Relative Bioavailability of BI 1810631 Following Oral Administration Under Fed and Fasted Conditions in Healthy Male Subjects (an Open-label, Randomised, Single-dose, Two-way Crossover Trial)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

BI-VQD-11906_40-106_AD-13 (8.0)
Clinical Trial Protocol
TITLE PAGE
Document Number:
c40254926-03
EU CT No.
2022-502860-19-00
UTN
U1111-1291-3312
BI Trial No.
1479-0010
BI Investigational
Medicinal Product
BI 1810631
Title
Relative bioavailability of BI 1810631 following oral 
administration 
 in healthy male 
subjects (an open-label, randomised, single-dose, two-way
crossover trial)
Lay Title
A study in healthy men to test how BI 1810631 is taken up in 
the body when
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
 Investigator
Phone:
Fax:
Current Version, Date
Version 3.0, 13 Nov 2023
Original Protocol Date
23 May 2023
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission
Boehringer 
\J1lll1v lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
23 May 2023
Revision date
13 Nov 2023
BI trial number
1479-0010
Title of trial
Relative bioavailability of BI 1810631 following oral administration 
 
 in healthy male subjects (an open-label, randomised, single-dose, 
two-way crossover trial)
 Investigator
Trial site
Clinical phase
I
Trial rationale
To assess the effect of a 
 on the pharmacokinetics of 
a single dose of BI 1810631 given as 
. The 
resulting data are required to inform recommendations for intake of BI 1810631 
Trial objective
To investigate the relative bioavailability of
of BI 1810631 
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of BI 1810631
Secondary endpoints: AUC0-of BI 1810631
Trial design
Randomised, open-label, single-dose two-way crossover design 
Number of subjects 
total entered
16
on each treatment
16
Diagnosis
Not applicable
Main inclusion criteria
Healthy male subjects, age of 18 to 55 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product
BI 1810631 
dose
mode of 
administration
Oral intake with 240 mL of water in 
 

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Duration of treatment
One day (single dose) for each treatment
Statistical methods
To assess the 
 on the relative bioavailability, the ratios of the geometric 
means (test/reference) for the primary and secondary endpoints will be estimated. 
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 
sequence, subjects nested within sequences, period 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 
drug administration) 
[h:min]
Approximate clock time
of actual day [h:min]
Event and comment9
Safety laboratory 8
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
x
1/2 (two identical periods separated by a wash-out interval of at least 
BI 1810631 administrations)
2/3
-1
-24:00
08:00
Admission to trial site11
B10
x
x
x5
-13:00
19:00
1
-2:00
06:00
Allocation to treatment2 (visit 2 only)
x2
x
-0:30
07:30
0:00
08:00
Drug administration: BI 1810631
x
0:30
08:30
x
x
1:00
09:00
x
x
1:30
09:30
x
x
2:00
10:00
240 mL fluid intake
x
x
3:00
11:00
x
x
4:00
12:00
240 mL fluid intake,
x
x
x
x
6:00
14:00
x
x
8:00
16:00
x
10:00
18:00
x
x
11:00
19:00
12:00
20:00
x
x 
2
24:00
08:00
B
x
x
x
x
36:00
20:00
x
x
3
48:00
08:00
Discharge from trial site
x
x
4
72:00
08:00
Ambulatory visit
x
x
5
96:00
08:00
Ambulatory visit
x
x
6
120:00
08:00
Ambulatory visit
B
x
x
7
144:00
08:00
Ambulatory visit
x
x
8
168:00
08:00
Ambulatory visit
x
x
FU
4
15 to 22
End of study (EoS) examination4
C
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and check of inclusion/exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time,
will be the last action.
4.
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.
5.
Review of relevant inclusion/exclusion criteria for confirmation of eligibility (in period 1 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.
8.
Letters A, B and C describe different sets of safety laboratory examinations. For details see Section 5.2.3
9. 
10. Including urine drug screening and alcohol breath test
11. SARS-CoV-2 PCR test will be performed if it is needed due to the current status of the pandemic.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS AND DEFINITIONS........................................................9
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................13
1.2.1
Mode of action.......................................................................................13
1.2.2
Data from studies in humans ...............................................................13
1.2.3
Residual Effect Period..........................................................................16
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................16
1.4
BENEFIT - RISK ASSESSMENT ...................................................................16
1.4.1
Benefits...................................................................................................16
1.4.2
Risks .......................................................................................................16
1.4.3
Discussion...............................................................................................20
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......22
2.1.1
Main objectives......................................................................................22
2.1.2
Primary endpoints ................................................................................22
2.1.3
Secondary endpoint ..............................................................................22
2.2.2.2
Safety and tolerability..............................................................23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 24
3.1
OVERALL TRIAL DESIGN............................................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................25
3.3.1
Main diagnosis for trial entry..............................................................25
3.3.2
Inclusion criteria...................................................................................25
3.3.3
Exclusion criteria ..................................................................................25
3.3.4
Withdrawal of subjects from treatment or assessments ...................27
3.3.4.1
Withdrawal from trial treatment ..............................................27
3.3.4.2
Withdrawal of consent to trial participation ............................28
3.3.4.3
Discontinuation of the trial by the sponsor..............................28

