change
Clarification
Section to be changed
4.2.1 Rescue medication, emergency procedures, and 
additional treatments
Description of change
“Based on the mode of action of empagliflozin and 
the results of previous trials in T1DM (for further 
details see Section 1), at randomisation on Day 1 
(Visit 6) and the initiation of study medication, 
Investigators are advised to reduce the patient’s total
insulin dose by 10% to avoid hypoglycaemia.  The 
actual reduction will be dependent upon individual 
glucose values.”
And
“Apart from the recommendation for an initial 
insulin reduction of 10% at the start of randomised 
treatment, there will be no protocol-defined 
algorithm towards insulin adjustment in this trial.”
And
“Ketones should also be determined in case of 
repeatedly elevated blood glucose levels (e.g. > 200 
- 240 mg/dL [> 11.1 - 13.3 mmol/L]) which cannot 
be explained.  Regular (e.g. 2-3 weekly) 
measurements before breakfast are recommended 
throughout the trial as from Visit 2.  More frequent 
(e.g. once daily) measurements before breakfast are 
recommended during the run-in phase and during the 
first 4 weeks of the treatment phase and might also 
be agreed upon with the patient afterwards if deemed 
necessary by the Investigator.”


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And
“Other concomitant therapies should be kept as 
stable as possible over the course of the trial but 
might be changed in case of medical need.  New 
anti-diabetic therapy should not be initiated during 
the Follow-up period.”
Has been changed to:
“Based on the mode of action of empagliflozin and 
the results of previous trials in T1DM (for further 
details see Section 1), at randomisation on Day 1 
(Visit 6) and the initiation of study randomised
medication, for patients with an HbA1c of 7.5 to < 
8% at Visit 5, Investigators are advised to reduce 
the patient’s total insulin dose by 10% to avoid 
hypoglycaemia.  For patients with an HbA1c of ≥
8% at Visit 5, Investigators are advised to adjust 
the patient’s total insulin dose based on need as 
assessed by frequent SBGM and close patient 
follow-up upon initiation of randomised study 
medication.  In all cases, the actual reduction will 
be dependent upon individual glucose values.”
And
“Apart from the recommendation for an initial 
insulin reduction as mentioned above at the start of 
randomised treatment, there will be no protocol-
defined algorithm towards insulin adjustment in this 
trial.”
And
“Ketones should also be determined in case of 
repeatedly elevated blood glucose levels (e.g. > 200 
- 240 mg/dL [> 11.1 - 13.3 mmol/L]) which cannot 
be explained.  Regular (e.g. 2-3 times a week) 
measurements before breakfast are recommended 
throughout the trial as from Visit 2.  More frequent 
(e.g. once daily) measurements before breakfast are 
recommended during the run-in period and during 
the first 4 weeks of the treatment period and might 
also be agreed upon with the patient afterwards if 
deemed necessary by the Investigator.”


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And
“Other concomitant therapies should be kept as 
stable as possible over the course of the trial but 
might be changed in case of medical need.  New 
anti-diabetic therapy should not be initiated during 
the randomised treatment period and the Follow-
up period.”
Rationale for change
Clarification and optimisation of suggested insulin
titration
Section to be changed
4.2.2.2 Restrictions on diet and life style
Description of change
“Extreme diets (e.g. ketogenic diets) should be 
avoided.”
Has been changed to:
“Extreme diets (e.g. ketogenic diets such as the 
Atkins diet) should be avoided.”
Rationale for change
Alignment project level patient information sheet 
text for Type 1 diabetes trials
Section to be changed
5.1.2 Secondary endpoints
Description of change
“Throughout this CTP, the term “baseline” refers to 
the 4 week period prior to randomisation for the rate 
of symptomatic hypoglycaemic AEs with confirmed 
plasma glucose < 54 mg/dL (< 3.0 mmol/L) and/or 
severe hypoglycaemic AEs and the 2 week placebo 
run-in period for the mean daily insulin requirement 
(1 week of evaluable data required).”
Has been changed to
“Throughout this CTP, the term “baseline” refers to 
the 4 week period prior to randomisation for the rate 
of symptomatic hypoglycaemic AEs with confirmed 
plasma glucose < 54 mg/dL (< 3.0 mmol/L) and/or 
severe hypoglycaemic AEs and the 2 week placebo 
run-in period for the mean daily insulin 
requirement.”
Rationale for change
Clarification
Section to be changed
5.1.2 Secondary endpoints
Description of change
“The following secondary endpoints will be assessed 
in an exploratory fashion.  For CGM the term 


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“baseline” refers to the 2 week placebo run-in period 
throughout this protocol (1 week of evaluable data 
required).

Change from baseline in the percentage of time 
spent in target glucose range of 70-180 mg/dL 
(3.9-10.0 mmol/L) as determined by CGM in 
Week 25 to 26

Change from baseline in interstitial glucose 
variability (inter quartile range, IQR) as 
determined by CGM in Week 25 to 26
Change from baseline in AUC for interstitial glucose 
(mmol/24 hour, average from evaluable data from 
CGM period, minimum of 1 week required) in Week 
25 to 26”
Has been removed
Rationale for change
Exploratory secondary endpoints moved from 
secondary endpoints to further endpoints to align 
with project standards
Section to be changed
Description of change


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Rationale for change
Section to be changed
5.3.2.2 Ketone measurement
Description of change
“Regular (e.g. 2-3 weekly) measurements before 
breakfast are recommended throughout the trial as 
from Visit 2.  More frequent (e.g. once daily) 
measurements before breakfast are recommended 
during the run-in phase and during the first 4 weeks 
of the treatment phase and might also be agreed 
upon with the patient afterwards if deemed necessary 
by the Investigator.”
Has been changed to:
“Regular (e.g. 2-3 times a week) measurements 
before breakfast are recommended throughout the 


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trial as from Visit 2.  More frequent (e.g. once daily) 
measurements before breakfast are recommended 
during the run-in period and during the first 4 weeks 
of the treatment period and might also be agreed 
upon with the patient afterwards if deemed necessary 
by the Investigator.”
Rationale for change
Clarification
Section to be changed
5.3.6.1 Definitions of AEs
Description of change
Added to Adverse events of Special Interest 
(AESIs):
“Events involving lower limb amputation
This definition includes amputation (i.e. resection of 
a limb through a bone), disarticulation (i.e. resection 
of a limb through a joint) and auto-amputations (i.e. 
spontaneous separation of non-viable portion of the 
lower limb).
Not included in this definition are debridement 
(removal of callus or dead tissue), procedures on a 
stump (like stump revision, drainage of an abscess, 
wound revision etc.) and other procedures (e.g., nail 
resection or removal) without a concomitant 
resection of a limb (amputation or disarticulation).
Each lower limb amputation, disarticulation, or auto-
amputation should be reported separately. The SAE 
report should include the date of the procedure, the 
level of amputation or disarticulation, the medical 
condition(s) leading to the procedure and if the 
patient had some of the known risk factor(s) for 
lower limb amputation.”
Rationale for change
To meet new regulatory requirements
Section to be changed
 
 


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Rationale for change
Correction of error/omission
Section to be changed
Multiple sections
Description of change
6.2.1.1 Screening visit (Visit 1)
6.2.1.2 T1DM therapy optimisation period (Visits 2, 
3 and 4T)
6.2.1.3 Placebo run-in period (Visit 5)
References to Section 5.2.3 have been changed to
Section 5.3.3
Rationale for change
Correction of errors
Section to be changed
6.2.1.2 T1DM therapy optimisation period (Visits 2, 
3 and 4T)
Description of change
“Visit 2 should be done with the patient in a fasted 
state (i.e. no food or drink except water for 10 hours) 
whereas Visits 3 does not need to be done with the 
patient in a fasted state (see Section 5.2.3)”
Has been changed to:
“Visit 2 should be done with the patient in a fasted 
state (i.e. no food or drink except water for 10 hours) 
(see Section 5.3.3)”
And the following item has been added:

Visit 3T, if performed as a telephone visit, 
does not require attendance at the clinic.  If 
performed as a clinic visit, Visit 3 does not 
need to be done with the patient in a fasted 
state (see Section 5.3.3)
Rationale for change
To increase flexibility for visit scheduling
Section to be changed
7.1 STATISTICAL DESIGN - MODEL
Description of change
“Following the analysis of the primary endpoint, 
change from baseline in HbA1c after 26 weeks, for 
the 2 higher doses, the error rate will be unequally 
split and transferred between the testing of the 
lowest dose empagliflozin 2.5 mg (with an allocated 


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alpha weight of 1/5) and the testing of key secondary 
endpoints (with an allocated alpha weight of 4/5) in 
a gatekeeping strategy.  If the null-hypothesis of 
“equal HbA1c change after 26 weeks between 
placebo and empagliflozin 2.5 mg” can be rejected, 
alpha of this test will be equally split and added to 
the alpha level for the test of the key secondary 
endpoints of the two higher doses.”
Has been changed to:
“Following the efficacy analysis (on-treatment 
data only) of the primary endpoint, change from 
baseline in HbA1c after 26 weeks, for the 2 higher 
doses, an effectiveness analysis (on-and off-
treatment data) of empagliflozin 10 mg and 25 
mg versus placebo will be performed in a 
hierarchical manner.  If the null hypothesis is 
rejected for both the efficacy and effectiveness 
analysis the error rate will be unequally split and 
transferred between the testing of the lowest dose 
empagliflozin 2.5 mg (with an allocated alpha 
weight of 1/5) and the testing of key secondary 
endpoints (with an allocated alpha weight of 4/5) in 
a gatekeeping strategy.  If the null-hypothesis of 
“equal HbA1c change after 26 weeks between 
placebo and empagliflozin 2.5 mg” can be rejected
using on-treatment data only, alpha of this test will 
be equally split and added to the alpha level for the 
test of the key secondary endpoints of the two higher 
doses.”
Rationale for change
Adjustments of the primary analysis based on 
regulatory feedback
Section to be changed
7.1 STATISTICAL DESIGN - MODEL
Description of change
“With regard to efficacy and safety endpoints, the 
term “baseline” refers to the last observed 
measurement prior to administration of any 
randomised study medication, the 4 week period 
prior to randomisation (Visit 4T to Visit 6) for the 
rate of hypoglycaemia and the 2 week run-in period 
for the mean daily insulin requirement.”
Has been changed to:
“With regard to efficacy and safety endpoints, the 


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term “baseline” refers to the last observed 
measurement prior to administration of any 
randomised study medication, the 4 week period 
prior to randomisation for the rate of hypoglycaemia 
and the run-in period from Visit 5 to Visit 6 for the 
mean daily insulin requirement.”
Rationale for change
Clarification
Section to be changed
7.1 STATISTICAL DESIGN - MODEL
Description of change
“The randomisation will be stratified by the Visit 5 
eGFR value (< 60 mL/min/1.73 m2 versus ≥ 60 
mL/min/1.73 m2), the Visit 5 HbA1c value (< 8.5% 
versus ≥ 8.5%), by the patients’ pre-existing insulin 
therapy (MDI versus CSII), and by the patient’s 
participation in the CGM substudy (CGM 
participation versus non-CGM participation).”
Has been changed to:
“The randomisation will be stratified by the Visit 5 
eGFR value (< 60 mL/min/1.73 m2 versus ≥ 60 
mL/min/1.73 m2), the Visit 5 HbA1c value (< 8.5% 
versus ≥ 8.5%), by the patients’ pre-existing insulin 
therapy (MDI versus CSII), and by the patient’s 
participation in the CGM substudy (CGM 
participation versus non-CGM participation). If 
necessary, and depending upon global 
distribution, entry of patients into a particular 
HbA1c stratum may be capped.”
Rationale for change
To ensure an adequate number of patients with an
HbA1c > 8.5% are included in the trial
Section to be changed
7.2 NULL AND ALTERNATIVE HYPOTHESES
Description of change
“The superiority of treatment with empagliflozin to 
placebo will be tested for HbA1c change from 
baseline at Week 26, via the pairwise comparison of 
the two higher empagliflozin doses against placebo, 
at α=0.025 level.  Both doses will be tested in 
parallel on the Full Analysis Set (FAS).
[…]
Following testing of the null hypotheses H0,0,1 and 
H0,0,2 for HbA1c, within each dose group 
(empagliflozin 10 and 25 mg) the remaining alpha 
will be unequally split for testing the superiority of 
empagliflozin 2.5 mg to placebo on the primary 
endpoint and for testing the superiority of the key 


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secondary endpoints for the higher doses as detailed 
below.”
Has been changed to:
“The superiority of treatment with empagliflozin to 
placebo will be tested for HbA1c change from 
baseline at Week 26, via the pairwise comparison of 
the two higher empagliflozin doses against placebo, 
at α=0.025 level.  Both doses will be tested in 
parallel on the Full Analysis Set (FAS) for the 
efficacy analysis and on the modified Intention-
to-Treat (mITT) set for the effectiveness analysis; 
see Section 7.3 for the analysis set definitions.  
Both analyses will test the same null hypothesis:
[…]
Following testing of the null hypotheses H0,0,1 and 
H0,0,2 for both efficacy and effectiveness for HbA1c,
within each dose group (empagliflozin 10 and 25 
mg) the remaining alpha will be unequally split for 
testing the superiority of empagliflozin 2.5 mg to 
placebo on the primary endpoint and for testing the 
superiority of the key secondary endpoints for the 
higher doses as detailed below.”
Rationale for change
Adjustments of the primary analysis based on 
regulatory feedback
Section to be changed
Table 7.2: 1 Summary of endpoint testing strategy
Description of change
Empagliflozin 10 mg
Empagliflozin 2.5 mg
Empagliflozin 25 mg
Step 1:
Primary 
endpoint
Bonferroni,
two-sided 
(alpha=0.025
)
If H0,0,1 for primary 
endpoint is rejected at 
alpha=2.5% level 
then go to step 2, 
otherwise procedure 
is stopped and 
subsequent tests will 
be done only for 
exploratory purposes.
If H0,0,2 for primary 
endpoint is rejected at 
alpha=2.5% level then 
go to step 2, otherwise 
procedure is stopped 
and subsequent tests 
will be done only for 
exploratory purposes.
Step 2: 
Primary 
endpoint 


