Profiling Study for the Hepatic Cytochrome P450 (CYP) Isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A in Healthy Subjects and in Patients With Stage 4 (F4) Liver Fibrosis / Cirrhosis by the Combined Administration of the Probe Substrates (the Cocktail) Caffeine, Warfarin, Omeprazole, Metoprolol, and Midazolam
Phase: NA
Conditions: Liver Cirrhosis
Sponsor: Boehringer Ingelheim

Boehringer 
lngelheim 
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 
c38905324-02 
2022-003668-26 
0352-2190 
NA 
Profiling study for the hepatic cytochrome P450 (CYP) isozymes 
CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A in healthy 
subjects and in patients with stage 4 (F4) liver fibrosis / cinhosis 
by the combined administration of the probe substrates (the 
cocktail) caffeine, warfarin, omeprazole, metoprolol, and 
midazolam 
A study to compare how different substances (caffeine, warfarin, 
omeprazole, metoprolol, and midazolam) are handled by the body 
of healthy people and people with liver cin-hosis 
NA 
Version 2.0, 24-Feb-2023 
Version 1.0, 07-Dec-2022 
Page 1 of 76 
Proprietary confidential information. 
2023 Boehtinge1· Ingelheim International GmbH or one or mo1·e of its affiliated companies. All lights reserved. 
This document may not • in full or in part - be passed on, reproduc-ed, published, or othe1wise used ,vithout prior written 
pemussion. 
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CLINICAL TRIAL PROTOCOL SYNOPSIS 
Company name 
Original Protocol 
date 
Revision date 
BI trial number 
Title of trial 
---------
Principal 
Investigator 
Trial site(s) 
Clinical phase 
Trial rationale 
Trial objective(s) 
Trial endpoints 
Trial design 
Boehringer Ingelheim 
Version 1.0, 06-Dec-2022 
24-Feb-2023 
0352-2190 
Profiling study for the hepatic cytochrome P45O (CYP) isozymes 
CYP1A2, CYP2C9, CYP2Cl9, CYP2D6 and CYP3A in healthy 
subjects and in patients with stage 4 (F4) liver fibrosis / ciIThosis by 
the combined administration of the probe substrates (the cocktail) 
caffeine, warfarin, omeprazole, metoprolol, and midazolam 
NA 
To understand whether liver ciIThosis itself, along with standard of 
care, can result in a change in activity of hepatic cytochrome P450 
(CYP) isozymes CYP1A2, CYP2C9, CYP2C19, CY2D6 and 
CYP3A in patients with F4 graded liver fibrosis / cinhosis compared 
to healthy subjects by using in vivo probe dtugs (the cocktail: 
caffeine, warfarin, omeprazole, metoprolol, and midazolam) 
recommended as sensitive substrates. 
Primaiy objective is to investigate whether the maximum 
concentration (Cmax), the area under the curve (AUCo.24 or AUCo-96) 
values for the different components in the CYP cocktail - caffeine, 
wai-farin, omeprazole, metoprolol, and midazolam (the cocktail) -
are similai· or different in F4 graded liver fibsosis ( ciIThosis) patients 
on standard thera 
com ared to health subjects. 
Primaiy endpoints: 
Cmax and AUCo.24 for caffeine, pai·axanthine, omeprazole, 5'-
hydt·oxyomeprazole, metoprolol, a-hydt·oxymetoprolol, midazolam 
and 1 '-hydroxymidazolam. Cmax and AUCo-96 for R-wai-farin and 
S-warfarin. 
Open label, single dose study 
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Number of patients 
treated 
Number of patients 
er treatment rou 
Diagnosis 
Main inclusion and 
exclusion criteria 
Group 1: NA (healthy subjects) 
Group 2: Patients with compensated liver cinhosis and advanced 
fibrosis grade F4 and hepatic impai.J.ment that meets the 
criteria for Child Pugh A 
Group 3: Patients with decompensated liver 
ci.J.Thosis and advanced fibrosis grade F4 and hepatic 
im ailment that meets the criteria for Child Pu h B 
Inclusion: 
Healthy subjects 
o Healthy male and female subjects accordi.J.1g to the 
assessment of the investigator, as based on a complete 
medical hist01y including a physical examination 
o Age of 18 to 75 years (inclusive) 
o Body mass index (BMI) of 18.5 to 35 kg/m2 (i.J.1clusive) 
Liver ci.J.Thosis patients 
o Male and female patients 
o 
18 to 75 years 
o BMI of 18.5 to 40.0 kg/m2 (inclusive) 
o Inclusion of 
o Patients with compensated liver ci.J.Thosis due to any 
underlying liver disease with advanced fibrosis (F4) and 
hepatic impainnent that meets the criteria for Child-Pugh A 
who are on stable standard of care treatment for at least 
4 weeks prior to study enrolment 
o Patients with decompensated liver ci.J.Thosis due to any 
underlying liver disease with advanced fibrosis (F4) and 
hepatic impai.J.ment that meets the criteria for Child-Pugh B 
who are on stable standard of care treatment for at least 
4 weeks prior to study enrolment 
OR 
OR 
OR 
o Diagnosis of compensated liver cin-hosis/F4 
• 
Historic (within 2 years) histological 
diagnosis of fibrosis stage F4 (NASH-CRN or 
META VIR scoring) 
• 
CmTent or historic increased liver stiffness of 
~ 18 kPa by Fibroscan or 5 kPa by MRE 
• 
CmTent or historic imaging of nodular surface 
with thrombocytopenia < 150/nL 
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
Chronic liver disease with clinical signs of 
portal hypertension (at least one out of the 
following)

Gastroesophageal varices (GEV) stage 
I (small)

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 warfarin, omeprazole, and 
midazolam, metoprolol within 4 weeks of enrolment into the 
study (caffeine: methylxanthine-containing drinks or foods 
such as coffee, tea, cola, energy drinks, or chocolate are not 
allowed within 48h before cocktail administration and during 
the in-house confinement at the trial site)
o
Subjects with any other condition that would preclude 
administration of caffeine, warfarin, omeprazole, metoprolol,
and midazolam (i.e., contraindicated as per Summary of 
Product Characteristics (SmPC)), such as hypersensitivity to 
active ingredient or any of the excipients or to any beta 
receptor blockers
o
Subjects taking medications known to be moderate or strong 
inhibitors of the following CYP enzymes: CYP1A2, 
CYP2C9, CYP2C19, CYP2D6, CYP3A
o
Subjects taking medications known to be moderate or strong 
inducers of the following CYP enzymes: CYP1A2, CYP2C9, 
CYP2C19, CYP2D6, CYP3A
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
Current smokers or ex-smoker who quit smoking less than 30 
days prior to screening examination
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

