Clinical trial NCT04590937
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2020-10-20; Completion date: 2021-01-11
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main objective of this trial is to investigate the effect of BI 730357 under steady state conditions on the pharmacokinetics of digoxin, furosemide, metformin and rosuvastatin given as a cocktail (Reference, R: cocktail alone; Test T: cocktail given under steady state conditions of BI 730357).

Detailed description:

Arms: arm 1: Cocktail treatment will be followed by the Test treatment in a fixed sequence. The treatment periods are separated by a wash-out phase of at least 14 days between the two cocktail administrations.
Interventions: intervention 1: BI 730357 intervention 2: CRESTOR® intervention 3: Lenoxin® intervention 4: MetfoLiquid GeriaSan® intervention 5: Lasix®
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet intervention 3: Tablet intervention 4: Oral solution intervention 5: Oral solution

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c32357152-03
EudraCT No.
EU Trial No.
  2020-003097-46 
BI Trial No.
  1407-0038
BI Investigational
Medicinal Product
BI 730357
Title
The effect of BI 730357 on the pharmacokinetics of rosuvastatin, 
digoxin, metformin and furosemide given as a cocktail – an open-
label, non-randomised, 2-period fixed-sequence trial in healthy 
subjects 
Lay Title
A study in healthy people to test whether BI 730357 affects how 
4 other medicines (rosuvastatin, digoxin, metformin, and 
furosemide) are taken up in the body
Clinical Phase
I
Clinical Trial Leader
Phone:
 Fax: 
Principal 
Investigator
Phone: 
, Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0  
Date: 19 October 2020
Page 1 of 82
Proprietary confidential information
© 2020 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
Company name
Boehringer Ingelheim
Protocol date
30 July 2020
Revision date
19 October 2020
BI trial number
1407-0038
Title of trial
The effect of BI 730357 on the pharmacokinetics of rosuvastatin, digoxin, 
metformin and furosemide given as a cocktail – an open-label, non-randomised, 2-
period fixed-sequence trial in healthy subjects
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
Evaluation of in-vivo effects of BI 730357 on drug transporter probe substrates
Trial objective
To assess the effect of multiple oral doses of BI 730357 on the pharmacokinetics of 
rosuvastatin, digoxin, metformin and furosemide given as a cocktail
Trial design
Non-randomised, open-label, 2-period fixed-sequence design
Trial endpoints:
Primary endpoints: AUC0-and Cmax of rosuvastatin, digoxin, metformin and 
furosemide
Secondary endpoints: AUC0-tz of rosuvastatin, digoxin, metformin and furosemide
Number of subjects 
total entered
15
each treatment
15
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male and female subjects, age of 18 to 55 years (inclusive), body mass 
index (BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Trial product 1
CRESTOR® 10 mg film-coated tablets (rosuvastatin)
Dose
1 x 1 tablet (10 mg rosuvastatin)
mode of admin.
Oral with 280 mL of water after a standardized breakfast
Trial product 2
Lenoxin® 0.25 mg tablets (digoxin)
Dose
1 x 1 tablet (0.25 mg digoxin)
mode of admin.
Oral with 280 mL of water after a standardized breakfast


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Trial product 3
MetfoLiquid GeriaSan®, 1000 mg / 5 mL oral solution (metformin)
Dose
1 x 0.05 mL oral solution (10 mg metformin)
mode of admin.
Oral with 280 mL of water after a standardized breakfast
Trial product 4
Lasix® liquidum 10 mg/mL oral solution (furosemide)
Dose
1 x 0.1 mL oral solution (1 mg furosemide)
mode of admin.
Oral with 280 mL of water after a standardized breakfast
Trial product 5
BI 730357, 100 mg tablets
Dose
2 x 3 tablets daily (= 600 mg BI 730357 per day) during treatment Test only
mode of admin.
Oral with 240 mL of water after a standardized meal
Duration of treatment
Rosuvastatin, digoxin, metformin and furosemide are given always together as a 
cocktail (the cocktail). The cocktail will be given single dose in both trial periods. 
Treatment Reference: the cocktail 
Treatment Test: 3 tablets BI 730357 bid on study days -7 until study day 6 (total of 
13 dosing days); on study day 1 the cocktail will be administered 1 hour after the 
morning dose of BI 730357
Statistical methods
The effect of BI 730357 on the pharmacokinetics of each of the cocktail 
components rosuvastatin, digoxin, metformin and furosemide will be estimated 
based on the ratio (test to reference) of the geometric means (gMeans) of the 
primary and secondary endpoints. Additionally, their two-sided 90% confidence 
intervals (CIs) will be provided. This method corresponds to the two one-sided t-
tests procedure, each at the 5% significance level. Since the main focus is on 
estimation and not testing, an acceptance range was not specified. 
The statistical model will be an analysis of variance (ANOVA) on the logarithmic 
scale including effects for ‘subject’ and ‘treatment’. CIs will be calculated based on 
the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART – TREATMENT REFERENCE
Period
Visit
Day
Planned time (relative to 
cocktail administration)
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory 7
PK blood, cocktail components
PK urine, cocktail components
6, 8
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 5
SCR
1
-21 to -2
Screening (SCR)1
A
x
x
x
1 
2   
-1
-13:00
20:00
Admission to trial site
x4
x
1
-2:00
07:00
x2
x2
x2
x2
x2
-1:30
07.30
Standardized breakfast
0:00
09:00
Cocktail dosing
▲
x
0:20
09:20
x
│
0:40
09:40
x
│
1:00
10:00
x
│
x
x
x
1:30
10:30
x
│
2:00
11:00
240 mL fluid intake
x
│
x
x
x
2:30
11:30
x
│
3:00
12:00
x
│
4:00
13:00
240 mL fluid intake, thereafter lunch3
x
┼
x
x
x
5:00
14:00
x
│
6:00
15:00
x
│
8:00
17:00
Extended snack3 (voluntary)
x
┼
x
10:00
19:00
x
│
10:30
19:30
Standardized dinner
│
12:00
21:00
x
┼
x 
2
24:00
09:00
Breakfast3
B
x
┼
x
x
x
28:00
13:00
Lunch
│
x
32:00
17:00
Snack (voluntary)
│
34:30
19:30
Dinner
│
36:00
21:00
x
┼
x
3
48:00
09:00
Discharge, breakfast (voluntary)3
x
▼
x
4
71:00
08:00
Ambulatory visit
x
x
5
95:00
08:00
Ambulatory visit
x
x
7
143:00
08:00
Ambulatory visit
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG (including rhythm stripe over 15 min), safety 
laboratory (including drug screening), demographics (including determination of body height and weight, smoking 
status and alcohol history), pregnancy test in females, 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 study drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
Only urine drug screening, alcohol breath test and pregnancy test in females.
5.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
6.
A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24, 24-36 and 36-48 h.
7.
Letters A and B define different sets of safety laboratory examinations (for details refer to Section 5.2.3).
 


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FLOW CHART – TREATMENT TEST
Period
Visit
Day
Planned time (relative 
to cocktail administra-
tion) [h:min]
Approx. clock time of 
actual day [h:min]
Event and comment
Safety laboratory 9
PK blood, cocktail components
PK blood, BI 730357
PK urine, cocktail components
7, 10
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs 
and concomitant 
therapy 6
2  
3 
-7
-170:30
06:30
Ambulatory visit, standardized breakfast
x5
x
x
-170:00
07:00
Dosing BI 730357
B
x
-158:30
18:30
Ambulatory visit, standardized dinner
-158:00
19:00
Dosing BI 730357
x
-6
-146:30
06:30
Ambulatory visit, standardized breakfast
-146:00
07:00
Dosing BI 730357
x
-134:30
18:30
Ambulatory visit, standardized dinner
-134:00
19:00
Dosing BI 730357
x
-5
-122:30
06:30
Ambulatory visit, standardized breakfast
-122:00
07:00
Dosing BI 730357
x
-110:30
18:30
Ambulatory visit, standardized dinner
-110:00
19:00
Dosing BI 730357
x
-4
-98:30
06:30
Ambulatory visit, standardized breakfast
-98:00
07:00
Dosing BI 730357
x
-86:30
18:30
Ambulatory visit, standardized dinner
-86:00
19:00
Dosing BI 730357
x
-3
-74:30
06:30
Ambulatory visit, standardized breakfast
x
x
-74:00
07:00
Dosing BI 730357
B
x
-62:30
18:30
Ambulatory visit, standardized dinner
-62:00
19:00
Dosing BI 730357
x
-2
-50:30
06:30
Ambulatory visit, standardized breakfast
-50:00
07:00
Dosing BI 730357
x
-38:30
18:30
Ambulatory visit, standardized dinner
-38:00
19:00
Dosing BI 730357
x
-1
-26:30
06:30
Ambulatory visit, standardized breakfast
-26:00
07:00
Dosing BI 730357
x
-14:00
19:00
Admission to trial site
x5
x
-13:30
19:30
Standardized dinner
-13:00
20:00
Dosing BI 730357
x8
x
1
-2:00
07:00
x2
x2
x2
x2
x2
-1:30
07:30
Standardized breakfast
-1:00
08.00
Dosing BI 730357
x8
x
0:00
09:00
Cocktail dosing
▲
x
0:20
09:20
x
│
0:40
09:40
x
│
1:00
10:00
x
│
x
x
x
1:30
10:30
x
│
2:00
11:00
240 mL fluid intake
x
│
x
x
x
2:30
11:30
x
│
3:00
12:00
x
│
4:00
13:00
240 mL fluid intake, thereafter lunch3
x
┼
x
x
x
5:00
14:00
x
│
6:00
15:00
x
│
8:00
17:00
Extended snack3 (voluntary)
x
┼
x
x
x
10:00
19:00
x
│
10:30
19:30
Standardized dinner
│
11:00
20:00
Dosing BI 730357
x8
│
x
12:00
21:00
x
┼
x


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FLOW CHART – Treatment Test, continued
Period
Visit
Day
Planned time (relative to 
cocktail administration)
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory 9
PK blood, cocktail components
PK blood, BI 730357
PK urine, cocktail components
7, 10
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
2
3
2
22:30
07:30
Standardized breakfast
│
23:00
08:00
Dosing BI 730357
x8
│
x
24:00
09:00
B
x
┼
x
x
x
28:00
13:00
Lunch
│
x
32:00
17:00
Extended snack3 (voluntary)
│
34:30
19:30
Standardized dinner
│
35:00
20:00
Dosing BI 730357
│
x
36:00
21:00
x
┼
x
3
46:30
07:30
Standardized breakfast
│
47:00
08:00
Dosing BI 730357
│
x
48:00
09:00
Discharge
x
▼
x
58:00
19:00
Ambulatory visit, standardized dinner
58:30
19:30
Dosing BI 730357
x
4
70:00
07:00
Ambulatory visit, standardized breakfast
70:30
07:30
Dosing BI 730357
x
71:00
08:00
x
82:00
19:00
Ambulatory visit, standardized dinner
82:30
19:30
Dosing BI 730357
x
5
94:00
07:00
Ambulatory visit, standardized breakfast
94:30
07:30
Dosing BI 730357
x
95:00
08:00
B
x
x
106:00
19:00
Ambulatory visit, standardized dinner
106:30
19:30
Dosing BI 730357
x
6
118:00
07:00
Ambulatory visit, standardized breakfast
118:30
07:30
Dosing BI 730357
x
119:00
08:00
x
130:00
19:00
Ambulatory visit, standardized dinner
130:30
19:30
Dosing BI 730357
x
8
167:00
08:00
Ambulatory visit
x
x
FU
4
14-
22
End of trial (EoTrial) examination4
C
x
x
x
1.
[For footnote 1 see Flow Chart of Treatment Reference]
2.
The time is approximate; the procedure is to be performed and completed within 3 h prior to first 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 in females, 
recording of AEs and concomitant therapies. 
5.
Only urine drug screening, alcohol breath test and pregnancy test in females
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24, 24-36 and 36-48 h.
8.
To be taken within 15 min prior to dosing
9.
Letters A, B, and C define different sets of safety laboratory examinations (for details refer to Section 5.2.3).


