The Effect of Multiple Doses of Itraconazole on the Pharmacokinetics of a Single Oral Dose of BI 1810631 in Healthy Male Subjects (an Open-label, Two-period, Fixed-sequence Trial)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

BI-VQD-11906_40-106_AD-13 (8.0)
Clinical Trial Protocol
 
Document Number:
c40240667-02
EudraCT No.
2022-003757-63
BI Trial No.
1479-0004
BI Investigational
Medicinal Product
BI 1810631
Title
The effect of multiple doses of itraconazole on the 
pharmacokinetics of a single oral dose of BI 1810631 in healthy 
male subjects (an open-label, two-period, fixed-sequence trial)
Lay Title
A study in healthy men to test how itraconazole influences the 
amount of BI 1810631 in the blood
Clinical Phase
I
Clinical Trial Leader
Phone:
 Fax: 
 Investigator
Phone: 
 Fax: 
Current Version, Date
Version 2.0, 22 Feb 2023
Original Protocol Date
27 Dec 2022
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Test product 2
Itraconazole oral solution (Sempera® Liquid 10 mg/mL Lösung zum Einnehmen)
dose
200 mg q.d.
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 9 h
Duration of treatment
Treatment Reference (R, BI 1810631 alone) – Period 1:
-
Single dose of 
mg BI 1810631 in the morning of Day 1
Treatment Test (T, itraconazole + BI 1810631) – Period 2:
-
14 days of itraconazole 200 mg q.d. in the mornings of Days -3 to 11
-
Single dose of 
mg BI 1810631 in the morning of Day 1
Statistical methods
The extent of the drug-drug interaction will be estimated by the ratios of the 
geometric means (test/reference) for the primary and secondary endpoints. 
Additionally, their two-sided 90% confidence intervals (CIs) will be provided. This 
method corresponds to the two one-sided t-test procedure, each at a 5% significance 
level. Since the main focus is on estimation and not testing, a formal hypothesis test 
and associated acceptance range is not specified. The statistical model will be an 
analysis of variance (ANOVA) on the logarithmic scale including effects for 
‘subject’ and ‘treatment’. CIs will be calculated based on the residual error from the 
ANOVA.
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART
Period
Visit
Day
Planned time (relative to 
BI 1810631 administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory 4
PK blood (BI 1810631)
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
A
x
x
Period 1 (Treatment R, BI 1810631 alone) 9
2
-1
-12:00
20:00
Admission to trial site8
x5,8
x8
1
-1:30
06:30
Allocation to subject number2
B2
x2
x2
x2
x2
0:00
08:00
Administration of BI 1810631
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
x
x
6:00
14:00
x
8:00
16:00
Snack3
x
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x 
2
24:00
08:00
Breakfast (voluntary)3,
discharge from trial site
B
x
x
x
x
34:00
18:00
Ambulatory visit
x
x
3
47:00
07:00
Ambulatory visit
x
x
4
71:00
07:00
Ambulatory visit
x
x
6
119:00
07:00
Ambulatory visit
x
x
8
167:00
07:00
Ambulatory visit
x
x

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FLOW CHART (cont’d)
Period
Visit
Day
Planned time (relative to 
BI 1810631 administration) 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory 4
PK blood (BI 1810631)
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Period 2 (Treatment T, itraconazole + BI 1810631) 9
3
-3
-73:00
07:00
Ambulatory visit, 
itraconazole administration
C10
x10
-2
-49:00
07:00
Ambulatory visit, 
itraconazole administration
x10
-1
-25:00
07:00
Ambulatory visit, 
itraconazole administration
C11
x10
-12:00
20:00
Admission to trial site8
x5,8
x8
1
-1:30
06:30
B2
x2
x2
x2
x2
-1:00
07:00
Itraconazole administration 
0:00
08:00
Administration of BI 1810631
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x 
2
23:00
07:00
Itraconazole administration
x10
24:00
08:00
Breakfast (voluntary)3,
discharge from trial site
B
x
x
x
x
34:00
18:00
Ambulatory visit
x
x
3
47:00
07:00
Ambulatory visit, 
itraconazole administration
x10
x10
4
71:00
07:00
Ambulatory visit, 
itraconazole administration
C
x10
x10
5
95:00
07:00
Ambulatory visit, 
itraconazole administration
x10
6
119:00
07:00
Ambulatory visit, 
itraconazole administration
C
x10
x10
7
143:00
07:00
Ambulatory visit, 
itraconazole administration
x10
8
167:00
07:00
Ambulatory visit, 
itraconazole administration
C
x10
x10
9
191:00
07:00
Ambulatory visit, 
itraconazole administration
x10
x10
10
215:00
07:00
Ambulatory visit, 
itraconazole administration
x10
x10
11
239:00
07:00
Ambulatory visit, 
itraconazole administration
x10
x10
12
263:00
07:00
Ambulatory visit
x
x
13
287:00
07:00
Ambulatory visit
x
x
FU
4
19-33
End of study (EoS) examination7
D
x
x
x

