Transporter Profiling Study for P-glycoprotein 1 (P-gp), Organic Anion Transporter 1 (OAT1), Organic Anion Transporter 3 (OAT3), Organic Cation Transporter 2 (OCT2), Multidrug and Toxin Extrusion Protein 1 (MATE1), Multidrug and Toxin Extrusion Protein 2-K (MATE2-K), Organic Anion Transporting Polypeptide 1B1 (OATP1B1), Organic Anion Transporting Polypeptide 1B3 (OATP1B3) and Breast Cancer Resistance Protein (BCRP) in Healthy Subjects and in Patients With Stage 4 (F4) Liver Fibrosis / Cirrhosis.
Phase: NA
Conditions: Liver Cirrhosis
Sponsor: Boehringer Ingelheim

Clinical Trial Protocol 
Document Number: 
EudraCT No. 
BI Trial No. 
BI Investigational 
Medicinal 
Product(s) 
Title 
Lay Title 
Clinical Phase 
Clinical Trial 
Leader 
Principal 
Investigator 
Current Version 
and Date 
Original Protocol 
Date 
2022-003667-25 
0352-2189 
NA 
Boehringer 
lngelheim 
c38905284-02 
T ranspo11er profiling study for P-glycoprotein 1 (P-gp ), organic 
anion transpo11er 1 (OATl ), organic anion trnnsporter 3 (OAT3), 
organic cation transporter 2 (OCT2), multidrng and toxin extn1sion 
protein 1 (MA TE 1 ), multidmg and toxin extrusion protein 2-K 
(MA TE2-K), organic anion trnnspo11ing poly-peptide 1 B 1 
(OATPIBl), organic anion transp011ing polypeptide 1B3 
(OATP1B3) and breast cancer resistance protein (BCRP) in healthy 
sub·ects and in atients with stage 4 
4 liver fibrosis / ciuhosis. 
A study to compare how different medicines (rosuvastatin, digoxin, 
metfomiin, and furosemide) are handled by the body of healthy 
le and eo le with liver cinhosis 
Version 2.0, 09-Mar-2023 
Version 1.0, 07-Dec-2022 
Page 1 of72 
P1·op1·ietuy confidential info1·mation. 
2023 Boehringer lngelheim Intel'Dational GmbH or one or more of its affiliated companies. All rights rese1-ved. 
This docwnent may not - in full or in pa.rt - be passed on, reproduced, published, or otherwise used without prior written 
pennission. 
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CLINICAL TRIAL PROTOCOL SYNOPSIS 
Company name 
Original Protocol 
date 
Revision date 
BI trial number 
Title of trial 
Boehringer Ingelheim 
07-Dec-2022 
08-Mar-2023 
0352-2189 
Transpo1ter profiling study for P-glycoprotein 1 (P-gp), organic anion 
transp01ter 1 (OATI), organic anion transp01ter 3 (OAT3), organic 
cation trnnspo1ter 2 (OCT2), multidrug and toxin extrnsion protein 1 
(MATE I\ multidrng and toxin extmsion protein 2-K (MA TE2-K), 
organic anion transporting polypeptide 1B1 (OATPIBI), organic 
anion transporting polypeptide 1B3 (OATP1B3) and breast cancer 
resistance protein (BCRP) in healthy subjects and in patients with 
sta _e 4 F4 liver fibrosis / cinhosis, 
---------
------------------
Principal 
Investigator 
Trial site(s) 
Clinical phase 
Trial rationale 
Trial objective(s) 
Trial endpoints 
Trial design 
Number of patients 
treated 
NA 
To understand whether liver cin-l10sis itself, along with standard of 
care per local guidelines, can result in a change in transporter activity 
of P-gp, OATI, OAT3, OCT2, MATE!, MATE2-K, OATP1B1, 
OATP1B3 and BCRP in patients with F4 graded liver fibrosis / 
ciIThosis com ared to health subjects, 
Prima1y objective is to investigate whether the maximum 
concentrntion (Cmax) and the area m1der the curve (AUCo-24) values 
for the different components in the transporter cocktail - digoxin (P-
gP), furosemide (OATI and OAT3), metfonnin (OCT2, MATEI and 
:tv1ATE2-K) androsuvastatin (OATPIBI, OATP1B3 and BCRP) are 
similar or different in F4 graded liver fibrosis (c:inhosis) patients on 
standard them 
com ared to health sub' ects, 
Primaiy endpoints: 
Cmax and AUCo-24 of rosuvastatin, digoxin, metfonnin, and 
furosemide 
Open label, single dose study 
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Number of patients 
per treatment group NA
Diagnosis
Group 1: NA (healthy subjects)
Group 2: Patients with compensated liver cirrhosis and advanced
fibrosis grade F4 and hepatic impairment that meets the
criteria for Child Pugh A
Group 3: Patients with decompensated liver
cirrhosis and advanced fibrosis grade F4 and hepatic
impairment that meets the criteria for Child Pugh B
Main inclusion and 
exclusion criteria
Inclusion:
Healthy subjects
o
Healthy male and female subjects according to the assessment 
of the investigator, as based on a complete medical history 
including a physical examination
o
Age of 18 to 75 years (inclusive)
o
Body mass index (BMI) of 18.5 to 35 kg/m2 (inclusive)
Liver cirrhosis patients
o
Male and female patients
o
18 to 75 years (inclusive)
o
BMI of 18.5 to 40.0 kg/m2 (inclusive)
o
Inclusion of
a) Patients with compensated liver cirrhosis due to any 
underlying liver disease with advanced fibrosis (F4) and 
hepatic impairment that meets the criteria for Child-Pugh 
A who are on stable standard of care treatment (per local 
guidelines) for at least 4 weeks prior to study enrolment
b) Patients with decompensated liver cirrhosis due to any 
underlying liver disease with advanced fibrosis (F4) and 
hepatic impairment that meets the criteria for Child-Pugh 
B who are on stable standard of care treatment (per local 
guidelines) for at least 4 weeks prior to study enrolment
o Diagnosis of compensated liver cirrhosis/F4
-
Historic (within 2 years) histological diagnosis of fibrosis 
stage F4 (NASH-CRN or METAVIR scoring)
OR
-
Current or historic increased liver stiffness of ≥18 kPa by 
Fibroscan or 5 kPa by MRE
OR
-
Current or historic imaging of nodular surface with 
thrombocytopenia < 150/nL
OR
-
Clinical signs of portal hypertension (at least one out of 
the following)

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
Gastroesophageal varices (GEV)

Splenomegaly (no hematological or infectious 
diseases, which could cause splenomegaly)

Thrombocytopenia < 120/nL
AND
-
No previous decompensation events
o Diagnosis of decompensated liver cirrhosis/F4
-
Any of the above
AND
-
At least one previous decompensation event
Exclusion:
Healthy subjects and F4 liver cirrhosis patients
o
Subjects already taking digoxin, furosemide, metformin or 
rosuvastatin within 4 weeks of enrolment into the study
o
Subjects with any other condition that would preclude 
administration of digoxin, furosemide, metformin or 
rosuvastatin (i.e., contraindicated as per Summary of Product 
Characteristics (SmPC)), such as hypersensitivity to active 
ingredient or any of the excipients or to sulphonamides, 
hypovolaemia or dehydration, and partial obstructions of 
urinary outflow (e.g., prostatic hypertrophy)
o
Any finding in the medical history or medical examination 
(including blood pressure (BP), pulse rate (PR) or 
electrocardiogram (ECG) deviating from normal and assessed 
as clinically relevant by the investigator
o
Smokers (more than 10 cigarettes or 3 cigars or 3 pipes per 
day)
o
Alcohol abuse (intake of more than 12 g per day for females 
and 24 g per day for males)
o
Drug abuse or positive drug screening
o
Laboratory test indicative of an ongoing SARS-CoV-2 
infection
o
Subjects taking medications known to be inhibitors of the 
following drug transporters: P-gp, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, MATE1, MATE2-K, OCT
o
Subjects taking medications known to be moderate or strong 
inhibitors of the following CYP enzymes: CYP2C9, 
CYP2C19, CYP3A
o
Subjects taking medications known to be moderate or strong 
inducers of the following CYP enzymes: CYP2C9, CYP2C19, 
CYP3A

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Test product(s) 1
Dose
Mode of 
Administration
CRESTOR® 10 mg film-coated tablets (rosuvastatin)
1 x 1 tablet (10 mg rosuvastatin)
Oral with 280 mL of water after a standardized breakfast
Test product(s) 2
Dose
Mode of 
Administration
Lanicor® 0.25 mg tablets (digoxin)
1 x 1 tablet (0.25 mg digoxin)
Oral with 280 mL of water after a standardized breakfast
Test product(s) 3
Dose
Mode of 
Administration
MetfoLiquid GeriaSan®, 1000 mg/5 mL oral solution (metformin)
1 x 0.05 mL oral solution (10 mg metformin)
Oral with 280 mL of water after a standardized breakfast
Test product(s) 4
Dose
Mode of 
Administration
Lasix® liquidum 10 mg/mL oral solution (furosemide)
1 x 0.1 mL oral solution (1 mg furosemide)
Oral with 280 mL of water after a standardized breakfast
Comparator 
product(s)
NA
Duration of 
treatment
Rosuvastatin, digoxin, metformin and furosemide are given always 
together as a cocktail (the cocktail). The cocktail will be given as a 
single dose.
Statistical methods
The pharmacokinetics of each of the cocktail components 
rosuvastatin, digoxin, metformin and furosemide will be estimated in 
F4 liver cirrhosis patients compared to healthy subjects, based on the 
ratio (F4 liver cirrhosis patients to healthy subjects) of the geometric 
means (gMeans) of the primary 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. A difference of 2-fold or more, either increase or 
decrease, will be determined as being a clinically significant change.
The statistical model will be an analysis of variance (ANOVA) on the 
logarithmic scale including effects for ‘group’, age, and BMI. CIs 
will be calculated based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.