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3.3.5
Replacement of subjects .......................................................................29
4.
TREATMENTS........................................................................................ 30
4.1
INVESTIGATIONAL TREATMENTS ..........................................................30
4.1.1
Identity of the Investigational Medicinal Products ...........................30
4.1.2
Selection of doses in the trial................................................................30
4.1.3
Method of assigning subjects to treatment groups ............................30
4.1.4
Drug assignment and administration of doses for each subject .......31
4.1.5
Blinding and procedures for unblinding ............................................32
4.1.6
Packaging, labelling, and re-supply ....................................................32
4.1.7
Storage conditions.................................................................................33
4.1.8
Drug accountability ..............................................................................33
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................34
4.2.1
Other treatments and emergency procedures....................................34
4.2.2
Restrictions............................................................................................35
4.2.2.1
Restrictions regarding concomitant treatment .........................35
4.2.2.2
Restrictions on diet and life style.............................................35
4.2.2.3
Contraception requirements.....................................................36
4.3
TREATMENT COMPLIANCE.......................................................................36
5.
ASSESSMENTS....................................................................................... 37
5.1
ASSESSMENT OF EFFICACY.......................................................................37
5.2
ASSESSMENT OF SAFETY............................................................................37
5.2.1
Physical examination ............................................................................37
5.2.2
Vital signs...............................................................................................37
5.2.3
Safety laboratory parameters..............................................................37
5.2.4
Electrocardiogram................................................................................39
5.2.5
Other safety parameters.......................................................................40
5.2.6
Assessment of adverse events...............................................................40
5.2.6.1
Definitions of adverse events...................................................40
5.2.6.1.1 Adverse event ............................................................40
5.2.6.1.2 Serious adverse event ................................................41
5.2.6.1.3 AEs considered ‘Always Serious’.............................41
5.2.6.1.4 Adverse events of special interest .............................41
5.2.6.1.5 Intensity (severity) of AEs.........................................42
5.2.6.1.6 Causal relationship of AEs ........................................43
5.2.6.2
Adverse event collection and reporting ...................................43
5.2.6.2.1 AE collection.............................................................43
5.2.6.2.2 AE reporting to the sponsor and timelines ................44
5.2.6.2.3 Pregnancy ..................................................................45
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................45
5.3.1
Assessment of pharmacokinetics .........................................................45
5.3.2
Methods of sample collection...............................................................45

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5.3.2.1
Blood sampling for pharmacokinetic analysis.........................45
5.4
ASSESSMENT OF BIOMARKERS................................................................46
5.5
BIOBANKING ...................................................................................................46
5.6
OTHER ASSESSMENTS .................................................................................46
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................46
6.
INVESTIGATIONAL PLAN.................................................................. 47
6.1
VISIT SCHEDULE............................................................................................47
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................47
6.2.1
Screening period....................................................................................47
6.2.2
Treatment periods.................................................................................47
6.2.3
Follow-up period and trial completion ...............................................48
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 49
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................49
7.2
PLANNED ANALYSES....................................................................................49
7.2.1
General considerations.........................................................................49
7.2.1.1
Analysis sets.............................................................................49
7.2.1.2
Pharmacokinetics.....................................................................49
7.2.2
Primary endpoint analyses...................................................................50
7.2.3
Secondary endpoint analyses ...............................................................51
7.2.5
Safety analyses.......................................................................................51
7.2.6
Interim analyses ....................................................................................52
7.3
HANDLING OF MISSING DATA ..................................................................53
7.3.1
Safety......................................................................................................53
7.3.2
Pharmacokinetics..................................................................................53
7.4
RANDOMISATION ..........................................................................................53
7.5
DETERMINATION OF SAMPLE SIZE ........................................................53
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 55
8.1
DATA QUALITY ASSURANCE .....................................................................55
8.2
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................55
8.3
RECORDS..........................................................................................................56
8.3.1
Source documents .................................................................................56
8.3.2
Direct access to source data and documents.......................................57

