A Meta-Analysis of Amputation Risk in Empagliflozin Studies (1245.25, 1245.110, 1245.121)
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
TITLE PAGE
TITLE PAGE
Non-interventional Study Protocol
Document Number:
c20771668-04
BI Study Number:
1245.171
BI Investigational
Product:
Empagliflozin
Title:
A Meta-Analysis of Amputation Risk in empagliflozin studies 
(1245.25, 1245.110, 1245.121)
Brief lay title
This study combines data from 3 other studies testing 
empagliflozin in patients with diabetes or with chronic heart 
failure. The study looks at the numbers of patients who had 
lower limb amputations
Protocol version 
identifier:
4.0
Date of last version of 
protocol:
10 April 2019
PASS:
Yes
EU PAS register 
number:
Study not yet registered and will be registered following protocol 
regulatory endorsement 
Active substance:
Empagliflozin
Medicinal product:
Jardiance®
Product reference:
Not applicable
Procedure number:
Jardiance: EMEA/H/C/002677/MEA
Synjardy: EMEA/H/C/003770/MEA
Glyxambi: EMEA/H/C/003833/MEA
Marketing authorisation 
holder:
Boehringer Ingelheim International GmbH
Binger Straße 173
55216 Ingelheim am Rhein
Germany
Joint PASS:
No
Research question and 
objectives:
The primary objective of this exploratory meta-analysis is to 
evaluate the frequencies, incidence rates, and hazard ratios of
lower-limb amputation (LLA) events (primary outcome) and of 
adverse events (AEs) related to amputation (secondary outcome)
in patients treated with empagliflozin compared with placebo in 
the pooled population of the long-term studies 1245.25, 
1245.110, and 1245.121 (SAF-M1), in the pooled population of 
studies 1245.110 and 1245.121 (SAF-M2), and in each of the 
3 studies separately. 

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The exploratory objectives are to evaluate the frequencies of 
recurrent LLA events and of AEs related to recurrent LLA 
events and to assess the frequencies and incidence rates of 
patients with AEs related to amputation preceding the 
amputation for empagliflozin compared with placebo in SAF-
M1, SAF-M2, and in each of the 3 studies separately. Further 
exploratory objectives are to evaluate the frequencies, incidence 
rates, and hazard ratios of the primary and secondary outcomes 
by subgroup and of the secondary outcome by grouped PTs for 
SAF-M1 and SAF-M2 as well as to assess details on LLA events
for SAF-M2 in patients treated with empagliflozin compared 
with placebo.
Countries of study:
Study 1245.25 (completed): multinational trial in 42 countries 
worldwide
Study 1245.110 (ongoing): multinational trial in approx. 
22 countries
Study 1245.121(ongoing): multinational trial in approx.
15 countries
Author:
MAH contact person:
EU-QPPV:
Signature of EU-
QPPV:
The signature of the EU-QPPV is provided electronically
Date:
10 April 2019
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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 10
6.
MILESTONES..................................................................................................... 11
7.
RATIONALE AND BACKGROUND................................................................ 12
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 14
9.
RESEARCH METHODS .................................................................................... 15
9.1
STUDY DESIGN............................................................................................ 15
9.2
SETTING........................................................................................................ 17
9.2.1
Study sites ............................................................................................... 17
9.2.2
Study population ..................................................................................... 18
9.2.2.1
Study 1245.25 .................................................................................. 18
9.2.2.2
Studies 1245.110 and 1245.121 ....................................................... 18
9.2.3
Study visits .............................................................................................. 19
9.2.3.1
Study 1245.25 .................................................................................. 19
9.2.3.2
Studies 1245.110 and 1245.121 ....................................................... 19
9.2.4
Study discontinuation.............................................................................. 19
9.3
VARIABLES .................................................................................................. 20
9.3.1
Exposures ................................................................................................ 20
9.3.2
Outcomes................................................................................................. 20
9.3.2.1
Primary outcomes............................................................................. 20
9.3.2.2
Secondary outcomes......................................................................... 21
9.3.3
Covariates................................................................................................ 21
9.4
DATA SOURCES........................................................................................... 26
9.5
STUDY SIZE.................................................................................................. 26
9.6
DATA MANAGEMENT................................................................................ 26
9.7
DATA ANALYSIS......................................................................................... 27
9.7.1
Main analysis........................................................................................... 30
9.7.2
Further analysis ....................................................................................... 30

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9.7.2.1
Further analyses of LLA events, AEs related to amputation, and details 
on LLA events.................................................................................. 30
9.7.2.2
Analysis of AEs................................................................................ 31
9.7.2.3
Subgroup analysis ............................................................................ 32
9.7.2.4
Other analysis................................................................................... 32
9.7.3
Handling of missing data......................................................................... 33
9.7.3.1
Missing amputation date .................................................................. 33
9.7.3.2
Missing AE onset date ..................................................................... 33
9.8
QUALITY CONTROL................................................................................... 33
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 33
9.10
OTHER ASPECTS ......................................................................................... 34
9.10.1
Data quality assurance............................................................................. 34
9.10.2
Study records........................................................................................... 35
9.10.2.1
Source documents ............................................................................ 35
9.10.2.2
Direct access to source data and documents .................................... 35
9.10.3
Completion of study................................................................................ 35
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 36
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 36
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 36
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 37
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 37
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING......................................................................................... 37
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 37
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 39
13.
REFERENCES .................................................................................................... 40
13.1
PUBLISHED REFERENCES......................................................................... 40
13.2
UNPUBLISHED REFERENCES................................................................... 40
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 41

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2.
LIST OF ABBREVIATIONS
AE
Adverse event
AESI
Adverse event of special interest
ASA
Acetylsalicylic acid
ATC
Anatomical-Therapeutic-Chemical classification
BI
Boehringer Ingelheim
BMI
Body mass index
CANVAS
Canagliflozin cardiovascular assessment study
CI
Confidence interval
CKD-EPIcr
Chronic Kidney Disease Epidemiology Collaboration Equation 
(based on serum creatinine value)
CRO
Contract research organisation
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
DBP
Diastolic blood pressure
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EF
Ejection fraction
EMPEROR
EMPagliflozin outcomE tRial in patients with chrOnic heaRt
failure (study 1245.110, EMPEROR-Preserved, and 1245.121, 
EMPEROR-Reduced)
GCP
Good clinical practice
HbA1c
Glycated haemoglobin
HF
Heart failure
HFpEF
Heart failure with preserved ejection fraction
HFrEF
Heart failure with reduced ejection fraction
HR
Hazard ratio
ICH
International Conference on Harmonization
IEC
Independent ethics committee
ITT
Intent to treat
IRB
Institutional review board
KM
Kaplan-Meier
LLA
Lower-limb amputation
LVEF
Left ventricular ejection fraction
MAH
Marketing authorisation holder
MDRD
Modification of diet in renal disease
MedDRA
Medical dictionary for regulatory activities
NT-proBNP
N-terminal of the prohormone brain natriuretic peptide
NYHA
New York Heart Association
PASS
Post-authorization safety study
PRAC
Pharmacovigilance Risk Assessment Committee
PT
Preferred term
QD/qd
Once daily
SAE
Serious adverse event
SAF
Safety analysis grouping
SAP
Statistical analysis plan

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SBP
Systolic blood pressure
SD
Standard deviation
SGLT2
Sodium-glucose cotransporter 2
SmPC
Summary of product characteristics
SoC
Standard of care
SOP
Standard operating procedure
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus

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3.
RESPONSIBLE PARTIES
This meta-analysis will be conducted by Boehringer Ingelheim (BI). The MAH contact 
person is:
Tel.:

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Jardiance®
Name of active ingredient:
empagliflozin
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
12 January 2018
1245.171
4.0
10 April 2019
Title of study:
A Meta-Analysis of Amputation Risk in empagliflozin studies 
(1245.25, 1245.110, 1245.121)
Rationale and 
background:
As an outcome of the Article 20 referral on the risk of lower-limb 
amputation (LLA) in the EU, Boehringer Ingelheim was requested to 
conduct a meta-analysis of the 2 chronic heart failure studies 
(1245.110 and 1245.121) together with the EMPA-REG OUTCOME 
trial (1245.25) as an additional pharmacovigilance activity.
To further investigate the risk for LLA, in ongoing and future long-
term clinical trials with empagliflozin (including 1245.110 and 
1245.121), LLA and events related to LLA are to be systematically 
captured.
This protocol specifies that a meta-analysis of 3 large and long-term 
studies (1245.25: completed; 1245.110 and 1245.121: ongoing) will be 
carried out to evaluate the risk for LLA.
Research question 
and objectives:
The primary objective of this exploratory meta-analysis is to evaluate 
the frequencies, incidence rates, and hazard ratios of lower-limb 
amputation (LLA) events (primary outcome) and of adverse events 
(AEs) related to amputation (secondary outcome) in patients treated 
with empagliflozin compared with placebo in the pooled population of
the long-term studies 1245.25, 1245.110, and 1245.121 (SAF-M1), in 
the pooled population of studies 1245.110 and 1245.121 (SAF-M2), 
and in each of the 3 studies separately. 
The exploratory objectives are to evaluate the frequencies of recurrent 
LLA events and of AEs related to recurrent LLA events and to assess 
the frequencies and incidence rates of patients with AEs related to 
amputation preceding the amputation for empagliflozin compared with
placebo in SAF-M1, SAF-M2, and in each of the 3 studies separately. 
Further exploratory objectives are to evaluate the frequencies, 
incidence rates, and hazard ratios of the primary and secondary 
outcomes by subgroup and of the secondary outcome by grouped PTs
for SAF-M1 and SAF-M2 as well as to assess details on LLA events
for SAF-M2 in patients treated with empagliflozin compared with 
placebo.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Jardiance®
Name of active ingredient:
empagliflozin
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
12 January 2018
1245.171
4.0
10 April 2019
Study design:
This is a meta-analysis of 3 studies (1245.25, 1245.110, and 
1245.121), which are randomised, placebo-controlled, double-blind, 
parallel-group, and event-driven studies
Population:
Study 1245.25 (completed): patients with type 2 diabetes mellitus and 
increased cardiovascular risk
Study 1245.110 (ongoing): patients with chronic heart failure with 
preserved ejection fraction
Study 1245.121 (ongoing): patients with chronic heart failure with
reduced ejection fraction
Variables:
LLA events and adverse events (AEs) related to amputation
Data sources:
Study databases of 1245.25, 1245.110, and 1245.121
Study size:
This meta-analysis will be based on treated patients.
Study 1245.25 (completed): 7020 patients treated with empagliflozin 
10 mg, empagliflozin 25 mg, or placebo in an approx. 1:1:1 ratio
Study 1245.110 (ongoing): approx. 4126 patients randomised to 
empagliflozin 10 mg or placebo in a 1:1 ratio
Study 1245.121 (ongoing): approx. 2850 patients randomised to 
empagliflozin 10 mg or placebo in a 1:1 ratio
Data analysis:
This meta-analysis will be exploratory, using frequency analyses, 
incidence rates, Kaplan-Meier estimates, and Cox proportional hazards 
models to compare empagliflozin with placebo
Milestones:
This meta-analysis will be event driven by the ongoing studies 
1245.110 and 1245.121, and the final report is expected in Q3 2022

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study protocol
Amendment or 
update
Reason
Version 1.0
12 Jan 2018
Not applicable 
Not applicable 
Initial version
Version 2.0
15 Jun 2018
Title page, 
Sections 2, 4 to 
9, and 13, 
Annex 1
Update
Comments 
from EMA’s 
PRAC and 
update
Version 3.0
07 Dec 2018
Title page, 
Sections 2, 4, 
5, 7 to 9, and 
13, Annex 1
Update
Comments 
from EMA’s 
PRAC and 
update
Version 4.0
10 Apr 2019
Title page, 
Sections 4 to 7, 
9.3.3, 9.7.2.1, 
and 9.9
Update
Comments 
from EMA’s 
PRAC and 
update

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6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
Not applicable for the meta-analysis
Start of data collection
Study 1245.25: 26 August 2010
Study 1245.110: 04 April 2017
Study 1245.121: 21 June 2017
End of data collection
Study 1245.25: 21 April 2015
Study 1245.110: ongoing and event driven, database 
lock expected in Q3 2021
Study 1245.121: ongoing and event driven, database 
lock expected in Q3 2020
Final report of study results:
Event driven, final report of the meta-analysis 
expected in Q3 2022

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7.
RATIONALE AND BACKGROUND
In the canagliflozin cardiovascular outcome studies CANVAS and CANVAS-R, the SGLT2
inhibitor canagliflozin was associated with an increased risk for lower-limb amputation 
(LLA; including minor and major amputations) versus placebo (HR 1.97, 95% CI 1.41, 2.75) 
in patients with type 2 diabetes and high cardiovascular risk [R17-3389].
In Europe, the review of canagliflozin was initiated at the request of the European 
Commission on 15 April 2016, under Article 20 of Regulation (EC) No 726/2004. The 
review was extended to include the other medicines in the same class, dapagliflozin and 
empagliflozin, on 7 July 2016. A thorough review of the clinical trial data of empagliflozin 
took place during that procedure. Since in completed empagliflozin trials (including 
1245.25), LLA or related events were not specifically captured on eCRF pages, they were 
identified via a systematic search of SAE narratives, from events reported as AEs, from those 
reported as a “medical procedure” under “concomitant therapy”, and from investigator 
comments describing the AEs. Overall, the clinical trial data did not show an increased risk 
of LLA or events potentially associated with LLA in patients treated with empagliflozin.
The PRAC concluded that LLA should be added as a new important identified risk for 
canagliflozin and as an important potential risk for empagliflozin and dapagliflozin. 
However, the data for empagliflozin (see above) and dapagliflozin have certain limitations. In 
addition, the PRAC was of the view that it was not possible to identify an underlying cause 
for the observed imbalances in amputation risk that would be specifically attributable to 
canagliflozin-containing medicines and not to the other products of the class.
A warning was added to the EU SmPC of the SGLT2 inhibitors reflecting the important 
identified risk of LLA for canagliflozin and the important potential risk for empagliflozin and 
dapagliflozin.
To further investigate the risk for LLA in patients treated with empagliflozin, events leading
to LLA are defined as AESIs in all ongoing and future clinical trials with treatment duration 
of >12 weeks (including 1245.110 and 1245.121), and specific information related to an LLA 
event is to be recorded on dedicated eCRF pages.
As an additional pharmacovigilance activity, BI was requested to conduct a meta-analysis of 
the 2 chronic heart failure studies (1245.110 and 1245.121) together with the EMPA-REG 
OUTCOME trial (1245.25).
At the time of writing of this protocol, 4 other clinical studies with empagliflozin are ongoing 
(1245.148, 1245.167, and 1245.168) or in preparation (1245.137; see Table 7: 1). The 
detailed data on LLA and related events will be included in the respective clinical trial reports 
(CTRs).