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FLO\iV CHART 
1111 -
I 
1111 -
1111 -
1111 -
1111 -------------------
I 
3 I -
creeuing1 
.... = .. e e 
8 
4 Liver cirrhosis patients 
ake their mornine: 
edication4 
-
aseline examinations 
tandardised light 
reakfast6,9,IO 
dministration of 
ocktail8•9 
40 mL fluid intake9 
nack ( optional)9 
inner9,IO 
reakfast10 ( optional) and 
ischarge from trial site 
ollow-up visit 1 
nd of trial v-isit11 
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1) For more details regarding screening procedUl'es refer to section 6.2 .1. In short: subject must be informed. and written 
informed. consent must 'be obtained. prior to starting any screening procedures. Screening procedures include an 
evaluation of safety parameters enslu·ed by a physical examination (see section 5.2.1) including the assessment of 
medical history and. concomitant medication, the assessment of smoking and drinking habits and review of inclusion and 
exclusion criteria. Further tests include the examination of vital signs (see section 5.2.2), safety laboratory tests (see 
section 5.2.3) which in addition to routine blood cell count and blood chemistry consists of a viral infection examination, 
alcohol breath testing (section 5.2.3), a lu·ine dmg screening (section 5.2.3), and a lll'ine pregnancy test for females 
(section 5.2.3). Twelve-lead resting ECG (see section 5.2.4) will be recorded using a computerised. electrocardiograph. 
Medical examination will be perforu1ed. according to section 5.2.5 
2) Uri:ne sample analysis at this timepoint includes only a drug screening, urinalysis (Stix), urine sedinient and uri:ne 
creati:nine and an urine pregnancy test for females (section 5.2.3) 
3) Safety laborato1y testing and urine sample analysis at this timepoint includes only a drug screening, a breath alcohol test, 
an lll'ine pregnancy test for females test (section 5.2.3) and a COVID-19 rapid test (section 10.2) 
4) Date, time, and dose of concomitant medication as well as the brand names must be documented 
5) A blank urine sample is to be obtained before cocktail administration. After providing a baseline uri:ne sample, subjects 
should. empty their bladder at the indicated timepoint (see "planned tin1e" -00:05) 
A standardized light breakfast see section 4.3.1 will be se1ved 1 h 30 min before the cocktail is administered 
or more u onnatton regar ng • 1g a uinistration see section 4.3.1 
From 1 h before dmg intake until huich, fluid intake is restricted to the water administered. with the cocktail and an 
additional 240 mL of water at 2 hand 4 h after cocktail administration (mandatory). From lw1ch lmtil 24 h post.<fose 
fluid is restricted to 3000 mL (see section 4.4.2.2) 
10) Meals will be given after all other procedures have been conducted. 
11) EoT visit will include a physical examination (see section 5.2.1), examination of vital signs (see section 5.2.2), twelve-
lead resting ECG (see section 5.2.4), safety laboratory tests (see section 5.2.3) which in addition to routine blood cell 
com1t and blood chemistty consists of a w-ine pregnancy test for females. Adverse Events (AEs) and concomitant therapy 
will be assessed.continuously from screening until the EoT visit (see section 6.2.3) 
a) Specified timepoints are only estimated. S=ple collection or measm·ements can be performed ± 15 m..i:11 
b) Urine pregnancy testing in females will 'be perfonued at the screening visit, upon admission to the site in the evening of 
Day -1 and as part of the Eo T examination. Dmg screening will only be pe1fo1111ed at the screening visit and upon 
admission to the site in the evening of Day -1 
c) AEs and concomitant medication will be documented throughout the whole trial but are specifically asked. for at these 
timepoints 
cl) A full physical examination is only needed if the subject reports any abnormalities or other health related changes since 
the screening visit (see section 5.2.1) 
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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS AND DEFINITIONS...........................................................................12
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................18
1.2.1
Rosuvastatin ........................................................................................................18
1.2.2
Digoxin .................................................................................................................18
1.2.3
Metformin............................................................................................................19
1.2.4
Furosemide ..........................................................................................................20
1.2.5
Residual Effect Period ........................................................................................20
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................20
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
1.4.1
Benefits.................................................................................................................21
1.4.2
Risks .....................................................................................................................21
1.4.2.1
Procedure-related risks..........................................................................................21
1.4.2.2
Drug-related risks related to the administration of the cocktail (without 
transporter inhibition) ...........................................................................................22
1.4.2.3
Drug-related risks related to the administration of the cocktail in the present of 
transporter inhibition (worst case scenario)..........................................................22
1.4.2.4
Drug-induced liver injury......................................................................................23
1.4.2.5
Safety measures.....................................................................................................24
1.4.2.6
Overall assessment................................................................................................24
1.4.2.7
Coronavirus Disease 2019 ....................................................................................24
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................25
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........25
2.1.1
Main objectives....................................................................................................25
2.2
MAIN ENDPOINTS ...........................................................................................25
2.3
PROPOSED FURTHER ENDPOINTS............................................................25
2.3.1
Biomarkers ..........................................................................................................26
2.3.1.1
Coproporphyrin I and III.......................................................................................26
2.3.1.2
N1-methylnicotinamide and N1-methyl adenosine (m1A)....................................26
2.3.1.3
Liquid biopsy and protein bining of selected cocktail components......................26
2.3.2
Safety endpoints:.................................................................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................27
3.1
OVERALL TRIAL DESIGN.............................................................................27
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................27

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3.3
SELECTION OF TRIAL POPULATION .......................................................28
3.3.1
Main diagnosis for trial entry ............................................................................28
3.3.2
Inclusion criteria .................................................................................................28
3.3.3
Exclusion criteria ................................................................................................30
3.4
DISCONTINUATION OF SUBJECTS FROM TREATMENT OR 
ASSESSMENTS..................................................................................................32
3.4.1
Discontinuation of trial treatment.....................................................................33
3.4.2
Withdrawal of consent to trial participation....................................................33
3.4.3
Discontinuation of the trial by the sponsor.......................................................33
4.
TREATMENTS...................................................................................................34
4.1
INVESTIGATIONAL TREATMENTS ...........................................................34
4.2
SELECTION OF DOSES IN THE TRIAL AND DOSE MODIFICATIONS35
4.3
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS ......35
4.3.1
Drug assignment and administration of doses for each patient......................35
4.3.2
Blinding and procedures for unblinding...........................................................36
4.3.3
Packaging, labelling, and re-supply...................................................................36
4.3.4
Storage conditions...............................................................................................36
4.3.5
Drug accountability.............................................................................................36
4.4
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................37
4.4.1
Other treatments and emergency procedures..................................................37
4.4.2
Restrictions ..........................................................................................................37
4.4.2.1
Restrictions regarding concomitant treatment ......................................................37
4.4.2.2
Restrictions on diet and lifestyle...........................................................................38
4.5
TREATMENT COMPLIANCE........................................................................38
5.
ASSESSMENTS..................................................................................................39
5.1
ASSESSMENT OF EFFICACY........................................................................39
5.2
ASSESSMENT OF SAFETY.............................................................................39
5.2.1
Physical examination ..........................................................................................39
5.2.2
Vital signs.............................................................................................................39
5.2.3
Safety laboratory parameters ............................................................................39
5.2.4
Electrocardiogram ..............................................................................................42
5.2.5
Medical examination...........................................................................................42
5.2.6
Assessment of AEs...............................................................................................42
5.2.6.1
Definitions of AE..................................................................................................43
5.2.6.2
Adverse event collection and reporting ................................................................45
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................47
5.3.1
Assessment of pharmacokinetics .......................................................................47
5.3.1.1
Blood sampling .....................................................................................................47
5.3.1.2
Urine sampling......................................................................................................48
5.3.2
Analytical determinations of pharmacokinetics...............................................49
5.3.2.1
Analytical determination of analyte plasma concentration...................................49
5.3.2.2
Analytical determination of analyte urine concentration......................................49

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5.3.3 
5.3.3.1 
5.3.3.2 
5.3.4 
5.3.4.1 
5.3.4.2 
5.3.5 
5.4 
5.5 
5.6 
6. 
6.1 
6.2 
6.2.1 
6.2.2 
6.2.3 
7. 
7.1 
7.2 
7.2.1 
7.2.2 
7.2.2.1 
7.2.2.2 
7.2.2.3 
7.2.3 
7.2.4 
7.2.4.1 
7.2.4.2 
7.2.4.3 
7.2.5 
7.2.6 
7.2.7 
7.3 
7.3.1 
7.3.2 
7.4 
7.5 
8. 
8.1 
8.2 
Assessment of biomarkers .................................................................................. 49 
Blood sampling ..................................................................................................... 49 
Urine sampling ...................................................................................................... 49 
Analytical determination of biomarkers ........................................................... 50 
Analytical detennination ofNMN, ml A, and CPI and CP III plasma 
concentration ......................................................................................................... 50 
Analytical detennination ofNMN and ml A urine concentration ........................ 50 
Further investigations ......................................................................................... 50 
BIOBANKIN"G .................................................................................................. 51 
OTHER ASSESSMENTS ................................................................................... 51 
APPROPRIATENESS OF MEASUREMENT ................................................ 52 
INVES TI GA TIO N AL PLAN ............................................................................. 53 
VISIT SCIIEDULE ............................................................................................. 53 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................. 53 
Screening ............................................................................................................ 51 
Treatment period(s) .......................................................................................... 54 
Follow-up period and trial completion (Eo T visit) .......................................... 54 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE55 
NULL AND ALTERNATIVE HYPOTHESES ............................................... 55 
PLANNED ANALYSES ..................................................................................... 55 
Handling of Intercurrent Events ....................................................................... 56 
Primary objective analyses ................................................................................. 56 
Sensitivity Analyses .............................................................................................. 5 7 
Subgroup Analyses ............................................................................................... 5 7 
Supple1nenta1y Analyses ....................................................................................... 57 
Secondary objective analyses ............................................................................. 57 
Further objective analyses .................................................................................. 58 
Phannacokinetic analyses ..................................................................................... 58 
Biomarker analyses ............................................................................................... 58 
Analysis for liquid biopsy ..................................................................................... 58 
Safety analyses ..................................................................................................... 58 
Other Analyses .................................................................................................... 59 
Interim Analyses ............................................................................................... 59 
HANDLING OF MISSING DATA ................................................................... 59 
Safety .................................................................................................................. 59 
Pharmacokinetics ................................................................................................ 59 
RANDOlVIISATION ........................................................................................... 59 
DETERMINATION OF SAMPLE SIZE ......................................................... 59 
I...NFORlVIED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........ 60 
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT60 
DATA QUALITY ASSURANCE ...................................................................... 61 
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8.3 
8.3.1 
8.3.2 
8.3.3 
8.4 
8.5 
8.5.1 
8.6 
8.7 
9. 
9.1 
9.2 
10. 
■ 
10.2 
11. 
RECORDS ........................................................................................................... 61 
Source documents ............................................................................................... 61 
Direct access to source data and documents ..................................................... 62 
Storage period of records ................................................................................... 62 
EXPEDITED REPORTING OF ADVERSE EVENTS .................................. 63 
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY ........ 63 
Collection, storage and future use of biological samples and corresponding 
data ....................................................................................................................... 63 
TRIAL MILESTONES ....................................................................................... 64 
ADMINISTRATIVE STRUCTURE OF THE TRIAL ................................... 64 
REFERENCES .................................................................................................... 66 
PUBLISHED REFERENCES ............................................................................ 66 
UNPUBLISHED REFERENCES ...................................................................... 68 
APPENDICES ..................................................................................................... 69 
COVID-19 RISK ASSESSMENT ...................................................................... 70 
DESCRIPTION OF GLOBAL AMENDMENT(S) ......................................... 71 
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ABBREVIATIONS AND DEFINITIONS
ABC
ATP-binding-cassette transporter family
ABCC
ATP-binding-cassette transporter sub-family C
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
APAP-Glu
Acetaminophen Glucuronide
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BCRP
Breast Cancer Resistance Protein
BI
Boehringer Ingelheim
BMI
Body Mass Index
BP
Blood Pressure 
CA
Competent Authority
CI
Confidence Interval
CKD EPI formula
Chronic Kidney Disease Epidemiology Collaboration formula
Cmax
Maximum Plasma Concentration
Cmin
Minimum Plasma Concentration
COVID-19
Coronavirus disease 2019
CP I
Coproporphyrin I 
CP III
Coproporphyrin III
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (or “eCRF”)
CRN
Clinical Research Network
CRO
Contract Research Organisation
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP450
Cytochrome P450

