A Phase I, Open-label Trial in Two Parallel Parts to Investigate Mass Balance, Metabolism, and Basic Pharmacokinetics of BI 1810631 (C-14) Administered as Oral Solution (Part A) and to Investigate Absolute Bioavailability of BI 1810631 Administered as Film-coated Tablet Together With an Intravenous Microtracer Dose of BI 1810631 (C-14) (Part B) in Healthy Male Volunteers
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

001-MCS-40-106_RD-13 (7.0) / Saved on: 22 Jun 2021
Clinical Trial Protocol
TITLE PAGE
Document Number:
c38775190-01
EU CT No.
Universal Trial 
Number
2022-503047-17-00
U1111-1291-2883
BI Trial No.
1479-0006
BI Investigational
Medicinal Product
BI 1810631
Title
A phase I, open-label trial in two parallel parts to investigate 
mass balance, metabolism, and basic pharmacokinetics of 
BI 1810631 (C-14) administered as oral solution (part A) and to 
investigate absolute bioavailability of BI 1810631 administered 
as film-coated tablet together with an intravenous microtracer 
dose of BI 1810631 (C-14) (part B) in healthy male volunteers
Lay Title
A study in healthy men to test how BI 1810631 is taken up and 
processed by the body
Clinical Phase
I
Clinical Trial Leader
Principal Investigator
Current Version, Date
Version 1.0, 21 Apr 2023
Original Protocol Date
21 Apr 2023
Page 1 of 83
Proprietary confidential information
© 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
21 Apr 2023
Revision date
Not applicable
BI trial number
1479-0006
Title of trial
A phase I, open-label trial in two parallel parts to investigate mass balance, 
metabolism, and basic pharmacokinetics of BI 1810631 (C-14) administered as oral 
solution (part A) and to investigate absolute bioavailability of BI 1810631 
administered as film-coated tablet together with an intravenous microtracer dose of 
BI 1810631 (C-14) (part B) in healthy male volunteers
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
Part A of this clinical trial investigates the basic pharmacokinetics of BI 1810631 
and total [14C]-radioactivity, including mass balance, metabolism, and excretion 
pathways following an oral dose of BI 1810631 (C-14).
Part B of this clinical trial investigates the absolute bioavailability of BI 1810631 
after administration of an oral dose of unlabelled BI 1810631 and an intravenous 
microtracer of BI 1810631 (C-14).
The data of this trial are required for an in-depth understanding of the 
pharmacokinetics of BI 1810631 and for submission to regulatory authorities.
Trial objectives
Part A – the main objectives are 

To assess the mass balance and total recovery of [14C]-radioactivity in 
urine and faeces after oral single dose administration of BI 1810631 (C-14) 
(test treatment T1) in healthy male subjects

To assess concentrations of BI 1810631 and [14C]-radioactivity in plasma 
Part B – the main objective is:

To investigate the absolute bioavailability of BI 1810631 administered as 
film-coated tablet (test treatment T2, not radio-labelled) compared with   
BI 1810631 (C-14) (reference treatment R) administered as intravenous 
microtracer

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Trial endpoints
Part A - Primary endpoints:
Primary endpoints will be the mass balance and total recovery of [14C]-radioactivity 
in urine and faeces:

feurine,0-tz (fraction excreted in urine as percentage of the administered dose 
over the time interval from 0 to the last quantifiable time point)

fefaeces,0-tz (fraction excreted in faeces as percentage of the administered 
dose over the time interval from 0 to the last quantifiable time point)
Part A – Secondary endpoints:
The following secondary endpoints will be evaluated for BI 1810631 and 
[14C]-radioactivity (assessed by [14C]BI 1810631-EQ) in plasma:

Cmax (maximum measured concentration of the analyte)

AUC0-tz (area under the concentration-time curve of the analyte over the 
time interval from 0 to the last quantifiable time point)
Part B - Primary endpoints:
The following primary endpoint will be determined in plasma for [14C]BI 1810631
after intravenous administration and for BI 1810631 after oral administration:

AUC0-∞(Area under the concentration-time curve of the analyte over the 
time interval from 0 extrapolated to infinity)
Part B - Secondary endpoints:
The following secondary endpoints will be determined in plasma for 
[14C]BI 1810631 after intravenous administration and for BI 1810631 after oral 
administration:

Cmax

AUC0-tz
Trial design
Non-randomized, open-label, single period design with two parallel parts
Number of subjects 
total entered
15
on each treatment
Part A (ADME part): 8
Part B (abs. BA part): 7
Diagnosis
Not applicable
Main inclusion criteria
Healthy male subjects, age of 18 to 55 years (inclusive), body mass index (BMI) of 
18.0 to 30.0 kg/m2 (inclusive)

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Test product 1
BI 1810631 (C-14) oral solution
dose
BI 1810631 (C-14)

In 
 oral solution

Concentration: 

Containing a radioactive dose of approximately 3.7 MBq
mode of 
administration
Oral with 240 mL of water 
Test product 2
BI 1810631 film-coated tablet, strength 
dose
mode of 
administration
Oral with 240 mL of water 
Reference product
BI 1810631 (C-14) 
dose
 BI 1810631 (C-14)

In 

Concentration: 

Containing a radioactive dose of approximately 0.03 MBq
mode of admin.
Intravenous 
 starting at 2:00 h after an orally administered dose 
of test product 2
Duration of treatment
Part A:

One single oral dose of test product 1 in the morning of Day 1
Part B:

One single oral dose of test product 2 in the morning of Day 1

One single intravenous 
 of reference product 
 following the 
administration of test product 2 in the morning of Day 1
Statistical methods
Part A: Descriptive statistics will be calculated for all endpoints.
Part B: 
Absolute bioavailability (F) will be estimated by the ratios of the geometric means 
(test treatment 2 [T2] / reference treatment [R]) for the primary endpoints (dose 
normalized) AUC0-∞. Additionally, their two-sided 90% confidence intervals (CIs) 
will be provided. This method corresponds to the two one-sided t-tests procedure, 
each at the 5% significance level. Since the main focus is on estimation and not 
testing, an acceptance range is not specified. The statistical model will be an 
analysis of variance (ANOVA) on the logarithmic scale including the fixed effect 
for ‘treatment’ and ‘subject’ as a random effect. CIs will be calculated based on the 
residual error from ANOVA.
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART PART A (ADME PART)
Visit
Day
Planned time (relative to drug 
administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment 9
Safety laboratory 15,17
Blood sampling for PK and total 
radioactivity12,14
Urine sampling 7
Faeces sampling  8
Vomit collection (if applicable)
Blood sampling for metabolic 
profiling 12
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-28 to -2
Screening (SCR)1
A
x
x
2
-2
-48:00
08:00
x
▲
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
-1
-18:00
14:00
Admission to site5
B5
x
-13:00
19:00
1
-2:00
06:00
x2,13
x2
x2
x2
x2
0:00
08:00
Oral solution 
administration 
(BI 1810631 (C-14))
▲
│
│
▲
│
│
▲
│
│
0:30
08:30
x
│
│
│
x
1:00
09:00
x13
x
│
│
│
x
1:30
09:30
x
│
│
│
2:00
10:00
240 mL fluid intake
x
│
│
│
x
2:30
10:30
x
│
│
│
3:00
11:00
x
│
│
│
4:00
12:00
240 mL fluid intake, 
x13
x
┼
│
│
│
│
│
x
x
x
5:00
13:00
x
│
│
│
6:00
14:00
x
│
│
│
8:00
16:00
x13
x
┼
│
│
x
10:00
18:00
x
│
│
│
11:00
19:00
│
│
│
12:00
20:00
x
┼
│
│
x
2
24:00
08:00
B13
x
┼
┼
▼
x
x
x
36:00
20:00
x
│
│
3
48:00
08:00
x
┼
┼
x
4
72:00
08:00
x
┼
┼
5
96:00
08:00
x
┼
┼
x
6
120:00
08:00
B
x
┼
┼
7
144:00
08:00
┼
┼
8
168:00
08:00
x
┼
┼
x
9
192:00
08:00
┼
┼
10
216:00
08:00
x
┼
┼
11
240:00
08:00
┼
┼
12
264:00
08:00
x
┼
┼
13
288:00
08:00
┼
┼
14
312:00
08:00
┼
┼
15
336:00
08:00
Discharge from site19,20
x
▼
▼
20
461:00
13:00
Start home collection10,11
▲
21
485:00
13:00
Admission to site11
▲
┼
22
509:00
13:00
Discharge from site11,19
▼
▼
27
629:00
13:00
Start home collection10,11
▲
28
653:00
13:00
Admission to site11
▲
┼
29
677:00
13:00
Discharge from site11,19
▼
▼
34
797:00
13:00
Start home collection10,11
▲
35
821:00
13:00
Admission to site11
▲
┼
36
845:00
13:00
Discharge from site11,19
▼
▼

