Bioequivalence of Zongertinib Tablets From Two Different Manufacturers Following Oral Administration in Healthy Male and Female Subjects (an Open-label, Randomised, Single-dose, Two-period, Two-sequence Crossover Trial)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

Clinical Trial Protocol
TITLE PAGE
Document Number:
c43691238-02
EU Trial No.
2023-510495-31-00
Universal Trial No. (UTN)
U1111-1303-4345
BI Trial No.
1479-0019
BI Investigational
Medicinal Product
Zongertinib (BI 1810631)
Title
Bioequivalence of zongertinib tablets from two different manufacturers following 
oral administration in healthy male and female subjects (an open-label, randomised, 
single-dose, two-period, two-sequence crossover trial) 
Lay Title
A study in healthy people to see how zongertinib is taken up into the blood when 
given as tablets made by two different manufacturers
Clinical Phase
I
Clinical Trial Leader
Investigator
Current Version, Date
Version 2.0, 14 Mar 2024
Original Protocol Date
01 Feb 2024
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Boehringer 
\J1lll1v lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
01 Feb 2024
Revision date
Not applicable
BI trial number
1479-0019
Title of trial
Bioequivalence of zongertinib tablets from two different manufacturers following 
oral administration in healthy male and female subjects (an open-label, randomised, 
single-dose, two-period, two-sequence crossover trial)
Investigator
Trial site
Clinical phase
I
Trial rationale
To establish bioequivalence between zongertinib tablets manufactured by two 
different manufacturers.
Trial objective(s)
To establish bioequivalence between zongertinib tablets manufactured by two 
different manufacturers.
Trial endpoints
Primary endpoints: AUC0-72h and Cmax of zongertinib
Secondary endpoints: tmax of zongertinib
Trial design
Randomised, open-label, two-period, two-sequence crossover trial
Number of subjects 
total entered
56
on each treatment
56
Diagnosis
Not applicable
Main inclusion criteria
Healthy male/female subjects, age of 18 to 50 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Test product(s)
Zongertinib (BI 1810631) – manufactured by 
dose
mode of 
administration
Oral 
 

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Reference product(s)
Zongertinib (BI 1810631) – manufactured by 
dose
mode of admin.
Oral 
 
Duration of treatment
Single dose for each treatment 
Statistical methods
The assessment of bioequivalence will be based upon 2-sided 90% confidence 
intervals (CIs) for the ratios of the geometric means (gMean) (test/reference) for the 
primary endpoints using an acceptance range of 80.00 to 125.00%. This method 
corresponds to the two one-sided t-tests procedure, each at a 5% significance level. 
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 and 
quantiles from the t-distribution.
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 comment
Safety laboratory
PK blood zongertinib
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
1/2 (two identical periods 
between zongertinib administrations)
2/3
-1
-13:00
19:00
Admission to trial site
x
17
-2:00
06:00
Allocation to treatment2 (visit 2 only)
B5
x2
x2
x2
x2
0:00
08:00
Drug administration: zongertinib
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00
x
2:30
10:30
x
3:00
11:00
x
3:30
11:30
x
4:00
12:00
x
x
5:00
13:00
6:00
14:00
x
8:00
16:00
x
10:00
18:00
x
11:00
19:00
12:00
20:00
x
x 
27
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
FU
4
15 to 18
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, Electrocardiogramm (ECG), safety laboratory (including 
drug screening, 
 test and pregnancy test in women), demographics (including determination of body height and 
weight, smoking status and alcohol history), relevant medical history, concomitant therapy and review 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, the
 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 (Adverse Events) and concomitant therapies. 
5.
Including drug screening, 
 test and alcohol breath test as well as pregnancy test in women will be done at this 
time
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.
Standardized
 throughout the day during stationary phase of the trial.

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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.................................................................................... 11
1.1
MEDICAL BACKGROUND............................................................................11
1.2
DRUG PROFILE...............................................................................................12
1.2.1
Zongertinib............................................................................................12
1.2.2
Residual Effect Period..........................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................18
1.4
BENEFIT - RISK ASSESSMENT ...................................................................18
1.4.1
Benefits...................................................................................................18
1.4.2
Risks .......................................................................................................18
1.4.3
Discussion...............................................................................................22
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 23
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......23
2.1.1
Main objectives......................................................................................23
2.1.2
Primary endpoint(s)..............................................................................23
2.1.3
Secondary endpoint ..............................................................................23
2.2.2.2
Safety and tolerability..............................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 25
3.1
OVERALL TRIAL DESIGN............................................................................25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................25
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 ..................................................................................26
3.3.4
Withdrawal of subjects from treatment or assessments ...................28
3.3.4.1
Withdrawal from trial treatment ..............................................28
3.3.4.2
Withdrawal of consent to trial participation ............................29
3.3.4.3
Discontinuation of the trial by the sponsor..............................29
3.3.5
Replacement of subjects .......................................................................30