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Table 7: 1
Other clinical studies with empagliflozin
Study
Brief description
Planned 
randomised 
patients
Duration of 
treatment
LLA and related 
events specifically 
captured?
Expected 
database 
lock
1245.148 Mechanistic cardiac physiology 
and metabolism in patients 
with heart failure; phase III
86 (43 to empa 
10 mg and 43 to 
placebo)
12 weeks
No (treatment 
duration of 
≤12 weeks)
Dec 2019
1245.167 Exercise ability in patients with 
chronic heart failure (preserved 
ejection fraction); phase III
300 (150 to 
empa 10 mg and 
150 to placebo)
12 weeks
No (treatment 
duration of 
≤12 weeks)
Jan 2020
1245.168 Exercise ability in patients with 
chronic heart failure (reduced 
ejection fraction); phase III
300 (150 to 
empa 10 mg and 
150 to placebo)
12 weeks
No (treatment 
duration of 
≤12 weeks)
Jan 2020
1245.137 Renal outcomes in patients 
with chronic kidney disease; 
phase III
5000 (2500 to 
empa 10 mg and 
2500 to placebo)
Event 
driven; up 
to 4 years
Yes
Jul 2022
Planned as of Feb 2019

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8.
RESEARCH QUESTION AND OBJECTIVES
The primary objective of this exploratory meta-analysis is to evaluate the frequencies, 
incidence rates, and hazard ratios of lower-limb amputation (LLA) events (primary outcome)
and of AEs related to amputation (secondary outcome) in patients treated with empagliflozin 
compared with placebo in the pooled population of the long-term studies 1245.25, 1245.110, 
and 1245.121 (SAF-M1), in the pooled population of studies 1245.110 and 1245.121 (SAF-
M2), and in each of the 3 studies separately.
The exploratory objectives are to evaluate the frequencies of recurrent LLA events and of 
AEs related to recurrent LLA events and to assess the frequencies and incidence rates of 
patients with AEs related to amputation preceding the amputation for empagliflozin
compared with placebo in SAF-M1, SAF-M2, and in each of the 3 studies separately. Further 
exploratory objectives are to evaluate the frequencies, incidence rates, and hazard ratios of 
the primary and secondary outcomes by subgroup and of the secondary outcome by grouped 
PTs for SAF-M1 and SAF-M2 as well as to assess details on LLA events for SAF-M2 in 
patients treated with empagliflozin compared with placebo.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a meta-analysis of 3 studies (1245.25, 1245.110, and 1245.121), which are 
randomised, placebo-controlled, double-blind, parallel-group, and event-driven studies. A 
meta-analysis of the 3 studies is considered appropriate to explore the risk for LLA events 
due to the large study size (approx. 14 000 patients in total in the 3 studies) and long-term 
exposure (median treatment exposure was 2.6 years in 1245.25; treatment exposure of up to 
3 years are expected in ongoing studies 1245.110 and 1245.121). Data from individual 
patients from the 3 studies, not the result estimates of the 3 studies, will be pooled in the 
meta-analysis.
Study 1245.25 has been completed and the CTR is available [c02695839]. The study title is
“A Phase III, multicentre, international, randomised, parallel group, double blind 
cardiovascular safety study of BI 10773 (10 mg and 25 mg administered orally once daily) 
compared to usual care in type 2 diabetes mellitus patients with increased cardiovascular 
risk”.
Study 1245.110 and 1245.121 are ongoing and the CTPs are available [c03946327, 
c09098452]. The study title of 1245.110 is “A phase III randomised, double-blind trial to 
evaluate efficacy and safety of once daily empagliflozin 10 mg compared to placebo, in 
patients with chronic heart failure with preserved ejection fraction”. The study title of 
1245.121 is “A phase III randomised, double-blind trial to evaluate efficacy and safety of 
once daily empagliflozin 10 mg compared to placebo, in patients with chronic heart failure 
with reduced ejection fraction”.
The overall designs of the studies are shown in Figure 9.1: 1.

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1245.25 (EMPA-REG OUTCOME), completed
1245.110 (EMPEROR-Preserved) and 1245.121 (EMPEROR-Reduced), both ongoing
Figure 9.1: 1 Design of studies 1245.25, 1245.110, and 1245.121
QD/qd, once daily; T2DM, type 2 diabetes mellitus; LVEF, left ventricular ejection fraction; SoC, standard of care
* Guideline-directed therapies
This meta-analysis will be exploratory. All analyses will be based on the treated set, which 
includes all patients treated with at least 1 dose of study medication (as randomised). Due to 
the different patient eligibility criteria (see Section 9.2.2) and methods in capturing LLA and 
related events (see Section 9.3.2.1), two analysis groupings will be used in the meta-analysis. 
SAF-M1 includes all 3 studies while SAF-M2 includes studies 1245.110 and 1245.121. All 
1245.110
1245.121

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analyses will be carried out separately for each SAF and for each study, unless otherwise 
indicated in Section 9.7.1 and 9.7.2.
The primary outcomes are LLA events (see Section 9.3.2.1). 
LLA events will be analysed using frequency analyses, incidence rates, Kaplan-Meier 
estimates, and Cox proportional hazards models to compare empagliflozin with placebo. For 
SAF-M2, where additional information on LLA events are collected on the eCRF, the reasons 
leading to LLA, the number of LLA episodes, level of LLA, etc., will be summarised.
As the primary analysis, the “on-treatment” approach will include events with an onset date 
within the treatment period (from first to last dose of study medication plus 7 days to account 
for the residual drug effect). An ITT approach will be used as a secondary analysis, which 
includes all events during the observation period after starting randomised treatment, 
regardless if the patient was taking study medication or not when the event occurred.
Since deaths are competing events to amputations, a competing risk analysis considering all-
cause death and a cumulative incidence analysis will be carried out.
Subgroups by demographics, baseline medical conditions, and baseline therapies will be 
analysed for LLA events for SAF-M1 and SAF-M2 (see Section 9.3.3 for subgroup 
variables).
The secondary outcomes are AEs related to amputation (see Section 9.3.2.2).
AEs related to amputation will be summarised using frequency analyses, incidence rates, and 
time to onset analyses for all patients. Additionally, AEs related to amputation preceding the 
amputation will be summarised for patients with amputation; AEs with onset after the 
amputation will not be considered in the analysis of this sub-population. Subgroup analyses 
for SAF-M1 and SAF-M2 will be carried out.
Patient disposition, demographics, baseline conditions, exposure, and concomitant diagnoses 
and therapies will also be summarised.
9.2
SETTING
9.2.1
Study sites
Study 1245.25 was conducted in 607 centres in 42 countries worldwide (Argentina, Australia, 
Austria, Belgium, Brazil, Canada, Columbia, Croatia, Czech Republic, Denmark, Estonia, 
France, Georgia, Greece, Hong Kong, Hungary, India, Indonesia, Israel, Italy, Japan, Korea, 
Malaysia, Mexico, Netherlands, New Zealand, Norway, Peru, Philippines, Poland, Portugal, 
Romania, Russia, Singapore, South Africa, Spain, Sri Lanka, Taiwan, Thailand, Ukraine, 
United Kingdom, and United States). Patient disposition by country and centre is detailed in 
CTR 1245.25 [c02695839, Appendix 16.1.9.2, Tables 1.1 and 1.2].
It is planned to randomise approx. 4126 patients in 500 centres from 22 countries in study 
1245.110 [c03946327, Section 3.3], and approx. 2850 patients in 350 centres from 

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15 countries in study 1245.121 [c09098452, Section 3.3]. Recruitments of these 2 studies are 
ongoing at the time of writing of this protocol.
9.2.2
Study population
9.2.2.1
Study 1245.25
Study 1245.25 included patients with type 2 diabetes mellitus and increased cardiovascular 
risk. Detailed eligibility criteria can be found in CTR 1245.25 [c02695839, Section 9.3] and 
the key criteria are summarised below.
The key inclusion criteria were:

Age ≥18 years, diagnosis of T2DM

Drug-naïve or pretreated with any background therapy 

HbA1c criteria 
o
Patients who were drug-naïve: HbA1c of 7 to 10% 
o
Patients with background therapy: HbA1c of 7 to 9% 