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o
Gastroesophageal varices (GEV) stage II or more 
(intermediate or large) or portosystemic shunts
o
Laboratory test indicative of an ongoing SARS-CoV-2 
infection
Test product(s) 1
Dose
Mode of 
Administration
Percoffedrinol® N 50 mg Tabletten (tablet strength: 50 mg)
100 mg caffeine (2 tablets) as single dose.
Oral with 240 mL of water after a standardized breakfast
Test product(s) 2
Dose
Mode of 
Administration
Coumadin® 5 mg (tablet strength: 5 mg)
5 mg warfarin sodium (1 tablet) as single dose.
Oral with 240 mL of water after a standardized breakfast
Test product(s) 3
Dose
Mode of 
Administration
Antra MUPS® 20 mg magensaftresistente Tabletten (tablet strength: 
20 mg).
20 mg omeprazole (1 tablet) as single dose.
Oral with 240 mL of water after a standardized breakfast
Test product(s) 4
Dose
Mode of 
Administration
Metoprolol-ratiopharm® 50 mg Tabletten (tablet strength: 50 mg)
50 mg metoprolol (1 tablet) as single dose.
Oral with 240 mL of water after a standardized breakfast
Test product(s) 5
Dose
Mode of 
Administration
Midazolam-ratiopharm® 2 mg/mL orale Lösung (strength: 2 mg/mL)
2 mg midazolam (1 mL) as single dose.
Oral with 240 mL of water after a standardized breakfast
Comparator 
product(s)
NA
Duration of 
treatment
Caffeine, warfarin, omeprazole, metopropol, and midazolam are 
given always together as a cocktail (the cocktail). The cocktail will 
be given as a single dose of 100 mg caffeine, 5 mg warfarin, 20 mg 
omeprazole, 50 mg metoprolol and 2 mg midazolam administered as 
drug cocktail.
Statistical methods
The pharmacokinetics of each of the cocktail components will be 
calculated for caffeine (paraxanthine), R-, and S- warfarin, 
omeprazole (5′‐hydroxyomeprazole), metoprolol, 
α-hydroxymetoprolol, midazolam, and 1′‐hydroxymidazolam, and
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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FLOWCHART 
2 I 
1111 -
1111 -
I Ill• 
1111 -
1111 -----------------------
I 
3
. 
4 I 
Screening1 
... = 
Q; s s 
8 
dmission to trial site 
4 Liver cill'hosis 
atients take their 
1onun medication4 
aseline examinations 
Standardised light 
reakfast5•7•8 
dministration of the 
ocktail6•7 
40 mL fluid intake7 
40 ml fluid intake / 
unch8 
Snack ( optional) 7 
inner7•8 
reakfast8 ( optional) 
nd discharge from 
-ial site 
ollow-up visit 1 
ollow-up visit 2 
nd of trial visit9 
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1) For more details regarding screening procedures 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 ensured 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 urine drug screening (section 5.2.3), and a urine 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 performed according to section 5.2.5
2) Safety laboratory testing includes a urine sample for a drug screening, urinalysis (Stix), urine sediment and urine 
creatinine and an urine pregnancy test for females at this timepoint (section 5.2.3)
3) Safety laboratory testing includes only a breath alcohol test, a COVID-19 rapid test (section 10.2) and a urine sample for 
a drug screening and urine pregnancy test for females (section 5.2.3).
4) Date, time, and dose of concomitant medication as well as the brand names must be documented
5) A standardized light breakfast (see section 4.3.1) will be served 1 h 30 min before the cocktail is administered
6) For more information regarding drug administration see section 4.3.1
7) From 1 h before drug intake until lunch, fluid intake is restricted to the water administered with the cocktail and an 
additional 240 mL of water at 2 h and 4 h after cocktail administration (mandatory). From lunch until 24 h post-dose 
fluid is restricted to 3000 mL (see section 4.4.2.2)
8) Meals will be given after all other procedures have been conducted
9) 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 
count and blood chemistry consists of a urine 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. Sample collection or measurements can be performed ± 15 min
b) 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 only be performed 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
d) A full physical examination is only needed if the subject reports any abnormalities or other health related changes since 
the last visit (see section 5.2.1)
e)
Additional administration of vitamin K to all patients with liver cirrhosis should be considered by the study physician

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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...............................................................................................15
1.1
MEDICAL BACKGROUND.............................................................................15
1.2
DRUG PROFILE................................................................................................16
1.2.1
Caffeine ................................................................................................................17
1.2.2
Warfarin ..............................................................................................................17
1.2.3
Omeprazole..........................................................................................................18
1.2.4
Metoprolol............................................................................................................18
1.2.5
Midazolam ...........................................................................................................19
1.2.6
Residual Effect Period ........................................................................................19
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................19
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
1.4.1
Benefits.................................................................................................................20
1.4.2
Risks .....................................................................................................................20
1.4.2.1
Procedure-related risks..........................................................................................20
1.4.2.2
Drug-related risks and safety measures ................................................................20
1.4.2.3
Drug-induced liver injury......................................................................................21
1.4.2.4
Safety measures.....................................................................................................21
1.4.2.5
Overall assessment................................................................................................21
1.4.2.6
Coronavirus Disease 2019 ....................................................................................22
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................23
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........23
2.1.1
Main objectives....................................................................................................23
2.2
MAIN ENDPOINTS ...........................................................................................23
2.3
PROPOSED FURTHER ENDPOINTS............................................................23
2.3.1
Biomarkers ..........................................................................................................24
2.3.1.1
Liquid biopsy, pharmacogenetic profiling and protein binding of selected cocktail 
components ...........................................................................................................24
2.3.1.2
Markers of functional impairment in hepatobiliary metabolism and transport ....24
2.3.2
Safety endpoints:.................................................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................25
3.1
OVERALL TRIAL DESIGN.............................................................................25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................26
3.3
SELECTION OF TRIAL POPULATION .......................................................26
3.3.1
Main diagnosis for trial entry ............................................................................26
3.3.2
Inclusion criteria .................................................................................................27

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3.3.3
Exclusion criteria ................................................................................................29
3.4
DISCONTINUATION OF SUBJECTS FROM TREATMENT OR 
ASSESSMENTS..................................................................................................32
3.4.1
Discontinuation of trial treatment.....................................................................32
3.4.2
Withdrawal of consent to trial participation....................................................32
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
MODIFICATIONS.............................................................................................35
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.............................................................................................37
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 ..............................................................................................41
5.2.5
Medical examination...........................................................................................42
5.2.6
Assessment of AEs...............................................................................................42
5.2.6.1
Definitions of AE..................................................................................................42
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
5.3.2
Analytical determinations of pharmacokinetics...............................................48
5.3.2.1
Analytical determination of analyte plasma concentration...................................48
5.3.3
Further investigations.........................................................................................48
5.4
BIOBANKING ....................................................................................................49
5.5
OTHER ASSESSMENTS...................................................................................49
-

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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 
7.2.5 
7.2.6 
7.2.7 
7.3 
7.3.1 
7.3.2 
7.4 
7.5 
8. 
8.1 
8.2 
8.3 
8.3.1 
8.3.2 
8.3.3 
8.4 
8.5 
8.5.1 
APPROPRIATENESS OF MEASUREMENT ................................................ 51 
INVESTIGATIONAL PLAN ............................................................................. 52 
VISIT SCHEDULE ............................................................................................. 52 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................. 52 
Screening .............................................................................................................. 52 
Treatment period(s) ............................................................................................ 53 
Follow-up period and trial completion (Eo T visit) .......................................... 54 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE ...................................................................................................................... 55 
NULL AND ALTERNATIVE HYPOTHESES ............................................... 55 
PLANNED ANALYSES ..................................................................................... 55 
Handling of Intercurrent Events ....................................................................... 56 
Primary objective analyses ................................................................................. 56 
Sensitivity Analyses .............................................................................................. 57 
Subgroup Analyses ............................................................................................... 57 
Supplementa1y Analyses ....................................................................................... 57 
Secondary objective analyses ............................................................................. 57 
Further objective analyses .................................................................................. 57 
Pha11nacokinetic analyses ..................................................................................... 57 
Analysis for liquid biopsy ..................................................................................... 58 
Safety analyses ..................................................................................................... 58 
Other Analyses .................................................................................................... 58 
Interim Analyses ................................................................................................. 58 
HANDLING OF MISSING DATA ................................................................... 59 
Safety .................................................................................................................... 59 
Pharmacokinetics ................................................................................................ 59 
RANDO MISA TIO N ........................................................................................... 59 
DETERMINATION OF SAMPLE SIZE ......................................................... 59 
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........ 60 
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ........................................................................................................... 60 
DATA QUALITY ASSURANCE ...................................................................... 61 
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 
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8.6
TRIAL MILESTONES.......................................................................................64
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................64
9.
REFERENCES....................................................................................................66
9.1
PUBLISHED REFERENCES............................................................................66
9.2
UNPUBLISHED REFERENCES......................................................................68
10.
APPENDICES.....................................................................................................69
10.2
COVID-19 RISK ASSESSMENT......................................................................70
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................71
11.1
GLOBAL AMENDMENT 1 ..............................................................................71
-