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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to the next administration
of study drug.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
A, B, C, and D designate different safety laboratory examination sets (see Section 5.2.3)
5.
Urine drug screening and alcohol breath test, only
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
At the end of study (synonym for end of trial), the EoS examination includes physical examination, vital signs, ECG, 
safety laboratory, recording of AEs and concomitant therapies.
8.
The time is approximate; procedures are to be performed and completed no later than 10 h prior to the next drug 
administration
9.
Administration of BI 1810631 in treatment R and T will be separated by a washout interval of at least 14 days.
10. Before itraconazole dosing
11. This safety laboratory needs to be medically evaluated before administration of study drugs on Day 1 of Period 2

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 31
3.1
OVERALL TRIAL DESIGN............................................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................31
3.3
SELECTION OF TRIAL POPULATION ......................................................32
3.3.1
Main diagnosis for trial entry..............................................................32
3.3.2
Inclusion criteria...................................................................................32
3.3.3
Exclusion criteria ..................................................................................32
3.3.4
Withdrawal of subjects from treatment or assessments ...................34
3.3.4.1
Withdrawal from trial treatment ..............................................35
3.3.4.2
Withdrawal of consent to trial participation ............................35
3.3.4.3
Discontinuation of the trial by the sponsor..............................36
3.3.5
Replacement of subjects .......................................................................36
4.
TREATMENTS........................................................................................ 37
4.1
INVESTIGATIONAL TREATMENTS ..........................................................37
4.1.1
Identity of the Investigational Medicinal Products ...........................37
4.1.2
Selection of doses in the trial................................................................37
4.1.3
Method of assigning subjects to treatment groups ............................38
4.1.4
Drug assignment and administration of doses for each subject .......38
4.1.5
Blinding and procedures for unblinding ............................................39
4.1.6
Packaging, labelling, and re-supply ....................................................39
4.1.7
Storage conditions.................................................................................39
4.1.8
Drug accountability ..............................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................40
4.2.1
Other treatments and emergency procedures....................................40
4.2.2
Restrictions............................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment .........................41
4.2.2.2
Restrictions on diet and life style.............................................41
4.2.2.3
Contraception requirements.....................................................42
4.3
TREATMENT COMPLIANCE.......................................................................42
5.
ASSESSMENTS....................................................................................... 43
5.1
ASSESSMENT OF EFFICACY.......................................................................43
5.2
ASSESSMENT OF SAFETY............................................................................43
5.2.1
Physical examination ............................................................................43
5.2.2
Vital signs...............................................................................................43
5.2.3
Safety laboratory parameters..............................................................43
5.2.4
Electrocardiogram................................................................................46
5.2.5
Other safety parameters.......................................................................46
5.2.6
Assessment of adverse events...............................................................46
5.2.6.1
Definitions of adverse events...................................................46

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5.2.6.1.1 Adverse event ............................................................46
5.2.6.1.2 Serious adverse event ................................................47
5.2.6.1.3 AEs considered ‘Always Serious’.............................47
5.2.6.1.4 Adverse events of special interest .............................48
5.2.6.1.5 Intensity (severity) of AEs.........................................49
5.2.6.1.6 Causal relationship of AEs ........................................49
5.2.6.2
Adverse event collection and reporting ...................................50
5.2.6.2.1 AE collection.............................................................50
5.2.6.2.2 AE reporting to the sponsor and timelines ................51
5.2.6.2.3 Pregnancy ..................................................................51
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................51
5.3.1
Assessment of pharmacokinetics .........................................................51
5.3.2
Methods of sample collection...............................................................51
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................51
5.4
ASSESSMENT OF BIOMARKERS................................................................52
5.5
BIOBANKING ...................................................................................................52
5.6
OTHER ASSESSMENTS .................................................................................53
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................53
6.
INVESTIGATIONAL PLAN.................................................................. 55
6.1
VISIT SCHEDULE............................................................................................55
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................55
6.2.1
Screening period....................................................................................55
6.2.2
Treatment periods.................................................................................56
6.2.3
Follow-up period and trial completion ...............................................56
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 57
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................57
7.2
PLANNED ANALYSES....................................................................................57
7.2.1
General considerations.........................................................................57
7.2.1.1
Analysis sets.............................................................................57
7.2.1.2
Pharmacokinetics.....................................................................57
7.2.2
Primary endpoint analyses...................................................................58
7.2.3
Secondary endpoint analyses ...............................................................59
7.2.5
Safety analyses.......................................................................................59
7.2.6
Interim analyses ....................................................................................60