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4.
TREATMENTS........................................................................................ 31
4.1
INVESTIGATIONAL TREATMENTS ..........................................................31
4.1.1
Identity of the Investigational Medicinal Products ...........................31
4.1.2
Selection of doses in the trial and dose modifications........................31
4.1.3
Method of assigning subjects to treatment groups ............................31
4.1.4
Drug assignment and administration of doses for each subject .......32
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............................................................................................34
4.2.2.1
Restrictions regarding concomitant treatment .........................34
4.2.2.2
Restrictions on diet and life style.............................................34
4.2.2.3
Contraception requirements.....................................................35
4.3
TREATMENT COMPLIANCE.......................................................................35
5.
ASSESSMENTS....................................................................................... 35
5.1
ASSESSMENT OF EFFICACY.......................................................................35
5.2
ASSESSMENT OF SAFETY............................................................................35
5.2.1
Physical examination ............................................................................35
5.2.2
Vital signs...............................................................................................35
5.2.3
Safety laboratory parameters..............................................................36
5.2.4
Electrocardiogram................................................................................38
5.2.5
Other safety parameters.......................................................................39
5.2.6
Assessment of adverse events...............................................................39
5.2.6.1
Definitions of adverse events...................................................39
5.2.6.1.1Adverse event...........................................................................39
5.2.6.1.2Serious adverse event...............................................................39
5.2.6.1.3AEs considered ‘Always Serious’ ...........................................40
5.2.6.1.4Adverse events of special interest............................................40
5.2.6.1.5Intensity (severity) of AEs.......................................................41
5.2.6.1.6Causal relationship of AEs.......................................................41
5.2.6.2
Adverse event collection and reporting ...................................42
5.2.6.2.1AE collection ...........................................................................42
5.2.6.2.2AE reporting to the sponsor and timelines...............................43
5.2.6.2.3Pregnancy.................................................................................43
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................44
5.3.1
Assessment of pharmacokinetics .........................................................44
5.3.2
Methods of sample collection...............................................................44

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5.3.2.1
Blood sampling for pharmacokinetic analysis.........................44
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................45
5.4
ASSESSMENT OF BIOMARKERS................................................................45
5.4.1
Drug-Drug Interaction Biomarkers ....................................................45
5.4.2
Pharmacodynamic biomarkers............................................................45
5.4.3
Pharmacogenomic biomarkers............................................................45
5.5
BIOBANKING ...................................................................................................45
5.6
OTHER ASSESSMENTS .................................................................................45
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................45
6.
INVESTIGATIONAL PLAN.................................................................. 46
6.1
VISIT SCHEDULE............................................................................................46
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................46
6.2.1
Screening and run-in period(s)............................................................46
6.2.2
Treatment period(s)..............................................................................46
6.2.3
Follow-up period and trial completion ...............................................47
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 48
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................48
7.2
PLANNED ANALYSES....................................................................................48
7.2.1
General considerations.........................................................................48
7.2.1.1
Analysis sets.............................................................................48
7.2.1.2
Pharmacokinetics.....................................................................49
7.2.2
Primary endpoint analyses...................................................................49
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 ..................................................................52
7.3.1
Safety......................................................................................................52
7.3.2
Pharmacokinetics..................................................................................52
7.4
RANDOMISATION ..........................................................................................52
7.5
DETERMINATION OF SAMPLE SIZE ........................................................52
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 54
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................54

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8.2
DATA QUALITY ASSURANCE .....................................................................55
8.3
RECORDS..........................................................................................................55
8.3.1
Source documents .................................................................................55
8.3.2
Direct access to source data and documents.......................................56
8.3.3
Storage period of records.....................................................................56
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................57
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......57
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................57
8.6
TRIAL MILESTONES .....................................................................................57
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................58
9.
REFERENCES......................................................................................... 60
9.1
PUBLISHED REFERENCES...........................................................................60
9.2
UNPUBLISHED REFERENCES.....................................................................61
10. APPENDICES .......................................................................................... 62
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 63

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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
AUC0-72h
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 72h
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
EoS
End of Study (synonym for End of Trial)
EudraCT
European Clinical Trials Database
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
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
PDX
Patient derived xenografts
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis set