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ABBREVIATIONS AND DEFINITIONS
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
BI
Boehringer Ingelheim
BMI
Body Mass Index
BP
Blood Pressure 
CA
Competent Authority
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
Cmin
Minimum Plasma Concentration
COVID-19
Coronavirus disease 2019
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
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

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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
HV
Healthy Volunteers
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
K-EDTA
Potassium Ethylenediaminetetraacetic Acid
LC-MS/MS
liquid chromatography tandem mass spectrometry
LGL syndrome
Lown Ganong Levine symdrome
LPLT
Last patient last treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
MR
Metabolic ratio
MRE
Magnetic Resonance Elastography
NASH
Non-Alcoholic SteatoHepatitis
OPU
Operative Unit
P-gp
P-glycoprotein
PK
Pharmacokinetics
PR
Pulse Rate
q.d.
quaque die (once a day)
RA
Regulatory Authority

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REP
Residual effect period
RNA
Ribo-Nucleic Acid
SAE
Serious Adverse Event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC
Steering Committee
SMC
Safety Monitoring Committee
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SAR
Serious Adverse Reactions
SUSAR
Suspected Unexpected Serious Adverse Reactions
tmax
Timepoint of maximum plasma concentration
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
t1/2
Half life
ULN
Upper limit of normal
WHO
World Health Organisation

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1. 
INTRODUCTION 
The trial will be perfonned to assess the influence of very advanced chronic liver disease 
(liver cinhosis) on the pha1macokinetics of caffeine (CYP1A2 probe drug), S-warfarin 
(CYP2C9 probe diug), omeprazole (CYP2C19 probe di11g), metoprolol (CYP2D6) and 
midazolam (CYP3A probe diug). 
The cunent 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: 06 F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (decompensated) 
Since this is a single dose explorato1y study, no clinical benefit will be obtained by the 
patients from the cmTent treatment. 
1.1 
MEDICAL BACKGROUND 
Impaired liver function can alter the kinetics of diugs substantially. Drug exposure is mostly 
increased in patients with liver cinhosis which possibly could lead to toxicity if exposmes are 
increased. Franz et al. assessed in 2013 in a retrospective study of 400 cinhotic patients the 
prevalence of inadequately dosed diugs and associated adverse di11g reactions as well as 
hospitalizations. Of all diugs prescribed, around 20 % were inconect in dosing and led to 210 
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adverse drng reactions and 24 hospitalisations. These data cleaiy shows the necessity of 
e impact 
on drng elimination by CYP isozymes was often shown to be quite different and dependent 
on the diug, the severity of the liver disease and CYP isozyme genotypes [R22-3873, R22-
3874]. Therefore, interpretation of data from clinical trials must always take in consideration 
that metabolism of the same di11g in a different patient population can differ significantly. 
The impact on individual CYP isozyme activities by different stages of different liver 
diseases in humans has not been thoroughly examined. Investigating the activity of CYP 
isozymes in patients with liver cinhosis in the compensated and decomensated sta es Child-
Puoh A and Child-Pu 
B res ectivel 
is therefore of im ortai1t value. 
valuable approach to investigate the metabolic activity of several CYP isozymes is within the 
"cocktail study". This method, in which a mixture of well-characterized probe di11gs is 
administered, is well established for investigating the metabolic activities of CYP isozymes. 
Both the European Medicines Agency (EMA) and the Food and Drng Administration (FDA) 
recommend the use of cocktail studies [P 15-06991], [R20-2271]. 
1.2 
DRUG PROFILE 
The activity of the CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A in 
both liver cinhosis patients and healthy subjects will be investigated by the combined 
administration of caffeine, wai-farin, omeprazole, metoprolol, and midazolam (Sanofi-Aventis 
cocktail [P 10-00100]). 
All the substances of the Sanofi-Aventis cocktail are approved diugs. For side effects and 
fmther details, please refer to the summaries of product characteristics of caffeine 
[R14-3265l, wai-farin [R22-4030], omeprazole [R22-4032), metoprolol [R22-4044], and 
midazolam [R22-4031]. A validation study has confnmed that the probe substrates of the 
Sanofi-Aventis cocktail ai·e safe and do not interact with each other when used in 
combination [Pl0-00100]. The Sanofi-Aventis cocktail was designed to overcome potential 
disadvantages of other four- and five-probe cocktails [P04-02457). hi comparison with the 
well-known 'Cooperstown 5+ 1 cocktail' [P03-09924], intravenous midazolam was replaced 
by oral midazolam in order to reflect combined CYP3A activity in the intestine and liver, and 
dextromethorphan was substituted by metoprolol which appears to be a better CYP2D6 probe 
substrate with less intra-individual vai·iability. Furthermore, the omeprazole dose could be 
reduced from 40 mg to 20 mg, and in contrast to mandato1y co-administration of vitamin Kl, 
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the investigator has now the responsibility to monitor the necessity of administering the 
warfarin antidote, and midazolam is used.
1.2.1
Caffeine
Caffeine is the most-commonly used substance for CYP1A2 phenotyping. The first step in its
metabolism is almost exclusively mediated by CYP1A2. Orally administered caffeine is well
absorbed by the small intestine within 45 min of ingestion, and then distributed throughout all 
tissues of the body. Peak blood concentrations are reached within 1 to 2 hours. Its volume of 
distribution is 0.52 to 1.06 L/kg. It has been shown that CYP1A2-mediated caffeine clearance 
accounts for more than 95 % of overall caffeine elimination from plasma. In healthy adults, 
the elimination half-life of caffeine is 4 to 5 h. Caffeine and its metabolites are predominantly 
eliminated by renal excretion [P05-10983, R06-0327, R14-3265].
The dose of 100 mg used in this study is a therapeutic dose. A single dose is not expected to 
have significant side effects in healthy volunteers. In patients with liver cirrhosis, a warning 
is included in the label about potential of accumulation, which is not applicable for a single 
dose application. Caffein has a potential for interaction with several drugs and drug classes; 
none of them is part of the usual therapy for patients with cirrhosis. For a complete listing of 
adverse reactions, including frequency of occurrence, please refer to the current Summary of 
Product Characteristics (SmPC) [R14-3265].
1.2.2
Warfarin
Warfarin sodium is an anticoagulant which acts by inhibiting vitamin K-dependent 
coagulation factors [R22-4030]. Warfarin sodium is completely absorbed after oral 
administration with the peak concentration attained within the first 4. Its volume of 
distribution is 0.12 L/kg. Orally administered warfarin sodium is a racemic mixture of the R-
and S-enantiomers. The half-life of R-warfarin sodium ranges from 37 to 89 h, while that of 
S-warfarin sodium ranges from 21 to 43 h. Approximately 80 to 85 % of S-warfarin 
elimination occurs through 6- or 7-hydroxylation via CYP2C9. 
Thus, the PK of S-warfarin is used to quantify real-time CYP2C9 activity [R98-2274]. The 
anticoagulant effect generally starts within after drug administration. However, peak 
anticoagulant effect may occur between 72 to 96 h. The duration of action of a single dose of 
racemic warfarin is 2 to 5 days [R22-4030].
The dose of 5 mg used in this study is a recommended starting dose when treatment with 
warfarin is needed. It is not expected that a single dose will cause major bleeding in healthy 
volunteers. In patients with impaired liver function, the activity of warfarin may be increased.
To minimize the risk in the patients with cirrhoisis in this study, patients with decompensated 
cirrhosis Child-Pugh C stage are excluded. Subjects at increased risk of bleeding are not 
allowed to participate in the study. The intake of antiaggregants or anticoagilants is not 
allowed. Patients with INR > 2.2 are excluded from the study. In case of bleeding, vitamine K 
will be applied by the investigator (see section 6.2.2). Many drugs may influence the effect of 
warfarin. However, in a single dose administration of warfarin, it is not expected that the 