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8.3.3
Storage period of records.....................................................................57
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................58
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......58
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................58
8.6
TRIAL MILESTONES .....................................................................................59
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................59
9.
REFERENCES......................................................................................... 61
9.1
PUBLISHED REFERENCES...........................................................................61
9.2
UNPUBLISHED REFERENCES.....................................................................62
10. APPENDICES .......................................................................................... 63
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 64
11.1
GLOBAL AMENDMENT 1 .............................................................................64
11.2
GLOBAL AMENDMENT 2 .............................................................................65

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ABBREVIATIONS AND DEFINITIONS
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTCAE
Common Terminology Criteria for Adverse Events
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EGFR
the epidermal growth factor receptor
EoS
End of Study (synonym for End of Trial)
ErbB
Epidermal growth factor
FU
Follow-up
GCP
Good Clinical Practice

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gCV
Geometric coefficient of variation
gMean
Geometric mean
HER2
Human epidermal growth factor receptor 2
HGB
Hemoglobin
IB
Investigator’s brochure
ICF
Informed consent form
iCF
intended commercial formulation
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
MRTpo
Mean residence time of the analyte in the body after oral administration
NF
New formulation
NSCLC
non-small-cell lung cancer
NTproBNP
N terminal prohormone of brain natriuretic peptide
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
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
transmembrane receptor tyrosine kinases
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
T
Test product or treatment
TF1
Trial Formulation 1
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set

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tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VS
Vital signs
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WOCBP
Women of child-bearing potential
YVMA
HER2 mutation with 12 base pair in-frame insertion YVMA (p.A775-
G776insYVMA)

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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
DRUG PROFILE
For a comprehensive description of BI 1810631 refer to the IB [c32836122].
1.2.1
Mode of action
BI 1810631 is an EGFR wild type sparing, selective HER2 inhibitor with potent inhibitory 
activity on 
 HER2 mutations including the HER2 YVMA insertion allele. It is 
intended to treat patients with advanced solid tumors with HER2 aberrations.
1.2.2
Data from studies in humans 
Prior to the current trial, BI 1810631 was administered in the ongoing first-in-man trial in 
patients with cancer 1479-0001 and in one PK study in healthy volunteers (trial 1479-0003).
A short summary of the trials and drug-related adverse events in these trials is provided here. 
For details on PK, safety, and efficacy refer to the IB [c32836122].
Short description of patient first-in-man trial 1479-0001
1479-0001 is an open-label, Phase I dose escalation trial, with dose confirmation and 
expansion, of BI 1810631 
 in patients with advanced or metastatic solid 
tumors with HER2 aberrations. Patients are continuously treated in different dose groups with 
 dosing schemes. PK, safety, and efficacy data are collected. So far,
were treated in the dose escalation part with BI 1810631 either in one of the
 
 or the
. 
described here is 09 Mar 2023.
Short description of healthy volunteer trial 1479-0003
At the time of CTP finalization, trial 1479-0003 is in the reporting phase. Trial 1479-0003 
was an open-label, randomized, 4-way crossover Phase I trial. The trial investigated relative 
bioavailability of BI 1810631 after administration as
on the 
pharmacokinetics of a single dose of BI 1810631 in plasma and investigated the effect of 
multiple-dose treatment with 
 on the pharmacokinetics of a single dose of 
BI 1810631. Thirteen healthy male volunteers were dosed with single doses of 
 
BI 1810631 in 4 treatment periods in randomized order, separated by wash-out intervals of  
. The 4 treatments were:
-
R: 
 BI 1810631 trial formulation 1 (TF1) 
-
T1: 
 BI 1810631 new formulation (NF) 
-
T2: 
 BI 1810631 NF after 
-
T3: 
 BI 1810631 NF after 
 
.
Safety and tolerability data of patient first-in-man trial 1479-0001 (preliminary data)
For an overview of available safety and tolerability data of trial 1479-0001 refer to the IB 
[c32836122]. The following text and tables in this protocol focus on drug-related AEs.