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7.3
HANDLING OF MISSING DATA ..................................................................60
7.3.1
Safety......................................................................................................60
7.3.2
Pharmacokinetics..................................................................................60
7.4
RANDOMISATION ..........................................................................................61
7.5
DETERMINATION OF SAMPLE SIZE ........................................................61
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 63
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................63
8.2
DATA QUALITY ASSURANCE .....................................................................64
8.3
RECORDS..........................................................................................................64
8.3.1
Source documents .................................................................................64
8.3.2
Direct access to source data and documents.......................................65
8.3.3
Storage period of records.....................................................................66
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................66
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......66
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................66
8.6
TRIAL MILESTONES .....................................................................................67
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................67
9.
REFERENCES......................................................................................... 69
9.1
PUBLISHED REFERENCES...........................................................................69
9.2
UNPUBLISHED REFERENCES.....................................................................70
10. APPENDICES .......................................................................................... 71
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 72
11.1
GLOBAL AMENDMENT 1 .............................................................................72

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EoS
End of Study (synonym for End of Trial)
EudraCT
European Clinical Trials Database
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
GMP
Good Manufacturing Practice
HER2
Human epidermal growth factor receptor 2
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Month-do-Date
NF
New formulation
NSCLC
Non-small-cell lung cancer
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
RTK
Receptor tyrosine kinases
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth 
factor receptor (EGFR) family of homologous transmembrane receptor tyrosine kinases. The 
family of ErbB transmembrane receptor tyrosine kinases (RTKs) consists of the four 
members EGFR (ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3) and HER4 (ErbB4), which 
fulfil essential functions during development [R20-1872, R09-6185, R20-1990]. ErbB 
signalling is initiated upon binding of the extracellular domains of EGFR, HER3 or HER4 to 
their respective ligands and subsequent homo- or heterodimerization of ErbB family 
members. HER2, for which no ligand has been identified, is the preferred dimerization 
partner for the other ErbB members. Once an active ligand-receptor complex has been 
formed, the intracellular tyrosine kinase domains of EGFR, HER2 or HER4 are activated by 
auto- or transphosphorylation and subsequently elicit a signal transduction cascade most 
notably engaging the mitogen-activated protein kinase and/or the phosphoinositide 3-kinase
pathways [R20-1872, R09-6185, R20-1990].
Aberrant ErbB signalling is implicated in several pathophysiological conditions including 
cancer or neurological diseases. In cancer, ErbB signalling is hyper-activated through 
mutations that render the RTK constitutively active by promoting dimerization or shifting the 
equilibrium towards the active conformer of the kinase and/or through amplification and 
consequent over-expression of the RTK. Both oncogenic mechanisms increase the net output 
of ErbB signalling and thereby promote cell survival, cell growth and proliferation [P15-
01211].
More recently, increasing attention has been given to the emerging impact of oncogenic 
HER2 activation through somatic gene mutation. The majority of these HER2 mutant cancers 
have not been associated with concurrent HER2 gene amplification. Mutations are found 
across all exons of the HER2 gene including exon 20, with significant heterogeneity both 
between and within human cancer types. The highest prevalence of HER2 mutations is 
observed in prostate neuroendocrine cancer, metastatic cutaneous squamous cell carcinoma, 
and bladder cancer (all >10% of cases). A significant HER2 mutation prevalence is also 
found in more common cancers, including lung, colorectal and breast cancers, indicating a 
large additional patient base that could potentially be targeted with HER2-directed therapies 
[P19-10412].
Mutations in HER2 have been identified as oncogenic drivers and occur in 2 to 3% of non-
small-cell lung cancer (NSCLC). HER2 mutations most commonly consist of a 12 base pair 
in-frame insertion YVMA (p.A775_G776insYVMA) in exon 20 [P19-00456, P20-09250]. 
There is no standard targeted treatment for NSCLC with HER2 aberrations including HER2 
exon 20 insertion mutations. Clinically approved tyrosine kinase inhibitors have not been 
shown to be efficacious in these patients, as they are limited by EGFR wild type mediated 
dose limiting toxicity. Therefore there is a clear unmet medical need for new treatment 
options for NSCLC patients with HER2 insertion mutations.

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1.2.2
Itraconazole
Absorption of itraconazole oral solution is fast with maximum plasma concentrations reached 
within 2.5 h after oral administration under fasting condition. Bioavailability of itraconazole 
liquid is higher by 30% when given under fasting condition compared to administration 
together with food [R23-0681]. Mean peak plasma concentrations were 545.7 ng/mL after a 
single dose of 200 mg itraconazole solution (fasting) and 1,965 ng/mL after 15 days of daily 
treatment with 200 mg itraconazole solution (fasting). Pharmacokinetics of itraconazole is 
non-linear. The half-life of itraconazole after multiple doses of 200 mg once daily with 
solution formulation was about 40 h [R17-3742].
In the liver, itraconazole is metabolised extensively to more than 30 metabolites [R17-3743].
Its main metabolite, hydroxy-itraconazole, accounts for about twice the concentration of 
plasma itraconazole at trough. It has been shown in vitro that CYP3A4 is mainly responsible 
for the formation of this metabolite [R23-0681]. 