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potentially increased exposure would lead to major bleeding; the effect of warfarin to reduce 
the coagulation is not direct. For a complete listing of adverse reactions, including frequency 
of occurrence, please refer to the current Summary of Product Characteristics (SmPC) [R22-
4030].
1.2.3
Omeprazole
Omeprazole is a proton pump inhibitor applied to treat ulcers, heartburn, gastroesophageal 
reflux, and Zollinger-Ellison syndrome [R22-4032]. The formation of 5-hydroxyomeprazole,
the major primary metabolite of omeprazole, is dependent on CYP2C19 activity. In addition,
omeprazole is metabolised by CYP3A to omeprazole sulphone. Since the affinity of
omeprazole to CYP2C19 is 10 times higher than to CYP3A, omeprazole interferes with the
metabolism of substrates for CYP2C19 but not of substrates for CYP3A [P96-3991].
Omeprazole has a small volume of distribution (0.3 L/kg). The plasma half-life is less than 
1 h. Plasma clearance was determined to be 0.3 to 0.6 L/min.
The dose of 20 mg used in this study is a therapeutic dose. A single dose is not expected to 
have significant side effects in healthy volunteers. Proton pump inhibitors are often used in 
patients with cirrhosis. The dose used in this study is within the recommended dose for 
patients with impaired liver function. A single dose is not expected to have significant side 
effects. In patients with cirrhosis already taking another proton pump inhibitor, a single dose 
of omeprazole is not expected to cause clinically significant overdose: proton pump inhibitors 
have a high therapeutic index. For a complete listing of adverse reactions, including 
frequency of occurrence, please refer to the current Summary of Product Characteristics 
(SmPC) [R22-4032].
1.2.4
Metoprolol
Metoprolol is a moderate sensitive substrate for CYP2D6. Hemeryck et al reported the 
administration of single doses of 100 mg metoprolol before and after paroxetine treatment
[R09-0632]. Paroxetine, a recommended inhibitor of CYP2D6, caused a 5-fold and 8-fold 
increase of S-metoprolol and R-metoprolol AUC (Cmax increased approximately 2-fold). The 
reported side effects were mild to moderate.
In this trial only 50 mg of metoprolol is given, which is half of the dose administered in the 
paroxetine study. It is not expected that 50 mg will have a significant clinical effect on 
healthy volunteers. Lower dose is recommended in patients with severe liver function 
impairment; in this study, patients with cirrhosis Child-Pugh C stage are excluded. Beta-
blockers may be part of the standard of care of some patients. To reduce the risk of side 
effects of the beta-blockers, patients with bradycardia, low blood pressure or heart conduction 
disorders are excluded from this study. For a complete listing of adverse reactions, including 
frequency of occurrence, please refer to the current Summary of Product Characteristics 
(SmPC) [R22-4044].

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1.2.5 
Midazolam 
Midazolam is a short acting benzodiazepine which is used for the treatment of insomnia and 
as sedative premedication before surgical or diagnostic procedmes. It has a volume of 
distribution of 0.7 to 1.2 L/kg at steady state. Its elimination half-life in young healthy 
volunteers ranges from 1.5 to 2.5 h. The plasma clearance was detennined to be 300 to 
500 L/min. Midazolam is almost eliminated by biotransfom1ation to 1-hyclroxymidazolam 
and this process is mediated by CYP3A enzymes [R22-4031]. In contrast to testosterone or 
erythromycin, which have also been proposed as probes to monitor CYP3A activity, 
midazolam is metabolised specifically by CYP3A and does not serve as a substrate for other 
CYP450 isoenzymes or the dtug transporter P-glycoprotein (P-gp). Intravenous midazolam is 
a sensitive in vivo probe of hepatic CYP3A activity, whereas orally adtninistered midazolam 
is metabolised by both, intestinal and hepatic CYP3A. 
The dose of 2 mg used in this study is below the therapeutic dose. A single dose is not 
expected to have significant effects in healthy volunteers. In patients with cirrhosis, the 
elimination may be increased. It is not expected that the small dose used in this study will 
have significant side effects in patients with cirrhosis. Patients with decreased level of 
consciousness are excluded from the study (hepatic encephalopathy higher than grade 2). For 
a complete listing of adverse reactions, including frequency of occurrence, please refer to the 
cmTent Surmnaiy of Product Characteristics (SmPC) [R22-4031]. 
1.2.6 
Residual Effect Period 
The Residual Effect Period (REP) of the cocktail is 9 days, referring to warfai·in, the dtug 
with the longest half-life among the cocktail components. This is the period after the last dose 
with measurable dtug levels and/or phaimacodynamic effects still likely to be present. 
1.3 
RATIONALE FOR PERFORMING THE TRIAL 
The rational for this study is to understand whether liver cirrhosis itself, along with standai·d 
of cai·e, can result in a change in activity of the isozymes CYP1A2, CYP2C9, CYP2C19, 
CYP2D6 and CYP3A in F4 liver cinhosis atients com ared to health sub· ects. 
Tra 1tiona y, t 1e c 1111ca p 1aimaco ogy pac age or :ug su m1ss10n 1s con ucte 
111 ea thy 
subjects m1less the disease is known to influence the kinetics of the dtug, then it is conducted 
in the patient population. Liver cirrhosis is a longitudinal disease, going from F0 through to 
F4 compensated then decompensated. The trial will be perfonned to assess the influence of 
liver cinhosis on the phaimacokinetics of caffeine (CYP1A2 probe dtug), S-warfarin 
(CYP2C9 probe dtug), omeprazole (CYP2C19 probe dt11g) metoprolol (CYP2D6 probe 
dt11g), and midazolam (CYP3A probe dtug). 
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The current study consists of 3 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)
The intention is to identify whether the pharmacokinetics of a drug, based on the activity of 
CYP isozymes, is significantly different in F4 liver cirrhosis patients on standard of care
compared to that observed in healthy subjects.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any therapeutic benefit for healthy subjects or
liver cirrhosis patients. Their participation, however, is of major importance for the 
development of future compounds in liver cirrhosis patients within Boehringer Ingelheim.
This importance is reflected in the understanding how drug exposures may differ in F4 liver 
cirrhosis patients, on standard of care, compared to healthy subjects, depending on which 
CYP isozymes are more active or inactive. Subjects are exposed to risks of study procedures 
and risks related to the exposure 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 venepuncture for e.g., blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects or 
liver cirrhosis patients is expected from withdrawal of this volume of blood.
1.4.2.2
Drug-related risks and safety measures
All five cocktail components are market-approved drugs.
Caffeine and Omeprazole
Caffeine and omeprazole have a large therapeutic window. Fluvoxamin, a potent inhibitor of
CYP1A2 and 2C19, caused a 5-fold increase of caffeine-AUC and a 4.5-fold increase of
omeprazole exposure in healthy subjects [P14-11944]. No side effects attributed to the intake
of caffeine and omeprazole have been reported by the authors. Comparable to this trial, doses
of 100 mg caffeine and 20 mg omeprazole have been used.

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Warfarin
The effect of warfarin on the production of vitamin K dependent coagulation factors can be
easily monitored by means of laboratory tests and clinical observation and antagonised by
administration of vitamin K1. The selected dose of 5 mg warfarin is recommended as a 
starting dose in patients with liver dysfunction (range 2.5-5 mg) and is lower than the dose 
range (20 to 30 mg), which often has been used in DDI studies in the past. Following single 
dose administration, the anticipated bleeding risk of 5 mg warfarin is considered to be low. In
previous DDI trials with warfarin, prothrombin time and INR values remained inside the
reference ranges after single doses of 10 mg warfarin [U09-1674-04] or increased up to 
2- times upper normal limit at 36 to 56 h after single dose administration of 25 mg warfarin
[U10-2984-01].
Metoprolol
Metoprolol is a selective β1-adrenergic blocker without internal sympathomimetic activity
which is clinically used in the treatment of arterial hypertension, coronary heart disease,
tachyarrhythmia, and for prophylaxis of myocardial infarction and migraine. For the
treatment of hypertension, the usual dose is 100 mg/day (dose range 50-200 mg/day).
Metoprolol is almost completely absorbed from the gastrointestinal tract, but bioavailability
is relatively low (about 50 %) because of first-pass metabolism. Peak plasma concentrations
occur about 1.5 to 2 h after dosing. Metoprolol crosses the blood-brain barrier and the
placenta and is found in breast milk. It is about 12 % bound to plasma protein. Metoprolol is
extensively metabolised in the liver, mainly by the cytochrome P450 enzyme CYP2D6, and
only 10 % of the administered drug is recovered unchanged in the urine. The average
elimination half-life of metoprolol is 3 to 5 [R22-4044].
Midazolam
The administration of an oral dose of 2 mg midazolam is without a major sedative effect
[P10-00100]. The therapeutic dose of midazolam is 7.5 to 15 mg.
1.4.2.3
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 
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).
1.4.2.4
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.
1.4.2.5
Overall assessment
Under consideration of their properties, all five probe substrates of the trial (caffeine, 
warfarin, omeprazole, metoprolol, and midazolam) are appropriate for phenotyping 
drug-metabolizing enzymes, are safe to use alone and in combination [P10-00100, 

