Clinical trial NCT03259490
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-08-31; Completion date: 2017-11-13
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To establish the bioequivalence of one fixed dose combination (FDC) tablet of empagliflozin/linagliptin/metformin extended release (XR) versus the free combination of empagliflozin tablet, linagliptin tablet, and metformin XR tablets administered as a single dose under fed conditions

Detailed description:

Arms: arm 1: High dose empagliflozin/linagliptin/metformin XR fixed dose combination tablet arm 2: Single tablets of empagliflozin + linagliptin + metformin XR
Interventions: intervention 1: Empagliflozin/linagliptin/metformin HCl intervention 2: Empagliflozin intervention 3: Linagliptin intervention 4: Metformin HCl
Intervention descriptions: intervention 1: Once daily intervention 2: Once daily intervention 3: Once daily intervention 4: Once daily

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c15273597-01
EudraCT No.:
BI Trial No.:
2017-000425-12
1361-0003
BI Investigational
Product:
Empagliflozin/linagliptin/metformin extended release fixed dose 
combination
Title:
Lay Title:
Bioequivalence of a fixed dose combination tablet of 
empagliflozin/linagliptin/metformin extended release compared to the 
free combination of empagliflozin, linagliptin, and metformin 
extended release tablets following oral administration in healthy male 
and female subjects (an open-label, randomised, single-dose, two-
period, two-sequence crossover study)
This study tests whether taking the medicines empagliflozin, 
linagliptin, and metformin together in 1 pill is the same as taking them 
in separate pills. The study is done in healthy men and women and 
measures the amount of each medicine in the blood
Clinical Phase:
I
Trial Clinical Monitor:
Phone: 
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol
Version and Date:
Version: 1.0
Date: 28 JUN 2017
Page 1 of 59
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:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Empagliflozin, linagliptin, metformin HCl
Protocol date:
Trial number:
Revision date:
Not applicable
28 JUN 2017
1361-0003
Title of trial:
Bioequivalence of a fixed dose combination tablet of empagliflozin/linagliptin/
metformin extended release compared to the free combination of empagliflozin, 
linagliptin, and metformin extended release tablets following oral administration in 
healthy male and female subjects (an open-label, randomised, single-dose, two-period, 
two-sequence crossover study)
Principal Investigator:
Trial site:
 
Clinical phase:
I
Objective:
To establish the bioequivalence of one fixed dose combination (FDC) tablet of 25 mg
empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) versus the 
free combination of one 25 mg empagliflozin tablet, one 5 mg linagliptin tablet, and 
two 500 mg metformin XR tablets administered as a single dose under fed conditions.
Methodology:
Randomised, open-label, two-way crossover design with 2 treatments (T and R) and 
2 treatment sequences (TR or RT)
No. of subjects: 
Total entered:
30
Each treatment:
30
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male and female subjects, age of 18 to 55 years, body mass index (BMI) of 
18.5 to 29.9 kg/m2
Test product:
25 mg empagliflozin/5 mg linagliptin/1000 mg metformin XR FDC film-coated tablet
Dose:
1 FDC tablet in treatment period T 
Mode of admin.:
Oral with 240 mL of water after a high-fat, high-calorie breakfast


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Empagliflozin, linagliptin, metformin HCl
Protocol date:
Trial number:
Revision date:
Not applicable
28 JUN 2017
1361-0003
Comparator products:
Comparator product 1:
Comparator product 2:
Comparator product 3:
The comparator products consist of an empagliflozin immediate release tablet, a 
linagliptin immediate release tablet, and multiples of a metformin extended release 
tablet.
Empagliflozin 25 mg film-coated tablet (Jardiance®)
Linagliptin 5 mg film-coated tablet (Tradjenta®)
Metformin XR 500 mg film-coated tablet (Glumetza®)
Dose:
1 x 25 mg empagliflozin + 1 x 5 mg linagliptin + 2 x 500 mg metformin XR
administered together in treatment period R
Mode of admin.:
Oral with 240 mL of water after a high-fat, high-calorie breakfast
Duration of treatment: Single dose for each treatment separated by a washout phase of at least 35 days
Criteria for
pharmacokinetics:
Primary endpoints: AUC0-tz and Cmax for empagliflozin and metformin, AUC0-72 and 
Cmax for linagliptin
Secondary endpoints: AUC0-for empagliflozin, linagliptin, and metformin
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, safety laboratory tests, 12-lead electrocardiogram (ECG), vital signs 
(blood pressure [BP], pulse rate [PR]) 
Statistical methods:
The assessment of bioequivalence will be based upon two-sided 90% confidence 
intervals (CIs) for the ratios of the geometric means (test/reference) for the primary 
endpoints using an acceptance range of 80.00-125.00%. This method is equivalent to 
the two one-sided t-tests procedure, each at the 5% significance level. The statistical 
model will be an ANOVA on the logarithmic scale including effects for ‘sequence’, 
‘subjects nested within sequences’, ‘period’, and ‘treatment’. CIs will be calculated 
based on the residual error from ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory
PKblood (empagliflozin,
linagliptin, and
metformin)
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy6
SCR
1
-21 to -1
Screening (SCR)1
x
x
x
x
1/2 (two identical periods with a washout of at least 35 days)
2/3
-7 to -1
Ambulatory visit (in Visit 3 only)
x
x
-1
-12:00
20:00
Admission to trial site7
x5,7
x7
1
-1:30
06:30
Allocation to treatment2 (Visit 2 only)
x2
x2
-0:30
07:30
High-fat, high-calorie breakfast
0:00
08:00
Drug administration
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake
x
5:00
13:00
Lunch3
x
x
6:00
14:00
x
7:00
15:00
x
8:00
16:00
x
10:00
18:00
Dinner3
x
x
12:00
20:00
x
2
24:00
08:00
Discharge from trial site, breakfast 
(voluntary)3
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
4
72:00
08:00
Ambulatory visit
x
x
EOT
4
8 to 14
End-of-trial (EOT) examination4
x
x
x
x
1.
Subjects must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening and 
pregnancy test), demographics (including determination of body height and weight, smoking status, and alcohol history), 
relevant medical history, concomitant therapy, and review of inclusion/exclusion criteria. Pharmacogenetic samples will 
be collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within 3 h prior to drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End-of-trial examination includes physical examination, vital signs, ECG, safety laboratory, pregnancy test, recording of 
AEs and concomitant therapies.
5.
Only urine drug screening and alcohol breath test, and pregnancy test in women.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in this Flow Chart.
7.
The time is approximate; admission is to be performed no later than 10 h prior to scheduled drug administration.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILES.............................................................................................12
1.2.1
Empagliflozin.........................................................................................12
1.2.2
Linagliptin .............................................................................................14
1.2.3
Metformin..............................................................................................15
1.2.4
Fixed dose combinations of empagliflozin, linagliptin, and/or 
metformin ..............................................................................................16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 17
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................17
2.2
TRIAL OBJECTIVES.......................................................................................17
2.3
BENEFIT - RISK ASSESSMENT ...................................................................17
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 21
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................21
3.1.1
Administrative structure of the trial...................................................21
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................22
3.3
SELECTION OF TRIAL POPULATION ......................................................22
3.3.1
Main diagnosis for study entry............................................................22
3.3.2
Inclusion criteria...................................................................................22
3.3.3
Exclusion criteria ..................................................................................23
3.3.4
Removal of subjects from therapy or assessments.............................24
3.3.4.1
Removal of individual subjects................................................24
3.3.4.2
Discontinuation of the trial by the sponsor..............................25
3.3.5
Replacement of subjects .......................................................................25
4.
TREATMENTS........................................................................................ 26
4.1
TREATMENTS TO BE ADMINISTERED....................................................26
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................26
4.1.2
Method of assigning subjects to treatment groups ............................27
4.1.3
Selection of doses in the trial................................................................27
4.1.4
Drug assignment and administration of doses for each subject .......27


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4.1.5
Blinding and procedures for unblinding ............................................29
4.1.6
Packaging, labelling, and re-supply ....................................................29
4.1.7
Storage conditions.................................................................................30
4.1.8
Drug accountability ..............................................................................30
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................30
4.2.1
Other treatments and emergency procedures....................................30
4.2.2
Restrictions............................................................................................31
4.2.2.1
Restrictions regarding concomitant treatment .........................31
4.2.2.2
Restrictions on diet and life style.............................................31
4.3
TREATMENT COMPLIANCE.......................................................................31
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 32
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................32
5.1.1
Endpoints of efficacy.............................................................................32
5.1.2
Assessment of efficacy...........................................................................32
..............................................................................................................32
5.2.1
Endpoints of safety................................................................................32
5.3
OTHER...............................................................................................................40
5.3.1
Pharmacogenomic evaluation..............................................................40
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................41
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................41
5.5.1
Pharmacokinetic endpoints..................................................................41
5.5.1.1
Primary endpoints....................................................................41
5.5.1.2
Secondary endpoints................................................................41
5.5.2
Methods of sample collection...............................................................42
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................42
5.5.3
Analytical determinations ....................................................................43
5.5.3.1
Analytical determination of empagliflozin plasma 
concentration............................................................................43
5.5.3.2
Analytical determination of linagliptin plasma concentration.43
5.5.3.3
Analytical determination of metformin plasma concentration 43
6.
INVESTIGATIONAL PLAN.................................................................. 44


