Clinical trial NCT02414958
Conditions: Diabetes Mellitus, Type 1
Sponsor: Boehringer Ingelheim
Start date: 2015-06-30; Completion date: 2017-10-23
Enrollment: 730 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Comparison of 2 doses of empagliflozin vs placebo in patients already using either an insulin regimen of multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). Randomisation to 3 treatments arms (equal assignment) following a screening period, an optimisation period and a run-in period. 52 week double-blind treatment period, and 3 week follow-up period.

Detailed description:

Arms: arm 1: Empagliflozin tablets once daily arm 2: Empagliflozin tablets once daily arm 3: Placebo tablets matching empagliflozin once daily
Interventions: intervention 1: Empagliflozin intervention 2: Empagliflozin intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

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:
c03024901-03
EudraCT No.:
2014-001922-14
BI Trial No.:
1245.69
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 52 weeks in patients with Type 1 Diabetes Mellitus (EASE-
2)
Brief Title:
Empagliflozin as Adjunctive to InSulin thErapy over 52 weeks in 
patients with Type 1 Diabetes Mellitus (EASE-2)
Clinical Phase:
III
Trial Clinical 
Monitor:
       Phone:
       Fax:
Coordinating 
Investigator:
 
             Phone:
             Fax:
Status:
Final Protocol (Revised Protocol based on Global Amendment 2)
Version and Date:
Version: 3.0
Date: 04-Jan-2017
Page 1 of 144
Proprietary confidential information.
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Name of active ingredient:
Empagliflozin
Protocol date:
12-Mar-2015
Trial number:
1245.69
Revision date:
04-Jan-2017
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 52 weeks in patients with Type 1 Diabetes Mellitus (EASE-
2)
Coordinating
Investigator:
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 10 mg and 25 mg 
in patients with Type 1 diabetes mellitus (T1DM) as adjunctive to insulin therapy
Methodology:
Randomised, double-blind, placebo-controlled parallel group comparison of 2 oral 
once daily doses (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 HbA1c (< 8.5% vs ≥ 8.5%)
No. of patients: 
total entered
(randomised):
720
each treatment:
240 patients per dose group
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.  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


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Name of active ingredient:
Empagliflozin
Protocol date:
12-Mar-2015
Trial number:
1245.69
Revision date:
04-Jan-2017
dose:
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
52 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 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 the percentage of time spent in target glucose range of
> 70 to ≤ 180 mg/dL (> 3.9 to ≤10.0 mmol/L) as determined by continuous 
glucose monitoring (CGM) in weeks 23 to 26

change from baseline in the inter quartile range (IQR) as determined by CGM 
in weeks 23 to 26

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):

hepatic injury

decreased renal function

diabetic ketoacidosis (DKA)


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Name of active ingredient:
Empagliflozin
Protocol date:
12-Mar-2015
Trial number:
1245.69
Revision date:
04-Jan-2017

severe hypoglycaemic episodes

events involving lower limb amputation
Frequency of patients with hypoglycaemia
Hypoglycaemia rate
Frequency of patients with adjudicated events:

cardiovascular

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 primary treatment comparisons will be the 
Bonferroni adjusted contrast between each dose of empagliflozin 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 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 endpoints of change from baseline in the percentage of time 
spent in target glucose range of > 70 to ≤180 mg/dL (> 3.9 to ≤10.0 mmol/L) as 
determined by CGM in weeks 23 to 26 and change from baseline in IQR as 
determined by CGM in weeks 23 to 26 will be analysed using analysis of 
covariance (ANCOVA), with terms for treatment, pre-existing insulin therapy, 
continuous baseline HbA1c, continuous baseline eGFR and continuous baseline of 
the respective CGM 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 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Name of active ingredient:
Empagliflozin
Protocol date:
12-Mar-2015
Trial number:
1245.69
Revision date:
04-Jan-2017
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 AEs 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 
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
11Z
12
13
14
15Z
16
EOTJ
eEOT
Early 
Discnn
OnlyG,J
17G
Study week
-9
-8
-6
-4
-2
1
4
12
18
22
26
34
43
48
52
55
Study day
-63
-56
-42
-28
-14
-2E
1
8
29
85
127
155
183
239
302
337
365
386
Visit window 
(days)A
-7/+4
+/-
2
+/-
2
+/-
2
+/-
3
+/-
1
n/a
+/-
2
+/-
7
+/-
7
+/-
7
+/-
7
+/-
3
+/-
5
+/-
3
+/-
7
+/-    
3
+/-
7
Fasting statusH
NF
F
NF
-
NF
-
F
NF
NF
F
NF
NF
F
NF
F
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
x
Vital signs
x
x
(x)
x
x
x
x
x
x
x
x
x
x
x
x
x
Physical 
examination
x
x
x
x
x
12-lead ECG
x
x
x
x
Safety laboratory, 
urinalysisK
xU
xY
x
xV
x
x
xV
x
xV
xV
xV
Blood ketones (site) 
– home monitoring 
deviceAA
x
(x)
x
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
11Z
12
13
14
15Z
16
EOTJ
eEOT
Early 
Discnn
OnlyG,J
17G
Study week
-9
-8
-6
-4
-2
1
4
12
18
22
26
34
43
48
52
55
Study day
-63
-56
-42
-28
-14
-2E
1
8
29
85
127
155
183
239
302
337
365
386
Visit window 
(days)A
-7/+4
+/-
2
+/-
2
+/-
2
+/-
3
+/-
1
n/a
+/-
2
+/-
7
+/-
7
+/-
7
+/-
7
+/-
3
+/-
5
+/-
3
+/-
7
+/-    
3
+/-
7
Fasting statusH
NF
F
NF
-
NF
-
F
NF
NF
F
NF
NF
F
NF
F
NF
F
F
F
Pregnancy testL
x
x
x
x
x
x
x
 
 
HbA1c
x
x
x
x
x
x
x
x
x
x
Dispense run-in 
medication (IRT)
x
Randomisation 
(IRT)
x
Dispense double-
blind medication 
(IRT)
x
x
x
x
x
x
x
Compliance/drug 
accountability 
check
x
x
x
x
x
x
x
x
x
x
x
x
Management of diet 
& physical activity, 
training on home 
monitoring deviceQ
Continuous
Home monitoringR
Continuous


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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
11Z
12
13
14
15Z
16
EOTJ
eEOT
Early 
Discnn
OnlyG,J
17G
Study week
-9
-8
-6
-4
-2
1
4
12
18
22
26
34
43
48
52
55
Study day
-63
-56
-42
-28
-14
-2E
1
8
29
85
127
155
183
239
302
337
365
386
Visit window 
(days)A
-7/+4
+/-
2
+/-
2
+/-
2
+/-
3
+/-
1
n/a
+/-
2
+/-
7
+/-
7
+/-
7
+/-
7
+/-
3
+/-
5
+/-
3
+/-
7
+/-    
3
+/-
7
Fasting statusH
NF
F
NF
-
NF
-
F
NF
NF
F
NF
NF
F
NF
F
NF
F
F
F
Training/start of 
blinded CGM 
periodsS
x
x
x
End of CGM 
periodsS
x
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
x
x
x
x
x
 
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Termination of trial 
medication
x
x
Vital status 
collection
x
x


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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 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
 
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 17, 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.  PK sampling can be omitted if the eEOT Visit is not performed within 24 hours of the last 
dose of study medication; the 8-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 17 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
J
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  
K
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
L
For female patients of child-bearing potential (local urine pregnancy test)
M
 
 
 
 
Q
Home monitoring device: meter for monitoring of blood (plasma) glucose and ketone levels at home
R
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 Footnote AA and Section 5.3.2.2
S
Patients should be trained in the correct use of the CGM device, including sensor exchange, before it is dispensed for the first CGM period at Visit 5.  Refresher training 
should be provided at Visits 11 and 15 as appropriate.  A change of CGM sensor is required every 7 days within each monitoring period.  The patient should change the 
sensor at home on days where a sensor change is due but where a clinic visit is not scheduled.  For further details see Sections 5.2.5 and 6.1


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T
  
U
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
V
At Visits 6, 12, 16, eEOT (if applicable) and 17 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
W
 
Y
For Visit 2, an abbreviated safety laboratory (fasting) will be performed as follows: C-peptide only.  For further details see Section 5.3.3
Z
If a country is not participating in the CGM assessment, it is not necessary for their patients to attend for Visits 11 and 15 and these visits can be skipped.  For further 
details see Sections 5.2.5 and 6.2.2.2
AA
Blood ketone measurements must be performed at the site using the home monitoring device.  At visits where such measurements are requested and a fasted safety 
laboratory is also part of that visit (i.e. Visits 2, 6, 9, 12, 14, 16/eEOT [if applicable] and 17), the measurements should be done directly before or directly after the 
collection of laboratory samples and also in a fasted state.  At visits with a non-fasting safety laboratory or without a safety laboratory assessment (i.e. Visits 3, 5, 7, 8, 10 
and 13) measurements can be done non-fasted.  Regular (e.g. 2-3 times a week) measurements at home before breakfast are recommended throughout the trial 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.  For further details see 
Section 5.3.2.2.   


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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...............................................................................................18
MEDICAL BACKGROUND.............................................................................18
1.1
DRUG PROFILE................................................................................................19
1.2
1.2.1
Non-clinical assessment of safety.......................................................................19
1.2.2
Clinical pharmacokinetics..................................................................................19
Clinical pharmacokinetics – Type 2 diabetes mellitus..........................................19
1.2.2.1
1.2.3
Clinical efficacy and safety.................................................................................21
Clinical efficacy and safety – Type 2 diabetes mellitus........................................21
1.2.3.1
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....24
RATIONALE FOR PERFORMING THE TRIAL.........................................24
2.1
TRIAL OBJECTIVES........................................................................................24
2.2
BENEFIT - RISK ASSESSMENT.....................................................................24
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................27
OVERALL TRIAL DESIGN AND PLAN .......................................................27
3.1
3.1.1
Administrative structure of the trial .................................................................28
Data Monitoring Committee.................................................................................28
3.1.1.1
Clinical Event Committee – cardiovascular events ..............................................28
3.1.1.2
Clinical Event Committee – severe hypoglycaemia, DKA...................................29
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 ............................................................................31
3.3.2
Inclusion criteria .................................................................................................31
3.3.3
Exclusion criteria ................................................................................................32
3.3.4
Removal of patients from therapy or assessments...........................................34
Removal of individual patients .............................................................................34
3.3.4.1
Discontinuation of the trial by the Sponsor ..........................................................35
3.3.4.2
4.
TREATMENTS...................................................................................................36
TREATMENTS TO BE ADMINISTERED.....................................................36
4.1