BMI ≤45 kg/m2

With high cardiovascular risk, defined as ≥1 of the following criteria
o
History of myocardial infarction (>2 months prior to enrollment)
o
Multi-vessel coronary artery disease: ≥2 major vessels or left main coronary 
artery
o
Single-vessel coronary artery disease with no scheduled 
revascularization/previously unsuccessful revascularization
o
Hospital discharge due to unstable angina pectoris (>2 months prior to 
enrollment)
o
History of stroke (>2 months prior to enrollment)
o
Peripheral occlusive arterial disease
The key exclusion criteria were:

Uncontrolled hyperglycemia: fasting plasma glucose >240 mg/dl

Severe renal impairment defined as eGFR <30 ml/min by MDRD formula

Intake of an investigational drug in another trial within 30 days prior to intake of 
study medication in this trial, or participating in another trial (involving an 
investigational drug and/or follow-up)
9.2.2.2
Studies 1245.110 and 1245.121
Study 1245.110 will include patients with chronic heart failure with preserved ejection 
fraction. Study 1245.121 will include patients with chronic heart failure with reduced ejection 
fraction. Detailed eligibility criteria can be found in CTPs [c03946327, c09098452, Section 
3.3] and the key criteria are summarised below.
The key inclusion criteria are:

Age ≥18 years (Japan, age ≥20 years)

Chronic HF NYHA class II to IV

Ejection fraction (EF) and NT-proBNP criteria

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o
1245.110: preserved EF (LVEF >40%) and elevated NT-proBNP 
(>300 pg/ml; >900 pg/ml for patients with atrial fibrillation)
o
1245.121: reduced EF (LVEF ≤40%) and elevated NT-proBNP (≥2500 pg/ml 
if EF 36 to 40%, ≥1000 pg/ml if EF 31 to 35%, ≥600 pg/ml if EF ≤30% or if 
EF ≤40% with documented hospitalisation for HF within 12 months prior to
screening; for patients with atrial fibrillation, double the level of NT-proBNP 
is applied for each EF category)

1245.110 only: structural heart disease within 6 months or documented hospitalisation 
for HF within 12 months prior to screening

1245.121 only: stable dose of medical therapy for HF consistent with local and 
international cardiology guidelines
The key exclusion criteria are:

Myocardial infarction, coronary artery bypass graft surgery or other major 
cardiovascular surgery, stroke or transient ischaemic attack ≤90 days before screening

Heart transplant recipient, or listed for heart transplant

Acute decompensated HF

SBP ≥180 mmHg at randomisation

Symptomatic hypotension and/or SBP <100 mmHg at screening or randomisation

Impaired renal function defined as eGFR (CKD-EPI)cr <20 ml/min/1.73 m2 or 
requiring dialysis at screening
9.2.3
Study visits
9.2.3.1
Study 1245.25
There was a 2-week placebo run-in period between screening and randomisation visits. 
During the randomised treatment period, visits were to occur every 4 weeks in the first 
4 months, every 12 weeks thereafter until the first year, every 14 months after the first year
(see Figure 9.1: 1). There was to be a follow-up visit 30 days after treatment stop. Details can 
be found in CTR 1245.25 [c02695839, Table 9.5.1: 1].
9.2.3.2
Studies 1245.110 and 1245.121
Randomisation (Visit 2) follows screening (Visit 1) with no placebo run-in. During the 
randomised treatment period, visits are planned at Week 4, 12, 32, 52, and every 24 weeks 
thereafter. Starting at Week 22, phone calls are planned between the on-site visits to monitor 
safety. There will be a follow-up visit 30 days after treatment stop. Details can be found in 
the flow charts in CTPs [c03946327, c09098452].
9.2.4
Study discontinuation
Study discontinuation is not applicable for this meta-analysis. Study 1245.25 has been 
completed. See CTPs 1245.110 and 1245.121 for rules on study discontinuation [c03946327, 
c09098452, Section 3.3.4].

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9.3
VARIABLES
There are no confirmatory endpoints in this study. All variables in this meta-analysis will be 
analysed in an exploratory manner.
9.3.1
Exposures
Exposure is defined as the time exposed to study medication (on-treatment approach; 
calculated as the difference between the date of last intake of study medication and the date 
of the first administration of the study medication plus 1 day) or the time under observation 
after starting randomised treatment (ITT approach; calculated as the difference between the 
date of last follow up and the date of the first administration of the study medication plus 
1 day; also see SAP [c16853237, Section 4.3.2.1]).
For incidence rate, the derivation of time at risk is as follows:
Patients with event:
time at risk in days = date of start of first event – treatment start date + 1
Patients without event:
time at risk in days = last date on treatment + 7 days* (or last date in study for secondary
analysis based on ITT approach) – treatment start date + 1
* This is according to the definition of the residual effect period of 7 days as defined in the trial protocols for safety analyses 
for treatment-emergent events (also see SAP [c16853237, Section 4.3].
9.3.2
Outcomes
The objective of the meta-analysis is to evaluate the risk for LLA in an exploratory manner.
All outcome data, including recurrent events, are collected over the full trial period even after 
the first amputation event.
9.3.2.1
Primary outcomes
The primary outcomes are LLA events.
In studies 1245.110 and 1245.121, events leading to LLA are defined as AESIs in the 
protocols (see below). Specific information related to an LLA event (as a therapy) is to be 
recorded on dedicated eCRF pages. The specific information include: medical history of 
LLA, the date of each LLA event, the level (location) of the LLA event, and the medical 
reason leading to the LLA event.
A major LLA represents amputation above the ankle (below knee, knee, above knee). A 
minor LLA represents amputation at the ankle and below (ankle, tarsometatarsal, 
transmetatarsal and toes).
In study 1245.25, LLAs were not pre-specified in the protocol or specifically captured on 
eCRF pages, they were identified via a systematic search of SAE narratives, from events 

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reported as AEs, from those reported as a “medical procedure” under “concomitant therapy”, 
and from investigator comments describing the AEs. For details see SAP [c16853237, 
Appendix 6.2].
Refer to Sections 9.7.1 and 9.7.2 for the planned analyses.
Definition and reporting of LLA events in the trial protocols (also see Section 11.1):
In the protocols of the ongoing studies 1245.110 and 1245.121, events leading to LLA are 
defined as AESIs and include any event leading to a lower-limb procedure of amputation, 
auto-amputation, or disarticulation. Amputation is defined as a resection of a limb through a 
bone. Auto-amputation is a spontaneous separation of non-viable portion of the lower limb.
Disarticulation is a resection of a limb through a joint. The following procedures are not 
included in the definition of events leading to LLA: debridement (removal of callus or dead 
tissue), procedures on a stump (such as stump revision, drainage of an abscess, wound 
revision, etc.), and other procedures (such as nail resection or removal) without a concomitant 
resection of a limb (amputation or disarticulation). The definitions are consistent with the 
2015 guidance from the
(website:
).
Each lower-limb amputation, disarticulation, or auto-amputation should be reported 
separately. The SAE report for this type of AESI is to 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 any of the known risk factor(s) for lower-limb amputation.
In the completed study 1245.25, events related to LLA were not defined as AESIs in the 
protocol, but were identified via a systematic search of the study database (see above).
9.3.2.2
Secondary outcomes
The secondary outcomes are AEs related to amputation.
A search with a pre-defined list of MedDRA PTs will be performed to identify all AEs 
related to amputation. These AEs include vascular disorders, diabetic-foot-related events, 
wound/infections, nervous system disorders, and volume depletion events. For the list of 
preferred terms for preceding/related events see SAP [c16853237, Appendix 6.1]. The 
occurrences of these AEs do not necessarily lead to amputation procedures.
Refer to Sections 9.7.1 and 9.7.2 for the planned analyses.
9.3.3
Covariates
Covariates such as demographics (sex, race, geographical region, age), baseline medical 
conditions (renal function, hypertension, diabetes, peripheral arterial occlusive disease, 
diabetic foot, coronary artery disease, diabetic neuropathy, diabetic retinopathy, history of 
lower-limb amputation, osteomyelitis, gangrene, nephropathy, HF at baseline, smoking 