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Gatekeeping
Step 3: 
Key
secondary 
endpoints 
Sequential 
testing, 
Gatekeeping 
with alpha 
based on the 
outcome of 
primary 
endpoint 
testing
Has been changed to:
Empagliflozin 10 mg
Empagliflozin 2.5 mg
Empagliflozin 25 mg
Step 1:
Primary 
endpoint
(efficacy)
Bonferroni,
two-sided 
(alpha=0.025)
If H0,0,1 for primary 
endpoint is rejected at 
alpha=0.025 level
using on-treatment 
data only then go to 
step 2, otherwise 
procedure is stopped 
and subsequent tests 
will be done only for 
exploratory purposes.
If H0,0,2 for primary 
endpoint is rejected 
at alpha=0.025 level 
using on-treatment 
data only then go to 
step 2, otherwise 
procedure is stopped 
and subsequent tests 
will be done only for 


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exploratory purposes.
Step 2: 
Primary 
endpoint 
(effectiveness
)
If H0,0,1 is rejected at 
alpha=0.025 level 
using all on- and off-
treatment data then 
go to step 3, 
otherwise procedure 
is stopped and 
subsequent tests will 
be done only for 
exploratory 
purposes
If H0,02 is rejected at 
alpha=0.025 level 
using all on- and 
off-treatment data 
then go to step 3, 
otherwise 
procedure is 
stopped and 
subsequent tests will 
be done only for 
exploratory 
purposes
Step 3: 
Primary 
endpoint 
Gatekeeping


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Step 4: 
Key
secondary 
endpoints 
Sequential 
testing, 
Gatekeeping 
with alpha 
based on the 
outcome of 
primary 
endpoint 
testing
Rationale for change
Adjustments of the primary analysis based on 
regulatory feedback; corrections for consistency
Section to be changed
7.3 PLANNED ANALYSES
Description of change
“To account for the testing of 2 doses of 
empagliflozin 25 and 10 mg, a Bonferroni 
adjustment will be applied to the type I error rate and 
tests for the primary endpoint will be conducted at 
the level of α=0.025 (two-sided). […]
The primary analysis will be performed on the FAS.  
The FAS is defined as all randomised patients who 
are treated with at least one dose of study 
medication, have a baseline HbA1c and at least one 
on-treatment HbA1c measurement.”
Has been changed to:
“To account for the testing of 2 doses of 
empagliflozin 25 and 10 mg, a Bonferroni 
adjustment will be applied to the type I error rate and 
tests for the primary endpoint (efficacy and 
effectiveness sequentially) will be conducted at the 
level of α=0.025 (two-sided). […]
The primary efficacy analysis for all empagliflozin 
doses will be performed on the FAS.  The FAS is 
defined as all randomised patients who are treated 
with at least one dose of study medication, have a 
baseline HbA1c and at least one on-treatment HbA1c
measurement.  The effectiveness analysis of the 


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primary endpoint for empagliflozin 10 mg and 25 
mg will be performed on the mITT set.  The 
mITT set is defined as all randomised patients 
who have a baseline HbA1c and at least one post 
randomisation HbA1c measurement.”
Rationale for change
Adjustments of the primary analysis based on 
regulatory feedback
Section to be changed
7.3.1.1 Primary analysis of the primary endpoint
Description of change
“The primary analysis will be performed on the FAS; 
patients will be assigned to the treatment they were 
randomised to and analysed according to the stratum 
to which they belong (regardless of any mis-
assignment based on identification of the wrong 
stratum).  Only on-treatment HbA1c values will be 
included in the primary analysis.”
Has been changed to:
“The primary efficacy analysis will be performed on 
the FAS; patients will be assigned to the treatment 
they were randomised to and analysed according to 
the stratum to which they belong (regardless of any 
mis-assignment based on identification of the wrong 
stratum).  Only on-treatment HbA1c values will be 
included in the primary analysis for efficacy.”
And the following paragraph has been added:
“For empagliflozin 10 mg and 25 mg, following 
the analysis of the efficacy estimand, an 
effectiveness analysis will be performed on the 
mITT set.  This will use the same model as 
described for the efficacy analysis, but include all 
available on- and off- treatment values.”
Rationale for change
Adjustments of the primary analysis based on 
regulatory feedback
Section to be changed
7.3.1.2.1 Sensitivity analyses
Description of change
Handling of missing data – The following sensitivity 
analyses has been removed:
“An MMRM analysis including all available on- and 
off-treatment data will be performed, using the same 
model as for the primary analysis.  This analysis will 
be performed on the FAS”


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Rationale for change
Adjustments of the primary analysis based on 
regulatory feedback
Section to be changed
7.3.2.2 Key secondary endpoints – secondary 
analyses
Description of change
The following analysis has been removed:
“A logistic regression will be performed to assess the 
proportion of patients experiencing symptomatic 
hypoglycaemic events with confirmed plasma 
glucose < 54 mg/dL (<3.0 mmol/L) and/or severe 
hypoglycaemic events confirmed by adjudication
during the respective time periods, while on 
treatment.  The model will include terms for 
treatment, baseline rate, baseline HbA1c, baseline 
eGFR and pre-existing insulin therapy”
Rationale for change
The logistic regression for proportion of patients 
experiencing an event will rather be included as a 
sensitivity analysis in the TSAP, if considered 
applicable
Section to be changed
7.3.2.3 Secondary endpoints
Description of change
This section has been deleted
Rationale for change
Exploratory secondary endpoints moved from 
secondary endpoints to further endpoints to align 
with project standards
Section to be changed
Description of change


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Rationale for change
Section to be changed
7.3.4 Safety analyses
Description of change
“All treated patients will be included in the safety 
evaluation (i.e. in the TS).  Safety analyses will 
assign patients to the treatment group as treated.”
Has been changed to:
“All treated patients will be included in the safety 
evaluation (i.e. in the TS).  Safety analyses will 
assign patients to the treatment group as
randomised.”
Rationale for change
To match project standards
Section to be changed
Description of change
 
 
”
Rationale for change
Correction of error/omission
Section to be changed
7.6 RANDOMISATION
Description of change
The following sentence was added:
“If necessary, and depending upon global 
distribution, entry of patients into a particular 
HbA1c stratum may be capped.”
Rationale for change
To ensure an adequate number of patients with an
HbA1c > 8.5% are included in the trial


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02993089
3.0
clinical-trial-protocol
A Phase III, randomised, double blind, placebo-controlled, parallel group, efficacy,
safety and tolerability trial of once daily, oral doses of Empagliflozin as Adjunctive
to inSulin thErapy over 26 weeks in patients with Type 1 Diabetes Mellitus
(EASE-3)
Author-Trial Clinical Monitor
21 Oct 2016 14:26 CEST
Approval-Therapeutic Area 
21 Oct 2016 14:51 CEST
Approval-Team Member Medicine
21 Oct 2016 15:51 CEST
Approval-Team Member Medicine
24 Oct 2016 13:17 CEST
Author-Trial Clinical
Pharmacokineticist
24 Oct 2016 20:12 CEST
Author-Trial Statistician
25 Oct 2016 15:37 CEST
Verification-Paper Signature
Completion
26 Oct 2016 17:34 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02993089
3.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c07659061-02
BI Trial No.:
1245.72
Title:
Investigational
Product(s):
A Phase III, randomised, double blind, placebo-controlled, parallel 
group, efficacy, safety and tolerability trial of once daily, oral 
doses of Empagliflozin as Adjunctive to inSulin thErapy over 26 
weeks in patients with Type 1 Diabetes Mellitus (EASE-3)
Including Protocol Amendment 2 1245.72 [c02993089-03]
Empagliflozin
Responsible trial 
statistician:
  Phone
  Fax: 
Date of statistical 
analysis plan:
  11 OCT 2017 REVISED
Version:
  Revised
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1
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................5
2
LIST OF ABBREVIATIONS ...............................................................6
3
INTRODUCTION..................................................................................9
4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY.......10
5
ENDPOINTS ........................................................................................11
5.1
PRIMARY ENDPOINT ....................................................................................11
5.2
SECONDARY ENDPOINTS............................................................................11
5.2.1
Key secondary endpoints..............................................................................11
5.2.2
Secondary endpoint.......................................................................................11
5.4.9
Safety data......................................................................................................27
6
GENERAL ANALYSIS DEFINITION.............................................28
6.1
TREATMENTS..................................................................................................28
6.2
IMPORTANT PROTOCOL VIOLATIONS (IPVS)......................................28
6.3
PATIENT SETS ANALYSED..........................................................................34
..............................................................................36
6.5
POOLING OF CENTERS ................................................................................41
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................42
6.6.1
Imputation methods ......................................................................................42
6.6.1.1
Original results (OR) analysis ....................................................................42
6.6.1.2
Observed cases (OC) analysis ....................................................................42
6.6.1.3
Observed cases - all data (OC-AD) analysis ..............................................43
6.6.1.4
Observed cases - Off Treatment (OC-OffT) analysis.................................43


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6.6.1.5
Last observation carried forward (LOCF)..................................................43
6.6.1.6
Multiple imputation (MI)............................................................................44
6.6.1.7
Non-completers considered failure (NCF) .................................................44
6.6.2
Safety and other variables ............................................................................44
6.6.3
Missing dates and times ................................................................................44
6.7
BASELINE, TIME WINDOW, AND CALCULATED VISITS....................46
7
PLANNED ANALYSES......................................................................53
7.1
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS......54
7.1.1
Baseline evaluation........................................................................................54
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................55
7.3
TREATMENT COMPLIANCE .......................................................................56
7.4
PRIMARY ENDPOINT ....................................................................................56
7.4.1
Primary analysis............................................................................................56
7.4.2
Model diagnostics ..........................................................................................57
7.5
SECONDARY ENDPOINTS............................................................................60
7.5.1
Key secondary endpoints..............................................................................60
7.5.1.1
Rate of symptomatic hypoglycaemic AEs with confirmed plasma glucose 
<54 mg/dL and/or severe hypoglycaemic events confirmed by adjudication
....................................................................................................................60
7.5.1.2
Change from baseline in body weight (kg) after 26 weeks ........................61
7.5.1.3
Change from baseline in total daily insulin dose (U/kg) after 26 weeks....61
7.5.1.4
Change from baseline in blood pressure after 26 weeks ............................62
7.5.2
(Other) Secondary endpoint.........................................................................63
..............................................................................63
7.7
EXTENT OF EXPOSURE................................................................................67
7.8
SAFETY ANALYSIS.........................................................................................67
7.8.1
Adverse events ...............................................................................................67
7.8.1.1
Assignment of AEs to treatment.................................................................68
7.8.1.2
Analysis of other significant AEs...............................................................68
7.8.1.3
AE summaries.............................................................................................69
7.8.1.4
AEs of special interest (AESI)....................................................................69
7.8.1.5
Other specific adverse events .....................................................................73
7.8.1.6
Events qualifying for external adjudication by the Clinical Event 
Committee (CEC).......................................................................................77
7.8.1.7
AEs while patients taking wrong medication.............................................78
7.8.2
Laboratory data.............................................................................................78
7.8.2.1
General laboratory evaluation ....................................................................78
7.8.2.2
Elevated liver enzymes...............................................................................79
7.8.2.3
Lipid parameters.........................................................................................79


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7.8.2.4
Renal laboratory parameters.......................................................................79
7.8.2.5
Blood beta-hydroxybutyrate (BHB) ...........................................................81
7.8.2.6
Urine ketone ...............................................................................................82
7.8.3
Vital signs.......................................................................................................82
7.8.4
ECG ................................................................................................................82
7.8.5
Others .............................................................................................................83
8
REFERENCES.....................................................................................83
9
9.2
SPECIAL SEARCH CATEGORIES AND ATC LEVELS FOR 
CONCOMITANT MEDICATION ..................................................................84
10
HISTORY TABLE...............................................................................90


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LIST OF TABLES
.....................16
.....................22
Table 6.2: 1
Important protocol violations..........................................................................29
Table 6.3: 1
Patient Sets Analysed ......................................................................................35
36
Table 6.7: 1
Endpoint specific follow-up period for the assignment to active treatment....48
Table 6.7: 2
Time windows for HbA1c measurements at scheduled visits after 
randomisation...................................................................................................................49
Table 6.7: 3
Time windows for blood pressure measurements at scheduled visits after 
randomisation...................................................................................................................50
..................................................84
..................................................85
..................................................87
..................................................89
Table 10: 1
History table ....................................................................................................90


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2
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ASA
Acetylsalicylic acid
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical classification
AUC
Area under the curve
BHB
Beta-hydroxybutyrate
BI
Boehringer Ingelheim
BIcMQ
BI-customised MedDRA query
BMI
Body mass index
CEC
Clinical event committee
CRF
Case report form
CSII
Continuous subcutaneous insulin infusion
CT
Concomitant therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBP
Diastolic blood pressure
DKA
Diabetic Ketoacidosis
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DST
Daylight saving time
ECG
Electrocardiogram
eCRF
Electronic case report form
e-diary
Electronic diary
EMA
European medicines agency
eGFR
Estimated glomerular filtration rate
EoT
End of treatment
FAS
Full analysis set
FPG
Fasting plasma glucose


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Term
Definition / description
GI
Genital infection
HbA1c
Glycated haemoglobin
HCRU
Health care resource utilisation
HLT
High level term
ICH
International Conference on Harmonisation
IPV
Important protocol violation
ITT
Intention to treat
IVRS
Interactive Voice Response System
LOCF
Last observation carried forward
MAGE
Mean amplitude of glucose excursions
MDG
Mean daily glucose
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified intention to treat
MMRM
Mixed model for repeated measures
NCF
Non-completers considered failure
O*C
Oracle Clinical
OC
Observed cases
OC-AD
Observed cases – all data
OC-H
Observed cases – excluding anti-hypertensives
OC-OffT
Observed cases – off-treatment
OC-P
Observed cases – excluding paracetamol
OR
Original results
PG
Plasma glucose
PK
Pharmacokinetics
PPS
Per protocol set
PT
Preferred term
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
RS
Randomised set
SBP
Systolic blood pressure


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Term
Definition / description
SCR
Screened set
SD
Standard deviation
SMQ
Standardised MedDRA query
SOC
System Organ Class
SSC
Special search category
TBL
Total bilirubin
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
UTI
Urinary tract infection
WHO
World health organisation


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3
INTRODUCTION
As per the ICH E9 guideline (1), the purpose of this document is to provide a more technical 
and detailed elaboration of the principal features of the analysis described in the protocol, and 
to include detailed procedures for executing the statistical analysis of the primary and 
secondary variables and other data.
The Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
SAS Version 9.4 or later version will be used for all analyses.