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6.1
VISIT SCHEDULE............................................................................................44
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................44
6.2.1
Screening................................................................................................44
6.2.2
Treatment periods.................................................................................44
6.2.3
End-of-trial period................................................................................45
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 46
7.1
STATISTICAL DESIGN – MODEL ...............................................................46
7.1.1
Objectives...............................................................................................46
7.1.2
Endpoints...............................................................................................46
7.1.3
Model......................................................................................................46
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................47
7.3
PLANNED ANALYSES....................................................................................48
7.3.1
Primary analyses...................................................................................48
7.3.2
Secondary analyses ...............................................................................49
7.3.4
Interim analyses ....................................................................................50
7.3.5
Pharmacokinetic analyses ....................................................................50
7.4
HANDLING OF MISSING DATA ..................................................................50
7.4.1
Safety......................................................................................................50
7.4.2
Plasma drug concentration-time profiles............................................50
7.4.3
Pharmacokinetic parameters...............................................................51
7.5
RANDOMISATION ..........................................................................................51
7.6
DETERMINATION OF SAMPLE SIZE ........................................................51
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 52
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................52
8.2
DATA QUALITY ASSURANCE .....................................................................53
8.3
RECORDS..........................................................................................................53
8.3.1
Source documents .................................................................................53
8.3.2
Direct access to source data and documents.......................................54
8.3.3
Storage period of records.....................................................................54
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................54
8.5
STATEMENT OF CONFIDENTIALITY.......................................................54
8.6
COMPLETION OF TRIAL..............................................................................54
9.
REFERENCES......................................................................................... 55
9.1
PUBLISHED REFERENCES...........................................................................55
9.2
UNPUBLISHED REFERENCES.....................................................................56
10. APPENDICES .......................................................................................... 58


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11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 59


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse event of special interest
ANOVA
Analysis of variance
AUC
Area under the concentration-time curve of the analyte in plasma
AUC0-72
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 72 h
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CML
Clinical Monitor Local
CRA
Clinical research associate
CRF
Case report form
CTSU
Clinical Trial Supplies Unit
CV
Cardiovascular
DEDP
Drug exposure during pregnancy
DILI
Drug induced liver injury
DKA
Diabetic ketoacidosis

Bioequivalence margin
DNA
Deoxyribonucleic acid
DPP-4
Dipeptidyl-peptidase 4
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
eGFR
Estimated glomerular filtration rate
EOT
End of trial
FDC
Fixed dose combination
gCV
Geometric coefficient of variation


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GIP
Glucose-dependent insulinotropic polypeptide
GLP-1
Glucagon-like peptide 1
H0
Null hypothesis
Ha
Alternative hypothesis
HPC
Human Pharmacology Centre
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLA
Lower limb amputation
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
p.o.
Oral
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
R
Reference treatment
RDC
Remote data capture
REP
Residual effect period
RS
Randomised set
SAE
Serious adverse event
SCR
Screening
SGLT-2
Sodium-dependent glucose co-transporter 2
SOP
Standard operating procedure
T
Test treatment
T2DM
Type 2 diabetes mellitus
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
tz
Time of last measurable concentration of the analyte in plasma
TDMAP
Trial Data Management and Analysis Plan


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TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
XR
Extended release


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Diabetes mellitus is characterised by either the pancreas not producing enough insulin (type 1 
diabetes) or increased peripheral insulin resistance and an insulin-secretory defect that varies 
in severity leading to raised blood glucose levels (type 2 diabetes). Type 2 diabetes mellitus 
(T2DM) accounts for 90 to 95% of all cases of diabetes and is an increasingly prevalent 
disease with over 300 million people estimated to be affected worldwide. Complications 
associated with T2DM, e.g. cardiovascular (CV) disease, lead to a significant reduction of 
life expectancy and are a major cause of morbidity. The risk of CV death and death from any 
cause is increased approximately 2-fold in patients with diabetes [R11-5199]. Diabetes-
related vascular complications are currently the most common cause of adult blindness, renal 
failure, and amputation and lead to a 2- to 4-fold increase in CV disease risk [R06-0179].
T2DM is now a common and serious global health problem, which for most countries has 
evolved in association with rapid cultural and social changes, ageing populations, increasing
urbanisation, dietary changes, reduced physical activity, and other unhealthy lifestyle and
behavioural patterns. 
Currently available oral antidiabetic drugs are efficacious, but still fail to achieve optimal 
blood glucose control in many patients. Modern T2DM therapy includes the combination of 
multiple drugs with complementary modes of action to achieve improved glycaemic control.
Besides, most of the currently available antidiabetic agents have significant side effects such 
as hypoglycaemia, weight gain, oedema and gastrointestinal discomfort.
Empagliflozin, linagliptin, and metformin are orally available antidiabetic drugs with 
different modes of action approved for the treatment of T2DM. When used in combination 
they are expected to show improved efficacy as compared to single treatment in terms of 
glucose control. Boehringer Ingelheim has now developed a triple fixed dose combination 
(FDC) tablet for once daily dosing containing empagliflozin, linagliptin, and metformin 
extended release [c01678844-09, c01838725-17].
1.2
DRUG PROFILES
1.2.1
Empagliflozin
Empagliflozin is an orally administered, potent, and selective inhibitor of the renal sodium-
dependent glucose co-transporter 2 (SGLT-2). 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 a low risk of 
hypoglycaemia, and a negative energy balance with weight reduction. Empagliflozin was 
developed by Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany, and has 
been approved as an adjunct to diet and exercise to improve glycaemic control in adult 
patients with T2DM in more than 70 countries including Europe, US, and Japan. The 
preferred brand name is Jardiance®. In a dedicated CV outcome trial (EMPA-REG 
OUTCOME®, [P15-09840]), empagliflozin showed a 38% risk reduction in CV death 
compared to placebo in patients with T2DM and established CV disease. In consequence, the 
indication for empagliflozin was extended to the reduction of the risk of CV death in patients 


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with T2DM with established CV disease. The standard therapeutic dose is 10 or 25 mg once 
daily [c01678844-09].
Empagliflozin shows mainly linear pharmacokinetics in humans reaching peak levels at 
approximately 1.5 h with a biphasic decline and a terminal elimination half-life of 12.4 h. 
Following oral administration of [14C]-empagliflozin, approximately 41.2 and 54.4% of drug-
related radioactivity was excreted in faeces and urine, respectively. None of the detected 
metabolites were major. Empagliflozin tablets can be administered with or without food. 
Empagliflozin exposure increases with hepatic and/or renal impairment; however, no dose 
adjustment is recommended as the observed changes in exposure are not clinically 
meaningful. No clinically relevant pharmacokinetic interactions have been observed 
[c01678844-09].
In completed clinical studies, empagliflozin was well tolerated in both normal healthy 
subjects and patients with T2DM up to the maximum treatment duration of 208 weeks. The 
frequency of overall adverse events (AEs), AEs leading to discontinuation, and serious AEs 
(SAEs) were comparable to placebo. There was no significant increase in the frequency of 
hypoglycaemia with empagliflozin compared to placebo except when used in combination 
with a sulphonylurea or basal insulin. Treatment with empagliflozin was associated with a
higher frequency of genital infections, increased urination, and increased thirst. There was a 
small increase in total cholesterol, low density lipoprotein cholesterol, and high density 
lipoprotein cholesterol but no significant changes in triglycerides. In addition, increases in 
haematocrit, haemoglobin, and red blood cells were observed with empagliflozin. No changes 
in heart rate and no QTc prolongation have been observed [c01678844-09].
In the recently performed cardiovascular EMPA-REG OUTCOME® study [P15-09840], the 
overall safety profile of empagliflozin was comparable to its previously known safety profile
[c01678844-09].
Empagliflozin is non-genotoxic. In a mouse carcinogenicity study, renal adenoma and 
carcinoma occurred in male mice upon exposures corresponding to approximately 45- and 
113-fold the exposure associated with the 25 and 10 mg doses in humans, respectively, but 
were considered irrelevant for humans based on the mode of action for these tumours. 
Likewise, benign vascular tumours (haemangioma) of the mesenteric lymph node occurred in 
rats but are considered secondary to severe body weight loss and have little, if any, relevance 
to humans.
Based on post-marketing experience, cases of diabetic ketoacidosis (DKA) have been 
reported in patients treated with empagliflozin, including fatal cases. DKA presentation was 
not always accompanied by typical hyperglycaemia. Very low carbohydrate diet, acute illness, 
insulin deficiency or dose reduction, alcohol abuse, severe dehydration, and a history of 
ketoacidosis may be DKA risk factors while taking empagliflozin.
Based on an increase in lower limb amputations (LLA) with the use of canagliflozin, a review 
of all completed Phase II and III clinical trials involving empagliflozin was performed to rule 
out a class effect of SGLT-2 inhibitors with regard to LLA. The incidence of LLA in patients 
treated with empagliflozin was not higher compared to patients treated with placebo or other 
comparators.


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For a more detailed description of the drug profile of empagliflozin refer to the current 
Investigator’s Brochure for empagliflozin [c01678844-09].
1.2.2
Linagliptin
Linagliptin inhibits dipeptidyl-peptidase 4 (DPP-4), an enzyme which rapidly degrades the 
incretin hormones glucagon-like peptide 1(GLP-1) and glucose-dependent insulinotropic 
polypeptide (GIP) [c01838725-17]. Both hormones are secreted from intestinal cells after the 
ingestion of meals and exert glucose-dependent insulinotropic actions thereby contributing to 
postmeal glycaemic control. Linagliptin was developed by Boehringer Ingelheim Pharma 
GmbH & Co. KG, Biberach, Germany. Linagliptin has been approved in over 90 countries 
and is marketed in the US under the brand name Tradjenta® (brand names in other countries: 
Trayenta®, Trazenta®, Trajenta®). The standard therapeutic dose is 5 mg once daily.
Linagliptin shows non-linear pharmacokinetics, both after oral and intravenous 
administration in the therapeutic dose range, with a less than dose-proportional increase in 
plasma concentrations. Clearance, volume of distribution, and amount excreted unchanged in 
urine increase with increasing doses, which is assumed to be a result of non-linear protein 
binding in the therapeutic plasma concentration range. Linagliptin is predominantly excreted 
unchanged in faeces. Renal excretion is considered to be a minor elimination pathway of 
linagliptin at therapeutic dose levels. The long terminal half-life of >100 h does not reflect the 
effective half-life, as steady state is reached within 2 to 7 days. The accumulation factors of 
peak plasma concentration and area under the curve range from 1.2 to 2 upon multiple 
dosing. No adjustment of linagliptin dosage based on the intrinsic factors age, BMI, weight, 
gender, or race is considered necessary. The absolute bioavailability of linagliptin is 
approximately 30%. Because coadministration of a high-fat meal with linagliptin had no 
clinically relevant effect on the pharmacokinetics, linagliptin may be administered with or 
without food. Linagliptin had no clinically relevant effect on the pharmacokinetics of 
metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin, or oral contraceptives
[c01838725-17].
Up to the date of the most recent version of the Investigator’s Brochure for linagliptin, more 
than 1200 healthy subjects and more than 6700 patients with T2DM had been administered 
linagliptin in a total of more than 35 clinical trials [c01838725-17].
The pooled safety data from completed Phase I studies in healthy subjects did not indicate 
any potential concern regarding subjects’ safety with headache (17.0%), nausea (2.9%), and 
nasopharyngitis (2.2%) being the most frequent AEs with linagliptin monotherapy, and 
headache (17.5%), diarrhoea (7.9%), and nausea (4.3%) being the most frequent AEs when 
linagliptin was given in combination with metformin. The higher rate of gastrointestinal
disorders, particularly diarrhoea, is in line with the known safety profile of the metformin 
component. The relatively high frequency of headache is not unusual for Phase I studies in 
healthy volunteers and possibly resulting from lack of caffeine and nicotine during the study.
In a pooled safety analysis of Phase I to III trials in T2DM patients receiving either 5 mg 
linagliptin or placebo, the percentages of patients with AEs were comparable between 
treatments (63.3% placebo, 59.1% linagliptin 5 mg). The number of patients with SAEs was 
low in both treatment groups (5.7% placebo, 4.9% linagliptin 5 mg). The most frequently 
reported AEs in either treatment group were nasopharyngitis (5.3% placebo, 5.8% linagliptin 