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART – TREATMENT REFERENCE ...........................................4
FLOW CHART – TREATMENT TEST..........................................................5
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 16
1.1
MEDICAL BACKGROUND............................................................................16
1.1.1
Retinoid acid-related orphan receptor γt (RORγt)............................16
1.1.2
Drug transporters .................................................................................16
1.2
DRUG PROFILE...............................................................................................17
1.2.2
Rosuvastatin ..........................................................................................19
1.2.3
Digoxin ...................................................................................................20
1.2.4
Metformin..............................................................................................20
1.2.5
Furosemide ............................................................................................21
1.2.6
Residual Effect Period..........................................................................22
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
1.4
BENEFIT - RISK ASSESSMENT ...................................................................22
1.4.1
Procedure-related risks ........................................................................22
1.4.2
Drug-related risks.................................................................................22
1.4.2.2
Risks related to the administration of the cocktail (without 
transporter inhibition) ..............................................................23
1.4.2.3
Risks related to a potential inhibition of drug transporters by BI 
730357 ...................................................................................23
1.4.2.4
Drug-induced liver injury ........................................................24
1.4.3
Safety measures.....................................................................................25
1.4.4
Overall assessment................................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 26
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......26
2.1.1
Main objectives......................................................................................26
2.1.2
Primary endpoints ................................................................................26
2.1.3
Secondary endpoint ..............................................................................26


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2.2.2.5
Safety and tolerability..............................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 30
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................31
3.3.1
Main diagnosis for trial entry..............................................................31
3.3.2
Inclusion criteria...................................................................................31
3.3.3
Exclusion criteria ..................................................................................31
3.3.4
Withdrawal of subjects from treatment or assessments ...................33
3.3.4.1
Discontinuation of trial treatment............................................34
3.3.4.2
Withdrawal of consent to trial participation ............................34
3.3.4.3
Discontinuation of the trial by the sponsor..............................34
3.3.5
Replacement of subjects .......................................................................35
4.
TREATMENTS........................................................................................ 36
4.1
INVESTIGATIONAL TREATMENTS ..........................................................36
4.1.1
Identity of the Investigational Medicinal Products ...........................36
4.1.2
Selection of doses in the trial................................................................37
4.1.3
Method of assigning subjects to treatment groups ............................37
4.1.4
Drug assignment and administration of doses for each subject .......38
4.1.5
Blinding and procedures for unblinding ............................................39
4.1.6
Packaging, labelling, and re-supply ....................................................39
4.1.7
Storage conditions.................................................................................40
4.1.8
Drug accountability ..............................................................................40
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................41
4.2.1
Other treatments and emergency procedures....................................41
4.2.2
Restrictions............................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment .........................41
4.2.2.2
Restrictions on diet and life style.............................................41
4.3
TREATMENT COMPLIANCE.......................................................................42
5.
ASSESSMENTS....................................................................................... 43
5.1
ASSESSMENT OF EFFICACY.......................................................................43


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5.2
ASSESSMENT OF SAFETY............................................................................43
5.2.1
Physical examination ............................................................................43
5.2.2
Vital signs...............................................................................................43
5.2.3
Safety laboratory parameters..............................................................43
5.2.4
Electrocardiogram................................................................................46
5.2.5
Assessment of adverse events...............................................................47
5.2.5.1
Definitions of adverse events...................................................47
Adverse event ............................................................47
5.2.5.1.1
Serious adverse event ................................................47
5.2.5.1.2
AEs considered ‘Always Serious’.............................48
5.2.5.1.3
Adverse events of special interest .............................48
5.2.5.1.4
Intensity (severity) of AEs.........................................49
5.2.5.1.5
Causal relationship of AEs ........................................50
5.2.5.1.6
5.2.5.2
Adverse event collection and reporting ...................................50
AE collection.............................................................50
5.2.5.2.1
AE reporting to the sponsor and timelines ................51
5.2.5.2.2
Information required..................................................51
5.2.5.2.3
Pregnancy ..................................................................52
5.2.5.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................53
5.3.1
Assessment of pharmacokinetics .........................................................53
5.3.2
Methods of sample collection...............................................................53
5.3.2.1
Blood sampling for pharmacokinetic analysis (cocktail 
components).............................................................................53
5.3.2.2
Blood sampling for pharmacokinetic analysis (BI 730357 
trough samples)........................................................................54
5.3.2.3
Urine sampling for pharmacokinetic analysis..........................54
5.3.2.4
Further investigations...............................................................55
5.4.2
Pharmacodynamic biomarkers............................................................58


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5.5
BIOBANKING ...................................................................................................58
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................58
6.
INVESTIGATIONAL PLAN.................................................................. 59
6.1
VISIT SCHEDULE............................................................................................59
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................59
6.2.1
Screening................................................................................................59
6.2.2
Treatment periods.................................................................................60
6.2.3
Follow-up period and trial completion ...............................................60
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 61
7.1
STATISTICAL DESIGN – MODEL ...............................................................61
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................61
7.3
PLANNED ANALYSES....................................................................................61
7.3.1
Primary endpoint analyses...................................................................62
7.3.2
Secondary endpoint analyses ...............................................................63
7.3.4
Safety analyses.......................................................................................64
7.4
INTERIM ANALYSES .....................................................................................65
7.5
HANDLING OF MISSING DATA ..................................................................65
7.5.1
Safety......................................................................................................65
7.5.2
Pharmacokinetics..................................................................................65
7.6
RANDOMISATION ..........................................................................................65
7.7
DETERMINATION OF SAMPLE SIZE ........................................................65
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 67
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................67
8.2
DATA QUALITY ASSURANCE .....................................................................68
8.3
RECORDS..........................................................................................................68
8.3.1
Source documents .................................................................................68
8.3.2
Direct access to source data and documents.......................................69
8.3.3
Storage period of records.....................................................................70
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................70
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......70


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8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................70
8.6
TRIAL MILESTONES .....................................................................................71
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................71
9.
REFERENCES......................................................................................... 73
9.1
PUBLISHED REFERENCES...........................................................................73
9.2
UNPUBLISHED REFERENCES.....................................................................77
10. APPENDICES .......................................................................................... 79
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 80
11.1
GLOBAL AMENDMENT 1 .............................................................................80
11.2
GLOBAL AMENDMENT 2 .............................................................................82


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ABBREVIATIONS
ABC
ATP-binding cassette
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC
Area under the concentration-time curve of the analyte in plasma
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
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
BA
Bioavailability
BCRP
Breast cancer resistance protein
BI
Boehringer Ingelheim
BID
Bis in die
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BU1
back-up sample
BU1 – BI
back-up may be used for BI 730357 analytics
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state
CML
Clinical Monitor Local
CRF
Case Report Form


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CRO
Clinical Research Organization
CT
Concomitant treatment
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P450
DDI
Drug-drug interaction
DNA
Desoxyribonucleic acid
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EMA
European Medicines Agency
EoTrial
End of trial
F
Absolute bioavailability factor
FDA
U.S. Food and Drug Administration
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
HMG-CoA
3-Hydroxy-3-methylglutaryl-coenzyme A
HR
Heart rate
IEC
Independent Ethics Committee
iPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
ITC
International Transporter Consortium
Ki
Inhibition constant
K3-EDTA
Tripotassium ethylenediaminetetraacetic acid
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography tandem mass spectrometry
MATE
Multidrug and toxin extrusion protein
MATE1
Multidrug and toxin extrusion protein 1
MATE2-K
Multidrug and toxin extrusion protein 2-K
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities


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NOA
Not analysed
NOR
No valid result
NOS
No sample available
OAT1
Organic anion transporter 1
OAT3
Organic anion transporter 3
OATP
Organic anion transporting polypeptide
OATP1B1
Organic anion transporting polypeptide 1B1
OATP1B3
Organic anion transporting polypeptide 1B3
OCT
Organic cation transporter
OCT2
Organic cation transporter 2
PD
Pharmacodynamic(s)
PE
Polyethylene
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PK D
Primary for digoxin
PK F
Primary for furosemide
PK M
Primary for metformin
PK R
Primary for rosuvastatin
PP
Polypropylene
PR
Pulse rate
q.d.
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
Heart frequency-corrected QT interval
R
Reference treatment
REP
Residual effect period
RS
Randomised set
SAE
Serious adverse event
SCR
Screening
SD
Single dose
SLC
Solute Carrier
SLC22A2
Gene encoding OCT2
SLC22A6
Gene encoding OAT1
SLC22A8
Gene encoding OAT3


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SLC47A1
Gene encoding MATE1
SLC47A2
Gene encoding MATE2-K
SLCO1B1
Gene encoding OATP1B1
SLCO1B3
Gene encoding OATP1B3
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
Ss
(at) steady state
T
Test treatment
T2DM
Type 2 diabetes mellitus
Tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
TSAP
Trial statistical analysis plan
Tz
Time of last measurable concentration of the analyte in plasma
ULN
Upper limit of normal
XTC
Ecstasy 


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1.
INTRODUCTION
BI 730357 is an antagonist at the retinoic acid-related orphan receptor γt (RORγt). It is being 
developed as an oral therapy for the treatment of patients with psoriasis as well as other 
Th17-mediated diseases. RORγ antagonism is a novel mechanism of action.
The trial will be performed to assess the influence of BI 730357 on the pharmacokinetics of 
rosuvastatin, digoxin, metformin and furosemide which are model substrates of clinically 
relevant drug transporters. The in-vivo effect of BI 730357 on these compounds should be 
used to predict potential transporter-based drug-drug interactions.
1.1
MEDICAL BACKGROUND
1.1.1
Retinoid acid-related orphan receptor γt (RORγt)
Retinoic acid-related orphan receptor γt (RORγt) is a nuclear hormone receptor/transcription 
factor expressed in Th17 cells (i.e., a subset of T helper cells which produce interleukin 17, 
and other signalling molecules) and in distinct subsets of lymphoid cells, including natural 
killer cells, innate lymphoid cells, and γδ T-cells. Upon cell activation, in response to 
multiple activation signals including cytokines and T cell receptor engagement, RORγt 
regulates the transcription of interleukin (IL)-17A, IL-17F, and IL-22 genes, and of the IL-23 
receptor gene. Emerging clinical science indicates a pivotal role for the Th17 axis in the 
pathogenesis of psoriasis, and other immunologically-mediated diseases. By blocking 
RORγt-mediated transcription of critical pro-inflammatory cytokines, and IL-23R, and 
consequently their downstream signalling, RORγt antagonism could prove efficacious in the 
treatment of Th17-mediated diseases [c09228382].
1.1.2
Drug transporters
Drug transporters play an important role in drug absorption, distribution, and excretion. 
Inhibition of drug transporters by concomitantly administered drugs may cause clinically 
relevant drug-drug interactions (DDI) [P14-07656], [R10-1157]. With increasing recognition 
and understanding of the involvement of drug transporters in clinically relevant DDIs, 
thorough investigation of transporter-mediated DDI has become indispensable during drug 
development.
Based on the recommendations of the International Transporter Consortium’s (ITC) white 
paper [R10-1157], regulatory agencies explicitly state drug transporters that should be 
investigated in vitro for inhibition by new investigational drugs during drug development. 
The specific transporters explicitly referred to by both the EMA guideline [P15-06991] and 
the FDA draft guidance [P12-05791] are the ABC transporters, P-glycoprotein (P-gp) and
breast cancer resistance protein (BCRP), and the SLC transporters, organic anion transporting 
polypeptide 1B1 (OATP1B1), OATP1B3, organic cation transporter 2 (OCT2), organic anion 
transporter 1 (OAT1), and OAT3.
If in vivo inhibition of a drug transporter known to be relevant for drug disposition cannot be 
excluded based on in vitro data, an in vivo study is recommended by regulatory agencies. A 
valuable approach to investigate several separate mechanisms underlying DDIs with the 


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investigational product as the perpetrator in one single study is the “cocktail study”. This 
method, in which a mixture of well-characterized probe drugs is administered together with 
the new investigational product, is well established for investigation of cytochrome P450 
(CYP)-mediated DDIs. Both the EMA and FDA recommend the use of cocktail studies also
for the investigation of transporter-mediated DDIs [P15-06991], [P12-05791].
A cocktail of drug transporter substrates has been developed by BI during the last years. This 
cocktail consists of 0.25 mg digoxin (substrate of P-gp), 10 mg rosuvastatin (substrate of 
OATP1B1, OATP1B3 and BCRP), 10 mg metformin (substrate of OCT2, MATE1 and 
MATE2-K) and 1 mg furosemide (substrate of OAT1 and OAT3), thus covering all 
transporters of potential clinical relevance recommended by EMA and FDA (see above). In 
the given doses the cocktail demonstrated no mutual interactions [R20-1915]. The 
metabolism of these drugs is minor facilitating the investigation of transporter-mediated 
DDIs without enzyme inhibition potentially confounding the results.
In this trial the BI transporter cocktail will be used for the first time to investigate the 
transporter-based DDI potential of a development compound.
1.2
DRUG PROFILE


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1.2.2
Rosuvastatin
Rosuvastatin is an HMG-CoA reductase inhibitor indicated for treatment of 
hypercholesterolemia and for prophylaxis of cardiovascular events. Inhibition of HMG-CoA 
decreases hepatic cholesterol production which, in turn, stimulates hepatocellular uptake of 
low-density lipoproteins [R17-2886]. 
After oral administration, maximal rosuvastatin plasma concentrations are reached at ~5 h. 
Oral bioavailability is ~20%, plasma protein binding is ~90%, and VZ/F is ~134 L. The liver 
is a principal compartment of distribution, with hepatocellular uptake being mediated mainly 
by OATP1B1 and, to a lesser degree, by OATP1B3. Elimination is mainly via faeces and to a 
lesser degree, via urine (principally via renal tubular secretion), with a t1/2 of 19 h
[R17-2886], [P14-07833].
In therapy, the initial rosuvastatin dose is 5-10 mg once daily (q.d.), and during therapy, the 
daily dose may be increased to up to 40 mg [R17-2886].