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4.1.1
Identity of BI investigational product and comparator product....................36
4.1.2
Method of assigning patients to treatment groups...........................................37
4.1.3
Selection of doses in the trial..............................................................................37
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 ........................................................................39
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................39
4.1.7
Storage conditions...............................................................................................39
4.1.8
Drug accountability.............................................................................................40
Patient treatment compliance................................................................................40
4.1.8.1
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................41
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
Further safety and tolerability endpoints ..............................................................47
5.1.3.2
ASSESSMENT OF EFFICACY........................................................................48
5.2
5.2.1
HbA1c
.....................................................................48
5.2.2
Weight ..................................................................................................................48
5.2.3
Electronic diary...................................................................................................48
5.2.4
Systolic/diastolic blood pressure and pulse rate (vital signs)..........................49
5.2.5
Continuous glucose monitoring .........................................................................50
ASSESSMENT OF SAFETY.............................................................................52
5.3
5.3.1
Physical examination ..........................................................................................52
5.3.2
Home monitoring ................................................................................................52
Self blood glucose monitoring..............................................................................52
5.3.2.1
Ketone measurement.............................................................................................53
5.3.2.2
5.3.3
Safety laboratory parameters ............................................................................54
Follow-up on suspicion for urinary tract infections..............................................56
5.3.3.1
5.3.4
Electrocardiogram ..............................................................................................57
5.3.5
Other safety parameters.....................................................................................57
Assessment of hypoglycaemia rate.......................................................................57
5.3.5.1
Criteria for hypoglycaemic events........................................................................57
5.3.5.2
Assessment of cardiovascular events (CEC adjudication)....................................58
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Assessment of severe hypoglycaemia and DKA (CEC adjudication)..................58
5.3.5.4
5.3.6
Assessment of adverse events.............................................................................58
Definitions of AEs ................................................................................................58
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................61
 
APPROPRIATENESS OF MEASUREMENTS..............................................68
5.7
6.
INVESTIGATIONAL PLAN.............................................................................69
VISIT SCHEDULE.............................................................................................69
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................69
6.2
6.2.1
Screening, T1DM therapy optimisation and placebo run-in periods.............69
Screening visit (Visit 1) ........................................................................................69
6.2.1.1
T1DM therapy optimisation period (Visits 2, 3/3T and 4T).................................69
6.2.1.2
Placebo run-in period (Visit 5)..............................................................................70
6.2.1.3
6.2.2
Randomised treatment period ...........................................................................70
Randomisation visit (Visit 6)................................................................................71
6.2.2.1
Interim visits (Visits 7-15)....................................................................................71
6.2.2.2
6.2.3
End of treatment and follow-up period.............................................................72
End of treatment – completers (Visit 16 EOT).....................................................72
6.2.3.1
End of treatment - early discontinuations (eEOT) and withdrawals.....................72
6.2.3.2
Follow-up visit (Visit 17) - completers.................................................................73
6.2.3.3
Follow-up visit (Visit 17) – early discontinuations (eEOT) and withdrawals......73
6.2.3.4
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................75
STATISTICAL DESIGN - MODEL.................................................................75
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................75
7.2
PLANNED ANALYSES.....................................................................................78
7.3
7.3.1
Primary endpoint analyses.................................................................................79
Primary analysis of the primary endpoint.............................................................79
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.....................................................................................................84
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
CTMF
Clinical Trial Master File
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
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
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
HPLC-MS
High performance liquid chromatography – tandem mass spectrometry
HRQoL
Health Related Quality of Life
IB
Investigator’s Brochure
ICU
Intensive Care Unit


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IDF
International Diabetes Federation
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
ITT
Intention-to-Treat
LOCF
Last Observation Carried Forward
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
OC
Observed Cases
OPU
Operative Unit
PD
Pharmacodynamic
PGx
Pharmacogenomic
PK
Pharmacokinetics
PPS
Per Protocol Set
PR
Pulse Rate
RDC
Remote Data Capture
REP
Residual Effect Period
ROW
Rest of World
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
SPC
Summary of Product Characteristics
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
TDMAP
Trial Data Management and Analysis Plan
TIA
Transient Ischaemic Attack


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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 sulphonylurea, 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 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 10 mg and 25 mg in human studies.
According to the medication assignment planned in this trial, 66% of the patients will receive 
empagliflozin, and 33% 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 2 doses of empagliflozin (10 mg and 25 mg) to placebo in patients with T1DM as 
adjunctive to insulin therapy.  In total, 720 patients with T1DM who meet the entry criteria 
will be entered (randomised) in the trial. The randomised treatment will be double-blind (i.e. 
each patient will take 2 tablets a day, receiving one active treatment and one placebo
matching the alternative active treatment, or two placebos).
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 52 week double-blind treatment 
period in which they will receive either one of the 2 doses of empagliflozin or placebo in 
addition to their regular insulin therapy.  
After the 52 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 17); 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 17 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 below.
Figure 3.1: 1    Trial Design


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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.
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 
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.  


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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. 
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 events, including liver enzyme elevations.
For qualifying events, relevant source documents generated from any medical evaluations of 
these events will be requested including laboratory values, histological analysis, results of 
ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical reports from other 
physicians.  All evaluations will be performed in a blinded fashion. The assessments will be 
analysed based on empagliflozin data combined from multiple trials (i.e. on project level).
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 


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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 six week T1DM therapy optimisation period, followed by a two 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 baseline CGM profiles and 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 randomised
period is planned for 52 weeks in order to collect safety data for one year in patients with
T1DM, and to repeat the analysis of relevant efficacy endpoints in an exploratory manner.  A 
duration of 52 weeks is also sufficient time to assess the rate of hypoglycaemia over a 
prolonged treatment period.  
The three 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.
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 720 patients from around 135 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 


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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
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


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
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)
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
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


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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
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. Patient is unwilling, based on the Investigator’s judgement, to avoid use of paracetamol
(acetaminophen) containing drugs throughout the CGM monitoring periods, since this
may falsely raise CGM glucose readings
16. 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 
17. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. 
malaria, babesiosis, haemolytic anaemia) at Visit 1
18. Women who are pregnant, nursing, or who plan to become pregnant whilst in the trial
19. Alcohol or drug abuse within the 3 months prior to Visit 1 that would interfere with trial 
participation based on Investigator’s judgement 
20. Intake of an investigational drug in another trial within 30 days prior to Visit 1


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21. Patient not able to understand and comply with study requirements, including the use of 
an e-diary, based on Investigator’s judgement
22. 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 Section4.2) 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)

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 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 the 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 very important that assessments for each planned visit are 
still performed in accordance with the Flow Chart even if patients discontinue trial treatment.  
Patients who discontinue treatment prematurely will be followed up until the end of the 
study, unless they withdraw their consent for this to happen.  All assessments related to the 
primary and key secondary endpoints still have to be performed as if the patient had remained 


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on trial treatment.  Details of procedures to be followed for patients prematurely terminating 
the trial can be found in Sections 6.2.2 and 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 product 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:
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 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


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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 ratio, to either:
(i)
empagliflozin 10 mg
(ii)
empagliflozin 25 mg 
(iii) 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 
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.
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 7 occasions as indicated in the Flow 


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Chart, covering a period of 52 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
10 mg
Empagliflozin
25 mg
Total # units 
per dose
Timing
Placebo run-in period (open-label):
All patients
Matching 
placebo
Matching 
placebo
2 tablets
Once daily, 
morning
Treatment period (double-blind)
    Dose group
10 mg
Empagliflozin 
10 mg
Matching 
placebo
2 tablets
Once daily, 
morning
25 mg
Matching 
placebo
Empagliflozin 
25 mg
2 tablets
Once daily, 
morning
Placebo
Matching 
placebo
Matching 
placebo
2 tablets
Once daily, 
morning
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 
approximately 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 


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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.
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 


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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
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):


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%
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). 
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, 
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 when the first CGM period begins, 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.


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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 17), further adjustments to insulin therapy (both basal and bolus insulin) may 
be implemented as necessary to avoid hypoglycaemia and also hyperglycaemia to ensure 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 the 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 
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 
the 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 


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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 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. hospitalised 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.
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 must not take any paracetamol (acetaminophen) containing drugs 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.  
Any patient who already uses real-time CGM as part of their therapy for T1DM may continue 
to do so throughout the trial.  In addition, patients must wear the (blinded) trial CGM system 


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starting from Visit 2 (beginning of the T1DM therapy optimisation period), as shown in the 
Flow Chart and Section 5.2.5.  
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 17) of this trial.
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 and CGM.  

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 Week 26 cut-off 
date (to be defined in the Trial Statistical Analysis Plan, TSAP)

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 
Week 26 cut-off date (to be defined in the TSAP)

Change from baseline in body weight (kg) after 26 weeks

Change from baseline in the percentage of time spent in target glucose range of > 70 to ≤
180 mg/dL (> 3.9 to ≤10.0 mmol/L) as determined by continuous glucose monitoring 
(CGM) in Weeks 23 to 26

Change from baseline in the inter quartile range (IQR) as determined by CGM in Weeks 
23 to 26

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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Further safety and tolerability endpoints
5.1.3.2
Further exploratory endpoints to assess safety and tolerability are as shown below.

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 4
o
the rate will be calculated from the date of first study medication intake up to Day 
28 (end of week 4) or date of last study medication intake + 1 day inclusive, 
whichever occurs first

Frequency of patients with AESIs up to 26 and 52 weeks of treatment

Frequency of patients with hypoglycaemia up to 52 weeks of treatment

Hypoglycaemia rate per patient-year up to 52 weeks of treatment

Frequency of patients with severe hypoglycaemic AEs (for further details see Section 
5.3.5.2) up to 26 and 52 weeks of treatment (CEC adjudication results)

Frequency of patients with DKA up to 26 and 52 weeks of treatment (CEC adjudication 
results)

Frequency of patients with cardiovascular events up to 26 and 52 weeks of treatment
(CEC adjudication results)
 


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ASSESSMENT OF EFFICACY
5.2
5.2.1
HbA1c
 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.
 
 
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.   
In order to get comparable body weight values, it should ideally be performed in the 
following way:

fasting (except for Visits 1, 5, and 8 where patients attend the visit non-fasted)

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 17), 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 


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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.
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.


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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.
5.2.5
Continuous glucose monitoring 
The CGM system will be a commercially available system with single-use disposable 
electrochemical sensing elements. It will allow glucose levels to be recorded for up to 7 days 
at a time, after which a sensor change is required to continue CGM. Glucose values recorded 
by the CGM system will be blinded to both the patient and the Investigator/ designated site-
personnel to ensure unbiased data.  However, sites will be able to access information 
regarding the use of the system.
Prior to the first CGM period, patients will be trained in the correct use of the CGM system, 
including its set-up, sensor insertion, exchange and removal, and calibration using the SBGM 
device.  Refresher training should be provided at subsequent timepoints (as deemed 
appropriate by the Investigator or designated site-personnel).
Three periods of CGM will take place starting at the timepoints indicated in the Flow Chart.  
The first CGM period will last for 14 days; the second and third CGM periods will have a 
duration of 28 days.  These durations account for the natural variation due to sleep/wake, 
eating and activity patterns.  Every seven days after starting each CGM period, the sensor 
must be exchanged; where a clinic visit is not scheduled for this day, the patient should 
change the sensor at home.  If all visits are conducted according to the Flow Chart, and 
without the use of the permitted visits windows, this equates to (see Figure 5.2.5: 1 below):

the patient changing the sensor at home on 7 occasions

designated site-personnel inserting, or removing the sensor in the clinic on 6 occasions 
If clinic visits are scheduled making use of permitted visit windows (see Section 6.1), sensor 
exchange may not match that shown in Figure 5.2.5: 1; sensor exchange must still occur 
every 7 days after insertion.  