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4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY
This TSAP assumes familiarity with changes made via Protocol Amendments, and therefore 
these changes are not listed here.
The derivation for total daily insulin dose will be based on 14 days prior to the visit rather 
than 7 days as specified in the CTP.
The back-up covariance structures, to be tested in the event that an MMRM analysis fails to 
converge using an unstructured covariance structure, have been updated to better fit the trial 
design and account for unequally spaced visits. Rather than testing compound symmetry and 
variance components, the following covariance structures will be tested instead:  Ante-
dependence ANTE(1), heterogeneous Toeplitz (TOEPH) and first-order autoregressive 
(AR(1)). Toeplitz (TOEP) will continue to be tested as planned.
Changes/adaptations included in the revised version of the TSAP:
 
 

Multiple imputation analysis for body weight and blood pressure will include baseline 
body weight and/or blood pressure respectively as additional effect.
 
 
 


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5
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint in this study is the change from baseline in HbA1c (%) at 26 weeks.
For the definition of baseline HbA1c refer to Section 6.7.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
For baseline definitions for each endpoint, refer to Section 6.7.  
The key secondary endpoints in this study are:

Rate of symptomatic hypoglycaemic AEs with confirmed plasma glucose <54 mg/dL 
(< 3.0 mmol/L) and/or severe hypoglycaemic events confirmed by adjudication per 
patient-year from Week 5 to Week 26.
o
All severe hypoglycaemic AEs that are confirmed by adjudication and all 
investigator reported AEs that have confirmed plasma glucose <54mg/dL 
(<3.0 mmol/L) with symptoms reported will be counted.

Rate of symptomatic hypoglycaemic AEs with confirmed plasma glucose <54 mg/dL 
(< 3.0 mmol/L) and/or severe hypoglycaemic events confirmed by adjudication per 
patient-year from Week 1 to Week 26
o
All severe hypoglycaemic AEs that are confirmed by adjudication and all 
investigator reported AEs that have confirmed plasma glucose <54mg/dL 
(<3.0 mmol/L) with symptoms reported will be counted.

Change from baseline in body weight (kg) at 26 weeks

Change from baseline in total daily insulin dose, U/kg, at 26 weeks

Change from baseline in systolic blood pressure (SBP), mmHg, at 26 weeks

Change from baseline in diastolic blood pressure (DBP), mmHg, at 26 weeks
5.2.2
Secondary endpoint
Since there are no secondary endpoints specified in the protocol, this section is not 
applicable. 


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5.4.9
Safety data
In addition to the standard adverse event attributes, laboratory endpoints, and vital signs the 
following safety endpoints will be analysed:

Change from baseline in lipid profile parameters. Lipid profile consists of total 
cholesterol, HDL cholesterol, LDL cholesterol, LDL/HDL cholesterol ratio, non-HDL 
cholesterol, triglycerides, free fatty acids, Apo A-1, and Apo B.


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6
GENERAL ANALYSIS DEFINITION
6.1
TREATMENTS
There will be six treatment phases in this trial: screening, T1DM therapy optimisation, 
placebo run-in, study treatment phase (with either BI-drug or matching placebo), post-
treatment and post-study, as follows.

The screening period starts from the date of informed consent and ends on the day 
before the start date of the T1DM therapy optimisation period.

The T1DM therapy optimisation period begins with the start date of the insulin 
therapy optimisation visit (Visit 2) up to the day before the date of first administration 
of placebo run-in medication (inclusive).

The placebo run-in period begins from the date of first administration of placebo run-
in medication up to the day before the date of first administration of randomised study 
medication (inclusive).

The on-treatment period begins from the date of first administration of study 
medication up to last intake of study drug + X days (inclusive) [see definition of X in 
Table 6.7: 1].

The post-treatment period begins from the last intake of study drug + X days + 1 day 
up to the last contact date (inclusive). The last contact date is defined as the maximum 
of (trial completion date, and [last study drug intake + X days + 1 day].

The post-study period begins from the last contact date +1 day and ends at trial 
database lock date. 
For efficacy and safety analyses, measurements will still be considered on-treatment during a 
follow-up period (X days) specific to each parameter. These follow-up periods are defined in 
Table 6.7: 1.
The efficacy analyses will follow the intention-to-treat (ITT) principle in assigning patients to 
treatment groups, i.e. patients will be analysed as randomised.
Safety analyses will assign patients to the treatment group as randomised.
If a patient erroneously receives the wrong trial drug, the patient will be analysed as 
randomised. In addition, AEs with an onset during the time of the incorrect study treatment 
will be tabulated and listed separately.
6.2
IMPORTANT PROTOCOL VIOLATIONS (IPVS)
There are two aspects that qualify a violation of the protocol to be important.
First, there are PVs that potentially affect the rights or safety of study patients. In this case, 
the sponsor needs to react immediately to such PVs to prevent recurrence. In most cases, 
these PVs do not have an impact on whether a patient can be included in an analysis, but they 
need to be described in the report.


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Second, a PV can potentially influence the primary outcome measure for the respective 
patients in a way that is neither negligible nor in accordance with the study objectives. 
Therefore, such PVs potentially affect the main study results and conclusions. This second 
category of important PVs forms the basis for the decision (during the DBL meeting) of 
whether a patient does or does not belong to an analysis set. All other PVs are of minor 
importance and it is not necessary to describe or list these PVs in the integrated clinical trial 
report (CTR).
The following table defines the different categories of IPVs. The final column describes 
which IPVs will be used to exclude patients from the Per Protocol analysis Set (PPS).
Table 6.2: 1
Important protocol violations
Category/Code
Description
Example/Comment
Excluded from
A
Entrance criteria not 
met
A1
Target indication not 
met
A1.02
Antidiabetic background 
therapy not as required
Inclusion criteria 4 not met
(No insulin recorded on eCRF 
Or
Total daily insulin dose < 0.3 U/kg or >1.5
U/kg at visit 1#
Or
MDI patients: fewer than 1 basal and 3 bolus 
injections per day at visit 1#
CSII patients: fewer than 5 months experience 
of using the pump prior to Visit 1#).
PPS
A1.03
No Type 1 Diabetes
Inclusion criteria 2 not met, with no date of 
diabetes mellitus type 1 first diagnosed 
known.
PPS
A1.05
Time since diagnosis out 
of range
Inclusion criteria 2 not met, with a date of 
diagnosis < 1 year prior to Visit 1.
PPS
A2
Inclusion criteria not 
met
A2.01
HbA1c out of range
HbA1c <7.3% or > 10.2% at Visit 5
Or
HbA1c increase > 0.5% from Visit 1 to Visit 5.
PPS
A2.02
Age out of range
Inclusion criteria 7 not met
Or 
Age < 18 years at Visit 1.
All


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Table 6.2: 1
Important protocol violations (continued)
Category/Code
Description
Example/Comment
Excluded from
A2.03
BMI out of range
Inclusion criteria 8 not met
Or
BMI <18 kg/m2 at Visit 1.
None
A2.04
eGFR out of range
Inclusion criteria 9 not met
Or
eGFR < 29.5 mL/min/1.73m2 according to 
CKD-EPI formula based on creatinine value at 
Visit 1.
Central laboratory values will be used to 
determine whether INC<9> is not met.
PPS
A2.06
Fasting C-peptide out of 
range 
Inclusion criteria 3 not met
Or
Fasting C-peptide ≥ 0.7 ng/mL at Visit 2.
PPS
A3
Exclusion criteria not 
met
A3.02
Additional background 
therapy
Exclusion criteria 3 checked
Or
Any antihyperglycaemic drug (e.g. metformin, 
AGI, GLP-1 analogues, SGLT-2 inhibitors, 
pramlintide, inhaled insulin, pre-mixed 
insulins etc.) except subcutaneous basal and 
bolus insulin recorded on eCRF within 3 
months prior to Visit 1#.
PPS
A3.03
Relevant concomitant 
diagnoses
Exclusion criteria 4, 5, 7, 9 or 15 checked
Or
Any of the following:

Severe hypoglycaemia involving coma 
and/or seizure that required 
hospitalisation or hypoglycaemia related 
treatment by an emergency physician or 
paramedic within 3 months prior to Visit 
1 and until randomisation#.

Occurrence of DKA within 3 months 
prior to Visit 1 and until randomisation#.

Acute coronary syndrome (non-STEMI, 
STEMI and unstable angina pectoris), 
stroke or transient ischaemic attack (TIA)
within 3 months prior to Visit 1#.

Diagnosis of brittle diabetes.

Medical history of cancer within the last 5 
years prior to Visit 1 (except resected 
basal cell carcinoma) #.
None


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Table 6.2: 1
Important protocol violations (continued)
Category/Code
Description
Example/Comment
Excluded from
A3.05
Blood dyscrasias or any 
disorder causing 
haemolysis or unstable 
red blood cell count
Exclusion criteria 16 checked
Or
Relevant diagnosis (e.g. malaria, babesiosis, 
haemolytic anaemia) at Visit 1#.
PPS
A3.06
Indication of liver 
disease
Exclusion criteria 10 checked
Or
ALT, AST or alkaline phosphate > 3*ULN at 
Visit 1 or Visit 5.
None
A3.10
Treatment with protocol 
excluded systemic 
steroids or recent change 
in thyroid hormone dose
Exclusion criteria 13 or 14 checked
Or
Treatment with systemic steroids or planned 
initiation of such therapy at Visit 1 and until 
randomisation# (excluding inhaled or topical 
use of corticosteroids).
Or
Change in dose of thyroid hormone within 6 
weeks prior to Visit 1 or planned change or 
initiation of such therapy at Visit 1 and until 
randomisation#.
Final decision at DBL meeting based on 
medical judgment.
PPS
A3.11
Intake of other 
investigational drug in 
another trial within 30 
days prior to intake of 
study medication in this 
trial
Exclusion criteria 19 checked
Or
Intake of another investigational drug in 
another trial within 30 days prior to Visit 1#.
Final decision at DBL meeting based on 
medical judgment.
PPS
A3.12
Specific exclusion 
criterion for pre-
menopausal women 
violated
Exclusion criteria 17 checked
Or
Positive pregnancy test or nursing at Visit 1 
and until randomisation#.
None
A3.13
Relevant alcohol or drug 
abuse and other 
conditions affecting 
study compliance
Exclusion criteria 18 checked
Or
Alcohol or drug abuse within 3 months prior 
to Visit 1#.
None


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Table 6.2: 1
Important protocol violations (continued)
Category/Code
Description
Example/Comment
Excluded from
A3.14*
Any other clinical 
condition unsafe for 
participation that would 
jeopardise patient safety 
while participating in this 
clinical trial
Exclusion criteria 21 checked
None
A3.21
History of T2DM, 
maturity onset diabetes 
of the young (MODY), 
pancreatic surgery or 
chronic pancreatitis
Exclusion criteria 1 checked
Or
Relevant condition listed as baseline condition 
in eCRF#.
PPS
A3.22
Diagnosis of severe 
gastroparesis
Exclusion criteria 8 checked
Or
Relevant diagnosis recorded as a baseline 
condition in the eCRF#.
PPS
A3.23
Eating disorders
Exclusion criteria 11 checked
Or
Diagnosis of eating disorder such as bulimia 
or anorexia nervosa listed as a baseline 
condition in the eCRF#.
PPS
B
Informed consent
B1
Informed consent not 
available
Inclusion criteria 1 not met
Or
Informed consent date missing#.
All
B2
Informed consent too late
Informed consent date was after Visit 1 date 
or after any study related procedure.
None
B3
Informed consent not 
available for substudy
No informed consent for the CGM substudy 
was obtained.
All CGM 
analyses
B4
Informed consent too late
for substudy
The informed consent for the CGM substudy 
was obtained too late.
None
C
Trial medication and 
randomisation
C1
Incorrect trial 
medication


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Table 6.2: 1
Important protocol violations (continued)
Category/Code
Description
Example/Comment
Excluded from
C1.02*
Incorrect trial medication 
taken
Wrong medication taken (different medication 
than the patient was randomised to i.e. drug 
kit recorded in eCRF is from a different 
treatment group than the drug kit assigned by 
IxRS) for more than 20% of the overall 
treatment duration or for more than 20% of 
the last visit interval before the primary 
endpoint assessment.
Can only be judged after DBL as requires 
unblinding information.
PPS
C2
Randomisation not 
followed
C2.01
Treated without 
randomisation
Patient treated according to eCRF, but not 
randomised according to IVRS.
RS, FAS, PPS
C3
Non-compliance
C3.01
Non-compliance with 
study drug intake
Overall compliance <80% or >120% from 
visit 6 onwards or since last visit prior to 
primary endpoint <80% or missing. For the 
calculation of compliance, refer to Section 7.3.
PPS
C4
Medication code 
broken
C4.01*
Medication code broken 
without just cause
Medication code broken whilst on-treatment 
without valid reason.
Final decision at the DBL meeting based on 
medical judgment.
PPS
D
Concomitant 
medication
D2
Prohibited medication 
use
D2.01*
Use of prohibited 
medication during 
treatment period
Review of eCRF for contraindicated drugs.
Final decision at the DBL meeting based on 
medical judgment.
PPS
I
Other safety related 
violations
I2
Pregnancy monitoring
I2.01
Pregnancy test not done 
for woman of child 
bearing potential for at 
least one visit before 
treatment discontinuation
Positive pregnancy test at any post-
randomisation visit
Or
Pregnancy during the trial#.
None
I2.03*
Nursing
Nursing during the trial.
None
# Criteria to be checked manually and inclusion/exclusion criteria changed if violated.
* Manual IPV (e.g. IPV that is too complex to program or cannot be detected through the data stored in the trial database).