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Adverse reactions to rosuvastatin are normally mild and transient. Myalgia and myopathy 
with concomitant increase of creatine kinase, and, in rare cases, rhabdomyolysis have been 
observed during rosuvastatin therapy. Moreover, as for other HMG-CoA reductase inhibitors, 
a dose-dependent increase of liver transaminases may be observed [R17-2886].
For a complete listing of adverse reactions, including frequency of occurrence, please refer to 
the current SmPC [R19-3033].     
1.2.3
Digoxin
The cardiac glycoside digoxin is a potent and specific inhibitor of the membrane-bound 
Na+/K+ ATPase. In cardiomyocytes, Na+/K+ ATPase inhibition increases intracellular Ca++
concentrations during electromechanic coupling. Digoxin has positive inotropic and 
bathmotropic and negative chronotropic and dromotropic cardial effects. Use of digoxin is 
indicated in patients with tachyarrhythmia absoluta due to atrial fibrillation or flutter, with 
congestive heart failure due to systolic dysfunction, or with paroxysmal atrial fibrillation or 
flutter [R16-2173].
Digoxin oral bioavailability is ~60-80%. Its volume of distribution is large at 510 L in 
healthy volunteers; plasma protein binding is ~20%. Digoxin is eliminated principally 
(~80%) by the kidney, with a t1/2 of approximately 40 h [R16-2173].
In therapy, digoxin is given first as a loading regime of up to 0.75 mg digoxin/day, followed 
by a maintenance regime controlled by therapeutic drug monitoring.
Adverse reactions to digoxin include cardiac arrhythmia, gastrointestinal complaints and 
diverse symptoms of the central nervous system such as headache or psychiatric disorders. 
Moreover, disturbances of colour vision may occur. In rare cases, gynecomasty, myasthenia, 
thrombocytopenia, hypersensitivity reactions or lupus erythematodes have been observed 
[R16-2173]. A complete listing of adverse reactions, including frequency of occurrence, may 
be found in the current SmPC.
Symptoms of digoxin toxicity include cardial, gastrointestinal, and central side effects. 
Moreover, hyperkalemia may occur in acute overdosing. Life-threatening intoxications were 
observed after doses of ≥ 10 mg digoxin [R16-2173].
For a complete listing of adverse reactions please refer to the current SmPC [R20-2007].
1.2.4
Metformin
Metformin is an oral antidiabetic that reduces plasma glucose concentrations by decreasing 
intestinal glucose absorption and hepatic glucose production and by enhancing glucose 
utilization in peripheral tissues. Thus, metformin reduces basal (fasting) and postprandial 
plasma glucose in patients with type 2 diabetes mellitus (T2DM). However, metformin does 
not stimulate insulin secretion and is not causally related to hypoglycaemia in patients with 
T2DM or in healthy volunteers. Metformin is used in patients with T2DM if sufficient 
reduction of plasma glucose is not reached by diet and exercise alone [R17-3544].
After oral administration, tmax is reached at ~2.5 h, and oral bioavailability (of 500-850 mg) is 
~50-60%. Plasma protein binding is negligible, however, metformin enters erythrocytes 
which probably compose a deep distribution compartment. CLR of metformin is high 


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(estimated population mean of 507 ± 129 mL/min) and the principal mode of elimination,
with a t1/2 of approximately 6.5 h [R17-3544], [P11-01873]. 
The initial metformin dose is normally 500-850 mg up to three times daily. The dose may be 
increased to up to 3000 mg per day [R17-3544].
Most frequent adverse reactions to metformin are gastrointestinal complaints such as nausea, 
vomiting, diarrhoea, abdominal pain, or appetite loss. Moreover, metformin may cause 
changed taste (e.g., metallic taste), and, very rarely or with unknown frequency, respectively, 
skin reactions or abnormal liver function tests. For a complete listing of adverse reactions, 
including frequency of occurrence, please refer to the current version of the SmPC 
[R17-3544].
In addition, metformin may, very rarely, cause lactic acidosis. This is a life-threatening 
disorder caused by metformin accumulation, principally in diabetic patients with severe renal 
insufficiency. In case of unspecific symptoms such as muscle cramps in combination with 
gastrointestinal disorder or severe asthenia, lactic acidosis needs to be taken into account. 
Other possible symptoms are dyspnoea, abdominal disorders, hypothermia, and coma 
[R17-3544]. To our knowledge, lactic acidosis has not been observed in healthy volunteers, 
so far. High doses of up to 85 g metformin did not cause hypoglycaemia. However, lactic 
acidosis has been observed with this severe overdosing [R17-3544].
For a more detailed description of metformin`s profile please refer to the current SmPC [R17-
3544].
1.2.5
Furosemide
Furosemide is a loop diuretic indicated for treatment of oedema (cardiac, hepatic, renal, or 
due to burns), arterial hypertension, oliguria or pulmonary oedema. By inhibition of the 
Na+/2Cl-/K+ carrier in the distal ascending limp of Henle’s loop, furosemide increases 
diuresis and excretion of sodium, potassium, calcium, and magnesium [R16-2538].
After administration of furosemide as an oral solution, oral bioavailability is ~80%. Maximal 
plasma concentrations (tmax) are observed at ~1 h. Plasma protein binding is 95%, and VZ/F is 
0.2 L/kg. Furosemide is eliminated principally as unchanged substance, to two thirds by the 
kidney (glomerular filtration and secretion) and to one third by excretion into bile 
[R16-2538].
In therapy, initial doses of oral furosemide are normally 40 mg, but higher doses of over 
200 mg are possible in individual cases when diuresis with lower doses is not sufficient. 
Maintenance dose is normally 40-80 mg/day [R16-2538].
Adverse reactions include mainly electrolyte disorders including dehydration and 
hypovolemia, hearing disorders and allergic reactions including skin reactions. 
Symptoms of overdosing are characterized by excessive loss of electrolytes which may lead 
to hypotension, syncope, or delirium [R16-2538].
For a complete listing of furosemide adverse reactions, including frequency of occurrence,
please refer to the current SmPC [R20-2008].


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1.2.6
Residual Effect Period
The Residual Effect Period (REP) of the cocktail is 10 days referring to digoxin, the drug 
with the longest half-life among the cocktail components. This is the period after the last dose 
with measurable drug levels and/or pharmacodynamic effects still likely to be present.
The Residual Effect Period (REP) 
 This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Based on non-clinical data, 
 
This trial 
aims to investigate the in-vivo effect of BI 730357 on these drug transporters by using the 
drug transporter model substrates rosuvastatin (OATP1, BCRP), digoxin (P-gp), metformin 
(MATE-1, MATE-2K) and furosemide (OAT1) which will be administered as a cocktail (see
Section 1.1.2). The results of this trial will guide predictions on the DDI potential of 
BI 730357 with respect to the inhibition of the investigated drug transporters.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 730357 which 
may help to treat patients with psoriasis or other Th-17 related diseases. Subjects are exposed 
to risks of study procedures and risks related to the exposure to the trial medication.
1.4.1
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
1.4.2
Drug-related risks


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1.4.2.2
Risks related to the administration of the cocktail (without transporter 
inhibition)
All four cocktail components are market-approved drugs. The doses used in this trial are 
within or below the therapeutic range (see Table 1.4.2.2: 1).
Table 1.4.2.2: 1
Doses of cocktail components used in this trial compared to their 
therapeutic doses and to reported doses that have been given to 
healthy volunteers (HV):
Drug
Dose in this trial
Therapeutic daily dose 
Dose tolerated by HV
digoxin
0.25 mg SD
0.2 – 0.4 mg [R16-2173]
0.75 mg SD [R17-1846]
furosemide
1 mg SD
40 – 80 mg [R16-2538]
80 mg SD [R17-1848]
metformin
10 mg SD
up to 3000 mg [R17-1837]
1000 mg SD [U13-2366-01]
rosuvastatin
10 mg SD
10 mg – 40 mg [R17-2886]
80 mg SD [R13-4572]
While digoxin and rosuvastatin are given in therapeutic doses, subtherapeutic doses are used 
for furosemide and metformin. All these doses have been well tolerated by healthy subjects in 
the cocktail validation studies [R17-0548, R18-0240, R20-1915, R20-1930].
1.4.2.3
Risks related to a potential inhibition of drug transporters by BI 730357
Rosuvastatin is a substrate of OATP1B1/OATP1B3 and BCRP. Rifampicin is a known strong 
inhibitor of OATP transporters. After combined administration of rifampin and rosuvastatin 
Lai et al. and Pruesaritanont et al. describe an about 10-13-fold increase of rosuvastatin Cmax


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and a 5-fold increase of rosuvastatin AUC [R15-4771], [R17-1790]. This effect size could be 
confirmed by our cocktail validation trial 352.2100, in which a dose of 10 mg rosuvastatin 
has been given together with rifampicin and was well tolerated [c23988236-01].
 
 In a DDI  
study with itraconzole using single doses of 80 mg rosuvastatin Cooper et al report a rosuva-
statin plasma exposure of AUC of 571 ng/mL*h and Cmax of 61 ng/mL, that was well 
tolerated by healthy subjects [R13-4572] providing a safety margin of 13 (AUC) and 14.7 
(Cmax) compared to the exposure after 10 mg rosuvastatin seen in 352.2082. This is assessed 
to be sufficient to cover the potential inhibition of OATP1B1/1B3 mediated by BI 730357. 
Clinical data on the effect size of a specific inhibition of BCRP are not available. Thus, the 
risk resulting from an increased rosuvastatin exposure following a potential combined 
inhibition of OATPs and BCRP by BI 730357 cannot be assessed.
Digoxin is a model substrate of P-gp. Several P-gp inhibitors have been tested with digoxin 
[P09-01856]. The greatest effect on digoxin exposure has been observed with valspodar 
which increased AUC and Cmax of digoxin by Factor 3 and 2.5 [R07-4702].
In this trial, 0.25 mg digoxin will be given. According to the literature, single doses of 
0.75 mg digoxin have been well tolerated by healthy subjects [R17-1846], [R17-1847]. 
Assuming dose-proportional kinetics, this would provide a safety margin of factor 3, which is 
assessed to be sufficient to cover the potential inhibition of P-gp mediated by BI 730357.
Metformin is a substrate of OCT2 and MATE-transporters. Cimetidine is a known strong 
inhibitor of these transporters. The greatest effect of cimetidine on metformin exposure has 
been reported by Somogyi et al. The combined administration of cimetidine and metformin 
increased metformin Cmax and AUC by 73% and 46%, respectively [R99-0743].
In this trial a dose of 10 mg metformin will be given. Considering that therapeutic doses of 
1000 mg metformin have been well tolerated by healthy subjects [U13-2366-01], no undue 
risk is expected from combined administration of metformin and BI 730357 in this study.
Furosemide is a substrate of OAT1 and OAT3. Probenecid is a known strong inhibitor of 
these drug transporters. Smith and Vree observed an approximately 3-fold increase of furo-
semide AUC after combined administration of probenecid and 40 mg [R17-1861] and 80 mg 
[R17-1859] furosemide. 
 