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Figure 5.2.5: 1 Trial timeline and CGM sensor changes
In case of sensor failure, or any difficulties with sensor exchange, patients will be instructed 
to contact the site.  In such cases the patients should be asked either to come to the site for 
sensor replacement or they must replace the sensor by themselves at home.
Sensors should be inserted at least 3 inches (7.62 cm) away from insulin infusion sets or 
injection sites.
The CGM data will be transferred to the vendor server for data collection and transfer.
CGM may not be performed in all countries participating in the trial; this will depend upon 
the local availability/importation of the chosen CGM system.
 
 
 
 
 
 
 
 


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ii.
90 minutes after beginning breakfast
 
 
 
 
 
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 17), 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 
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 an 8-point plasma glucose 
profile (for further details see Section 5.2.6).  Additional tests should be done as 


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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 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, 
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 


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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, 
12, 14, 16, eEOT (if applicable), and 17.  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, 
basophils, 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)

Triglycerides
o
direct measurement of LDL 
cholesterol (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, 12, 16, eEOT (if applicable) and 17
4
iPTH will be only be assessed at Visits 6, 8, 16 and eEOT (if applicable)
5
TSH will only be assessed at Visit 1 
6
Lipids will only be assessed at Visits 6, 12, 16, eEOT (if applicable), and 17


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Table 5.3.3: 2
Laboratory parameters – urine
Semi-quantitative (dipstick) urinalysis

Nitrite1

Protein

Ketones

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
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:

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 


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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 
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.


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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.
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.


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The latest list of “Always Serious AEs” can be found in the Remote Data Capture (RDC) 
system. These events should always be reported as SAEs as described in Section 5.3.7
Adverse events of Special Interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class.
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, 
unexplained 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.
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.


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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)
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


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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.
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


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
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).  
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 


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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. 
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].
Electronic devices have been selected as the method for PROs.  Use of a PRO instrument is 
advised when measuring a concept best known by the patient or best measured from the 
patient perspective (e.g. symptoms associated with hypoglycaemia).  PRO instruments should 
be shown to measure the concept they are intended to measure, and steps should be taken to 
ensure that patients are making entries according to the design of the trial and not, for 
example, just before a clinic visit [R12-5607].  Hence the selection of an electronic device 
over a paper-based alternative.      


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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 permitted visit windows 
are applied to a visit involving CGM, it must be ensured that the CGM sensor is still 
exchanged within its period of stability (i.e. 7 days since insertion), despite the use of the 
window.
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. At the relevant visits, it must also be ensured that the CGM 
sensor is still exchanged within its period of stability (i.e. 7 days since insertion) despite the 
re-scheduling of a visit.
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, 3/3T 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

From Visit 5, eligible patients will also start the first CGM period (in participating 
countries) and will continue this until Visit 6. If the patient wishes to perform the first 2 
hour start up calibration of the CGM system (using his/her glucose meter) whilst at the 
site, this should be taken into consideration when planning the order of assessments at 
this visit (for further details, refer to CGM system user guide).  If deemed necessary by 
the site personnel, patients can be contacted by phone in between these visits to ensure the 
correct performance of the CGM device.  Patients must also be reminded to change the 
CGM sensor at home, 7 days after its insertion at Visit 5

 
6.2.2
Randomised treatment period
The randomised treatment period is from Visit 6 to Visit 16 EOT. 
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. 


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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 7-15)
6.2.2.2

Visits 9, 12 and 14 should be done with the patient in a fasted state (i.e. no food or drink 
except water for 10 hours); Visits 7, 8, 10, 11, 13 and 15 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

 
 
 

At Visit 11, the second CGM period starts (for participating countries), and continues for 
28 days until Visit 12.   If deemed necessary by the site personnel, patients can be 
contacted by phone in between visits to ensure the correct performance of the CGM 
device.  Patients must also be reminded to change the CGM sensor at home, every 7 days 


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after its insertion at Visit 11.  For countries not participating in the CGM assessment, 
Visit 11 is not required  

At Visit 15, the third CGM period starts (for participating countries), and continues for 28 
days until Visit 16 at which point the transmitter and sensor will be removed from the 
patient.   If deemed necessary by the site personnel, patients can be contacted by phone in 
between visits to ensure the correct performance of the CGM device.  Patients must also 
be reminded to change the CGM sensor at home, every 7 days after its insertion at Visit 
15.  For countries not participating in the CGM assessment, Visit 15 is not required    

 
6.2.3
End of treatment and follow-up period
End of treatment – completers (Visit 16 EOT)
6.2.3.1
Patients who successfully complete the 52 week treatment period should have the 
assessments for Visit 16 performed, as indicated in the Flow Chart.  Patients who complete 
the full 52 week treatment period should be registered as completed in the IRT system.

Visit 16 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 17

 

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 17
End of treatment - early discontinuations (eEOT) and withdrawals
6.2.3.2
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 at Week 22
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 52 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 17

 

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 17) - completers
6.2.3.3
Patients who successfully complete the 52 week treatment period should have the 
assessments for Visit 17 performed, as indicated in the Flow Chart.  For these patients:

Visit 17 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 17 is complete
Follow-up visit (Visit 17) – early discontinuations (eEOT) and withdrawals
6.2.3.4
For patients who discontinue treatment prematurely prior to completion of 52 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 17.  Visit 17
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 17 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 12 (Week 26) – i.e. at Week 27 -
would next be followed up for Visit 13 (Week 34) after having completed an eEOT visit 
as soon as possible after Week 27, and a Visit 17 at Week 30  

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 12 (Week 26) and Visit 16 (Week
52) 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 key 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, CGM periods (in patients from participating countries) and the 


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collection of AEs and changes in concomitant therapy).  All other assessments 
 

Visit 16 EOT at 52 weeks will be the last visit for these patients, since Visit 17 will 
already have been completed 3 weeks after the eEOT Visit as explained above.  At Visit 
16 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 complete
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, and at the main analysis after 52 weeks, to collect data about the vital status as a 
minimum.
If study treatment is stopped prior to completion of 52 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 17 (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 study to
assess the efficacy, safety, tolerability, and PK of once daily oral doses of empagliflozin 10 
mg and 25 mg compared to placebo in patients with T1DM as adjunctive to insulin therapy.
This is a 52 week trial; however the efficacy endpoints will be assessed primarily in a 
confirmatory manner on 26 week data, and only assessed at 52 weeks in an exploratory 
manner. All analyses will be done after final database lock at 52 weeks.
The superiority of 2 doses of empagliflozin will be tested against placebo. A Bonferroni 
adjustment will correct for the parallel testing of the 2 doses in order to maintain a type I 
error rate of 0.05.  Each dose 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, 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 key secondary endpoints will be tested for superiority 
using a gatekeeping approach and sequential testing to maintain the type I error rate, see 
Section 7.2.
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, and CGM.
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%), and by the patients’ 
pre-existing insulin therapy (MDI versus CSII).  If necessary, and depending upon global 
distribution, entry of patients into a particular HbA1c stratum may be capped.  
NULL AND ALTERNATIVE HYPOTHESES
7.2
The following testing procedure will be used to evaluate the superiority for the primary 
endpoint for both empagliflozin 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 each individual empagliflozin dose 
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) for the 


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effectiveness analysis; see Section 7.3 for the analysis set definitions.  Both analyses will test 
the same null hypothesis:
H0,1: Mean change from baseline in HbA1c (%) after 26 weeks in the empagliflozin XXmg 
group = Mean change from baseline in HbA1c (%) after 26 weeks in the placebo group
will be tested against
H1,1: Mean change from baseline in HbA1c (%) after 26 weeks in the empagliflozin XXmg ≠ 
Mean change from baseline in HbA1c (%) after 26 weeks in the placebo group
where empagliflozin XXmg stands for empagliflozin 10 mg or 25 mg.
Following testing of the null hypothesis for both efficacy and effectiveness for HbA1c, within 
each dose group the alpha will be unequally split for testing the superiority of the key 
secondary endpoints. All tests will be two-sided. The null hypotheses for the key secondary 
endpoints are as follows:
H0,2: Mean change from baseline in body weight (kg) after 26 weeks in the empagliflozin 
XXmg group = Mean change from baseline in body weight (kg) after 26 weeks in the placebo
group
H0,3: Mean change from baseline in % time in range as determined by CGM in Weeks 23 to
26 in the empagliflozin XXmg group = Mean change from baseline in % time in range as 
determined by CGM in Weeks 23 to 26 in the placebo group
H0,4: Mean change from baseline in IQR as determined by CGM in Weeks 23 to 26 in the 
empagliflozin XXmg group = Mean change from baseline in IQR as determined by CGM in 
Weeks 23 to 26 in the placebo group
H0,5: Mean change from baseline in TDID (U/kg) after 26 weeks in the empagliflozin XXmg 
group = Mean change from baseline in TDID (U/kg) after 26 weeks in the placebo group
H0,6: Incidence rate of hypoglycaemia from Week 5 to Week 26 in the empagliflozin XXmg
group = Incidence rate of hypoglycaemia from Week 5 to Week 26 in the placebo group
H0,7: Incidence rate of hypoglycaemia from Week 1 to Week 26 in the empagliflozin XXmg 
group = Incidence rate of hypoglycaemia from Week 1 to Week 26 in the placebo group
H0,8: Mean change from baseline in SBP after 26 weeks in the empagliflozin XXmg group = 
Mean change from baseline in SBP after 26 weeks in the placebo group
H0,9: Mean change from baseline in DBP after 26 weeks in the empagliflozin XXmg group = 
Mean change from baseline in DBP after 26 weeks in the placebo group


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One-tenth of the alpha (α=0.0025) will be used to sequentially test H0,2, H0,3, H0,4 and H0,5. 
Nine-tenths of the alpha (α=0.0225) will be used to sequentially test H0,6 and H0,7. Depending 
on the success of each sequential testing, the alpha will contribute towards the significance
level for the sequential testing of H0,8 and H0,9 as follows:

If H0,2, H0,3, H0,4 and H0,5 are all rejected, but H0,6 or H0,7 are not rejected then 
α=0.0025 will contribute towards the testing of H0,8 and H0,9

If H0,6 and H0,7 are both rejected, but H0,2, H0,3, H0,4 or H0,5 are not rejected then
α=0.0225 will contribute towards the testing of H0,8 and H0,9

If all null hypotheses (H0,2 to H0,7) are rejected, H0,8 and H0,9 will be tested at the level 
α = 0.0025 + 0.0225 = 0.025 
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.
Table 7.2: 1 Summary of endpoint testing strategy
Empagliflozin 10 mg
Empagliflozin 25 mg
Step 1:
Primary 
endpoint
(efficacy)
Bonferroni,
two-sided 
(alpha=0.025)
If H0,1 is rejected at α=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 H0,1 is rejected at α=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 H0,1 is rejected at α=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 H0,1 is rejected at α=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


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Step 3: Key
secondary 
endpoints 
Sequential 
testing, 
Gatekeeping
PLANNED ANALYSES
7.3
To account for the testing of two doses of empagliflozin, 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 and 
sequential testing strategy will then be employed for tests of the key secondary endpoints 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).