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Visit
Day
Planned time (relative to drug 
administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment 9
Safety laboratory 15,17
Blood sampling for PK and total 
radioactivity12,14
Urine sampling 7
Faeces sampling  8
Vomit collection (if applicable)
Blood sampling for metabolic 
profiling 12
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
41
965:00
13:00
Start home collection10,11
▲
│
│
▼
42
989:00
13:00
Admission to site11
▲
┼
43
1013:00
13:00
Discharge from site11,19
▼
▼
3
16 to 43
End of study (EoS) 
examination4
B
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug and alcohol
screening), demographics (including determination of body height and weight, smoking status and alcohol history), 
relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
4.
At the end of study (synonym for end of trial), the EoS examination includes physical examination, vital signs, ECG, 
safety laboratory, recording of AEs and concomitant therapies. The end of study visit is to be performed within 7 days 
after last discharge from the study centre, or, if all once-weekly 24 h sampling periods are needed, prior to discharge on 
Day 43.
5.
Including urine/serum drug screening and urine alcohol test. To be taken and evaluated within 26 hours before drug 
administration. Admission can be done anytime within -26 hours and -10 hours before drug administration.
6.
AEs and concomitant therapies will be recorded throughout the trial. During in-house days subjects will be specifically 
asked for AEs and concomitant therapies twice daily.
7.
Urine collection intervals (for PK of BI 1810631, [14C]-radioactivity, and for metabolic profiling): On Day -1 or Day 1 
(within 18 hours prior to dosing) a predose (blank) spot sample; on Day 1 prior to start of urine collection voiding of the 
bladder; 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264, 
264-288, 288-312, and 312-336 h after administration of BI 1810631 (C-14). Thereafter, if warranted, 24 h collections 
are to be performed every 7 days on days 21-22, 28-29, 35-36, and 42-43. Urine sampling will be stopped when release 
criteria for radioactivity recovery (see Section 3.1) have been met (earliest stopping on Day 15). “┼” means end of last 
collection interval, start of following collection interval. For details on sample usage please refer to Section 5.3.2.1.3
8.
Stool collection (for [14C]-radioactivity assessment and metabolic profiling): A blank sample will be collected before 
drug administration on Day -2, Day -1 or Day 1 (at home or at the site) in specific containers provided by
Collection of this pre-dose faeces sample will start from approximately planned time -48:00 h. Following drug 
administration, all stools will be collected quantitatively in portions in the following sampling intervals: 0-24, 24-48,
48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264, 264-288, 288-312, and 312-336 h after
administration of BI 1810631 (C-14). Thereafter, if warranted, 24-h collections are to be performed every 7 days on 
days 21-22, 28-29, 35-36, and 42-43. Faeces sampling will be stopped when the release criteria for radioactivity 
recovery (Section 3.1) have been met (earliest stopping on Day 15). “┼” means end of last collection interval, start of 
following collection interval. For details on sample usage please refer to Section 5.3.2.1.4.
9.
10. Subjects are to collect faeces at home within 24 h intervals before admission to once-weekly in-house collection 
intervals. Home collection intervals: Day 20-21, 27-28, 34-35, and 41-42. If faeces are collected in the subsequent in-
house collection interval, faeces collected at home will be discarded. If no faeces is collected in the subsequent in-house 
collection interval (no defecation), faeces collected at home will be used instead for analysis.
11. The planned times for admission, discharge, start and end of urine and faeces collection intervals are approximate. The 
procedures are to be performed within a time window of ± 4 h to the planned time. However, the duration of each once 
weekly on-site collection interval should be as close to 24 h as possible.
12. Blood volumes: see Appendix 10.1
13. At this time point, a sample for hematocrit measurement is taken.
14. BI 1810631 in plasma and [14C]-radioactivity in whole blood and plasma (see Section 5.3.2.1.1 and Appendix 10.1)
15. Letters A and B describe different sets of safety laboratory examinations (see Table 5.2.3: 1)
16. Time window of ± 1 hour

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17. SARS-CoV-2 Polymerase chain reaction (PCR) testing will be done as needed based on the current status of the 
pandemic. 
18. Time window of ± 2 hours
19. After formal assessment and confirmation of the subject’s fitness
20. Discharge may be in the time window from planned time until 4 h later

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FLOW CHART PART B (ABSOLUTE BIOAVAILABILITY PART)
Visit
Day
Planned time (relative to first
drug administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment 8
Safety laboratory 7,9
PK plasma (BI 1810631)
PK plasma ([14C]BI 1810631)
PK plasma ([14C]-radioactivity)
Local tolerability assessment12
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-28 to -2
Screening (SCR)1
A
x
x
2
-1
-18:00
14:00
Admission to trial site5
B5
▲
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
▼
-13:00
19:00
1
-2:00
06:00
x2
x2
x2
x2
x2
0:00
08:00
Oral drug administration 
(BI 1810631, film-coated tablet)
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:30
10:30
x
x
x
2:45
10:45
x
x
3:00
11:00
x
x
x
3:30
11:30
x
x
4:00
12:00
240 mL fluid intake, 
x
x
x
x
x
x
5:00
13:00
x
x
x
6:00
14:00
x
x
x
8:00
16:00
x
x
x
10:00
18:00
x
x
x
11:00
19:00
12:00
20:00
x
x
x
x
2
24:00
08:00
B
x
x
x
x
x
x
36:00
20:00
x
x
x
3
48:00
08:00
x
x
x
4
72:00
08:00
x
x
x
5
96:00
08:00
x
x
x
6
120:00
08:00
B
x
x
x
8
168:00
08:00
Discharge from trial site11,13
x
x
x
3
15 to 22
End of study (EoS) examination4
B
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug and alcohol 
screening), demographics (including determination of body height and weight, smoking status and alcohol history), 
relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. 
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to first drug 
administration.
3.
4.
At the end of study (synonym for end of trial), the EoS examination includes physical examination, vital signs, ECG, 
safety laboratory, recording of AEs and concomitant therapies. 

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5.
Including urine/serum drug screening and urine alcohol test. To be taken and evaluated within 26 hours before drug 
administration. Admission can be done anytime within -26 hours and -10 hours before first drug administration.
6.
AEs and concomitant therapies will be recorded throughout the trial. During in-house days subjects will be specifically 
asked for AEs and concomitant therapies twice daily.
7.
Letters A and B describe different sets of safety laboratory examinations (see Table 5.2.3: 1)
8.
9.
SARS-CoV-2 PCR testing will be done as needed based on the current status of the pandemic. 
10. Time window of ± 2 hours
11. After formal assessment and confirmation of the subject’s fitness
12. For details see Section 5.2.5.1
13. Discharge may be in the time window from planned time until 4 h later
14. Time window of ± 1 hour
15. PK sample to be taken before 
 exactly on planned time.
16. Immediately before 

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART PART A (ADME PART) .......................................................5
FLOW CHART PART B (ABSOLUTE BIOAVAILABILITY 
PART)...........................................................................................................8
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS AND DEFINITIONS..................................................... 15
1.
INTRODUCTION.................................................................................... 18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE...............................................................................................19
1.2.1
Mode of action.......................................................................................19
1.2.2
Data from studies in humans ...............................................................19
1.2.3
Residual Effect Period..........................................................................22
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
1.4
BENEFIT - RISK ASSESSMENT ...................................................................22
1.4.1
Benefits...................................................................................................22
1.4.2
Risks .......................................................................................................22
1.4.3
Discussion...............................................................................................26
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 28
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......28
2.1.1
Main objectives......................................................................................28
2.1.2
Primary endpoints ................................................................................28
2.1.3
Secondary endpoints.............................................................................28
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS .........................29
2.2.1
Further objectives.................................................................................29
2.2.2
Further endpoints .................................................................................29
2.2.2.1
Part A - further pharmacokinetic endpoints of BI 1810631 ....29
2.2.2.2
Part A - further pharmacokinetic endpoints of [14C]-
radioactivity .............................................................................30
2.2.2.3
Part B - further pharmacokinetic endpoints of BI 1810631.....31
2.2.2.4
Part B - further pharmacokinetic endpoints of [14C]BI 1810631 
and [14C]-radioactivity .............................................................31
2.2.2.5
Part A: Determination of blood cell/plasma and blood/plasma 
ratios
...................................................................................32
2.2.2.6
Safety and tolerability..............................................................32
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 34
3.1
OVERALL TRIAL DESIGN............................................................................34