1.4.2.4
Drug-induced liver injury
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 


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follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.5.1.4, adverse events of special interest.
1.4.3
Safety measures
For safety measures and assessments such as screening examination, AE/CT questioning, 
laboratory examinations, in-house periods or ECG/vital signs measurements, refer to the 
Flow Chart and Section 5.2. The safety measures are adequate to address the potential risks 
of the trial drugs to the volunteers.
1.4.4
Overall assessment
Digoxin, metformin, rosuvastatin and furosemide have been well tolerated after increase of 
their exposure mediated by established inhibitors [c23988236-01]. Thus, a potential increase 
in drug exposure of rosuvastatin, digoxin, metformin and furosemide mediated by BI 730357 
administration is covered by the experience made in previous trials (Section 1.2.1.3).
Considering the good tolerability of BI 730357 observed so far in healthy subjects and in 
patients, the sponsor feels that the benefit of a successful development of BI 730357
outweighs the potential risks to healthy participants.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the effect of BI 730357 under steady state 
conditions on the pharmacokinetics of digoxin, furosemide, metformin and rosuvastatin given 
as a cocktail (Reference, R: cocktail alone; Test T: cocktail given under steady state 
conditions of BI 730357).
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for rosuvastatin, digoxin, 
metformin and furosemide:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity )

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for rosuvastatin, digoxin, 
metformin and furosemide:

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)


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2.2.2.5
Safety and tolerability
Safety and tolerability of BI 730357, rosuvastatin, digoxin, metformin and furosemide 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)


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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 non-randomised, open-label, 2-period fixed-sequence trial
in healthy male and female subjects in order to compare the test treatment (T) to the reference 
treatment (R). An overview of both treatments is given below, for details refer to Section 4.1.
Treatment Reference (R)

The cocktail (consisting of 10 mg rosuvastatin, 0.25 mg digoxin, 10 mg metformin 
and 1 mg furosemide) given alone on Day 1 of period 1
Treatment Test (T)

The cocktail given one hour after the morning administration of  BI 730357 on Day 1
of period 2; pre-dosing with BI 730357 occurred on Day -7 to -1; dosing of BI 730357 
will be continued until Day 6; dosing regimen of BI 730357 is 300 mg bid for 13 days
All treatments will be given after a standardised meal. Reference treatment will always be 
followed by the Test treatment in a fixed sequence.
 
The subjects will be divided into 2 cohorts. The first cohort should contain not more than 6
subjects. Dosing of the 2nd cohort should start at least 5 days after the first cohort.
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.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
For this trial, the crossover design is preferred because of its efficiency: since each subject 
serves as his/her own control, the comparison between treatments is based on an intra-subject 
comparison, thus removing inter-subject variability from the comparison between treatments
[R94-1529].
Because of the different treatment time schedules, 
a fixed-sequence design was 
selected, in which BI 730357 was administered in the second study period only. The fixed-
sequence design is not expected to lead to systematic errors in the estimation of the treatment 
effects since non-specific time-effects are unlikely due to the short trial duration.
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma and urine concentrations of the analytes, which are provided by 
a bioanalytical laboratory that is blinded to treatment allocation.
 


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3.3
SELECTION OF TRIAL POPULATION
It is planned that 15 healthy male and female subjects (if feasible at least 5 of each sex) 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 (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy subjects according to the assessment of the investigator, as 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 (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
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 from at least 30 
days before the first administration of trial medication 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) 
-
Surgically sterilised (including hysterectomy or bilateral tubal occlusion)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in 
questionable cases a blood sample with 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) deviating from 
normal and assessed 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


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3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or 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 of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
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 (intake 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 of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or 
any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
23. Male subjects with WOCBP partner who are unwilling to use male contraception
(condom or sexual abstinence) from time point of first administration of trial medication 
until 30 days after the last administration of trial medication
24. For female subjects, positive pregnancy test, pregnancy, or plans to become pregnant 
within 30 days after study completion


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25. For female subjects, lactation period
26. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
27. Hypokalemia, hypomagnesemia, or hypercalcemia
28. PQ interval greater than 220 ms in the ECG at screening
29. Marked conductivity disorders (e.g. sinu-atrial blocks of II° or III°) or sick sinus 
syndrome, thoracic aneurysm of the aorta
30. Known or suspicion of pre-excitation syndrome (WPW- or LGL syndrome)
31. Known myopathy, personal or family history of hereditary muscular disorders, or history 
of muscular toxicity with another statin or fibrate; Asian ancestry; hypothyroidism 
32. Hereditary fructose intolerance, lactose intolerance, glucose-galactose malabsorption, 
sucrose-isomaltase deficiency
33. History of nephrolithiasis
34. Gout or clinically relevant elevation of uric acid 
35. Clinically relevant hypoproteinemia at screening
36. TSH exceeds upper limit of norm at screening, confirmed by a repeat test
37. Creatinine clearance (according to CKD EPI formula) is lower than 80 ml/min confirmed 
by a repeat test
38. Subjects with any other condition that would preclude administration of digoxin, 
furosemide, metformin or rosuvastatin (i.e. contraindicated as per SmPC), such as 
hypersensitivity to active ingredient or any of the excipients or to sulphonamides, active 
liver disease including elevations of serum transaminases exceeding 2 times the upper 
limit of normal upon repeat test, hypovolaemia or dehydration, partial obstructions of 
urinary outflow (e.g. prostatic hypertrophy)
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. 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 
REP (see Section 1.2.3), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 


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and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to 
Section 5.2.5.2.4.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as pregnancy,
surgery, adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and 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
6. In addition to these criteria, the investigator may discontinue subjects at any time based 
on his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant adverse events 


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of moderate or severe intensity, or if at least 1 drug-related serious adverse event is 
reported
2. Violation of GCP, or the CTP impairing the appropriate conduct of the trial
3. The sponsor decides to discontinue the further development of the investigational product
3.3.5
Replacement of subjects
In case more than 3 subjects do not complete the trial, the Clinical Trial Leader 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 trial subject number.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 730357 will be provided by BI Pharma GmbH & Co. KG, Germany. Rosuvastatin, 
digoxin, metformin and furosemide will be obtained from a public pharmacy.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the trial products are given below:
Trial product 1
Name:
* CRESTOR® 10 mg Film-coated tablet
Substance:
Rosuvastatin (as rosuvastatin calcium)
Pharmaceutical formulation:
Film-coated tablet
Holder of marketing authorization:
Unit strength:
10 mg
Posology:
1 – 0 – 0 (cocktail component)
Route of administration:
Oral
Duration of use:
single dose on Day 1 of visit 2 and 3
Trial product 2
Name:
* Lenoxin® 0,25 mg tablets
Substance:
Digoxin
Pharmaceutical formulation:
Tablet
Holder or marketing authorization:
Unit strength:
0.25 mg
Posology:
1 – 0 – 0 (cocktail component)
Route of administration:
Oral
Duration of use:
single dose on Day 1 of visit 2 and 3
Trial product 3
Name:
* MetfoLiquid GeriaSan® 1000 mg/5 ml oral solution
Substance:
Metformin hydrochloride
Pharmaceutical formulation:
Oral solution
Holder of marketing authorization:
Co-marketing: 
 
Unit strength:
1000 mg/5 mL
Posology:
0.05 mL (10 mg) – 0 – 0 (cocktail component)
Route of administration:
Oral
Duration of use:
single dose on Day 1 of visit 2 and 3


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Trial product 4
Name:
* Lasix® liquidum 10 mg/ml oral solution
Substance:
Furosemide (as furosemide sodium)
Pharmaceutical formulation:
Oral solution
Holder of marketing authorization:
Unit strength:
10 mg/mL
Posology:
0.1 mL (1 mg) – 0 – 0 (cocktail component)
Route of administration:
Oral
Duration of use:
single dose on Day 1 of visit 2 and 3
* These trial products may be replaced by generics which will be announced via a non-
substantial CTP amendment.
Trial product 5
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
3 – 0 – 3
Route of administration:
Oral
Duration of use:
from Day -7 to Day 6 of Visit 3 (13 days in total)
4.1.2
Selection of doses in the trial
0.25 mg digoxin, 1 mg furosemide, 10 mg metformin hydrochloride and 
10 mg rosuvastatin (see Section 1, Introduction).
4.1.3
Method of assigning subjects to treatment groups
There is only one treatment sequence investigated in this trial, and each subject will be 
allocated to the same treatment sequence (R-T). The subjects will be allocated to a study 
subject number by drawing lots prior to first administration of trial medication in the morning 
of Day 1 of Visit 2.


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Once a subject number has been assigned, it cannot be reassigned to any other subject.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a non-randomised 2-period fixed-sequence study. All subjects will receive the 
two treatments in a fixed sequence (Reference always followed by Test). The treatments to be 
evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total daily 
dose
R (cocktail)
Digoxin
Furosemide
Metformin
Rosuvastatin
Tablet
Oral solution
Oral solution
Film-coated 
tablet
0.25 mg
10 mg/mL
1000 mg/5mL
10 mg
1 tablet as single dose
0.1 mL (1 mg) as single dose
0.05 mL (10 mg) as single dose
1 tablet as single dose
0.25 mg
1 mg
10 mg
10 mg
T
BI 730357
Digoxin
Furosemide
Metformin
Rosuvastatin
Film-coated 
tablet
Tablet
Oral solution
Oral solution
Film-coated 
tablet
100 mg
0.25 mg
10 mg/mL
1000 mg/5mL
10 mg
3 tablets (300 mg) bid for 13 days   
on Day 1 the morning dose is
given 1 h prior to the cocktail
1 tablet as single dose
0.1 mL (1 mg) as single dose
0.05 mL (10 mg) as single dose
1 tablet as single dose
600 mg
0.25 mg
1 mg
10 mg
10 mg
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water (BI 730357) or 280 ml (for the cocktail) to subjects who 
are in standing position. For drug administration, the so-called four-eye principle (two-person 
rule) should be applied. For this, one authorised employee of the trial site should witness the 
administration of trial medication, and – if applicable – its preparation (e.g. reconstitution), if 
correct dosage cannot be ensured otherwise.
Fed conditions
A standardized meal (bread roll with butter, cheese and/or sliced sausage) will be served 30 
min before each BI 730357 administration. The subjects must completely consume the meal 
prior to drug intake. To assure comparable conditions for the cocktail administration, the 
standardised meal will be served also in the Reference treatment 90 min prior to the planned 
dosing of the cocktail (the meal is to be consumed within 30 min).


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Thereafter, complete drug administration is assumed.
All components of the cocktail should be administered within 2 minutes. 
After cocktail administration (in R and T)
Subjects will be kept under close medical surveillance until 48 h following cocktail
administration. During the first 4 h after cocktail administration, they are not allowed to lie 
down (i.e. no declination of the upper body of more than 45 degrees from upright posture), 
unless required for medical procedures. For restrictions with regard to diet, see 
Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
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, because the dose of trial medication is known to 
investigators and subjects.
PK 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
BI 730357
BI 730357 tablets will be provided by BI. They will be packaged and labelled in accordance 
with local law and the principles of Good Manufacturing Practice. For details of packing and 
the description of the label, refer to the ISF.


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The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided 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. 
No re-supply is planned.
Rosuvastatin, digoxin, metformin and furosemide
Rosuvastatin, digoxin, metformin and furosemide will be obtained by the clinical trial site 
from a public pharmacy. The drug will be dispensed out of the original, unmodified 
packages.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If 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 contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
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 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 
CTP.
The investigator or designee 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 medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that all unused or partially used drug supplies have been 
returned by the clinical trial subject and that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.


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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, if adverse events require 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 results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed except for hormonal contraceptives or ovary 
hormone replacement. 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 4 h after intake of the cocktail.
On Day 1 of both treatment periods from 1 h before (first) drug intake until lunch, fluid 
intake is restricted to the water administered with the drugs, and an additional 240 mL of 
water at 2 h and 4 h after cocktail administration (mandatory for all subjects). 
In all periods total fluid intake on Day 1 is restricted to 3000 mL from lunch until 24 h post-
dose. From 24 h – 48 h post-dose (in-house confinement) the total fluid intake is restricted to 
4000 mL. The term “post-dose” refers to the cocktail administration in both trial periods. 
Green tea, 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 study drug administration until last PK sampling of 
the trial.
Alcoholic beverages are not permitted starting 48 h before the first study drug administration 
until last PK sampling of the trial.
Methylxanthine-containing drinks or foods (such as coffee, white or black tea, cola, energy 
drinks, and chocolate) are not allowed from 12 h before administration of trial medication 
until subsequent discharge from the study site.
Smoking is not allowed during in-house confinement at the trial site.