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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 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 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 
primary endpoint will be excluded from the PPS. Details regarding the definitions of IPVs 
will be provided in the 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 


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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
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
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.
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 change from baseline in percentage time spent in target glucose range and the change 
from baseline in IQR in Weeks 23 to 26 weeks as determined by CGM will be analysed using 
an ANCOVA model.  The statistical model will be:
<CGM endpoint> change from baseline =  overall mean + treatment + pre-existing insulin 
therapy + continuous baseline HbA1c + continuous 
baseline eGFR + continuous baseline <respective 
CGM endpoint> + random error 
Treatment and pre-existing insulin therapy are fixed classification effects and baseline HbA1c,
baseline eGFR and baseline <CGM endpoint> are linear covariates. The random error is 
assumed to be normally distributed with mean 0 and unknown variance σ2. The analysis will 
be performed on the FAS, including all available on-treatment data. 
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 Week 26 cut-off date.  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 


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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 Week 26 cut-off date.
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 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 


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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 see 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, % time in range as 
determined by CGM, IQR as determined by CGM, 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 2 active 
dose groups of empagliflozin.  Patients will be randomised in blocks to the 3 study treatments 
in a 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%), and by the patients’ pre-existing insulin therapy 
(MDI versus CSII).  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.


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DETERMINATION OF SAMPLE SIZE
7.7
Based on previous experience with empagliflozin in 
 it is 
estimated that the change in HbA1c from baseline after 26 weeks of treatment is 0.3% in 
empagliflozin (10 mg and 25 mg) and 0% in placebo and that the standard deviation of this 
difference is 0.9%. 
As 2 dose levels of empagliflozin are being investigated, 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%.  
Software package nQuery version 7.0 was used to derive the sample size.
Given that there are 3 treatment groups, a total sample size of 720 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 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
12-Apr-2016
EudraCT number
2014-001922-14
BI Trial number
1245.69
BI Investigational Products
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 52 weeks in patients with Type 1 Diabetes 
Mellitus (EASE-2)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
x
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Main criteria for inclusion:  
“Insulin should be either MDI or CSII with a total 
daily dose ≤ 1.5 U/kg at Visit 1”
Has been changed to:
“Insulin should be either MDI or CSII with a total 
daily dose ≥ 0.3 U/kg and ≤ 1.5 U/kg at Visit 1”
Rationale for change
Correction of omitted text in original protocol
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Endpoints:

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 
continuous glucose monitoring (CGM) in 


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weeks 23 to 26
Has been changed to:

change from baseline in the percentage of 
time spent in target glucose range of > 70 to ≤
180 mg/dL (> 3.9 to ≤10.0 mmol/L) as 
determined by continuous glucose monitoring 
(CGM) in weeks 23 to 26
Rationale for change
Clarification
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Statistical methods: 
“The primary treatment comparisons will be the 
Bonferroni adjusted contrast between each dose of 
empagliflozin and placebo at week 26.
The key secondary endpoints will then be analysed 
using a gatekeeping approach, with unequal 
splitting of the alpha, and sequential testing.”
And
“The key secondary endpoint of 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 after 26 weeks will be 
analysed using analysis of covariance (ANCOVA), 
with terms for treatment, pre-existing insulin 
therapy, continuous baseline HbA1c, continuous 
baseline eGFR and continuous baseline time in 
target range.”
Has been changed to:
“The primary treatment comparisons will be the 
Bonferroni adjusted contrast between each dose of 
empagliflozin 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 


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hypothesis is rejected for both the efficacy and 
effectiveness analysis then the key secondary 
endpoints will be tested in a confirmatory way 
using a gatekeeping approach, with unequal 
splitting of the alpha, and sequential testing.”
And:
“The key secondary endpoint of change from 
baseline in the percentage of time spent in target 
glucose range of > 70 to ≤180 mg/dL (> 3.9 to ≤
10.0 mmol/L) as determined by CGM after 26 
weeks will be analysed using analysis of 
covariance (ANCOVA), with terms for treatment, 
pre-existing insulin therapy, continuous baseline 
HbA1c, continuous baseline eGFR and continuous 
baseline time in target range.”
Rationale for change
Adjustments based on regulatory feedback; 
clarification
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
Row for vital signs – brackets have been added 
around the assessment at Visit 3/3T
Rationale for change
If Visit 3 is performed as a telephone visit, vital 
signs are not required
Section to be changed
FLOW CHART
Description of change
“Blood ketones (site) – home monitoring deviceAA” 
has been added as an assessment at the following 
visits: 2, 3, 5 (-14), 6, 7, 8, 9, 10, 12, 13, 14, 16 
EOT, eEOT Early Discnn Only, and 17.
For Visit 3/3T – brackets have been added around 
the assessment
Footnote AA has been added: 
“Blood ketone measurements must be performed at 
the site using the home monitoring device.  At 


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visits where such measurements are requested and 
a fasted safety laboratory is also part of that visit 
(i.e. Visits 2, 6, 9, 12, 14, 16/eEOT [if applicable] 
and 17), the measurements should be done directly 
before or directly after the collection of laboratory 
samples and also in a fasted state.  At visits with a 
non-fasting safety laboratory or without a safety 
laboratory assessment (i.e. Visits 3, 5, 7, 8, 10 and 
13) measurements can be done non-fasted.  Regular 
(e.g. 2-3 times a week) measurements at home 
before breakfast are recommended throughout the 
trial 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.  For further details see Section 5.3.2.2.”   
Rationale for change
Additional safety monitoring and alignment with 
sister trial 1245.72   
If Visit 3 is performed as a telephone visit, blood 
ketones 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
Alignment with sister trial 1245.72
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 


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telephone visit (3T), if deemed sufficient based 
on Investigator judgement, or a clinic visit; if 
performed as a telephone visit, assessments in 
brackets do not have to be performed”
Description of 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.”
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 R
“For further details see Section 5.3.2.2”
Has been changed to: 
“For further details see Footnote AA and Section 
5.3.2.2”
Rationale for change
Addition of new footnote AA
Section to be changed
FLOW CHART
Description of change
Footnote S
“The patient must change the sensor at home on 
days where a sensor change is due but where a 
clinic visit is not scheduled.  For further details see 
Sections 5.2.5 and 6.1”
Has been changed to:
“The patient should change the sensor at home on 


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days where a sensor change is due but where a 
clinic visit is not scheduled.  For further details see 
Sections 5.2.5 and 6.1”
Rationale for change
Clarification
Section to be changed
ABBREVIATIONS
Description of change
The following abbreviations have been added:
“CV
Coefficient of Variation
IQR
Inter Quartile Range
MAGE
Mean Amplitude of Glycaemic 
Excursions
mITT
Modified Intention-to-Treat”
Rationale for change
New abbreviation required due to modified text in 
the revised protocol
Section to be changed
1.2.3.1 Clinical efficacy and safety – Type 2 
diabetes mellitus
Description of change
“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:
“Approximately 8700 patients with T2DM have 
been treated with empagliflozin in research studies, 
of which approximately 4900 have been treated for 
more than 52 weeks.  At the end of 2014 
approximately 8000 patients are still participating 
in ongoing long-term studies with empagliflozin.”  
Rationale for change
Alignment of protocol with latest edition of 
Investigator’s brochure for empagliflozin
Rationale for 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


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Section to be changed
In all of the above sections “c01838761”
Has been changed to:
“c01678844”
Description of change
Administrative change
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.  
……..
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 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.


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…….
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; additional safety monitoring and 
alignment with sister trial 1245.72
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.”  
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
3.1.1.4 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 


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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.”
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 events, 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
3.3.2 Inclusion criteria
Description of change
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 > 0.3% between Visit 1 and Visit 
5
Has been changed to:
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
Rationale for change
Alignment with sister trial 1245.72
Section to be changed
3.3.3 Exclusion criteria
Description of change
4.
Occurrence of severe hypoglycaemia 
involving coma and/or seizure that required 


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hospitalisation or hypoglycaemia-related 
treatment by an emergency physician or 
paramedic within 3 months prior to 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
Rationale for change
Adjustment of eligibility for safety reasons, and 
clarification
Section to be changed
3.3.3 Exclusion criteria
Description of change
5.
Occurrence of severe DKA (i.e. a pH of < 7.0
or prolonged Intensive Care Unit [ICU]
admission exceeding two days) requiring 
hospitalisation within 3 months prior to 
Visit 1 
Has been changed to:
5.
Occurrence of DKA within 3 months prior to 
Visit 1 and until randomisation
Rationale for change
Adjustment of eligibility for safety reasons, 
alignment with sister trial 1245.72, and 
clarification
Section to be changed
3.3.3 Exclusion criteria
Description of change
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
Has been changed to:
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
Rationale for change
Clarification


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Section to be changed
3.3.3 Exclusion criteria
Description of change
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:
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
Clarification
Section to be changed
3.3.3 Exclusion criteria
Description of change
15. Patient must be 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
Has been changed to:
15. Patient is unwilling, based on the 
Investigator’s judgement, to avoid use of
paracetamol (acetaminophen) containing 
drugs throughout the CGM monitoring 
periods, since this may falsely raise CGM 
glucose readings
Rationale for change
Correction
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
“Patients who discontinue or withdraw from the 
study after randomisation will be considered as 
“early discontinuations” and the reason for this 
premature discontinuation must be recorded in the 
eCRF. The data will be included in the trial 
database and will be reported.
Patients who discontinue treatment prematurely 
will be followed up until the end of the study.  
Details of procedures to be followed for patients 
prematurely terminating the trial can be found in 
Section 6.2.3.”  