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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 (HR), e.g. using the method of 
Fridericia (QTcF) or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
T
Standard operating procedure
Test
TMF
Trial master file
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
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration

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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
1.2.1
Zongertinib
A summary of the drug profile is provided below. For detailed information, refer to the 
current Investigator’s Brochure [c32836122].
Mode of action
Zongertinib is an EGFR wild type sparing, selective HER2 inhibitor with potent inhibitory 
activity on all oncogenic HER2 mutations including the HER2 YVMA insertion allele.
Data from non-clinical studies
Non-clinical pharmacology
Non-clinical pharmacokinetics

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Safety pharmacology / Toxicology
Data from clinical studies 
Prior to the current trial, BI 1810631 was administered in the ongoing first-in-man trial in
patients with cancer 1479-0001 and in five PK studies in healthy volunteers (trial 1479-0003, 
1479-0004, 1479-0006, 1479-0010, 1479-00011).
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 as monotherapy in patients with advanced or metastatic solid
tumors with HER2 aberrations. Patients are continuously treated in different dose groups with
 PK, safety, and efficacy data are collected.
Patients were treated in the dose escalation phase with escalating doses of zongertinib (BI 
1810631) monotherapy administered
 
 
 as well as in the dose expansion phase 
with
 (38 patients) and 
(41 patients). 
Overall, the median treatment duration was 147 days and the exposure ranged from 1 to 568 
days during the dose escalation at data cut-off; during the dose expansion, the median 
treatment duration was 64 days and the exposure ranged from 1 to 147 days.
Data cut time point for the data described here is 15 Sep 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

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bioavailability of BI 1810631 after administration as two different formulations (trial
formulation 1 [TF1] and new formulation [NF]), investigated the
. Thirteen healthy male volunteers were dosed with single doses of 
BI 1810631 in 4 treatment periods in randomized order, 
 The 4 treatments were:
- R: 
I 1810631 trial formulation 1 (TF1)
- T1
BI 1810631 new formulation (NF)
- T2
BI 1810631 NF
- T3
BI 1810631 NF
rabeprazole.
Short description of healthy volunteer trial 1479-0004
In trial 1479-0004, th
of BI 1810631 in 16 healthy
male subjects (an open-label, two-period, fixed-sequence trial) was tested.
Short description of healthy volunteer trial 1479-0006
In trial 1479-0006, a phase I, open-label trial in two parallel parts investigated
mass balance, metabolism, and basic pharmacokinetics of BI 1810631 
 
 and investigated absolute bioavailability of BI 1810631
 
 in 15 healthy male volunteers.
Short description of healthy volunteer trial 1479-0010
In trial 1479-0010, the relative bioavailability of
 BI 1810631 following oral
administration 
 in 16 healthy male subjects (an open-label, 
randomised, single-dose, two-way crossover trial) was tested. 
Short description of healthy volunteer trial 1479-0011
In trial 1479-0011,
of BI 1810631 was tested in 16 healthy
male subjects (an open-label, two-period, fixed-sequence trial).
Safety and tolerability data of patient first-in-man trial 1479-0001 (preliminary data)
Overall, zongertinib (BI 1810631) was well tolerated in patients in trial 1479-0001 and the
majority of drug-related Adverse Events (AEs) was manageable. The MTD has not been 
reached in both
treatment schedules. AEs leading to dose reductions, treatment interruptions, and treatment