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................35
3.3
SELECTION OF TRIAL POPULATION ......................................................36
3.3.1
Main diagnosis for trial entry..............................................................36
3.3.2
Inclusion criteria...................................................................................36
3.3.3
Exclusion criteria ..................................................................................37
3.3.4
Withdrawal of subjects from treatment or assessments ...................39
3.3.4.1
Withdrawal from trial treatment ..............................................39
3.3.4.2
Withdrawal of consent to trial participation ............................40
3.3.4.3
Discontinuation of the trial by the sponsor..............................40
3.3.5
Replacement of subjects .......................................................................40
4.
TREATMENTS........................................................................................ 41
4.1
INVESTIGATIONAL TREATMENTS ..........................................................41
4.1.1
Identity of the Investigational Medicinal Products ...........................41
4.1.2
Selection of doses in the trial................................................................42
4.1.3
Method of assigning subjects to treatment groups ............................42
4.1.4
Drug assignment and administration of doses for each subject .......43
4.1.5
Blinding and procedures for unblinding ............................................44
4.1.6
Packaging, labelling, and re-supply ....................................................44
4.1.7
Storage conditions.................................................................................45
4.1.8
Drug accountability ..............................................................................45
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................46
4.2.1
Other treatments and emergency procedures....................................46
4.2.2
Restrictions............................................................................................47
4.2.2.1
Restrictions regarding concomitant treatment .........................47
4.2.2.2
Restrictions on diet and life style.............................................47
4.2.2.3
Contraception requirements.....................................................48
4.3
TREATMENT COMPLIANCE.......................................................................48
5.
ASSESSMENTS....................................................................................... 49
5.1
ASSESSMENT OF EFFICACY.......................................................................49
5.2
ASSESSMENT OF SAFETY............................................................................49
5.2.1
Physical examination ............................................................................49
5.2.2
Vital signs...............................................................................................49
5.2.3
Safety laboratory parameters..............................................................49
5.2.4
Electrocardiogram................................................................................52
5.2.5
Other safety parameters.......................................................................52
5.2.5.1
Local tolerability (part B only) ................................................52
5.2.6
Assessment of adverse events...............................................................53
5.2.6.1
Definitions of adverse events...................................................53

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5.2.6.1.1 Adverse event ............................................................53
5.2.6.1.2 Serious adverse event ................................................53
5.2.6.1.3 AEs considered ‘Always Serious’.............................53
5.2.6.1.4 Adverse events of special interest .............................54
5.2.6.1.5 Intensity (severity) of AEs.........................................55
5.2.6.1.6 Causal relationship of AEs ........................................55
5.2.6.2
Adverse event collection and reporting ...................................56
5.2.6.2.1 AE collection.............................................................56
5.2.6.2.2 AE reporting to the sponsor and timelines ................57
5.2.6.2.3 Pregnancy ..................................................................57
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................57
5.3.1
Assessment of pharmacokinetics .........................................................57
5.3.2
Methods of sample collection...............................................................58
5.3.2.1
Sample collection in Part A (ADME part)...............................58
5.3.2.1.1 Part A (ADME part) – sampling of blood for analysis 
of [14C]-radioactivity in plasma and whole blood and 
for analysis of BI 1810631 in plasma........................58
5.3.2.1.2 Part A (ADME part) – sampling of plasma for 
metabolic profiling ....................................................58
5.3.2.1.3 Part A (ADME part) – urine sampling for analysis of 
[14C]-radioactivity, of BI 1810631, and for metabolic 
profiling.....................................................................58
5.3.2.1.4 Part A (ADME part) – faeces sampling for analysis of 
[14C]-radioactivity and metabolic profiling...............59
5.3.2.1.5 Part A (ADME part) – handling of vomit .................59
5.3.2.2
Sample collection in Part B (absolute BA part).......................59
5.3.2.2.1 Part B (absolute BA part) – plasma sampling for BI 
1810631 analysis .......................................................59
5.3.2.2.2 Part B (absolute BA part) – plasma sampling for 
[14C]BI 1810631 analysis ..........................................60
5.3.2.2.3 Part B (absolute BA part) – plasma sampling for total 
[14C]-radioactivity analysis........................................60
5.3.2.3
Parts A (ADME) and B (absolute BA) – further investigations..
...................................................................................60
5.3.3
Analytical determinations in Part A (hADME part).........................60
5.3.3.1
Determination of [14C]-radioactivity in plasma, whole blood, 
urine, and faeces.......................................................................60
5.3.3.2
Analytical determination of BI 1810631 concentrations in 
plasma
...................................................................................61
5.3.3.3
Analytical determination of BI 1810631 concentrations in urine
...................................................................................61
5.3.3.4
Metabolic profiling in plasma, urine, and faeces.....................61
5.3.4
Analytical determinations in part B (absolute BA part)...................61

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5.3.4.1
Analytical determination of BI 1810631 concentrations in 
plasma
...................................................................................61
5.3.4.2
Analytical determination of [14C]BI 1810631 concentrations in 
plasma
...................................................................................61
5.3.4.3
Analytical determination of total [14C]-radioactivity in plasma ..
...................................................................................61
5.4
ASSESSMENT OF BIOMARKERS................................................................61
5.5
BIOBANKING ...................................................................................................61
5.6
OTHER ASSESSMENTS .................................................................................62
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................62
6.
INVESTIGATIONAL PLAN.................................................................. 63
6.1
VISIT SCHEDULE............................................................................................63
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................63
6.2.1
Screening period....................................................................................63
6.2.2
Treatment periods.................................................................................63
6.2.2.1
Treatment periods in part A (ADME part) ..............................63
6.2.2.2
Treatment periods in part B (absolute BA part).......................64
6.2.3
Follow-up period and trial completion ...............................................64
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 66
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................66
7.2
PLANNED ANALYSES....................................................................................66
7.2.1
General considerations.........................................................................66
7.2.1.1
Analysis sets.............................................................................66
7.2.1.2
Pharmacokinetics.....................................................................67
7.2.2
Primary endpoint analyses...................................................................67
7.2.3
Secondary endpoint analyses ...............................................................68
7.2.4
Further endpoint analyses....................................................................69
7.2.4.1
Pharmacokinetic analyses........................................................69
7.2.5
Safety analyses.......................................................................................69
7.2.6
Interim analyses ....................................................................................70
7.3
HANDLING OF MISSING DATA ..................................................................70
7.3.1
Safety......................................................................................................70
7.3.2
Pharmacokinetics..................................................................................70
7.4
RANDOMISATION ..........................................................................................70
7.5
DETERMINATION OF SAMPLE SIZE ........................................................70
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 71
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................71

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8.2
DATA QUALITY ASSURANCE .....................................................................72
8.3
RECORDS..........................................................................................................72
8.3.1
Source documents .................................................................................72
8.3.2
Direct access to source data and documents.......................................73
8.3.3
Storage period of records.....................................................................73
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................74
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......74
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................74
8.6
TRIAL MILESTONES .....................................................................................75
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................75
9.
REFERENCES......................................................................................... 77
9.1
PUBLISHED REFERENCES...........................................................................77
9.2
UNPUBLISHED REFERENCES.....................................................................78
10. APPENDICES .......................................................................................... 79
10.1
BLOOD VOLUMES FOR PART A (ADME PART).....................................79
10.2
BLOOD VOLUMES FOR PART B (ABSOLUTE BA PART).....................80
10.3
RADIOACTIVE BURDEN CALCULATION FOR PART A (ADME 
PART) .................................................................................................................81
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 83

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

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ErbB
Epidermal growth factor
EU CT number
European Union Clinical Trial number
F
Absolute bioavailability factor
feurine, t1-t2
Fraction excreted in urine as percentage of the administered dose over 
the time interval from t1 to t2
feurine, 0-tz
Fraction excreted in urine as percentage of the administered dose over 
the time interval from 0 to the last quantifiable time point
fefaeces, t1-t2
Fraction excreted in faeces as percentage of the administered dose over 
the time interval from t1 to t2
fefaeces, 0-tz
Fraction excreted in faeces as percentage of the administered dose over 
the time interval from 0 to the last quantifiable time point
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
HER2
Human epidermal growth factor receptor 2
hADME
Human ADME (absorption, distribution, metabolism, and excretion)
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
ICF
Informed consent form
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
MBq
Megabecquerel
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRTin
Mean residence time of the analyte in the body after intravascular
administration
MRTex
Mean residence time of the analyte in the body after extravascular
administration
mSv
Millisievert
NF
New formulation
NSCLC
Non-small cell lung cancer
PE
Polyethylene

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PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT interval
ECG interval from the start of the QRS complex to the end of the T 
wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
RTK
Receptor tyrosine kinases
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
ss
(at) steady state
SUSAR
Suspected unexpected serious adverse reaction
T
Test product or treatment
TF1
Trial Formulation 1
TMF
Trial master file
t1/2
Terminal half-life of the analyte
tmax
Time from dosing to maximum measured concentration of the analyte
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
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
WOCBP
Women of child-bearing potential
YVMA
HER2 mutation with 12 base pair in-frame insertion YVMA (p.A775-
G776insYVMA)

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1.
INTRODUCTION
Part A of this clinical trial investigates the basic pharmacokinetics of BI 1810631 and total 
[14C]-radioactivity, including mass balance, metabolism, and excretion pathways following 
an oral dose of BI 1810631 (C-14).
Part B of this clinical trial investigates the absolute bioavailability of BI 1810631 after 
administration of an oral dose of unlabelled BI 1810631 and an intravenous (i.v.) microtracer 
of BI 1810631 (C-14).
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