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Table 1.4.2: 1 Overview of trial-related risks for this trial (cont’d)
Investigational Medicinal Product: Itraconazole
Side effects described in 
the SmPC of Sempera 
Liquid 10 mg/ml Lösung 
zum Einnehmen [R23-
0681]
Gastrointestinal side effects 
including hepatotoxicity are 
amongst the side effects that 
are most frequently reported. 
Other potential side effects 
are described in the SmPC of 
Sempera® Liquid 10 mg/mL.
Overall, the risks associated 
with 14-day treatment with 
200 mg/day itraconazole are 
considered acceptable.
# AE questioning (see Flow Chart)
# Instruction of subjects to report 
AEs spontaneously
# Safety laboratory at pre-defined 
time points during itraconazole 
dosings (see Flow Chart and 
Section 5.2.3)
# Stringent in- and exclusion criteria 
define a relatively homogenous 
population and exclude subjects 
that might be at increased risk for 
AEs (see Section 3.3)
# Criteria for withdrawal of 
individual subjects from trial 
treatment are defined in Section 
3.3.4.1
Potential interaction between itraconazole and BI 1810631
Perpetrator: itraconazole
Victim: BI 1810631
Preclinical data (refer to IB 
[c32836122]) indicate a risk 
for increased plasma 
exposure of BI 1810631 
when administered with 
itraconazole
# A low dose of BI 1810631 is used 
for this study (see Section 4.1.2) 
to ensure that BI 1810631 plasma 
concentrations remain within the 
range of concentrations that were 
explored in the dose escalation 
part of first-in-man trial 
1479-0001 (see Section 1.2.1.3.1) 
and that showed good safety and 
tolerability (see Section 1.2.1.3.3).
# Subjects are in-house under close 
observation for at least 24 hours 
following administration of 
BI 1810631
# AE questioning (see Flow Chart)
# Instruction of subjects to report 
AEs spontaneously
# ECG, VS, and safety laboratory 
will be performed as scheduled in 
the Flow Chart

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Table 1.4.2: 1 Overview of trial-related risks for this trial (cont’d)
Trial procedures
Blood sampling:
Bruising and, in rare 
cases, phlebitis, or nerve 
injury, potentially 
resulting in paraesthesia, 
reduced sensibility, and/or 
pain 
General risk by venipuncture
for blood sampling,
acceptable in the framework 
of trial participation.
Medical expertise of the trial site 
ECG recording:
Skin irritation, redness, 
itching
General risk by ECG 
electrodes, acceptable in the 
framework of trial 
participation.
Exclusion of subjects from trial 
participation with known clinically 
relevant hypersensitivity reactions to 
adhesive tapes.
Other risks
SARS-CoV-2 infection
# Participation in this trial 
may increase the risk of 
COVID-19 exposure due to 
travels to the study site and 
completion of protocol-
defined procedures at the 
site.
# To date there is no evidence 
suggesting an association 
between Covid-19 and 
HER2 inhibition targeted 
by BI 1810631. 
# Available non-clinical data 
have not shown an 
increased risk of infections 
due to treatment with 
BI 1810631 (see IB 
[c32836122])
# A risk management plan has been 
set up at the clinical site that 
details precautionary measures 
(e.g., hygiene rules, wearing of 
face masks, physical distancing) 
and screening for SARS-CoV-2 
infection.
# During the Covid-19 pandemic, 
subjects with laboratory results 
indicative of a SARS-CoV-2 
infection are excluded from trial 
participation (see exclusion 
criterion 24 in Section 3.3.3) 
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
1.4.3
Discussion
There is significant medical need in cancer patients harbouring HER2 mutations for effective, 
safe and well-tolerated therapies. BI 1810631 is an EGFR wild-type sparing selective HER2 
inhibitor with potent inhibitory activity on all major HER2 mutations.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objective
The main objective of this trial is to investigate the effect of multiple oral doses of the strong 
CYP3A inhibitor and recommended P-gp inhibitor itraconazole on the pharmacokinetics of a 
single dose of BI 1810631 in plasma following oral administration. 
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 1810631:
#
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
#
Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for BI 1810631:
#
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 1810631 and itraconazole will be assessed based on:  
#
Adverse events (including clinically relevant findings from the physical examination)
#
Safety laboratory tests
#
12-lead ECG
#
Vital signs (blood pressure, pulse rate)