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Overall,
had an AE assessed as drug-related by the investigator. The 
most common drug-related AEs were
According to the IB there are two further cases of drug related 
 
 after the data lock point for the IB and this protocol (9 Mar 2023) with the follow up 
for the clinical course ongoing [c32836122].
Table 1.2.2: 1
Number (%) of patients with drug-related AEs by dose group and 
preferred term- on treatment period,
cohorts (preliminary data)
Preferred term
[N (%)]
[N (%)]
[N (%)]
[N (%)]
[N (%)]
Number of patients
Total with drug-related AEs

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Table 1.2.2.: 2
Number (%) of patients with drug-related AEs by dose group and 
preferred term- on-treatment period,
cohorts (preliminary data)
Preferred term
[N (%)]
[N (%)]
[N (%)]
[N (%)]
[N (%)]
Number of patients
Total with drug-related AEs

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Safety and tolerability data of healthy volunteer trial 1479-0003
In trial 1479-0003, in which oral single doses of 
 BI 1810631 were administered to 
healthy volunteers, 
For more details 
refer to the IB [c32836122].
1.2.3
Residual Effect Period
The Residual Effect Period (REP) of 
 
 This is the period after the last dose during which measurable drug levels and/or 
pharmacodynamic effects are still likely to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
In previous trial 1479-0003, a 
 
 observed for BI 1810631
(see Section 1.2.2). The
 It is required for the final label and to obtain market approval for BI 1810631 in e.g. 
 to investigate
in 1479-0003 trial. Thus, the rationale for performing the trial is to assess 
BI 
1810631 given
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 1810631 for 
treatment of patients with advanced solid tumours with HER2 aberrations.
1.4.2
Risks
Subjects are exposed to risks of trial procedures and risks related to the exposure to the trial 
medication. An overview of trial-related risks is given in Table 1.4.2: 1.

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Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product: BI 1810631

AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Protection of subjects by 
administration of only two single 
doses with appropriate wash-out



defined in the Flow Chart
Interstitial lung disease 
(ILD) and Pneumonitis

Not observed for
BI 1810631 so far, 
however reported from 
other tyrosine kinase 
inhibitors
Subjects are protected from this 
finding by administration of only 
two single doses with appropriate 
wash-out
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Subjects with pre-existing 
ILD/pneumonitis or other 
respiratory disorder are excluded 
from trial participation (see 
exclusion criteria 4 and 5)

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy

AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Physical examination of subjects 
at end-of-study visit 
Protection of subjects by 
administration of only two single 
doses

Safety laboratory (see Section 
5.2.3) includes 
Protection of subjects by 
administration of only two single 
doses with appropriate wash-out

AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Protection of subjects by 
administration of only two single 
doses with appropriate wash-out
Following administration of BI 
1810631, subjects will be in-house 
under close observation for at 
least 48 hours

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy


Drug-related AEs 
observed in patients in 
trial 1479-0001
After multiple dosing with 
BI 1810631, AEs assessed as 
drug-related were reported 
(see Section 1.2.2.)
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Following administration of 
BI 1810631, subjects will be in-
house under close observation for 
at least 48 hours 
Protection of subjects by 
administration of only two single 
doses with appropriate wash-out
Uncertainties due to the 
early stage of 
development
. However, 
BI 1810631 is currently in 
early development and there 
may be unknown risks of 
treatment with BI 1810631
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Following administration of 
BI 1810631, subjects will be in-
house under close observation for 
at least 48 hours 
Safety Lab, VS and ECGs after 
dosing (see Flow Chart)
Protection of subjects by 
administration of only two single 
doses with appropriate wash-out

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Rare but severe event, thus 
under constant surveillance 
by sponsors and regulators.
Only healthy volunteers will be 
included in the trial and exposed 
to a maximum two doses of BI 
1810631.


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.
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 
 HER2 mutations.