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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.
1.2
DRUG PROFILE
For a comprehensive description of BI 1810631 refer to the IB [c32836122]. 
1.2.1
Mode of action
BI 1810631 is an EGFR wild type sparing, selective HER2 inhibitor with potent inhibitory 
activity on
HER2 mutations including the HER2 YVMA insertion allele. It is 
intended to treat patients with advanced solid tumors with HER2 aberrations.
1.2.2
Data from studies in humans
Prior to the current trial, BI 1810631 was administered in the ongoing first-in-man trial in 
patients with cancer 1479-0001 and in one PK study in healthy volunteers (trial 1479-0003).
A short summary of the trials and drug-related adverse events in these trials is provided here. 
For details on PK, safety, and efficacy refer to the IB [c32836122].
Short description of patient first-in-man trial 1479-0001
1479-0001 is an open-label, Phase I dose escalation trial, with dose confirmation and 
expansion, of BI 1810631 as monotherapy in patients with advanced or metastatic solid 
tumors with HER2 aberrations. Patients are continuously treated in different dose groups with 
 dosing schemes. PK, safety, and efficacy data are collected. So far,
patients
were treated in the dose escalation part with BI 1810631 either in one of the 
 cohorts 
 
or the 
 cohorts 
Data cut time point for the data described here is 09 Mar 2023.
Short description of healthy volunteer trial 1479-0003
At the time of CTP 1479-0011 finalization, trial 1479-0003 is in the reporting phase. Trial 
1479-0003 was an open-label, randomized, 4-way crossover Phase I trial. The trial 
investigated relative bioavailability of BI 1810631 after administration as two different 
formulations (trial formulation 1 [TF1] and new formulation [NF]), investigated the food 
effect on the pharmacokinetics of a single dose of BI 1810631 in plasma and investigated the 
effect of multiple-dose treatment with rabeprazole on the pharmacokinetics of a single dose 
of BI 1810631. Thirteen healthy male volunteers were dosed with single doses of 
BI 1810631 in 4 treatment periods in randomized order, separated by wash-out intervals of  
 The 4 treatments were: 
-
R: 
 BI 1810631 trial formulation 1 (TF1) under fasted conditions
-
T1:
BI 1810631 new formulation (NF) under fasted conditions
-
T2:
BI 1810631 NF after a high-fat, high-calorie breakfast

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-
T3: 
 BI 1810631 NF after a 5-day pre-treatment with the proton-pump inhibitor 
rabeprazole.
Safety and tolerability data of patient first-in-man trial 1479-0001 (preliminary data)
For an overview of available safety and tolerability data of trial 1479-0001 refer to the IB 
[c32836122]. The following text and tables in this protocol focus on drug-related AEs.
Overall,
 The 
most common drug-related AEs were
 In total, 
One
 
Table 1.2.2: 1
Number (%) of patients with drug-related AEs by dose group and 
preferred term – on-treatment period, b.i.d. cohorts (preliminary data)
Preferred term
[N (%)]
[N (%)]
[N (%)]
[N (%)]
[N (%)]
Number of patients
Total with drug-related AEs

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Table 1.2.2: 2
Number (%) of patients with drug-related AEs by dose group and 
preferred term – on-treatment period, q.d. cohorts (preliminary data)
Preferred term
[N (%)]
[N (%)]
[N (%)]
[N (%)]
[N (%)]
Number of patients
Total with drug-related AEs
Safety and tolerability data of healthy volunteer trial 1479-0003
In trial 1479-0003, in which oral single doses of 
 BI 1810631 were administered to 
healthy volunteers, there were 
 in trial 1479-0003. 
For more details refer to the IB [c32836122].

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1.2.3
Residual Effect Period
The Residual Effect Period (REP)
 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
Part A of this clinical trial investigates the basic pharmacokinetics of BI 1810631 and total 
[14C]-radioactivity, including mass balance, metabolism, and excretion pathways following 
an oral dose of BI 1810631 (C-14).
Part B of this clinical trial investigates the absolute bioavailability of BI 1810631 after 
administration of an oral dose of unlabelled BI 1810631 and an intravenous (i.v.) microtracer 
of BI 1810631 (C-14).
The data of this trial are required for an in-depth understanding of the pharmacokinetics of 
BI 1810631 and for submission to regulatory authorities.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 1810631 for 
treatment of patients with advanced solid tumors 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.
Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product: BI 1810631

 [c32836122]

AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Protection of subjects by 
administration of only single 
doses 


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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Interstitial lung disease 
(ILD) and Pneumonitis
Not observed for 
BI 1810631 so far, however 
reported for other tyrosine 
kinase inhibitors
Subjects are protected from this by 
administration of only single 
doses
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Subjects with pre-existing 
ILD/pneumonitis or other 
respiratory disorder are excluded 
from trial participation (see 
exclusion criteria 4 and 5)

 [c32836122]

 [c32836122])
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Physical examination of subjects 
at end-of-study visit 
Protection of subjects by 
administration of only single 
doses

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy

[c32836122]

[c32836122]
Safety laboratory (see Section 
5.2.3)
Protection of subjects by 
administration of only single 
doses 

[c32836122]

 [c32836122])
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Protection of subjects by 
administration of only single 
doses 

([c32836122]).





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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Drug-related AEs 
observed in patients in 
trial 1479-0001
After multiple dosing with 
BI 1810631, AEs assessed 
as drug-related were 
reported (see Section 1.2.2)
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Following administration of 
BI 1810631, subjects will be in-
house under close observation for 
at least 14 days (part A) or for at 
least 7 days (part B)
Protection of subjects by 
administration of only single 
doses 
Uncertainties due to the 
early stage of 
development
 However, 
BI 1810631 is currently in 
early development and there 
may be unknown risks of 
treatment with BI 1810631
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Following administration of 
BI 1810631, subjects will be in-
house under close observation for 
at least 14 days (part A) or for at 
least 7 days (part B)
VS, ECGs, and safety laboratory 
after dosing (see Flow Chart)
Protection of subjects by 
administration of only single 
doses 
Drug-induced liver injury 
(DILI)
Rare but severe event, thus 
under constant surveillance 
by sponsors and regulators.
Timely detection, evaluation, and 
follow-up of laboratory alterations in 
selected liver laboratory parameters 
to ensure subjects´ safety.
Trial procedures
Blood sampling:
Bruising and, in rare 
cases, phlebitis, or nerve 
injury, potentially 
resulting in paraesthesia, 
reduced sensibility, and/or 
pain 
General risk by venipuncture 
for blood sampling,
acceptable in the framework 
of trial participation.
Medical expertise of the trial site 

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
ECG recording:
Skin irritation, redness, 
itching
General risk by ECG 
electrodes, acceptable in the 
framework of trial 
participation.
Exclusion of subjects from trial 
participation with known clinically 
relevant hypersensitivity reactions to 
adhesive tapes.
Other risks
Radiation burden
In Part A of this trial a 
radioactive dose of 
approximately 3.7 MBq of 
14C is administered 
corresponding, in a worst-
case scenario, to 
approximately 
In Part B of this trial, a 
radioactive microtracer
dose of approximately 0.03 
MBq of 14C is 
administered, 
corresponding to 
Part A: 
 
[R18-1836, 
R18-1905]
Part B: 
 
 [R18-1836, 
R18-1905]
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (500 mL; see Appendices 10.1 and 10.2). No health-
related risk to healthy subjects is expected from withdrawal of this volume of blood.
1.4.3
Discussion
There is significant medical need in cancer patients harbouring HER2 mutations for effective, 
safe and well-tolerated therapies. BI 1810631 is an EGFR wild-type sparing selective HER2 
inhibitor with potent inhibitory activity on
HER2 mutations. It provides a unique 
opportunity for the treatment of NSCLC patients harbouring HER2 mutations, and data 
further suggest that BI 1810631 could be efficacious in all HER2-dependent cancers.
BI 1810631 has been adequately characterized in preclinical studies. Preclinically identified 
toxicities are addressed by appropriate mitigation (see Section 1.4.2). Moreover, data from 
two clinical trials are available (see Section 1.2.2 and IB [c32836122]) that support the single 
doses of BI 1810631 planned for the current trial. In particular, BI 1810631 has been given at 
multiple doses of up to 
and of up to
 to patients in first-in-man trial 
1479-0001, and in that study, BI 1810631 was 
 
The radiation burden in part A of this trial (hADME part) of approximately
(worst 
case) is necessary, as the respective radioactive dose of approximately 3.7 MBq of 14C is 
required for metabolite identification (see also Section 4.1.2). It is in the range of 

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 In part B of this trial (absolute BA part), only a radioactive microtracer
dose of approximately 0.03 MBq is administered corresponding to a burden of 
 
The current study is necessary to support the development of BI 1810631: The trial 
investigates the basic pharmacokinetics of BI 1810631 including mass balance, metabolism, 
and excretion pathways, and including investigation of absolute bioavailability. The data of 
this trial are required for an in-depth understanding of the pharmacokinetics of BI 1810631.
Considering the medical need for an effective and safe treatment of solid tumours with HER2 
mutations, the benefit of this trial is assessed to outweigh the potential risks.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
Part A – the primary objective is

To assess the mass balance and total recovery of [14C]-radioactivity in urine and 
faeces after oral single dose administration of BI 1810631 (C-14) (test treatment T1) 
in healthy male subjects
Part A – the secondary objective is

To assess concentrations of BI 1810631 and [14C]-radioactivity in plasma 
Part B – the primary objective is:

To investigate the absolute bioavailability of BI 1810631 administered as film-coated 
tablet (test treatment T2, not radio-labelled) compared with BI 1810631 (C-14) 
(reference treatment R) administered as intravenous microtracer
2.1.2
Primary endpoints
Part A – Primary endpoints will be the mass balance and total recovery of [14C]-radioactivity 
in urine and faeces:

feurine, 0-tz (fraction excreted in urine as percentage of the administered dose over the 
time interval from 0 to the last quantifiable time point)

fefaeces, 0-tz (fraction excreted in faeces as percentage of the administered dose over the 
time interval from 0 to the last quantifiable time point)
Part B – The following primary endpoint will be determined in plasma for [14C]BI 1810631 
after intravenous administration and for BI 1810631 after oral administration:

AUC0-∞(area under the concentration-time curve of the analyte over the time interval 
from 0 extrapolated to infinity)
2.1.3
Secondary endpoints
Part A – The following secondary endpoints will be evaluated for BI 1810631 and for [14C]-
radioactivity (assessed by [14C]BI 1810631-EQ) in plasma: 

Cmax (maximum measured concentration of the analyte)

AUC0-tz (area under the concentration-time curve of the analyte over the time interval 
from 0 to the last quantifiable time point) 

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Part B – The following secondary endpoints will be determined in plasma for 
[14C]BI 1810631 after intravenous administration and for BI 1810631 after oral 
administration:

Cmax

AUC0-tz
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS
2.2.1
Further objectives
Further objectives are the evaluation of additional pharmacokinetic parameters, metabolite 
profiling and structural identification of metabolites, and the assessment of safety and 
tolerability. More specifically further objectives are:
Part A:

Determination of further PK parameters for BI 1810631, as feasible

Determination of further PK parameters for [14C]-radioactivity in whole blood and 
plasma, as feasible

Determination of routes and rates of elimination of BI 1810631 after oral 
administration

Determination of the metabolic pattern of BI 1810631 in plasma, urine, and faeces, 
including structure elucidation of the metabolites (to be reported separately)

Determination of blood cell/plasma and blood/plasma ratios of [14C]-radioactivity

Evaluation of safety and tolerability of a single oral dose of 
BI 1810631 (C-14) 
oral solution
Part B:

Determination of further PK parameters for BI 1810631, for [14C]BI 1810631, and for 
[14C]-radioactivity, as feasible

Evaluation of safety and tolerability of a single oral dose of
BI 1810631 
together with a single intravenous dose of 
BI 1810631 (C-14) 
2.2.2
Further endpoints
2.2.2.1
Part A - further pharmacokinetic endpoints of BI 1810631
Further PK endpoints will be calculated as appropriate for BI 1810631 in plasma or urine, 
and may include, but are not limited to:

AUC0-∞in plasma

%AUCtz-∞(the percentage of AUC0-∞obtained by extrapolation) in plasma

tmax (time from dosing to maximum measured concentration of the analyte) in plasma

λz (terminal rate constant) in plasma

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
t1/2 (terminal half-life of the analyte) in plasma

AUCt1-t2 (area under the concentration-time curve of the analyte over the time interval 
t1 to t2) in plasma

MRTex (mean residence time of the analyte in the body after extravascular 
administration) in plasma

CL/F (apparent clearance of the analyte after extravascular administration) in plasma

Vz/F (apparent volume of distribution during the terminal phase after extravascular 
administration) in plasma

Aeurine, t1-t2 (amount of analyte that is eliminated in urine from time point t1 to t2)

Aeurine, 0-tz (amount of analyte that is eliminated in urine from time point 0 to last 
quantifiable time point)

feurine, t1-t2 (fraction excreted in urine as percentage of the administered dose over the 
time interval from t1 to t2) 

feurine, 0-tz

CLR, t1-t2 (renal clearance of the analyte in plasma from the time point t1 to t2)
2.2.2.2
Part A - further pharmacokinetic endpoints of [14C]-radioactivity
Further PK endpoints will be calculated as appropriate for [14C]-radioactivity in plasma, 
whole blood, urine or faeces, and may include, but are not limited to:

AUC0-tz in whole blood

Cmax in whole blood

AUC0-∞in plasma and whole blood

%AUCtz-∞in plasma and whole blood

tmax in plasma and whole blood

λz in plasma and whole blood

t1/2 in plasma and whole blood

AUCt1-t2 in plasma and whole blood

MRTex in plasma 

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
Aeurine, t1-t2

Aeurine, 0-tz

feurine, t1-t2

Aefaeces, t1-t2 (amount of analyte that is eliminated in faeces from time point t1 to t2)

Aefaeces, 0-tz (amount of analyte that is eliminated in faeces from time point 0 to last 
quantifiable time point)

fefaeces, t1-t2 (fraction of administered drug excreted unchanged in faeces from time 
point t1 to t2) 
2.2.2.3
Part B - further pharmacokinetic endpoints of BI 1810631
Further PK endpoints will be calculated as appropriate for BI 1810631 in plasma, and may 
include, but are not limited to:

%AUCtz-∞

tmax 

λz 

t1/2

AUCt1-t2

MRTex

CL/F 

Vz/F 
2.2.2.4
Part B - further pharmacokinetic endpoints of [14C]BI 1810631 and 
[14C]-radioactivity
Further PK endpoints will be calculated as appropriate for [14C]BI 1810631 and 
[14C]-radioactivity in plasma, and may include, but are not limited to:

AUC0-∞  for [14C]-radioactivity

AUC0-tz  for [14C]-radioactivity

Cmax for [14C]-radioactivity

%AUCtz-∞

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
tmax 

λz 

t1/2

AUCt1-t2

MRTin (mean residence time of the analyte in the body after intravascular 
administration) 

CL (total clearance of the analyte after intravenous administration, only for parent 
compound [14C]BI 1810631)

Vz (apparent volume of distribution during the terminal phase after intravascular 
administration, only for parent compound [14C]BI 1810631)

Vss (calculated volume of distribution at steady state after intravascular 
administration, only for parent compound [14C]BI 1810631)
2.2.2.5
Part A: Determination of blood cell/plasma and blood/plasma ratios
The ratio of concentration of [14C]-radioactivity in blood cells and plasma will be calculated 
at time points with haematocrit (HC) measurement (see Flow Chart) according to the 
formula:
C
C
C
C
C
plasma
plasma
blood
plasma
bloodcells
HC
HC)
1(
/



C bloodcells
= concentration of [14C]-radioactivity in blood cells
C plasma
= concentration of [14C]-radioactivity in plasma
C blood
= concentration of [14C]-radioactivity in whole blood
HC
= haematocrit in decimal (e.g. 0.42)
Additionally, the ratio of concentration of [14C]-radioactivity in blood and plasma will be 
calculated at all time points (indicated in the Flow Chart) when radioactivity is above LLOQ 
in plasma and blood.
2.2.2.6
Safety and tolerability
Safety and tolerability of BI 1810631 will be assessed based on:  

Adverse events (including clinically relevant findings from the physical examination
and assessment of local tolerability)

Safety laboratory tests

12-lead ECG

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
Vital signs (blood pressure, pulse rate)

Part B only: Local tolerability at the 
site assessed by investigator or designee

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
Part A – ADME part
Part A will be performed as an open-label, single-arm, single-dose trial part in healthy male 
subjects in order to investigate the basic pharmacokinetics of BI 1810631 and 
[14C]-radioactivity, including mass balance, excretion pathways, and metabolism following a 
single oral dose of 
BI 1810631 (C-14) containing a radioactive dose of approximately 
3.7 MBq. For details of the drug product refer to Section 4.1.
A total of 8 healthy male subjects is planned to participate in Part A. On Day 1, subjects will 
receive the [14C]-labelled drug product, and will then stay in the study centre up to the 
morning of Day 15 for collection of samples of blood, urine, and faeces. 
Release criteria (to be applied on data of individual subjects):
-
Recovery of >90% of administered radioactivity in urine and faeces combined 
and
-
<1% of administered radioactivity has been collected in urine and faeces within two 
separate, consecutive days or visits (considering a 24-h collection interval)
In case total recovery is ≤90% and <1% of administered radioactivity has been collected in 
urine and faeces within at least 3 separate, consecutive days or visits (considering a 24-h 
collection interval), investigator, Clinical Trial Leader and Trial Clinical Pharmacologist may 
agree to stop collection in the respective subject (considering that total recovery of >90% will 
not be reached).
In case total recovery of >90% is reached and, during the once-weekly sampling periods, 
<1% of administered radioactivity has been collected in urine and faeces in one visit, the 
investigator together with the Clinical Trial Leader and Trial Clinical Pharmacologist may 
decide to stop further sampling in this subject considering that further sampling would not be 
expected to contribute to the scientific objective of the study.
Subjects will be readmitted to the study centre for 24 h collection intervals of urine and
faeces on Days 21, 28, 35, and 42, if release criteria have not been met before. Within 24 h 
before each of these once-weekly in-house collection intervals, subjects are to collect faeces 
at home. This 24-h interval home collection faeces will be used for analysis in case no 
defecation occurs in the subsequent 24 h in-house collection interval. Otherwise it will be 
discarded. If a subject is unable to attend one of the once-weekly collection interval visits, 
they may be allowed to reschedule the visit if needed. Irrespective of whether release criteria 
have been met or not after collection interval Day 42-43, no further collections are planned.
For determination of whether release criteria have been reached for individual subjects, 
[14C]-radioactivity will be measured in excreta (urine and faeces). The actual recovery results 
will be reported as a percentage of the administered dose.  
Note, for calculation of release criteria (in subjects who did not meet them up to Day 15), the 
fraction of administered [14C]-dose will be rather underestimated as it will be based on the 
available samples, only. For the final analysis, the total excreted [14C]-radioactivity will be 