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P03-09924, P10-05867], and have, with exception of warfarin, a very large therapeutic 
window. Previously, a comparable cocktail study was performed by the Sponsor with another 
investigational product. In this trial, the probe drugs midazolam (2 mg), warfarin (10 mg), 
omeprazole (20 mg), metoprolol (50 mg), caffeine (100 mg), and digoxin (0.25 mg) (full 
Sanofi Cocktail + digoxin) were well tolerated by the healthy subjects [c03142665]. Due to 
the increased activity of warfarin in patients with liver impairment, the warfarin dose was 
lowered to 5 mg. Hence, overall benefit-risk is considered adequate.
1.4.2.6
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 metabolism activity of selected CYP 
isozymes caffeine (CYP1A2 probe drug), S-warfarin (CYP2C9 probe drug), omeprazole 
(CYP2C19 probe drug), metopolol (CYP2D6 probe drug), and midazolam (CYP3A probe 
drug) are similar or different in F4 liver cirrhosis patients on standard therapy compared to 
healthy subjects. Cmax, AUC
and RAUCM/P values will be calculated for all drugs and their 
respective metabolites except warfarin. For R- and S- warfarin, Cmax, and AUC
will be 
calculated.
This study will be conducted as an open label, single dose study, where PK samples will be 
assessed up to 96 h 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 CYP-cocktail containing caffeine, 
warfarin, omeprazole, metoprolol, and midazolam.
-
AUC
(area under the concentration time curve of the analyte in plasma over the time 
interval from 0 to 
) for caffeine, omeprazole, metoprolol, and midazolam
-
AUC
(area under the concentration time curve of R-warfarin and S-warfarin in 
plasma over the time interval from 0 to 
)
-
Cmax (maximum measured concentration of the analyte in plasma) for each component
of the CYP-cocktail: caffeine, R-warfarin, S-warfarin, omeprazole, metoprolol, and 
midazolam
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)
1111 
-
1111 
-

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CIJF (apparent clearance of the analyte in the plasma after extravascular 
administration) 
Vz/F (apparent volume of distribution during the te1minal phase after extravascular 
administration) 
RAUCM/P ratio of AUCo.24 for metabolite to parent for caffeine (paraxanthine), 
omeprazole ( 5 '-hydroxyomeprazole ), metoprolol, a-hydroxymetoprolol, Inidazolam 
(I 'hydroxymidazolam) 
2.3.1 
Biomarkers 
-
I 
I 
2.3.1.2 
Markers of functional impainnent in hepatobiliaiy metabolism and transport 
Quantification of acute-phase-markers (high sensitivity C-reactive protein, 
interleukin-6) in serum as mediators of a negative acute-phase-response 
Quantification of total senun bile acids as a marker of hepatic trai1sport impai1ment 
2.3.2 
Safety endpoints: 
Adverse events (AEs) including clinically relevant findings 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 cocktail, the 
phannacokinetic profiles for each of the cocktail components ( caffeine, warfarin, 
omeprazole, metoprol~d midazolam) up to■ 
or-postdose, calculating the 
resulting Cinax and AU'--1111 or AUcll. RAUCm1p valueille 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 cocktail components. Othen¥ise, the resulting chug concentrations of that moiety will not 
be meaningful in the cmTent study. 
The cmTent 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) 
For safety reasons, emolment of group 3 will be initiated after safety and tolerability in at 
least 8 treated pa1ticipants of group 2 was confnmed. A documented safety review (see 
section 7 .2. 7) must take place prior to sta1t of ch11g administration in group 3. Fmthe1more, an 
unscheduled safety review meeting can be requested anytime by the Principal Investigator 
(PI) (or an authorised deputy) or the sponsor of the study (for instance, due to the occmTence 
of any unforeseen adverse events). 
The minimum data set for review of group 2 consists of the following: 
• 
AEs that were rep01ted until REP, including clinically relevant findings from ancilla1y 
safety testing listed below (Note: AEs may be ongoing at the time of safety reviews and 
AE infonnation may be subject to change prior to database lock (DBL)) 
• 
12-lead ECG as repo1ted as an adverse event 
• 
Vital signs 
• 
Clinical laborato1y tests 
• 
Check of criteria for stopping subject treatment as per section 3.4.3 
The decision proceeding to include pruticipants from group 3 will be made jointly by the PI 
(or an authorised deputy), the sponsor's Safety Representative (or an authorised deputy) and 
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the CT Leader (or an authorised deputy) after in-depth analysis of all available safety data, 
especially SAEs (if occurred), AEs, and out-of-range laboratory results (if considered 
clinically significant). In addition, and depending on the results and findings, suitable experts 
from the sponsor or external institutions may be consulted on an as needed basis. In these 
cases, expert recommendations will be documented in the minutes of the Safety Review and 
considered for the decision making. Drug administration in group 3 will only be permitted if 
no safety concerns exist neither in the opinion of the PI (or an authorised deputy) or the 
sponsor.
The CT Leader is responsible for the organisation and minutes of the reviews. Minutes will 
be signed off by the Principal Investigator (or an authorised deputy) and the CT Leader (or an 
authorised deputy) and will be filed in the Investigator Site File (ISF) and Trial Master File 
(TMF).
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 preferred. The open-label
treatment is not expected to bias results, since the primary study endpoints are quantitative 
endpoints derived from measurement of plasma concentrations of the analytes. The control 
group are healthy volunteers, where feasible, will matched in terms of age (± 10 years), BMI 
(± 20 %) and sex. The analysis will look at group effects, not at direct match comparisons. 
This may result in the liver cirrhosis 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.
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)

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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
(except from caffeine: methylxanthine-containing drinks or foods such as coffee, tea, 
cola, energy drinks, or chocolate are not allowed within 48 h before and during the in-
house confinement at the trial site)
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, alkaline phosphatase ≤ULN, total bilirubin ≤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

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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. Furthermore, patients can 
only be included into the trial a) if they are in constant specialist care at the timepoint of 
enrollment into the study and b) if they are willing to continue to be in specialist care 
after participation in the 0352.2190 study
12. 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 (seeTable 3.3.2: 1)
OR
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 (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.
Chronic liver disease with clinical signs of portal hypertension (at least one 
out of the following)
1. Gastroesophageal varices (GEV) grade 1 (small)
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)
-
Diagnosis of decompensated cirrhosis/F4
Any of the above (diagnosis of compensated cirrhosis/F4)
AND
At least one previous decompensation event

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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 any components in the cocktail or esomeprazole within 4 weeks 
before cocktail administration (except from caffeine: methylxanthine-containing drinks or 
foods such as coffee, tea, cola, energy drinks, or chocolate are not allowed within 48 h 
before and during the in-house confinement at the trial site)
2. Subjects with any other condition that would preclude administration of caffeine, 
warfarin, omeprazole, metoprolol, and midazolam (i.e., contraindicated as per Summary 
of Product Characteristics (SmPC)), such as hypersensitivity to active ingredient or any of 
the excipients or to any beta receptor blockers
3. Subjects taking medications known to be moderate or strong inhibitors of the following 
cytochrome P450 (CYP) enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A
(see section 4.4.2)
4. Subjects taking medications know to be moderate or strong inducers of the following 
P450 (CYP) enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A (see 
section 4.4.2)
5. 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 65 to 90 bpm
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)