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This design is not expected to lead to systematic errors in the estimation of the treatment 
effects since nonspecific time effects are unlikely due to the short trial duration. For 
itraconazole studies, this design is recommended by the Innovation and Quality in 
Pharmaceutical Development’s Clinical Pharmacology Leadership Group (CPLG) [R17-
3744].
For this PK drug-drug interaction trial, open-label treatment is acceptable, because the 
primary and secondary endpoints of this trial are PK endpoints derived from measurement of 
plasma concentrations of BI 1810631. These endpoints are not expected to be affected by 
knowledge of treatment.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy male subjects will enter the trial. They will be recruited from the 
volunteers' pool of the trial site.
Only male subjects will be included in the trial because of the reproduction toxicity reported 
from nonclinical studies with itraconazole. 
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 50 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator

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2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant chronic or acute infections
10. Any documented active or suspected malignancy or history of malignancy 
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
12. 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 or any kind of vaccination)
13. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
14.
15.
16. Alcohol abuse (consumption of more than 24 g per day)
17. Drug abuse or positive drug screening
18. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
19. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms) 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)

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23. 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 
24. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
25. Subjects with WOCBP partner who are unwilling to use highly effective contraception 
from time point of first administration of BI 1810631 until 30 days after the last 
administration of BI 1810631. Highly effective methods of contraception are:
- Subject is sexually abstinent
- Subject is vasectomized (with appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate) and uses condom
- Use of intrauterine device or intrauterine hormone-releasing system by female partner 
plus use of condom
- Use of progestogen-only hormonal contraception by female partner that inhibits 
ovulation (injectables or implants) plus use of condom
- Use of combined (estrogen and progestogen containing) hormonal contraception by 
female partner that prevents ovulation (oral, intravaginal, or transdermal) plus use of 
condom
- Bilateral tubal occlusion in the female partner plus use of condom
Sperm donation is not allowed from the time point of first administration of BI 1810631 
until 30 days after the last administration of BI 1810631
26. Liver enzymes (ALT, AST, GGT) above upper limit of normal at the screening 
examination, confirmed by a repeat test
27. History of drug-induced liver injury, heart failure, or any evidence of ventricular 
dysfunction
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Sections 3.3.4.1 and 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR).
If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.

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If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.3, the 
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer
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, the safety of the 
subject cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events (AEs), or diseases). This may include:
-
The subject has an elevation of AST and/or ALT ≥3-fold ULN
-
For the safety laboratory on Period 2, Day -1: The subject has an elevation of AST 
and/or ALT≥55 U/L 
-
The subject has a serious adverse reaction or a CTCAE Grade 3 non-serious adverse 
reaction
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
subjects or take any other appropriate action to guarantee the safety of the trial subjects.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.

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3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reasons 4 and/or 5 are met, the trial should be discontinued 
immediately):
1. Failure to meet expected enrolment goals
2. The sponsor decides to discontinue the further development of the investigational 
products
3. Deviation from GCP, or the CTP, impairing the appropriate conduct of the trial
4. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment (see Section 3.3.4.1)
5. More than 50% of the subjects show drug-related and clinically relevant adverse events of 
CTCAE grade 2 severity (except for grade 2 headache), or if grade 3 drug-related non-
serious adverse events occur in at least two subjects, or if at least one drug-related serious 
adverse event is reported
3.3.5
Replacement of subjects
In case more than 4 subjects do not complete the trial (including subjects non-evaluable for 
PK), subjects may be replaced if considered necessary to reach the objectives of the trial.
Subjects who withdraw or are withdrawn from treatment or assessments because of a drug-
related adverse event will not be replaced. The Clinical Trial Leader together with the Trial
Clinical Pharmacologist and the Trial Statistician are to decide, if and how many subjects will 
be replaced. The total number of replacements may not exceed 4 subjects (1/3 of the total 
number of evaluable subjects required to complete the trial). A replacement subject will be 
assigned a unique trial subject number.

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The BI 1810631 administrations will be separated by a wash-out interval of at least 14 days.
4.1.5
Blinding and procedures for unblinding
This non-randomised open-label Phase I trial will be handled in an open fashion throughout. 
The treatment assignment will be available to all involved parties.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal product BI 1810631 will be provided by BI. It will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice
(GMP). 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms.
Itraconazole will be obtained by the trial site from a public pharmacy. The drug will be 
dispensed out of the original, unmodified packages.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:
#
Approval of the clinical trial protocol by the IRB / ethics committee
#
Approval/notification of the regulatory authority, e.g. competent authority
#
Availability of the curriculum vitae of the Principal Investigator
#
Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
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.