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Has been changed to:
“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 the 
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 very important 
that assessments for each planned visit are still 
performed in accordance with the Flow Chart 
even if patients discontinue trial treatment.  
Patients who discontinue treatment prematurely 
will be followed up until the end of the study, 
unless they withdraw their consent for this to 
happen.  All assessments related to the primary 
and key secondary endpoints still have to be 
performed as if the patient had remained on 
trial treatment.  Details of procedures to be 
followed for patients prematurely terminating the 
trial can be found in Sections 6.2.2 and 6.2.3.”  
Rationale for change
Adjustments based on regulatory feedback and 
alignment with sister trial 1245.72
Section to be changed
4.1.8.1 Patient treatment compliance
Description of change
“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 
formula:”
And
“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.”
Has been changed to:


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“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):”
And
“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
“From Visit 2, therapy for T1DM should be 
optimised (e.g. review of 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.”  
Has been changed to:
“From Visit 2, therapy for T1DM should be 
optimised (e.g. review of blood glucose values,
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.”  
Rationale for change
Alignment with sister trial 1245.72
Section to be changed
4.2.1 Rescue medication, emergency procedures, 
and additional treatments
Description of change
“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 hypoglycaemia despite adequate 
carbohydrate intake.


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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.  Thereafter and until the 
end of the trial (Visit 17), further adjustments to 
insulin therapy (both basal and bolus insulin) may 
be implemented as necessary to avoid 
hypoglycaemia.
The Sponsor will also 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 is started and stopped 
respectively. Any insulin dose change or 
adjustment must be based on laboratory tests or 
SBGM.”
Has been changed to:
“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 


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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 17), further adjustments to insulin 
therapy (both basal and bolus insulin) may be 
implemented as necessary to avoid hypoglycaemia 
and also hyperglycaemia to ensure 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 the 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 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 the trial to allow 
Investigators to follow their local standard of 
care guidelines for the management of blood 
glucose.” 
Rationale for change
Clarification and optimisation of suggested insulin 
titration; additional safety monitoring and 
alignment with sister trial 1245.72
Section to be changed
4.2.2.2 Restrictions on diet and life style
Description of change
“Any patient who already uses real-time CGM as 
part of their therapy for T1DM should refrain from 
using the system throughout the trial starting from 
Visit 2 (beginning of the T1DM therapy 


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optimisation period) until Visit 16/eEOT 
(whichever comes first).”   
And
“Patients will be reminded to follow the 
recommended dietary and physical activity plan 
during the study.  Extreme diets (e.g. ketogenic 
diets) should be avoided.”
Has been changed to:
“Any patient who already uses real-time CGM as 
part of their therapy for T1DM may continue to 
do so throughout the trial.  In addition, patients 
must wear the (blinded) trial CGM system 
starting from Visit 2 (beginning of the T1DM 
therapy optimisation period), as shown in the 
Flow Chart and Section 5.2.5.”   
And
“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.”
Rationale for change
Alignment with sister trial 1245.72 and 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 and CGM (1 week of evaluable 
data required).”  
And

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 continuous 
glucose monitoring (CGM) in Weeks 23 to 26 


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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 and CGM.” 
And

Change from baseline in the percentage of time 
spent in target glucose range of > 70 to ≤180 
mg/dL (> 3.9 to ≤10.0 mmol/L) as determined 
by continuous glucose monitoring (CGM) in 
Weeks 23 to 26 
Rationale for change
Clarification
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section to be changed
5.2.2 Weight
Description of change

fasting (except for Visits 1, 5, and 8)
Has been changed to:

fasting (except for Visits 1, 5, and 8 where 
patients attend the visit non-fasted)
Rationale for change
Clarification
Section to be changed
5.2.4 Systolic/diastolic blood pressure and pulse 
rate (vital signs)
Description of change
“The BP measurement should be performed three 
times at each timepoint and the mean value of the 
measurements will be entered in the eCRF.”
And
“For calculation of mean values, decimal places 


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should be rounded to integers (e.g. a DBP of 94.5 
would be rounded to 95 mmHg and a DBP of 109.4 
would be rounded to 109 mmHg).”
Has been changed to:
“The BP measurement should be performed three 
times at each timepoint and the mean value of the 
measurements will be analysed.”
Rationale for change
Correction of errors
Section to be changed
5.2.5 Continuous glucose monitoring
Description of change
“Every seven days after starting each CGM period, 
the sensor must be exchanged; where a clinic visit 
is not scheduled for this day, the patient must 
change the sensor at home.”  
Has been changed to:
“Every seven days after starting each CGM period, 
the sensor must be exchanged; where a clinic visit 
is not scheduled for this day, the patient should
change the sensor at home.”  
Rationale for change
Clarification
Section to be changed
5.3.2.2 Ketone measurement
Description of change
“Regular (e.g. once daily) measurements might 
also be agreed upon with the patient 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) or 
contact their trial site.”
Has been changed to:
“Regular (e.g. 2-3 times a week) measurements 
before breakfast are recommended throughout 
the trial 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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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.”
Rationale for change
Additional safety monitoring, alignment with sister 
trial 1245.72
Section to be changed
 
 
 
 
 
Section to be changed
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)
Description of change
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
Title “T1DM therapy optimisation period (Visits 2, 
3 and 4T)”
Has been changed to:
“T1DM therapy optimisation period (Visits 2, 3/3T
and 4T)”


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And

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)

 
 

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
6.2.1.3 Placebo run-in period (Visit 5)
Description of change

….. “If the patient wishes to perform the 2 hour 
start up calibration of the CGM system (using 
his/her glucose meter) whilst at the site, this 
should be taken into consideration when 
planning the order of assessments at this visit 
(for further details, refer to CGM system user 
guide).”…….  
Has been changed to:

….. “If the patient wishes to perform the first 2 
hour start up calibration of the CGM system 
(using his/her glucose meter) whilst at the site, 
this should be taken into consideration when 
planning the order of assessments at this visit 
(for further details, refer to CGM system user 
guide).”…….  


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Rationale for change
Clarification
Section to be changed
6.2.3.1 End of treatment – completers (Visit 16 
EOT)
Description of change

Visit 16 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, and to bring all 
used/unused medication with them to the visit.
Has been changed to:

Visit 16 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.
Rationale for change
Clarification
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, the 
key secondary endpoints will be tested for 
superiority using a gatekeeping approach and 
sequential testing to maintain the type I error rate, 
see Section 7.2.
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 2 week run-in period for 
the mean daily insulin requirement, and CGM 
(only 1 week of available data required).”
Has been changed to:
“Following the efficacy analysis (on-treatment 
data only) of the primary endpoint, change from 
baseline in HbA1c after 26 weeks, an effectiveness 
analysis (on-and off-treatment data) will be
performed in a hierarchical manner.  If the null 


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hypothesis is rejected for both the efficacy and 
effectiveness analysis the key secondary endpoints 
will be tested for superiority using a gatekeeping 
approach and sequential testing to maintain the 
type I error rate, see Section 7.2.
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, 
and CGM (only 1 week of available data 
required).”
Rationale for change
Adjustments based on regulatory feedback
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%), and by the patients’ pre-existing 
insulin therapy (MDI versus CSII).”
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%), and by the patients’ pre-existing 
insulin therapy (MDI versus CSII).  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 HYPOTHESIS
Description of change
“Both doses will be tested in parallel on the Full 
Analysis Set (FAS).”
And
“Following testing of the null hypothesis for 
HbA1c, within each dose group the alpha will be 
unequally split for testing the superiority of the key 


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secondary endpoints.”  
Has been changed to:
“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) for 
the effectiveness analysis; see Section 7.3 for the 
analysis set definitions.  Both analyses will test 
the same null hypothesis:”
And
“Following testing of the null hypothesis for both 
efficacy and effectiveness for HbA1c, within each 
dose group the alpha will be unequally split for 
testing the superiority of the key secondary 
endpoints.”  
Rationale for change
Adjustments based on regulatory feedback
Section to be changed
Table 7.2: 1 Summary of endpoint testing strategy
Description of change
“Step 1: Primary endpoint
Bonferroni, two-sided (alpha=0.025)
Empagliflozin 10 mg
If H0,1 is rejected at α=0.025 level then go to step 2, 
otherwise procedure is stopped and subsequent 
tests will be done only for exploratory purposes
Empagliflozin 25 mg
If H0,1 is rejected at α=0.025 level then go to step 2, 
otherwise procedure is stopped and subsequent 
tests will be done only for exploratory purposes”
Has been changed to:
“Step 1: Primary endpoint (efficacy)
Bonferroni, two-sided (alpha=0.025)
Empagliflozin 10 mg
If H0,1 is rejected at α=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


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Empagliflozin 25 mg
If H0,1 is rejected at α=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”
Rationale for change
Adjustments based on regulatory feedback
Section to be changed
Table 7.2: 1 Summary of endpoint testing strategy
Description of change
“Step 2: Key secondary endpoints”
Has been changed to:
“Step 3: Key secondary endpoints”
Rationale for change
Adjustments based on regulatory feedback
Section to be changed
Table 7.2: 1 Summary of endpoint testing strategy
Description of change
The following text has been added:
“Step 2: Primary endpoint (effectiveness)
Empagliflozin 10 mg
If H0,1 is rejected at α=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
Empagliflozin 25 mg
If H0,1 is rejected at α=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”
Rationale for change
Adjustments based on regulatory feedback
Section to be changed
7.3 PLANNED ANALYSES
Description of change
“To account for the testing of two doses of 
empagliflozin, 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).”  
And
“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 


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least one on-treatment HbA1c measurement.”
Has been changed to:
“To account for the testing of two doses of 
empagliflozin, 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).”  
And
“The primary efficacy 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.  The 
effectiveness analysis of the primary endpoint 
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 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 text has been added to the end of 


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the section:
“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 based on regulatory feedback
Section to be changed
7.3.1.2.1 Sensitivity analyses
Description of change
“In order to check the robustness of the primary 
analysis result to missing data handling or 
premature treatment discontinuation, sensitivity 
analyses will be performed as follows:

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

Multiple imputation of HbA1c change from 
baseline after 26 weeks is planned for on- and 
off-treatment values for the three treatment 
groups individually.  This analysis will be 
performed based on all randomised patients 
who have a baseline HbA1c measurement”
Has been changed to:
“In order to check the robustness of the primary 
analysis result to missing data handling or 
premature treatment discontinuation, sensitivity 
analyses will be performed as follows:

Multiple imputation of HbA1c change from 
baseline after 26 weeks is planned for on- and 
off-treatment values for the three treatment 
groups individually.  This analysis will be 
performed based on all randomised patients 
who have a baseline HbA1c measurement” 
Rationale for change
Adjustments based on regulatory feedback
Section to be changed
7.3.2.1 Key secondary endpoints – confirmatory 
analyses
Description of change
“The analysis will be performed on the FAS of 
patients with at least 1 week of evaluable CGM 


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data at baseline and 1 week of evaluable CGM data 
between Week 23 and 26, including all available 
on-treatment data.”
And
“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.”  
Has been changed to:
“The analysis will be performed on the FAS, 
including all available on-treatment data.”
And
“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.”  
Rationale for change
Clarification; correction of error
Section to be changed
 
 
 
Section to be changed
7.4 INTERIM ANALYSES
Description of change
“There is no interim analysis planned for this trial.”