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discontinuations were infrequent.
During dose escalation, the most frequent AEs were diarrhoea (24 patients, 39.3%), followed
by anaemia (13 patients, 21.3%), ALT increased (11 patients, 18.0%), AST increased
(11 patients, 18.0%), blood alkaline phosphatase increased (10 patients, 16.4%), blood
creatinine increased (10 patients, 16.4%) and COVID-19 (7 patients, 11.5%).
Dose limiting toxicities during the MTD evaluation period were diarrhoea Grade 3 
) and platelet count decreased Grade 3 
). In total, 25 (41%)
patients had an SAE, with 1 patient (1.6%) having SAEs that were considered drug-related by
the investigator (Grade 3 ALT increased and Grade 3 AST increased). Reported fatal AEs
were not drug-related.
During dose expansion, most frequent AEs were diarrhoea (28 patients, 35.4%), anaemia
(15 patients, 19%), ALT increased (10 patients, 12.7%), AST increased (10 patients, 12.7%),
decreased appetite (9 patients, 11.4%), lymphocyte count decreased (9 patients, 11.4%) and
dysgeusia (8 patients, 10, 1%). Dose limiting toxicities during the MTD evaluation period
were diarrhoea Grade 3, febrile neutropenia Grade 3 and immune thrombocytopenia Grade 4
(all at 240 mg QD). SAEs were reported in 9 (11.4%) of patients. SAEs assessed as drug-
related by the investigator occurred in 5 patients (6.3%). These were ALT increased and AST
increased (in 2 patients each, 2.5%), as well as hepatic failure, immune thrombocytopenia,
intestinal obstruction and neutrophil count decreased (in 1patient each, 1.3%). Reported fatal
AEs were not drug-related.
Hepatotoxicity
Elevations of liver enzymes and bilirubin have been reported during treatment with
zongertinib (BI 1810631) in trial 1479-0001. AEs in the SMQ liver related investigations,
signs and symptoms occurred in 20 patients (32.8%) during dose escalation and in 19 patients
(24.1%) during dose expansion. During dose escalation, liver related investigations were
Grade 3 in 6 patients (9.8%) and during dose expansion, Grade 3 or 4 in 2 patients (2.5%)
each. First onset of the liver related investigations was within 30 days in 13 patients (21.3%)
during dose escalation and in 16 patients (20.3%) during dose expansion. During dose
escalation, liver related investigations led to interruption of trial medication in 5 patients
(8.2%) and to permanent treatment discontinuation or dose reduction in 1 patient each
(1.6%). During dose expansion, liver related investigations led to dose reduction or treatment
interruption in 2 patients (2.8%) each.
Two cases of severe hepatic AEs have been reported.
A patient had occasional right hypochondrium pain, choluria, progressive jaundice, and
diarrhoea starting on Day 36 of treatment with 
 zongertinib (BI 1810631) 
. One
week later the patient was admitted to the hospital with hepatic failure and prolonged
prothrombin time. During hospitalisation, study medication was interrupted, and the patient
was treated with N-acetylcysteine and methylprednisolone over 7 days. After discharge from

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the hospital treatment continued with 50 mg prednisolone. The patient was recovering and 
restarted study drug on Day 63 
. Liver enzymes and bilirubin
were further normalising. The patient had COVID-19 infection and was treated with
Remdisivir starting on Day 25 of study treatment as possible confounding factors.
A second patient who was treated with
 zongertinib (BI 1810631) 
 over 42 days
developed, despite interruption of study drug due to ALT, AST Grade 2 and total bilirubin
Grade 1, further increases of ALT and AST up to Grade 4 (>20.0x ULN), increased total
bilirubin up to Grade 3 (>3x ULN), and coagulopathy Grade 3 on Day 55. On Day 57, the
patient had developed subacute hepatic failure Grade 4, cholestasis Grade 4 and 
hypoalbuminaemia Grade 2. Treatment of the AEs included hepatoprotective and 
anticholestatic agents as well as dexamethasone. Liver enzymes and total bilirubin were
improving between Days 66 and 76. During the further course the patient developed infection
(on Day 81) and subsequent sepsis (on Day 86) with fatal outcome 7 days later. Further
evaluations are ongoing.
Diarrhoea
Diarrhoea was reported during treatment with zongertinib (BI 1810631) and was of mainly of
Grade 1 and 2. Diarrhoea occurred in 24 patients (39.3%) during dose escalation and in
28 patients (35.4%) during dose expansion. Diarrhoea was Grade 3, in 3 patients (4.9%)
during dose escalation, and in 2 patients (2.5%) during dose expansion. Due to observed
long-lasting periods in some patients, a proactive management of diarrhoea including
adequate hydration combined with anti-diarrhoeal agents should start at first signs of
diarrhoea.
Preclinical Embryotoxicity
Based on findings from animal studies and its possible mechanism of action, zongertinib
(BI 1810631) could cause fetal harm when administered to a pregnant woman. In animal
reproduction studies, administration of zongertinib (BI 1810631) to pregnant rats during
organogenesis caused embryo-fetal death. Pregnant women are not to be treated with
zongertinib (BI 1810631).
Females of reproductive potential and male patients with female partners of reproductive
potential are to be advised to use dual highly effective contraception (meaning e.g. the use of
one highly effective non-barrier method and one barrier method resulting in a low failure rate
of less than 1% per year) during treatment and for at least 30 days after the last dose.
Safety and tolerability data of healthy volunteer trial 1479-0003
In trial 1479-0003, in which oral 
 BI 1810631 were administered to
healthy volunteers, there were no SAEs, no Adverse events of special interest (AESI), and no 
other significant AEs. All AEs
were of CTCAE Grade 1 or 2 severity, and none of the AEs were assessed as drug-related.