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status; for patients with diabetes: HbA1c), and baseline therapies (diuretics, loop diuretics, 
anticoagulants, anti-platelets; for patients with diabetes: insulin, metformin, sulphonyl urea) 
will be investigated in subgroup analyses of the LLA events and AEs related to amputation.
In addition, further demographic and baseline variables will be descriptively summarised (i.e. 
ethnicity, BMI, weight, time since diagnosis of diabetes, blood pressure).
All demographic and baseline variables with categories are shown in Table 9.3.3: 1 (also see 
the SAP [c16853237, Table 4.3: 2]).
Table 9.3.3: 1 Demographic and baseline variables with categories
Variable
Demographics/Baseline characteristics
Categories
Sex
Male
Female
Race
White
Black/African
Asian
Hawaiian/Pacific Islander
Amer. Ind./ Alaska Nat.
Ethnicity
Hispanic/Latino
Not Hispanic/Latino
Geographical region&
Europe
Africa/Middle East
North America
Latin America
Asia
Other (if any)
Age (years) categories
Version 1
<65
65 to <75
75 to <85
≥85
Version 2
<65
65 to <75
≥75
(Decision will be taken on which version to use based on the 
size of the elderly population group ≥85 years of age)
BMI (kg/m2)
<25
25 to <30
30 to <35
≥35
Weight (kg)
≤70
>70 to ≤80
>80 to ≤90
>90
To be continued

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Table 9.3.3: 1 Demographic and baseline variables with categories (continued)
Variable
Demographics/Baseline characteristics
Categories
Smoking status
Never smoked
Ex-smoker
Currently smokes
Time since diagnosis of diabetes 
Version 1 for SAF-M1 pool:
≤1 year
>1 year to 5 years
>5 years to 10 years
>10 years
Not applicable (as no diabetes diagnosed)
Version 2 for SAF-M2 pool:
≤1 year
>1 year to 5 years
>5 years to 10 years
>10 years to 20 years
>20 years
Not applicable (as no diabetes diagnosed)
Baseline HbA1c (%)
Version 1 
Version 2
<8.5
<8
≥8.5
8 to <9
(for diabetic patients only)
Blood pressure (mmHg)
≥130/80
<130/80 (controlled)*
Renal function (eGFR) (CKD-Epi) 
(mL/min/1.73m2)
<30
30 to <45
45 to <60
60 to <90
≥90 
Insulin use
Yes/No
Metformin use 
Yes/No
Sulphonyl urea use
Yes/No
Loop diuretics
Yes/No
Diuretics 
Yes/No
Anticoagulant use 
Yes/No
Anti-platelet use 
Yes/No
Hypertension
Yes/No
Diabetes 
T1DM
T2DM
No Diabetes
Peripheral arterial occlusive disease 
Yes/No
Diabetic foot at baseline
Yes/No
Coronary artery disease 
Yes/No
To be continued

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Table 9.3.3: 1 Demographic and baseline variables with categories (continued)
Variable
Demographics/Baseline characteristics
Categories
Diabetic neuropathy
Yes/No
Diabetic retinopathy 
Yes/No
History of lower limb amputation
Yes/No
Osteomyelitis
Yes/No
Gangrene
Yes/No
Nephropathy
Yes/No
Heart failure at baseline
Yes/No
* Patients must have both SBP below 130 and DBP below 80 to be considered controlled.
& Australia included in North America and South Africa included in Africa/Middle East. 
All subgroup variables with categories are shown in Table 9.3.3: 2 (also see the SAP 
[c16853237, Table 4.3: 3].

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Table 9.3.3: 2 Subgroup variables and categories
Variable
Subgroup Analysis 
Categories
Sex
Male
Female
Race
White
Black/African
Asian
Other
Geographical region
Europe
Africa/Middle East
North America
Latin America
Asia
Other (if any)
Age (years) categories
Version 1
<65
65 to <75
75 to <85
≥85
or Version 2
<65
65 to <75
≥75
In case of low number of events for patients ≥85
Renal function (eGFR) (CKD-Epi) 
(mL/min/1.73m2)
<30
30 to < 45
45 to <60
60 to <90 
≥90 
Insulin use
Yes/No (Diabetic patients only)
Metformin use 
Yes/No (Diabetic patients only)
Sulphonyl ureas use
Yes/No (Diabetic patients only)
Loop diuretics
Yes/No
Baseline HbA1c (%)
<8.0, ≥8.0
Baseline HbA1c (%)
<8.5, ≥8.5
Anticoagulant use 
Yes/No
Anti-platelets use
Yes/No
Diuretics 
Yes/No
Hypertension
Yes/No
Diabetes 
T1DM
T2DM
No Diabetes
(Diabetes yes/no if number of events too low)
To be continued

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Table 9.3.3: 2 Subgroup variables and categories (continued)
Variable
Subgroup Analysis 
Categories
Peripheral arterial occlusive disease 
Yes/No
Diabetic foot at baseline
Yes/No
(Diabetic patients only)
Coronary artery disease 
Yes/No
Diabetic neuropathy
Yes/No
Diabetic retinopathy 
Yes/No
(Diabetic patients only)
History of lower limb amputation
Yes/No
Osteomyelitis
Yes/No
Gangrene
Yes/No
Nephropathy
Yes/No
HF at baseline
Yes/No
Smoking status
current smoker
ex-smoker
never smoked
9.4
DATA SOURCES
The data source for this meta-analysis is the study databases for 1245.25, 1245.110, and 
1245.121. All 3 studies are large, long-term, randomised, placebo-controlled, double-blind, 
parallel-group, and event-driven. Data from individual patients from the 3 studies, not the 
result estimates of the studies, will be pooled in the meta-analysis. See Section 9.1 for more 
details.
9.5
STUDY SIZE
This meta-analysis will be based on patients treated with at least 1 dose of study medication 
(“treated set”) in the 3 studies. Patients are assigned to treatment groups according to 
randomisation.
Study 1245.25 included 7020 patients treated with empagliflozin 10 mg (N = 2345), 
empagliflozin 25 mg (N = 2342), or placebo (N = 2333). 
Study 1245.110 will randomise approx. 4126 patients to empagliflozin 10 mg or placebo in a 
1:1 ratio. Study 1245.121 will randomise approx. 2850 patients to empagliflozin 10 mg or 
placebo in a 1:1 ratio. Almost all randomised patients are expected to be treated.
9.6
DATA MANAGEMENT
The study databases for 1245.25, 1245.110, and 1245.121 will be used. The data is collected 
and managed according to the respective clinical trial protocols. SAS data sets from 

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individual trials will be combined for the meta-analysis based on individual patient data. All 
statistical analyses will be implemented using the statistical software SAS® 9.4 or higher.
9.7
DATA ANALYSIS
This meta-analysis will be exploratory. For the primary outcome of LLA events and for the 
secondary outcome of AEs related to amputation, a Cox proportional hazards regression 
model for modelling the time to first event will be used, including the factors study, diabetes 
mellitus status (T1DM, T2DM, no diabetes), and treatment (all empa vs. placebo). Study is 
assumed as fixed effect in this meta-analysis. For treatment comparison, hazard ratios with 
corresponding 95% CIs as well as corresponding p-values will be presented (see the SAP 
[c16853237, Section 4.3]).
All analyses will be based on the treated set, which includes all patients treated with at least 
1 dose of study medication (as randomised). Due to the different patient eligibility criteria
(see Section 9.2.2) and methods in capturing LLA and related events (see Section 9.3.2.1), 
two analysis groupings will be used in the meta-analysis. SAF-M1 includes all 3 studies 
while SAF-M2 includes studies 1245.110 and 1245.121 (Table 9.7: 1; also see the SAP 
[c16853237, Table 3.1.2: 1]). All analyses will be carried out separately for each SAF and for 
each study, unless otherwise indicated in Table 9.7: 2.
Table 9.7: 1
Overview of analysis groupings and individual studies
Grouping
Description
Studies 
Purpose
SAF-M1
All studies
1245.25
1245.110
1245.121
Frequencies, incidence rates and 
time to onset of amputation events 
Frequencies, incidence rates and 
time to onset for related events based 
on selected adverse events
SAF-M2
Chronic heart 
failure studies
1245.110
1245.121
Frequencies, incidence rates and 
time to onset of amputation events 
Frequencies, incidence rates and 
time to onset for related events based 
on selected adverse events
Details on lower limb amputations
The results of the meta-analysis will be presented mainly in tabular form, and when 
appropriate, in graphical form.
Tabulations of frequencies for categorical data will include all different categories and 
display the number of observations and the percentage (%) in a category relative to the 
respective treatment group (placebo, empa 10 mg, 25 mg, all empa). The category "missing" 
will be displayed if there are actually missing values. Percentages will be based on all 
patients in the respective patient set whether they have non-missing values or not.