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7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant (other than HBV or HCV) chronic or acute infections (including an ongoing 
SARS-CoV-2 infection)
10. Patients receiving antiviral therapy at the time of inclusion into the trial
11. 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
12. Intake of a) a non-authorized drug in another clinical trial within 60 days of planned 
administration of the drug cocktail in the current trial, or b) an authorised drug in another 
clinical trial within 5 times of haf-life of the trial drug prior to the planned administration 
of the drug cocktail in the current trial.
13. Current smoker or ex-smoker who quit smoking less than 30 days prior to screening 
examination
14. Use of nicotine replacement devices within 2 weeks prior to administration of trial 
medication or during the trial
15. Alcohol abuse (intake of more than 12 g per day for females and 24 g per day for males)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. 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
21. 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
22. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
23. For female subjects, positive pregnancy test, pregnancy, or plans to become pregnant 
within 30 days after study completion
24. For female subjects, lactation period
25. Subjects who, in the investigator’s judgement, are perceived as having an increased risk
of bleeding, for example because of:
-
Variceal hemorrhage within 3 months prior enrolment
-
Patient currently undergoing endoscopic treatment of esophagogastral varices or 
within the last 3 months prior enrolment
-
Haemorrhagic disorder or bleeding diathesis
-
Trauma or surgery within the last 4 weeks or as long as an excessive risk of bleeding
persists after these events
-
Planned surgery during trial participation
-
History of arteriovenous malformation or aneurysm
-
History of gastroduodenal ulcer disease or gastrointestinal haemorrhage
-
History of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intraarticular 
bleeding

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26. Within 10 days prior to administration of trial medication, use of any drug that could
affect blood coagulation (e.g., acetylsalicylic acid, heparin)
27. Thrombocytopenia (platelet count less than 100 /nL) or low haemoglobin count
(Haemoglobin less than 11.6 g/dL for females and 13.5 g/dL for males) at screening
28. PQ interval greater than 220 ms or atrioventricular block of II° or III° in the ECG at 
screening
29. Marked conductivity disorder (e.g., sinoatrial blocks of II° or III°, any pathological sinus 
node function) in the ECG at screening
30. Cardiac insufficiency
31. Bronchial hyperreactivity, e.g., asthma bronchiale
32. Severe peripheral circulatory disorder (pheochromocytoma)
33. TSH exceeds upper limit of norm at screening, confirmed by a repeat test
34. 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
35. 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 and including monoamine oxidase A inhibitors)
Exception: already discussed baseline medication for standard of care per local 
guidelines.
For study restrictions, refer to section 4.4.2.
Healthy subjects only
36. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
37. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
38. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or 
hormonal disorders
39. 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
40. Patients are excluded if they meet the following criteria at the screening visit:
AST and/or ALT ≥5xULN
41. Patients with hepatic encephalopathy grade > 2
42. Patients are excluded if they meet the following criteria at the screening visit:
INR > 2.2 ULN
43. Gastroesophageal varices (GEV) stage II or more (intermediate or large) or portosystemic 
shunts

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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 section 3.4.1 and 
section 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).
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). Remedial pain therapy by ibuprofen is allowed. 
If possible, only a minimal dose should be taken.
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.

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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
4. a) The occurrence of a serious adverse reaction (SAR)
or
b) The occurrence of two severe non-serious related AEs
or
c) The occurrence of an AESI (hepatic injury)
or
d) The occurrence of a Liver decompensation event
will cause a temporary halt and initiate a a safety data review by the PI and the 
sponsor's medical representative. The trial may continue after a positive outcome of 
the safety data review.
The investigator/trial site will be reimbursed for reasonable expenses incurred in case of trial
termination.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Caffeine, warfarin, omeprazole, metoprolol, and midazolam will be obtained from a public 
pharmacy.
Trial product 1
Name:
*Percoffedrinol® N 50 mg Tabletten
Substance:
Caffeine
Pharmaceutical formulation:
Tablet
Holder of marketing authorization: Aristo Pharma GmbH, Germany
Unit strength:
50 mg
Posology:
2 – 0 – 0 (cocktail component)
Route of administration:
Oral
Duration of use:
single dose on Day 1
Trial product 2
Name:
*Coumadin® 5 mg
Substance:
Warfarin sodium
Pharmaceutical formulation:
Tablet
Holder or marketing authorization: Teofarma S.r.I., Italy
Unit strength:
5 mg
Posology:
1 – 0 – 0 (cocktail component)
Route of administration:
Oral
Duration of use:
single dose on Day 1
Trial product 3
Name:
*Antra MUPS® 20 mg magensaftresistente Tabletten
Substance:
Omeprazole
Pharmaceutical formulation:
Gastro-resistant tablet
Holder of marketing authorization: Cheplapharm, Arzneimittel GmbH, Germany
Unit strength:
20 mg
Posology:
1 – 0 – 0 (cocktail component)
Route of administration:
Oral
Duration of use:
single dose on Day 1
Trial product 4
Name:
*Metoprolol-ratiopharm® 50 mg Tabletten
Substance:
Metoprolol
Pharmaceutical formulation:
Tablet
Holder of marketing authorization: Ratiopharm GmbH, Germany
Unit strength:
50 mg tartrate
Posology:
1 – 0 – 0 (cocktail component)
Route of administration:
Oral
Duration of use:
single dose on Day 1

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Trial product 5
Name:
*Midazolam-ratiopharm® 2 mg/mL orale Lösung
Substance:
Midazolam
Pharmaceutical formulation:
Oral solution
Holder of marketing authorization: Ratiopharm GmbH, Germany
Unit strength:
2 mg/mL
Posology:
1 mL – 0 – 0
Route of administration:
Oral
Duration of use:
single dose on Day 1
*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
Single doses of caffeine 100 mg, warfarin 5 mg, omeprazole 20 mg, metoprolol 50 mg, and 
midazolam 2 mg are standard doses used in clinical DDI trials. The doses were selected based 
on their tolerability and the ability to show a PK interaction if present. For caffeine, 100 mg 
was chosen as it is approximately the amount of caffeine in one cup of coffee. For warfarin,
5 mg is a starting dose in patients with liver dysfunction. For omeprazole, a dose of 20 mg 
once a day is used in the treatment of symptomatic gastrooesophageal reflux disease and 
duodenal ulcer. For metoprolol, daily doses from 50 to 200 mg are used in the treatment of 
hypertension. For midazolam, an oral dose of about 2 mg should lead to significant systemic 
exposure without major sedative effect [P10-00100].
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 an 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: 1 Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total 
daily 
dose
Cocktail
Caffeine
Warfarin
Omeprazole
Metoprolol
Midazolam
Tablet
Tablet
Tablet
Tablet
oral solution
50 mg
5 mg
20 mg
50 mg
2 mg/mL
2 tablets as single dose
1 tablet as single dose
1 tablet as single dose
1 tablet as single dose
1 mL
100 mg
5 mg
20 mg
50 mg
2 mg

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Standardized light breakfast 
A standardized meal (bread roll or similar with butter, cheese and/or sliced sausage) will be 
served l h 30 min before the cocktail is administered. 
4.3.2 
Blinding and procedures for unblinding 
This Phase 1 trial will be handled in an open fashion throughout (that is, dming 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 
Caffeine, warfarin, omeprazole, metoprolol, and midazolam will be obtained by the clinical 
trial site from a public pha1macy. 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 recommended (labelled) storage conditions. If necessaiy, a 
temperature log must be maintained to make ce1iain that the drug supplies are stored at the 
conect temperatme. 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. 
joot-MCS-40-106 RD-03 (20.0) I Saved on: 20 Apr 2021! 