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DDI
Drug-Drug Interactions
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EMA
European Medicines Agency
EoT
End of Trial
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FDA
The Food and Drug Administration
GEV
Gastroesophageal varices 
GFR
Glomerular Filtration Rate
gMeans
Geometric Means
HA
Health Authority
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HMG-CoA
3-Hydroxy-3-Methylglutaryl Coenzyme A
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
ITC
International Transporter Consortium’s
K-EDTA
Potassium Ethylenediaminetetraacetic Acid
LC-MS/MS
liquid chromatography tandem mass spectrometry
LGL syndrome
Lown Ganong Levine symdrome
LPLT
Last patient last treatment
m1A
N1 –methyl adenosine
MATE
Multidrug and toxin extrusion protein

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MATE1
Multidrug and toxin extrusion protein 1
MATE2-K
Multidrug and toxin extrusion protein 2-K
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRE
Magnetic Resonance Elastography
MRP
Multidrug resistance-associated protein
MRP 2
Multidrug resistance-associated protein 2
MRP 3
Multidrug resistance-associated protein 3
NASH
Non-Alcoholic SteatoHepatitis
NMN
N1-methylnicotinamide
OAT1
Organic anion transporter 3
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
OPU
Operative Unit
P-gp
P-glycoprotein
PK
Pharmacokinetics
PR
Pulse Rate
q.d.
quaque die (once a day)
RA
Regulatory Authority
REP
Residual effect period
RNA
Ribo-Nucleic Acid
SAE
Serious Adverse Event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC
Steering Committee
SLC
Solute Carrier Transporter Family
SMC
Safety Monitoring Committee
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
tmax
Timepoint of maximum plasma concentration

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TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
T2DM
Type 2 Diabetes Mellitus
t1/2
Half lifetime
ULN
Upper limit of normal
WHO
World Health Organisation

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1. INTRODUCTION 
The cmTent study consists of 3 different groups: 
Healthy subjects 
Group 1: 12 healthy subjects 
Liver cirrhosis patients 
Group 2: 12 F4 Child-Turcotte-Pugh class A (Child-Pugh A) subjects (compensated) 
Group 3: 6 F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (decompensated) 
The intention is to identify whether transpo11er activity in F4 liver cinhosis patients on 
standard of care is similar or different from those in healthy subjects. The overall question 
this study will address, is how potential dmg exposures may change, depending on their 
routes of metabolism and/or elimination from the body in F4 liver citThosis patients on 
standard of care compared to healthy subjects. 
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1.1 
MEDICAL BACKGROUND 
Based on the recommendations of the International Transporter Conso11iwn's (ITC) white 
paper [RI 0-11571, regulat01y agencies explicitly state drng transpo11ers that should be 
investigated in vitro for inhibition by new investigational dmgs during dmg development. 
The specific transpo11ers explicitly referred to by both the EMA guideline [P 15-06991] and 
the FDA draft guidance [R20-2271) are the ATP-binding-cassette (ABC) transporter family, 
P-gp and BCRP, as well as the solute canier (SLC) transporter family, OATPIBl, OATP1B3, 
OCT2, OATl, and OAT3. 
If in vivo inhibition of a dmg transp01ter known to be relevant for dtug disposition cam1ot be 
excluded based on in vitro data, an in vivo study is reconnnended by regulato1y agencies. A 
valuable approach to investigate the activities of several different drng transporters in one 
single study is the "cock-tail study". This method, in which a mixture of well-characterized 
probe dt11gs is administered together with the new investigational product, is well established 
for investigation of cytochrome P450 (CYP450) mediated DD Is. Both the Emopean 
Medicines Agency (EMA) and the Food and Dmg Administration (FDA) recommend the use 
of cocktail studies also for investigating the activity of dtug transporters f Pl 5-06991, R20-
2271 ]. 
A cock-tail of drng transporter substrates has been developed by BI dming the last years. This 
cocktail consists of 0.25 mg digoxin (substrate of P-gp), 10 mg rosuvastatin (substrate of 
OATPlBl, OATP1B3 and BCRP), 10 mg metfonnin (substrate ofOCT2, MATEl and 
MATE2-K) and 1 mg furosemide (substrate of OATl and OAT3), thus covering all 
transpo11ers of potential clinical relevance recommended by EMA and FDA (see above). In 
the given doses the cocktail demonstrated no mutual interactions [R20-1915]. 
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1.2
DRUG PROFILE
1.2.1
Rosuvastatin
Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (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 [R22-4022].
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 [R22-4022, 
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 [R22-4022].
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 [R22-4022].
Several drugs are known to influence the exposure of rosuvastatin. These drugs are forbidden 
in the study (antiviral drugs, ezetimibe and fibrates) In addition, subjects on the maximal dose 
(as per SmPC) of any statin would be excluded.
For a complete listing of adverse reactions, including frequency of occurrence, please refer to 
the current Summary of Product Characteristics (SmPC) [R22-4022].
1.2.2
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 [R22-4044].
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 [R22-4044].
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. 

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Moreover, disturbances of colour vision may occur. In rare cases, gynecomasty, myasthenia, 
thrombocytopenia, hypersensitivity reactions or lupus erythematodes have been observed 
[R22-4044]. 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 [R22-4044].
In this study, digoxin will be used in single dose, lower than the dose used to achieve an 
immediate effect on the cardiovascular (CV) system. In patients with cirrhosis, no dose 
reduction is needed. Nevertheless, patients with relevant CV conditions are excluded from the 
study (see section 3.3.2). Many drugs may increase the effect of digoxin on the CV system. 
The use of low single dose is not expected to lead to severe CV effects in the partcipants in 
this study. The study drug furosemide is used in a very small dose, and it is not expected to 
have any influence the electrolytes which may increase the risk of CV effects of digoxin.
For a complete listing of adverse reactions please refer to the current SmPC [R22-4044].
1.2.3
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 [R22-4021].
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
(estimated population mean of 507 ± 129 mL/min) and the principal mode of elimination, 
with a t1/2 of approximately 6.5 h [R22-4021, 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 [R22-4021].
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 [R22-
4021]. 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 
considered. Other possible symptoms are dyspnoea, abdominal disorders, hypothermia, and 
coma [R22-4021].To our knowledge, lactic acidosis has not been observed in healthy 

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volunteers, so far. High doses ofup to 85 g metfonnin did not cause hypoglycaemia. 
However, lactic acidosis has been obse1ved with this severe overdosing [R22-4021]. 
In this study, ve1y low dose of 10 mg will be used. It is not expected that this dose will have 
significant clinical effect in the study participants. 
For a more detailed description of metfonnin' s profile please refer to the ctment SmPC [R22-
4021]. 
1.2.4 Furosemide 
Furosemide is a loop diuretic indicated for treatment of oedema ( cardiac, hepatic, renal, or 
due to bums), a1terial hypertension, oliguria, or puhnona1y oedema. By inhibition of the 
Na+12c1-;K+ canier in the distal ascending limp ofHenle's loop, furosemide increases 
dimesis and excretion of sodium, potassimn, calcium, and magnesium [R22-4020]. 
After administration of furosemide as au oral solution, oral bioavailability is ~80 %. Maximal 
plasma concentrations (tmax) are observed at~ I h. Plasma protein binding is 95 %, and V z/F 
is 0.2 U kg. Furosemide is eliminated principally as unchanged substance, to two thirds by the 
kidney (glomernlar filtration and secretion) and to one third by excretion into bile [R22-4020]. 
In therapy, initial doses of oral furosemide are nonnally 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 n01mally 40-80 mg/day [R22-4020]. 
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 [R22-4020]. 
In this study, very low dose of 1 mg will be used. It is not expected that this dose will have 
significant clinical effect in the study participants. 
For a complete listing of furosemide adverse reactions, including frequency of occmTence, 
please refer to the cunent SmPC [R22-4020]. 
1.2.5 Residual Effect Period 
The Residual Effect Period (REP) of the cock-tail is 10 days refeITing to digoxin, the drng 
with the longest half-life among the cocktail components [R22-3893, R22-3889, R22-3891, 
R22-3890, R14-0150]. This is the period after the last dose with measurable dtug levels 
and/or phannacodynamic effects still likely to be present. 
1.3 
RATIONALE FOR PERFORMING THE TRIAL 
The rationale for this study is to understand whether liver cinhosis itself, along with standard 
of care, can result in a change in transporter activity of P-gp, OATl, OAT3, OCT2, MA TEI, 
MATE2-K, OATPlBl OATP1B3 and BCRP in F4 liver cnThosis atients com ared to 
health sub· ects. 
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Liver ciIThosis is a longitudinal disease, going from F0 through to F4 compensated then 
decompensated. The current published data on NASH patients suggests that MRP2 is reduced 
due to it being mislocated, BCRP activity is increased and OA TP 1 B3 activity is reduced. It is 
not clear whether this occms in all stages of liver c:inhosis patients or only in the most severe 
stages of the disease [R22-3893, R22-3889, R22-389 1J. Thus, the cunent study is to fill this 
infom1ation gap. 
The intention is to identify whether the pha1macokinetics of a dtug, based on transpo11er 
activity, is significantly different in F4 liver cinhosis patients on standard of care compared 
to that obse1ved in healthy subjects. The overall question this study will address, is how 
potential dmg exposures may change, depending on their routes of metabolism and/or 
elimination from the body in F4 liver ciIThosis patients on standard of care compared to 
health sub·ects. 
1.4 
BENEFIT - RISK ASSESSMENT 
1.4.1 Benefits 
Participation in this clinical trial is without any therapeutic benefit for healthy subjects or 
liver ciIThosis patients. Their pa11icipation, however, is of major importance for the 
development of future compOlmds in liver cirrhosis patients within Boehringer Ingelheim. 
Understanding how drug exposures may differ in F4 liver cilThosis patients, on standard of 
care, compared to healthy subjects, depending on which transpo11ers are involved in the 
absorption and disposition of the drug. Subjects are exposed to risks of sh1dy procedures and 
risks related to the exposme to the trial medication, which are already marketed products. 
1.4.2 Risks 
1.4.2.1 
Procedure-related risks 
The use of an indwelling venous catheter or veneptmch1re for e.g., blood sampling may result 
in mild bruising, and in rare cases, in transient inflalll1llation of the wall of the vein, or neIVe 
injmy, 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 or 
liver cilThosis patients is expected from withdrawal of this volume of blood. 
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1.4.2.2
Drug-related 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 [R22-4044]
0.75 mg SD [R17-1846]
Furosemide
1 mg SD
40 – 80 mg [R22-4020]
80 mg SD [R17-1848]
Metformin
10 mg SD
up to 3000 mg [R22-4021]
1000 mg SD [U13-2366-01]
Rosuvastatin
10 mg SD
10 mg – 40 mg [R22-4022]
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
Drug-related risks related to the administration of the cocktail in the present of 
transporter inhibition (worst case scenario)
A potential inhibition of the investigated drug transporters by the comedications which the 
liver cirrhosis patients may be on (standard of care) is expected to increase the exposure of 
rosuvastatin, digoxin, metformin, and furosemide. However, none of these potential increases 
following a single dose of the cocktail are regarded as being detrimental to the safety and 
health of F4 liver cirrhosis patients as the doses of all four cocktail components are 
sufficiently low.
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 maximum concentration (Cmax) and a 5-fold increase of rosuvastatin area under 
the curve (AUC) values [R15-4771, R17-1790]. This effect size could be confirmed by our 
cocktail validation trial 0352-2100, in which a dose of 10 mg rosuvastatin has been given 
together with rifampicin and was well tolerated [c23988236-01].
The administration of 10 mg rosuvastatin alone in the trial 0352-2082 resulted in a mean 
AUC0-∞of 93.4 nM*h (=44.9 ng/mL*h) and Cmax of 8.61 nM (4.14 ng/mL) [c02586759-02]. 
In a DDI study with itraconazole using single doses of 80 mg rosuvastatin Cooper et al report 
a rosuvastatin 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 0352-2082. This is assessed 