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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, treatment with ultraviolet light
(e.g. PUVA), or medication with known phototoxicity potential (e.g, doxycycline) should be 
avoided from the first administration of BI 730357 until the EoTrial examination. The use of 
sunscreens is mandatory during that time.
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 
and urinary excretion of trial medication 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, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported), 
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG (including rhythm strip), laboratory tests, and 
physical examination. 
At the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, and physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap Pro 100,
 at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 10 h
with the exception of safety lab B which may be taken under non-fasted conditions. For 
retests, at the discretion of the investigator or designee, overnight fasting is not required.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively. Blood sampling for lymphocyte differentiation may be separated from the rest 
of safety lab B, should safety lab B fall on a Sunday. In these cases blood for lymphocyte 
differentiation will be withdrawn in an additional blood sample on Sunday evenings to ensure 
sufficient stability of samples until measurement the next day. This is acceptable since it is 
only a logistical step which ensures sample stability but does not influence the timepoint of 
availability of these safety data, i.e. only on the Monday either way, and has no impact on 
subjects’ safety.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
-
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
-
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Lymphocyte 
differentiation 
(relative and absolute; 
except for ratio)
T cells (CD3+), T helper cells (CD3+CD4+), cytotoxic T 
cells (CD3+CD8+), B cells (CD19+), natural killer cells 
(CD16+CD56+CD3-), double-positive T cells 
(CD3+CD4+CD8+), CD4:CD8 ratio
X
X
X
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time - INR (International Normalization Ratio)
X
X
-
-
X
X
Enzymes
AST [Aspartate transaminase] /GOT
ALT [Alanine transaminase] /GPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated]
X
X
X
X
X
-
X
X
X
X
X
-
X
X
X
X
X
-
Hormones
Thyroid Stimulating Hormone 
X
-
-
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI3
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
Uric Acid
X
X
X
X
X
X
X
X
-
X
-
-
-
-
X
-
-
X
-
X
X
X
X
-
Electrolytes
Sodium
Potassium
Calcium
Magnesium
Chloride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Cont’d
Table 5.2.3: 1
Routine laboratory tests
Urinalysis2 (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Urine sediment2
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
1
A to be done at screening examination, B during the trial, C at EoTrial examination. 
2
Microscopic examination if erythrocytes, leukocytes, or protein are abnormal in urine
3
Estimated glomerular filtration rate according to CKD-EPI formula [R12-1392]
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, upon 
admission in the evening of Day -1 of both treatment periods, prior to the first administration 
of BI 730357, and as part of the end of trial examination. Drug screening will be performed at 
screening and upon admission in the evening of Day -1 of both treatment periods.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. AlcoTrue® 
M, 
) will be performed upon admission in the 
evening of Day -1 of both treatment periods, and may be repeated at any time during the 
study at the discretion of an investigator or designee. The results will not be included in the 
CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at
 
, with the exception of 
drug screening and pregnancy tests. These tests will be performed at the trial site using 
M-10/14-PDT Multiline test and HCG-K20 test, respectively, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
 
) at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). Electrode placement will be performed according to the 


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method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Assessment of adverse events
5.2.5.1
Definitions of adverse events
Adverse event
5.2.5.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.2.5.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 


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
Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.5.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in Section 5.2.5.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor 
and timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.5.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.5.2.2.


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The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects 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 that these parameters are analyzed, 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.

Severe infections (grading according to Rheumatology Common Toxicity Criteria
[RCTC] developed by OMERACT [R13-3515])

Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including polyomavirus-
associated nephropathy, cytomegalovirus, posttransplant lymphoproliferative disorder 
(Epstein-Barr virus), progressive multifocal leukoencephalopathy, bartonellosis 
(disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), hepatitis B virus reactivation, herpes 
simplex (invasive only), herpes zoster, strongyloides (hyperinfection syndrome and 
disseminated forms only), paracoccidioides, penicillium marneffei, sporothrix 
schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis 
(visceral only), trypanosoma cruzi Infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due 
to vibrio vulnificus), hepatitis C virus progression.
Intensity (severity) of AEs
5.2.5.1.5
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities


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Causal relationship of AEs
5.2.5.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.5.2
Adverse event collection and reporting
AE collection
5.2.5.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 


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Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
5.2.5.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.5.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.


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Pregnancy
5.2.5.2.4
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood and urine samples will be collected at the time 
points / time intervals indicated in the Flow Chart. The actual sampling times will be 
recorded and used for determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis (cocktail components)
For quantification of digoxin, furosemide, metformin and rosuvastatin plasma concentrations 
(cocktail components to be analysed from primary aliquots; 
 
 
 7.5 mL of blood will be taken from an antecubital or forearm 
vein into K2-EDTA anticoagulant blood drawing tubes 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 at least 15 min at 
approximately 2000 x g to 4000 x g and at 4 to 8 °C. Centrifugation should be started within 
45 minutes after sampling. Seven plasma aliquots (4 primaries and 3 back-ups) will be 
obtained and stored in polypropylene tubes. The primary aliquots should contain at least 0.4
mL plasma, the back-up aliquots 0.4 ml (BU1 and BU2), and approximately 0.8 ml (BU3).
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 until 
centrifugation. 
 
For each aliquot, the time when the sample was placed in the freezer will be documented.
Until transfer on dry ice, the aliquots will be stored upright at about -20°C or below at the 
trial site. The primary aliquots will be sent to the bioanalytical laboratory first. They will be 
sent in two shipments; the second shipment will be sent only after the bioanalytical laboratory 
has acknowledged safe arrival of the first shipment. At the bioanalytical laboratory, the 
primary aliquots 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 number, aliquot and planned sampling time. Further information such as 
matrix may also be provided. Aliquot names are planned as follows:
-
“A1 - PK D” 
= primary for digoxin 
-
“A2 - PK F” 
= primary for furosemide
-
“A3 - PK M”
= primary for metformin 


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-
“A4 - PK R” 
= primary for rosuvastatin
5.3.2.2
Blood sampling for pharmacokinetic analysis (BI 730357 trough samples)
For quantification of BI 730357 plasma concentrations 2.7 mL of blood will be taken from an 
antecubital of forearm vein into a separate K2-EDTA (dipotassium ethylenediaminetetra-
acetic acid as anticoagulant) blood drawing tubes at the times indicated in the Flow Chart. 
Blood will be withdrawn by means of either an indwelling venous catheter or by veni-
puncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and at 4 to 8 °C. Two plasma aliquots will be obtained 
and stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma.
The process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 120 min with interim storage of blood samples at room temperature and 
without exposition to direct sunlight. 
The time each aliquot was placed in the freezer will be documented. Until transfer on dry ice 
to the analytical laboratory, BI 730357 aliquots will be stored upright at approximately -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 BI trial number, subject number, visit, 
planned sampling time, and the analyte (e.g. ‘BI 730357’). Further information such as 
matrix may also be provided.
5.3.2.3
Urine sampling for pharmacokinetic analysis
A blank urine sample will be collected before administration of trial medication (see Flow 
Chart) and aliquots will be retained to check for analytical interference. All urine voided 
during the sampling intervals indicated in the Flow Chart will be collected in 2 L 
polyethylene (PE) containers and stored at room temperature. Subjects are told to empty their 
bladders at the end of each sampling interval.
The urine weight/volume for each collection interval will be documented (however, no 
correction for the specific gravity of urine is done, i.e. 1 L is defined to be equal to 1 kg). 
Aliquots will be stored in polypropylene (PP) tubes for bioanalytical measurement. In case 
more than one collection container is used in an interval, the contents of all containers are to 
be mixed before aliquots are prepared. Mixing should be done by transferring the entire 
content of all collection containers into a single PE/PP or glass container, and stirring the 
mixed fractions for about 1 min (manually or using a stir bar or other stirring device made of 
PE, PP, Teflon or glass).
For each sampling interval or time point seven urine aliquots of at least 2 mL will be obtained 
(4 primaries, 2 back-ups
 


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For the 4 primaries and the 2 back-ups: Until transfer on dry ice, the urine samples will be 
stored at about -20C or below at the trial site. For all treatment periods, the primary aliquots 
will be sent to the bioanalytical laboratory first. They will be sent in two shipments; the 
second shipment will be sent only after the bioanalytical laboratory has acknowledged safe 
arrival of the first shipment. At the bioanalytical laboratory, the primary aliquots will be 
stored at about -20°C or below until analysis. 
The back-up aliquots will only be transferred to the analytical laboratory analysing cocktail 
components if needed (primary aliquots are foreseen for these analyses). In any case, back-up 
aliquots will only be shipped from the clinical site once the bioanalyst has acknowledged safe 
arrival of the primary aliquots at the analytical laboratory.
At minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit number, aliquot, and planned collection interval or time point, as 
applicable. Further information, such as matrix, may also be provided. 
The aliquot names are planned as follows:
-
“A1 - PKU D” 
= primary for digoxin 
-
“A2 - PKU F” 
= primary for furosemide 
-
“A3 - PKU M”
= primary for metformin 
-
“A4 - PKU R” 
= primary for rosuvastatin
5.3.2.4
Further investigations
After completion of the analysis of plasma and urine samples for concentrations of digoxin, 
furosemide, metformin, and rosuvastatin, the plasma and urine samples (including back-ups 
and left-over sample volumes from pre-specified analyses) may be used as follows:
-
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
-
For analyses of the concentrations of BI 730357 and its metabolites
Results of further investigations are not planned to be part of the trial report; however, results 
of further investigations may be part of the trial report, if required.


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The study samples will be discarded after completion of the additional investigations, but not 
later than 5 years after the CTR is archived.


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5.4.2
Pharmacodynamic biomarkers
Not applicable.
5.5
BIOBANKING
Not applicable.
5.7
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 5.3 are 
generally used assessments of drug exposure. The biomarkers outlined in Sections 5.4 are of 
exploratory nature, only.


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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 the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration are to be performed and completed within a 2h-period prior to the next trial 
drug administration, if not indicated otherwise in the FlowChart.
For ambulatory administration of BI 730357 prior to Day -1 of Visit 3, a time window of ± 
70 minutes will be allowed.
Following administration of trial drugs in Visits 2 and 3, the acceptable deviation from the 
scheduled time for vital signs, ECG, and laboratory tests will be ± 30 min on Day 1 and ± 45 
minutes from 28 hours onwards.
The acceptable deviation from the scheduled time for all meals on Day 2 in Period 1 is ± 2 h 
to allow, that subjects may have their meal together. 
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 venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times and urine collection intervals, 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 the determination of pharmacokinetic parameters.
For cocktail PK blood sampling on Day 7 of Visit 2 and Days 6 and 8 of Visit 3, respectively, 
a time window of ± 60 minutes will be allowed.
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 provide 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.


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6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days -1 to 7 in period 1 and 
Days -7 to Day 8 in Period 2). In the 2nd treatment period ambulatory dosing of BI 730357 
(300 mg bid) starts on Day -7 to achieve steady state of the perpetrator drug.
 
 
In the 2
treatment period twice daily dosing of BI 730357 is continued until Day 6.
In the evening of Day -1 of each treatment period, study participants will be admitted to the 
trial site and kept under close medical surveillance for at least 60 hours. The subjects will 
then be allowed to leave the trial site after formal assessment and confirmation of their 
fitness. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for BI 730357 dosing, collection of plasma and 
urine samples for PK analysis, refer to the Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination but will specifically asked for at the timepoints 
specified in the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up 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 EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as 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 EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the pharmacokinetics of digoxin, furosemide,
metformin and rosuvastatin given as a cocktail alone (Reference, R) and as a cocktail 
together with BI 730357 (Test, T) following oral administration on the basis of the primary 
and secondary pharmacokinetic endpoints, as listed in Sections 2.1.2 and 2.1.3. The trial is 
designed to allow intra-subject comparisons and will be evaluated statistically by use of a 
linear model for logarithmically transformed PK endpoints. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of digoxin, rosuvastatin, metformin and furosemide (the cocktail) 
given alone compared with a combined administration with BI 730357 will be estimated by 
the ratios of the geometric means (test/reference) for the primary and secondary PK endpoints
and their corresponding 2-sided 90% confidence intervals (CIs) will be provided. This 
method corresponds to the two one-sided t-test procedure, each at the 5% significance level. 
Since the main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who signed informed consent
and were treated with at least one dose of study drug. The treated set will be used for 
safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). 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.
Descriptive and model based analyses of PK parameters will be based on the PKS.


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Adherence to the protocol will be assessed by the trial team. Important protocol deviations
(iPD) categories will be suggested in the TSAP; iPDs will be identified no later than in the 
Report Planning Meeting, and iPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Sections 2.1
will be calculated according to 
the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma and urine 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 deviation 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 CTR.
Relevant protocol deviations may be

Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

The subject experienced emesis that occurred at or before two 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
Plasma/urine concentration data and parameters of a subject which is flagged for exclusion 
will be reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the 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). 
7.3.1
Primary endpoint analyses
Primary analyses
The primary endpoints are specified in Section 2.1.2. The analysis will be based on the PKS 
and will be descriptive in nature.