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5 mg), hyperglycaemia (9.4% placebo, 5.8% linagliptin 5 mg) as well as hypoglycaemia 
(8.7% placebo, 8.7% linagliptin 5 mg). Drug-related AEs had comparable frequencies in the 
placebo and linagliptin group (14.2% placebo, 12.5% linagliptin 5 mg). 
In the Phase III studies, an overall assessment of cumulative evidence was performed in order 
to identify any side effects that are possibly associated with linagliptin treatment. For 
monotherapy (and all backgrounds) with linagliptin nasopharyngitis, cough, hypersensitivity, 
pancreatitis, and increased lipase in clinical laboratory have been identified as possibly 
related AEs. Hypoglycaemia was identified as an AE related to linagliptin only when added 
to a background treatment of metformin plus sulphonylurea. Hypertriglyceridaemia was 
identified as a possibly related AE only on a background of sulphonylurea. Hyperlipidaemia
and weight increased were AEs possibly related to linagliptin when used in combination with 
pioglitazone. Constipation was identified as a possibly related AE only on a background of 
insulin. The safety of the combination of linagliptin with metformin plus pioglitazone was 
comparable to the profile defined for linagliptin, linagliptin plus metformin, and linagliptin 
plus pioglitazone. Based on post-marketing data, angioedema, urticaria, rash, mouth 
ulceration, and bullous pemphigoid are listed as side effects for linagliptin (any background)
[c01838725-17].
No effect on the QT interval was observed in a thorough QT study following single-dose 
administration of 5 and 100 mg linagliptin [c01838725-17].
For a more detailed description of the drug profile of linagliptin refer to the current 
Investigator’s Brochure for linagliptin [c01838725-17].
1.2.3
Metformin
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and 
postprandial plasma glucose. Unlike sulfonylureas (such as glyburide), metformin alone does 
not increase insulin secretion and is not associated with hypoglycaemia in either patients with 
T2DM or healthy volunteers. The most common adverse reactions of metformin are 
gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain, and loss of 
appetite [R17-0574].
The absolute bioavailability of metformin is 50 to 60% under fasting conditions. The intake 
of food decreases the extent of absorption. A 40% lower peak plasma concentration and a 
25% lower area under the curve were reported following a single-dose administration of 
850 mg metformin with food. Studies using single oral doses of 500 to 1500 mg metformin 
indicated that there is a lack of dose proportionality with increasing doses due to decreased 
absorption. Metformin is negligibly bound to plasma proteins. The drug partitions into 
erythrocytes, most likely as a function of time. Intravenous single-dose studies in healthy
subjects demonstrated that metformin is excreted unchanged in the urine and undergoes 
neither hepatic metabolism nor biliary excretion. Following oral administration 
approximately 90% of the absorbed drug is eliminated via the renal route within the first 
24 h, with a plasma elimination half-life of approximately 6.2 h [R15-4930]. 
Metformin is available as immediate release and extended release (XR) tablets. The 
maximum recommended daily dose is 3000 mg for the immediate release tablet [R17-0574] 


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or 2000 mg for the XR tablet [R17-1647]. The standard therapeutic dose is 500 to 2000 mg 
once daily for metformin XR.
For a more detailed description of the drug profiles of metformin and metformin XR refer to 
the summary of product characteristics for Glucophage® [R17-0574] and the prescribing 
information for Glumetza® [R17-1647].
1.2.4
Fixed dose combinations of empagliflozin, linagliptin, and/or metformin
Fixed dose combinations of empagliflozin and linagliptin (Glyxambi®), empagliflozin and 
metformin (Synjardy®), and linagliptin and metformin (Jentadueto®) have been developed by 
Boehringer Ingelheim and have been approved for treatment of T2DM in many countries.
Furthermore, FDCs of empagliflozin and metformin XR (Synjardy XR®) and linagliptin and 
metformin XR (Jentadueto XR®) have been approved in the US. For information about the 
drug profiles of these FDCs refer to the Investigator’s Brochures for empagliflozin 
[c01678844-09] and linagliptin [c01838725-17].
The newly developed FDC tablet containing all 3 antidiabetic agents (empagliflozin, 
linagliptin, and metformin XR) was administered to healthy subjects for the first time in 
study 1361.1 that investigated the relative bioavailability of 2 strengths of the FDC tablet
compared with the free combination of the 3 components under fed and fasted conditions
[c12820904-01]. In this study, the administration of empagliflozin (10 or 25 mg), linagliptin 
(5 mg), and metformin XR (1000 mg) was well tolerated either as FDC or as free 
combination with the most frequently reported AEs being headache, nausea, diarrhoea, 
dizziness, and upper abdominal pain. All AEs were of mild or moderate intensity and no 
serious AEs were reported. The relative bioavailability of the 3 drugs was similar when 
administered as FDC or as free combination with the exception of linagliptin Cmax (at the 
25 mg empagliflozin dose), which was approximately 17% higher when administered as FDC
under fasted conditions.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
The aim of combination drug therapy in T2DM is to improve compliance and provide 
improved glycaemic control. This can be achieved by combining drugs with different 
mechanisms of action which work together to have an additive or synergistic antidiabetic 
effect. The orally available antidiabetic drugs empagliflozin, linagliptin, and metformin XR 
are commonly administered together and it is expected that providing the 3 drugs in a single 
FDC tablet for once daily dosing will make medication intake easier for patients and reduce 
the risk of medication errors. 
The purpose of the present study is to establish the bioequivalence of a newly developed 
25 mg empagliflozin/5 mg linagliptin/1000 mg metformin XR FDC tablet compared with the 
free combination of empagliflozin (Jardiance®), linagliptin (Tradjenta®), and metformin XR 
(Glumetza®) tablets under fed conditions.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to establish the bioequivalence of a 25 mg 
empagliflozin/5 mg linagliptin/1000 mg metformin XR FDC tablet (Test, T) compared with 
the same doses of the individual components given in separate tablets (Reference, R) when 
administered together after a high-fat, high-calorie meal.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of a triple 
antidiabetic drug FDC that is expected to facilitate medication intake for patients with T2DM, 
to minimise the risk of medication errors, and to improve patient compliance. The
participating subjects are exposed to the risks of the study procedures and the risks related to 
the exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.


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Drug-related risks and safety measures
Empagliflozin
Empagliflozin was well tolerated when administered to healthy subjects in the dose range
from 0.5 to 800 mg per single dose and up to 50 mg in multiple dose studies [c01838761-13]. 
In healthy subjects, the most frequently reported AEs with empagliflozin were headache, 
nasopharyngitis, nausea, and diarrhoea. Only 1 subject had an SAE (migraine with aura with 
empagliflozin 25 mg) that required hospitalisation and 2 subjects had AEs leading to 
discontinuation (gastroenteritis with empagliflozin 50 mg, migraine with empagliflozin 
5 mg). 
In patients who received empagliflozin in placebo-controlled clinical studies the following 
adverse reactions were reported [R17-1650]: 
Very common (>1/10): hypoglycaemia when empagliflozin was used in combination with 
sulphonylurea or insulin 
Common (≥1/100 to <1/10): genital infections, urinary tract infection, generalised pruritus, 
increased urination, and thirst
Uncommon (≥1/1000 to <1/100): volume depletion, dysuria, increased blood creatinine, 
decreased glomerular filtration rate, increased haematocrit, and increased serum lipids
Rare (≥1/10 000 to <1/1000): diabetic ketoacidosis (DKA). DKA was reported 
infrequently and at similar rates in the empagliflozin and placebo treatment groups 
[c01678844-09]; for more information refer to Section 1.2.1. 
No cases of ketoacidosis have been reported in studies with healthy subjects and ketoacidosis 
is unlikely to occur after single-dose administration of empagliflozin.
Linagliptin
In a single rising dose study in healthy subjects [U05-2072], linagliptin was very well 
tolerated up to and including the highest administered dose of 600 mg. The pooled safety data 
from 511 healthy subjects treated in Phase I trials with linagliptin did not indicate any 
potential concerns regarding subjects’ safety upon exposure to the drug (see also 
Section 1.2.2). 
In patients who were treated with linagliptin alone or in combination with metformin the 
following adverse reactions were reported [R17-1649]: 
Common (≥1/100 to <1/10): increased lipase
Uncommon (≥1/1000 to <1/100): nasopharyngitis, cough, rash, increased amylase, 
hypersensitivity (e.g. bronchial hyperreactivity)
Rare (≥1/10 000 to <1/1000): angioedema and urticaria
Not known (that is, frequency cannot be estimated from the available data): pancreatitis 
and bullous pemphigoid 
Only when linagliptin was added to a sulphonylurea (on a background of metformin), the 
incidence of hypoglycaemia was increased over that of placebo. 
In post-marketing experience of linagliptin there have been spontaneously reported adverse 
reactions of acute pancreatitis. Pancreatitis was reported more often in patients randomised to 
linagliptin (5 events in 4302 patients receiving linagliptin versus 1 event in 2364 patients 
receiving placebo). This safety finding was not reported in any of the 3 large controlled 