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to be sufficient to cover the potential inhibition of OATP1B1/1B3 mediated by any 
comedications for the F4 liver cirrhosis patients.
In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were 
modestly increased. In patients with Child-Pugh A disease, Cmax and AUC were increased by 
60 % and 5 %, respectively, as compared with patients with normal liver function. In patients 
with Child-Pugh B disease, Cmax and AUC were increased 100 % and 21 %, respectively, 
compared with patients with normal liver function
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 comedications 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 factors 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 comedications for the F4 liver 
cirrhosis patients.
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 comedications for the F4 
liver cirrhosis patients 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. This effect size could be confirmed by our cocktail validation trial 
0352-2100, in which a dose of 1 mg furosemide has been administered together with 
probenecid [c23988236-01].
In the cocktail validation study 352.2082 a single dose of 20 mg furosemide has been well 
tolerated by healthy subjects [c02586759-02]. Assuming dose-proportional kinetics, this 
would provide a safety margin of 20 to the furosemide dose used in this study (1 mg), which 
is assessed to be sufficient to cover the potential inhibition of OAT1/OAT3 by comedication 
for the F4 liver cirrhosis patients.
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 5.2.6.1, adverse events of special interest (AESIs).
1.4.2.5
Safety measures
For safety measures and assessments such as screening examination, AE questioning, 
laboratory examinations, in-house periods, or electrocardiogram (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 subjects.
1.4.2.6
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 
comediations being taken by the F4 liver cirrhosis patients (standard of care) administration 
is covered by the experience made in previous trials. However, the benefit of the resulting 
data for future drug development outweights any potential risks to both healthy subjects and 
F4 liver cirrhosis patients.
1.4.2.7
Coronavirus Disease 2019
At the time of this original protocol, the COVID-19 pandemic is still active in many 
countries. Given the unique circumstances created by the pandemic, specific consideration 
has been given to the benefits and risks of the trial as they relate to the pandemic and 
potential SARS-CoV-2 infection; see section 10.2.

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2. TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main trial objective, is to ascertain whether the transport activity of P-gp, OAT1, OAT3, 
OCT2, MATE1, MATE2-K, OATP1B1, OATP1B3 and BCRP, given by the Cmax and 
AUC0-24 values for the different components in the transporter cocktail containing digoxin (P-
gp) furosemide (OAT1 and OAT3), metformin (OCT2, MATE1 and MATE2-K) and 
rosuvastatin (OATP1B1, OATP1B3 and BCRP) are similar or different in F4 liver cirrhosis 
patients on standard therapy compared to healthy subjects.
This study will be conducted as an open label, single dose study, where PK samples will be 
assessed up to 
 postdose following dosing of the cocktail.
2.2
MAIN ENDPOINTS
Primary endpoint(s) is to determine the following pharmacokinetic parameters for the 
different components following a single dose of the transporter cocktail containing digoxin 
(P-gp), furosemide (OAT1 and OAT3), metformin (OCT2, MATE1 and MATE2-K) and 
rosuvastatin (OATP1B1, OATP1B3 and BCRP).
-
AUC
(area under the concentration time curve of the analyte in plasma over the time 
interval from 0 to 
) for each component of the transporter cocktail: digoxin, 
furosemide, metformin, and rosuvastatin. 
-
Cmax (maximum measured concentration of the analyte in plasma) for each component 
of the transporter cocktail: digoxin, furosemide, metformin, and rosuvastatin.
Secondary endpoint(s):
-
none
2.3
PROPOSED FURTHER ENDPOINTS
If the data allows additional PK parameters not exclusive to those below, may also be
calculated if required:
-
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)
-
%AUCtz-∞ (the percentage of AUC0-∞ obtained by extrapolation)
-
tmax (time from dosing to maximum measured concentration 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)
-
λz (terminal rate constant in plasma)
-
t1/2 (terminal half-life of the analyte in plasma)
-
AUCt1-t2 (area under the concentration-time curve of the analyte in plasma over the time 
interval t1 to t2)
-
CL/F (apparent clearance of the analyte in the plasma after extravascular 
administration)
-
-

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V zfF ( apparent volume of distribution during the tenninal phase after extravascular 
administration) 
Aetl-t2 (amount of analyte that is eliminated in mine from the time inte1val tl to t2) 
Fet1-t2 (fraction of given drug excreted unchanged in urine from time point tl to t2) 
CLRt1-t2 (renal clearance of the analyte in plasma from the time point t1 to t2) 
2.3.1 Biomarkers 
2_3_1.l 
Coproporphyrin I and III 
Coproporphyrin I and III (CPI and CP III) will be investigated as novel endogenous 
substrates of OATPlBl and OATPIB3. The following parameters for CPI and CP III will be 
determined if the data allows: 
AUCo-12 (area under the concentration-time curve of the analyte in plasma over the time 
i.nte1val from 0 to the last quantifiable data point) 
Cmax (maximmn measured concentration of the analyte in plasma) 
tmax(time from dosing to maximum measured concentration of the analyte in plasma) 
2.3.1.2 
N1-methylnicotinainide and N1-methyl adenosine (mlA) 
N1-methylnicotinamide (NMN) and N1-methyl adenosine (mlA) will be investigated as a 
novel endogenous marker for evaluating the potential of inhibition of organic cation (OCT) 
and MA TE transporters. 
Note: these markers will only be measmed up to■ 
postdose. The following parameters 
will be detennined if the data allows: 
CLRt1-t2 (renal clearance of the analyte in plasma from the time point t1 to t2, over the 
12 h postdose period), this is the prima1y outcome for NMN and ml A 
AUCo-tz (area under the concentration-time curve of the analyte in plasma over the time 
inte1val from Oto the last quantifiable data point) 
Cmax (maximum measured concentration of the analyte in plasma) 
tmax (time from dosing to maximum measmed concentration of the analyte in plasma) 
Aetl£iamount of analyte that is eliminated in urine from the time interval t1 to t2, over 
the-
postdose period) 
Further parameters could be calculated as appropriate. 
I 
I -
2.3.2 Safety endpoints: 
AEs including clinically relevant fmdings from the physical examination 
Safety laborato1y tests 
12-leadECG 
Vital signs (BP, PR) 
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3. DESCRIPTION OF DESIGN AND TRIAL POPULATION 
3.1 
OVERALL TRIAL DESIGN 
Study Design 
This study will primarily investigate, following a single dose of the cock.-tail, the 
pham1acokinetic profiles for each of the cock.tail components ( digoxin, ftu-osemide, 
metfonnin and rosuvastatin) up to-
postdose, calculating the resulting Cmax and AUCII 
values. Urinary excretion will also be investigated as a further endpoint. The cocktail will be 
given after a standardized breakfast. 
Note: The cocktail should only be given to subjects/patients who are not already on any of 
the cock."tail components. Othen:vise, the resulting drng concentrations of that moiety will not 
be meaningful in the cmTent study. 
An explorato1y analysis of endogenous biomarkers CPI, CP III NMN, and ml A will be 
undertaken if the data allows. 
The current study consists of 3 groups: 
Healthy subjects 
Group 1: 12 healthy subjects (matched as far as possible (see section 3.2) to the patients 
in group 2) 
Liver cirrhosis patients 
Group 2: 12 F4 Child-Turcotte-Pugh class A (Child-Pugh A) subjects (compensated) 
Group 3: 06 F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (decompensated) 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) 
For this trial, as there is only one treatment, an open label study is prefe1Ted. The open-label 
treatment is not expected to bias results, since the primary study endpoints are quantitative 
endpoints derived from measmement of plasma concentrations of the analytes. The control 
group are healthy volunteers, where feasible, will be matched in te1ms of age (± 10 years), 
BMI (± 20 %) and sex. This may result in the liver cinhosis patients as a group being 
different from the healthy subjects, if the number of liver cirrhosis patients are outside the 
BMI range for healthy subjects. However, all comparisons will be conducted on a group 
basis, not on individual matched subjects. 
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3.3
SELECTION OF TRIAL POPULATION
It is planned that 12 healthy subjects, 12 compensated F4 Child-Pugh A patients and a 
minimum of 6 decompensated Child-Pugh B patients following clinical confirmation (see 
section 3.3.2 and section 3.3.3) will enter the study. The healthy subjects will be recruited 
from the volunteers' pool of the trial site. The liver cirrhosis patients will be recruited from a 
population of patients enriched for disease activity and fibrogenesis. This trial is planned to 
be conducted without the use of biopsies for either eligibility or efficacy assessments. Thus, 
the definition of liver cirrhosis and staging will be non-invasive.
3.3.1
Main diagnosis for trial entry
Please refer to section 8.3.1 for the documentation requirements pertaining to the in- and 
exclusion criteria for:
-
Healthy subjects
Group 1: 12 healthy subjects
-
Liver cirrhosis patients
Group 2: 12 F4 Child-Turcotte-Pugh class A (Child-Pugh A) subjects (compensated)
Group 3: 06 F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (decompensated)
3.3.2
Inclusion criteria
Healthy subjects and patients will only be included in the trial if they meet the following 
criteria:
Healthy subjects and F4 liver cirrhosis patients
1. Signed and dated written informed consent in accordance with the International 
Conference on Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation
prior to admission to the trial
2. Either male subject, or female subject who meets any of the following criteria for a highly 
effective contraception from at least 30 days before the first administration of trial 
medication until 30 days after trial completion:
-
Use of combined (estrogen and progestogen containing) hormonal contraception that 
prevents ovulation (oral, intravaginal, or transdermal), plus condom
-
Use of progestogen-only hormonal contraception that inhibits ovulation (only 
injectables or implants), plus condom
-
Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
-
Sexually abstinent
-
A vasectomised sexual partner who received medical assessment of the surgical success 
(documented absence of sperm) and provided that the partner is the sole sexual partner 
of the trial participant
-
Surgically sterilised (including hysterectomy)
-
Postmenopausal, defined as no menses for 1 year without an alternative medical cause
(in questionable cases a blood sample with levels of FSH above 40 U/L and estradiol 
below 30 ng/L is confirmatory)
3. Not taking any components in the cocktail within 4 weeks of enrolment