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These records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, 
and the unique code numbers assigned to the investigational medicinal product and trial 
subjects. The investigator or designee will maintain records that document adequately that the 
subjects were provided the doses specified by the CTP and reconcile all investigational 
medicinal products received from the sponsor. At the time of disposal of remaining trial 
medication, the investigator or designee must verify that no remaining supplies are in the 
investigator’s possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history not mandatory to be entered into CRF or to be 
reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 12-
lead ECG, laboratory tests, and a physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, 
 at the times indicated in the 
Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm, 
if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 9 h. 
For retests, at the discretion of the investigator or designee, overnight fasting is not required.
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
--
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
--
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes; Neutrophils Bands, absol.; 
Eosinophils/Leukocytes; Eosinophils, absol.; Basophils/ 
Leukocytes; Basophils, absol.; Monocytes/Leukocytes; 
Monocytes, absol.; Lymphocytes/Leukocytes; Lymphocytes, 
absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time (Quick)
Prothrombin time – INR (International Normalization Ratio)
X
X
X
X
X
X
--
--
--
X
X
X
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT 
ALT [Alanine aminotransferase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Lactic Dehydrogenase
Lipase
Troponin T ultrasensitive
NT-proBNP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
X
X
X
X
--
--
--
--
X
X
X
X
X
X
--
--
Hormones
Thyroid Stimulating Hormone
X
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
Cholesterol, total 
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
X
X
X
X
X
X
--
--
--
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine HGB (qual)
Urine leukocyte esterase (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment 1
Only positive findings will be reported 2 
1 microscopic examination if erythrocytes, leukocytes, nitrite, or protein are abnormal in urine
2 e.g., the presence of sediment bacteria, casts in sediment, squamous epithelial cells, erythrocytes, leukocytes
A, B, C, D: different sets of safety laboratory. For time points see Flow Chart.

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The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and at admission to in-house stay during each
treatment period.
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/Ecstasy
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)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. AlcoTrue® M, 
 will be performed at admission to in-house stay during
each treatment period, and may be repeated at any time during the trial at the discretion of an 
investigator or designee. The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
, with the exception of 
drug screening tests. These tests will be performed at the trial site using M-10/14-PDT 
Surestep Multiline test, or comparable test systems.
In case of positive drug screen, confirmatory test may be done at 
 
.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the Investigator are to be reported as adverse events 
(please refer to Section 5.2.6). 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4). 

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5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (
, 
) at the times provided in the Flow Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other trial procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the subject will be removed from 
the trial and will receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
Not applicable.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
#
Worsening of the underlying disease or of other pre-existing conditions 

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#
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
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 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
5.2.6.1.3
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 to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. 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.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.

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5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
#
Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.

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5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of AEs should be classified and recorded in the CRF according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [R18-1357].
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
#
The event is consistent with the known pharmacology of the drug 
#
The event is known to be caused by or attributed to the drug class
#
A plausible time to onset of the event relative to the time of drug exposure
#
Evidence that the event is reproducible when the drug is re-introduced
#
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)
#
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)
#
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
#
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
#
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

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#
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
5.2.6.2.1
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. In addition, each subject will be 
regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, subjects will be questioned for AEs (and 
concomitant therapies) at the time points indicated in the Flow Chart. Assessment will be 
made using non-specific questions such as ‘How do you feel?’. Specific questions will be 
asked wherever necessary in order to more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
#
From signing the informed consent onwards until an individual subject’s end of trial
(the End of Study (EoS) visit): 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR.
#
After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new 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 BI SAE form (see Section 5.2.6.2.2), but not on the CRF.

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5.2.6.2.2
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 BI SAE form to the sponsor’s unique entry point within 
24 hours of becoming aware of the event, the country specific reporting process will be 
provided in the ISF. The same timeline applies if follow-up information becomes available. 
On specific occasions, the Investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and send the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
Pregnancy
Once the subject has been enrolled in the clinical trial and has taken BI 1810631, and if a 
partner of the male trial participant becomes pregnant, the investigator must report any BI 
1810631 exposure during pregnancy in a partner of the male trial participant by means of Part 
A of the Pregnancy Monitoring Form to the sponsor’s unique entry point, after a written 
consent of the pregnant partner. Reporting and consenting must be in line with local 
regulations. 
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 Part B).
As the female partner’s pregnancy itself is not to be reported as an AE, only the Pregnancy 
Monitoring Form for Clinical Trials and not the SAE form is to be completed.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 1810631 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 

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be withdrawn by means of either an indwelling venous catheter or by venipuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 120 min, with interim storage of blood samples and aliquots at room 
temperature. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
Further use of samples
After analysis, the plasma samples may be used for further methodological investigations
(e.g. for stability testing or assessment of metabolites), to address Health Authority questions 
regarding the results/methodology, or to measure concentrations of itraconazole and/or its 
metabolites. However, only data related to the analyte and/or its metabolite(s) including anti-
drug antibodies (if applicable) will be generated by these additional investigations. The trial
samples will be discarded after completion of the additional investigations but not later than 5
years after the CTR is archived.
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.
5.5
BIOBANKING
Not applicable.