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6.3
PATIENT SETS ANALYSED

Screened set (SCR):
This patient set includes all patients screened for the trial, with informed consent given and 
who completed at least one screening procedure at Visit 1.

Randomised set (RS):
This patient set includes all patients from the screened set who were randomised to study 
drug, regardless of whether any study drug was taken.

Treated set (TS):
This patient set includes all patients who are treated with at least one dose of randomised 
study drug. The TS is the basis for safety analyses.

Full analysis set (FAS):
This patient set includes all randomised patients who are treated with at least one dose of 
study drug, have a baseline HbA1c and at least one on-treatment HbA1c measurement. The 
FAS is the basis for the primary efficacy analysis.

Modified Intention-to-Treat Set (mITT):
This patient set includes all randomised patients who are treated with at least one dose of 
study drug, have a baseline HbA1c and at least one post baseline HbA1c measurement. The 
mITT is the basis for the primary effectiveness analysis.

Per protocol set (PPS):
This patient set includes all patients in the FAS who do not have any IPV which can be 
expected to have a distorting influence on the assessment of the primary endpoint. IPVs are 
detailed in Table 6.2: 1.


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Table 6.3: 1
Patient Sets Analysed
Patient set
Class of endpoint
SCR
TS
RS
mITT
FAS
PPS
Disposition
OR
Demographics
OR1
OR
Baseline variables
OR
Background 
total daily insulin 
dose/concomitant 
medications
OR
Concomitant 
diagnoses/relevant 
medical history
OR
Exposure/
compliance
OR
Primary endpoint
 
 
Primary 
effectiveness 
analysis (OC-AD)
Primary efficacy 
analysis (OC)
 
Key secondary 
endpoints: hypos
 
Primary analysis
(OC)
Key secondary 
endpoint: body 
weight, TDID
 
Primary (OC) &
Key secondary 
endpoint: SBP, DBP
 
Primary (OC-H) 
 
 
Safety endpoints 
OR
SCR=screened set, RS=randomised set, mITT=modified intention-to treat set, FAS=full analysis set, PPS=per protocol set. Patient sets are 
defined in Section 6.3. 
OR=original results, OC=observed cases, OC-AD=observed cases-all data, OC-P=observed cases excluding paracetamol, OC-H= observed 
cases excluding anti-hypertensives, MI=multiple imputation, PMM=pattern mixture model, NCF=Non-completers considered failures. 
Handling of missing data is described in Section 6.6.
1 Presented in 16.1.9.2 for EudraCT
2 MI and PMM are applied to all randomised patients with a baseline measurement.


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6.5
POOLING OF CENTERS
For descriptive statistics by centre, data from small centres within the same country will be 
pooled. The data from centres with fewer than 8 patients will be combined into the category 
'Fewer than 8 patients' for each individual country that has centres with fewer than 8 patients. 
Analysis to explore centre effects includes the calculation of descriptive statistics of the 
primary endpoint.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Based on the different reasons of patients' data missing for different endpoints, various 
methods will be used to assess the impact of missing data on the efficacy endpoints of this 
trial, depending upon the type of the endpoint.
6.6.1
Imputation methods
6.6.1.1
Original results (OR) analysis
Original result analysis implies the analysis of data exactly as observed. OR analysis will be 
performed on endpoints where it is not meaningful to apply any imputation rule on them for 
replacing missing values.
6.6.1.2
Observed cases (OC) analysis
For all efficacy endpoints, it is planned to analyse only the available data that were observed 
while patients were on-treatment, i.e., excluding the missing data and any values collected 
after treatment discontinuation. In other words, OC-analysis will be performed and missing 
data in the analysis will not be replaced.
The OC-technique represents the primary data selection tool that will be used for the primary 
efficacy analysis in this trial. Subsequent handling of missing data will be performed via a 
likelihood-based method, and in the case of the primary analysis, will use the mixed-effect 
model repeated measures (MMRM).
For blood pressure endpoints (SBP and DBP), the OC-technique will be adapted to set values 
measured after a change in antihypertensive therapy to missing. This technique will be called 
Observed Cases without values following a change in antihypertensive therapy (OC-H). The 
following 3 situations are considered to be the start of a change in anti-hypertensive therapy:

Initiation of additional antihypertensive medication

Change in dose of antihypertensive medication

Discontinuation of antihypertensive medication
Antihypertensive medications will be identified based on WHO DD special search categories 
as specified in Section 9.2.
 
 
 
 
 
Concomitant therapies containing paracetamol will be identified using a WHO DD BI 
customized query (BIcQ) based on Preferred Name (PN) "Paracetamol". This includes all 
monotherapy and fixed dose combinations (FDC).
Values for total daily insulin dose at each visit will be calculated as the mean total daily dose 
over the 14 days immediately prior to the visit (excluding the visit day). If there are <4 days 


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of valid insulin data during the 14 day period, the mean will not be calculated and the visit 
value will be set to missing. The same rule will apply for total daily bolus, total daily basal 
and number of injections per day endpoints as well. Subsequent handling of missing data will 
be performed via a likelihood-based method and will use the mixed-effect model repeated 
measures (MMRM).
6.6.1.3
Observed cases - all data (OC-AD) analysis
Additionally, it is planned to perform effectiveness analyses including all available data that 
were observed, i.e. both on- and off-treatment values. Missing data in the analysis will not be 
replaced. Subsequent handling of missing data will be performed via a likelihood-based 
method and will use the mixed-effect model repeated measures (MMRM).
For blood pressure endpoints, data after a change in anti-hypertensive therapy will not be 
excluded.
 
 
 
A similar approach will be applied to insulin endpoints if both on- and off-treatment data is 
available in the 14 days prior to a visit.
For pulse rate, the OC-AD imputation will be used to present descriptive statistics analyses. 
For blood pressure endpoints, the OC-AD imputation will serve for descriptive statistics and 
sensitivity analyses.
6.6.1.4
Observed cases - Off Treatment (OC-OffT) analysis
 
 
6.6.1.5
Last observation carried forward (LOCF)
An alternative method for quantitative endpoints is to replace missing values of a patient by 
his/her last observed measurement on-treatment.
The last observation on-treatment need not necessarily be a value selected as a visit value if 
multiple measurements were performed within a time window for a visit. In this case the last 
on-treatment value within the time window will be carried forward, while the visit value can 
be the value that was observed closest to the planned visit date or the first value observed in 
the time window. See Table 6.7: 2 for further details.
Missing values within a course of measurements on-treatment will be interpolated based on 
the last observed value before the missing visit and the first observed value after the missing 
visit. This is independent from the selection of a value as the picked visit value to be used in 
the descriptive analysis by visit (as described in Section 6.7).
Let:


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D0 = date of a visit with a missing endpoint value;
D1 = date of the next visit (with endpoint value non-missing) after the visit with missing 
endpoint;
D-1 = date of the previous visit (with endpoint value non-missing) before the visit with 
missing endpoint;
Ei = endpoint values for visits Di for i= -1, 0 and 1
Then the missing endpoint value can be interpolated as:
E0 = E-1 + ((E1 - E-1) x (D0 - D-1) / (D1 - D-1)).
Missing data will only be imputed up to the planned visit to be reached by all randomised 
patients (week 26).
If there are no on-treatment measurements, the value from pre-treatment or baseline will not 
be carried forward to populate the missing on-treatment values according to the FAS 
definition.
6.6.1.6
Multiple imputation (MI)
A multiple imputation approach will be used as a sensitivity analysis for the primary 
endpoint. Further details can be found in Section 7.4.2.
6.6.1.7
Non-completers considered failure (NCF)
For binary endpoints, like the occurrence of a response, a conservative method to replace 
missing values is to consider them as "failures". Off-treatment values will be set to missing. 
Missing data due to early discontinuation of treatment per the completer definition will be 
replaced as "failure" (e.g. non-responder) up to the planned timepoint for the analysis. 
6.6.2
Safety and other variables
Missing safety data will not be replaced. 
An analysis of the changes from baseline to the last available value under treatment and the 
minimum and maximum post baseline will be determined for quantitative safety laboratory 
variables.
6.6.3
Missing dates and times
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (6).
If the date of first drug administration is missing but the patient was randomised, the date of 
the first drug administration will be set to the date of randomisation. If the date of first 
administration is partially missing with the month and year present, the day will be set to the 
date of randomisation if randomisation was in the same month. If randomisation was in the 
month prior to the first drug administration the missing day will be imputed as the first day of 
the month.


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A missing time of first drug administration will be imputed as 08:00 o'clock in the morning, 
missing administration times at on-treatment visits will be imputed by 08:00 o'clock in the 
morning.
As a general rule a missing drug stop date will be imputed according to the following 
principles:

If an End of Treatment (EoT) visit or visit 11 is documented, it should be the date of 
the EoT visit.

If the date is incomplete with only month and year and the EoT visit is missing, it 
should be the first day of the following month.

If the patient is lost to follow-up it should be the date of the last visit + the longest 
treatment duration based on drug supply + 1 day. 

If a patient died during the course of the trial and no additional information about 
drug stop date are available, the date of death will be used as drug stop date assuming 
that the patient took the medication until the day of death.

All other cases need to be assessed by the trial team on an individual basis, trying to 
use the points above as guidance.
If only the year of birth is known, the day and month of birth will be imputed as 01 January.
For partial start and stop dates for concomitant therapies (CT) the following derivations will 
be used to impute 'worst case' values:

If the day of the end date is missing then the end date is set to last day of the month.

If the day and month of the end date are missing then end date is set to 31st December 
of the year.

If the day of the start date is missing the start date is set to first day of the month.

If the day and month of the start date are missing then the start date is set to 1st 
January of the year.
For other incomplete date information (except to assess the overall compliance, see below) 
always the midpoint of the possible interval will be used. If only the year is present the day 
and month will be imputed as 01 July, if year and month is present the day will be imputed as 
15. If the year is missing, the date will be considered missing.
In case of missing visit date for a compliance record, the following hierarchy will be used to 
select a date to impute the missing visit date: 

The visit date registered in the IRT system

The date of the vital sign measurement

The date of the safety laboratory sampling 

The start date of the CGM period (only applicable to Visit 11)
All other cases need to be assessed by the trial team on an individual basis, using the above 
points as guidance.


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6.7
BASELINE, TIME WINDOW, AND CALCULATED VISITS
With regard to efficacy and safety endpoints, the term "baseline" refers to the last observed 
measurement prior to administration of any randomised study medication. For specific 
endpoints, baseline definitions are as follows:
Serum beta-hydroxybutyrate (BHB) 

Serum BHB sampled at the site and analysed at the central laboratory
Baseline will be defined as the fasted measurement observed at Visit 6, before first drug 
intake.

Capillary patient self-measured BHB via the ketone meter and reported in the diary
For the analysis on morning or daily measurements (see Section 7.8.2.5), baseline will be 
defined as the mean of morning or daily measurements reported during the run-in period, 
respectively (Visit 5 to Visit 6, including the day of first administration of trial drug).
 
Hypoglycaemia rate
The event rate of hypoglycaemia (using the respective endpoint definition) during the 4 
weeks prior to randomisation (from Day -28 up to Day -1). Collapsing will be performed as 
per the rules in Sections 5.4.6.3 and 5.4.7. Rates will be presented per 30 days and also per 
patient year.
Insulin dose (total daily, total daily basal or total daily bolus)
Mean daily insulin requirement during the run-in period (Visit 5 to Visit 6, excluding day of 
randomisation). If < 4 days of valid insulin data is reported during the run-in period then the 
measurement will be considered missing. For data handling rules see Section 5.4.6.2.
 
 
 
 


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Table 6.7: 1
Endpoint specific follow-up period for the assignment to active 
treatment 
Endpoint
Last day of assignment to treatment phase
(days after study drug stop date)
Efficacy
HbA1c
7
FPG
1
MDG
1
CGM
*
Body weight
1
Blood pressure
1
Waist circumference
7
Insulin dose
0
Hypoglycaemia
1
UACR
1
Health economics and QoL
1
Safety
Adverse events
7
Hypoglycaemia [1]
1
Hepatic injury [2]
30
Safety laboratory measurements
3
AST/ALT/TBL [3]
30
Pulse rate
1
*Refer to Section 5.4.4 for the assignment of CGM measurements to the on-treatment period
[1] Refer to all hypoglycaemia analyses except the general hypoglycaemia AE analysis by SOC and PT. 
[2] Refer to a sensitivity analysis including all hepatic injuries with an onset date up to 30 days after the study 
treatment stop (see Section 7.8.1.4).         
[3] Refer to a sensitivity analysis on elevated liver enzymes, for which events with an onset date up to 30 days 
after the study treatment stop will be included in the analysis.
Measurements taken after the last intake of study drug and after the end of the endpoint 
specific follow-up period will be considered off-treatment values.
Efficacy, safety, 
 will be assigned to visits based on 
time windows around the planned visit dates. These time windows are defined based on the 
planned number of days after the date of first administration of study drug (see Table 6.7: 2).


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Table 6.7: 2
Time windows for HbA1c measurements at scheduled visits after 
randomisation
Time window (actual days on 
treatment)
Visit number
Visit label
Planned days
Start
EndA
6
Baseline
0
NA
1B
8
Week 4
28
2
56
9
Week 12
84
57
105
10
Week 18
126
106
154
11
Week 26
182
155
Study drug stop 
date + X days
A  In case of premature discontinuation of the study drug an eEOT visit has to be performed. 
Measurements from the eEOT visit will be assigned to the appropriate visit according to the table. In 
this case the time window for the visit that includes the eEOT visit will end X days after the study drug 
stop date, including Day X. The definition of X is endpoint specific, cf. Table 6.7: 1. Patients will then 
be asked to continue in the study according to the visit schedule. Off-treatment measurements will be 
assigned to visits in the same manner. No time window for optional visit is planned.   
B     Only values taken prior to the start of treatment with randomised study drug can be considered baseline 
values. Time windows will be used for assignment of measurements to scheduled visits. 
The mid-point between two visits defines the end of a time window, with the midpoint being 
included in the time window of the preceding visit. The end of the time window of the last 
on-treatment visit (end of treatment (EoT)) is endpoint dependent (cf. Table 6.7: 1). As 
endpoints are planned to be measured according to different visit schedules, this midpoint 
algorithm will be applied and the time windows modifed accordingly. 
For example, the time windows for the blood pressure endpoints have been detailed in Table 
6.7: 3.