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It provides a unique opportunity for the treatment of NSCLC patients harbouring HER2
mutations, and data further suggest that BI 1810631 could be 
BI 1810631 has been adequately characterized in preclinical studies. Preclinically identified 
toxicities are addressed by appropriate mitigation (see Section 1.4.2). Moreover, preliminary
data from two clinical trials are available (see Section 1.2.2) that support the
 planned for the current trial. In particular, BI 1810631
has been given at multiple doses of up to
and of up to
over at least 
21 days to patients in first-in-man trial 1479-0001, and in that study, BI 1810631 
This trial is required to inform the label of BI 1810631 and to acquire market approval in e.g. 
 The resulting data are used to assess the
Considering the medical need for an effective and safe treatment of solid tumours with HER2 
mutations, the benefit of this trial is assessed to outweigh the potential risks.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of a
of BI 1810631
 
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 1810631:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time from 0 to the last quantifiable data point) 

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-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

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

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as an open-label, randomised, single-dose, two-way crossover 
trial in healthy male subjects in order to compare the test treatment (T) to the reference 
treatment (R). The treatments will be
of BI 1810631
administered to 
subjects
 (Test, T) and
of BI 1810631
administered to 
subjects in the
(Reference, R). The subjects will be randomly allocated to the 2 
treatment sequences (R-T or T-R). For details, refer to Section 4.1.
There will be a washout period of 
between the administrations of BI 1810631 
in subsequent treatment periods. A graphic of the trial design is displayed in Figure 3.1: 1 
below.
Figure 3.1: 1
Trial design
Each treatment sequence (A, B) includes 8 healthy volunteers, i.e., 16 volunteers in total. In each treatment period (1, 2), the 
healthy volunteers receive
of BI 1810631
.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For relative bioavailability the crossover design is preferred because of its efficiency: since 
each subject serves as his own control, the comparison between treatments is based on an 
intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
The washout phase of 
 between the drug administrations of subsequent 
treatment periods is chosen to diminish the impact of possible carryover effects.
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of BI 1810631, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
between the 
administrations of BI 1810631
R
T
T
R
Treatment periods
1
2
Treatment
sequences
A
B

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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 no data on reproductive toxicology 
are available at this time.
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 55 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
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders

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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 within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin
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 and any kind of vaccination)
13. Intake of an investigational drug in another clinical trial within 60 days or within five 
half-lives, whichever is longer 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
of the trial site
21. A marked prolongation of QT/QTcF interval (such as QTcF 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)
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. Male subjects with WOCBP partner who are unwilling to use highly effective 
contraception from time point of administration of BI 1810631 until 30 days after the last 
administration of BI 1810631. Highly effective methods of contraception are:
- Subject is sexually abstinent, if this is in line with his usual lifestyle.

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- 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.
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.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.2) the
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP, in order to 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 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

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4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events (AEs), or diseases). 
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
6. The subject has a QTcF increase of greater than 60 ms from baseline in connection with 
absolute QTc greater than 500 ms, as confirmed by a repeat ECG recording.
7. The subject experiences a drug-related adverse event of severe intensity or a serious 
adverse event.
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.
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 overall or at a particular trial site
2. The sponsor decides to discontinue the further development of the investigational 
products
3. Deviation from GCP, or the CTP or the contract with BI 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 or grade 3 severity (except for grade 2 headache), or if at least one drug-
related serious adverse event is reported
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).

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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 objective 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 
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. A replacement subject will be 
assigned a unique randomization number, and will be assigned to the same treatment
sequence as the subject he replaces.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
BI 1810631 will be provided by BI Pharma GmbH & Co. KG, Germany.
Substance:
BI 1810631
Pharmaceutical formulation:
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
Mode of administration:
Oral
Duration of use:
Single dose in treatment R and T
4.1.2
Selection of doses in the trial
The dose selected for this trial is expected
4.1.3
Method of assigning subjects to treatment groups
The randomisation scheme will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
scheme will be allocated to the subjects according to respective internal regulation. Subjects 
are then assigned to a treatment sequence according to the randomisation scheme.
Once a randomization number has been assigned to the subject, it cannot be reassigned to any 
other subject.
For safety considerations, the subjects will be divided into at least 2 cohorts, with at
maximum 6 subjects in the first cohort. Cohort 1 and Cohort 2 will be separated by at least 1 
week (between dosings in treatment period 1).
The randomisation procedure is described in Section 7.4.