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Available safety data including AEs, Electrocardiogram (ECGs), VS, and safety laboratory 
indicate that 
 BI 1810631 were safe and well tolerated in trial 1479-0003. For more details
refer to the IB [c32836122].
Safety and tolerability data of healthy volunteer trial 1479-0004
There were no deaths, no serious AEs, no CTCAE grade 3, 4, or 5 AEs, and no protocol-
specified AEs of special interest reported. A grade 1 AE of diplopia led to the premature 
discontinuation
 in 1 subject (6.3%) and was the only significant AE in the 
trial, according to ICH E3. The event was considered related to trial drug and resolved 
without therapy. All AEs were reported as resolved by the end of the trial, except an AE of 
hand fracture which was not considered related to trial drug. No relevant changes in
laboratory values, vital signs, or ECGs were reported as AEs.
Preliminary Safety and tolerability data of healthy volunteer trial 1479-0006
There were no SAEs, no AESIs, and no other significant AEs. All AEs
were of CTCAE Grade 1 severity. In part A and B, only Diarrhoea (in 2 HVs) and abdominal 
pain (all Grade 1) were assessed as drug-related.
Available safety data including AEs, ECGs, VS, and safety laboratory indicate that 
 BI 1810631 were safe and well tolerated in trial 1479-0006.
Preliminary Safety and tolerability data of healthy volunteer trial 1479-0010
There were no SAEs, no AESIs, and no CTCAE grade 3, 4 and 5 AEs. 
Available safety data including AEs, ECGs, VS, and safety laboratory indicate that 
 BI 1810631 were safe and well tolerated in trial 1479-0010.
Preliminary Safety and tolerability data of healthy volunteer trial 1479-0011
There were no SAEs, no AESIs, and no other significant AEs. All AEs
were of CTCAE Grade 1 severity. One HV had fatigue Grade 1 assessed as drug-related,
Available safety data including AEs, ECGs, VS, and safety laboratory indicate that 
 BI 1810631 were safe and well tolerated in trial 1479-0011.
Clinical Pharmacology
Preliminary, exploratory PK analysis in trial 1479-0001 indicated
 
 
 The observed PK profile of zongertinib appears to be compatible with 
 
dosing to achieve efficacious plasma exposure, which is also suggested by the observed 
clinical responses in the respective 
 dose groups.

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PK results of trial 1479-0003 in healthy volunteers indicate similar bioavailability between 
the original formulation and a new formulation, that is functionally similar to the 
 
formulation used in further clinical development. The new formulation showed a negative 
 and its bioavailability was
 
1.2.2
Residual Effect Period
The Residual Effect Period (REP) of single doses of BI 1810631 is conservatively estimated 
as 14 days. 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
Zongertinib tablets were manufactured by two different manufacturers
). It 
is required to demonstrate bioequivalence between tablets 
 
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 zongertinib 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 for this 
trial
Summary of data, rationale for the risk
Mitigation strategy
Investigational Medicinal Product: Zongertinib (BI 1810631)
Unexpected AEs and 
laboratory abnormalities 
Risk is due to limited clinical experience with 
zongertinib 
(BI 1810631)
Close monitoring of safety data.

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Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale for the 
risk
Mitigation strategy
Investigational Medicinal Product: Zongertinib (BI 1810631)

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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
In summary, safety measures are implemented in the trial to mitigate possible risks. 
Considering the medical need for the development of a better tolerated and more effective 
treatment for patients diagnosed with solid tumors the expected benefit outweighs 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 establish the bioequivalence of 
of zongertinib  
tablet manufactured by 
(Test, T) compared with 
 of zongertinib tablet 
manufactured by 
(Reference, R) following oral administration.
2.1.2
Primary endpoint(s)
The following pharmacokinetic parameters will be determined for zongertinib:

AUC0-72h (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 72h)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for zongertinib:

tmax (time from dosing to maximum measured concentration of the analyte in plasma)