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The statistical model used for the analysis of the primary endpoints AUC0-∞and Cmax of each 
of the variables rosuvastatin, digoxin, metformin and furosemide will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: ‘subjects’ and ‘treatment’. The 
effect 'subject' will be considered as random, whereas the effect 'treatment' will be considered 
as fixed. The model is described by the following equation:
ykm = + k + sm +ekm, where
ykm = logarithm of response measured on subject m receiving treatment k,
= the overall mean,
k = the kth treatment effect, k = 1, 2,
sm = the effect associated with the mth subject, m = 1, 2, ..., 15
ekm = the random error associated with the mth subject who received treatment k.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
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).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.3.2
Secondary endpoint analyses
The secondary endpoint (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will be assessed statistically using the same 
methods as described for the primary endpoints.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset of AE) to the 
subject will be used (any deviations from the planned treatment will be discussed in the 
minutes of the Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between trial medication intake and end of REP 
(see Section 1.2.3) will be assigned to the treatment period. Events occurring after the REP 
but prior to next intake or end of trial termination date will be assigned to ’follow-up’. In case 
of two or more treatments, the follow-up will be summarized according to the previous 
treatment. These assignments including the corresponding time intervals will be defined in 
detail in the TSAP. Note that AEs occurring after the last per protocol contact but entered 
before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.5.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.


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7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
This is a non-randomised trial. 
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 15 subjects in the trial, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratio of geometric means (test/reference) can be expected with 
95% probability. Precision is defined as the ratio of upper CI limit to the relative BA 
estimate. Note that the precision is independent of the actual ratio of geometric means.
For various assumptions around the gCV of 30% , Table 7.7: 1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (test/reference). For 
illustrative purposes, the expected 90% confidence intervals are displayed for different values 
of the ratios T/R of geometric means.


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Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a 2-period fixed-sequence trial
(N=15)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
20.0
1.18
100
84.73
118.02
20.0
1.18
150
127.10
177.03
20.0
1.18
200
169.47
236.04
25.0
1.23
100
81.39
122.87
25.0
1.23
150
122.08
184.31
25.0
1.23
200
162.77
245.74
30.0
1.28
100
78.23
127.83
30.0
1.28
150
117.34
191.75
30.0
1.28
200
156.45
255.67
35.0
1.33
100
75.25
132.89
35.0
1.33
150
112.87
199.34
35.0
1.33
200
150.50
265.78
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit, = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.6.1.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the  subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, 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 (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.


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For subjects enrolled during the COVID-19 pandemic: In addition to the study specific 
informed consent, separate written consent will be obtained for testing on SARS-CoV-2 
infection.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the
Phase I unit – the 
validated ClinBaseTM system is used 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
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.


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If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment in a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. Data in ClinBaseTM are available for inspection at any time.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source docu-
ments/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents descry-
bed in Section 8.3.1. The sponsor will also monitor compliance with the protocol and GCP.


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8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements 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 and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
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.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
ICF.


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8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) 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.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the 
 
, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Clinical trial Leader, responsible for coordinating all required trial 
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, and investigators of participating trial sites
The trial medication (BI 730357) will be provided by the 
 
. Digoxin, rosuvastatin, metformin and 
furosemide will be purchased by the clinical site at a public pharmacy.
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).
The analyses of digoxin, furosemide, metformin, rosuvastatin and cimetidine concentrations 
in plasma and urine will be performed under the responsibility of the Department of 
 


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 at 
contract research organisations (CROs) 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs.
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 ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
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Fenner KS, Troutman MD, Kempshall S, Cook JA, Ware JA, Smith DA, 
Lee CA. Drug-drug interactions mediated through P-glycoprotein: clinical 
relevance and in vitro-in vivo correlation using digoxin as a probe drug. 
Clin Pharmacol Ther 2009 ; 85(2) ; 173-181.
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Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong 
TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, 
Williams KM, Clinical pharmacokinetics of metformin, Clin 
Pharmacokinet 2011 ; 50(2) ; 81-98.
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U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER). 
Guidance for industry: drug interaction studies - study design, data analysis, 
implications for dosing, and labeling recommendations (draft guidance, 
February 2012 (this guidance document is being distributed for comment 
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Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER); 2012.
P14-07656
 Fromm MF. Transporter-mediated drug-drug interactions. 
Pharmacogenomics 2011;12(7):1017-1037.
P14-07833
Neuvonen PJ, Backman JT, Niemi M, Pharmacokinetic comparison of the 
potential over-the-counter statins simvastatin, lovastatin, fluvastatin and 
pravastatin. Clin Pharmacokinet 2008 ; 47(7) ; 463-474.       
P15-06991
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions (21 
June 2012, CPMP/EWP/560/95/rev. 1 corr. 2). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidel
ine/2012/0 7/WC500129606.pdf (access date: 8 July 2015) ; London: 
European Medicines Agency (EMA); 2012.
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) 2002:1-
9.
R07-4702
Kovarik JM, Rigaudy L, Guerret M, Gerbeau C, Rost KL. Longitudinal 
assessment of a P-glycoprotein-mediated drug interaction of valspodar on 
digoxin. Clin Pharmacol Ther 1999 ; 66(4) ; 391-400. 


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R08-1147
Posner K. State of the science: measurement of suicidal adverse events and 
the Columbia Suicide Severity Rating Scale. 47th NCDEU Ann Mtg, Boca 
Raton, 11 - 14 Jun 2007. 2007:15
R10-1157
International Transporter Consortium. Membrane transporters in drug 
development. Nat Rev Drug Discov 2010;9:215-236.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R12-1392
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology, A new equation to estimate glomerular filtration 
rate. Ann Intern Med 2009 ; 150(9) ; 604-612.    
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, Tsuji 
W, Stevens R, Fries J, Witter J, Johnson K, Lassere M, Brooks P. 
Standardizing assessment and reporting of adverse effects in rheumatology 
clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0. J 
Rheumatol 2007 ; 34(6) ; 1401-1414.       
R13-4572
Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini 
MV. Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clin 
Pharmacol Ther 2003;73(4):322-329.
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide.
http://www.statsols.com/wp-
content/uploads/2013/10/nQ70_version2_manual.pdf 
(access date: 20 March 2015) ; Los Angeles: Statistical Solutions; 2007.
R15-4771
Prueksaritanont T, Chu X, Evers R, Klopfer SO, Caro L, Kothare PA, 
Dempsey C, Rasmussen S, Houle R, Chan G, Cai X, Valesky R, Fraser IP, 
Stoch A. Pitavastatin is a more sensitive and selective organic anion-
transporting polypeptide 1B clinical probe than rosuvastatin. Br J Clin 
Pharmacol 2014. 78(3):587-598.
R16-2173
Lanicor 0,25 mg Digoxin/Tablette (Teofarma), prescription only 
(Prescribing information, as of 11/2013).
R16-2538
Lasix liquidum 10mg/ml oral solution (Sanofi-Aventis), prescription only 
(Prescribing information, as of February 2016)
R17-0548
 et al. 
Pharmacokinetic evaluation of a drug transporter cocktail consisting of 
digoxin, furosemide, metformin and rosuvastatin. 2016 
R17-1790
Lai Y, Mandlekar S, Shen H, Holenarsipur VK, Langish R, Rajanna P, et al. 
Coproporphyrins in plasma and urine can be appropriate clinical biomarkers 
to recapitulate drug-drug interactions mediated by organic anion 
transporting polypeptide inhibition. J Pharmacol Exp Ther 2016;358:397-
404.


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R17-1837
Glucophage 500 mg/- 850 mg/- 1000 mg film-coated tablets (Merck 
Serono), prescription only (summary of product characteristics, information 
of: January 2017).
R17-1846
Cohen E, Almog S, Staruvin D, Garty M. Do therapeutic doses of acarbose 
alter the pharmacokinetics of digoxin? Isr Med Assoc J 2002;4(10):772-
775.
R17-1847
Tarral A, Francheteau P, Guerret M. Effects of terbinafine on the 
pharmacokinetics of digoxin in healthy volunteers. Pharmacotherapy 
1997;17(4):791-795.
R17-1848
Shoaf SE, Bramer SL, Bricmont P, Zimmer CA. Pharmacokinetic and 
pharmacodynamic interaction between tolvaptan, a non-peptide AVP 
antagonist, and furosemide or hydrochlorothiazide. J Cardiovasc Pharmacol 
2007;50(2):213-222.
R17-1859
Vree TB, Biggelaar-Martea M van den, Verwey-van Wissen CPWGM. 
Probenecid inhibits the renal clearance of frusemide and its acyl 
glucuronide. Br J Clin Pharmacol 1995;39:692-695.
R17-1861
Smith DE, Gee WL, Brater DC, Lin ET, Benet LZ. Preliminary evaluation 
of furosemide-probenecid interaction in humans. J Pharm Sci 
1980;69(5):571-575.
R17-2886
Crestor 5 mg/10 mg/20 mg film-coated tablets (AstraZeneca), prescription 
only (prescribing information (summary of product properties / SPC), 
information characteristics: December 2016)
R17-3544
MetfoLiquid 1000 mg/5 ml oral solution (GeriaSan), prescription only
(prescribing information, information of: February 2017).
R18-0240
 
Effects of metformin and furosemide on rosuvastatin pharmacokinetics in 
healthy volunteers: implications for their use as probe drugs in a transporter 
cocktail. Juli 2017
R19-3033
Prescribing information Crestor 5 mg/10 mg/20 mg film-coated tablets. 
information of: Juni 2019
R20-1915
 
Optimization of a drug transporter probe cocktail: potential screening tool 
for transporter-mediated drug-drug interactions. 2018
R20-1930
 
et al. Validation of a drug transporter probe cocktail using the 
prototypical inhibitors rifampin, probenecid, verapamil, and cimetidine.   
2020
R20-2007
Prescribing information Lenoxin tablets, Lenoxin Liquidum. information 
of: 2019
R20-2008
Prescribing information Lasix liquidum, information of: 2019


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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, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
R99-0743
Somogyi A, Stockley C, Keal J, Rolan P, Bochner F. Reduction of 
metformin renal tubular secretion by cimetidine in man. Br J Clin 
Pharmacol 1987;23:545-551.


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version  
c03246006-01
. Relative bioavailability of a single 
oral dose of digoxin, furosemide, metformin, and rosuvastatin given alone 
and all together as a cocktail, and investigation of the effect of increased 
doses of metformin or furosemide on relative bioavailability of the other 
cocktail compounds in healthy male subjects. Trial 352.2082. July 2015.
c08983809-01
 The effect of different doses of 
metformin or furosemide on rosuvastatin pharmacokinetics following oral 
administration in healthy male subjects (an open-label, randomised, single-
dose,six-way crossover study). Trial 352.2094. August 2016.
c09228382
Investigator Brochure BI 730357. Psoriasis - 1407.P01; Current version.
c13060859-01
 Investigation of mutual 
pharmacokinetic interactions of digoxin, furosemide, metformin, and 
rosuvastatin given all together as a probe cocktail for key drug transporters 
(an open-label, randomised, single-dose, five-way crossover study). Trial 
352.2096. July 2017
c16462083-01
 CTR 1407-0001, A partially 
randomised, single-blind, placebo-controlled trial to investigate safety, 
tolerability, pharmacokinetics and pharmacodynamics of single rising doses 
of BI 730357 administered as oral solution and tablets to healthy human 
subjects, and a randomized, open-label, single-dose, three-way cross-over 
bioavailability comparison of BI 730357 as tablet versus oral solution and 
tablet with ...; July 2018
c23988236-01
, Report 352.2100, The effect of 
potent inhibitors of drug transporters (verapamil, rifampin, cimetidine, 
probenecid) on pharmacokinetics of a transporter probe drug cocktail 
consisting of digoxin, furosemide, metformin and rosuvastatin (an open-
label, randomised, crossover trial in three parts). April 2019
c25766034-01
 CTR 1407-0002, Phase Ib 
evaluation of the safety and tolerability and effect on midazolam 
metabolism of the administration of multiple rising doses of BI 730357 to 
healthy volunteers. April 2019
c26494034-01
, CTR 1407-0031, A phase I, open-
label, single-dose trial to investigate metabolism and pharmacokinetics of 
BI 730357 BS (C-14) administered as oral solution in healthy male 
volunteers. September 2019.