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Healthy subjects only
4. Healthy male or female 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
5. Age of 18 to 75 years (inclusive)
6. BMI of 18.5 to 35 kg/m2 (inclusive). A BMI of ≥30 is no exclusion criterion when the
subject can be considered healthy apart from the elevated BMI
7. Subjects to be matched for age (± 10 years), BMI (± 20 %) and sex to subjects in Group 2
8. Have no known or suspected hepatic impairment and meet the following criteria at the 
screening visit: alanine aminotransferase (ALT) ≤ULN, aspartate aminotransferase 
(AST) ≤ULN, total bilirubin ≤ULN, albumin ≤ULN, prothrombin time ≤ULN
Note: subjects with a history of Gilbert syndrome (and hence elevated total bilirubin) are 
eligible provided that direct bilirubin level ≤ULN, ALT ≤ULN, AST ≤ULN, alkaline 
phosphatase ≤ULN, haemoglobin ≤ULN, and reticulocyte count ≤ULN
F4 liver cirrhosis patients only
9. Male and female subjects, 18 to 75 years
10. BMI of 18.5 to 40.0 kg/m2 (inclusive)
11. Stable treatment for at least 4 weeks prior to taking the cocktail
12. A) Patients with compensated liver cirrhosis due to any underlying liver disease with
13. advanced fibrosis (F4) and hepatic impairment that meets the criteria for 
Child-Pugh A (see Table 3.3.2: 1)
OR
B) Patients with decompensated liver cirrhosis due to any underlying liver disease with
14. advanced fibrosis (F4) and hepatic impairment that meets the criteria for
Child-Pugh B (see Table 3.3.2: 1)
-
Diagnosis of compensated cirrhosis/F4
I.
Historic (within 2 years) histological diagnosis of fibrosis stage F4 (NASH-
CRN or METAVIR scoring)
OR
II.
Current or historic increased liver stiffness of ≥18 kPa by Fibroscan or 5 kPa 
by MRE
OR
III.
Current or historic imaging of nodular surface with thrombocytopenia 
< 150/nL
OR
IV.
Clinical signs of portal hypertension (at least one out of the following)
1. Gastroesophageal varices (GEV)
2. Splenomegaly (no hematological or infectious diseases, which could cause 
splenomegaly)
3. Thrombocytopenia < 120/nL
AND
V.
No previous decompensation events (e.g., aszites, variceal bleeding, hepatic 
encephalopathy, hepato-renal syndrome)

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-
Diagnosis of decompensated cirrhosis/F4
Any of the above (diagnosis of compensated cirrhosis/F4)
AND
At least one previous decompensation event
Table 3.3.2: 1 Child-Turcotte-Pugh Scoring Method
Clinical and laboratory criteria
Points1
1
2
3
Encephalopathy
None
Mild to moderate
(Grade 1 or 2)
Severe
(Grade 3 or 4)
Ascites
Absent
Slight
Moderate
Bilirubin (mg/dL)
Bilirubin (μmol/L)
< 2
< 34.2
2–3
34.2–51.3
> 3
> 51.3
Albumin (g/dL)
Albumin (g/L)
> 3.5
> 35
2.8–3.5
> 28–35
< 2.8
< 28
Prothrombin time (seconds 
prolonged)
Or INR2
< 4
< 1.7
4–6
1.7–2.3
> 6
> 2.3
1)
Child-Turcotte-Pugh class obtained by adding score for each parameter (total score)
Child-Turcotte-Pugh A = 5–6 points (mild)
Child-Turcotte-Pugh B = 7–9 points (moderate)
Child-Turcotte-Pugh C = 10–15 points (severe)
2)
International normalized ratio (INR) will be used to calculate Child-Turcotte-Pugh score by sponsor
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
Healthy subjects and F4 liver cirrhosis patients
1. Subjects already taking digoxin, furosemide, metformin or rosuvastatin within 4 weeks of 
enrolment into the study. Furthermore, patients taking ezetimibe, fibrates, or the maximal 
dose (per SmPC) of any statin are excluded from this study.
2. Subjects with any other condition that would preclude administration of digoxin, 
furosemide, metformin or rosuvastatin (i.e., contraindicated as per Summary of Product 
Characteristics (SmPC)), such as hypersensitivity to active ingredient or any of the 
excipients or to sulphonamides, hypovolaemia or dehydration, and partial obstructions of 
urinary outflow (e.g., prostatic hypertrophy)
3. Repeated measurement of systolic blood pressure outside the range of 90 to 150 mmHg, 
diastolic blood pressure outside the range of 50 to 95 mmHg, or pulse rate outside the 
range of 60 to 90 bpm
4. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
5. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
6. History of relevant orthostatic hypotension, fainting spells, or blackouts

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7. Relevant (other than HBV or HCV) chronic or acute infections (including an ongoing 
SARS-CoV-2 infection)
8. Patients receiving antiviral therapy at the time of inclusion into the trial
9. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin
10. 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.
Exception: participation in this BI trial 0352-2189 is allowed following participating in 
the BI trial 0352-2190 after an at least 14-day washout period (between cocktail 
administrations) due to single administration and the very low dose of the cocktail
components in the BI trial 0352-2190
11. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
12. Inability to refrain from smoking on specified trial days
13. Alcohol abuse (intake of more than 12 g per day for females and 24 g per day for males)
14. Drug abuse or positive drug screening
15. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
16. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
17. Inability to comply with the dietary regimen of the trial site
18. 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
19. 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
20. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
21. For female subjects, positive pregnancy test, pregnancy, or plans to become pregnant 
within 30 days after study completion
22. For female subjects, lactation period
23. Hypokalemia, hypomagnesemia, or hypercalcemia
24. PQ interval greater than 220 ms or atrioventricular block of II° or III° in the ECG at 
screening
25. Marked conductivity disorder (e.g., sinoatrial blocks of II° or III°, any pathological sinus 
node function) in the ECG at screening
26. Thoracic aneurysm of the aorta
27. Known or suspicion of pre-excitation syndrome (Wolff Parkinson White (WPW) or Lown
Ganong Levine (LGL) syndrome)
28. Known myopathy, personal or family history of hereditary muscular disorders, or history 
of muscular toxicity with another statin or fibrate; Asian ancestry; hypothyroidism
29. History of nephrolithiasis
30. Gout or clinically relevant elevation of uric acid
31. Clinically relevant hypoproteinemia at screening
32. TSH exceeds upper limit of norm at screening, confirmed by a repeat test

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33. Estimated glomerular filtration rate (according to the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula) is lower than 50 ml/min confirmed by 
a repeat test
34. 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)
35. Subjects taking medications known to be inhibitors of the following drug transporters: P-
gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2-K, OCT
36. Subjects taking medications known to be moderate or strong inhibitors of the following 
CYP enzymes: CYP2C9, CYP2C19, CYP3A
37. Subjects taking medications known to be moderate or strong inducers of the following 
CYP enzymes: CYP2C9, CYP2C19, CYP3A
For study restrictions, refer to section 4.4.2.
Healthy subjects only
38. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
39. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
40. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or 
hormonal disorders
41. Any other finding in the medical examination (including BP, PR, or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
Patients with F4 liver cirrhosis
42. Patients are excluded if they meet the following criteria at the screening visit: AST and/or 
ALT ≥3xULN
3.4
DISCONTINUATION 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 3.4.1 and 
sections 3.4.2 below. However, if the subjects agree, they should stay in the trial. Even if 
continued trial treatment is not possible, they should attend further trial visits to ensure their 
safety and to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal.
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for AE collection reporting (please see section 5.2.6.2).

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3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if any of the following criteria apply:
Healthy subjects and F4 liver cirrhosis patients
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 (except from already discussed 
baseline medication for standard of care per local guidelines)
4. In addition to these criteria, the investigator may discontinue subjects at any time based 
on his or her clinical judgment
5. The participant experiences an infection with SARS-CoV-2 as confirmed by the 
COVID-19 rapid test at the admission to the trial site or based on the investigator’s 
judgement on day 1.
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.
3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate conduct 
of the trial
3. The sponsor decides to discontinue the trial due to business reasons
The investigator/trial site will be reimbursed for reasonable expenses incurred in case of trial
termination (except in case of the third reason).

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4. TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Rosuvastatin, digoxin, metformin and furosemide will be obtained from a public pharmacy.
Trial product 1
Name:
*CRESTOR® 10 mg Film-coated tablet
Substance:
Rosuvastatin (as rosuvastatin calcium)
Pharmaceutical formulation:
Film-coated tablet
Holder of marketing authorization: AstraZeneca GmbH, Germany
Unit strength:
10 mg
Posology:
1 – 0 – 0 (cocktail component)
Route of administration:
Oral
Duration of use:
single dose on Day 1
Trial product 2
Name:
*Lanicor® 0,25 mg tablets
Substance:
Digoxin
Pharmaceutical formulation:
Tablet
Holder or marketing authorization: Teofarma S.r.I., Italy
Unit strength:
0.25 mg
Posology:
1 – 0 – 0 (cocktail component)
Route of administration:
Oral
Duration of use:
single dose on Day 1
Trial product 3
Name:
*MetfoLiquid GeriaSan® 1000 mg/5 ml oral solution
Substance:
Metformin hydrochloride
Pharmaceutical formulation:
Oral solution
Holder of marketing authorization: Rosemont Pharmaceuticals Ltd, United Kingdom
Co-marketing:
INFECTOPHARM Arzneimittel und Consilium GmbH, 
Germany
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
Trial product 4
Name:
*Lasix® liquidum 10 mg/ml oral solution
Substance:
Furosemide (as furosemide sodium)
Pharmaceutical formulation:
Oral solution
Holder of marketing authorization: Sanofi-Aventis Deutschland GmbH, Germany
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