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randomised CV outcome trials SAVOR (saxagliptin), EXAMINE (alogliptin), and TECOS 
(sitagliptin) [R13-3903, R13-3902, R15-3017] and is thus still under debate. However, a
meta-analysis of these CV outcome studies of DPP-4 inhibitors found a significantly 
increased risk of acute pancreatitis, though still a rare event, which was suggested to be a 
class effect [R17-1673]. In Boehringer Ingelheim’s premarketing studies involving healthy 
subjects there was no event of acute pancreatitis. Hence, the risk of pancreatitis is considered 
minimal after single-dose administration of linagliptin in this study. Nevertheless, subjects 
will be closely monitored for clinical symptoms and laboratory signs of acute pancreatitis. 
Metformin
Adverse reactions which may occur under treatment with metformin are [R17-0574]:
Very common (≥1/10): gastrointestinal disorders (nausea, vomiting, diarrhoea, abdominal 
pain, and loss of appetite)
Common (≥1/100 to <1/10): taste disturbance
Very rare (<1/10 000): skin reactions (erythema, pruritus, urticaria), abnormalities in liver 
function tests, hepatitis (reversible after discontinuation of medication), decrease of 
vitamin B12 absorption with decrease of serum levels during long-term use of metformin, 
and lactic acidosis
Gastrointestinal disorders occur most frequently during initiation of metformin therapy and 
could therefore also occur after single-dose administration in the current trial. Usually, 
gastrointestinal disorders disappear within a short period of time and do not represent any 
safety risk for healthy subjects. Lactic acidosis is a metabolic complication with high 
mortality rate if not treated promptly. Risk factors for developing a lactic acidosis are renal 
insufficiency, impaired hepatic function, excessive alcohol intake, vigorous physical activity, 
and heavy fasting. Until now, a lactic acidosis in healthy volunteers has not been reported in 
the literature. In the current trial, renal and liver functions will be checked thoroughly as part 
of the screening examination; alcoholic beverages and unusual physical activities are
restricted during the study.
Combination of empagliflozin, linagliptin, and metformin
In the relative bioavailability study 1361.1, 50 healthy subjects were administered single 
doses of 10 or 25 mg empagliflozin, 5 mg linagliptin, and 1000 mg metformin XR as FDC 
and free combination. The overall frequency of AEs and also the frequency of drug-related 
AEs were similar between the FDC and the free combination. No SAEs and no AEs of 
special interest were reported. The most frequently reported AEs were headache, nausea, 
diarrhoea, dizziness, and upper abdominal pain as had been expected based on the known 
safety profiles of the 3 drugs [c12820904-01]. 
For further information on clinical safety refer to the drug profiles of empagliflozin, 
linagliptin, metformin, and their combination in Section 1.2.
In the present study, subjects are exposed to 2 single doses of 25 mg empagliflozin, 5 mg 
linagliptin, and 1000 mg metformin XR separated by a washout phase of at least 35 days. 
Based on previous experience with empagliflozin and linagliptin and their combination with 
metformin in healthy subjects and in patients, the risk for subjects participating in this trial is
considered minimal and acceptable. The risk of hypoglycaemia is considered low since 


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neither empagliflozin, nor linagliptin or metformin act primarily insulinotropic. In clinical 
settings hypoglycaemia was more common with these drugs when they were coadministered 
with insulin secretagogues such as sulfonylurea or insulin itself. Although rare, a potential for 
drug-induced liver injury (DILI) is under constant surveillance by sponsors and regulators. 
Therefore, this trial requires timely detection, evaluation, and follow-up of laboratory 
alterations in selected liver laboratory parameters to ensure subjects’ safety (see also 
Section 5.2.2.1).


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, two-way crossover trial in healthy 
male and female subjects in order to compare the test treatment (T) to the reference 
treatment (R). The subjects will be randomly allocated to the 2 treatment sequences TR or 
RT. The treatments will be:
Test treatment (T):
1 FDC tablet 25 mg empagliflozin/5 mg linagliptin/1000 mg 
metformin XR in the fed state
Reference treatment (R): free combination of 1 tablet 25 mg empagliflozin, 1 tablet 5 mg
linagliptin, and 2 tablets 500 mg metformin XR in the fed state
There will be a washout period of at least 35 days between the 2 treatments.
For details on the treatments refer to Section 4.1. An overview of all relevant trial activities is 
provided in the Flow Chart. For visit schedule and details of trial procedures at selected 
visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany. 
The trial will be conducted at the Human Pharmacology Centre (HPC) of BI Pharma GmbH 
& Co. KG, Biberach, Germany, under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
The analyses of empagliflozin concentrations in plasma will be performed at 
 The analyses of linagliptin 
concentrations in plasma will be performed at 
 
 The analyses of metformin concentrations in plasma will be performed at 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management will be done by BI according to BI SOPs. Statistical tasks and 
programming will be performed by 
 
according to BI SOPs.


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Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the investigator site file (ISF).
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
For bioequivalence trials, the crossover design is preferred due to its efficiency: since each 
subject serves as his or her own control, the comparison between treatments is based on a 
comparison within subjects rather than between subjects. This trial design therefore removes 
intersubject variability from the comparison between treatments [R94-1529].
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analytes provided by bioanalytical
laboratories which are blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 30 healthy male and female subjects will enter the study. They will be 
recruited from the volunteers’ pool of the trial site.
A log of all subjects enrolled into the trial (that is, having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male or female subjects according to the assessment of the investigator, based on 
a complete medical history including a physical examination, vital signs (BP, PR), 
12-lead ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
5. Male subjects, or female subjects who meet any of the following criteria starting from at 
least 30 days before the first administration of trial medication and until 30 days after trial 
completion:
-
Use of adequate contraception, e.g. any of the following methods plus condom:
implants, injectables, combined oral or vaginal contraceptives, intrauterine device
-
Sexually abstinent
-
A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)


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-
Surgically sterilised (including hysterectomy)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in
questionable cases a blood sample with simultaneous levels of FSH above 40 U/L and 
estradiol below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR, or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for
males)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within 1 week prior to administration of
trial medication or during the trial
19. Inability to comply with dietary regimen of trial site


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20. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study
Female subjects will not be allowed to participate if any of the following applies:
21. Positive pregnancy test, pregnancy, or plans to become pregnant within 30 days after 
study completion
22. Lactation period
In addition, the following trial-specific exclusion criterion applies:
23. Men and women with serum creatinine levels of 1.3 mg/dL and 1.1 mg/dL, respectively, 
or higher values
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational product 
or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as pregnancy,
surgery, AEs, or diseases)
4. The subject shows 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) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report. If a subject is removed from or 
withdraws from the trial after first administration of trial medication, this will be documented 
and the reason for discontinuation must be recorded in the CRF. In this case, the data will be 
included in the CRF/trial database and will be reported in the clinical trial report. At the time 
of discontinuation a complete end-of-trial examination will be performed if possible and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
residual effect period (REP; see Section 5.2.2.2), the discontinued subject should, if possible,
be questioned for AEs and concomitant therapies at or after the end of the REP in order to 
ascertain collection of AEs and concomitant therapies throughout the REP, if not contrary to 
any consent withdrawal of the subject. These discontinuations will be discussed in the clinical 
trial report.


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If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication has to be stopped immediately, and the subject has to be removed from the trial. 
The subject is to be followed until she has given birth or until the end of pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the clinical trial report. For reporting of pregnancy and events refer to 
Section 5.2.2.2.
3.3.4.2
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial at any time for any of the following reasons:
1. New toxicological findings or SAEs invalidate the earlier positive benefit-risk-
assessment. More specifically, the trial will be terminated if more than 50% of the 
subjects show drug-related and clinically relevant AEs of moderate or severe intensity, or 
if at least 1 drug-related SAE is reported
2. The expected enrolment goals are not met
3. Violation of GCP or the clinical trial protocol, disturbing the appropriate conduct of the 
trial
4. The sponsor decides to discontinue the further development of the investigational product
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the Trial Clinical Monitor together with the 
Trial Pharmacokineticist and the Trial Statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique study subject number and will 
be assigned to the same treatment sequence as the subject he or she replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product and comparator products
The characteristics of the test product are given below:
Test product:
Substances:
Empagliflozin/linagliptin/metformin HCl
Pharmaceutical formulation: Film-coated FDC tablet, extended release (metformin)
Source:
Distributed by BI Pharma GmbH & Co. KG, Germany; 
manufactured by Patheon Pharmaceuticals Inc., Cincinnati, 
USA
Unit strength:
25 mg/5 mg/1000 mg 
Posology:
1-0-0
Route of administration:
p.o.
The characteristics of the reference products are given below:
Reference product 1:
Name:
Jardiance®
Substance:
Empagliflozin
Pharmaceutical formulation: Film-coated tablet
Source:
Distributed by BI Pharma GmbH & Co. KG, Germany;
manufactured by BI Pharmaceuticals, Inc., Ridgefield, USA,
and Eli Lilly and Company, Indianapolis, USA
Unit strength:
25 mg
Posology:
1-0-0
Route of administration:
p.o.
Reference product 2:
Name:
Tradjenta®
Substance:
Linagliptin
Pharmaceutical formulation: Film-coated tablet
Source:
Distributed by BI Pharma GmbH & Co. KG, Germany; 
manufactured by BI Pharmaceuticals, Inc., Ridgefield, USA,
and Eli Lilly and Company, Indianapolis, USA
Unit strength:
5 mg


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Posology:
1-0-0
Route of administration:
p.o.
Reference product 3:
Name:
Glumetza®
Substance:
Metformin HCl
Pharmaceutical formulation: Film-coated tablet, extended release
Source:
Distributed by BI Pharma GmbH & Co. KG, Germany; 
manufactured by Santarus Inc., San Diego, USA
Unit strength:
500 mg
Posology:
2-0-0
Route of administration:
p.o.
4.1.2
Method of assigning subjects to treatment groups
The randomisation list of study subject numbers and assigned treatment sequences will be 
provided to the trial site in advance. According to the planned sample size, 2 cohorts are 
planned. Prior to start of the study, subjects willing to participate will be recruited to cohorts 
according to their temporal availability. In the morning of Day 1 (Visit 2), subjects will be 
allocated to treatment sequences prior to first administration of trial medication. For this 
purpose, the subjects will be allocated to a study subject number by drawing lots, and then 
assigned to the corresponding treatment sequence by the randomisation list. Subjects will be
assigned to the 2 possible treatment sequences in a 1:1 ratio. Once a subject number has been 
assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
The doses selected for this trial reflect standard clinical doses (see Section 1.2).
4.1.4
Drug assignment and administration of doses for each subject
This trial is a two-way crossover study. All subjects will receive the 2 treatments in 
randomised order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below.