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For continuous variables the set of summary statistics in tables is: N (number of patients with 
non-missing values) / Mean / SD / Min / Q1 (lower quartile) / Median / Q3 (upper quartile) / 
Max.
For frequency analyses based on pooled data the estimates for the relative frequency is 
defined as follows:






k
i
ji
k
i
ji
ji
j
w
p
w
p
1
1


, where
pji
relative frequency in treatment group j and study (i=1,.., k) 


i
ji
ji
ji
n
n
w
denotes the weight of study i, i=1,…,k in treatment group j
nji number of patients in treatment group j and study i (i=1, ..k)
The frequency (%) of AEs does not take into account the duration of treatment. This is 
particularly important when studies with different treatment durations are pooled for analysis. 
In this case incidence rates may provide more accurate comparisons among groups.
Incidence rate is the number of new cases of an event occurring in a specified time period 
divided by the cumulative time at risk (see Section 9.3.1 for the derivation). 
The incidence rate per 100 patient-years is calculated as follows:
Incidence rate [1/100 pt-yrs] = 100 * number of patients with event / sum of time at risk over
all patients [years].
The estimate for a pooled incidence rate in treatment group j is defined as follows: 






k
i
ji
k
i
ji
ji
j
w
R
I
w
R
I
1
1


, where
IRji
Incidence rate in treatment group j and study (i=1,.., k) 


i
ji
ji
ji
t
t
w
denotes the weight of study i, i=1,…,k in treatment group j

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

i
ji
ji
ji
t
t
w
denotes the weight of study i, i=1,…,k in treatment group j
tji sum of time at risk in treatment group j and study i (i=1, ..k)
Due to the different study designs, not all analyses will be performed for each of the 2 pools. 
Table 9.7: 2 indicates which safety analyses will be performed for which pool and the 
individual studies (also see the SAP [c16853237, Table 4.3: 1]).
Table 9.7: 2
Overview of analyses that will be performed for the different study poolings 
and for the individual study
Poolings and individual study
Endpoint
SAF-
M1
SAF-
M2
Study 
1245.25
Study 
1245.110
Study 
1245.121
Disposition, demographics, exposure
Yes
Yes 
Yes
Yes
Yes
Concomitant diagnoses and therapies
Yes
Yes 
Yes
Yes
Yes
Lower limb amputation
Frequencies
Incidence rates
Time to onset analyses
Time to onset analyses with 
competing risk
Sensitivity analyses (heterogeneity 
analyses, forest plot)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
-
Yes
Yes
Yes
Yes
-
-
Yes
Yes
Yes
-
-
Yes
Yes
Yes
-
-
Adverse events related to amputations 
(definition based on list of PTs)
All patients
Frequencies
Incidence rates
Time to onset analyses
Patients with amputations only, i.e. preceding 
events
Frequencies
Incidence rates
Time to onset analyses (KM only)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Lower limb amputation events occurring after 
the first LLA event
Descriptive Statistics (Frequency 
tables with absolute and relative 
frequencies)
Yes
Yes
Yes
Yes
Yes
Adverse Events related to amputations 
occurring after the first LLA event
Descriptive Statistics (Frequency 
tables with absolute and relative 
frequencies)
Yes
Yes
Yes
Yes
Yes

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9.7.1
Main analysis
LLA events (primary outcome) and AEs related to amputation (secondary outcome) will be 
analysed using frequency analyses, incidence rates, Kaplan-Meier estimates, and Cox 
proportional hazards models to compare empagliflozin with placebo in the pooled 
populations of SAF-M1, SAF-M2, and for each of the 3 studies (1245.25, 1245.110, and 
1245.121) separately. Kaplan-Meier analyses (cumulative incidence functions) for time to 
first event will be provided by treatment and stratified by study. 
Cox proportional hazards models will include the factors study, diabetes mellitus status 
(T1DM, T2DM, no diabetes), and treatment (all empa vs placebo).
As the primary analysis, the “on-treatment” approach will include events with an onset date 
within the treatment period (from first to last dose of study medication plus 7 days to account 
for the residual drug effect). 
9.7.2
Further analysis
9.7.2.1
Further analyses of LLA events, AEs related to amputation, and details on LLA 
events
LLA events
Subgroups by demographics, baseline medical conditions, and baseline therapies will be 
analysed for LLA events for SAF-M1 and SAF-M2 (see Section 9.3.3 for subgroup variables 
and categorisation and Section 9.7.2.3).
An ITT approach will be used as a secondary analysis, which includes all events during the 
observation period after starting randomised treatment, regardless if the patient was taking 
study medication or not when the event occurred.
Since deaths are competing events to amputations, a competing risk analysis considering all-
cause mortality and a cumulative incidence analysis will be carried out. The regression model 
will include the following co-variables: study, diabetes mellitus status (T1DM, T2DM, no 
diabetes), and treatment (all empa vs. placebo). Cumulative incidence for amputations and 
the competing events of deaths will also be displayed graphically.
The number of LLA episodes per patient will be summarised in a frequency table. 
A listing of patients with recurrent events will be provided. Descriptive statistics (frequency 
tables with absolute and relative frequencies) will be provided to summarise all amputation 
events occurring after the first LLA event.
AEs related to amputation
Subgroup analyses for SAF-M1 and SAF-M2 will be carried out.
For AEs related to amputation, analyses for different grouped events will be performed (see 
the SAP [c16853237, Appendix 6.1]). Cumulative proportions of patients and the number of 
patients at risk will be provided. In addition, Cox regression analyses will be performed for 
vascular AEs, diabetic-foot-related AEs, wound/infection, nervous system disorders, and 

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volume depletion events if the sample size is statistically sufficient, i.e. at least 14 patients 
with events in total over the 2 treatment groups have been reported.
An ITT approach will be used as a secondary analysis, which includes all events during the 
observation period after starting randomised treatment, regardless if the patient was taking 
study medication or not when the event occurred.
A listing of AEs with onset during any treatment other than the randomised treatment will be 
provided.
Additionally, AEs related to amputation preceding the amputation will be summarised for 
patients with amputation; AEs with onset after the amputation will not be considered in the 
analysis of this sub-population. 
AEs related to amputations occurring after the first amputation event will be summarised 
using descriptive statistics (frequency tables with absolute and relative frequencies).
Details on LLA events
For SAF-M2, where additional information on LLA events are collected on the eCRF, the 
following analyses will be performed:

Frequencies of reasons leading to the LLA 

Number of LLA episodes per patient

Number of LLA episodes per patient excluding those due to trauma and tumor

Level of amputation for the first LLA, excluding amputation due to trauma and tumor 
(highest)

Number of patients having a major LLA as first LLA  

Number of patients with any major LLA

Number of patients having a knee or above knee LLA as first LLA

Number of patients with any knee or above knee LLA
9.7.2.2
Analysis of AEs
AEs will be coded using the most recent version of the MedDRA coding dictionary. All 
analyses of AEs will be based on the number of patients with AEs (not the number of AEs). 
For this purpose, AE data will be combined in a 2-step procedure into AE records. In a first 
step, AE occurrences, i.e. AE entries on the CRF, will be collapsed into AE episodes 
provided that all of the following applies:

The same MedDRA lowest level term was reported for the occurrences

The occurrences were time-overlapping or time-adjacent (time-adjacency of
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence

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

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In a second step, AE episodes will be condensed into AE records provided that the episodes 
were reported with the same term on the respective MedDRA level and that the episodes are 
assigned to the same treatment. Internal BI guidelines will be followed for the handling of AE 
data. Frequency tables of patients with AEs by system organ class and preferred terms will be 
provided and sorted by frequency (within system organ class).
The primary analysis for AEs, the “on-treatment” approach, will be based on the concept of 
treatment-emergent AEs. That means all AEs with an onset date between first drug intake 
(post run-in) until 7 days after last drug intake (or time to last follow-up for analyses up to 
last follow-up) will be assigned to the randomised study drug (1245.25) or first study drug 
taken (1245.110, 1245.121). 
An ITT approach will be used as a secondary analysis. All AEs with an onset date between 
first drug intake (post run-in) until time to last follow-up will be assigned to the randomised 
study drug (1245.25) or first study drug taken (1245.110, 1245.121).
9.7.2.3
Subgroup analysis
All subgroup variables with categories are shown in Table 9.3.3: 2. Subgroup analyses for 
SAF-M1 and SAF-M2 will be provided for frequency and incidence rate tables, KM 
analyses, and for Cox models. Subgroup analyses will be performed for LLA events and AEs 
related to amputation. 
For Cox models for time to first event analysis, the following factors will be included in the 
model: study, treatment, <subgroup>, treatment-by-<subgroup> interaction.
For time-to-event endpoints, at a minimum, a count of events will be provided, and if sample 
size is statistically sufficient, i.e. 14 patients with events in total over the 2 treatment groups 
for each subgroup category, a statistical analysis using the Cox regression model will be 
performed. If the affected category is too small (<14 patients with events), the category may 
be only described descriptively and no inferential analysis is performed, or the category may 
be pooled with another category if this is justifiable from a scientific perspective. 
9.7.2.4
Other analysis
Patient disposition, demographics, baseline conditions, exposure, and concomitant diagnoses 
and therapies will also be summarised based on the treated set. The disposition will show 
patients randomised and completed, patients who withdrew after randomisation and 
categorised reason for withdrawal. In addition, a table summarising patients with diabetes and 
the type of diabetes will be shown. Demographic and baseline variables with categories are 
shown in Table 9.3.3: 1. Concomitant diagnoses will be summarised by system organ class 
and preferred term. Relevant diabetic medical history by treatment group will also be 
presented. Concomitant medications will be summarised by ATC3 and preferred name, for 
medications taken at baseline and those initiated on randomised treatment. Antidiabetic,
antihypertensive, ASA, and lipid-lowering medications will also be summarised.

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9.7.3
Handling of missing data
9.7.3.1
Missing amputation date
In studies 1245.110 and 1245.121, the date and other details on LLA events are to be 
captured on eCRF pages; therefore, no missing dates are expected. However, LLA events 
were not specifically captured via eCRF in study 1245.25.
For any missing date of the LLA event, the date is imputed as the date of admission to the 
hospital or the date of the diagnosis of the event triggering the amputation, whichever is later. 
In case the date information is incomplete (e.g. only year and month are reported), the mid-
point of the possible interval will be used according to BI standard imputation rules for 
concomitant therapies.
For LLA event, a sensitivity analysis will be conducted for incidence rate calculation in SAF-
M1 and SAF-M2 excluding all patients with amputations with missing onset dates. This 
analysis will only be performed if >10% of onset dates are missing.
9.7.3.2
Missing AE onset date
Adverse events with missing or incomplete onset dates will be imputed according to a BI 
standard algorithm, which is based on a conservative approach. In short, this approach
ensures that all AEs with missing dates will be counted as “on-treatment” unless there is 
well-documented data showing otherwise. For the calculation of time to event, the earliest 
possible date on-treatment (i.e. date of start of treatment) will be used to impute missing 
onset dates. Partially missing onset dates will also be imputed with the corresponding earliest 
possible date (e.g. if only the year and month are available, use the first day of the month or 
the date of start of treatment, whichever is later).
9.8
QUALITY CONTROL
Standard operating procedures are used to guide the conduct of the studies. These procedures 
include internal quality audits, rules for secure and confidential data storage, methods to 
maintain and archive project documents, quality-control procedures for programming, 
standards for writing statistical analysis plans, and requirements for senior scientific review. 
9.9
LIMITATIONS OF THE RESEARCH METHODS
This will be a meta-analysis of 3 studies with heterogeneous patient populations. Patients
with type 2 diabetes mellitus and increased cardiovascular risk (1245.25) will be pooled 
together with patients with chronic heart failure with preserved (1245.110) or reduced 
(1245.121) ejection fraction (see Section 9.2.2 for more detailed eligibility criteria) in SAF-
M1. In general, some heterogeneity between the studies can be expected due to the different 
populations involved in the trials to be pooled. The degree of heterogeneity of the treatment 
effect between studies will be assessed statistically and clinically/visually. For time-to-event 
outcomes, visual inspection of heterogeneity includes a forest plot of the individual study 
hazard ratios, alongside the corresponding estimate from the individual patient data meta-
analysis in SAF-M1 and SAF-M2. For statistical assessment of heterogeneity, a Cox model 
will be provided including in addition the treatment-by-study interaction term. The p-value of 

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the interaction term from the Cox model in SAF-M1 and SAF-M2 will be used as a statistical 
measure for heterogeneity. For binary outcomes (frequencies and incidence rates of LLAs 
and AEs related to amputation), visual inspection of heterogeneity will be performed using 
forest plots. These will display the frequencies/incidence rates per treatment arm within each 
study, alongside the corresponding estimate from the pooled analysis in SAF-M1 and SAF-
M2. For statistical assessment of heterogeneity, I2 will be calculated for the relative risk of an 
LLA or AEs related to amputation. If heterogeneity between studies is present, potential 
sources of variability will be assessed clinically and conclusions outlined in the final report.
The Cox model is based on the proportional hazards assumption. The proportional hazards 
assumption will be explored by plotting log(-log(survival function)) against the log of time 
by treatment group and checked for parallelism. The interaction of treatment with log of time 
will be included in the model described above for an exploratory analysis. Further, 
Schoenfeld residuals for each covariate and treatment will be plotted against time and 
log(time). If the proportional hazards assumption cannot be verified, potential sources will be 
assessed clinically and conclusions outlined in the final report.
Considering the potential differences in patient populations, subgroup analyses by 
demographic and baseline conditions will be carried out to assess any potential impact of 
these differences on the results (see Section 9.3.3).
For study 1245.25, LLA-related events were not pre-specified in the protocol or specifically 
captured on eCRF pages (see Section 9.3.2.1). Therefore, the extent of reporting may be 
different from studies 1245.110 and 1245.121. As details on LLA events collected in studies 
1245.110 and 1245.121 (the reasons leading to LLA, the number of LLA episodes, level of 
LLA, etc.) are not available in 1245.25, SAF-M2 is created for the purpose of analysing these 
specific details.
Although approx. 14 000 patients are expected to be included in this meta-analysis (see 
Section 9.5), the number of studies involved is low (N=3). The 3 studies were designed to 
investigate empagliflozin’s effect on cardiovascular events, and not specifically designed or
powered to investigate LLA events. As all 3 studies are event-driven, duration of treatment 
and observation will be different for each patient, which will be taken into account using 
“time at risk” to adjust the incidence of outcomes (see Section 9.3.1). As all 3 studies 
investigate patients who meet the specific study entry criteria, the patients in this meta-
analysis may not exactly reflect the circumstances in which empagliflozin is used in the 
routine clinical practice, thereby limiting the generalisability of the results.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
Data-quality assurance measures according to BI standards have been implemented in study 
1245.25 (see details in CTR [c02695839, Section 9.6]) and will be implemented in studies 
1245.110 and 1245.121 (see CTPs [c03946327, c09098452, Section 8.2]).
The collection of LLA events is detailed in Section 9.3.2.1.