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* These trial products may be replaced by generics which will be announced via a non-
substantial CTP amendment 
4.2 
SELECTION OF DOSES IN THE TRIAL AND DOSE MODIFICATIONS 
Based on results of trials 0352-2082 (c02586759-02], 0352-2094 (c08983809-01],0352-2096 
(c13060859-01], and 0352-2100 f c23988236-01] the established cocktail of drng transporter 
substrates consists of O .25 mg digoxin, 1 mg furosemide, 10 mg metfonnin hydrochloride and 
10 mg rosuvastatin (see section 1.2). 
4.3 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS 
After the assessment of all in- and exclusion criteria, each eligible subject will receive a 
single dose of the cocktail. Everyone will receive the same doses. 
4.3.1 Drug assignment and administration of doses for each patient 
This trial is au open label, non-randomised, single dose study. All subjects will receive a 
single dose of the cocktail. The treatments to be evaluated are outlined in Table 4.3.1: 1 
below. 
Table 4.3.1: I Dosage and treatment schedule 
Total 
Tl'eatment 
Substance 
Fol'mulatiou 
Unit stl'ength 
Dosage 
daily 
dose 
Cocktail 
Digoxin 
Tablet 
0.25 mg 
l tablet as single dose 
0.25 mg 
Furosemide 
Oral solution 
l0mg/mL 
0.1 mL (1 mg) as single dose 
1 mg 
Metfonnin 
Oral solution 
l 000mg/5 mL 
0.05 mL (10 mg) as single dose 10mg 
Rosuvastatin 
Film-coated tablet 
10mg 
l tablet as single dose 
10mg 
Standardized light breakfast 
A standardized meal (bread roll or similar with butter, cheese and/or sliced sausage) will be 
served I h 30 min before the cocktail is administered. 
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After cocktail administration 
Subjects will be ke 
administration. 
4.3.2 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. 
4.3.3 Packaging, labelling, and re-supply 
Rosuvastatin, digoxin, metfonnin and furosemide will be obtained by the clinical trial site 
from a public phannacy. The drug will be dispensed out of the original, unmodified 
packages. 
4.3.4 Storage conditions 
Drng supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recormnended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drng supplies are stored at the 
c01Tect 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. 
4.3.5 Drug accountability 
Only authorised personnel documented in the trial team log may dispense medication to trial 
subjects. Tue trial medication must be administered in the manner specified in the CTP. The 
investigator or designee must maintain records of the product's delive1y 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, expiiy ('use-by') dates, and the 
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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. At the time of disposal of remaining trial medication, the investigator or designee 
must verify that all unused or partially used drng supplies have been disposed of 
4.4 
OTHER TREATlVIENTS, EMERGENCY PROCEDURES, RESTRICTIONS 
4.4.1 Other treatments and emergency procedures 
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if AEs requii-e tieatment, the investigator can authorise symptomatic 
therapy. In those cases, subjects will be tJ:eated as necessary and, if required, kept under 
supervision at the trial site or transfe1Ted to a hospital until all results of medical evaluations 
are acceptable. 
4.4.2 Restrictions 
4.4.2.1 
Restrictions regarding concomitant treatment 
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4.4.2.2 
Restrictions on diet and lifestyle 
4.5 
TREATMENT COMPLIANCE 
Compliance will be assured by administration of trial medication in the study centre under 
supervision of the investigating physician or a designee by the so-called four-eye principle 
(two-person rnle). 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 
conect dosage cannot be ensured othe1w ise. The measured plasma concentrations and urina1y 
excretion of trial medication will provide additional confomation 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 fmiher procedures, please see section 3.4). 
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5. ASSESSMENTS 
5.1 
ASSESSlVIENT OF EFFICACY 
Not applicable 
5.2 
ASSESSMENT OF SAFETY 
5.2.1 Physical examination 
A complete physical examination will be perfom1ed at visit 1 (screening visit/on 
day -21 to -1) at visit 2 (treatment visit/on day 1 and 2), at visit 3 (follow-up visit 1/on day 5), 
and at visit 4 (Eo T visit/on day 11 to 18). It includes at a minimum appearance, neck, lungs, 
cardiovascular system, abdomen, extremities, and skin. 
The physical examination can be omitted at visit 2 (treatment visit/on day 1) if the subject 
does not report any health-related changes or abno1malities since the screening visit (see flow 
chait). 
5.2.2 Vital signs 
Vital signs will be evaluated at the time points specified in the flow chart prior to blood 
sampling. This includes systolic and diastolic blood pressure and pulse rate ( electrnnically or 
by palpation count for 1 min) in a seated or supine position after 5 min of rest. All recordings 
should be made using the same type of blood pressure recording instmment on the same ann 
if possible. The results must be included in the source documents available at the site. 
5.2.3 Safety laboratory parameters 
that will be detennined are listed in Table 5.2.3: 1 and Table 5.2.3: 2. 
Reference ranges will be provided in the ISF. Manual differential white blood cell count or 
urine sediment examinations will only be perfonned if there is an abnonnality in the 
automatic blood cell count or in the urinalysis, respectively. 
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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
X
X
X
-
-
-
-
-
X
X
X
X
X
Automatic WBC 
differential, absolute
Neutrophil, absolute
Eosinophils, absolute
Basophils, absolute
Monocytes, absolute
Lymphocytes, absolute
X
X
X
X
X
-
-
-
-
-
X
X
X
X
X
Coagulation
Activated Partial Thromboplastin Time
Prothrombin time - INR
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 [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
Glomerular Filtration Rate (GFR)/CKD-EPI3
Bilirubin, Total
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
Uric Acid
Albumin
Globulin
Albumin/Globulin ratio
X
X
X
X
X
X
X
X
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
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
-
-
-
-
-
-
-
-
-
X
X
X
X
X
X
X
X
X

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Table 5.2.3: 1 Routine laboratory tests (cont’d)
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
Urine sediment2
Only positive findings will be reported (for instance, 
the presence of sediment bacteria, casts in sediment, 
squamous epithelial cells, erythrocytes, leukocytes)
Urine creatinine4
Urine creatinine will be determined in urine aliquots 
obtained from urine collected for PK (in blank 
sample and in urine from each collection interval)
1) A to be done at screening, B to be done in the morning of day 1, C to be done in the morning of day 2, at the 
follow-up visit 1 and at the EoT 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]
4) Urine creatinine is not a safety parameter but for technical reasons needs to be listed here as such
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 
clinical trial report (CTR). Urine pregnancy testing in females will be performed at the 
screening visit, upon admission to the site in the evening of Day -1 and as part of the EoT 
examination. Drug screening will be performed at the screening visit and upon admission to 
the site in the evening of Day -1.
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., Alcotest® 
6820 med., Dräger AG, Lübeck, Germany) will be performed during the screening visit, upon 
admission in the evening of Day -1 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 in Table 5.2.3: 1 and Table 5.2.3: 2 except from the drug 
screening and pregnancy tests will be performed by the local safety laboratory of the trial site.
Drug screening and pregnancy tests will be performed at the trial site using SureStep ML 10 
Scr Test Device; Abbott Rapid Diagnostics, Germany and TestPack+Plus hCG Urine OBC; 

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Abbott Rapid Diagnostics, Germany, or comparable test systems. Laboratory data will be 
transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
The 12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) must be administered by a qualified 
technologist and results will be recorded as scheduled 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. The 
investigator or a designee will evaluate whether the ECG is normal or abnormal and assess 
clinical relevance. ECGs may be repeated for quality reasons and a repeated recording used 
for analysis.
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. Additional ECGs may be recorded for 
safety reasons. Dated and signed printouts of ECG with findings should be documented in 
patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
5.2.5
Medical examination
The medical examination will include:
-
Demographics (height in cm, body weight in kg, age on the day of informed consent
(in years), sex (male, female to describe the subject`s sex at birth), gender identity 
(male, female, and other to describe how the subject self identifies regardless of their 
genotypic or phenotypic sex)
-
Smoking and alcohol history
-
Assessment of smoking and drinking habits at the timepoint of screening
-
Relevant medical history (including trial indication and concomitant diseases, if 
applicable)
-
Relevant concomitant therapy (including start date, if applicable)
-
Review of inclusion and exclusion criteria (see section 3.3.2 and 3.3.3)
-
For females: of childbearing potential yes/no to characterize the patient population 
and as a basis for contraception requirements
5.2.6
Assessment of AEs
Data and information necessary for the thorough assessment of AEs, SAEs and AESIs will be 
reported to the sponsor via eCRF. This may include specific data and information not 
prospectively specified in this protocol.

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5.2.6.1
Definitions of AE
Adverse event (AE)
An 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 considered related or not.
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 exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
Serious adverse event (SAE)
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 or prolongation of existing hospitalisation
-
Results in persistent or significant disability or incapacity
-
Is a congenital anomaly/birth defect
-
Is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medial 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”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered “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. A copy of 
the latest list of “Always Serious AEs” will be provided upon request. These events should 
always be reported as SAEs as described in section 5.2.6.2. Every occurrence of cancers of 
new histology and exacerbations of existing cancer must be classified as a serious event
regardless of the time since discontinuation of the drug and must be reported as described in 
section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and timelines”.

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Adverse events of special interest (AESis) 
The te1m adverse events of special interest (AESI) relate to any specific AE that has been 
identified at the project level as being of paiiicular 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 
Phaimacovigilance Depaiiment within the same timeframe that applies to SAEs, please see 
section 5.2.6.2. 
I 
I 
Intensity (severity) of AEs 
The intensity (severity) of adverse events should be classified and recorded in the CRF 
according to the Common Te1minology Criteria for Adverse Events (CTCAE) version 5.0. 
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Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the trial treatment, 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 trial 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 trial drug 
concerned).
-
Continuation of the event despite the withdrawal of the medication, considering 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.
-
There is an 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.
5.2.6.2
Adverse event collection and reporting
AE Collection
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.
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 