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Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substances
Formulation
Unit strength Dosage
Total dose
T (Test)
Empagliflozin/ 
linagliptin/ 
metformin HCl 
FDC film-coated
tablet, extended 
release 
25 mg/5 mg/ 
1000 mg
1 FDC tablet (single dose),
fed
25 mg/5 mg/ 
1000 mg
R (Reference) Empagliflozin
Linagliptin
Metformin HCl
Film-coated tablet
Film-coated tablet
Film-coated tablet, 
extended release
25 mg
5 mg
500 mg
1 tablet (single dose), fed
1 tablet (single dose), fed
2 tablets (single dose), fed
25 mg
5 mg
1000 mg
The medication will be administered as a single oral dose together with about 240 mL of 
water to a subject in the standing position under supervision of the investigating physician or 
an authorised designee. The so-called four-eye principle (two-person rule) should be applied 
for administration of trial medication and – if applicable – its preparation (e.g. reconstitution), 
if correct dosage cannot be ensured otherwise. 
In each treatment period, a high-fat, high-calorie meal will be served 30 min before drug 
administration. The meal must be completely consumed prior to drug administration. The 
composition of the standard high-fat, high-calorie meal will be in compliance with the FDA 
guidance ‘Food-Effect Bioavailability and Fed Bioequivalence Studies’ [R03-2269] as 
detailed in Table 4.1.4: 2.
Table 4.1.4: 2
Composition of the high-fat, high-calorie meal
Ingredients
Energy content
[kcal]
2 chicken eggs (whole content) for scrambled eggs
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
1.
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal as carbohydrate, and 
500 to 600 kcal as fat. 
Subjects will be kept under close medical surveillance until 24 h following drug 
administration. During the first 5 h after drug administration, they are not allowed to lie down 
(that is, no declination of the upper body of more than 45 degrees from upright posture). For 
restrictions with regard to diet see Section 4.2.2.2.
The treatments will be separated by a washout phase of at least 35 days.


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4.1.5
Blinding and procedures for unblinding
No blinding was performed because the treatments are distinguishable from each another.
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, since all subjects receive the same dose of 
different tablet formulations in an open-label design.
Pharmacokinetic samples will be labelled in such a way that treatment allocation cannot be 
derived by the analytical site.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of BI
Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Smaller bottles within 
the clinical trial supply containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Batch number
The telephone number of the sponsor and name, address, and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
As the trial is covered by the FDA requirements 21CFR320, packaging and labeling will be
performed in such a way that the required reserve samples are available for storage by the
investigational site and that the trial materials can be chosen in a random way by the
Investigator. The retained medication will be stored for a minimum of 5 years after trial
completion.
No re-supply is planned.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB/ethics committee 

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 clinical trial protocol
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the clinical trial protocol. All unused medication will be disposed locally by the 
trial site upon written authorisation by the clinical monitor. Receipt, usage, and disposal must 
be documented on the respective forms. Account must be given for any discrepancies. 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the disposal of unused products. 
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 subjects. The 
investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the clinical trial protocol, and that reconcile all investigational products 
received from the sponsor. At the time of disposal, the investigator must verify that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of AEs in need of treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all medical evaluation 
results have returned to an acceptable level.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed except for hormonal contraceptives. All 
concomitant or rescue therapies will be recorded (including time of intake on study days) on 
the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 5 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 2), the water administered with the drug, and an additional 
240 mL of water at 2 and 4 h post dose (mandatory for all subjects). From lunch until 24 h
post dose, total fluid intake is restricted to 3000 mL.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products including St. John’s wort (Hypericum perforatum) are not permitted starting 
7 days before the first administration of trial medication until after the last pharmacokinetic
sample of each study period is collected.
Alcoholic beverages are not permitted from 72 h before the administration of trial medication 
until after the last pharmacokinetic sample of each study period is collected.
Smoking is not allowed during in-house confinement at the trial site.
Also, methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during in-house confinement at the trial site.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end-of-trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
If female subjects of child bearing potential are included, adequate contraception is to be 
maintained throughout the course of the trial (see Section 3.3.2 for adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures see Section 3.3.4.1).


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2.1
Endpoints of safety
Safety and tolerability of the investigational drugs will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3).
 
 
 
 
 
 
 
 


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5.3
OTHER
5.3.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
taken at the screening examination from each subject whose genotype has not been 
previously determined. Separate informed consent for genotyping will be obtained from each 
volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the
pharmacogenomic data in the final report. However, the data may be part of the report if 
necessary.


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 are 
generally used assessments of drug exposure. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded.
Exact time points of plasma sampling will be derived from the study management system 
ClinBase™ and documented in the CRFs by the medical personnel or sent as electronic files
to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
The following primary endpoints will be determined:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point) for empagliflozin and 
metformin

AUC0-72 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 72 h) for linagliptin

Cmax (maximum measured concentration of the analyte in plasma) for empagliflozin, 
linagliptin, and metformin
5.5.1.2
Secondary endpoints
The following secondary endpoint will be evaluated for empagliflozin, linagliptin, and 
metformin:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
 


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of empagliflozin, linagliptin, and metformin plasma concentrations, 
7.5 mL of blood will be taken from an antecubital or forearm vein into an K3-EDTA 
(tripotassium ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times 
indicated in the Flow Chart. Blood will be withdrawn by means of either an indwelling 
venous catheter or by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 x g to 4000 x g and at 4 to 8 °C. Six plasma aliquots (2 aliquots each for empagliflozin, 
linagliptin, and metformin) will be obtained and stored in polypropylene tubes. The first 
aliquots should contain at least 0.5 mL plasma. The process from blood collection until 
transfer of plasma aliquots into the freezer should be completed within 90 min, with interim 
storage of blood samples in ice water or on ice. For each aliquot the time when the sample 
was placed in the freezer will be documented. Until transfer on dry ice to the analytical 
laboratory, the aliquots will be stored upright at about -20°C or below at the trial site. The 
second aliquot will be transferred to the analytical laboratory after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory the plasma samples 
will be stored at about -20°C or below until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, planned sampling time, name of analyte and ‘Ali-1’ or ‘Ali-2’. Further 
information such as matrix may also be provided. 
Plasma samples for empagliflozin analyses will be shipped to:
Plasma samples for linagliptin analyses will be shipped to:


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Plasma samples for metformin analyses will be shipped to:
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of empagliflozin plasma concentration
Empagliflozin concentrations in plasma will be determined by a validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) assay at 
 
. All details of the analytical method will be available 
prior to the start of sample analysis. During sample analysis, the bioanalyst will be blinded to 
subject allocation and will have no access to the random code.
5.5.3.2
Analytical determination of linagliptin plasma concentration
Linagliptin concentrations in plasma will be determined by a validated LC-MS/MS assay at 
. All details of the analytical method will be 
available prior to the start of sample analysis. During sample analysis, the bioanalyst will be 
blinded to subject allocation and will have no access to the random code.
5.5.3.3
Analytical determination of metformin plasma concentration
Metformin concentrations in plasma will be determined by a validated LC-MS/MS assay at 
. All details of the analytical method will be 
available prior to the start of sample analysis. During sample analysis, the bioanalyst will be 
blinded to subject allocation and will have no access to the random code.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end-of-trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration. 
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Pharmacogenomic genotyping will be performed in those volunteers whose genotypes are not 
known (for details see Section 5.3).
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days -1, 1, 2, 3, and 4 in each 
period). The 2 treatment periods will be separated by at least 35 days between drug 
administrations. Within 7 days prior to the drug administration in the second treatment period 
(Visit 3), the subjects will have an ambulatory appointment for safety laboratory blood 
sampling.
On Day -1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration on 
Day 1. The subjects will then be allowed to leave the trial site after formal assessment and 


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confirmation of their fitness. On all other study days, the study will be performed in an 
ambulatory fashion.
For details on time points and procedures for collection of plasma samples for 
pharmacokinetic analysis, refer to Flow Chart and Section 5.5.2.
 
6.2.3
End-of-trial period
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end-of-trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end-of-trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to establish the bioequivalence of an FDC tablet 
containing 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin XR compared with the 
free combination of empagliflozin (25 mg), linagliptin (5 mg), and metformin XR (2 x 
500 mg) tablets after a high-fat, high-calorie meal. The FDC tablet will be regarded as the test 
treatment (T) and the free combination of empagliflozin, linagliptin, and metformin XR 
tablets will be regarded as the reference treatment (R). The trial is designed to allow 
intrasubject comparisons and will be evaluated statistically by use of an appropriate linear 
model.
 
7.1.2
Endpoints
Bioequivalence is to be determined on the basis of the primary pharmacokinetic endpoints
(see Section 5.5.1.1). The secondary parameter (see Section 5.5.1.2) will be analysed 
analogously but will not be interpreted in a confirmatory sense. All pharmacokinetic 
endpoints (see Section 5.5.1) will be calculated and analysed descriptively.
 