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5.6
OTHER ASSESSMENTS
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. 

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The scheduled measurements will allow monitoring of changes in vital signs, standard 
laboratory values, and ECG parameters that might occur as a result of administration of trial 
medication. The safety assessments are standard, are accepted for evaluation of safety and 
tolerability of an orally administered drug, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined in Section 5.3 are generally used 
assessments of drug exposure.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
In treatment period T, a time window of ± 120 min around planned time applies to 
itraconazole dosings in the morning of Days -3 and -2. In the morning of Day -1, a time 
window of ± 60 min around planned time applies to itraconazole dosing.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs, ECG, and laboratory tests will be ± 60 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned 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.
At visits 2 and 3, for PK samples, itraconazole administrations and safety laboratory tests at 
planned time +47 h and later, a time window of ± 120 min around planned time applies.
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 period
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 trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.5.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.6).

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6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days -1 to Day 8 in period 1 
and Days -3 to Day 13 in period 2). At least 14 days will separate administrations of 
BI 1810631 in the first and second treatment periods.
In the evening of Day -1 of each treatment period, trial participants will be admitted to the 
trial site and kept under close medical surveillance for at least 24 h following BI 1810631
administration. The subjects will then be allowed to leave the trial site after formal 
assessment and confirmation of their fitness. On all other trial days, subjects will be treated in 
an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
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 EoS Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained. 

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 1810631 in plasma when given as a single dose together
with multiple oral doses of Itraconazole (T) versus a single dose of BI 1810631 alone (R) 
will be estimated by the ratios of the geometric means (test/reference), and their 
corresponding 2-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at the 5% significance level. Since the 
main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:
#
Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.
# Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the IPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for drug BI 1810631 will be 
calculated according to the relevant BI internal procedures. 
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.

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Important protocol deviations may be
#
Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to
#
Incorrect dose of trial medication taken
#
Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example
#
The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),
#
A predose concentration of BI 1810631 is >5% Cmax value of that subject in the 
respective treatment period,
#
Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which are 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). 
7.2.2
Primary endpoint analyses
Primary analyses
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: subject and treatment. The effect 
'subject' will be considered as random, whereas the effect ‘treatment’ will be considered as 
fixed. The model is described by the following equation:
ykm = ∃+ sm + %k + ekm, where
ykm = logarithm of response measured on subject m receiving treatment 
k,
∃= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n
%k = the kth treatment effect, k = 1, 2,

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ekm = the random error associated with the mth subject who received
treatment k,
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with
‘subject’ considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.2.3
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the relevant 
BI internal procedures and will be assessed statistically using the same methods as described 
for the primary endpoints.
7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the assigned treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.

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Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between first trial medication intake and end of REP 
(see Section 1.2.3) will be assigned to the treatment period. Events occurring after the REP 
but prior to next intake or end of trial termination date will be assigned to ’follow-up’. In case 
of two or more treatments, the follow-up will be summarized according to the previous 
treatment. These assignments including the corresponding time intervals will be defined in 
detail in the TSAP. Note that AEs occurring after the last per protocol contact but entered 
before unblinding the trial will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.2.6
Interim analyses
No interim analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures. 

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Table 7.5: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a 2-period fixed-sequence trial 
(N=12)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(∃T)/exp(∃R).
The expected 90% confidence interval limits in the table were derived by
CI limit, = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 4.2.1.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC 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 
will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject according to ICH-GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional subject-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject 
information must be given to each subject.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.

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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. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the 
 Phase I unit – the 
validated ClinBaseTM system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as database. Instead of being entered into CRFs, selected data are directly 
entered into the ClinBaseTM system.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject 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 subject, documented 
in their medical records, would be acceptable.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 

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

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The accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular
#
Sample and data usage have to be in accordance with the informed consent
#
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage 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 (e.g. 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

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#
Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).
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 laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the
, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF. The investigators will have access to the BI web portal Clinergize to access 
documents provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required trial activities, in order to 
#
Manage the trial in accordance with applicable regulations and internal SOPs
#
Direct the clinical trial team in the preparation, conduct, and reporting of the trial
#
Ensure appropriate training and information of local Clinical Trial Mangers
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites

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The BI 1810631 trial medication will be provided by the
 and itraconazole oral solution will be 
obtained by the trial site from a pharmacy.
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).
Analyses of BI 1810631 concentrations in plasma will be performed at
 
.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or by a contract research 
organization appointed by BI.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.