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Table 6.7: 3
Time windows for blood pressure measurements at scheduled visits 
after randomisation
Time window (actual days on 
treatment)
Visit number
Visit label
Planned days
Start
EndA
6
Baseline
0
NA
1B
7
Week 1
7
2
17
8
Week 4
28
18
56
9
Week 12
84
57
105
10
Week 18
126
106
154
11 EOT
Week 26/EoT
182
155
Study drug stop 
date + X days
A  In case of premature discontinuation of the study drug an eEOT visit has to be performed. 
Measurements from the eEOT visit will be assigned to the appropriate visit according to the table. In 
this case the time window for the visit that includes the eEOT visit will end X days after the study drug 
stop date, including Day X. The definition of X is endpoint specific, cf. Table 6.7: 1. Patients will then 
be asked to continue in the study according to the visit schedule. Off-treatment measurements will be 
assigned to visits in the same manner. No time window for optional visit is planned.   
B     Only values taken prior to the start of treatment with randomised study drug can be considered baseline 
values. Time windows will be used for assignment of measurements to scheduled visits. 
For insulin endpoints, as data is available on an ongoing basis, a value will be derived using 
the 14 days prior to drug stop date and time windowing will be applied as outlined above 
based on the drug stop data. Only data from within the visit window will be used to derive the 
visit value.
 
 


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Repeated and unscheduled efficacy and safety measurements will be assigned to the nominal 
visits and listed in the subject data listings according to the time windows described above. 
Only one observation per time window will be selected for analysis. For OC analyses, only 
on-treatment values will be considered. For OC-AD analyses, both on- and off-treatment 
values will be considered. If there are multiple values within a time-window, the value closest 
to the protocol planned visit day will be selected. If there are two observations which have 
the same difference in days to the planned day or if there are two observations on the same 
day, the earliest value will be used. If an observation is available on the last day of treatment, 
this observation will be preferably selected over any later observation that is still within the 
time window. If there are multiple values within the time window of the last visit, including a 


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value on the last day of drug intake, the value on the last day of drug intake is used as the 
value of the last visit.
For pre-treatment time points, data will be assigned to nominal visits. Unscheduled visits will 
only be considered if the data would otherwise be missing for that time point.
Data prior to randomisation will be based on nominal visits and time windowing will not be 
applied.  For these time points, data from the scheduled visit will always be selected. 
Unscheduled visits will only be considered if no data from the scheduled visit is available. If 
no data from a scheduled visit is available and multiple unscheduled values are available for a 
visit, the first value will be selected.
For standard descriptive tables of laboratory parameters by visit (created by the BI standard 
macro XLAB2), in case of multiple measurements within a post-baseline time window for a 
visit, the worst value of these multiple measurements will be used for calculations.
Note: for LOCF imputation, the last observed on-treatment value will be carried forward, 
whether or not it was selected in the previous time window. Also for interpolation any valid 
values can be used, regardless of whether they were selected as visit values. For more details 
on LOCF refer to Section 6.6.


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7
PLANNED ANALYSES
Disposition of the patient population participating in the trial will be analysed by treatment 
groups and presented in the clinical trial report as a frequency-distribution. 
The number of patients participating (screened, randomised, screened but not randomised, 
etc.) in the study by region, country and, for treated patients, centre, will also be analysed by 
treatment group and presented as a frequency distribution. The reason for not randomising 
screened patients will also be summarised. See Table 9.1: 1 for assignment of countries 
within region.
In addition, the number of patients who discontinued trial medication due to fatal and non-
fatal adverse events will be displayed in Appendix 16.1.9.2, as well as the number of 
screened patients by country and the number of screened patients by age groups. These 
analyses will be done for public data disclosure on European Union Drug Regulating 
Authorities Clinical Trials (EudraCT).
A summary of the number of patients in each randomisation stratum per treatment will also 
be shown. This summary will be based upon the data received from the IxRS provider.
For efficacy analyses, patients will be analysed according to the stratum to which they belong 
(regardless of any mis-assignment based on identification of the wrong stratum). For patients 
who were mistakenly randomised on both MDI and CSII at baseline, the stratification factor 
from IxRS will be used.
A frequency of patients with IPVs, also summarised by whether the IPV led to exclusion 
from the PPS, will be presented by treatment group for the randomised set. The frequency of 
patients in different analysis sets will also be analysed for each treatment group.
For in-text tables presenting descriptive analysis of the endpoints and other variables 
(analysed in original scale), the set of summary statistics is: N (number of patients with non-
missing values), mean, standard deviation (SD).
For End-Of-Text (EoT) tables, the set of summary statistics is: N (number of patients with 
non-missing values) / Mean / SD / standard error (SE) / Min / Q1 (lower quartile)/ Median / 
Q3 (upper quartile)/ Max. 
For the in-text, end-of-text and appendix tables presenting descriptive analysis of the 
endpoints and other variables (analysed on logarithmic scale), the respective summary 
statistics (e.g., gMean, gCV, etc.) will be used.
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline "Reporting of Clinical Trials and Project Summaries" (7).
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.


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Treatment comparison
In all specified statistical analyses, treatment comparisons will be made between each 
randomised Empagliflozin group (2.5, 10 and 25 mg) and placebo. 
7.1
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
7.1.1
Baseline evaluation
Descriptive analysis of the following demographic variables measured at baseline will be 
presented:
Sex, race, ethnicity, region, age (years), age-groups, BMI (kg/m^2) categories, height (cm), 
smoking history and alcohol status, time since diagnosis of diabetes (years) (continuous and 
in categories), eGFR by CKD-EPI creatinine equation (continuous and in categories) and 
eGFR by CKD-EPI creatinine-cystatin C (continuous and in categories). 
See Section 7.8.2.4 for details on the derivation of eGFR endpoints.
Descriptive analysis of the following variables measured at baseline will be presented:
HbA1c (%) (continuous and in categories), FPG (mg/dL) (continuous and in categories), 
weight (kg) (continuous and in categories), waist circumference (cm), blood pressure 
(mmHg) (continuous and in categories), UACR (mg/gcrea) (continuous and in categories), 
fasted serum BHB (mmol/L) (continuous and in categories), capillary daily patient self-
measured BHB (mmol/L) (continuous and in categories) and capillary morning patient self-
measured BHB (mmol/L) (continuous and in categories).
Baseline hypoglycaemia rates will be presented in a separate table, displaying both the rate 
(per 30 days) and the frequency (from day -28 to day -1, inclusive) of 'severe hypoglycaemia 
events confirmed by adjudication' and 'symptomatic hypoglycaemia AEs with confirmed 
plasma glucose <54mg/dL and/or severe hypoglycaemia events confirmed by adjudication'. 
For the rates, the statistics will include the number of patients overall (N), the number of 
patients with at least 1 event (Nh), mean, SD, SE, min, 5th percentile (P5), P10, P25, median, 
P75, P90, P95, and max.
 
 
 
Categories for baseline characteristics are defined in Section 6.4.
Demographic and baseline characteristics tables will be presented on the FAS.
The demographic analysis will be repeated on the randomised population in Appendix 
16.1.9.2 for disclosure on EudraCT.
 
 


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report using the FAS.


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Concomitant medication use will be summarised by Anatomical-Therapeutic-Chemical 
classification level 3 (ATC3) and preferred name. Summaries will be presented for 
concomitant therapies taken during randomised treatment and those taken at baseline. 
Separate summaries of use of antihypertensives, ASA or lipid lowering drugs at baseline by 
preferred name will be presented. The displayed categories and defining ATC levels and 
ATC codes are shown in Table 9.2: 1.
Background pre-existing insulin therapy, including a categorisation of patients using MDI 
versus CSII will be presented. This summary will include background total daily insulin dose 
at baseline in insulin 'unit' and ‘units/kg’ as units of insulin per kg body weight at baseline. 
The table will also display the total daily basal insulin dose and the total daily bolus insulin 
dose at baseline. The number of insulin injections at baseline will be presented for MDI 
patients.
Concomitant diseases will be summarised by MedDRA System Organ Class (SOC) and 
preferred term (PT). Relevant diabetic medical history will also be presented by treatment 
group.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
Frequency distribution of patients with an overall compliance between 80% and 120% 
(inclusive) will be reported, as well as patients outside this range.
The overall compliance will be calculated as a weighted average of reported compliance. The 
sum of all reported compliance over the planned visits (disregarding of run-in) will be 
divided by the total duration (until last visit where medication is returned). 
Refer to Section 6.6.3 for how handling a single missing visit date for a compliance record, in 
the overall compliance calculation.
If compliance is missing at more than one on-treatment visit (>1), the overall compliance will 
be set to missing.
If a patient has a temporary treatment interruption, this should be reflected in the calculation 
of compliance.
If a patient prematurely discontinues from treatment, compliance will be calculated until last 
study drug intake. Missing compliance values for off-treatment visits will not be considered 
in the calculation for overall compliance.
The FAS patient set will be considered.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis
The primary endpoint in this trial is the change from baseline in HbA1c (%) at 26 weeks. 
Efficacy and effectiveness will be tested in a hierarchical manner.
The primary efficacy analysis will be performed on the FAS (OC). Patients will be assigned 
to the treatment they were randomised to. Only on-treatment HbA1c values will be included 


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in the primary analysis. Only data up to the Week 26 timepoint will be included. All 
randomised treatment groups will be included in the same analysis. 
Mean changes from baseline in HbA1c after 26 weeks will be analysed using a restricted 
maximum likelihood-based repeated measures approach (MMRM analysis). Analyses will 
include the fixed categorical effects of treatment, pre-existing insulin therapy, week and 
treatment by week interaction, as well as the continuous, fixed covariates of baseline HbA1c, 
baseline eGFR and baseline HbA1c by week interaction. Patient will be included as random 
effect. 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: first-order 
ante-dependence (ANTE(1)), heterogeneous Toeplitz (TOEPH), Toeplitz (TOEP) and first-
order autoregressive (AR(1)). The (co)variance structure converging to the best fit, as 
determined by Akaike’s information criterion, will be used as the primary analysis.
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 = 0.025 (two-
sided 97.5% confidence intervals). The residuals are assumed to have a multivariate normal 
distribution with zero means and covariance matrix as specified above. The primary 
treatment comparisons will be the contrasts between active treatments and placebo at Week 
26.
The statistical model will be:
HbA1c change from baseline = overall mean + continuous baseline HbA1c + pre-existing 
insulin therapy + continuous baseline eGFR + treatment + week + baseline HbA1c by week 
interaction + treatment by week interaction + random error
If the null hypothesis is successfully rejected for the efficacy analysis, then an effectiveness 
analysis will be performed on the mITT (OC-AD), including both on- and off-treatment data. 
The model will be the same as the model for the efficacy analysis described above.
7.4.2
Model diagnostics
In order to check the validity of assumptions used in the primary efficacy and effectiveness 
analysis models, model diagnostics will be performed as follows:

Residuals from the primary model will be checked for normality using a Q-Q plot.

Variance homogeneity across treatment groups, potential outliers and leverage points 
will be inspected using descriptive statistics and graphical methods.
These analyses will be reported in Section 16.1.9.2 of the trial report.
 


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
7.5.1.1
Rate of symptomatic hypoglycaemic AEs with confirmed plasma glucose <54 
mg/dL and/or severe hypoglycaemic events confirmed by adjudication
Confirmatory analysis
The analysis of the rate of symptomatic hypoglycaemic AEs with confirmed plasma glucose 
<54 mg/dL and/or severe hypoglycaemic events confirmed by adjudication will utilise a 
negative binomial model, with terms for treatment, continuous baseline rate, continuous 
baseline HbA1c, continuous baseline eGFR and pre-existing insulin therapy as fixed effects 
and log(time at risk) as an offset.  The results will be presented as a rate per patient-year. This 
analysis will be performed on the FAS (OC).
The baseline rate of symptomatic hypoglycaemic AEs with confirmed plasma glucose < 54 
mg/dL and/or severe hypoglycaemic events confirmed by adjudication will be calculated 
based on the event rate during the 4 weeks prior to randomisation, see Section 6.7.
The analysis of the rate from Week 5 to Week 26 will include all on-treatment events from 
the start of Week 5 (Day 29) until one day after treatment stop date. This period will also 
define the time at risk.
The analysis of the rate from Week 1 to Week 26 will include all on-treatment events from 
the date of first study drug intake until one day after treatment stop date. This period will also 
define the time at risk.


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7.5.1.2
Change from baseline in body weight (kg) after 26 weeks
Confirmatory analysis
The analysis of change from baseline in body weight after 26 weeks will follow the strategy 
for the primary endpoint, MMRM. The model will include the fixed categorical effects of 
treatment, pre-existing insulin therapy, week and treatment by week interaction, as well as the 
continuous, fixed covariates of baseline HbA1c, baseline eGFR, baseline body weight and 
baseline body weight by week interaction. This analysis will be performed on the FAS (OC), 
including all available on-treatment data up to the Week 26 timepoint.
A descriptive statistics table will present body weight (kg) and body weight change from 
baseline over time on the FAS (OC, OC-AD).
The treatment response over the treatment period will be illustrated on the FAS (OC) for each 
visit by plotting the adjusted means (SE) for change from baseline in body weight (kg) at 
each visit based on the MMRM model. A similar graphic will be created plotting the 
descriptive mean body weight (kg) at each visit using the FAS (OC).
 