7.1.3
Model
For the bioequivalence analyses, pharmacokinetic endpoints will be log-transformed (natural 
logarithm) prior to fitting the ANOVA (analysis of variance) model (see below).
The statistical model used for the analysis of primary and secondary endpoints will be an
ANOVA model on the logarithmic scale. This model will include effects accounting for the 
following sources of variation: ‘sequence’, ‘subjects within sequences’, ‘period’, and 
‘treatment’. The effect ‘subjects within sequences’ will be considered as random, whereas the 
other effects will be considered as fixed. The model is described by the following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response (endpoint) measured on subject m in 
sequence i receiving treatment k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni


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j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
For each endpoint, the difference between the expected means for log(T)-log(R), will be
estimated by the difference in the corresponding adjusted means (Least Squares Means), and 
a two-sided 90% confidence interval (CI) based on the t-distribution will be computed. These 
quantities will then be back-transformed to the original scale to provide the point estimate 
and 90% CIs for each endpoint.
As a sensitivity analysis, this ANOVA will be repeated for the primary and secondary 
endpoints with all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, 
‘treatment’) considered as fixed effects.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The assessment of bioequivalence will be based upon two-sided 90% CIs for the ratio of the 
geometric means (test/reference) for the primary endpoints using an acceptance range of 
80.00-125.00%. This method is equivalent to the two one-sided t-tests procedure, each at the 
5% significance level (on the log scale).
In general, the hypothesis of inequivalence is tested:
Null hypothesis H0 (inequivalence):
δ
μ
μ
δ
μ
μ
R
T
R
T





or
where 
T

and R
are the means of the log-transformed endpoint for the test and 
reference treatments, respectively, and δ is the bioequivalence limit that defines the 
acceptance range on the logarithmic scale.
Thus the null hypothesis is that the difference of the population average responses is either 
less than or equal to the lower bound or greater than or equal to the upper bound of the 
acceptance range.
Alternative hypothesis Ha (equivalence):
δ
μ
μ
δ
R
T




that is, the difference of the population average responses is both greater than the 
lower bound and less than the upper bound of the acceptance range.
In this trial, the bioequivalence limit δ is ln(1.25). By back-transforming (exponentiating), 
this translates to an acceptance range of 80.00 to 125.00% for the ratio of the geometric 
means (test/reference) for endpoints on the original (linear) scale.
The above null hypothesis H0 of inequivalence and its alternative Ha can be decomposed into 
two one-sided null hypotheses, H01 and H02, with their accompanying alternatives:
H01:
δ
μ
μ
R
T



vs.
Ha1:
δ
μ
μ
R
T



H02:
δ
μ
μ
R
T


vs.
Ha2:
δ
μ
μ
R
T




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Due to the nature of normal-theory CIs, the test of the null hypothesis H0 at the level of 
significance of = 0.05 is equivalent to carrying out two one-sided tests of the above null 
hypotheses H01 and H02 each at the level of significance of = 0.05. The rejection of both 
null hypotheses at the = 0.05 level is equivalent to the inclusion of the 90% CI for 
R
T



in the acceptance range (-δ, δ).
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The pharmacokinetic endpoints listed in Section 5.5.1 will be calculated according to the BI 
SOP ‘Standards and processes for analyses performed within Clinical Pharmacokinetics/
Pharmacodynamics’ [001-MCS-36-472].
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
violation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the clinical trial 
report.
Relevant protocol violations may be:

Incorrect trial medication taken, that is, the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if
for example:

The subject experiences emesis that occurred at or before 2 times median tmax of the 
respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis)

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
The following analysis sets will be defined for this trial:

Randomised set (RS):
This subject set includes all randomised patients, whether treated or not

Treated set (TS):
This subject set includes all subjects from the RS who were documented to have
received one dose of study drug. This is the full analysis set population in the sense of
ICH-E9

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one primary or 
secondary PK parameter that was not excluded according to the description above. 


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Thus, a subject will be included in the PKS, even if he/she contributes only one PK 
parameter value for one period to the statistical assessment
It will also be decided in the Report Planning Meeting which subjects are to be included in 
the respective analysis sets.
Point estimates of the ratios of the geometric means (test/reference) for the primary and 
secondary endpoints (see Sections 5.5.1.1 and 5.5.1.2), and their two-sided 90% CIs will be 
provided.
Bioequivalence is considered established if the 90% CIs of the ratios of the geometric means 
for the primary endpoints (see Section 5.5.1.1) are contained in the predefined acceptance 
range (see Section 7.2).
7.3.2
Secondary analyses
The secondary parameter (refer to Section 5.5.1.2) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ [001-MCS-36-472] and will statistically be assessed using the same 
methods as described for the primary endpoints.
Additionally, the pharmacokinetic parameters listed in Section 5.5.1.3 will be calculated and 
analysed descriptively, if feasible.
 
 
 
 
 
 
 
 
 
 


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7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 will be calculated according to the 
relevant BI SOP [001-MCS-36-472].
Individual plasma concentration data and the pharmacokinetic parameters will be tabulated, 
graphically displayed and summarized by descriptive statistics. Descriptive and inferential 
statistics of PK endpoints will be based on PKS. 
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration-time profiles
Handling of missing pharmacokinetic data will be performed according to the relevant BI 
SOP [001-MCS-36-472].


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Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies to the lag phase, including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing pharmacokinetic data will be performed according to the relevant BI 
SOP [001-MCS-36-472].
For the non-compartmental analysis, concentration data identified with NOS, NOR, or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
Subjects will be randomised to 1 of the 2 treatment sequences in a 1:1 ratio. The block size 
will be documented in the clinical trial report.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
Maximum observed intrasubject geometric coefficients of variation (gCV) for AUC and Cmax
were taken as 13% (linagliptin, parameter AUC), 14% (empagliflozin, parameter Cmax), and 
11% (metformin, parameter Cmax) from a previous trial (1361.1) in order to determine the 
sample size for this trial.
The power was calculated for the highest gCV and different expected ratios (test/reference). 
In order to get an overall power of at least 90%, a target power of 97% (=100*0.9^(1/3)) was 
defined, assuming that the 3 analytes are not correlated.
Using this gCV and the sample size of 26, the power to reject the null hypothesis of bio-
inequivalence for one parameter in favour of equivalence at the 5% level of significance is 
displayed in Table 7.6: 1 under various assumptions for the intrasubject ratio.


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Table 7.6: 1
Overall power for concluding bioequivalence in a two-way crossover 
trial (N=26) based on a geometric coefficient of variation of 14% (for 
empagliflozin), 13% (for linagliptin), and 11% (for metformin) and an 
acceptance range of 80-125% for different expected ratios of 
corresponding geometric means (test/reference)
Ratio1
90%
92%
94%
96%
98%
Power
83.5%
95.1%
98.8%
99.8%
100.0%
1.
Ratio of the geometric means (test/reference) for a PK endpoint defined by exp(µT)/exp(µR) (Section 7.2)
From Table 7.6: 1, a sample size of 26 will have approximately 98.8% power to conclude 
bioequivalence if the geometric mean ratio is 94%. Considering the expected power instead
[R11-0474], the overall probability for trial success would be approximately 78%. In 
addition, based on the table above, the overall power to conclude bioequivalence if the 
treatments differ up to 10% (ratio scale) would still be greater than 80%. Accounting for up 
to 4 PK non-evaluable subjects, 30 subjects will be included in the study.
The calculation was performed as described by Diletti et al. [R94-1445] using the function 
power.TOST() and exppower.TOST() of the package PowerTOST Version 1.4-3 in R 
Version 3.3.2.
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
As a general rule, no trial results should be published prior to finalisation of the clinical trial 
report.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject 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 subject information form are to be retained by the 


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investigator as part of the trial records. A copy of the signed and dated written informed 
consent and any additional subject information must be given to each subject.
The subject must be informed that his or her personal trial-related data will be used by BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by BI, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, 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.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the trial master file 
(TMF).
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM:
In the Human Pharmacology Centre (HPC) – BI’s Phase I unit – the validated ClinBaseTM
system is operated for processing information and controlling data collected in clinical 
studies. In addition to its function as a procedure control system, ClinBaseTM serves as data 
base. Instead of being entered into CRFs, selected data are directly entered into the system.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data is entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.


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8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor or auditor and for inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on-site monitor and auditor may review all CRFs and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this clinical trial protocol.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’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, that is, the CA.
8.6
COMPLETION OF TRIAL
The IEC/competent authority needs to be notified about the end of the trial (last subject /
subject out, unless specified differently in Section 6.2.3 of the clinical trial protocol) or early
termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P15-09840
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, 
Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, 
EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular 
outcomes, and mortality in type 2 diabetes. New England Journal of 
Medicine, published on September 17, 2015, doi: 
10.1056/NEJMoa1504720; 2015. p. 2117-2128.
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence
studies. In: U.S. Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER); 2002. p. 
1-9.
R06-0179
Stumvoll M, Goldstein BJ, Haeften TW van. Type 2 diabetes: principles of 
pathogenesis and therapy. Lancet 2005;365:1333-1346.
R11-0474
O'Hagan A, Stevens JW, Campbell MJ. Assurance in clinical trial design. 
Pharm Stat 2005;4:187-201.
R11-5199
Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, 
and risk of cause-specific death. N Engl J Med 2011;364(9):829-841.
R13-3902
White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, 
Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, 
Zannad F, EXAMINE Investigators. Alogliptin after acute coronary 
syndrome in patients with type 2 diabetes. New England Journal of 
Medicine, published on September 2, 2013 doi: 10.1056/NEJMoa1305889; 
2013. p. 1327-1335.
R13-3903
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et 
al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes
mellitus. New England Journal of Medicine, published on September 2, 
2013, doi: 10.1056/NEJMoa1307684; 2013. p. 1317-1326.
R15-3017
Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, 
Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, 
Standl E, Stein PP, Suryawanshi S, Werf F van de, Peterson ED, Holman 
RR, TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes 
in type 2 diabetes. New England Journal of Medicine, published on June 8, 
2015, doi: 10.1056/NEJMoa1501352; 2015. p. 232-242.
R15-4930
Glucophage (metformin hydrochloride) tablets, Glucophage XR (metformin
hydrochloride) extended-release tablets (Bristol-Myers Squibb) (U.S.
prescribing information, rev June 2015). 2015