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4.1.4
Drug assignment and administration of doses for each subject
This is a 2-way crossover trial. All subjects will receive the 2 treatments in randomised order. 
The treatments to be evaluated are summarised in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T (Test )
BI 1810631
R (Reference)
BI 1810631
Administration of trial medication in the Reference period
. The 
investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a standing or sitting position. For 
drug administration, the so-called four-eye principle (two-person rule) should be applied. For 
this, one authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot 
be ensured otherwise.
In one treatment period (Treatment T), the subjects
Table 4.1.4: 2
Subjects will be kept under close medical surveillance until 48 h after drug administration. 
During the first 4 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture). For 

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measurement of vital signs and ECGs a resting time of at least 5 minutes in the supine 
position is permitted.
The treatments will be separated by a wash-out phase of 
between BI 1810631
administrations.
4.1.5
Blinding and procedures for unblinding
The table below summarizes the masking/blinding level of individual functions, roles and 
responsibilities involved in the trial.
Table 4.1.5: 1
Blinding level of individual functions
Role/function
Timing of Unblinding / receiving access to the treatment information 
(including rationale)
Subject/Participant
This open label trial will provide the subject treatment information as 
soon as treatment has been assigned.
Investigator/Site Staff
As requested to prepare trial site prior to first subject entered.
The randomization scheme will be provided to the trial site prior to 
randomization for preparation of medication.
Sponsor trial team 
and data
Unblinded as requested.
Bioanalytical Staff
Persons directly involved in bioanalyses of PK samples will be blinded 
to trial treatments. 
Pharmacologist/
Pharmacometrician
As requested for analysis.
Unblinded Pharmacist/ 
Pharmacy staff
Prior to first subject entered if necessary
During the time a role/function is blinded according to the table above, the randomisation 
schemes and medication kit lists (i.e. the treatment information) are kept restricted by the 
global Randomization Team per Sponsor SOP.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
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).
The label will be prepared according to regulation (EU) No 536/2014, Annex 6, omitting
certain particulars with the following justification:
The "keep out of reach of children" statement was omitted from the label because the product
will remain at the clinical site.
The investigator name was omitted from the label because it is included on the Trial
Identification Card (TIC), which will be issued to each trial participant.

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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 including the name of the investigator are provided in the subject information form. The
EU CT number, the Sponsor study number, and the trial site study number are indicated on
the title page of this protocol as well as on the subject information and informed consent
forms.
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

Availability of a signed and dated clinical trial contract between the sponsor or 
delegate and the investigational site

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. 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.

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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.
In case of

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Table 4.2.1: 1
Grade-specific treatment recommendations of 
 
Severity (CTCAE 
grading)
Description
Treatment recommendations
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on trial days) on the appropriate pages of the CRF.
In case of AEs requiring analgesic / antiphlogistic treatment such as headache, short-term use 
of ibuprofen is acceptable.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to 
those provided by the staff.
From 1 h before drug intake until
, fluid intake is restricted 
 
, the water administered with the drug, and an 
additional 240 mL of water
(mandatory for all subjects). From 
 
until 24 h post-dose, total fluid intake is restricted to 3000 mL.

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Alcoholic beverages are forbidden from 4 days before the first administration of trial 
medication until after the last PK sample taken of the trial.
are not permitted from 7 
days before the first administration of trial medication until after the last PK sample of the 
trial is collected.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
4.2.2.3
Contraception requirements
Subjects whose sexual partner is a WOCBP must be sexually abstinent or use highly effective 
contraception starting from the first dose of BI 1810631 and for at least 30 days after the last 
dose of BI 1810631. See Section 3.3.3 for required contraceptive measures.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight
and BMI, smoking and alcohol history (alcohol history not mandatory to be entered into CRF 
or to be reported), relevant medical history and concomitant therapy, check of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests (including 
drug screening and alcohol breath test), 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 (Philips
IntelliVne MP70/X2)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
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
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
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT 
ALT [Alanine aminotransferase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
X
X
X
X
X
X
X
X
X
X
X
--
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
X
--
X
--
X
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
Cholesterol, total 
Triglyceride
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
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 leucocyte esterase (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment1
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
1 microscopic examination if erythrocytes, leukocytes, nitrite, or protein are abnormal in urine
A: Safety laboratory at screening, B: Safety laboratory during the study and C: safety laboratory at end-of-trial visit