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9.10.2
Study records
Electronic CRFs via remote data capture were used for all patients in study 1245.25 
[c02695839, Section 9.6] and will be used in studies 1245.110 and 1245.121 [c03946327, 
c09098452, Section 8.3] according to BI standards.
9.10.2.1
Source documents
Source documents have been documented in study 1245.25 [c02695839, Section 9.6] and will 
be documented in studies 1245.110 and 1245.121 [c03946327, c09098452, Section 8.3.1] 
according to BI standards.
9.10.2.2
Direct access to source data and documents
Direct access to source data and documents is described for study 1245.25 [c02695839, 
Section 9.6] and for studies 1245.110 and 1245.121 [c03946327, c09098452, Section 8.3.2].
9.10.3
Completion of study
The EC/competent authority in each participating EU member state has been notified about 
the end of the study 1245.25, and will be notified about the end of the studies or early 
termination of the studies 1245.110 and 1245.121. 

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10.
PROTECTION OF HUMAN SUBJECTS
Study 1245.25 was carried out in compliance with the protocol, the principles laid down in 
the Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and in accordance with applicable regulatory requirements. 
Contract research organisations (CROs) involved in trial conduct could follow their own 
standard operating procedures (SOPs) as long as the SOP content was consistent with BI 
standards, GCP requirements, and requirements of local law [c02695839, Section 5].
Studies 1245.110 and 1245.121 will be carried out in compliance with the protocol, the 
principles laid down in the Declaration of Helsinki, in accordance with the ICH Harmonised 
Tripartite Guideline for GCP and in accordance with applicable regulatory requirements 
[c03946327, c09098452, Section 8].
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
Standard procedures for study approval, patient information, and informed consent have been 
or will be applied. See details in CTR 1245.25 [c02695839, Section 5] and CTPs 1245.110 
and 1245.121 [c03946327, c09098452, Section 8.1].
10.2
STATEMENT OF CONFIDENTIALITY
Standard procedures to ensure confidentiality have been or will be applied. See details in 
CTR 1245.25 [c02695839, Section 5.3] and CTPs 1245.110 and 1245.121 [c03946327, 
c09098452, Section 8.5].

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
The definitions of AEs follow ICH E6 (Good Clinical Practice) and BI standards and can be 
found in CTR 1245.25 [c02695839, Section 9.5.3.2.1] and CTPs 1245.110 and 1245.121
[c03946327, c09098452, Section 5.3.7.1].
In the protocols of the ongoing studies 1245.110 and 1245.121, events leading to LLA are 
defined as AESIs and include any event leading to a lower-limb procedure of amputation, 
auto-amputation, or disarticulation. Amputation is defined as a resection of a limb through a 
bone. Auto-amputation is a spontaneous separation of non-viable portion of the lower limb. 
Disarticulation is a resection of a limb through a joint. The following procedures are not 
included in the definition of events leading to LLA: debridement (removal of callus or dead 
tissue), procedures on a stump (such as stump revision, drainage of an abscess, wound 
revision, etc.), and other procedures (such as nail resection or removal) without a concomitant 
resection of a limb (amputation or disarticulation). The definitions are consistent with the
2015 guidance from the
(website: 
).
Each lower-limb amputation, disarticulation, or auto-amputation should be reported
separately. The SAE report for this type of AESI is to 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 any of the known risk factor(s) for lower-limb amputation.
In the completed study 1245.25, events related to LLA were not defined as AESIs in the 
protocol, but were identified via a systematic search of the study database (see Section 
9.3.2.1).
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
All data including (S)AEs have been (1245.25) or are collected (1245.110 and 1245.121) in 
the context of the 3 trials and no additional AE collection is required for this meta-analysis.
The collection and reporting of (S)AEs follow BI standards and can be found in CTR 1245.25 
[c02695839, Section 9.5.3.2.2] and CTPs 1245.110 and 1245.121 [c03946327, c09098452, 
Section 5.3.7.2]. All (S)AEs collected in the trials included in this meta-analysis have been 
reported in the CTR 1245.25 and will be reported in the CTRs for 1245.110 and 1245.121.
In studies 1245.110 and 1245.121, events leading to LLA are defined as AESIs. The 
collection and reporting of AESIs follow the rules for SAEs, which require expedited 
reporting on the BI SAE form (within 24 hours) and the collection of post-study events.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local
and international regulatory requirements. Reporting of (S)AEs to health authorities has been 

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(1245.25) or is carried out (1245.110 and 1245.121) in the context of the 3 trials and no 
additional reporting is required for this meta-analysis.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The meta-analysis report will be submitted to the EMA in line with the agreed milestone.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
R17-3389
Neal B, Perkovic V, Mahaffey KW, Zeeuw D de, Fulcher G, Erondu N, et 
al, CANVAS Program Collaborative Group. Canagliflozin and 
cardiovascular and renal events in type 2 diabetes. N Engl J Med 
2017;377(7):644-657.
13.2
UNPUBLISHED REFERENCES
c16853237-05
1245.171: A Meta-Analysis of Amputation Risk in empagliflozin studies 
(1245.25, 1245.110, 1245.121). Statistical Analysis Plan for trial 
1245.171. Version 5.0, 10 Apr 2019.
c02695839-01
A Phase III, multicentre, international, randomised, parallel group, double
blind cardiovascular safety study of BI 10773 (10 mg and 25 mg 
administered orally once daily) compared to usual care in type 2 diabetes 
mellitus patients with increased cardiovascular risk. CTR 1245.25. 12 Oct 
2015.
c03946327-03
A phase III randomised, double-blind trial to evaluate efficacy and safety 
of once daily empagliflozin 10 mg compared to placebo, in patients with 
chronic Heart Failure with preserved Ejection Fraction (HFpEF). 
EMPEROR-Preserved, CTP 1245.110. Version 3.0, 19 Jul 2018.
c09098452-03
A phase III randomised, double-blind trial to evaluate efficacy and safety 
of once daily empagliflozin 10 mg compared to placebo, in patients with 
chronic Heart Failure with reduced Ejection Fraction (HFrEF). 
EMPEROR-Reduced, CTP 1245.121. Version 3.0, 18 Jul 2018.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference 
Number
Date
Title
1
c16853237-05
10 Apr 2019
1245.171: A Meta-Analysis of 
Amputation Risk in empagliflozin
studies (1245.25, 1245.110, 
1245.121). Statistical Analysis Plan 
for trial 1245.171
2
c03946327-03
19 Jul 2018
A phase III randomised, double-
blind trial to evaluate efficacy and 
safety of once daily empagliflozin 
10 mg compared to placebo, in 
patients with chronic Heart Failure 
with preserved Ejection Fraction 
(HFpEF). EMPEROR-Preserved, 
CTP 1245.110
3
c09098452-03
18 Jul 2018
A phase III randomised, double-
blind trial to evaluate efficacy and 
safety of once daily empagliflozin 
10 mg compared to placebo, in 
patients with chronic Heart Failure 
with reduced Ejection Fraction 
(HFrEF). EMPEROR-Reduced, 
CTP 1245.121
4
c02695839-01
12 Oct 2015
A Phase III, multicentre, 
international, randomised, parallel 
group, double blind cardiovascular 
safety study of BI 10773 (10 mg 
and 25 mg administered orally 
once daily) compared to usual care 
in type 2 diabetes mellitus patients 
with increased cardiovascular risk. 
CTR 1245.25.