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R17-0574
Glucophage 500 mg and 850 mg film coated tablets (Merck) (summary of 
product characteristics updated 19-Jan-2017).
https://www.medicines.org.uk/emc/print-document?documentId=1043 
(access date: 15 February 2017); 2017.
R17-1647
Glumetza (metformin hydrochloride extended-release tablets), for oral use
(Salix Pharmaceuticals), prescription only (U.S. prescribing information,
revised: 04/2017). https://shared.salix.com/shared/pi/glumetza-pi.pdf 
(access date: 10 May 2017); 2017.
R17-1649
Trajenta 5 mg film-coated tablets (Boehringer Ingelheim) (summary of 
product characteristics, manufacturer(s) responsible for batch release, 
conditions or restrictions regarding supply and use, other conditions and 
requirements of the marketing authorisation, conditions or restrictions with 
regard to the safe and effective use of the medicinal product, labelling and 
package leaflet, last updated: 11/04/2017). 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/ human/002110/WC500115745.pdf (access date: 10 
May 2017); 2017.
R17-1650
Jardiance 10 mg film-coated tablets, 25 mg film-coated tablets (Boehringer
Ingelheim) (summary of product characteristics, manufacturer responsible 
for batch release, conditions or restrictions regarding supply and use, other
conditions and requirements of the marketing authorisation, conditions or
restrictions with regard to the safe and effective use of the medicinal
product, labelling and package leaflet, last updated: 30/03/2017). 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002677/WC500168592.pdf (access date: 10 
May 2017); 2017.
R17-1673
Tkac I, Raz I. Combined analysis of three large interventional trials with
gliptins indicates increased incidence of acute pancreatitis in patients with
type 2 diabetes. Diabetes Care 2017;40:284-286.
R94-1445
Diletti E, Hauschke D, Steinijans VW. Sample size determination for 
bioequivalence assessment by means of confidence intervals. Int J Clin
Pharmacol Ther Toxicol 1992;30(Suppl 1):S51-S58.
R94-1529
Chow SC, Liu JP. Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
001-MCC-05-001_RD-03 GPV Compendium: Adverse Events of Special Interest “AESI”. 
Current version
c01678844-09
Investigator’s Brochure. Empagliflozin (BI 10773). Version 16. 19 May
2017


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001-MCS-40-106-RD-13 (5.0) / Saved on: 25 Jun 2014
c01838725-17
Investigator’s Brochure. Linagliptin (BI 1356). Version 15. 17 Nov 2016
c01838761-13
Investigator’s Brochure. Empagliflozin (BI 10773). Version 10. 06 May 
2014
c12820904-01
Relative bioavailability of two FDC tablet strengths of empagliflozin/ 
linagliptin/metformin extended release compared to the free combination of 
empagliflozin, linagliptin and metformin extended release following oral 
administration in healthy male and female subjects (an open-label, 
randomised, single-dose, two-period, two-sequence crossover study). 
1361.1. 19 May 2017
U05-2072
Safety, tolerability, pharmacokinetics and pharmacodynamics of single 
rising oral doses of BI 1356 as a solution at dose levels 2.5 -5 mg and 
tablets at dose levels 25 - 600 mg administered to healthy male subjects. A 
randomised, double-blind, placebo-controlled trial, including an intra-
subject bioavailability comparison of 100 mg BI 1356 as tablet and as 
solution. BI 1356 as tablet and as solution. 1218.1. 17 Aug 2005


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10.
APPENDICES
Not applicable. 


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15273597
1.0
clinical-trial-protocol
Bioequivalence of a fixed dose combination tablet of
empagliflozin/linagliptin/metformin extended release compared to the free
combination of empagliflozin, linagliptin, and metformin extended release tablets
following oral administration in healthy male and female subjects (an open-label,
randomised, single-dose, two-period, two-sequence crossover study)
Approval-Therapeutic Area 
28 Jun 2017 17:51 CEST
Author-Trial Clinical
Pharmacokineticist
29 Jun 2017 08:44 CEST
Author-Trial Clinical Monitor
29 Jun 2017 11:01 CEST
Approval-Team Member Medicine
29 Jun 2017 12:19 CEST
Author-Trial Statistician
29 Jun 2017 13:50 CEST
Verification-Paper Signature
Completion
29 Jun 2017 14:44 CEST


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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15273597
1.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c20692486-01
BI Trial No.:
1361.3
Title:
Bioequivalence of a fixed dose combination tablet of 
empagliflozin/linagliptin/metformin extended release compared to 
the free combination of empagliflozin, linagliptin, and metformin 
extended release tablets following oral administration in healthy 
male and female subjects (an open-label, randomised, single-dose, 
two-period, two-sequence crossover study)
Investigational
Products:
Empagliflozin/linagliptin/metformin extended release fixed dose 
combination
Responsible trial 
statisticians:
Phone:
Fax:
Phone:
Fax:
Date of statistical 
analysis plan:
08 DEC 2017 SIGNED
Version:
FINAL
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
5.3
FURTHER ENDPOINTS.....................................................................................9
5.4
OTHER VARIABLES........................................................................................10
5.4.1 
Demographic and other baseline characteristics .............................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATION......................................................12
6.3
PATIENT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........19
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................19
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINTS...................................................................................20
7.5
SECONDARY ENDPOINTS.............................................................................21
7.5.1
Key secondary endpoints....................................................................................21
7.5.2
Secondary endpoints...........................................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................22
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse events.....................................................................................................22
7.8.2
Laboratory data ..................................................................................................24
7.8.3
Vital signs.............................................................................................................25
7.8.4
ECG......................................................................................................................25
7.8.5
Others...................................................................................................................25
8.
REFERENCES....................................................................................................26


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10.
HISTORY TABLE..............................................................................................28


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................11
Table 6.2: 1
Important protocol violations...........................................................................14
Table 6.3: 1
Subject sets analysed........................................................................................16
Table 10: 1
History table .....................................................................................................28


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ANOVA
Analysis of variance
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-72
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to 72 hours
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BWC
Bioavailability/Bioequivalence, within-subject design, time-controlled
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DILI
Drug induced liver injury
ECG
Electrocardiogram 
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDC
Fixed dose combination
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference on Harmonisation
LLT
Lower level term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum


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Term
Definition / description
N
Number non-missing observations
O*C
Oracle Clinical
PK
Pharmacokinetics
PKS
PK parameter set
PT
Preferred term
PV
Protocol violation
qd
Quaque die (daily)
R
Reference treatment
RAGe
Report Appendix Generator system
REP
Residual effect period
RPM
Report planning meeting
SAS®
Statistical Analysis System
SD
Standard deviation
SOC
System organ class
T
Test treatment
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis
XR
Extended release


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3.
INTRODUCTION
As per ICH E9 (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.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP). 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.
Study data will be stored in a trial database within the Oracle ClinicalTM (O*C) system.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a 
number of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; 
Report Appendix Generator system (RAGe) for compilation/formatting of the CTR 
appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. The following change compared to the protocol will be made:
No ‘Randomised set’ will be defined in the TSAP as data of subjects randomised but 
discontinued before first administration of trial medication will not be entered in the case 
report form. A correct display of the ‘Randomised set’ would not be possible.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 5.5.1.1 of the CTP: The following primary endpoints will be determined:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point) for empagliflozin and 
metformin

AUC0-72 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 72 h) for linagliptin

Cmax (maximum measured concentration of the analyte in plasma) for empagliflozin, 
linagliptin, and metformin
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 5.5.1.2 of the CTP: The following secondary endpoint will be evaluated for 
empagliflozin, linagliptin, and metformin:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
5.3
FURTHER ENDPOINTS
Pharmacokinetic (PK):
Pharmacokinetic parameters are further parameters of interest. For more detail see CTP 
Section 5.5.1.3.
Safety:
Section 5.2.1 of the CTP: Safety and tolerability of the investigational drugs will be assessed 
based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG


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
Vital signs (blood pressure, pulse rate)
5.4
OTHER VARIABLES
5.4.1 
Demographic and other baseline characteristics
Section 5.2.5.2 of the CTP: At screening, the medical examination will include 
demographics including height and body weight, smoking and alcohol history, relevant 
medical history and concomitant therapy […].
Age [years] will be determined as the difference between year of informed consent and year 
of birth.
BMI will be calculated as weight [kg] / (0.01 * height [cm]2).


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment sequences, 
and selection of doses, please see CTP, Sections 3 and 4.
The study will be performed as a randomised, open-label, two-way crossover trial with 2
treatments (T and R) and 2 treatment sequences (TR or RT). 
In total, it was planned to assign 30 healthy male and female subjects to the two treatment 
sequences in a 1:1 ratio.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
Short label for 
footnote
T
Empagliflozin 25/Linagliptin 5/
Metformin XR 1000  FDC, fed
FDC25 fed
Empa25/Lina5/
Met1000 FDC 
fed
R
Empagliflozin 25 + Linagliptin 5 
+ Metformin XR 2*500, fed
E25+L+M fed
Empa25+Lina5
+Met1000 Tab 
fed
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00 h on day of informed consent until first administration 
time of study drug)

On treatment (including residual effect period (REP); i.e. ranging from the time of 
administration of the respective treatment until 7 days thereafter) 

Follow-up (ranging from end of on treatment phase until next drug administration or 
0:00 h on the day after trial termination date, according to previous treatment (labelled 
“FU-Test”, “FU-Ref”))
Displays of AEs will be presented separately for the following treatments during on treatment 
phase:

Empagliflozin 25/Linagliptin 5/Metformin XR 1000  FDC, fed (labelled “FDC25 fed“)

Empagliflozin 25 + Linagliptin 5 + Metformin XR 2*500, fed (labelled “E25+L+M 
fed“)


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Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.9.2.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening and follow-up periods will not be included in this analysis. 
The following total will be provided in addition (Section 15.3 only):

a total over all on treatment phases included in this analysis ("Total on treatment")
B) Section 15.4 and Appendix 16.1.9.2.8 (except for ClinicalTrials.gov and EudraCT) of the 
CTR displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))

Follow-up (“FU-Test” and “FU-Ref”)
In Section 16.1.9.2.8 AE tables, the following totals will be provided in addition:

a total over all study phases ("Total")
Tables of vital signs and laboratory values will present results by the above mentioned on
treatment phase.
For detailed information on the handling of the treatments in the O*C views refer to 
Technical TSAP ADS plan. In particular, AEs will be counted for test or reference treatment 
if they occur up to the end of the residual effect period (REP) of 7 days.
6.2
IMPORTANT PROTOCOL VIOLATION
Data discrepancies and deviations from the CTP will be identified for all randomised
subjects. Listings of protocol deviations and of unresolved discrepancies will be provided to 
be discussed at the combined report planning and database lock meeting (RPM/DBLM), e.g. 
deviations in drug administration, in blood sampling etc. At this meeting, it will be decided 
whether the discrepant data can be used as they are or whether the data have to be corrected 
in the clinical database.
Each protocol deviation must be assessed to determine whether it is an important protocol 
violation. A protocol violation (PV) is important if it affects the rights or safety of the study 
subjects or if it can potentially influence the primary outcome measure(s) for the respective 
subjects in a way that is neither negligible nor in accordance with the study objectives. This 
last category of important PV forms the basis for the decision of whether a subject does or 
does not belong to an analysis set. PVs that do not influence the subject's rights and safety or 
the evaluability of the subjects for the main study objectives are called non-important PVs. 
These are only considered when checking the trial quality in general.