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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 the time points indicated by the 
Flow Chart.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
THC
Cocaine 
Methadone
Methamphetamines/MDMA/Ecstasy
Morphine
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 (Dräger Alcotest®)
will be performed prior to 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 
SURESTEP Urine drug Test Cassette or comparable 
test systems. The SARS-CoV-2 PCR test will be performed at 
prior to admission, if it is 
needed due to the current status of the pandemic.
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). 
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
 
at the times provided in the Flow Chart. 

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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.
All locally printed ECGs will be signed and dated by the investigator or a designee and 
evaluated in the SDB. 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 

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.

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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 Section 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
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:

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
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.


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].

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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

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. 

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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 and/or delegated study team members on behalf of 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.
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.
For reporting of safety information to the Agency by the sponsor please refer to section 8.4.

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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 Studies 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,
of blood will be drawn 
from an antecubital or forearm vein into an
drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle.
The
 blood samples will be centrifuged for
. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least
of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 
, with interim storage of blood samples and aliquots
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 
 
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 
 or below 
until analysis
At a minimum, the sample tube labels should list BI trial number, barcode, subject number, 
visit, and planned sampling time.

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After analysis, the plasma samples may be used for further methodological investigations
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte and/or 
its metabolite(s) 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.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure. 

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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.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs, ECG, and safety laboratory tests will be ± 30 min.
If scheduled in the Flow Chart at the same time 
, 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.
For procedures scheduled for days 4, 5, 6, 7 and 8, 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.
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days -1 to Day 8 in each 
period).
will separate drug administrations in the first and second treatment 
periods.
In the morning 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 48 h following BI 1810631
administration. The subjects will then be allowed to leave the trial site after formal 

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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 
 
 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/she 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.
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.
Important protocol deviations may be:

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
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

Incorrect intake 
 

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

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: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment 
k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2,

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sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., 8
j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm 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.
 
 
 
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.

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For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the 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 1.2.2) 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 data base lock will be reported to Pharmacovigilance only and will not be captured in 
the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), 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.
For laboratory data and vital signs baseline is defined as the last measurement prior to trial 
medication intake of respective treatment period.
Relevant ECG findings will be reported as AEs.
7.2.6
Interim analyses
No interim analysis is planned.

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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. 
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.4
RANDOMISATION
Subjects will be randomised to one of the 2 treatment sequences (R-T, T-R) in a 1:1 ratio.
The block size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation scheme will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation scheme will contain additional blocks to allow for subject replacement 
(refer to Section 3.3.5).
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 16 subjects in the trial, including up to 4 dropouts or non-PK 
evaluable subjects, because this sample size is considered sufficient to achieve the aims of 
this exploratory trial. With this sample size, the following precision in estimating the ratio of 
geometric means (test/reference) can be expected with 95% probability. Precision is defined 
as the ratio of upper CI limit to the relative BA estimate. Note that the precision is 
independent of the actual ratio of geometric means.
The observed intra-individual coefficient of variation (gCV) for BI 1810631 in previous trial 
1479-0003 [c40238670] was 
.
For various assumptions the gCV is considered
 and up to
. 
Table 7.5: 1 provides an overview of the achievable precision for estimating the ratio of 
geometric means (test/reference) based on the ratios of geometric means observed in the 
previous trial 1479-0003, i.e. gMean ratio around 
and
 For 
illustrative purposes, the expected 90% confidence intervals are displayed for different values 
of the ratios T/R of geometric means based on a sample size of N=12, 14 and 16 evaluable 
subjects.

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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 2x2 crossover trial (N=12, 14, 
16)
N
gCV 
[%]
Precision 
upper CL** 
/ relative BA 
estimate
90% CI [%] of respective ratio*
50
75
100
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
**Confidence interval limit
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 4.1.2.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles. 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. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract.
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
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.
8.2
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.

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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.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
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, 
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:

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
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.
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. 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 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.