 
 
 
 
 
 
 
 
 
7.5.1.3
Change from baseline in total daily insulin dose (U/kg) after 26 weeks
Confirmatory analysis
The analysis of change from baseline in total daily insulin dose after 26 weeks will follow the 
strategy for the primary endpoint, MMRM. The model will include the fixed categorical 


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effects of treatment, pre-existing insulin therapy, week and treatment by week interaction, as 
well as the continuous, fixed covariates of baseline HbA1c, baseline eGFR, baseline total 
daily insulin dose  and baseline total daily insulin dose by week interaction. This analysis will 
be performed on the FAS (OC), including all available on-treatment data up to the Week 26 
timepoint. 
The baseline total daily insulin dose will be calculated based on the mean daily insulin 
requirement during the run-in period (Visit 5 to Visit 6). The total daily insulin dose will be 
calculated for each visit, based on the mean daily insulin requirement over the 14 days prior 
to the visit (excluding the day of the visit). If <4 days of valid insulin data is available, the 
visit value will be set to missing. The source data for the total daily insulin dose is the e-diary 
and this does not undergo a cleaning process. For data handling rules, see Section 5.4.6. 
A descriptive statistics table will present total daily insulin dose (U/kg), total daily insulin 
dose absolute change from baseline and total daily insulin dose relative change from baseline 
over time on the FAS (OC, OC-AD).
The treatment response over the treatment period will be illustrated on the FAS (OC) for each 
visit by plotting the adjusted means (SE) for change from baseline in total daily insulin dose 
(U/kg) at each visit based on the MMRM model. A similar graphic will be created plotting 
the descriptive mean total daily insulin dose (U/kg) at each visit using the FAS (OC).
 
 
 
 
 
 
 
 
7.5.1.4
Change from baseline in blood pressure after 26 weeks
Confirmatory analysis
The analysis of change from baseline in blood pressure after 26 weeks will follow the 
strategy for the primary endpoint, MMRM.  The model will include the fixed categorical 
effects of treatment, pre-existing insulin therapy, week and treatment by week interaction, as 
well as the continuous, fixed covariates of baseline HbA1c, baseline eGFR, baseline blood 
pressure and baseline blood pressure by week interaction. This analysis will be performed on 
the FAS (OC), including all available on-treatment data up to the Week 26 timepoint.


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A descriptive statistics table will present blood pressure (mmHg) and blood pressure change 
from baseline over time on the FAS (OC, OC-AD).
The treatment response over the treatment period will be illustrated on the FAS (OC) for each 
visit by plotting the adjusted means (SE) for change from baseline in blood pressure (mmHg) 
at each visit based on the MMRM model. A similar graphic will be created plotting the 
descriptive mean blood pressure (mmHg) at each visit using the FAS (OC).
All analyses will be performed separately for SBP and DBP.
 
 
 
 
 
 
 
 
 
 
 
 
7.5.2
(Other) Secondary endpoint
This section is not applicable as no secondary endpoints have been specified in the protocol. 


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7.7
EXTENT OF EXPOSURE
A descriptive statistics table with mean, SD, median and range of the number of days a 
patient was on treatment will be provided for the treated set. The tables will also provide the 
sum of the total time (in years) that all patients pooled together were on each treatment. 
A separate listing will be created of any patients that switched treatment at any time 
indicating exposure to each treatment.
A frequency table of number and percent of patients belonging to each categorical range of 
exposure weeks will be provided:
> 0 to 1 week, > 1 to 4 weeks, > 4 to 8 weeks, > 8 to 16 weeks, > 16 to 24 weeks, > 24 to 28 
weeks, > 28 weeks. Note that "> 1 to 4 weeks" stands for 8 to 28 days. 
In addition, the following exposure cumulative categories will be provided: 
≥1 day, ≥1 week, ≥4 weeks, ≥8 weeks, ≥16 weeks, ≥24 weeks, ≥28 weeks. Note that "≥1 
week" category refers to 7 days.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set, except one hypoglycaemia analysis 
that will also be performed on the FAS for a sensitivity purpose (refer to Section 7.8.1.5).
7.8.1
Adverse events
AEs will be coded using the latest version of the MedDRA coding dictionary at database 
lock.
Any clinically significant new finding in the physical examination, vital signs (pulse 
symptoms) and in the 12-lead ECG starting after visit 6 (randomisation visit) will be 
considered as an AE and will be reported as such.
Unless otherwise specified (refer to Section 7.8.1.4 for analysis on number of hypoglycaemia 
events, and respectively to Section 7.8.1.5 for analysis on number of DKA events) the 
analyses of adverse events will be descriptive in nature and analyses of AEs will be based on 
the number of patients with AEs (not the number of AEs).
For analysis of AE attributes such as duration, severity, etc. multiple AE occurrence data on 
the CRF, will be collapsed into AE episodes provided that all of the following applies:

The same MedDRA lowest level term was reported for the occurrences.

The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).

In addition certain analyses (other than the general analyses by SOC and PT produced 
by the XAE macro) will have their own collapsing rules. This concerns the following 
endpoints: 
o
Genital infection events will not be collapsed if they are representative of 
different types (i.e. fungal balanitis or vulvovaginitis versus other than fungal 
balinitis or vulvovaginitis);


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o
Sepsis events will not be collapsed if they are representative of different 
sources of infection (i.e. urinary tract (urosepsis) versus other than urinary 
tract);
o
Severe hypoglycaemia endpoint confirmed by adjudication will not be 
collapsed;
o
Hypoglycaemia adverse events will not be collapsed (except in case of 
occurrences with identical onset date, time and glucose value);
o
Lower limb amputation endpoint will not be collapsed

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence.
For further details on summarization of AE data, please refer to (8).
7.8.1.1
Assignment of AEs to treatment
In general, the analysis of adverse events will be based on the concept of treatment emergent 
adverse events. Exceptions are: malignancy events, bone fractures and lower limb amputation 
(see below). This means that all adverse events occurring between first drug intake until 7 
days after last drug intake will be assigned to the randomised treatment. All adverse events 
occurring before first drug intake will be assigned to 'screening' and all adverse events 
occurring after last drug intake + 7 days will be assigned to 'post-treatment'. For details on the 
treatment definition, see Section 6.1.
Malignancy, bone fracture and lower limb amputation events
For malignancy (and respectively bone fracture and lower limb amputation), in addition to 
the standard ‘7-day-on-treatment approach’ detailed above, all malignancy adverse events 
(respectively bone fracture and lower limb amputation adverse events) that occurred between 
first study drug intake up to the trial termination date, will be pooled and analysed together in 
Section 15 of the trial report. 
In general, in-text AE tables will only present AEs assigned to the randomised treatment
taken except drug-related AEs which will also be presented as actual treatment taken at each 
given timepoint. Appendix 16.1.9.2 will display in addition AEs observed 'pre-treatment' 
(including AEs observed during screening, T1DM therapy optimisation and placebo run-in 
regardless of treatment group). In particular, summaries will be created to include an analysis 
where AEs and SAEs are assigned to the following phases: Screening, each treatment group, 
and post-treatment for each treatment group.
7.8.1.2
Analysis of other significant AEs
Other significant AEs will be reported and summarised according to ICH E3 criterion. Thus, 
AEs classified as 'other significant' will include those non-serious and non-significant adverse 
events with:

‘action taken = discontinuation’ or ‘action taken = reduced’, or


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
Marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality 
Review meeting or Blinded Report Planning Meeting.
7.8.1.3
AE summaries
An overall summary of adverse events will be presented.
The frequency of patients with adverse events will be summarised by treatment, primary 
system organ class and preferred term. AEs will also be reported by intensity. Separate tables 
will be provided for patients with other significant adverse events according to ICH E3 (9), 
for patients with adverse events of special interest (AESI), for patients with serious adverse
events, for patients with AEs leading to discontinuation, and for patients with drug-related 
AEs.
The system organ classes will be sorted according to the standard sort order specified by 
EMA, preferred terms will be sorted by frequency (within system organ class).
Appendix 16.1.9.2 will include the following analyses:

an analysis on patients with adverse events by outcome,

an analysis on the frequency of patients with non-serious adverse events occurring 
with incidence in preferred term greater than 5 % by treatment for disclosure on 
clinicaltrials.gov website.
The following analyses will also be reported in Appendix 16.1.9.2 for disclosure on 
EudraCT:

AEs per treatment arm
This analysis includes the number of patients with serious AEs, the number of patients with 
non-serious AEs >5%, the total number of deaths (all causes), as well as the total number of 
deaths resulting from drug-related adverse events.

Number of patients with non-serious AEs > 5% within any treatment arm, for each 
preferred term (grouped by standard SOC terms)

Number of patients with serious AEs on preferred term level (grouped by standard 
SOC terms)
7.8.1.4
AEs of special interest (AESI)
The protocol defines the following adverse events that for analysis purposes will be 
considered as AESIs:

Decreased renal function

Hepatic injury

Ketoacidosis 

Severe hypoglycaemia (i.e. severe hypoglycaemic episodes as defined in the CTP)

Lower limb amputation


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Events of these AESIs are identified through the AE being flagged by the investigator as an 
AESI on the case report form (CRF). For further details on the definition of these events, 
refer to Section 5.3.6.1 of the CTP. 
The AESI decreased renal function will be summarised by SOC and PT based on the 
following narrow SMQ:
Renal:      

Acute renal failure: 20000003 (narrow SMQ)
This display will be replicated to present serious events and then events leading to 
discontinuation.
The acute renal kidney injury will also be discussed based on the creatinine laboratory data 
increase as detailed in Section 7.8.2.4.
The AESI hepatic event will be summarised by SOC and PT based on the following narrow 
SMQs:
Hepatic:

Liver related investigations, signs and symptoms: 20000008 (narrow SMQ)

Cholestasis and jaundice of hepatic origin: 20000009 (narrow SMQ)

Hepatitis, non-infectious: 20000010 (narrow SMQ)

Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions: 
20000013 (narrow SMQ)
This display will be replicated to present serious events and then events leading to 
discontinuation. A final display will summarise the AEs related to hepatic injury that 
occurred from baseline up to 30 days after the last dose of study medication.
Further laboratory analyses will support the hepatic evaluation. See Section 7.8.2.2 for further 
details on elevated liver enzyme analyses.
Ketoacidosis:

CEC confirmed ketoacidosis and ketosis endpoints
o
Analysis of number of patients with ketoacidosis
A frequency table will first summarize the results of the CEC adjudication committee for 
ketoacidosis events (refer to Section 7.8.1.6 for further details on the adjudication process). 
This summary will present the number of patients with CEC confirmed certain ketoacidosis, 
potential ketoacidosis, unlikely ketoacidosis, unlikely ketoacidosis but ketosis, or 
unclassifiable events, by worst severity and requirement of hospitalisation. 
A second frequency analysis will be created and will display the characteristics of 
ketoacidosis for patients with CEC certain ketoacidosis. These characteristics will include 
outcome, severity of the worst episode, time to onset of first episode, and lowest blood pH. 
This analysis will be successively repeated for ketoacidosis endpoints considered by the CEC 
as potential, as well as for ketoacidosis endpoints considered by the CEC as certain or 
potential.


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Time to onset of the first CEC certain ketoacidosis event will be analysed by Kaplan-Meier 
estimates. The onset date determined by the adjudication committee will be used as date of 
event. The time to the occurrence of the event will be computed as date of the event minus 
date of first drug intake plus one day. 
The Kaplan-Meier graph will present data up to the end of the treatment period.
Patient without an event will be considered censored at the date of the last trial drug intake 
plus seven day. 
A log-rank test will be then computed to test the equality of the survival curves.
The Kaplan-Meier analysis and the log-rank test will then be performed for CEC certain or 
potential ketoacidosis event.
Frequency of patients with CEC certain ketoacidosis (and respectively CEC potential 
ketoacidosis) will be planned by preferred term from the specified trigger search terms for 
DKA.
o
Analysis of frequency of ketoacidosis episodes 
An overview table will first summarize the results of the CEC adjudication committee on 
ketoacidosis episodes by worst severity. 
The CEC certain ketoacidosis episodes will be tabulated by treatment and characteristics of 
ketoacidosis (e.g. outcome, severity, pre-existing factors, blood pH).
When appropriate, the number of episodes per 100 patient-years will be calculated in addition 
to the number of episodes according to the following formula:
100*(number of ketoacidosis events /time at risk [patient-years] to report a diabetic 
ketoacidosis event)
Where time at risk [patient-years] is calculated as time from first administration of study drug 
until last administration of study drug + 7 days, summed up over all patients per treatment 
group, and divided by 365.25. 
The same ketoacidosis episode analysis will be presented for CEC potential ketoacidosis, as 
well as for CEC certain or potential ketoacidosis.

Other ketoacidosis endpoints
Patients with investigator defined AESI ketoacidosis will be tabulated by event 
characteristics; as well as the number of investigator defined AESI ketoacidosis episodes.
Frequency of patients with investigator defined AESI ketoacidosis will in addition be 
tabulated by SOC and PT, as well as using specified trigger search terms for DKA.

Ketosis endpoints
Additional analyses will be produced to assess the risk of ketosis. Patient with ketosis are 
patients with either: 
-
CEC unlikely ketoacidosis but ketosis, or 


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-
Single or multiple BHB readings (i.e. capillary patient-self measures or serum 
measurements) between ˃1.5 and ˂ 3.8 mmol/L without accompanying typical 
ketoacidosis symptoms, hospitalisation or serious adverse event. As documented in 
the DKA CEC charter, these types of events are not considered trigger events for the 
adjudication
The number of patients with any ketosis events will be summarised as well as the number of 
ketosis episodes. 
Ketosis episodes are defined as:

CEC unlikely ketoacidosis but ketosis, or

Single or multiple consecutive BHB readings >1.5 (i.e. capillary patient-self measures 
or serum measurements, within 24 hours of the previous reading for consecutive 
measurements) that do not trigger adjudication and that are not followed by an event 
triggering adjudication within 24 hours. 
Severe hypoglycaemia adverse events:
In this section, only severe hypoglycaemia reported by the investigators as AESI, or severe 
hypoglycaemia that have been confirmed by the adjudication committee will be considered. 
Also note that 'CEC confirmed severe hypoglycaemia' refers to the exact same endpoint as 
'severe hypoglycaemia confirmed by adjudication' that was the terminology used in the 
efficacy section. 
Refer to Section 9.3 for further details on the derivation of the severe hypoglycaemia adverse
event endpoints analysed in this section.