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derived including an interpolation method to account for the time periods without samples 
taken, if applicable (see Section 7.2.2).
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.
Part B – Absolute BA part
Part B will be performed as an open-label, single-arm, single-period trial part in healthy male 
subjects in order to compare the test treatment (T2) to the reference treatment (R). A total of 
7 healthy male subjects is planned to participate in Part B. The treatments will be
BI 1810631 administered to subjects orally
(T2) followed by
of 
 BI 1810631 (C-14) 
 later (R). The radioactive dose of the 
is approximately 0.03 MBq (expected to result in
 radiation burden 
 
 For details refer to Section 4.1.
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
Part A – ADME part
This is a common design for a [14C] study in humans for investigation of absorption, 
metabolism, and excretion including determination of mass balance. Inclusion of a control 
group is not required for this investigation.
Eight healthy volunteers are included to ensure at least 6 evaluable subjects as requested by 
FDA guideline [R22-3641]. This accounts for subjects potentially vomiting within 2x tmax, for 
early drop outs or for any other reason that subjects would not be evaluable.
Shortest sampling duration is up to Day 15 (336 h post drug administration), 
 
[c32836122]). This minimal sampling period 
would cover
 Maximal sampling 
duration is up to Day 43 (1013 h post drug administration), i.e.
This 
maximal sampling duration would also cover 
Randomisation is not possible, because all subjects receive the same treatment. Blinding is 
not necessary, because the main and secondary endpoints refer to the drug’s 
pharmacokinetics that are not influenced by the knowledge of treatment.
Part B – Absolute BA part
For absolute bioavailability trials, the cross-over design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between formulations is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
[R94-1529]. Compared to the traditional cross-over design (i.e., two trial periods separated by 

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a wash-out period), the chosen microtracer approach is considered more favourable, because 
both treatments are administered on the same day (resulting in 1 trial period with overlapping 
intervals of PK sampling).
Seven volunteers are included to ensure 6 evaluable subjects. This is considered necessary to 
allow an accurate determination of absolute BA. One subject less than in the hADME part is 
entered in this study part, in consideration of the shorter duration of the absolute BA part and 
thus lower risk for drop outs.
Sampling duration is up to Day 8 (168 h after BI 1810631 administration), 
 
which is considered sufficient for accurate determination of absolute 
bioavailability.
Randomisation is not possible, because all subjects receive the same treatment. Blinding is 
not necessary, because the main and secondary endpoints refer to the drug’s 
pharmacokinetics that are not influenced by the knowledge of treatment. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 15 healthy male subjects will enter the trial. They will be recruited from the 
volunteers' pool of the trial site, or, if necessary, via external databases and advertisements.
Subjects who were entered (i.e. dosed) in Part A of the study are not allowed to be entered in 
Part B of the study and vice versa.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (inclusive) 
3. BMI of 18.0 to 30.0 kg/m2 (inclusive) 
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial

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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 145 mmHg, 
diastolic blood pressure outside the range of 45 to 90 mmHg, or pulse rate outside the 
range of 40 to 100 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant chronic or acute infections
10. Any documented active or suspected malignancy or history of malignancy 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 (including any kind of vaccination) within 28 days of planned
administration of trial medication that might reasonably influence the results of the trial 
(including drugs that cause QT/QTc interval prolongation). Dietary supplements (e.g. 
vitamins, minerals) are allowed until 8 days before study drug administration.
Paracetamol and ibuprofen are allowed before and during the study.
13. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
14.
15. Average intake of more than 24 units of alcohol per week (1 unit of alcohol equals 
approximately 250 mL of beer, 100 mL of wine, or 35 mL of spirits)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial

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18. Intention to perform excessive physical activities within 4 days prior to the administration 
of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. 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 
23. Male subjects with WOCBP partner who are unwilling to use highly effective 
contraception from time point of administration of study drug until 90 days afterwards. 
Highly effective methods of contraception are:
-
Subject is sexually abstinent if this is in line with the preferred and usual lifestyle of 
the subject
-
Subject is vasectomized (with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate) and uses condom
-
Use of intrauterine device or intrauterine hormone-releasing system by female partner 
plus use of condom
-
Use of progestogen-only hormonal contraception by female partner that inhibits 
ovulation (injectables or implants) plus use of condom
-
Use of combined (estrogen and progestogen containing) hormonal contraception by 
female partner that prevents ovulation (oral, intravaginal, or transdermal) plus use of 
condom
-
Bilateral tubal occlusion in the female partner plus use of condom
Sperm donation is not allowed from the time point of administration of study drug until 
90 days afterwards.
24. Participation in another ADME study with a radiation burden ≥0.1 mSv within 12 months 
prior to dosing
25. For Part A (ADME part) only: Exposure to radiation for diagnostic reasons in the period 
of 1 year prior to planned administration of study drug
26. For Part A (ADME part) only: Irregular defecation pattern (less than a mean of one bowel 
movement per 2 days)
For restrictions of the trial, refer to Section 4.2.2.

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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 1.2.3, the 
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer.
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, the safety of the 
subject cannot be guaranteed as he 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, or with the outcome of the study.
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events (AEs), or diseases).
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF.
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
subjects or take any other appropriate action to guarantee the safety of the trial subjects.

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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, if applicable, 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 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 CTCAE Grade 3 (except for Grade 2 headache), or if at least one 
drug-related serious adverse event is reported
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 2 subjects in part A and/or more than one subject in part B do not complete 
the trial (including subjects non- evaluable for assessment of primary and secondary 
endpoints), subjects may be replaced if considered necessary to reach the objective of the 
trial. Subjects who withdraw or are withdrawn from treatment or assessments because of a
drug-related adverse event will not be replaced. The Clinical Trial Leader together with the 
Trial Pharmacologist and the Trial Statistician are to decide in mutual agreement with the 
principal investigator, if and how many subjects will be replaced. A replacement subject will 
be assigned a unique trial subject number and will be assigned to the same treatment as the 
subject he replaces.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Part A (ADME part): The oral solution contains a mixture of pure [14C]-labelled BI 1810631  
(“hot”) drug substance, and BI 1810631, i.e. unlabelled (“cold”) drug substance.
Part B (absolute BA part): 

The
 contains a mixture of pure [14C]-labelled BI 1810631 (“hot”) 
drug substance and BI 1810631, i.e. unlabelled (“cold”) drug substance.

The oral dose will be 
 BI 1810631 (unlabelled).
4.1.1
Identity of the Investigational Medicinal Products
Part A (ADME part) - the characteristics of the test product 1 are given below:
Name:
BI 1810631 (C-14) oral solution
Substance:
unlabelled BI 1810631 mixed with labelled [14C]BI 1810631
Pharmaceutical formulation: Oral solution
Source:
Unit strength:
Dose:
 BI 1810631 (C-14), containing a radioactive 
dose of approximately 3.7 MBq
Posology:
1-0-0
Mode of administration:
Oral
Duration of use:
One single dose in the morning of Part A, Visit 2, Day 1, 
 
as treatment Test 1 (T1)
Part B (absolute BA part) – the characteristics of the reference product are given below:
Name:
BI 1810631 (C-14) 
Substance:
unlabelled BI 1810631 mixed with labelled [14C]BI 1810631
Pharmaceutical formulation:
Source:
Unit strength:
Dose:
 = 
 BI 1810631 (C-14), containing a radioactive 
dose of approximately 0.03 MBq
Posology:
1-0-0
Mode of administration:
intravenous (i.v.) 
Duration of use:
One single dose in the morning of Part B, Visit 2, Day 1; 
as treatment Reference (R)

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Part B (absolute BA part) – the characteristics of the test product 2 are given below:
Name:
BI 1810631 film-coated tablets
Substance:
cold BI 1810631 
Pharmaceutical formulation: Film-coated tablets
Source:
BI Pharma GmbH & Co. KG, Germany 
Unit strength:
Dose:
Posology:
-0-0
Mode of administration:
oral
Duration of use:
One single dose in the morning of Part B, Visit 2, Day 1, 
 
as treatment Test 2 (T2)
4.1.2
Selection of doses in the trial
The dose of
BI 1810631
 and using this dose in the current trial is expected to deliver 
results meaningful and supportive for the development of BI 1810631. Based on available 
data from clinical trials (see Section 1.2.2 and the IB [c32836122]),
Part A – ADME part: The oral solution of BI 1810631 (C-14) administered in Part A is a 
mixture of 14C-labelled and unlabelled drug substance. The planned dose is characterized by 
a radioactivity of approximately 3.7 MBq, corresponding to an effective radioactive burden 
of approximately
(see Appendix 10.3). This radioactive dose is considered to be
necessary to provide an adequate analytical sensitivity to enable metabolite quantification in a 
sufficiently low range.
Part B – absolute BA part: In this trial part an
containing a microtracer
of BI 1810631 (C-14) is administered. The planned dose of 
 is characterized by a 
radioactivity of approximately 0.03 MBq which is considered to be sufficient for PK 
measurements.
The higher radioactive dose in Part A compared to Part B is due to the needs of metabolic 
profiling in Part A. The amount of radioactivity related to metabolites is split into a number 
of metabolites, i.e. each metabolite contains only a fraction of the total radioactive dose. 
4.1.3
Method of assigning subjects to treatment groups
Part A (ADME part):
This is a single-period phase I trial. All subjects receive the same treatment. All subjects form 
one treatment group and can be treated in one cohort (i.e. may be dosed on the same day). In 
case this is not feasible (e.g., due to logistical or recruitment reasons), the group may be split 
into several cohorts as required. 
Each subject will be assigned a subject number prior to dosing on Day 1 of Visit 2. Once a 
subject number has been assigned, it cannot be reassigned to any other subject.