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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements including Clinical Trial Regulation Art. 42.
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.
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a participant identification number instead of the trial 
participant’s name. The code is only available at the site and must not be forwarded to the 
sponsor. In case participant’s records will be forwarded e.g. for SAE processing or 
adjudication committees, personal data that can identify the trial participant will be redacted 
by the site prior to forwarding. Access to the participant files and clinical data is strictly 
limited: personalised treatment data may be given to the trial participant’s personal physician 
or to other appropriate medical personnel responsible for the trial participant’s welfare. Data 
generated at the site as a result of the trial need to be available for inspection on request by 
the participating physicians, the sponsor’s representatives, by the IRB/IEC and the regulatory 
authorities.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs/IECs and trial 
participants will be informed as appropriate.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, 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

Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF

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8.6
TRIAL MILESTONES
The first act of recruitment represents the start of the trial and is defined as the date when the 
first trial participant (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 Managers
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites
The trial medication will be provided by the
.
Safety laboratory tests will be performed by the local 
 
).

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Analyses of BI 1810631 concentrations in plasma will be 
 
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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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P15-01211
Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery 
tobasic science to mechanism-based cancer therapeutics. Cancer Cell; 
2014;25(3); 282-303. Cancer Cell 25, March 17, 2014 ª2014 Elsevier Inc. 
303.
P19-00456
Wang Y, Jiang T, Qin Z, Jiang J, Wang Q, Yang S, et al. HER2 exon 20
insertions in non-small-cell lung cancer are sensitive to the irreversible pan-
HER receptor tyrosine kinase inhibitor pyrotinib. Annals of Oncology. 31 
December 2018. 447-455.
P19-10412
Connell CM Doherty GJ. Activating HER2 mutations as emerging targets 
in multiple solid cancers. ESMO Open; 2, p. e000279; 2017.
P20-09250
Jebbink M Langen AJ de Boelens MC Monkhorst K Smit EF. The force of 
HER2 - a druggable target in NSCLC? Cancer Treat Rev; 86, p. 101996; 
2020.
R09-6185
Hynes NE MacDonald G. ErbB receptors and signaling pathways in cancer. 
Curr Opin Cell Biol; 21, p. 177-184; 2009.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
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; 7, p. 505-516; 2006.
R20-1990
Wang Z. ErbB receptors and cancer. Methods Mol Biol; 1652, p. 3-35; 
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Chow SCLiu JP. Design and Analysis of Bioavailability and 
Bioequivalence Studies.; 1992.

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9.2
UNPUBLISHED REFERENCES
c32836122
 Investigator's
Brochure BI 1810631 1479-P01. Current version.
c40238670

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10.
APPENDICES
Not applicable

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
08 Aug 2023
EUCT No.
2022-502860-19-00
BI Trial number
1479-0010 
BI Investigational Medicinal 
Product(s)
BI 1810631
Title of protocol
Relative bioavailability of BI 1810631 following 
oral administration
in healthy male subjects (an open-label, 
randomised, single-dose, two-way crossover trial)
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment
Non-substantial Global Amendment
Section to be changed
3.3.3
Description of change
Further specification of exclusion criteria #13
Rationale for change
To exclude intake of investigational drug in another 
trial within 60 days or within five half-lives, 
whichever is longer.
Request from competent authorities.
Section to be changed
5.2.6.2.2 and 8.4
Description of change
Addition of obligation of the sponsor to report 
safety information to the agency.
Rationale for change
Request from competent authorities

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BI Trial No.: 1479-0010
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Trial Protocol
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11.2
GLOBAL AMENDMENT 2
Date of amendment
13 Nov 2023
EUCT No.
2022-502860-19-00
BI Trial number
1479-0010 
BI Investigational Medicinal 
Product(s)
BI 1810631
Title of protocol
Relative bioavailability of BI 1810631 following 
oral administration
in healthy male subjects (an open-label, 
randomised, single-dose, two-way crossover trial)
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment
Non-substantial Global Amendment
Section to be changed
Title Page
Description of change
Clinical Trial Leader changed
Rationale for change
Change in Clinical Trial Leader

 
 
 
 
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clinical-trial-protocol-version-03
Relative bioavailability of BI 1810631 following oral administration 
 in healthy male subjects (an open-label, randomised, single-dose,
two-way crossover trial)
Boehringer 
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