CEC confirmed severe hypoglycaemia endpoint
o
Analysis of number of patients with severe hypoglycaemia adverse event
A frequency table will first summarize the results of the adjudication committee on 
hypoglycaemic events that had been sent to the CEC for adjudication.
Kaplan-Meier graphs will be plotted for the time to first onset of CEC confirmed severe 
hypoglycaemia. The onset date determined by the adjudication committee will be used as 
date of event. The time to the occurrence of the event will be computed as date of the event 
minus date of first drug intake plus one day. 
The Kaplan-Meier graph will present data up to the end of the treatment period.
Patient without an event will be considered censored at the date of the last trial drug intake 
plus one day. 
A log-rank test will be computed to test the equality of the survival curves. 
Patients with CEC confirmed severe hypoglycaemia will be tabulated by treatment and 
characteristics of hypoglycaemia including minimum glucose level and time to onset of first 
episode. The frequency of severe nocturnal hypoglycaemia AE (i.e. any hypoglycaemia event 
with an onset from 0:00 midnight to 5:59 a.m.) will also be evaluated as part of these 
characteristics. 


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Finally, the severe hypoglycaemia considered serious or requiring third person assistance will 
be tabulated using the narrow SMQ Hypoglycaemia. This analysis will be restricted to 
patients with CEC confirmed severe hypoglycaemia.
o
Analysis of frequency of hypoglycaemia adverse events
The number of CEC confirmed severe hypoglycaemic episodes will be first tabulated by 
treatment and characteristics of hypoglycaemia. When appropriate, the number of episodes 
per patient-year will be provided in this analysis. The time at risk for severe hypoglycaemia 
[patient-years] will be derived similarly as for ketoacidosis, but in using 1 day of washout 
instead of 7 days in the calculation. 
A negative binomial model will be fitted to analyse the event rate of CEC confirmed severe 
hypoglycaemia per patient-years, with terms for treatment, continuous baseline rate, 
continuous baseline HbA1c, continuous baseline eGFR (CKD-EPI, creatinine) and pre-
existing insulin therapy as fixed effects and log(time at risk) as an offset.
In addition, the severe hypoglycaemic episodes that have been confirmed by the adjudication 
committee will we represented on a graph by hour of the day (from midnight to 11:59 pm).  

Investigator defined AESI severe hypoglycaemia adverse event endpoint
Patients with investigator defined AESI severe hypoglycaemia will also be summarised by 
treatment and event characteristics, as well as the investigator defined AESI severe 
hypoglycaemic episodes.
Patients with investigator defined AESI severe hypoglycaemia will additionally be 
summarised by SOC, PT and treatment group. 
Lower limb amputation 
A frequency table summarising the investigator defined AESI lower limb amputation events 
will be created by SOC and PT. The table will be then repeated for serious events, and for 
events leading to treatment discontinuation.
Patients with events detected based on project-defined preferred term lists for respectively 
vascular AEs, wound/infections, diabetic foot related AEs, nervous system disorders and 
volume depletion will be additionally summarised. All PTs associated to these events 
occurring before (<=) the lower limb amputation procedure will be included in this analysis.
Finally, the characteristics of the lower limb amputation procedures (associated to the 
investigator defined AE) will be summarised. The reasons of the amputation and the level of 
the amputation will be the main characteristics of interest. All procedures that occurred 
between first study drug intake up to the later between the trial termination and the last AE 
onset date will be summarised.
7.8.1.5
Other specific adverse events
Hypoglycaemia

Hypoglycaemia adverse events


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In this sub-section, only hypoglycaemia reported by the investigator as adverse events will be 
discussed. For specifications on analyses on severe hypoglycaemia adverse event, refer to 
Section 7.8.1.4.
Refer to Section 9.3 for details on the derivation of the hypoglycaemia adverse event 
endpoints listed below.
Every episode of PG ≤ 70 mg/dL should be documented with the respective time and date of 
occurrence. This includes hypoglycaemia with glucose values < 54 mg/dL and all 
symptomatic and all severe hypoglycaemic events. On the basis of this information the 
hypoglycaemic adverse event will be classified according to the following protocol defined 
categories:
- Asymptomatic hypoglycaemia with PG ≤ 70 mg/dL 
- Documented symptomatic hypoglycaemia with 54 mg/dL ≤ PG ≤ 70 mg/dL and 
typical symptoms
- Documented symptomatic hypoglycaemia with PG < 54 mg/dL and typical 
symptoms and no need for external assistance
- Severe hypoglycaemia, events requiring assistance
o
Analysis of number of patients with hypoglycaemia adverse events
The frequency of patients with protocol defined hypoglycaemia adverse event will be 
presented by treatment.
The frequency of patients with hypoglycaemia adverse event according to investigator's 
judgment will be tabulated by treatment, SOC and preferred term.
o
Analysis of frequency of hypoglycaemic adverse events
Similarly as for the analysis on patient level, a summary on the number of protocol defined 
hypoglycaemia adverse event episodes will be produced per patient-years.
Then, descriptive statistics will be produced for the predefined protocol further safety 
endpoint “rate of symptomatic hypoglycemic AE with confirmed PG<54 mg/dL and/or 
severe hypoglycaemic AE confirmed by the adjudication, per 30 days, from Week 1 to Week 
4”. A negative binomial model with terms for treatment, baseline rate, continuous baseline 
HbA1c, continuous baseline eGFR (CKD-EPI, creatinine) and pre-existing insulin therapy as 
fixed effects and log (time at risk [30 days]) as an offset will also be prepared. These two 
analyses will furthermore be replicated on the FAS. 
Step 1 and Step 2 of the TSAP Section 5.4.7 collapsing rules will apply, in order to avoid the 
double-counting of episodes between adjudicated severe hypoglycaemia data and 
hypoglycamia AE data.

Patient-reported hypoglycaemia events
The endpoints describe in this sub-section will be exclusively based on patient-reported 
hypoglycaemia data.


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A summary presenting the number of patients with the following endpoints will be tabulated:
- Asymptomatic hypoglycaemia with PG ≤ 70 mg/dL
- Symptomatic hypoglycaemia with PG ≤ 70 mg/dL
- Asymptomatic hypoglycaemia with PG < 54 mg/dL
- Symptomatic hypoglycaemia with PG < 54 mg/dL
- Nocturnal symptomatic hypoglycaemia with PG ≤ 70 mg/dL
- Nocturnal symptomatic hypoglycaemia with PG ≤ 70 mg/dL
- Nocturnal asymptomatic hypoglycaemia with PG < 54 mg/dL
- Nocturnal asymptomatic hypoglycaemia with PG < 54 mg/dL
The number of episodes per patient-year will be analysed for these endpoints as well, for 
which the TSAP Section 5.4.6.3 collapsing rules will apply.
A negative binomial model will be fitted to analyse the symptomatic hypoglycaemia with PG 
< 54 mg/dL, with terms for treatment, continuous baseline HbA1c, continuous baseline eGFR 
(CKD-EPI, creatinine) and pre-existing insulin therapy as fixed effects and log(time at risk) 
as an offset.
Urinary and genital infections
The following additional specific adverse events will also be assessed and be tabulated by 
treatment group:

Genital tract infections (narrow BIcMQ, investigator assessment)

Urinary tract infections (UTI) (narrow BIcMQ, investigator assessment)
The serious genital infection events as well as the genital infection events leading to 
treatment discontinuation will additionally be summarised using the narrow project defined 
PT list.
Similarly, the serious UTI events as well as the UTIs leading to treatment discontinuation 
will be summarised using the BIcMQ.
A frequency table for complicated urinary tract infections/pyelonephritis/urosepsis where 
‘complicated urinary tract infections’ are defined as serious AEs from the narrow BIcMQ 
UTI, all events included in the sub-BIcMQ pyelonephritis and all events of preferred term 
urosepsis will in addition be provided .
Genital infections based on investigator assessment will additionally be summarised by type 
(fungal balanitis or fungal vulvovaginitis, genital infection other than fungal balanitis or 
fungal vulvovaginits), intensity (mild, moderate or severe),  time to onset of first episode 
(within the first 3 months of treatment or after), duration (<7 days, 7-14 days and >14 days), 
how the event was treated (no treatment, therapy assigned, hospitalisation), treatment (0, 1, 2, 
>2 antimicrobials needed to treat), duration of treatment (≤7 days, >7 days),  whether leading 
to discontinuation of treatment, and the number of episodes per patient.


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Furthermore, the above mentioned displays on genital infections based on investigator 
assessment will be repeated by the type of infection (fungal balanitis or fungal vulvovaginitis, 
or genital infection other than fungal balanitis or fungal vulvovaginitis).
UTIs based on investigator assessment will additionally be summarised by intensity (mild, 
moderate or severe),  time to onset of first episode (within the first 3 months of treatment or 
after), duration (<7 days, 7-14 days and >14 days), anatomical location (upper UTI, lower 
UTI), how the event was treated (no treatment, therapy assigned, hospitalisation), treatment 
(0, 1, 2, >2 antimicrobials needed to treat), duration of treatment (≤7 days, >7 days),  whether 
leading to discontinuation of treatment, and the number of episodes per patient.
Kaplan-Meier graphs will also be created for time to onset of the first investigator defined 
UTI and for time to onset of the first investigator defined genital infections. For both 
endpoints, the time to the occurrence of the event will be computed as date of the event minus 
date of first drug intake plus one day. The same censoring date rules as the ones defined in 
Section 7.8.1.4 for time to onset to ketoacidosis endpoint will be used for patient without an 
event. The onset date of the first UTI episode will be used in case of multiple episodes.
The Kaplan-Meier graph will present data up to the end of the treatment period.
In the number of episodes analysis of UTI and genital infection AEs will be collapsed within 
each SSC regardless of preferred term with the collapsing following the description at the 
start of Section 7.8.1 but the condensing will not be conducted in order to maintain multiple 
episodes per patient.
Acute pyelonephritis, sepsis, and asymptomatic bacteriuria
The following specific adverse event based on investigator assessment will be tabulated by 
treatment group:

Acute Pyelonephritis: patient incidence overall and by intensity, and treatment 
required (0, 1, 2, >2 antimicrobials needed to treat)

Sepsis: patient incidence overall and by source of infection

Asymptomatic Bacteriuria: patient incidence overall
Bone fractures 
Frequency of patients with bone fracture will be provided by event characteristics (e.g.type of 
fracture, intensity, and time to onset of first fracture). Bone fracture will also be displayed by 
SOC and PT using the BIcMQ. The BIcMQ analysis will be repeated for serious bone 
fracture events and for bone fractures leading to treatment discontinuation. Finally, the bone 
fracture events that occurred between first study drug intake and up to study end will be 
pooled together and analysed based on the BIcMQ in a separate analysis. 


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Volume depletion
Frequency table of patients with volume depletion will be constructed based on preferred 
terms:

Volume depletion: (BIcMQ)
Malignancy
AE frequency table will be created for malignancies based on the following narrow SMQs:

Malignancies: The following Sub-SMQs of SMQ Malignancies (20000090) will be 
used: Sub-SMQ Malignant or unspecified tumors (20000091) and Sub-SMQ 
Malignancy related conditions (20000092).
This analysis will be then replicated for serious malignancy, and for malignancy leading to 
treatment discontinuation. 
Finally, all malignancy adverse events that occurred between first study drug intake up to 
study end will be pooled together and analysed based on the narrow SMQ search in a separate 
analysis. 
7.8.1.6
Events qualifying for external adjudication by the Clinical Event Committee (CEC)
Independent external CECs regularly review cardiovascular, neurovascular, hepatic, severe 
hypoglycaemia, and ketoacidosis events and evaluate whether pre-specified criteria for these 
adjudication endpoints are met. Details on composition of the CECs, responsibilities and 
clinical event definitions are provided in separate CEC charters. Events qualifying for 
adjudication will be selected based on the latest CEC charter versions.
The CECs will be provided with additional, specified background material on the patients 
with these events and perform an assessment of the events. Adjudication assessments will be 
incorporated to the database.
Refer to Section 7.8.1.4 for details on analyses for severe hypoglycaemia and ketoacidosis 
events confirmed by adjudication. 
Frequency table by treatment group will be provided for the adjudicated cardiovascular and 
neurological endpoints and for the preferred terms in the specified SMQs of events. Table 
will also be provided for events that were confirmed or non-assessable.
The cardiovascular and neurovascular events qualifying for adjudication will be selected 
based on the following SMQs:

Ischemic heart disease, excluding PTs “Blood creatine phosphokinase abnormal” and 
“Blood creatine phosphokinase increased”

Cardiac failure, excluding PTs “Oedema”, “Oedema peripheral” and “Peripheral 
swelling” unless there are reported as serious events

Torsade de pointes / QT prolongation

Cerebrovascular disorders, excluding PT “Fahr's disease”


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
Further simple preferred terms 

All fatal cases
7.8.1.7
AEs while patients taking wrong medication
A listing will be provided for AEs that occurred while a patient was taking the wrong 
medication.
7.8.2
Laboratory data
For continuous safety laboratory parameters standardised and normalised values will be 
derived as well as the differences to baseline. The process of standardisation and 
normalisation as well as standard analyses for safety laboratory data are described in the BI 
guidance for the Display and Analysis of Laboratory Data (10). All analyses considering 
multiple of times upper limit of normal (ULN) will be based on original and not normalized 
data.
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards. 
Results of laboratory analyses will be presented based on both SI units and US conventional 
units.
Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomised study drug. In general, laboratory measurements taken up to 3 days after 
the last administration of randomised study drug will be considered as on-treatment. The 
exception will be for the liver enzyme elevation analysis (see below).
Only patients with at least one available on-treatment value will be included in the analysis of 
an individual laboratory parameter. All individual data will be presented in listings.
7.8.2.1
General laboratory evaluation
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of patients within and outside the reference range at baseline and the 
last measurement on treatment. Descriptive statistics will be provided by treatment group for 
baseline, on-treatment values and for changes from baseline based on normalised values, as 
well as on the basis of standardized values for parameters with an incomplete reference range 
(e.g. ALT).
Descriptive statistics will in addition be calculated for the change from baseline in 
haematocrit over time, including during the follow-up period.  In particular, statistics will be 
provided for last-value on-treatment, follow-up, change from baseline from last on-treatment 
value and follow-up, and change from last on-treatment assessment to follow-up.
Frequency tables will summarise the number of patients with potentially clinically significant 
abnormalities as defined for the new XLAB macro (version 2.03) and the criteria for 
clinically significant abnormalities based on normalised laboratory values will be listed. 