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R17-3742
Barone JA, Moskovitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman 
RH, et al. Food interaction and steady-state pharmacokinetics of 
itraconazole oral solution in healthy volunteers. Pharmacotherapy 1998; 
18(2):295-301.
R17-3743
Willems L, Geest R van der, Beule K de. Itraconazole oral solution and 
intravenous formulations: a review of pharmacokinetics and 
pharmacodynamics. J Clin Pharm Ther 2001; 26:159-169.
R17-3744
Liu L, Bello A, Dresser MJ, Heald D, Komjathy SF, O'Mara E, et al. Best 
practices for the use of itraconazole as a replacement for ketoconazole in 
drug-drug interaction studies. J Clin Pharmacol 2016. 56(2):143-151.
R18-0241
Guidance for industry: clinical drug interaction studies - study design, data 
analysis, and clinical implications (draft guidance, this guidance document 
is being distributed for comment purposes only) (October 2017, clinical 
pharmacology). 
https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf (access 
date: 19 January 2018); Silver Spring: U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER) 2017.
R18-1357
U.S. Department of Health and Human Services. Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published: November 27, 
2017). U.S.Department of Health and Human Services, National Institutes 
of Health, National Cancer Institute; 2017.
R20-1872
Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat 
Rev Mol Cell Biol; 2006; 7; 505-516. JULY 2006
R20-1990
Wang Z. ErbB receptors and cancer. Methods in Molecular Biology; 
2017;1652; 3-35. vol. 1652, DOI 10.1007/978-1-4939-7219-7_1, © 
Springer Science+Business Media LLC 2017
R23-0681
Sempera Liquid 10 mg/ml, Lösung zum Einnehmen (Janssen-Cilag) 
(Fachinformation, Stand der Information: Dezember 2022). 2022.
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
c32836122
 Investigator's Brochure BI 1810631 1479-P01 
Version 2.0. 12 Jan 2022

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10.
APPENDICES
Not applicable.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
22 Feb 2023
EudraCT number
EU number
2022-003757-63
BI Trial number
1479-0004
BI Investigational Medicinal 
Product(s)
BI 1810631
Title of protocol
The effect of multiple doses of itraconazole on the 
pharmacokinetics of a single oral dose of BI 
1810631 in healthy male subjects (an open-label, 
two-period, fixed-sequence trial) 
Substantial Global Amendment due to urgent safety reasons 
To be implemented immediately in order to eliminate hazard – IEC / Competent 
Authority to be notified of change with request for approval.
Substantial Global Amendment 
e.g. changes in safety or physical or mental integrity of trial subjects, or in inter-
pretation of scientific documents/value of the trial, or in conduct/management of 
the trial, or change/addition of principal investigators, co-ordinating investigators, 
or trial sites – implementation only after IEC / Competent Authority approval.
Non-substantial Global Amendment 
e.g. changes that involve logistical or administrative aspects, or exploratory 
endpoints only – can be implemented without IEC / Competent Authority approval
Section to be changed
1. Flow Chart
2. Section 3.3.4.1
3. Synopsis and Section 3.3.2
4. Section 5.2.3: Table 5.2.3.1
5. Section 3.3.3
6. Section 3.3.3
7. Section 8.1
8. Section 3.3.4.3
9. Sections 1.2.2, 1.4.2 and 4.2.2.1
Description of change
1. Addition of safety laboratory C on Days -1, 4 
and 6 of period 2, deletion of safety lab on Day 
5 of period 2. Addition of footnote 11 to safety 
laboratory C on Day -1 (safety laboratory to be 
medically evaluated before dosing on Day 1)

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2. Addition of text “For the safety laboratory on 
Period 2, Day -1: The subject has an elevation 
of AST and/or ALT≥55 U/L” to individual 
withdrawal criterion 4
3. Reduction of upper age limit to 50 years
4. Addition of troponin t ultrasensitive and NT-
proBNP to safety laboratory set A
5. Adaptation of exclusion criterion 10 so that 
subjects with any documented active or 
suspected malignancy or history of malignancy 
are now excluded from trial participation
6. Adaptation of exclusion criterion 2: Increase of 
lower acceptable pulse limit from 45 bpm to 
50 bpm
7. Deletion of the subject’s legally accepted 
representative
8. Criterion 5 has been modified so that the study 
needs to be stopped in case of drug-related 
Grade 3 events in at least two subjects
9. Replacement of reference to SmPC Sempera®
Liquid 10 mg/ml Lösung zum Einnehmen by 
current version (December 2022)
Rationale for change
1. Request from Ethics Committee
2. Request from Ethics Committee
3. Request from Competent Authority
4. Request from Competent Authority
5. Request from Competent Authority
6. Request from Competent Authority
7. Request from Competent Authority
8. Request from Competent Authority
9. Request from Competent Authority

 
 
 
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