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2.2.2.2
Safety and tolerability
Safety and tolerability of zongertinib 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, randomized, single-dose, two period, two-
sequence crossover trial in healthy male and female subjects in order to compare the test 
treatment (T) to the reference treatment (R). The treatments will be 
 zongertinib
tablet manufactured by 
 (T) administered to subjects 
 
zongertininib tablet manufactured by 
(R) administered to subjects 
 
 The subjects will be randomly allocated to the 2 treatment sequences (T-R or R-T). For 
details, refer to Section 4.1.
There will be a washout period
 between the treatments.
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(S)
For bioequivalence trials, the crossover design is preferred because of its efficiency: since 
each subject serves as his/her own control, the comparison between treatments is based on an 
intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of the analyte, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 56 healthy male and female subjects will enter the trial. They will be 
recruited from the volunteers' pool of the trial site.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not.
3.3.1
Main diagnosis for trial entry
The 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:

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1. Healthy male or female subjects according to the assessment of the investigator, as based 
on a complete medical history including a physical examination, vital signs (blood 
pressure (BP), PR), 12-lead ECG, and clinical laboratory tests 
2. Age of 18 to 50 years (inclusive) 
3. BMI (Body mass index 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
5. Either male subject, or female subject who meet any of the following criteria for a highly 
effective contraception from at least 30 days before the first administration of trial 
medication until 30 days after trial completion:
-
Use of progestogen-only hormonal contraception that inhibits ovulation (only 
injectables or implants), plus condom
-
Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
-
Sexually abstinent
-
A vasectomised sexual partner who received medical assessment of the surgical 
success (documented absence of sperm) and provided that partner is the sole sexual 
partner of the trial participant
-
Surgically sterilised (including hysterectomy or bilateral tubular occlusion)
-
Postmenopausal, defined as no menses for 1 year without an alternative medical cause
(in questionable cases a blood sample with levels of FSH above 40 U/L and estradiol 
below 30 ng/L is confirmatory)
3.3.3
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 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)

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7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant 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)
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.
 is defined as currently 
15. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per day for
males)
16. Drug abuse, positive 
 test or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Ovum or sperm donation is not permitted until 30 days after last drug administration.
19. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms in males or repeatedly greater than 470 ms in females) or any other 
relevant ECG finding at screening
22. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
23. 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. Women of childbearing potential (WOCBP) and men able to father a child who are 
unwilling to use highly effective methods of birth control per ICH M3 (R2) that result in a 
low failure rate of less than 1% per year when used consistently and correctly in 
combination with a barrier method.

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25. For female subjects: Lactation, pregnancy, or plans to become pregnant during the trial or 
within 30 days after trial completion
26. For female subjects: Positive pregnancy test.
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 / she is not willing or able to adhere to the trial 
requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as pregnancy, 
surgery, adverse events (AEs), or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF

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In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.6.2.3.
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 3 severity, or if more than two subjects have drug-related severe non-
serious adverse events, 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 
Clinical Pharmacologist and the Trial Statistician are to decide, if and how many subjects 
will be replaced. The total number of replacements may not exceed 17 subjects. A 
replacement subject will be assigned a unique trial subject number, and will be assigned to 
the same treatment sequence as the subject he or she replaces.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Name:
Zongertinib
Substance:
BI 1810631
Pharmaceutical formulation: Film-coated tablet (Test)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
Mode of administration:
Oral
The characteristics of the reference product are given below:
Name:
Zongertinib 
Substance:
BI 1810631
Pharmaceutical formulation: Film-coated tablet (Reference)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
Mode of administration:
Oral
4.1.2
Selection of doses in the trial and dose modifications
The dose selected for this trial is 
 used for further development of 
zongertinib (see Section 1.2).
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 rules. Subjects are 
then assigned to a treatment sequence according to the randomisation scheme.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
Due to logistical the group will be split into several cohorts as required. 
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
Film-coated 
tablet
R (Reference)
BI 1810631
Film-coated 
tablet
Administration of trial medication will be performed after subjects have
 
 The investigator (or 
authorised designee) will administer the trial medication as an oral dose 
 
 to subjects who are in a standing position. For drug administration, the so-
called four-eye principle (two-person rule) should be applied. For this, one authorised 
employee of the trial site should witness the administration of trial medication, and – if 
applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
Subjects will be kept under close medical surveillance until 48 h after drug administration. 
During the first 5 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).
The treatments will be separated by a wash-out phase 
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP). 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form.

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The label will be prepared according to regulation (EU) No 536/2014, Annex 6, omitting 
certain particulars with the following justifications:

The “keep out of reach of children” statement was omitted from the label because the 
product will remain at the clinical site.