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c27425119-01
, CTR 1407-0015, Safety, 
tolerability, and pharmacokinetics of single rising oral doses of BI 730357 
in Japanese healthy male subjects (double-blind, randomised, placebo-
controlled, parallel group design). November 2019.
c27699953-01
, CTR 1407-0014, Relative 
bioavailability of a single oral dose of BI 730357 when administered alone 
or in combination with multiple oral doses of itraconazole in healthy male 
subjects (an open-label, one-way crossover study). December 2019
c27700144-01
 CTR 1407-0033, Investigation of 
pharmacokinetics and absolute oral bioavailability of BI 730357 
administered as an oral dose with an intravenous microtracer dose of BI 
730357 BS (C-14) in healthy male volunteers. January 2020
c28904523-01
 CTR 1407-0032, Relative 
bioavailability of intended commercial formulations (iCF) of BI 730357 
versus BI 730357 trial formulation 1 and bioavailability comparison of 
three different iCF batches following oral administration in healthy subjects 
(an open-label, single-dose, randomised, 2-way and 3-way crossover trial). 
February 2020.
U13-2366-01
 Bioequivalence of 
empagliflozin/metformin fixed dose combination tablets compared to single 
tablets administered together in healthy male and female volunteers under 
fed and fasted conditions (an open-label, randomised, single-dose, 
crossover study). Trial 1276.8. October 2013.


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10.
APPENDICES
Not applicable. 


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
01 October 2020
EudraCT number
EU number
2020-003097-46
BI Trial number
1407-0038
BI Investigational 
Medicinal Product(s)
BI 730357
Title of protocol
The effect of BI 730357 on the pharmacokinetics of 
rosuvastatin, digoxin, metformin and furosemide 
given as a cocktail – an open-label, non-
randomised, 2-period fixed-sequence trial in healthy 
subjects
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
Flow Chart
Column “Safety laboratory”
Flow Chart
Column “Planned time”
Flow Chart
Foot note Section
4.1.4
Drug assignment and administration of doses for 
each subject
5.2.3
Safety laboratory parameters
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis 
(cocktail components)
5.3.2.3
Urine sampling for pharmacokinetic analysis
6.1
Investigational plan
Description of change
Flow Chart
Flow Chart
Flow Chart
4.1.4
5.2.3
Clarified timepoint where safety lab is taken 
relative to breakfast
Corrected one value in the “planned time” column
 
 
 
Clarified the allowed time period (2 min) for intake 
of cocktail probes
 clarified that 
safety lab B may taken under non-fasted condition


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5.3.2
5.3.2.1
5.3.2.3
6.1
Anticoagulant blood drawing tubes have been 
changed into K2-EDTA
Deleted “and analyses”; further: Clarified that the 
primaries will be sent in two shipments
 
 
Clarified that the primaries will be sent in two 
shipments
Added time tolerances for study procedures
Rationale for change
Flow Chart
To Clarify that safety lab B may be taken under 
non-fasted condition
Flow Chart
Incorrect planned time
Flow Chart
Clarification of logistical aspects to facilitate study 
conduct
4.1.4
Clarification of logistical aspects to facilitate study 
conduct
5.2.3
 
 
 
Further, to clarify that safety lab B may be taken 
under non-fasted condition
5.3.2
Availability of collection tubes
5.3.2.1
There is no need to wait for the analyses of 
primaries before shipping backup samples since 
the primary aliquots contain enough material; 
further: To increase sample safety, primaries will 
be shipped in two shipments
5.3.2.3
 
 further: There is no need to 
wait for the analyses of primaries before shipping 
backup samples since the primary aliquots contain 
enough material;
 
 further: 
To increase sample safety, primaries will be 
shipped in two shipments
6.1
To facilitate study setup and conduct


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11.2
GLOBAL AMENDMENT 2
Date of amendment
19 October 2020
EudraCT number
EU number
2020-003097-46
BI Trial number
1407-0038
BI Investigational Medicinal 
Product(s)
BI 730357
Title of protocol
The effect of BI 730357 on the pharmacokinetics of 
rosuvastatin, digoxin, metformin and furosemide 
given as a cocktail – an open-label, non-
randomised, 2-period fixed-sequence trial in healthy 
subjects
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
5.2.3
Safety laboratory parameters
Description of change
5.2.3
Described that safety lab B may be split (blood 
sampling for lymphocyte differentiation later on the 
same day) for logistical reasons (sample stability)
Rationale for change
5.2.3
Purely logistical step to ensure sample stability for 
lymphocyte differentiation which cannot be 
performed by the safety lab on Sundays. No impact 
on subjects’ safety is foreseen thus this change is 
non-substantial from a regulatory view point.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32357152
3.0
clinical-trial-protocol-version-03
The effect of BI 730357 on the pharmacokinetics of rosuvastatin, digoxin, metformin
and furosemide given as a cocktail – an open-label, non-randomised, 2-period
fixed-sequence trial in healthy subjects 
Author-Clinical Trial Leader
20 Oct 2020 11:46 CEST
Approval-Team Member Medicine
20 Oct 2020 13:17 CEST
Author-Trial Clinical
Pharmacokineticist
20 Oct 2020 13:19 CEST
Verification-Paper Signature
Completion
21 Oct 2020 06:16 CEST
Approval-
 Medicine
21 Oct 2020 10:05 CEST
Author-Trial Statistician
21 Oct 2020 10:15 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32357152
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c34122641-01
BI Trial No.:
1407-0038
Title:
The effect of BI 730357 on the pharmacokinetics of rosuvastatin, 
digoxin, metformin and furosemide given as a cocktail – an open-
label, non-randomised, 2-period fixed-sequence trial in healthy 
subjects
Revised protocol #1, 2 (c32357152-03)
Investigational
Products:
CRESTOR® (rosuvastatin), Lenoxin® (digoxin), MetfoLiquid 
GeriaSan® (metformin), Lasix® (furosemide), BI 730357
Responsible trial 
statistician:
  Phone: 
Date of statistical 
analysis plan:
12 Feb 2021 SIGNED 
Version:
1
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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 ENDPOINT..................................................................................9
5.2.1
Key secondary endpoint........................................................................................9
5.2.2
Secondary endpoint...............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED ...........................................................................14
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 ......................................................................................17
7.2
CONCOMITANT DISEASES AND MEDICATION......................................18
7.3
TREATMENT COMPLIANCE ........................................................................18
7.4
PRIMARY ENDPOINTS ...................................................................................18
7.5
SECONDARY ENDPOINT................................................................................19
7.5.1
Key secondary endpoints ....................................................................................19
7.5.2
Secondary endpoint.............................................................................................19


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7.8
SAFETY ANALYSIS..........................................................................................20
7.8.1
Adverse Events ....................................................................................................20
7.8.2
Laboratory data...................................................................................................22
7.8.3
Vital signs.............................................................................................................22
7.8.4
Others ...................................................................................................................22
8.
REFERENCES ....................................................................................................23
10.
HISTORY TABLE..............................................................................................25


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LIST OF TABLES
Table 6.1: 1
Analysis phases.................................................................................................12
Table 6.2: 1
Handling of important protocol deviations (iPDs) ...........................................13
Table 6.2: 2
Handling of non-important COVID-19 related protocol deviations ................14
Table 6.3: 1
Subject sets analysed ........................................................................................15
Table 10: 1
History table .....................................................................................................25


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
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-∞
Area under the concentration-time curve of the analyte in plasma from 0 to
infinity
BI
Boehringer Ingelheim
BP
Blood pressure
Cmax
Maximum measured concentration of the analyte in plasma
COVID-19
Coronavirus disease 2019
CTP 
Clinical trial protocol
CTR 
Clinical trial report
ECG
Electrocardiogram
EoT
End-Of-Text
ICH 
International Council for Harmonisation
iPD 
Important protocol deviations
IQRMP 
Integrated quality and risk management plan
MedDRA 
Medical dictionary for regulatory activities
PK 
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set


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Term
Definition / description
PR
Pulse rate
REP 
Residual effect period
RPM 
Report planning meeting
SAE 
Serious adverse event
SOC 
System organ class
TS
Treated set
TSAP 
Trial statistical analysis plan


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3.
INTRODUCTION
As per ICH E9, 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), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomization.
SAS® Version 9.4 will be used for all analyses.
Pharmacokinetics (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described
in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
As defined in Section 2.1.2 and 7.3.1 of the CTP, the primary endpoints are the following:
The change from visit 2 of 

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity) and

Cmax (maximum measured concentration of the analyte in plasma)
of rosuvastatin, digoxin, metformin and furosemide in plasma measured at visit 3 at steady 
state conditions of BI 730357.
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoint
Not applicable, as no key secondary endpoints were defined.
5.2.2
Secondary endpoint
The secondary endpoint is as defined in the Section 2.1.3 and 7.3.2 of the CTP:
The change from visit 2 of

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)
of rosuvastatin, digoxin, metformin and furosemide in plasma measured at visit 3 at steady 
state conditions of BI 730357.


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5.3.3
Safety parameters
Further safety parameters will be used as defined in Section 2.2.2.5 and Section 5.2 of the
CTP:

Adverse events (AEs) (including clinically relevant findings from the physical 
examinations)

Safety laboratory tests

12-lead Electrocardiograms (ECGs)

Vital signs (systolic and diastolic blood pressures (BP), pulse rate (PR))


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For information on treatments to be administered, assignment of treatment groups, selection 
of doses, cf. Section 4 of the CTP. 
The study will be performed as a non-randomised, open-label, 2-period fixed-sequence trial.
In the first treatment period, subjects will receive a single dose of the cocktail (consisting of 
rosuvastatin, digoxin, metformin and furosemide) on Day 1 (reference treatment). In the 
second treatment period, the subjects will receive BI 730357 twice daily on Day -7 to Day 6 
(13 days) with an administration of a single dose of the cocktail on Day 1 one hour after the 
morning administration of BI 730357 (test treatment).
 
The sequence 
of these treatment periods is fixed and the same for all subjects.
An overview of all relevant trial activities is provided in the Flow Charts in the CTP. For visit 
schedule and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2 of the 
CTP, respectively.
For statistical analyses of safety, separate analysis phases will be defined for each subject as 
given in Table 6.1:1. The phase ‘Cocktail + BI’ refers to the time interval, where the cocktail 
REP of the first cocktail administration overlaps with the start of the BI dosing in period 2. 
The phase ‘BI + Cocktail’ refers to the time after the second cocktail administration with BI at 
steady state.
AE displays in CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 will 
present results for the four on-treatment phases only.
In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 
AE tables), the following total will be provided in addition:

"Total on-trt", defined as the total over all on-treatment phases.
In Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 no total columns will be included in 
the tables. 
CTR Appendix 16.1.13.1.8.1 displays will present results for the screening, on-treatment and 
follow-up phases.
Additionally to the total defined above, the following total will be provided in CTR Section 
16.1.13.1.8.1 AE tables:

"Total", defined as the total over all study phases (screening + on-treatment + follow-
up).