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Has been changed to:
“There is no interim analysis planned for this trial 
but the conduct of the trial will be monitored by 
a DMC.  For further details see Section 3.1.1.1.”
Rationale for change
Alignment with sister trial 1245.72
Section to be changed
7.6 RANDOMISATION
Description of change
“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 with entry into the ≥ 60 
mL/min/1.73 m2 strata capped at 85% of the total 
trial population), baseline HbA1c (< 8.5% versus ≥ 
8.5%), and by the patients’ pre-existing insulin 
therapy (MDI versus CSII).”  
Has been changed to:
“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%), and by the patients’ pre-existing insulin 
therapy (MDI versus CSII).  If necessary, and 
depending upon global distribution, entry of 
patients into a particular HbA1c stratum may be 
capped.”     
Rationale for change
Correction of error; to ensure an adequate number 
of patients with an HbA1c > 8.5% are included in 
the trial
Section to be changed
8. INFORMED CONSENT, DATA 
PROTECTION, TRIAL RECORDS
Description of change
“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).”
Has been changed to:
“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 


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protocol or of ICH GCP.”
Rationale for change
Correction of error


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Number of global amendment
2
Date of CTP revision
04-Jan-2017
EudraCT number
2014-001922-14
BI Trial number
1245.69
BI Investigational Products
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 52 weeks in patients with Type 1 Diabetes 
Mellitus (EASE-2)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
x
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Endpoints:

…..

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 the percentage of time 
spent in target glucose range of > 70 to ≤ 180 
mg/dL (> 3.9 to ≤ 10.0 mmol/L) as determined 
by continuous glucose monitoring (CGM) in 
weeks 23 to 26

change from baseline in systolic blood pressure 
(SBP) after 26 weeks

…..
And
Safety criteria:
“…..


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Frequency of patients with adverse events of 
special interest (AESIs):

hepatic injury

decreased renal function

diabetic ketoacidosis (DKA)

severe hypoglycaemic episodes
Frequency of patients with hypoglycaemia
…..”
And
Statistical methods:
“The key secondary endpoint of change from 
baseline in the percentage of time spent in target 
glucose range of > 70 to ≤ 180 mg/dL (> 3.9 to ≤ 
10.0 mmol/L) as determined by CGM after 26 
weeks will be analysed using analysis of 
covariance (ANCOVA), with terms for treatment, 
pre-existing insulin therapy, continuous baseline 
HbA1c, continuous baseline eGFR and continuous 
baseline time in target range.”
Has been changed to:

…..

change from baseline in body weight (kg) after 
26 weeks

change from baseline in the percentage of 
time spent in target glucose range of > 70 to 
≤ 180 mg/dL (> 3.9 to ≤ 10.0 mmol/L) as 
determined by continuous glucose 
monitoring (CGM) in weeks 23 to 26

change from baseline in the inter quartile 
range (IQR) as determined by CGM in 
weeks 23 to 26

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

…..
And 
“…..
Frequency of patients with adverse events of 
special interest (AESIs):


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
hepatic injury

decreased renal function

diabetic ketoacidosis (DKA)

severe hypoglycaemic episodes

events involving lower limb amputation
Frequency of patients with hypoglycaemia
…..”
And
“The key secondary endpoints of change from 
baseline in the percentage of time spent in target 
glucose range of > 70 to ≤ 180 mg/dL (> 3.9 to ≤ 
10.0 mmol/L) as determined by CGM in Weeks 23 
to 26 and change from baseline in IQR as 
determined by CGM in Weeks 23 to 26 will be 
analysed using analysis of covariance (ANCOVA), 
with terms for treatment, pre-existing insulin 
therapy, continuous baseline HbA1c, continuous 
baseline eGFR and continuous baseline of the 
respective CGM endpoint.”
Rationale for change
To highlight the importance of CGM-related 
endpoints “time in range” and “IQR” as key 
secondary endpoints given that SGLT-2 inhibitor 
treatment in Type 1 diabetes mellitus may improve 
the burden of glycaemic variability which remains 
a fundamental treatment challenge in the 
management of this disease.
To meet new regulatory requirements
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:


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“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 sulphonylurea, a PPARγ agonist, dipeptidyl 
peptidase-4 inhibitors, or insulin.”
Rationale for change
Alignment of protocol with latest edition of
Investigator’s brochure for empagliflozin
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criteria 10:
“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 
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 no longer accepted as a method 
of permanent sterilisation.  Instead it is considered 
a highly effective birth control method.   
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


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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 requiring screen failure of 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 randomisation 
Section to be changed
4.2.1 Rescue medication, emergency procedures, 
and additional treatments
Description of change
“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:
“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
Section to be changed
5.1.2 Secondary endpoints
Description of change

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  


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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 the percentage of time 
spent in target glucose range of > 70 to ≤180 
mg/dL (> 3.9 to ≤10.0 mmol/L) as determined 
by continuous glucose monitoring (CGM) in 
Weeks 23 to 26 

Change from baseline in systolic blood pressure 
(SBP) after 26 weeks

Change from baseline in diastolic blood 
pressure (DBP) after 26 weeks
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 


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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 Week 26 cut-off 
date (to be defined in the Trial Statistical 
Analysis Plan, TSAP)

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 Week 
26 cut-off date (to be defined in the 
TSAP)

Change from baseline in body weight (kg) after 
26 weeks

Change from baseline in the percentage of 
time spent in target glucose range of > 70 to 
≤180 mg/dL (> 3.9 to ≤10.0 mmol/L) as 
determined by continuous glucose 
monitoring (CGM) in Weeks 23 to 26

Change from baseline in the inter quartile 
range (IQR) as determined by CGM in 
Weeks 23 to 26

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
Rationale for change
To highlight the importance of CGM-related 
endpoints “time in range” and “IQR” as key 
secondary endpoints given that SGLT-2 inhibitor 
treatment in Type 1 diabetes mellitus may improve 
the burden of glycaemic variability which remains 


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a fundamental treatment challenge in the 
management of this disease.
Clarification
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section to be changed
5.3.6.1 Definitions of AEs
Description of change
The following text has been 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).


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Not included in this definition are debridement 
(removal of callus or dead tissue), procedures on a 
stump (like stump revision, drainage of an abscess, 
wound revision etc.) and other procedures (e.g., 
nail resection or removal) without a concomitant 
resection of a limb (amputation or disarticulation).
Each lower limb amputation, disarticulation, or 
auto-amputation should be reported separately. The 
SAE report should include the date of the 
procedure, the level of amputation or 
disarticulation, the medical condition(s) leading to 
the procedure and if the patient had some of the 
known risk factor(s) for lower limb amputation.”
Rationale for change
To meet new regulatory requirements
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 for the rate of 
hypoglycaemia and the run-in period from Visit 5 
to Visit 6 for the mean daily insulin requirement,
and CGM (only 1 week of available data 
required).”
Has been changed to:
“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, 
and CGM.”
Rationale for change
Clarification
Section to be changed
7.2 NULL AND ALTERNATIVE HYPOTHESIS
Description of change
“H0,2: Mean change from baseline in body weight 
(kg) after 26 weeks in the empagliflozin XXmg 
group = Mean change from baseline in body weight
(kg) after 26 weeks in the placebo group


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H0,3: Mean change from baseline in TDID (U/kg) 
after 26 weeks in the empagliflozin XXmg group = 
Mean change from baseline in TDID (U/kg) after
26 weeks in the placebo group
H0,4: Mean change from baseline in % time in 
range as determined by CGM after 26 weeks in the 
empagliflozin XXmg group = Mean change from 
baseline in % time in range as determined by CGM
after 26 weeks in the placebo group
H0,5: Incidence rate of hypoglycaemia from Week 5 
to Week 26 in the empagliflozin XXmg group = 
Incidence rate of hypoglycaemia from Week 5 to 
Week 26 in the placebo group
H0,6: Incidence rate of hypoglycaemia from Week 1 
to Week 26 in the empagliflozin XXmg group = 
Incidence rate of hypoglycaemia from Week 1 to 
Week 26 in the placebo group
H0,7: Mean change from baseline in SBP after 26 
weeks in the empagliflozin XXmg group = Mean 
change from baseline in SBP after 26 weeks in the
placebo group
H0,8: Mean change from baseline in DBP after 26 
weeks in the empagliflozin XXmg group = Mean 
change from baseline in DBP after 26 weeks in the
placebo group
One-tenth of the alpha (α=0.0025) will be used to 
sequentially test H0,2, H0,3 and H0,4.  Nine-tenths of 
the alpha (α=0.0225) will be used to sequentially 
test H0,5 and H0,6.  Depending on the success of 
each sequential testing, the alpha will contribute 
towards the significance level for the sequential 
testing of H0,7 and H0,8 as follows:

If H0,2, H0,3 and H0,4 are all rejected, but 
H0,5 or H0,6 are not rejected then α=0.0025 
will contribute towards the testing of H0,7 
and H0,8

If H0,5 and H0,6 are both rejected, but H0,2, 
H0,3 or H0,4 are not rejected then α=0.0225 
will contribute towards the testing of H0,7 


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and H0,8

If all null hypotheses (H0,2 to H0,6) are 
rejected, H0,7 and H0,8 will be tested at the 
level α = 0.0025 + 0.0225 = 0.025 
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.”
Has been changed to:
“H0,2: Mean change from baseline in body weight 
(kg) after 26 weeks in the empagliflozin XXmg 
group = Mean change from baseline in body weight
(kg) after 26 weeks in the placebo group
H0,3: Mean change from baseline in % time in 
range as determined by CGM in Weeks 23 to 26 
in the empagliflozin XXmg group = Mean 
change from baseline in % time in range as 
determined by CGM in Weeks 23 to 26 in the 
placebo group
H0,4: Mean change from baseline in IQR as 
determined by CGM in Weeks 23 to 26 in the 
empagliflozin XXmg group = Mean change from 
baseline in IQR as determined by CGM in 
Weeks 23 to 26 weeks in the placebo group
H0,5: Mean change from baseline in TDID (U/kg) 
after 26 weeks in the empagliflozin XXmg group = 
Mean change from baseline in TDID (U/kg) after
26 weeks in the placebo group
H0,6: Incidence rate of hypoglycaemia from Week 5 
to Week 26 in the empagliflozin XXmg group = 
Incidence rate of hypoglycaemia from Week 5 to 
Week 26 in the placebo group
H0,7: Incidence rate of hypoglycaemia from Week 1 
to Week 26 in the empagliflozin XXmg group = 
Incidence rate of hypoglycaemia from Week 1 to 
Week 26 in the placebo group
H0,8: Mean change from baseline in SBP after 26 


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weeks in the empagliflozin XXmg group = Mean 
change from baseline in SBP after 26 weeks in the
placebo group
H0,9: Mean change from baseline in DBP after 26 
weeks in the empagliflozin XXmg group = Mean 
change from baseline in DBP after 26 weeks in the
placebo group
One-tenth of the alpha (α=0.0025) will be used to 
sequentially test H0,2, H0,3, H0,4 and H0,5.  Nine-
tenths of the alpha (α=0.0225) will be used to 
sequentially test H0,6 and H0,7.  Depending on the 
success of each sequential testing, the alpha will 
contribute towards the significance level for the 
sequential testing of H0,8 and H0,9 as follows:

If H0,2, H0,3, H0,4 and H0,5 are all rejected, 
but H0,6 or H0,7 are not rejected then 
α=0.0025 will contribute towards the 
testing of H0,8 and H0,9

If H0,6 and H0,7 are both rejected, but H0,2, 
H0,3, H0,4 or H0,5 are not rejected then
α=0.0225 will contribute towards the 
testing of H0,8 and H0,9

If all null hypotheses (H0,2 to H0,7) are 
rejected, H0,8 and H0,9 will be tested at the 
level α = 0.0025 + 0.0225 = 0.025 
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.”
Rationale for change
To highlight the importance of CGM-related 
endpoints “time in range” and “IQR” as key 
secondary endpoints given that SGLT-2 inhibitor 
treatment in Type 1 diabetes mellitus may improve 
the burden of glycaemic variability which remains 
a fundamental treatment challenge in the 
management of this disease.
Section to be changed
Table 7.2: 1 Summary of endpoint testing strategy
Description of change
Step 3: Key secondary endpoints
Sequential testing, Gatekeeping
Empagliflozin 10 mg


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And
Empagliflozin 25 mg
Has been changed to:
Empagliflozin 10 mg


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And
Empagliflozin 25 mg
Rationale for change
To highlight the importance of CGM-related 
endpoints “time in range” and “IQR” as key 
secondary endpoints given that SGLT-2 inhibitor 
treatment in Type 1 diabetes mellitus may improve 


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the burden of glycaemic variability which remains 
a fundamental treatment challenge in the 
management of this disease.
Section to be changed
7.3 PLANNED ANALYSIS
Description of change
“…. Details regarding the definitions of IPVs will 
be provided in the Trial Statistical Analysis Plan 
(TSAP).”
Has been changed to:
“…. Details regarding the definitions of IPVs will 
be provided in the TSAP.”
Rationale for change
Administrative change
Section to be changed
7.3.2.1 Key secondary endpoints – confirmatory 
analyses
Description of change
“The change from baseline in percentage time 
spent in target glucose range after 26 weeks as 
determined by CGM will be analysed using an 
ANCOVA model.  The statistical model will be:
% time in range change from baseline =  overall 
mean + treatment + pre-existing 
insulin therapy + continuous baseline 
HbA1c + continuous baseline eGFR + 
continuous baseline % time in range 
+ random error 
Treatment and pre-existing insulin therapy are 
fixed classification effects and baseline HbA1c,
baseline eGFR and baseline % time in range are 
linear covariates. The random error is assumed to 
be normally distributed with mean 0 and unknown 
variance σ2. The analysis will be performed on the 
FAS, including all available on-treatment data. 
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 


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from the FAS, including all available on-treatment 
events from the start of Week 5 (Day 29) up to one 
day after treatment stop or 26 weeks + 1 day (Day 
183) after treatment start, whichever comes first.  
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 or 26 weeks + 1 day (Day 183) after 
treatment start, whichever comes first.”
Has been changed to:
The change from baseline in percentage time spent 
in target glucose range and the change from 
baseline in IQR in Weeks 23 to 26 as determined 
by CGM will be analysed using an ANCOVA 
model.  The statistical model will be:
<CGM endpoint> change from baseline =  overall 
mean + treatment + pre-existing 
insulin therapy + continuous baseline 
HbA1c + continuous baseline eGFR + 
continuous baseline <respective 
CGM endpoint> + random error 
Treatment and pre-existing insulin therapy are 
fixed classification effects and baseline HbA1c,
baseline eGFR and baseline <CGM endpoint> are 
linear covariates. The random error is assumed to 
be normally distributed with mean 0 and unknown 
variance σ2. The analysis will be performed on the 
FAS, including all available on-treatment data. 
The analysis of the incidence rate of symptomatic


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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 
Week 26 cut-off date.  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 Week 26 cut-off 
date.”
Rationale for change
To highlight the importance of CGM-related 
endpoints “time in range” and “IQR” as key 
secondary endpoints given that SGLT-2 inhibitor 
treatment in Type 1 diabetes mellitus may improve 
the burden of glycaemic variability which remains 
a fundamental treatment challenge in the 
management of this disease.
Clarification
 
 
 
 
 
…..


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Section to be changed
7.5 HANDLING OF MISSING DATA
Description of change
“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, % 
time in range as determined by CGM, SBP and 
DBP.”
Has been changed to:
“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, % 
time in range as determined by CGM, IQR as 
determined by CGM, SBP and DBP.”
Rationale for change
To highlight the importance of CGM-related 
endpoints “time in range” and “IQR” as key 
secondary endpoints given that SGLT-2 inhibitor 
treatment in Type 1 diabetes mellitus may improve 
the burden of glycaemic variability which remains 
a fundamental treatment challenge in the 
management of this disease.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03024901
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 52 weeks in patients with Type 1 Diabetes Mellitus
(EASE-2)
Approval–Clinical Monitor
10 Jan 2017 15:28 CET
Author-Statistician
10 Jan 2017 15:50 CET
Approval-Team Member Medicine
10 Jan 2017 15:58 CET
Approval-Team Member Medicine
10 Jan 2017 21:43 CET
Approval-Clinical 
17 Jan 2017 15:25 CET
Verification-Paper Signature
Completion
19 Jan 2017 07:49 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03024901
3.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c14640701-02
BI Trial No.:
1245.69
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 52
weeks in patients with Type 1 Diabetes Mellitus (EASE-2)
Including Protocol Amendment 2 1245.69 [c03024901-03]
Empagliflozin
Responsible trial 
statistician:
Phone :
Fax: 
Date of statistical 
analysis plan:
08 NOV 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 ...............................................................5
3
INTRODUCTION..................................................................................8
4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY.........9
5
ENDPOINTS ........................................................................................10
5.1
PRIMARY ENDPOINT ....................................................................................10
5.2
SECONDARY ENDPOINTS............................................................................10
5.2.1
Key secondary endpoints..............................................................................10
5.2.2
Secondary endpoints .....................................................................................10
..................................................................................11
...........................................................................11
...................................................12
...........................................................................................13
.................................................................................14
................................................................................14
................................................................................14
.................................................................................14
........................................................................14
........................................................................14
........................................................................18
........................................................................19
........................................................................22
..................................................................................................23
........................................................................................................23
........................................24
........................................26
..........................................................................27
..........................................................................27
..........................................................................27
6
GENERAL ANALYSIS DEFINITION.............................................28
6.1
TREATMENTS..................................................................................................28
6.2
IMPORTANT PROTOCOL VIOLATIONS (IPVS)......................................29
6.3
PATIENT SETS ANALYSED ..........................................................................35
....................................................................................................37
6.5
POOLING OF CENTERS ................................................................................43
6.6
HANDLING OF MISSING DATA AND OUTLIERS
.................43
6.6.1
Imputation methods ......................................................................................43
6.6.1.1
Original results (OR) analysis ....................................................................43
6.6.1.2
Observed cases (OC) analysis ....................................................................43
6.6.1.3
Observed cases - all data (OC-AD) analysis ..............................................44
6.6.1.4
Observed cases - Off Treatment (OC-OffT) analysis.................................44


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6.6.1.5
Last observation carried forward (LOCF)..................................................44
6.6.1.6
Multiple imputation (MI)............................................................................45
6.6.1.7
Non-completers considered failure (NCF) .................................................45
6.6.2
Safety and other variables ............................................................................45
6.6.3
Missing dates and times ................................................................................46
6.7
BASELINE, TIME WINDOW, AND CALCULATED VISITS....................47
7
PLANNED ANALYSES......................................................................54
7.1
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS......55
7.1.1
Baseline evaluation........................................................................................55
...............................................55
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................56
7.3
TREATMENT COMPLIANCE .......................................................................57
7.4
PRIMARY ENDPOINT ....................................................................................57
7.4.1
Primary analysis............................................................................................57
7.4.2
Model diagnostics ..........................................................................................58
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 ........................62
7.5.1.3
Change from baseline in CGM endpoints after 26 weeks..........................62
7.5.1.4
Change from baseline in total daily insulin dose (U/kg) after 26 weeks....64
7.5.1.5
Change from baseline in blood pressure after 26 weeks ............................64
7.5.2
(Other) Secondary endpoint(s).....................................................................65
...............................................................................65
7.7
EXTENT OF EXPOSURE................................................................................68
7.8
SAFETY ANALYSIS.........................................................................................68
7.8.1
Adverse events ...............................................................................................68
7.8.1.1
Assignment of AEs to treatment.................................................................69
7.8.1.2
Analysis of other significant AEs...............................................................70
7.8.1.3
AE summaries.............................................................................................70
7.8.2
Laboratory data.............................................................................................79
7.8.2.1
General laboratory evaluation ....................................................................80


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7.8.3
Vital signs.......................................................................................................84
7.8.4
ECG ................................................................................................................84
7.8.5
Others .............................................................................................................85
8
REFERENCES.....................................................................................86
................................................................87
..........................................................................87
.................................................................88
.................................................................................................90
............................90
............................................90
............................................90
...........................................91
............................................92
10
HISTORY TABLE...............................................................................93


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LIST OF TABLES
......................16
......................22
Table 6.2: 1
Important protocol violations..........................................................................29
Table 6.3: 1
Patient Sets Analysed ......................................................................................36
........................................................................37
Table 6.7: 1
Endpoint specific follow-up period for the assignment to active treatment....49
Table 6.7: 2
Time windows for HbA1c measurements at scheduled visits after 
randomisation...................................................................................................................50
Table 6.7: 3
Time windows for blood pressure measurements at scheduled visits after 
randomisation...................................................................................................................51
................................................................52
...............................................................87
...............................................................88
Table 10: 1
History table ....................................................................................................93
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


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Term
Definition / description
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
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


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Term
Definition / description
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
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.
In CTP amendment 2 (c03024901-03, 4th Jan 2017) the testing strategy was updated and a 
new graphical illustration added to Section 7.2. Unfortunately, the original illustration was 
not deleted so both are present. Only the updated illustration is valid.
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 the percentage of time spent in target glucose range of >70 to 
≤180 mg/dL (>3.9 to ≤10.0 mmol/L) as determined by continuous glucose monitoring 
(CGM) in Weeks 23 to 26

Change from baseline in interstitial glucose variability based on IQR as determined by 
continuous glucose monitoring (CGM) in Weeks 23 to 26

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 endpoints
Since there are no secondary endpoints specified in the protocol, this section is not 
applicable. 


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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 empagliflozin 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.
A cut-off date will be used for the analyses at week 26, and will be defined as follows: 

For patients who are still on-treatment at the week 26 visit date:
o
The actual week 26 visit date, if the week 26 visit is within the time window 
defined in table 6.7: 2.
o
The planned study day 182, if there is no week 26 visit date or if the actual 
week 26 visit falls outside of the time window for the week 26 visit. 