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4.3.5 
Drug accountability 
Only authorised personnel documented in the trial team log may dispense medication to trial 
subjects. The trial medication must be administered in the manner specified in the CTP. The 
investigator or designee must maintain records of the product's delivery to the trial site, the 
inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch/serial numbers, expiiy ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products. At the tune of disposal of remaining trial medication, the investigator or designee 
must verify that all unused or partially used drug supplies have been disposed of. 
4.4 
OTHER TREATl\tIENTS, 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 treatment, the investigator can authorise symptomatic 
therapy. In those cases, subjects will be treated as necessaiy and, if required, kept under 
supervision at the trial site or transfeued to a hospital until all results of medical evaluations 
are acceptable. 
4.4.2 
4.4.2.1 
Restrictions 
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 othe1wise. The measured plasma concentrations of trial 
medication will provide additional confumation of compliance. 
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see section 3.4). 
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5. 
ASSESSMENTS 
5.1 
ASSESSMENT OF EFFICACY 
Not applicable 
5.2 
ASSESSMENT OF SAFETY 
5.2.1 
Physical examination 
A complete physical examination will be perfo1med at visits. It includes at a minimum 
appearance, neck, lungs, cardiovascular system, abdomen, extremities, and skin. 
The physical examination can be omitted at visit 2 and visit 3, if the subject does not rep01t 
any health-related changes or abno1malities since the respective last visit (see flow chart). 
5.2.2 
Vital signs 
Vital signs will be evaluated at the time points specified in the flow chrut prior to blood 
sampling. This includes systolic and diastolic blood pressme and pulse rate ( electronically or 
by palpation count for I min) in a seated position after 5 min of rest. All recordings should be 
made using the same type of blood pressure recording instrnment on the same rum if possible. 
The results must be included in the source documents available at the site. 
5.2.3 
Safety laboratory parameters 
For the assessment of laborat01 
ammeters, blood and urine sam les will be collected b 
trial site 
T 1e parameters 
that will be dete1mined are listed in Table 5.2.3: 1 and Table 5.2.3: 2. Reference rru1ges will 
be provided in the ISF. Manual differential white blood cell count or urine sediment 
examinations will only be perfo1med if there is an ab1101mality in the automatic blood cell 
count or in the urinalysis, respectively. 
Table 5.2.3: I Routine laborat01y tests 
Ftmctional lab group 
BI test name [comment/abbreviation] 
Al 
Bl 
ci 
Haematology 
Haematocrit 
X 
X 
X 
Haemoglobin 
X 
X 
X 
Red Blood Cell Count/Erythrocytes 
X 
X 
X 
White Blood CeUs/Leucocytes 
X 
X 
X 
Platelet Cotmt/Thrombocytes (quant) 
X 
X 
X 
Automatic WBC 
N eutrophils/Leukocytes 
X 
-
X 
differential, relative 
Eosinophils/Leukocytes 
X 
-
X 
Basophils/Leukocytes 
X 
-
X 
Monocytes/Leukocytes 
X 
-
X 
Lymphocytes/Leukocytes 
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
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
Prothrombin time - INR (International Normalization 
Ratio)
X
X
X
X
X
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
Serum total bile acids
Protein, Total
C-Reactive Protein (Quant)
hsCRP
Interleukin-6
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
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
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, visit 
3, visit 4 and at the EoT examination
2) Microscopic examination if erythrocytes, leukocytes, or protein are abnormal in urine

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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). 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; 
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 

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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.
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):

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-
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”.
Adverse events of special interest (AESIs)
The term adverse events of special interest (AESI) relate to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g., the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.

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I 
I 
Intensity (severity) of AEs 
The intensity (severity) of adverse events should be classified and recorded in the CRF 
according to the Common Tenninology Criteria for Adverse Events (CTCAE) version 5.0. 
Causal relationship of AEs 
Medical judgement should be used to detennine 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 histo1y. 
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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 
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.

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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 exeption 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.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B). As 
pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE and / 
or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form is 
to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE form 
must be completed in addition.
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5.3 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS 
5.3.1 
Assessment of pharmacokinetics 
For the assessment of phaimacoki.netics, blood will be collected at the time points/time 
intervals indicated in the flow cha.ii. The actual sampling times will be recorded and used for 
dete1mination of phaimacokinetic pai·ameters. 
5.3.1.1 
Blood sampling 
For quantification of caffeine, R- and S-warfai·in, omeprazole, metopro~dazolam 
( compounds of the CYP probe cocktail) and their relevant metabolites, -- blood will 
be taken from an antecubital or foreaim vein into a potassium ethylenediaminetetraacetic acid 
(K2-EDTA) anticoagulant blood drawing tube at the times indicated in the flow cha.it and 
TablelO. l.J... Blood will be withdrawn by meai1s of either an indwelling venous catheter or 
by venipuncture with a metal needle. 
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5.3.2 
5.3.2.1 
Analytical determinations of pharmacokinetics 
Analytical detennination of analyte plasma concentration 
a) Anal ical detennination of caffeine lasma concentration 
b) Anal ical determination of warfarin lasma concentration 
d) Anal ical detennination of midazolam lasma concentration 
All PK plasma aliquots will be transfened to the analytical laborato1y on dry ice: 
5.3.3 
Further investigations 
After completion of the analysis of plasma samples for concentrations of caffeine, R- and S-
warfarin, omeprazole, metoprolol, and midazolam, the plasma samples (including back-ups 
and left-over sample volumes from pre-specified analyses) may be used as follows: 
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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 could possibly serve as potential 
indicators for the activity of CYP isozymes 
Results of fmiher investigations are not planned to be pali of the trial repo1i; however, results 
of fmiher investigations may be paii of the trial repoli, 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. 
5.4 
BIO BANKING 
Not applicable. 
5.5 
OTHER ASSESSMENTS 
There will be a single blood draw for the liquid biopsy analysis ai1d for the phannacogenetic 
profiling. However, sepai·ate infonned consent for pharmacogenetic profiling must be 
obtained from each subject. Only if the subject is willing to consent for the phai1nacogenomic 
profiling, she or he can pa1ticipate in the trial. Subjects whose genotype has been previously 
detennined do not need to sign ai1 extra consent f 01m . 
• 
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• 
• 
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5.6
APPROPRIATENESS OF MEASUREMENT
All measurements performed during this trial are standard measurements and will be 
performed to monitor subjects’ safety and to determine pharmacokinetic parameters in an 
appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur because of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in section 5.3.1
are generally used assessments of drug exposure.

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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 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.

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The screening visit includes the following procedures:
-
Physical examination (see section 5.2.1)
-
Examination of vital signs (see section 5.2.2)
-
Blood draw for safety laboratory tests including a test for viral 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)
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 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, for the pharmacogenetic 
profiling and for the protein binding analysis of selected cocktail components before cocktail 
administration. However, separate informed consent for genotyping (pharmacogenetic 
profiling) must be obtained from each subject. If the genotype of the subject is already 
known, there is no need for an extra blood draw vial and therefore no need for signing an 
extra consent form for pharmacogenetic profiling.
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. Additional administration of vitamin K to all 
patients with liver cirrhosis should be considered by the study physician.

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6.2.3
Follow-up period and trial completion (EoT visit)
There will be three 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)
-
Blood draw for PK and biomarkers (see section 5.3).
Follow-up visit 2 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)
-
Blood draw for PK and biomarkers (see section 5.3).
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 caffeine, R- and S-
warfarin, omeprazole, metprolol, and midazolam given as a cocktail following oral 
administration based on the primary pharmacokinetic endpoints, as listed in sections 2.2. 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.
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 caffeine, R- and S-warfarin, omeprazole, metoprolol, and 
midazolam 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 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 
identified no later than in the Report Planning Meeting, and iPD categories will be updated as 
needed.