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Part B (absolute BA part):
This is a fixed-sequence crossover study with a timely overlap of PK sampling intervals. All 
subjects receive an oral single dose followed by an intravenous
 All subjects 
form one treatment group and can be treated in one cohort (i.e. may be dosed on the same 
day). In case this is not feasible (e.g., due to logistical or recruitment reasons), the group may 
be split into several cohorts as required. 
Each subject will be assigned a subject number prior to dosing on Day 1 of Visit 2. Once a 
subject number has been assigned, it cannot be reassigned to any other subject.
4.1.4
Drug assignment and administration of doses for each subject
Part A (ADME part)
All subjects will receive the treatment as shown in Table 4.1.4: 1 below.
Table 4.1.4: 1
Dosage and treatment schedule in part A
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T1 (Test 1)
BI 1810631 
(C-14)
Oral solution
One single dose of 
 
(corresponding to 
 
BI 1810631 (C-14))
Administration of trial medication will be performed 
 The investigator (or 
authorised designee) will administer the trial medication as an oral dose
 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, if correct dosage cannot be ensured otherwise.
Subjects will be confined to bed in half-supine or sitting position for the first 4 hours after 
drug administration. Subjects will be kept under close medical surveillance for at least 14 
days (until Day 15), by when all subjects will be discharged from the trial site irrespective of 
whether the release criteria are reached. As long as release criteria are not reached, subjects 
will return to the site for up to four once-weekly urine and faeces sampling intervals.

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Part B (absolute BA part): 
All subjects will receive first the oral dose of
BI 1810631 (Test 2) followed by an 
intravenous
 of 
BI 1810631 (C-14) (Reference). Details of both treatments are 
given in Table 4.1.4: 2 below: 
Table 4.1.4: 2
Dosage and treatment schedule in part B
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T2 (Test 2)
BI 1810631 
Film-coated 
tablet
One single dose of 
 
BI 1810631 
R (Reference)
BI 1810631 
(C-14)
One single dose of 
 (100 µg 
BI 1810631 (C-14))
Treatment T2: Administration of 
 BI 1810631 will be performed 
 
 The investigator (or authorised designee) will administer the trial medication as an 
oral dose together with about 240 mL of water to subjects who are in a standing or sitting 
position. 
Treatment R: For administration of the BI 1810631 (C-14) 
an
is placed into an arm vein of the subject.
used for collection of blood samples will be placed on the contralateral arm. The BI 1810631 
(C-14) 
will be administered as
 under supervision of the investigating physician 
or an authorised designee. The
after administration of treatment T2. 
Start and end time of 
will be recorded. 
All treatments: 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, if correct dosage cannot be ensured otherwise.
Subjects will be confined to bed with a bed in half-supine or sitting position for the first 4 
hours after administration of treatment T2. Subjects will be kept under close medical 
surveillance until planned discharge from the trial site in the morning of Day 8.
4.1.5
Blinding and procedures for unblinding
This non-randomised open-label Phase I trial will be handled in an open fashion throughout. 
The treatment assignment will be available to all involved parties.
4.1.6
Packaging, labelling, and re-supply
The BI 1810631 film-coated tablets (for part B) will be provided to
by the 
 
They will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice (GMP). The label will be prepared according to regulation 
(EU) No 536/2014, Annex 6, omitting certain particulars with the following justification:

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
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
Drug product manufacturing of radiolabeled BI 1810631 (C-14) oral solution for Part A and 
of radiolabeled BI 1810631 (C-14)
for Part B is done by 
 The 
final clinical trial supply of the warm drug products consists of amber glass bottles containing 
oral solution (strength:
 for Part A and of vials containing the 
(strength: 
) for Part B. The trial medication will be labelled according to GMP. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EU CT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs (BI 1810631 tablets) 
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  
will provide the investigational drugs manufactured by
(BI 1810631 
(C-14) oral solution and BI 1810631 (C-14)
) upon availability of a valid 
prescription from the investigator. The investigator will order the drugs after the following 
requirements are fulfilled:

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
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 'Site Signature Delegation Log' may 
dispense investigational drugs to trial subjects. Investigational drugs are not allowed to be 
used outside of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
In case of 
 

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Table 4.2.1: 1
Grade-specific treatment recommendations of 
 
Severity (CTCAE 
grading)
Description
Treatment recommendations
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on trial days) on the appropriate pages of the CRF.
In case of AEs requiring analgesic / antiphlogistic treatment such as headache, ibuprofen or 
paracetamol may be given.
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. 
From 1 h before intake of the oral trial medication until 
 fluid intake is restricted to the 
water administered with the drug, and an additional 240 mL of water at planned times +2 h 

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and +4 h (mandatory for all subjects). From 
 until planned time of +24 h, total fluid 
intake is restricted to 3000 mL.
On days of urine collection, subjects will be advised that total fluid intake should be at least 
1500 mL but should not exceed 3500 mL.
 and dietary 
supplements
 are not 
permitted from 7 days before the administration of trial medication until after the last PK 
sample is collected.
 should not be consumed starting 2 days before trial drug 
administration until discharge from the site.
Alcoholic beverages are not permitted starting 2 days before first trial drug administration 
until discharge from the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 4 days before 
the administration of trial medication until the end of trial examination.
4.2.2.3
Contraception requirements
Subjects whose sexual partner is a WOCBP must be sexually abstinent or use highly effective 
contraception starting from dosing with BI 1810631 and for at least 90 days afterwards (see 
Section 3.3.3 for the definition of adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and urinary and faecal excretion of trial medication will provide additional confirmation of 
compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
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.
Demographics information includes trial participant’s age on the day of informed consent, 
subject’s sex at birth, and ethnicity and race in order to sufficiently characterize the trial 
population and to support possible subgroup analyses if needed.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 4 
hours. 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.
At the time points described in the Flow Chart, haematocrit measurements will be performed.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
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
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes 
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; Monocytes, 
absol.; Lymphocytes, absol.
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal and in 
accordance with 
Clinical laboratory 
standard 
procedures)
Neut. Poly (segs)/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes
Manual differential 
red blood count (if 
there is an 
abnormality in the 
blood cell count in 
accordance with 
Clinical laboratory 
standard 
procedures)
Only positive findings will be reported (for instance, the presence of 
microcytes)
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
Hormones
Thyroid Stimulating Hormone
X
--
Substrates
Glucose (Serum)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
Cholesterol, total
Triglyceride
Uric acid
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
Electrolytes
Sodium
Potassium
Calcium
X
X
X
X
X
X

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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
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 sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes, nitrite or 
protein are abnormal in 
urine)
Only positive findings will be reported (for instance, the presence of 
sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visits 2 and 3 (for time points refer to Flow Chart)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and on Day -1 of both trial parts.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/Ecstasy
Opiates 
Phencyclidine
Cotinine
Drug screening (serum)
Tricyclic antipressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a urine alcohol test will be performed at 
screening and on Day -1 of each trial part, 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.

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The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at the safety 
laboratory of
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 at the times provided in the Flow Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other trial procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven. 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings observed during the trial will be reported as AEs (during the trial), if assessed to be 
clinically relevant by the investigator. Of note, ECG findings at the screening visit that are 
assessed as clinically relevant by the investigator, lead to exclusion of the subject (see 
exclusion criterion 20 in Section 3.3.3). 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
5.2.5.1
Local tolerability (part B only)
In part B (absolute BA part), local tolerability will be assessed by the investigator on the 
basis of swelling, induration, heat, redness, pain, and other findings. Local findings assessed 
as clinically relevant by the investigator must be recorded as AE.

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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation, or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 

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considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in Section 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.


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

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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.

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 

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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
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, if applicable. The investigator must 
report any BI 1810631 exposure during pregnancy in a partner of the male trial participant by 
means of Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point. 
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), if applicable.
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. 
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood, urine, and faeces samples will be collected at 
the time points / time intervals indicated in the Flow Chart. The actual sampling times will be 
recorded and used for determination of pharmacokinetic parameters. More details of sample 
processing can be found in the laboratory manual. Changes to conditions of sample 
processing described in this CTP may be implemented via non-substantial amendment.
The labelled drug material corresponds to the total radioactivity measured in the different
matrices and is expressed as [14C]-radioactivity or [14C]BI 1810631-EQ.