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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 to describe an 
AE more precisely.
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:
•
All AEs (serious and non-serious) and all AESIs
•
The only exception to this rule are AEs (serious and non-serious) and AESIs of 
subjects who 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:
•
The investigator does not need to actively monitor the subject for AEs but should 
only report any occurrence of cancer and trial treatment related SAEs and trial 
treatment related AESIs of which the investigator may become aware of by any 
means of communication, e.g., phone call. Those AEs should be reported on the 
 SAE from, but not in the CRF.
The investigator shall maintain and keep detailed records of all AEs in the patient files.
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the 
 SAE form to the sponsor’s unique entry point within 24 
hours of becoming aware of the event, the country specific process will be specified 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 the 
 SAE form.
With receipt of any further information to these events, a follow-up SAE form must be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient 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.
I 
I 
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The outcome of the pregnancy associated with the dmg exposure during pregnancy must be 
followed up and repo11ed to the sponsor's unique entJ.y point on the Pregnancy Monitoring 
Fann for Clinical Studies (Pali B). 
The ISF will contain the Pregnancy Monitoring Fonn for Clinical Studies (Part A and B). As 
pregnancy itself is not to be reported as an AE, i.n the absence of an accompanying SAE and / 
or AESI, only the Pregnancy Monitoring Fonn for Clinical Studies and not the SAE fonn is 
to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE fonn 
must be completed in addition. 
5.3 
DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS 
5.3.1 Assessment of pharmacokinetics 
For the assessment of phannacokinetics, blood and urine samples will be collected at the time 
points/time intervals indicated in the flow cha11. The achial sampling times will be recorded 
and used for detennination of pha1macokinetic parameters. 
5.3.1.1 
Blood sampling 
For quantification of digoxin, fnrose1nide, metfonni.n, rosuvastatin, CP I, CP III and 
-
1
th lnicotinamide (NMN) and N 1-methyladenosine (mlA) plasma concentrations, 
blood will be taken from an antecubital or forearm vein into a potassium 
y 
iaminetetraacetic acid (K.2-EDTA) anticoaoulant blood drawin tube at the times 
indicated in the flow chai1 and Table 10.1: 1. 
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5.3.1.2 
Urine sampling 
A blank urine sample will be collected before administration of trial medication and aliquots 
will be retained to check for anal ical interference. All urine voided durino the sampling 
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5.3.2 Analytical determinations of pharmacokinetics 
5.3.2.1 
Analytical detennination of analyte plasma concentration 
Digoxin, furosemide, metfonnin, and rosuvastatin concentrations in plasma will be 
determined by validated liquid chromatography tandem mass spectrometly (LC-MS/MS) 
assa s. All details of the anal ical methods will be available rior to the staii of anal sis. 
5.3.2.2 
Analytical determination of analyte urine concentration 
Digoxin, furosemide, metfonnin, and rosuvastatin concenti·ations in urine will be detennined 
by validated LC-MS/MS assays. All details of the anal ical methods will be available rior 
to the staii of sam le anal sis. 
5.3.3 Assessment of biomarkers 
5.3.3.1 
Blood sampling 
The endogenous biomarkers CP I, CP III NMN and ml A serving as potential indicators of 
ti·ansporter activity will be measured 
. Please see section 5 .3 .1.1 for 
sample processing. 
5.3.3.2 
Urine sampling 
Urinaiy NMN and ml A concenti·ation will be measured after cocktail administi·ation. Please 
see section 5. 3 .1.2 for sample processing. 
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5.3.4 Analytical determination of biomarkers 
5.3.4.1 
Analytical detemlination ofNMN, mlA, and CPI and CP III plasma 
concentration 
5.3.4.2 
Analytical detennination ofNMN and mlA urine concentration 
5.3.5 Further investigations 
After completion of the trial analysis of plasma and mine samples for concentrations of 
digoxi:n, furosemide, metf01min, 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 or to address Health Authority questions regarding the 
results/methodology. However, only data related to the analyte and/or its 
metabolite(s) will be generated by these additional investigations 
For analyses of endogenous substances that are substrates of membranous 
transportproteins or substrates or products of enzymes or that could othe1wise 
possibly se1ve as potential indicators for the activity of membranous transport 
proteins or enzymes 
Results of fm1her investigations are not planned to be part of the trial repo11; however, results 
of further investigations may be pa11 of the trial repo1t, if required. 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 
BIOBANKING 
Not applicable. 
5.5 
OTHER ASSESSMENTS 
There will be a single blood draw for the liquid biopsy analysis and protein binding of 
selected cocktail components. 
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5.6 
APPROPRIATENESS OF MEASUREMENT 
All measurements perfo1med during this trial are standard measurements and will be 
perfo1med to monitor subjects' safety and to dete1mine phaimacokinetic pai·ameters in an 
appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laborat01y values, and ECG parameters that might occur because of 
administration of trial medication. The safety assessments ai·e standard, are accepted for 
evaluation of safety and tolerability of an orally administered diug and are widely used in 
clinical trials. The pham1acokinetic parameters and measurements outlined in section 5.3.1 
are generally used assessments of diug exposure. The biomai·kers outlined in sections 5.3.3 
and other assessments outlined in section 5.5 ai·e of explorato1y nature only. 
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6. INVESTIGATIONAL PLAN
In the event of force majeure or other disruptive circumstances (e.g., pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. If 
alternative methodology is implemented, the deviations from the original plan will be 
precisely documented.
6.1
VISIT SCHEDULE
Written informed consent must be obtained before any protocol specific screening 
assessments are performed. Informed consent may be signed by the patient prior to the 
screening visits. All study visits should be performed according to the acceptable time 
windows for screening until the end of trial examination provided in the flow chart. Exact 
times of measurements outside the permitted time windows will be documented.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration are to be performed and completed like indicated in the flow chart.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests 
will be ± 15 min.
If several activities are scheduled at the same time point, ECG should be the first and meal 
the last activity. Furthermore, if several measurements including venipuncture are scheduled 
for the same time, venipuncture should be the last of the measurements due to its 
inconvenience to the subject and possible influence on physiological parameters.
For planned 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.
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.
The screening visit includes the following procedures:
-
Physical examination (see section 5.2.1)
-
Examination of vital signs; BP & PR (see section 5.2.2)
-
Blood draw for safety laboratory tests including a test for viral/bacterial infections, a 
breath alcohol test (see section 5.2.3)
-
A urine sample for safety measurmensts, the drug screening and pregnancy testing in 
females (see section 5.2.3)
-
Twelve-lead resting ECG (see section 5.2.4)
-
Medical examination (see section 5.2.5)

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6.2.2
Treatment period(s)
Each subject is expected to participate only once in the study. In the evening of Day -1, study 
participants will be admitted to the trial site and kept under close medical surveillance for at 
least 24 hours following cocktail administration. The subjects will then be allowed to leave 
the trial site after formal assessment and confirmation of their fitness.
Note: COVID-19 testing will be performed one day before treatment at admission to the trial 
site. In case of a confirmed infection, subjects will not be treated.
For details on time points and collection of blood and urine samples for PK and biomarkers
refer to the flow chart and section 5.3.
The safety measurements performed during the treatment period are specified in the flow 
chart and section 5.2.3.
Additionally, there will be a single blood draw for the liquid biopsy and for the protein 
binding analysis of selected cocktail components before cocktail administration.
AEs and concomitant therapy will be assessed continuously from screening until the EoT 
visit but will specifically asked for at the timepoints specified in the flow chart.
For details on all other trial procedures, refer to the corresponding sections in the protocol
and the flow chart. For restrictions regarding concomitant therapy, diet and lifestyle during 
the treatment period refer to section 4.4.2.
6.2.3
Follow-up period and trial completion (EoT visit)
There will be two follow-up visits after release from the study site.
Follow-up visit 1 includes the following procedures:
-
Physical examination (see section 5.2.1)
-
Examination of vital signs; BP & PR (see section 5.2.2)
-
Blood draw for safety laboratory (see section 5.2.3)
The EoT visit includes the following procedures:
-
Physical examination (see section 5.2.1)
-
Examination of vital signs; BP & PR (see section 5.2.2)
-
Blood draw for safety laboratory (see section 5.2.3)
-
A urine sample for safety measurments and pregnancy testing in females (see 
section 5.2.3)
-
Twelve-lead resting ECG (see section 5.2.4)
AEs and concomitant therapy will be assessed continuously from screening until the EoT 
visit but will specifically asked for at the timepoints specified in the flow chart. 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 EoT 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
The main objective of this trial is to investigate the pharmacokinetics of digoxin, furosemide, 
metformin and rosuvastatin given as a cocktail following oral administration based on the 
primary pharmacokinetic endpoints, as listed in sections 2.2 and section 2.3. The trial is 
designed to allow comparisons between compensated and decompensated F4 graded liver 
fibrosis (cirrhosis) patients (Child-Pugh A and Child-Pugh B) versus healthy subjects 
(reference) and will be evaluated statistically by use of a linear model for logarithmically 
transformed PK endpoints.
A further objective is to evaluate and compare further pharmacokinetic parameters between 
the treatments. These pharmacokinetic parameters will be assessed by descriptive statistics.
Biomarker endpoints will be analyzed by descriptive statistics.
The assessment of safety and tolerability is a further objective of this trial and will be 
evaluated by descriptive statistics for the parameters specified in section 2.2.
7.1
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in a confirmatory sense.
The relative bioavailability of rosuvastatin, digoxin, metformin, and furosemide in
compensated and decompensated F4 liver cirrhosis patients (Child-Pugh A and Child-Pugh 
B) compared with healthy subjects (reference) will be estimated by the ratios of the geometric 
means (test/reference) for all 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 focus is on estimation and not testing, 
a formal hypothesis test and associated acceptance range is not specified.
7.2
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets
-
Enrolled set (ES): This subject set includes all subjects having signed informed 
consent and who were screened for inclusion into the study. The enrolled set will be 
used for analyses of subject disposition.
-
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 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’).
Descriptive and model-based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviations
(iPD) categories will be suggested in the Trial Statistical Analysis Plan (TSAP); iPDs will be 

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identified no later than in the Report Planning Meeting, and iPD categories will be updated as 
needed.
Pharmacokinetics
The pharmacokinetic parameters listed in sections 2.2 and sections 2.3 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 or 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)
-
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).
Biomarkers
Exploratory biomarker endpoints of a subject will be included in the statistical biomarker 
analyses if the are not flagged for exclusion due to a protocol deviation relevant to the 
evaluation of biomarkers (to be decided no later than in the Blinded Report Planning 
Meeting). Exclusion of a subject’s data will be documented in the CTR
Relevant protocol deviations may be incorrect dose of trial medication taken or use of 
restricted medications
7.2.1
Handling of Intercurrent Events
No intercurrent events are defined in this part of the trial.
7.2.2
Primary objective analyses
Primary analyses
The primary endpoints as specified in section 2.2 will be calculated according to the BI 
Standard Operating Procedure(SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). 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 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: ‘group’, age, and BMI. All effects
will be considered as fixed. The model is described by the following equation:
ykm = + k + agem + BMIm + ekm, where
-
ykm = logarithm of response measured on subject m receiving treatment k,
-
= the overall mean,
-
k = the kth group effect, i.e. degree of hepatic impairment, k = 1 for healthy/normal 
(Group 1), 2 for Group 2 or 3 for Group 3 respectively,
-
agem = the age of the subject m,
-
BMIm = the BMI of the subject m,
-
ekm = the random error associated with the kth group effect for subject m 
-
where e ~ N	0, σ
 i.i.d,
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see section 2.2) 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 backtransformed to the original scale to provide the point estimate and 90 % CIs for 
each endpoint.
Further exploratory analyses
In addition to the model-based approach all parameters will be calculated and analysed 
descriptively.
7.2.2.1
Sensitivity Analyses
Not applicable.
7.2.2.2
Subgroup Analyses
Not applicable.
7.2.2.3
Supplementary Analyses
Not applicable.
7.2.3
Secondary objective analyses
Not applicable.

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7.2.4
Further objective analyses
7.2.4.1
Pharmacokinetic analyses
Further PK endpoints will be analysed descriptively.
7.2.4.2
Biomarker analyses
Biomarker endpoints will be analysed descriptively. The same statistical model as stated in
section 7.2.2 will be done for further PK endpoints. In addition to the model-based approach 
all parameters will be calculafted and analysed descriptively.
7.2.4.3
Analysis for liquid biopsy
If data allows correlation between CL/F of cocktail components and mRNA or protein 
expression of respective PK protein in small extravellular vesicle in plasma will be explored
outside of this report.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 10 days after trial
medication intake, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e., all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the trial and at the end-of-trial evaluation will be assessed with regard to 
possible changes compared to findings before start of treatment.