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7.8.2.2
Elevated liver enzymes
Special attention will be paid to parameters characterising liver function. These include liver 
enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (AP)) and total bilirubin.
The frequency of the number of patients with AST/ALT elevations >= 3xULN, >= 5xULN, 
>= 10xULN, and >= 20xULN will be displayed.
To support analyses of liver related adverse drug effects, patients with AST and/or ALT 
>=3xULN with concomitant or subsequent TBILI>=2xULN in a 30 day period after 
AST/ALT elevation are of special interest. The start of the 30 day time span is triggered by 
each liver enzyme elevation above the defined thresholds. Patients who fulfil one or two of 
the criteria for AST/ALT or total bilirubin elevations above and has no information available 
for the remaining parameter(s) at the same time-point or within the 30 day time window will 
not be listed under "ALT and/or AST >= 3xULN with Total Bilirubin >= 2xULN". 
Patients with elevations as defined above by ALT and/or AST, total bilirubin and AP 
combinations, will be summarised and stratified by Alkaline phosphatase < 2xULN and 
>=2xULN. 
Details on patients with elevated liver enzymes will be listed.
In addition to the standard ‘3-day-on-treatment approach’ detailed above, all liver enzyme 
elevation with an onset date up to 30 days after the treatment stop will be analysed for further 
displays in Section 15 of the CTR.
7.8.2.3
Lipid parameters
Descriptive statistics will be shown over time for the treated set (LOCF and OC) including 
change from baseline and percent change from baseline. For each lipid parameter, separate 
ANCOVA models will be fitted on the treated set (OC) for both change from baseline at 
week 26 and percent change from baseline at week 26 as dependent variables. The models 
will include treatment and pre-existing insulin therapy as fixed effects, and baseline lipid, 
baseline HbA1c, baseline eGFR (CKD-EPI, creatinine) are linear covariates. 
The residuals from the ANCOVA models will be checked for normality using a Q-Q plot and 
documented in Appendix 16.1.9.2.
7.8.2.4
Renal laboratory parameters
Creatinine and eGFR
All calculations for the grading of renal function will be based on the originally measured 
laboratory values and the ULNs given by the laboratory, not on normalised values with BI 
standard reference ranges.  
The glomerular filtration rate will be first estimated according to the following CKD-EPI 
creatinine equation, and stored in the trial database:
eGFR (ml/min/1.73 m2) = 141 x min (serum creatinine [umol/L]/88.4/k, 1)a
     x max (serum creatinine [umol/L]/88.4/k, 1)-1.209
     x 0.993Age x [1.018 if female] x [1.159 if of African origin]


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Where:
- k is 0.7 for females and 0.9 for males,
- a is -0.329 for females and -0.411 for males,
- min indicates the minimum between (serum creatinine/k) and 1,
- max indicates the maximum between (serum creatinine/k) and 1.
For the analysis of eGFR (CKD-EPI, creatinine) and for the covariates in the efficacy 
statistical modelling the values calculated from the above formula using the serum creatinine 
values from the central laboratory will be used, and not the eGFR values provided by the 
central laboratory.
The glomerular filtration rate will also be derived according to the following CKD-EPI 
creatinine-cystatin C equation:
eGFR (mL/min/1.73 m2) =      135 × min (serum creatinine [mg/dL]/ k, 1) a
× max (serum creatinine [mg/dL]/ k, 1) -0.601 
× min (standardized serum cystatin C [mg/L]/0.8, 1) -0.375 
× max (standardized serum cystatin C [mg/L]/0.8, 1) -0.711 
× 0.995Age 
× 0.969 [if female] 
× 1.08 [if black]
Where:
- k is 0.7 for females and 0.9 for males,
- a is 0.248 for females and -0.207 for males,
- min (serum creatinine/ k, 1) indicates the minimum between (serum creatinine/k) and 1,
- max (serum creatinine/ k, 1) indicates the maximum between (serum creatinine/k) and 1,
- min (standardized serum cystatin C / 0.8, 1) indicates the minimum between (standardized 
serum cystatin C /0.8) and 1,
- max (standardized serum cystatin C / 0.8, 1) indicates the maximum between (standardized 
serum cystatin C /0.8) and 1
- Age is expressed in years.
The endpoint eGFR (CKD-EPI, creatinine-cystatin C) will be derived at the visits where both 
serum creatinine and serum cystatin C are measured at the central laboratory. 
The following additional rules will apply to derive these two eGFR renal endpoints:


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
In case of mixed race, if ‘Black or African American’ is one of the patient races, 
eGFR will be by default derived as if the patient is of African origin.

Age will be considered as a discrete variable for the above calculations, and the age 
will be from the same visit as the other variables. The age at a specific visit where 
eGFR is calculated will be derived as follows:  
age [years] = (date of eGFR laboratory measurement – birth date + 1) / 365.25
A shift table from baseline to last value on treatment, (and from baseline to minimum value 
on treatment) will be provided for eGFR (CKD-EPI, creatinine) and for eGFR (CKD-EPI, 
creatinine-cystatin C) endpoints.
Descriptive statistics will also be created for creatinine, eGFR (CKD-EPI, creatinine) and 
eGFR (CKD-EPI, creatinine-cystatin C) values over time by treatment and presented in 
tables.
Additionally, a summary will be created representing the number of patients per treatment 
group that experienced a doubling in creatinine on treatment that was out of the normal range 
as compared to baseline.
Other renal endpoints
The following renal endpoint will be analysed:

Doubling of serum creatinine accompanied by eGFR (CKD-EPI, creatinine) <= 45 
mL/min/1.73m2. For this endpoint, the doubling of serum creatinine level 
corresponds to the increase of serum creatinine level to 2.0 fold from baseline.
Patients who already fulfil the above condition at baseline or without post-baseline laboratory 
measurements are not considered in the number of patients at risk for this endpoint. If a 
baseline laboratory measurement is not available for the parameter of interest, it is assumed 
that the patient did not experience the condition corresponding to the endpoint at baseline.
The number of patients with the event will be provided. 
7.8.2.5
Blood beta-hydroxybutyrate (BHB)
Refer to Section 6.7 for the baseline definition of BHB endpoints.

Serum BHB sampled at the site and analysed at the central laboratory
All the analyses described for this endpoint will be performed on fasted measurements only.
Descriptive statistics for baseline, actual values and change from baseline over time will be 
calculated. Descriptive statistics will also be provided to characterize the follow-up period.
The median and the corresponding confidence interval using SD will be plotted over time 
including the follow-up period. A box-plot presenting the value at baseline and over time will 
also be produced per treatment group.
A shift table from baseline to last value on treatment, (and from baseline to maximum value 
on-treatment) will also be provided by baseline values (<0.6 mmol/L, 0.6 to <=1.5 mmol/L, 
>1.5 to <3.8 mmol/L, >=3.8 to ≤8.0 mmol/L, > 8.0 mmol/L).


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An additional shift table will display the number of patients in these BHB categories over 
time.

Capillary self-measured BHB via the ketone meter and reported in the diary
Elevated ketone readings above >1.5 mmol/L that have not been confirmed by the 
investigator will not be included in any analysis of this section. Refer to Section 5.4.6.1 for 
further details on the ketone reading confirmation process. 
Morning and daily endpoints
For all analyses specified in this section, capillary BHB readings reported as “HI” will be 
imputed to 8.1 mmol/L. 
The periods of time of interest will be the following ones: week 1, week 2, week 3, week 4, 
week 5 to week 6, week 7 to week 8, week 12, week 18, week 22 and week 26. 
Descriptive statistics will be produced on the average of morning BHB measurement values 
over the specific periods of time defined above.
The same descriptive statistics will be produced on the average of daily BHB measurement 
values over time, using the same periods of time defined above.
High BHB measurements
The analysis described in this paragraph will focus on high BHB measurement values that a 
patient may have reported in the diary. For this analysis, "HI" readings will be considered as 
such and not be replaced by a numerical value (for instance 8.1 mmol/L).
7.8.2.6
Urine ketone
Refer to Section 6.7 for the baseline definition of urine ketone endpoints.
The analyses described for this endpoint will be performed on fasted measurements only.
Analysis of categorical urine ketone data (negative, trace, 1+/small, 2+/moderate, 3+/large, 
4+/large+) will be performed by value at baseline, over time, and worst value on treatment. 
The analysis will be presented as frequency table and graphically on pie charts.
7.8.3
Vital signs
Other than the analysis of SBP and DBP as key secondary endpoints, only descriptive 
statistics are planned for the summary of pulse rate (bpm) and change from baseline in pulse 
rate over time based on the treated set (OC, OC-AD).
7.8.4
ECG
12-lead ECG measurements will be taken at baseline (visit 6) and at EOT (visit 11). ECG-
findings before first intake of trial drug will be considered as baseline condition. Any 
clinically significant new findings in the ECG measurement after the first ECG will be 
considered as AEs and analysed as planned in Section 7.8.1.


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7.8.5
Others
Not applicable
8
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9,
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
Service FJ; Glucose Variability; Diabetes 62:1398-1404, 2013 [R14-4138]
3
Baghurst PA.; Calculating the mean amplitude of glycemic excursion from continuous 
glucose monitoring data: an automated algorithm; Diabetes Technology & Therapeutics 
2011; 13(3):296-302 [R14-4136]
4
Fritzsche G, Kohnert KD, Heinke P, Vogt L, and Salzsieder E; The use of a computer 
program to calculate the mean amplitude of glycemic excursions; Diabetes Technology 
& Therapeutics 2011; 13(3)L319-325 [R14-4137]
5
001-MCS 36-472: "Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
6
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", version 2.0; 
IDEA FOR CON.
7
001-MCG-159, "Reporting of clinical trials and project summaries", current version; 
IDEA FOR CON.
8
001-MCG-156: «Handling and summarisation of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA FOR CON.
9
CPMP/ICH/137/95:  "Structure and content of clinical study reports", ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version.
10
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.


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9
ADDITIONAL SECTIONS
 
9.2
SPECIAL SEARCH CATEGORIES AND ATC LEVELS FOR CONCOMITANT 
MEDICATION
The defining ATC levels and ATC codes of the WHO DD special search categories for the 
use of antihypertensives, ASA and lipid lowering drugs and are shown in Table 9.2:1.


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Medications in the categories C02, C03, C07, C08 and C09 that have a missing ATC3 code 
will also be considered antihypertensives and will be presented in the respective table by their 
preferred name under antihypertensives. 
Table 9.2: 1 WHO DD special search categories 
WHO DD special search categories
SSC
Displayed category
ATC level
ATC code
ASA
ASA
ATC4
B01AC
Antihypertensives
Antiadrenergic agents, 
centrally acting
ATC3
C02A
Antiadrenergic agents, 
ganglion-blocking
ATC3
C02B
Antiadrenergic agents, 
peripherally acting
ATC3
C02C
Arteriolar smooth muscle, 
agents acting on
ATC3
C02D
Other antihypertensives
excluding magnesium and 
magnesium sulfate
ATC3
C02K*
Antihypertensives and 
diuretics in combination
ATC3
C02L
Combinations of 
antihypertensives in atc-gr. 
C02
ATC3
C02N
Low-ceiling diuretics, 
thiazides
ATC3
C03A
Low-ceiling diuretics, excl. 
thiazides
ATC3
C03B
High-ceiling diuretics
ATC3
C03C
Potassium-sparing agents
ATC3
C03D
* C02K excluding the terms magnesium and magnesium sulphate


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WHO DD special search categories (cont.)
SSC
Displayed category
ATC level
ATC code
Diuretics and potassium-
sparing agents in 
combination
ATC3
C03E
Other diuretics
ATC3
C03X
Beta blocking agents
ATC3
C07A
Beta blocking agents and 
thiazides
ATC3
C07B
Beta blocking agents and 
other diuretics
ATC3
C07C
Beta blocking agents, 
thiazides and other diuretic
ATC3
C07D
Beta blocking agents and
vasodilators
ATC3
C07E
Beta blocking agents and 
other antihypertensives
ATC3
C07F
Selective calcium channel 
blockers with mainly vas
ATC3
C08C
Selective calcium channel 
blockers with direct car
ATC3
C08D
Non-selective calcium 
channel blockers
ATC3
C08E
Calcium channel blockers 
and diuretics
ATC3
C08G
ACE inhibitor, plain
ATC3
C09A
ACE inhibitor, 
combinations
ATC3
C09B
Angiotensin II antagonists, 
plain
ATC3
C09C
Angiotensin II antagonists, 
combinations
ATC3
C09D
Other agents acting on the 
86ennin-angiotensin system
ATC3
C09X
Lipid lowering drugs
Niacin
ATC4 [nicotinic acid 
and derivatives]
C10AD
Fibrates
ATC4 [Fibrates]
C10AB
Statins
ATC4 [HMG COA 
reductase inhibitors]
C10AA
Other
Other lipid modifying 
agents
C10AX
Bile acid sequestrants
C10AC


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10 HISTORY TABLE
Table 10: 1
History table
Version
Date
Author
Sections 
changed
Brief description of change
Final
17-MAY-17
None
This is the final TSAP without any 
modification
Revised
11-OCT-17
6.7
7.5.1.2
7.5.1.4
7.8.1.4
7.8.1.5



Follow-up period for the 
assignment to active treatment 
for hepatic injury added

Multiple imputation analysis 
for body weight and blood 
pressure adapted


Definition of ketosis episodes 
added

A negative binomial model 
will be fitted to analyse the 
symptomatic hypoglycaemia 
with PG < 54 mg/dL

Minor changes in the wording 
and correction of typos