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Pharmacokinetics
The pharmacokinetic parameters listed in sections 2.2 and sections 2.3 will be calculated 
according to the relevant guidelines, process documents and manuals of the Sponsor.
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
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 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 concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS. Only 
concentration values within the validated concentration range and actual sampling times will 
be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
7.2.1
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’s
relevant standards and processes. The analysis will be based on the PKS and will be 
descriptive in nature.
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 effect
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,

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-
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.
7.2.4
Further objective analyses
7.2.4.1
Pharmacokinetic analyses
Further PK endpoints will be analysed descriptively. In addition, the RAUCM/P ratios (Ratio 
of AUC0-24 for metabolite to parent) for caffeine (paraxanthine), omeprazole (5’-
hydroxyomeprazole), metoprolol, α-hydroxymetoprolol, midazolam (1’hydroxymidazolam)
will also be analyzed as outline in 7.2.3.

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7.2.4.2
Analysis for liquid biopsy
If data allows correlation between CL/F of cocktail components and mRNA, protein 
expression or enzyme activity 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.
7.2.6
Other Analyses
No other analyses are planned.
7.2.7
Interim Analyses
Safety laboratory testing is performed for each participant according to the flowchart and no 
formal interim analysis is planned. However, to ensure that drug administration was well 
tolerated by the compensated liver cirrhosis patients before starting with cocktail 
administration in decompensated liver cirrhosis patients, a preliminary analysis of available 

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safety data of group 2 will be implemented. This analysis is planned as soon as 8 subjects of 
group 2 have completed the treatment and were followed up for at least 9 days (REP of the 
cocktail is 9 days, referring to warfarin, the drug with the longest half-life), before proceeding 
to enrolment of group 3.
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 
procedures. 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 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.
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.

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For the CRF, data must be derived from source documents, for example:
-
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. Exemptions from expedited reporting are described in section 5.2.6,
if applicable.
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 
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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. 
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
-
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 ISP. 
Data Management and Statistical Evaluation will be done by BI according to BI SOPs. 
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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P03-09924
Chainuvati S, Nafziger AN, et al. Combined phenotypic assessment of 
cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A, Nacetyltransferase-2, and 
xanthine oxidase activities with the 'Cooperstown 5 + 1 cocktail'. Clin 
Pharmacol Ther 2003; 74 (5); 437-47.
P04-02457
Zhou H, Tong Z, et al. 'Cocktail' approaches and strategies in drug
development: valuable tool or flawed science? J Clin Pharmacol 2004; 44
(2): 120-134.
P05-07385
Delco F, Tchambaz L, et al. Dose adjustment in patients with liver disease. 
Drug Saf. 2005;28(6):529–45.
P05-10983
Faber MS, Jetter A, et al. Assessment of CYP1A2 activity in clinical 
practice: why, how, and when? Basic Clin Pharmacol Toxicol 2005; 97(3): 
125-134.
P10-00100
Turpault S, Brian W, et al. Pharmacokinetic assessment of a five-probe 
cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol 
2009; 68(6): 928-935.
P10-03451 
Johnson TN, Boussery K, et al. A semi-mechanistic model to predict the 
effects of liver cirrhosis on drug clearance. Clin Pharmacokinet. 
2010;49(3):189–206.
P10-05867
Dumond JB, Vourvahis M, et al. A phenotype-genotype approach to 
predicting CYP450 and P-glycoprotein drug interactions with the mixed 
inhibitor/inducer tipranavir/ritonavir. Source: Clin Pharmacol Ther 2010; 
87(6) ;735-742.
P14-09296
Franz CC, Hildbrand C, et al. Dose adjustment in patients with liver 
cirrhosis: impact on adverse drug reactions and hospitalizations. Eur J Clin 
Pharmacol. 2013; 69(8):1565–73.
P14-11944
Christensen M. Low daily 10-mg and 20-mg doses of fluvoxamine inhibit 
the metabolism of both caffeine (cytochrome P4501A2) and omeprazole 
(cytochrome P4502C19). Clin Pharmacol Ther 2002; 71(3):141.
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.
P96-3991
Andersson T. Pharmacokinetics, metabolism and interactions of acid pump 
inhibitors: focus on omeprazole, lansoprazole and pantoprazole. Clin 
Pharmacokinet 1996; 31(1): 9-28.
R06-0327
Kalow W, Tang BK. The use of caffeine for enzyme assays: a critical 
appraisal. Clin Pharmacol Ther 1993; 53(5): 503-514.
R09-0632
Hemeryck A, Lefebvre RA, et al. Paroxetine affects metoprolol 
pharmacokinetics and pharmacodynamics in healthy volunteers. Clin 
Pharmacol Ther 2000; 67 (3): 283-291.

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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.
R14-3265
Percoffedrinol® N 50 mg Tabletten (Aristo Pharma), Fachinformation, May 
2014.
R20-1307
Woolsey SJ, Mansell SE, et al. CYP3A Activity and Expression in 
Nonalcoholic Fatty Liver Diseases. Drug Metab Dispos 43:1484–1490, 
October 2015
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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)
R22-3870
Jamwal R., de la Monte SM, et al. Nonalcoholic Fatty Liver Disease and 
Diabetes Are Associated with Decreased CYP3A4 Protein Expression and 
Activity in Human Liver Pharmaceutics 2018, 15, 2621−2632© 2018 
R22-3871
Li H, Canet MJ, et al. Pediatric Cytochrome P450 Activity Alterations in 
Nonalcoholic Steatohepatitis. Drug Metab Dispos 45:1317–1325, 
December 2017
R22-3872
Merrell MD, Cherrington NJ. Drug metabolism alterations in nonalcoholic 
fatty liver disease. Drug Metabolism Reviews, 2011; 43(3): 317–334
R22-3873
Duthar U, Bachmann F, et al. Liver Cirrhosis Affects the Pharmacokinetics 
of the Six Substrates of the Basel Phenotyping Cocktail Differently. Clin 
Pharmacokinet. 2022 Jul;61(7):1039-1055. doi: 10.1007/s40262-022-
01119-0. Epub 2022 May 16. PMID: 35570253; PMCID: PMC9287224.
R22-3874
Adedoyin A, Arns PA, et al. Selective effect of liver disease on the 
activities of specific metabolizing enzymes: investigation of cytochromes 
P450 2C19 and 2D6. Clin Pharmacol Ther. 1998;64(1):8–17.
R22-3895
Taegtmeyer AB, Haschke M, et al. A study of the relationship between 
serum bile acids and propranolol pharmacokinetics and pharmacodynamics 
in patients with liver cirrhosis and in healthy controls. PLoS ONE. 
2014;9(6): e97885.
R22-4030
Fachinformation Coumadin® 5mg Tabletten (2021)
R22-4031
Fachinformation Midazolam-ratiopharm® 2mg/mL Lösung (2021)
R22-4032
Fachinformation Antra MUPS® 10mg magensaftresistente Tabletten (2022)
R22-4044
Fachinformation Metoprolol-ratiopharm® 50mg Tabletten (2020)
R98-2274
Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major 
importance in human drug metabolism. Br J Clin Pharmacol 1998; 45:525-
538.

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10. 
APPENDICES 
10.1 
TIME SCHEDULE FOR PK- SAMPLING 
Tablel0.1: 1 Time schedule for blood 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 pharmacological, non-clinical and clinical data do not indicate an 
increased risk of contracting SARS-CoV-2 or aggravated clinical courses due to the treatment 
with the “cocktail”. However, participants with active SARS-CoV-2 infection (e.g.,
confirmed by the COVID-19 rapid test performed at admission to trial site or confirmed by 
PCR test before) will be excluded from the trial.
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. 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 performed at the participant’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 recommended 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 rules, wearing of face masks, and physical 
distancing
-
SARS-CoV-2 testing (COVID-19 rapid test) will be performed one day before 
treatment at admission to the trial site. Participants positive in the SARS-CoV-2 test are 
not eligible and will be excluded from the trial
-
Any participant with suspected or diagnosed COVID-19 will be referred to health care 
professionals in charge to receive treatment according to standard of care
Based on these considerations, the benefit/risk assessment for the administration of the 
“cocktail” remains unaltered despite the COVID-19 pandemic.

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