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7.2.6
Other Analyses
No other analyses are planned.
7.2.7
Interim Analyses
No interim analysis planned
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planeed to impute missing values for safety parameters.
7.3.2
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.
7.4
RANDOMISATION
This is a non-randomised trial.
7.5
DETERMINATION OF SAMPLE SIZE
No official sample size will be conducted. This is an exploratory study, following numbers of 
subjects in each of the defined groups:
-
Healthy subjects
Group 1: 12 healthy subjects
-
Liver cirrhosis patients
Group 2: 12 F4 Child-Turcotte-Pugh class A (Child-Pugh A) subjects (compensated)
Group 3: 06 F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (decompensated)
is fit for purpose.

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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 directive 
2001/20/EC/EU regulation 536/2014 and other relevant regulations. Investigators and site 
staff must adhere to these principles. Deviation from the protocol, the principles of ICH GCP 
or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor or delegate immediately of any urgent safety 
measures taken to protect the trial patients 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. The rights of the investigator and of the sponsor 
about publication of the results of this trial are described in the investigator contract. As a 
rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients and is 
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT 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 patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent, and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or his 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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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 or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, 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. There is no need for rules about 
emergency code breaks (see section 4.3.2). For drug accountability, refer to section 4.3.5.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. 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.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Before providing any copies of source documents to the Sponsor or designee the investigator 
must ensure that all patient identifiers (e.g., patient’s name, initials, address, phone number, 
social security number etc) have properly been removed or redacted from any copy of the 
patients’ source documents.
If the patient is not compliant with the protocol, any corrective action e.g., re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

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-
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)
-
Patient participation in the trial (substance, trial number, patient number, date patient
was informed)
-
Dates of patient’s visits, including dispensing of trial medication
-
Medical history (including trial indication and concomitant diseases, if applicable)
-
Medication history
-
Adverse events and outcome events (onset date (mandatory), and end date (if 
available))
-
Serious adverse events (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)
-
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
-
Prior to allocation of a patient to a treatment into 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 patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
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 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must always be available for review by the CRA, 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 described in section 8.3.1. The 
sponsor or delegate will also monitor compliance with the protocol and GCP.
In the event of force majeure or other disrupting circumstances (e.g., pandemic, war), site 
access may be restricted, thus limiting the ability to perform standard site monitoring 
activities on site such as on-site source data review and source data verification. Therefore, 
some of these activities may be performed remotely or replaced by centralized monitoring to 
the extent possible, based on a documented risk assessment and in alignment with local 
regulations.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.

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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 PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook. 
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a patient identification number instead of the patient’s 
name. The code is only available at the site and must not be forwarded to the sponsor. In case 
patient’s records will be forwarded e.g., for SAE processing or adjudication committees, 
personal data that can identify the patient will be redacted by the site prior to forwarding. 
Access to the patient files and clinical data is strictly limited: personalised treatment data may 
be given to the patient’s personal physician or to other appropriate medical personnel 
responsible for the patient’s welfare. Data generated 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.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs/IECs and patients will 
be informed as appropriate.
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 and future use of 
biological samples and clinical data, in particular:
-
Sample and data usage must be in accordance with the informed consent
-
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external 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 when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely). Individual investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to 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 IEC/competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data 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 CRS 
Clinical Research Services Mannheim GmbH (Grenadierstr. 1, 68167 Mannheim) 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. The trial will be 
performed in accordance with applicable regulations and BI SOPs together with a Contract 
Research Organisation (CRO) based on a contract. The CRO will perform project 
management, clinical field monitoring, medical monitoring, and reporting. A central 
laboratory service and a local safety laboratory will be used in this trial. Details will be 
provided in the Central Laboratory Manual, available in the ISF.
BI has appointed a Clinical Trial Leader (CTL), responsible for coordinating all required trial 
activities, to:
-
Manage the trial in accordance with applicable regulations and internal SOPs
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Direct the clinical trial team in the preparation, conduct, and reporting of the trial
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Ensure appropriate training and information of CRAs, and investigators of the 
participating trial site

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Tasks and functions assigned to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local infonnation can be 
found in the ISF. 
Data Management and Statistical Evaluation will be done by BI according to BI SOPs. 
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9. REFERENCES
9.1
PUBLISHED REFERENCES
P09-01856
Fenner KS, Troutman MD, et al. 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.
P11-01873
Graham GG, Punt J, et al. Clinical pharmacokinetics of metformin, Clin 
Pharmacokinet 2011; 50(2); 81-98.
P14-07656
Mueller F, Fromm MF. Transporter-mediated drug-drug interactions. 
Pharmacogenomics 2011;12(7):1017-1037.
P14-07833
Neuvonen PJ, Backman JT, et al. 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.
R07-4702
Kovarik JM, Rigaudy L, et al. Longitudinal assessment of a P-glycoprotein-
mediated drug interaction of valspodar on digoxin. Clin Pharmacol Ther 
1999; 66(4); 391-400.
R10-1157
International Transporter Consortium. Membrane transporters in drug 
development. Nat Rev Drug Discov 2010; 9:215-236.
R12-1392
Levey AS, Stevens LA, et al. Chronic Kidney Disease Epidemiology, A 
new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 
150(9); 604-612.
R13-4572
Cooper KJ, Martin PD, et al. Effect of itraconazole on the pharmacokinetics 
of rosuvastatin. Clin Pharmacol Ther 2003;73(4):322-329.
R14-0150
Hardwick RN, Ferreira DW, et al. Altered UDP-Glucuronosyltransferase 
and Sulfotransferase Expression and Function during Progressive Stages of 
Human Nonalcoholic Fatty Liver Disease. Cherrington Drug Metab Dispos 
41:554–561, March 2013
R15-4771
Prueksaritanont T, Chu X, et al. 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.
R17-0548
Stopfer P, Giessmann T, et al. Pharmacokinetic evaluation of a drug 
transporter cocktail consisting of digoxin, furosemide, metformin and 
rosuvastatin. 2016
R17-1790
Lai Y, Mandlekar S, 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.
R17-1846
Cohen E, Almog S, et al. Do therapeutic doses of acarbose alter the 
pharmacokinetics of digoxin? Isr Med Assoc J 2002;4(10):772-775.

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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, et al. 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, et al. 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, et al. Preliminary evaluation of furosemide-probenecid 
interaction in humans. J Pharm Sci 1980;69(5):571-575.
R18-0240
Stopfer P, Giessmann T, et al. Effects of metformin and furosemide on 
rosuvastatin pharmacokinetics in healthy volunteers: implications for their 
use as probe drugs in a transporter cocktail. Juli 2017
R20-1915
Stopfer P, Giessmann T, et al. Optimization of a drug transporter probe 
cocktail: potential screening tool for transporter-mediated drug-drug 
interactions. 2018
R20-1930
Wiebe ST, Giessmann T, et al. Validation of a drug transporter probe 
cocktail using the prototypical inhibitors rifampin, probenecid, verapamil, 
and cimetidine. 2020
R20-2271
U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER). Clinical 
Drug Interaction Studies_Cytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions_Guidance for Industry; 
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-
transporter-mediated-drug-interactions (January 2020); U.S. Department of 
Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER)
R22-3889 
Ali I, Slizgi JR, et al. Transporter-Mediated Alterations in Patients With 
NASH Increase Systemic and Hepatic Exposure to an OATP and MRP2 
Substrate Clinical Pharmacology & Therapeutics, Vol 104 No 4, Oct 2018
R22-3890 
Canet MJ, Merrell MD, et al. Altered Regulation of Hepatic Efflux 
Transporters Disrupts Acetaminophen Disposition in Pediatric 
Nonalcoholic Steatohepatitis. Drug Metab Dispos 43:829–835, June 2015
R22-3891 
Thakkar N, Slizgil JR, et al. Effect of Liver Disease on Hepatic Transporter 
Expression and Function. J Pharm Sci. 2017 September; 106(9): 2282–
2294. 
R22-3893
Anna Vildhede A, Kimoto E, et al. Quantitative Proteomics and 
Mechanistic Modeling of Transporter-Mediated Disposition in 
Nonalcoholic Fatty Liver Disease. Clinical Pharmacology & Therapeutics, 
Vol 107 No 5, May 2020
R22-4020
Fachinformation Lasix Liquidum 10mg/mL Lösung (2022)
R22-4021
Fachinformation MetfoLiquid GeriaSan® 1000mg/5mL Lösung (2022)
R22-4022
Fachinformation Crestor® 10mg Filmtabletten (2022)
R22-4044
Fachinformation Lanicor® 0,25mg Digoxin Tablette (2018)

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R99-0743 
■ 
Somogyi A, Stockley C, et al. Reduction of metfonnin renal tubular 
secretion by cimetidine in man. Br J Clin Phaimacol 1987; 23:545-551. 
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10. APPENDICES 
10.1 TIME SCHEDULE FOR PK- AND BIOlVIARKER SAMPLING (BLOOD AND 
URINE) 
Table 10.1: 1 Timescheduleforbloodsampling 
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Table 10.1: 2 Time schedule for urine sampling 
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10.2 COVID-19 RISK ASSESSMENT 
Potential risks for trial participants due to the COVID-19 pandemic have been evaluated. The 
modes of action, available phatmacological, non-clinical and clinical data do not indicate an 
increased risk of contracting SARS-Co V-2 or aggravated clinical courses due to the treatment 
with the "cocktail". However, participants with active SARS-CoV-2 infection (e.g., 
confumed by the COVID-19 rapid test performed at admission to hi.al site or confumed by 
PCR test before) will be excluded from the trial. 
COVID-19 testing will be perfo1med one day before treatment at admission to the trial site. 
In case of a confinned infection, subjects will not be treated. During a period of an increased 
risk of SARS-CoV-2 infection, the EoT visit may be replaced with a remote visit to reduce 
the risk of contracting SARS-CoV-2 during travel or at the trial site. Procedures (including 
lab testing) will be perfonned at the paiticipant's home to the extent possible. 
In this Phase I setting, subjects stay in-house in small groups and there is a potential risk for 
spreading the SARS-CoV-2 across the subject group or site staff. Some trial procedures, e.g., 
collecting blood samples, recording of ECG, or assessing vital signs, may not allow keeping 
the recormnended distance of 1.5 to 2 meters to prevent the transmission of SARS-CoV-2. 
Risk mitigation: 
A risk management plan has been set up at the clinical site detailing specific 
precautionary measures, e.g., hygiene mles, wearing of face masks, and physical 
distancing 
SARS-CoV-2 testing (COVID-19 rapid test) will be perfonned one day before 
treatment at admissiou to the n·ial site. Pa1ticipants positive iu the SARS-CoV-2 test are 
not eligible and will be excluded from the trial. If a test perfonned due to developed 
symptoms is positive on day 1, the patient cannot continue to participate in the trial and 
will be discharged from the st11dy center. 
Any pa1ticipant with suspected or diagnosed COVID-19 will be referred to health care 
professionals in charge to receive n·eatment according to standard of care 
Based on these considerations, the benefit/risk assessment for the adminisn·ation of the 
"cock.iail" remains unaltered despite the COVID-19 pandemic. 
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