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Table 6.1: 1
Analysis phases
Study analysis 
phase
Label
Start
End
Screening
Screening
Date of informed 
consent
Date/time of first 
administration of the 
cocktail
On treatment 
cocktail
Cocktail
Date/time of first 
administration of the 
cocktail
Date/time of first 
administration of BI 
730357 or 
date/time of first 
administration of the 
cocktail + Residual 
effect period (REP) (10 * 
24h), whatever occurs 
earlier
On treatment 
Cocktail + BI
730357
Cocktail + BI
Date/time of first 
administration of BI 
730357
Date/time of first 
administration of the 
cocktail + Residual 
effect period (REP) (10 * 
24h)
On treatment 
BI 730357
BI
Date/time of first 
administration of BI 
730357 or 
date/time of first 
administration of the 
cocktail + Residual 
effect period (REP) (10 
* 24h), whatever 
occurs later
Date/time of second 
administration of the 
cocktail
On treatment  
Steady state BI
730357 + cocktail
BI + Cocktail
Date/time of second 
administration of the 
cocktail
Date/time of last 
administration of BI 
730357 + Residual effect 
period (REP) (7 * 24h) 
Or 12:00 a.m. on day 
after subject's trial 
termination date, 
whatever occurs earlier.
Follow-up
F/U
Date/time of last 
administration of BI 
730357 + REP (7 * 
24h)
12:00 a.m. on day after 
subject's trial termination 
date


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Statistical analyses of 
 PK parameters will be conducted by treatment period 
(cocktail vs. BI + cocktail).
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
According to Section 1.2.6 of the CTP, the REP of the cocktail is 10 days. This is the period 
after the last dose with measurable drug levels and/or pharmacodynamic effects still likely to 
be present.
 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Table 6.2: 1
Handling of important protocol deviations (iPDs)
iPD code
iPD Category & Brief Description
Excluded from 
which analysis set
A1
Inclusion Criteria Not Met
None
A2
Exclusion Criteria violated
None
B1
Informed consent not available/not done
TS, PKS
B2
Informed consent too late
None
C1
Incorrect trial medication intake
PKS
C3
Non-compliance
PKS
C4
Medication code broken inappropriately
None
C5
Incorrect intake of trial medication
PKS
C6
Improper washout between treatments
PKS
D1
Prohibited medication use
PKS
D2
Mandatory medication not taken
PKS
D3
Improper washout of concomitant medication
PKS
E1
Certain violations of procedures used to
measure primary or secondary data
PKS
F1
Certain violations of time schedule used to measure 
primary or secondary data
PKS
G1
Incorrect intake of meal
PKS


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Table 6.2: 2
Handling of non-important COVID-19 related protocol deviations
PD code
PD Category
Excluded from 
which analysis set
Q1
Missed examination
None
Q2
(Partially) missed visit
None
Q3
Drug shipment
None
Consistency check listings (for identification of deviations from time windows) and a list of
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will
be provided to be discussed at the Report planning meeting (RPM). At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an iPD and whether it is COVID-19 related. For definition of iPDs, and for the 
process of identification of these, refer to the BI reference document "Identify and Manage 
Important Protocol Deviations (iPD)" (1).
If any iPDs are identified, they are to be summarised into categories and will be captured in
the RPM minutes. Categories which are considered to be iPDs in this trial are defined
in the integrated quality and risk management plan (IQRMP). If the data show other iPDs, the
definition in the IQRMP will be supplemented accordingly by the time of the RPM.
IPDs will be summarised and listed. Additionally, protocol deviations associated with 
COVID-19 disruption (non-important and important protocol deviations) will be summarised
and listed.
6.3
SUBJECT SETS ANALYSED
The following subject sets will be defined for statistical analysis:

Treated set (TS): 
The treated set includes all subjects who signed informed consent and were treated 
with at least one dose of study drug. 
The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): 
This set includes all subjects in the TS who provide at least one PK endpoint that was 
defined as primary or secondary and was not excluded due to a protocol deviation 
relevant to the evaluation of PK or due to PK non-evaluability (as specified in the 
subsection ‘Pharmacokinetics’ in section 7.3 in the CTP). 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.
Descriptive and model based analyses of PK parameters will be based on the PKS.
Thus, the primary and secondary analyses will be based on the PKS.


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Relevant protocol deviations may be
• Incorrect trial medication taken
• 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 experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),
• A predose concentration of BI 730357 is >5% Cmax value of that subject in the
respective treatment period
• Missing samples/concentration data at important phases of PK disposition curve
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
x
Treatment exposure
x
IPDs
x
Demographics/baseline endpoints
x
Safety parameters
x
PK endpoints
x


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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
In CTP Section 7.5 the handling of missing data is defined.
Data of screened subjects who were withdrawn from the trial prior to first administration of
any study drug will not be reported in the CTR.
Data of subjects who failed to complete all periods of the study (dropouts or withdrawals) will
be reported in the CTR as far as their data are available. All withdrawals will be documented
and the reason for withdrawal recorded in the CTR.
It is not planned to impute missing values for safety parameters.
The only exceptions where imputation might be necessary for safety evaluation are AE dates.
Missing or incomplete AE dates are imputed according to BI standards (2).
Missing data and outliers of PK data are handled according to the relevant BI internal 
procedures. PK parameters that cannot be reasonably calculated based on the available drug
concentration-time data will not be imputed. PK data will be excluded of analysis as described
in Section 7.3 of the CTP.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline will be defined as the last available value before the administration of the cocktail in
period 1 (Visit 2). Note that this baseline definition will be used for evaluation of data of all 
on-treatment periods (“cocktail”, “BI + cocktail”, “BI”, “cocktail + BI”, as defined in Section 
6.1).
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM.
Unscheduled measurements of laboratory data or vital signs data will be assumed to be repeat 
measurements of the most recent scheduled measurement (e.g. for follow-up or confirmation 
of a particular value). Therefore, unscheduled measurements will be assigned to the planned 
time point of the previous scheduled measurement. Descriptive statistics of on-treatment 
laboratory data will be calculated by planned time point based on the worst value of the 
subject at that planned time point (or assigned to that planned time point). For vital signs, 
descriptive statistics will be calculated by planned time point based on the last value of the 
subject at that planned time point (or assigned to that planned time point).


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the standards defined in the BI corporate
guideline “Reporting of clinical trials and project summaries” (3).
For End-Of-Text (EoT) tables, the set of summary statistics of continuous variables will be: 
N 
number of non-missing observations
Mean
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max
maximum
For plasma 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
For PK parameters the following descriptive statistics will additionally be calculated:
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the
data format of the respective concentrations. 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 (%) relative to the 
respective treatment group (unless otherwise specified, all subjects in the respective subject
set whether they have non-missing values or not). 


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Percentages will be rounded to integer numbers. The category missing will be displayed if and 
only if there actually are missing values.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of Medical 
Dictionary For Regulatory Activities (MedDRA). Concomitant medication will be coded 
according to the most recent version of the World Health Organisation – Drug Dictionary.
CTP Section 7.3.4:
Previous and concomitant therapies will be presented per treatment group without
consideration of time intervals and treatment periods.
Clarification: As all subjects belong to the same treatment group, previous and concomitant 
therapies will be presented for all subjects together.
A medication will be considered concomitant, if it 

is ongoing at the time of first study drug administration, or 

starts within one of the on-treatment analysis phases (see Section 6.1 for a definition 
of treatments and analysis phases).
Concomitant medication and drug therapies will be grouped by preferred term.
Only descriptive statistics are planned for this section of the report.
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
Treatment compliance will not be analysed as a specific endpoint.
7.4
PRIMARY ENDPOINTS
Analysis of relative bioavailability of primary endpoints AUC0-∞and Cmax of rosuvastatin, 
digoxin, metformin and furosemide in plasma will be performed in the PKS as defined in 
Sections 7.1 and 7.3.1 of the CTP. The analysis will be descriptive in nature.
There will be eight ANOVA models, as there are two primary endpoints and four drugs to be
analysed.  
The statistical model for the primary analysis defined in the CTP is an analysis of variance
(ANOVA) model on the logarithmic scale including "treatment" as fixed effect and "subject"
as random effect. 


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Primary PK endpoints will be assessed descriptively. The analysis of standard PK parameters
is calculated according to the relevant BI internal procedures. See Sections 7.3 and 7.5.2 of 
the CTP for details regarding exclusion of PK parameters and plasma concentrations.
7.5
SECONDARY ENDPOINT
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 endpoint
Analysis of relative bioavailability of the AUC0-tz of rosuvastatin, digoxin, metformin and 
furosemide in plasma will be performed in the same way as for the primary endpoints. This 
results in 4 ANOVA models: for rosuvastatin, digoxin, metformin and furosemide.
Additionally, the secondary PK endpoint will be assessed descriptively. 
The analysis of standard PK parameters is calculated according to the relevant BI internal 
procedures. See Sections 7.3 and 7.5.2 of the CTP for details regarding exclusion of PK 
parameters and plasma concentrations.
7.6.1
Safety parameters
Safety and tolerability will be analysed as described in Section 7.8 of this TSAP.


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7.8
SAFETY ANALYSIS
The safety analyses are described in the CTP Section 7.3.4. All safety analyses will be 
performed on the TS.
The safety analyses will be descriptive in nature. No hypothesis testing is planned.
CTP 7.3.4:
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned 
to treatments (see Section 4.1) based on the actual treatment at the planned time of the
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication 
will be assigned to the screening period, those between trial medication intake and end of 
REP (see Section 1.2.3) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
In case of two or more treatments, the follow-up will be summarized according to the 
previous treatment. These assignments including the corresponding time intervals will be 
defined in detail in the TSAP. Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be
captured in the trial database.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA. The analysis of AEs will be 
descriptive in nature. All analyses of AEs will be based on the number of subjects with AEs 
and not on the number of AEs.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs occurring between first drug intake till last drug intake + REP will be assigned to the 
on-treatment phases as defined in Table 6.1:1. All AEs occurring before first drug intake will 
be assigned to ‘screening’ and all AEs occurring after the last drug intake and the REP will be 
assigned to ‘follow-up’. For details on the treatment definition, see Section 6.1.
AEs will be analysed based on the actual treatment at the recorded time of AE onset. Any 
deviations from the planned treatment will be discussed in the minutes of the RPM.


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Pre-defined adverse events of special interest (AESIs) are defined in the CTP Section 
5.2.5.1.4. Hepatic injury, severe infections and opportunistic and mycobacterium tuberculosis 
infections are considered AESIs. The investigator classifies on the eCRF whether an observed 
AE was an AESI or not.
According to ICH E3 (3), in addition to Deaths and Serious Adverse Events and AESIs, 
‘other significant’ AEs need to be listed in the clinical trial report. These will be any non-
serious adverse event that led to an action taken with study drug (e.g. discontinuation or dose 
reduced or interrupted). SARS-CoV-2 infections and AEs related to SARS-CoV-2 will also 
be listed. 
An overall summary of AEs will be presented. 
The frequency of subjects with AEs will be summarised by treatment, primary system organ
class (SOC) and preferred term. AEs which were considered by the investigator to be drug
related (primary endpoint) will be summarised separately. A separate table will also be
provided for subjects with serious adverse events (SAEs). A table will be provided for
subjects with pre-specified AESIs, summarised by SOC and PT. The frequency of subjects 
with AEs will also be summarised by maximum intensity, primary SOC and preferred term.
The SOC will be sorted alphabetically, preferred terms will be sorted by frequency (within 
SOC). 
Post-hoc AESIs may be defined at a later time point and summarised separately.
For further details on summarization of AE data, please refer to "Analysis and Presentation of
Adverse Event Data from Clinical Trials" (4) and "Handling of missing and incomplete AE
dates" (5).
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of subjects with AEs, the 
frequency of subjects with non-serious AEs with an incidence of greater than 5 % (in 
preferred terms) and the frequency of subjects with SAEs will be summarised. Furthermore, 
the total number of treated subjects by country and by age group will be summarised.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be
summarised by treatment, primary system organ class and preferred term.
For the subgroup of subjects with SARS-CoV-2 infection while on treatment with study drug
the number of subjects with AEs, with AEs by SOC and preferred term, with AEs leading to 
discontinuation by SOC and preferred term and with SAEs by SOC and preferred term will be 
summarised.


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7.8.2
Laboratory data
CTP 7.3.4: 
Laboratory data will be compared to their reference ranges. Values outside the reference
range as well as values defined as possibly clinically significant will be highlighted in the
listings. Additionally, differences from baseline will be evaluated.
The analyses of laboratory data will be descriptive in nature and will be based on BI standards
"Display and Analysis of Laboratory Data" (6).
Analyses will be based on normalised values, which means transforming to a standard unit
and a standard reference range. The original values will be analysed if the transformation into
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on
treatment with respect to the reference range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in
the Investigator's comments or at the RPM at the latest. It is the Investigator's
responsibility to decide whether a lab value is clinically significant abnormal or not. Standard
or project-specific rules for flagging clinically significant values in an automated manner will
not be applied in this study.
Clinically relevant changes in laboratory test results will be reported as AE and summarised 
as such. 
Urine creatinine will be excluded from the tables and listings of safety laboratory data. A
separate listing of urine creatinine data will be provided.
7.8.3
Vital signs
Descriptive statistics including change from baseline (see Section 6.7) are planned for this 
section of the report.
Clinically relevant changes in vital signs will be reported as AE and summarised as such.
7.8.4
Others
Physical examination findings as well as relevant ECG findings will be reported as AE and 
will be summarised as such. No separate listing or analysis of physical examination or ECG 
findings will be prepared.


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8.
REFERENCES
1.
001-MCS-40-413: “Identify and Manage Important Protocol Deviations (iPD)”, current 
version, Group “Clinical Operations”, IDEA for CON.
2.
BI-KMED-BDS-HTG-0035: “Handling of missing and incomplete AE dates", current
version; KMed
3.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project 
Summaries”, current version, KMed
4.
BI-KMED-BDS-HTG-0066: “Analysis and Presentation of
Adverse Event Data from Clinical Trials”, current version, Kmed
5.
BI-KMED-BDS-HTG-0035: “Handling of missing and incomplete AE
Dates”, current version, Kmed
6.
BI-KMED-BDS-HTG-0042: “Display and Analysis of Laboratory Data”, current 
version, Kmed


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1 
12-Feb-21
None
This is the final TSAP.