The visit number is not relevant for 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.
As per FDA requirement reserve samples are available for storage by the investigational site 
and that the trial materials can be chosen in a random way by the Investigator.
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 

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products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed except for hormonal contraceptives. All
concomitant or rescue therapies will be recorded (including time of intake on trial days) on 
the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised
 at the times
indicated in the Flow Chart.
From 1 h before drug intake 
 is restricted to the water administered 
 (mandatory for all 
subjects).
 until 24 h post-dose, total fluid intake is restricted to 3000 mL.
Alcoholic beverages,
, and 
dietary supplements
) are not 
permitted from 7 days before the first administration of trial medication until EoS.
 
 are not allowed from 24 h before until 24 h after each administration of trial 
medication.
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.

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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.
WOCBP (for the definition please refer to Section 3.3.2 and men able to father a child must 
abstain from intercourse or use two medically approved methods of birth control throughout 
the trial, and for a period of at least 30 days after last trial drug intake, one barrier method, 
and one highly effective non-barrier method.
Additionally ovum or sperm donation is not permitted until 30 days after last drug 
administration.
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).
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history not mandatory to be entered into CRF or to be 
reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 12-
lead ECG, laboratory tests, and a physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured at the times indicated in the

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Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm, 
if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
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
Neutrophils, 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
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 
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
Cholesterol, total 
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 RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine 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: parameters to be determined at screening examination
B: parameters to be determined during the study (for time points refer to Flow Chart)
C:  parameters to be determined at end of trial examination

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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 pregnancy tests, 
 test and drug screening, it is planned to perform 
these tests during screening only. Pregnancy testing in women will be performed at 
screening, prior to each treatment period, and as part of the end of trial examination. Drug 
screening and 
 test will be performed at screening and prior to each treatment period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/ Methylenedioxyamphetamine (MDA)
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/Ecstasy
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
 test (urine)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with 
 
 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 the local 
laboratory of the trial site, with the exception of drug screening and 
 tests.
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 the times provided in the Flow Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.

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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. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). Precise electrode placement will be marked with an 
indelible mark on the skin to allow reproducible placement throughout the trial.
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the subject will be removed from 
the trial and will receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
Not applicable
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

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 electronic case report form (eCRF) only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

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
Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation, or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 

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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.
No AESIs have been defined for this trial.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of AEs should be classified and recorded in the CRF according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [R18-1357].
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)

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

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
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.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
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 pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.

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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 1810631 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood 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 EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed in less than 60 min, with interim storage of blood samples and aliquots at room 
temperature. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis
At a minimum, the sample tube labels should list BI trial number, barcode, subject number, 
visit, and planned sampling time. 
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.

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5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.
5.4.1
Drug-Drug Interaction Biomarkers
Not applicable.
5.4.2
Pharmacodynamic biomarkers
Not applicable.
5.4.3
Pharmacogenomic 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 laboratory tests will be ± 30 min.
If scheduled in the Flow Chart at the same time as a 
 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.
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 and run-in period(s)
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 period(s)
Each subject is expected to participate in 2 treatment periods. 
will separate 
drug administrations in the first and second treatment periods.
On 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 drug administration. The subjects 
will then be allowed to leave the trial site after formal assessment and confirmation of their 
fitness as indicated in the Flow Chart. 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.

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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
Although there are multiple primary endpoints, an alpha adjustment is not needed because it 
is required that all primary endpoints meet the equivalence criterion as described below 
simultaneously. Therefore, a one-sided alpha of 5% will be used for testing.
The assessment of bioequivalence will be based upon two-sided 90% confidence intervals 
(CIs) for the ratio of the geometric means (test/reference) for the primary and secondary
endpoints using an acceptance range of 80.00 - to 125.00%. This method is equivalent to the 
two-sided t-test procedure, each at the 5% significance level.
The following hypotheses are tested:
Null hypothesis H0 (Inequivalence):
δ
μ
μ
δ
μ
μ
R
T
R
T





or
where 
T

and 
R

are the means of the log-transformed endpoint for the test and reference 
treatments, respectively, and δ is the bioequivalence limit that defines the acceptance range 
on the logarithmic scale. Alternative hypothesis Ha (Equivalence):
δ
μ
μ
δ
R
T




In this trial, the bioequivalence limit δ is ln(1.25). By back-transforming (exponentiating), 
this translates to an acceptance range of 80.00 to 125.00% for the ratio of the geometric 
means (test/reference) for endpoints on the original scale.
The rejection of the null hypothesis at the = 0.05 level is equivalent to the inclusion of the 
90% confidence interval for 
R
T



in the acceptance range (-δ, δ).
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.