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If any important PVs are identified, they are to be summarised into categories and will be 
captured in the RPM/DBLM minutes via an accompanying Excel spreadsheet [001-MCS-50-
413_RD-02] (2). The following table contains the categories which are considered to be 
important protocol violations in this trial. If the data show other important PVs, this table will 
be supplemented accordingly by the time of the RPM/DBLM.


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Table 6.2: 1
Important protocol violations
Category
/Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomisation not followed
C3
Non-compliance
C4
Medication code broken inappropriately
C5
Incorrect intake of trial medication
C6
Improper washout between treatments
D
Concomitant medication
D1
Prohibited medication use 
D2
Mandatory medication not taken
D3
Improper washout of concomitant medication
E
Missing data 
E1
Certain violations of procedures used to measure primary or secondary data
F
Incorrect timing1
F1
Certain violations of time schedule used to measure primary or secondary data
G
Other trial specific important violations
G1
Incorrect intake of meal
G2
PVs affecting safety and rights
1 Time deviations will only be flagged as important PV, when leading to exclusion of the entire subject from an analysis set
Source: ‘Protocol Violation Handling Definitions’ [001-MCS-50-413_RD-01] (3)


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6.3
PATIENT SETS ANALYSED

Treated set (TS):
This subject set includes all subjects who were documented to have received one dose of 
study drug.
This is the full analysis set population in the sense of ICH-E9.
It is used for safety analyses.
Section 7.3.1 of the CTP: Plasma concentration data and parameters of a subject will be 
included in the statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion 
due to a protocol violation relevant to the evaluation of PK (to be decided no later than in the 
Report Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, 
based on the criteria specified below). Exclusion of a subject’s data will be documented in 
the clinical trial report.
Relevant protocol violations may be:

Incorrect trial medication taken, that is, the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example:

The subject experiences emesis that occurred at or before 2 times median tmax of the 
respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis)

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve

PK parameter set (PKS): 
This subject set includes all subjects in the TS who provide at least one primary or 
secondary PK parameter that was not excluded according to the description above. Thus, 
a subject will be included in the PKS, even if he/she contributes only one PK parameter 
value for one period to the statistical assessment.
The descriptive analysis of PK concentrations will be based on the analysis data set (ADS) 
ADPC as described at the beginning of Section 7.


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Table 6.3: 1
Subject sets analysed
Analysis set
Class of endpoint
TS
PKS
Analyses of primary and secondary PK endpoints 
X
Safety endpoints 
X
Demographic/baseline endpoints
X
Important protocol violations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.4.
The only exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For vital signs and laboratory parameters the baseline is defined as the measurement at 
screening.
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and end-of-trial examination 
are given in the CTP Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.


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Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.9.2.
Inferential statistical analyses of PK endpoints (refer to Section 7.4 and Section 7.5.2) will 
also be performed by 
and will be presented in Section 15.5 of 
the CTR and in Appendix 16.1.9.3.
Descriptive data analysis of PK parameters and concentrations will be performed by BI and 
presented in Section 15.6 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations.
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number, visit and actual treatment (if appropriate). The listings will be included in 
Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
The descriptive statistics of PK parameters will be calculated using the individual values with 
the number of decimal places as provided by the evaluation program. Then the individual 
values as well as the descriptive statistics will be reported with three significant digits in the 
CTR.
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 (%) for each 
treatment group. Percentages will be rounded to one decimal place and will be based on all 
subjects in the respective subject set whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are actually missing values.


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Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
The analysis data set (ADS) ADPP contains column variables APEXC and APEXCO
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is APEXCO is equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’ the value will be excluded from half-life calculation only; the value is 
included for all other analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (11).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment sequence and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.


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The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM. 
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations will provide additional confirmation of compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
Bioequivalence is to be determined on the basis of the primary pharmacokinetic endpoints
(see Section 5.1).
Section 7.1.3 of the CTP: For the bioequivalence analyses, pharmacokinetic endpoints will 
be log-transformed (natural logarithm) prior to fitting the ANOVA (analysis of variance) 
model (see below).
Primary analysis
The statistical model used for the analysis of primary and secondary endpoints will be an 
ANOVA model on the logarithmic scale. This model will include effects accounting for the 
following sources of variation: ‘sequence’, ‘subjects within sequences’, ‘period’ and 
‘treatment’. The effect ‘subjects within sequences’ will be considered as random, whereas the 
other effects will be considered as fixed. The model is described by the following equation:
yijkm = + ζi + sim + j + k + eijkm, where
yijkm = logarithm of response (endpoint) measured on subject m in sequence i 
receiving treatment k in period j,
= the overall mean,
ζi = the ith sequence effect, i = 1, 2
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2
k = the kth treatment effect, k = 1, 2
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.


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The following SAS code can be used to fit the model:
PROC MIXED DATA=indata; 
CLASS subject treatment sequence period; 
MODEL logkp = treatment sequence period / DDFM=KR HTYPE=2 
SOLUTION CL ALPHA=0.1; 
RANDOM subject(sequence) / S; 
LSMEANS treatment / PDIFF=CONTROL(“Ref_trt”) CL ALPHA=0.1; 
RUN;
The implementation for this analysis will be accomplished by using the XPKISTAT macro, 
based on PKS, and option BWC (Bioavailability/Bioequivalence, within-subject design, time-
controlled).
Section 7.1.3 of the CTP: For each endpoint, the difference between the expected means for 
log(T)-log(R), will be estimated by the difference in the corresponding adjusted means (Least 
Squares Means), and a two-sided 90% confidence interval (CI) based on the t-distribution 
will be computed. These quantities will then be back-transformed to the original scale to 
provide the point estimate and 90% CIs for each endpoint. 
Further analysis
As a sensitivity analysis, this ANOVA will be repeated for the primary and secondary 
endpoints with all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, 
‘treatment’) considered as fixed effects. This analysis will be done using PROC GLM.
The following SAS code can be used to fit the model:
PROC GLM DATA=indata; 
CLASS subject treatment sequence period; 
MODEL logkp = treatment sequence period subject(sequence);
LSMEANS treatment / PDIFF=CONTROL(“Ref_trt”) CL ALPHA=0.1; 
RUN;
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
The secondary PK parameter AUC0-∞will be assessed using the same methods as described 
for the primary endpoints but will not be interpreted in a confirmatory sense.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (8).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:


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
All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AE of special interest)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started within one hour after end of 
the first occurrence).
For further details on summarization of AE data, please refer to [001-MCG-156] (8,4).
Section 5.2.2.1 of the CTP: The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters:
o
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, and/or
o
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure these parameters are analysed, if necessary in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the procedures described 
in the DILI checklist should be followed.

Pancreatitis

Hypersensitivity defined as angioedema, severe cutaneous adverse reactions or 
anaphylactic responses

Ketoacidosis
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events.
Section 5.2.2.2 of the CTP: The REP for the combined treatment with empagliflozin, 
linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects are 
still likely to be present, is defined as 7 days after the last administration of trial medication. 
Therefore, all AEs which occur through the treatment phase and throughout the REP will be 
considered as on treatment […].


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All adverse events occurring before first drug administration will be assigned to ‘screening’, 
those between intake of trial medication and end of the 7-day REP will be assigned to the 
corresponding treatment (‘on treatment’). AEs occurring after the REP but prior to next drug 
administration or termination date will be assigned to ‘follow-up’. The follow-up will be 
summarized according to previous treatment.
Section 7.3.3 of the CTP: AEs occurring after the last per protocol contact but entered 
before database lock will be reported to drug safety only and will not be captured in the trial 
database.
For more detail see the TSAP ADS plan.
According to ICH E3 (9), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant
therapy as identified by the Clinical Monitor/Investigator at the Report Planning Meeting. 
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with other 
significant AEs according to ICH E3 (9), for subjects with serious AEs, for subjects with 
drug-related AEs, for subjects with drug related serious adverse events and for subjects with 
AESIs.
The SOC and PTs will be sorted by frequency. The MedDRA version number will be 
displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
Descriptive statistics will be calculated for screening and end-of-trial visits as well as for the 
difference from baseline (=screening). The summary statistics will be provided in total.
Laboratory data assessed within 7 days prior to the drug administration in the second 
treatment period will only be listed. 
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as clinically 
relevant will be flagged in the data listings.


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Frequency tables of changes with respect to the reference range between baseline and last 
value on treatment will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the eCRF or at the RPM/DBLM at the latest. It is the 
investigator's responsibility to decide whether a lab value is clinically significantly abnormal 
or not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study.
The analyses of laboratory data will be based on BI standards [001-MCG-157] (10).
7.8.3
Vital signs
Descriptive statistics will be performed for vital signs (blood pressure and pulse rate) for both 
treatment sequences together (in total).
Section 7.3.3 of the CTP: For vital signs the difference from baseline (screening 
measurements) will be evaluated.
As vital signs are just measured at screening and post examination only these differences 
from screening will be calculated and presented in a table. In the listing the difference from 
screening will also be displayed.
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as adverse events 
(when they occurred during treatment).
7.8.5
Others
This section is not applicable as no other variables have been specified in the protocol.


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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.
 
 
 
 
 
 
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.
 
 


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
08-DEC-17
None
This is the final TSAP without any 
modification