For patients who prematurely discontinued the treatment prior to week 26:
o
The minimum between (drug stop date + X days) and the actual week 26 visit 
date, if the week 26 visit is within the time window. 
o
The minimum between (drug stop date + X days) and day 182, if there is no 
week 26 visit date or if the actual week 26 visit falls outside of the time 
window for the week 26 visit. 


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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.
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).
As the primary endpoint is analysed after 26 weeks, IPVs related to efficacy that occur 
between week 26 and 52 will not lead to exclusion from analysis sets.
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


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Table 6.2: 1
Important protocol violations (continued)
Category/Code
Description
Example/Comment
Excluded from
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
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 INC9 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


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Table 6.2: 1
Important protocol violations (continued)
Category/Code
Description
Example/Comment
Excluded from
A3.03
Relevant concomitant 
diagnoses
Exclusion criteria 4, 5, 7, 9 or 16 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 randomization#.

Occurrence of DKA within 3 months 
prior to Visit 1 and until randomization#.

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
A3.05
Blood dyscrasias or any 
disorder causing 
haemolysis or unstable 
red blood cell count
Exclusion criteria 17 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 
randomization (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 
randomization#.
PPS


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Table 6.2: 1
Important protocol violations (continued)
Category/Code
Description
Example/Comment
Excluded from
A3.11
Intake of other 
investigational drug in 
another trial within 30 
days prior to intake of 
study medication in this 
trial
Exclusion criteria 20 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 18 checked
Or
Positive pregnancy test or nursing at Visit 1 
and until randomization#.
None
A3.13
Relevant alcohol or drug 
abuse and other 
conditions affecting 
study compliance
Exclusion criteria 19 checked
Or
Alcohol or drug abuse within 3 months prior 
to Visit 1*#.
None
A3.14*
Any other clinical 
condition unsafe for 
participation that would 
jeopardise patient safety 
while participating in this 
clinical trial
Exclusion criteria 22 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


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Table 6.2: 1
Important protocol violations (continued)
Category/Code
Description
Example/Comment
Excluded from
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
C
Trial medication and 
randomisation
C1
Incorrect trial 
medication
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, mITT, 
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


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Table 6.2: 1
Important protocol violations (continued)
Category/Code
Description
Example/Comment
Excluded from
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
Sensitivity 
analysis 
(MI/PMM)2
Primary 
effectiveness 
analysis (OC-AD)
Primary efficacy 
analysis (OC)
Sensitivity 
analysis
(OC)
Key secondary 
endpoints: hypos
Sensitivity 
analysis (OC-AD)
Primary analysis
(OC)
Key secondary 
endpoint: body 
weight, TDID
Sensitivity 
analysis (MI)2
Primary (OC) &
Sensitivity 
analysis (OC-
AD)
Key secondary 
endpoint: CGM 
Sensitivity 
analysis (MI)2
Primary (OC-P) 
& Sensitivity 
analysis (OC-
AD)
Key secondary 
endpoint: SBP, DBP
Sensitivity 
analysis (MI)2
Primary (OC-H) 
& Sensitivity 
analysis (OC-
AD)
Further efficacy 
endpoints 
OC, OC-AD, 
NCF
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 6 patients will be combined into the category 
'Fewer than 6 patients' for each individual country that has centres with fewer than 6 patients. 
Analysis to explore centre effects includes the calculation of descriptive statistics of the 
primary endpoint.
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.
For CGM endpoints, the OC-technique will be adapted to exclude data measured from the 
date of first intake of paracetamol until the date of last intake of paracetamol + 1 day 
(inclusive) from the derivation of the endpoints. This technique will be called Observed 
Cases without values following intake of paracetamol (OC-P). Missing values for entire 
CGM periods will not be replaced. 


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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 
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.
For CGM endpoints, if both on- and off treatment data are available, OC-AD will consider all 
measurements in the derivation of the endpoints, regardless of whether on- or off-treatment.  
For more details of the derivation of CGM endpoints, see section 5.4.4. Additionally, data 
after the intake of paracetamol will not be excluded from the derivation of the endpoints. 
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
For CGM and insulin endpoints, if >=4 days (for insulin endpoints) or 24 hourly bins (for 
CGM) of off-treatment data is available during a derivation period, a purely off-treatment 
value will be derived for potential separate analyses, considering only off-treatment data. For 
more details of assigning CGM measurements to on- or off-treatment, see Section 5.4.4. Note 
this is only applicable after study drug discontinuation; prior to data will be identical to OC.
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.


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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:
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 52).
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 7.4.3.1.
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. 
For binary endpoints that are derived from quantitative endpoints (e.g. HbA1c), NCF will not 
apply to missing values at Week 26 within the course of measurements on-treatment. Instead 
these values will be interpolated based on the last value observed before the missing Week 26 
value and the first value observed after the missing Week 26 value (independent of the 
selection of a value as the picked visit value described in section 6.7), and the binary endpoint 
derived from the resulting interpolated value. 
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.


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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.
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 16 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.


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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.
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:
 
 
 
 
 
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
Body weight
1
Blood pressure
1
Insulin dose
0
Hypoglycaemia
1
Safety
Adverse events
7
Hypoglycaemia [1]
1
 
*Refer to section 5.4.4 for the assignment of CGM measurements to the on-treatment period
[1] Refers to all hypoglycaemia analyses except the general hypoglycaemia AE analysis by SOC and PT.          
 
 
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
12
Week 26
182
155
241
14
Week 43
301
242
332
16
Week 52/EOT
364
333
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 modified 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
12
Week 26
182
155
210
13
Week 34
238
211
269
14
Week 43
301
270
318
15
Week 48
336
319
350
16
Week 52/EOT
364
351
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 date. 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 
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 the Week 26 primary analysis, this is applicable if study drug is 
stopped during the time window of the Week 26 visit.


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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 overall disposition information will be presented as well as the disposition status at week 
26.
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.
These two IPV analyses will be presented at week 26 and an additional overall IPV table will 
be created to summarize all the IPVs up to week 52.
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 (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/m2) 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.
A separate table will display baseline CGM variables, including time spent in target glucose 
range of >70 to ≤180 mg/dL (%), time spent in hypoglycaemia (%), time spent in 
hyperglycaemia (%), IQR, MAGE, %CV, hourly mean area under the median curve over 24 
hours. 
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.
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. 
The summary on concomitant therapies during randomised treatment will be presented up to 
week 26 as well as up to week 52.


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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 compliance analysis will be reported up to week 26 as well as up to week 52. 
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 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. 


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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


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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 the Week 26 cut-off date (as defined in section 6.1). 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 the Week 26 cut-off date (as defined in section 6.1).  
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 CGM endpoints after 26 weeks
Confirmatory analysis
The change from baseline in the percentage of time spent in target glucose range as 
determined by CGM after 26 weeks will be analysed using an ANCOVA model. The 
statistical model will be:


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% time in target range change from baseline = overall mean + continuous baseline HbA1c + 
pre-existing insulin therapy + continuous baseline eGFR + treatment + continuous baseline % 
time in range + random error
Treatment and pre-existing insulin therapy are fixed classification effects and baseline HbA1c, 
baseline eGFR and baseline % time in target range are linear covariates. The random error is 
assumed to be normally distributed with mean 0 and unknown variance σ².
This analysis will be performed on the FAS (OC-P). All evaluable on-treatment data will be 
used. 
The Week 26 value used for the analysis of change from baseline will be derived from the 
evaluable data from Week 23 to Week 26. Patients who do not have evaluable data at both 
Baseline and Week 26 will be excluded from the analysis. See section 5.4.4 for details.
A descriptive statistics table will present time in target range (%) and time in target range 
change from baseline at week 26 on the FAS (OC, OC-P).
The change from baseline in IQR (mg/dL) as determined by CGM after 26 weeks will be 
analysed using a similar ANCOVA model, replacing % time in target range with IQR.
 
 
 
 
 
 
 
 
 
 
 


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7.5.1.4
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 
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 5.4.6.2. 
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).
 
 
 
 
 
 
 
 
7.5.1.5
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 


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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 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.
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(s)
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 4 weeks, > 4 to 8 weeks, > 8 to 16 weeks, > 16 to 24 weeks, > 24 to 32 weeks, > 32 to 
40 weeks, > 40 to 46 weeks, > 46 to 54 weeks, > 54 weeks. Note that "> 4 to 8 weeks" stands 
for 29 to 56 days. 
In addition, the following exposure cumulative categories will be provided: 
For the analysis at week 26, the following exposure cumulative categories will also 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.
For the analysis at week 52, the following exposure cumulative categories will also be 
provided:  ≥1 day, ≥4 weeks, ≥8 weeks, ≥16 weeks, ≥24 weeks, ≥32 weeks, ≥40 weeks, ≥46 
weeks, ≥54 weeks.
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).
The safety analysis will be primarily performed up to 26 weeks of treatment, and then 
repeated up to 52 weeks of treatment. 
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:


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
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);
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. 
 
 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.
 
 
 
 
 
 
 
 


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For all adverse event analyses at week 26 except the specific analyses on hypoglycaemia (i.e. 
not the general hypoglycaemia AE analysis by SOC and PT), all adverse events with an onset 
date up to the minimum of (treatment stop + 7 days) and the week 26 cut-off date will be 
included. Events occurring after this date will be censored for the week 26 analysis. Refer to 
Section 6.1 for details on the week 26 cut-off date definition.
For the specific analyses on hypoglycaemia, the events with an onset date up to the minimum 
of (treatment stop + 1 day) and the week 26 cut-off date will be included. 
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

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


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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)
 
 
 
 
 
 
      
 
 
 
 


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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.


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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).
For all laboratory analyses at week 26, all laboratory parameters measured up to the 
minimum of (treatment stop + 3 days) and the week 26 cut-off date will be included. 
Laboratory measures observed after this date will be censored for the week 26 analysis. Refer 
to section 6.1 for details on the week 26 cut-off date definition. 
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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7.8.3
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).
Pulse rate observation measured up to the minimum of (treatment stop + 1 day) and the week 
26 cut-off date will be included in the week 26 analysis. Pulse rate observation observed after 
this date will be censored for the week 26 analysis. Refer to Section 6.1 for details on the 
week 26 cut-off date definition. 
7.8.4
ECG
12-lead ECG measurements will be taken at baseline (visit 6), at visit 12 and at EOT (visit 
16). 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


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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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10 HISTORY TABLE
Table 10: 1
History table
Version
Date
Author
Sections 
changed
Brief description of change
Final
12-JUN-17
None
This is the final TSAP without any 
modification
Revised
08-NOV-17
7.5.1.2
7.5.1.5

Multiple imputation analysis 
for body weight and blood 
pressure adapted

 
 
 
 

Minor changes in the wording 
and correction of typos