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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 zongertinib 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

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A predose concentration 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 

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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,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
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.
Bioequivalence is considered established if the 90% confidence intervals of the geometric 
means for the primary endpoints are contained in the pre-defined acceptance range, see 
Section 7.1.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.

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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 descriptively.
7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the 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 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 sequence without 
consideration of time intervals and treatment periods.

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Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.2.6
Interim analyses
No interim analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures. 
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 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
The sample size for this trial was determined using assumptions on the intra-individual
variability of the primary endpoints based on the results reported in previous BI trials 1479-
0003(c40238724) and 1479-0004 (c42362953).
We assumed an intra-individual coefficients of variation (gCV) of 20% and 30% for AUC0- 72
and Cmax for zongertinib, respectively. The gCV for AUC0-72 was decided based on the 
values of 14.2% and 13.8% for AUC0-∞ and AUC0-tz   in trial 1479-0003 and 18.0% and 20.4% 
for AUC0-∞and AUC0-tz in trial 1479-0004, respectively. The gCV of 30% for Cmax was also 
decided based on the value of 30.5% and 28.7% for Cmax in trial 1479-0003 and trial 1479-
0004. 

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A sample size of 52 subjects is needed to achieve 90% power to reject both one-sided null 
hypotheses for Cmax  each at the 5% level of significance in favour of bioequivalence. While 
a sample size of 26 subjects would suffice to achieve the analogous result for AUC0-72.
Due to the high correlation between the primary endpoints, only Cmax will be considered for 
power calculations. Using a sample size of 52 subjects (26 per sequence group), the power to 
reject both one-sided null hypotheses for one parameter each at the 5% level of significance 
in favour of bioequivalence is displayed in Table 7.5: 1, under various assumptions for the 
T/R ratio. To account for the uncertainty of the assumed gCV, a range of gCVs around 30% 
is also presented.
Table 7.5:1 
Power for concluding bioequivalence (acceptance range 80-125%) 
based on a geometric coefficient of variation (gCV) around 30% and 
for different expected ratios of geometric means (test/reference) in a 
2×2 crossover trial (N=52)
Ratio[%]*
gCV[%]
95
100
105
20
99.7
100.0
99.7
25
96.9
99.6
97.2
30
90.2
97.1
90.9
35
80.7
90.2
81.6
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R)
From the above table, a sample size of 52 will yield approximately 90% power to conclude 
bioequivalence for an assumed gCV of 30% if the ratio is not more than 5% different from 
the ratio of 100% which reflects no difference in exposure. In addition, this sample size still 
provides approximately 80% power in case the gCV is 35%.
Accounting for up to 4 dropouts or non PK evaluable subjects, a total of N = 56 subjects are 
planned to be entered into the trial.
The calculations were performed as described by Diletti et al. [R94-1445] using the function 
power.TOST()of the R package PowerTOST Version 1.5-4 in R Version 4.2.1.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
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
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject according to ICH-GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional subject-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject 
information must be given to each subject or the subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.

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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See Section 4.1.5 for rules 
about emergency code breaks. 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.

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For the CRF, data must be derived from source documents, for example:

Subject identification: gender, 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.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.

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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 
.
The trial will be conducted at 
, under the supervision of the Principal Investigator. Relevant documentation on the 
participating (Principal) Investigators (e.g. their curricula vitae) will be filed in the ISF. The 
investigators will have access to the BI web portal Clinergize to access documents provided 
by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required trial activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local Clinical Trial Mangers
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites
The trial medication will be provided by the 
The contracted laboratory for safety laboratory tests is 
Analyses of BI 1810631 concentrations in plasma will be performed at
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.

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Data management and statistical evaluation will be done by BI and/or a Contract Research 
Organisation according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P11-09424
P15-01211
P19-00456
P19-10412
P20-09250
R09-6185
R18-1357            
R20-1872
R20-1990
R94-1445
R94-1529 

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9.2
UNPUBLISHED REFERENCES
c32836122
c40238724
c42362953

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10.
APPENDICES
Not applicable.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c43691238
2.0
clinical-trial-protocol-version-02
Bioequivalence of zongertinib tablets from two different manufacturers following
oral administration in healthy male and female subjects (an open-label, randomised,
single-dose, two-period, two-sequence crossover trial)
Approval
15 Mar 2024 09:27 CET
Approval-Clinical Program
15 Mar 2024 10:11 CET
Author-Trial Statistician
18 Mar 2024 11:18 CET
Verification-Paper Signature
Completion
18 Mar 2024 11:47 CET
Boehringer 
~11111~ lngelhein1 

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c43691238
2.0