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5.3.2
Methods of sample collection
5.3.2.1
Sample collection in Part A (ADME part)
5.3.2.1.1
Part A (ADME part) – sampling of blood for analysis of [14C]-radioactivity in 
plasma and whole blood and for analysis of BI 1810631 in plasma

For quantification of [14C]-radioactivity in whole blood, blood will be drawn from an 
antecubital or forearm vein into
blood drawing tubes at the times indicated in the Flow Chart.

For quantification of [14C]-radioactivity in plasma, blood will be drawn from an 
antecubital or forearm vein into
blood drawing tubes at the 
times indicated in the Flow Chart.

For quantification of BI 1810631 in plasma, blood will be drawn from an antecubital 
or forearm vein into
blood drawing tubes 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.
For blood volumes see Appendix 10.1.
For a detailed description of sample handling / processing, sample storage, labelling, and 
shipment, refer to the laboratory manual.
5.3.2.1.2
Part A (ADME part) – sampling of plasma for metabolic profiling
For metabolic profiling, different volumes of blood will be drawn from an antecubital or 
forearm vein into
blood drawing tubes 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.
For blood volumes see Appendix 10.1.
For a detailed description of sample handling / processing, sample storage, labelling, and 
shipment, refer to the laboratory manual.
5.3.2.1.3
Part A (ADME part) – urine sampling for analysis of [14C]-radioactivity, of 
BI 1810631, and for metabolic profiling
All urine samples are planned to be used for determination of [14C]-radioactivity and 
BI 1810631 concentrations. Samples for metabolic profiling will be selected according to the 
levels of radioactivity in each urine sample.
A blank urine sample will be collected before administration of trial medication (see Flow 
Chart) to check for analytical interference by concomitant or rescue medication. 
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
2 L polyethylene (PE) containers and stored at 
during the sampling interval. Subjects 

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are told to empty their bladders before the first sampling interval and at the end of each 
sampling interval. 
The exact start and end times of the urine collection intervals will be recorded in the CRF.
For a detailed description of sample handling / processing, sample storage, labelling, and 
shipment, refer to the laboratory manual.
5.3.2.1.4
Part A (ADME part) – faeces sampling for analysis of [14C]-radioactivity and 
metabolic profiling
A blank sample will be taken within approximately 48 hours prior to study drug 
administration. If several samples are available, the sample closest to drug administration will 
be used for analyses.
All faeces samples are planned to be used for determination of [14C]-radioactivity. Samples 
for metabolic profiling will be selected according to the levels of radioactivity in each faeces 
sampling interval.
All stools will be collected continuously and quantitatively in portions as shown in the 
Flow Chart. The weight of the faeces and the exact times of faeces collection will be recorded 
in the CRF.
If release criteria are not reached until Day 15 (see Section 3.1 for release criteria), subjects 
are to collect faeces at home within 24 h intervals before admission to once-weekly in-house 
collection intervals. For home-collection intervals and once-weekly in-house collection 
intervals see the Flow Chart. If faeces is collected during an in-house collection interval, this 
faeces sample will be used for analysis and the prior home-collection faeces sample will be 
discarded. If no faeces is collected during an in-house collection interval, the prior home-
collection faeces sample will be used.
For a detailed description of faeces labelling, storage and collection of faeces samples refer to 
the laboratory manual.
5.3.2.1.5
Part A (ADME part) – handling of vomit
If vomiting occurs within 24 hours after study drug administration, the vomit should be 
collected to calculate the weight and [14C]-radioactivity levels. 
Details of vomit sample preparation and processing, storage, labelling, and sample shipment 
are described in the laboratory manual.
5.3.2.2
Sample collection in Part B (absolute BA part)
5.3.2.2.1
Part B (absolute BA part) – plasma sampling for BI 1810631 analysis
For quantification of BI 1810631 in plasma, blood will be drawn from an antecubital or 
forearm vein into
blood drawing tubes 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.
For blood volumes see Appendix 10.2.

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For a detailed description of sample handling / processing, sample storage, labelling, and 
shipment, refer to the laboratory manual.
5.3.2.2.2
Part B (absolute BA part) – plasma sampling for [14C]BI 1810631 analysis
For quantification of [14C]BI 1810631 in plasma, blood will be drawn from an antecubital or 
forearm vein into
blood drawing tubes 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.
For blood volumes see Appendix 10.2.
For a detailed description of sample handling / processing, sample storage, labelling, and 
shipment, refer to the laboratory manual.
5.3.2.2.3
Part B (absolute BA part) – plasma sampling for total [14C]-radioactivity analysis
For quantification of total [14C]-radioactivity in plasma, blood will be drawn from an 
antecubital or forearm vein into
blood drawing tubes 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.
For blood volumes see Appendix 10.2.
For a detailed description of sample handling / processing, sample storage, labelling, and 
shipment, refer to the laboratory manual.
5.3.2.3
Parts A (ADME) and B (absolute BA) – further investigations
Back-up and left-over samples (whole blood, plasma, urine, faeces) may be used for 
metabolic profiling if not needed for their primary purpose. 
In addition, back-up and left-over samples (whole blood, plasma, urine, faeces), if not needed 
for their primary purpose anymore, may be used for further methodological investigations,
e.g. for stability testing of drug and/or its metabolites, or for assessment of the drug or drug 
metabolites or to address Health Authority questions regarding the results / methodology. 
However, only data related to BI 1810631 and/or its metabolite(s) 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 has been archived.
5.3.3
Analytical determinations in Part A (hADME part)
5.3.3.1
Determination of [14C]-radioactivity in plasma, whole blood, urine, and faeces
Determination of total [14C]-radioactivity in plasma, whole blood, urine, and faeces will be 
done by means of Liquid Scintillation Counting (LSC).
For the name and address of the laboratory refer to Section 8.7.

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5.3.3.2
Analytical determination of BI 1810631 concentrations in plasma
BI 1810631 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. 
For the name and address of the laboratory refer to Section 8.7.
5.3.3.3
Analytical determination of BI 1810631 concentrations in urine
BI 1810631 concentrations in urine will be determined by a validated LC-MS/MS assay. All 
details of the analytical method will be available prior to the start of sample analysis. 
For the name and address of the laboratory refer to Section 8.7.
5.3.3.4
Metabolic profiling in plasma, urine, and faeces
Metabolic profiling will be done by mass spectrometry analysis and by radioprofiling. For the 
name and address of the laboratories refer to Section 8.7.
Metabolic profiling data will be reported separately from CTR.
5.3.4
Analytical determinations in part B (absolute BA part)
5.3.4.1
Analytical determination of BI 1810631 concentrations in plasma
Plasma concentrations of BI 1810631 will be determined by a validated LC-MS/MS assay. 
All details of the analytical method will be available prior to the start of sample analysis.
For the name and address of the laboratory refer to Section 8.7.
5.3.4.2
Analytical determination of [14C]BI 1810631 concentrations in plasma
Plasma concentrations of [14C]BI 1810631 will be determined by means of accelerator mass 
spectrometry (AMS).
For the name and address of the laboratory refer to Section 8.7.
5.3.4.3
Analytical determination of total [14C]-radioactivity in plasma
Total [14C]-radioactivity in plasma will be determined by means of accelerator mass 
spectrometry (AMS).
For the name and address of the laboratory refer to Section 8.7.
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.
5.5
BIOBANKING
Not applicable.

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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, to determine pharmacokinetic parameters and 
to perform metabolic profiling 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 (Parts A and B) or 
intravenously (Part B) 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 
(first) 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 meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first, with blood sampling for PK and metabolite 
profiling to be done as closely as possible to the scheduled time point if not specified 
otherwise in the Flow Chart. Furthermore, if several measurements including venipuncture 
are scheduled for the same time, venipuncture should be the last of the measurements due to 
its inconvenience to the subject and possible influence on physiological parameters.
For planned blood sampling times and urine/faeces collection intervals, refer to the Flow 
Chart. While these nominal times should be adhered to as closely as possible, the actual 
sampling times will be recorded and used for the determination of pharmacokinetic 
parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.5.
6.2.2
Treatment periods
6.2.2.1
Treatment periods in part A (ADME part)
Each subject is expected to participate in one treatment period. The subjects will be admitted 
to the trial site on Day -1 (start of faeces collection at home is on Day -2), and kept under 
close medical surveillance until discharge from the trial site on Day 15. On the day of 
discharge, the subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness (fitness to be assessed by a physician).

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If release criteria (see Section 3.1) are not met on Day 15, subjects are to return for once-
weekly 24 h in-house confinements with urine and faeces sampling. In the 24 h intervals 
directly before each once-weekly in-house confinement, subjects are to collect faeces at 
home. For time intervals see the Flow Chart.
Once the release criteria are reached for an individual subject, the once-weekly collection 
intervals will be stopped for this subject. Irrespective of whether the criteria have been met or 
not after collection interval Day 42-43, no further collections are planned.
For details on time points and procedures for collection of whole blood, plasma, urine, and 
faeces samples for PK analysis, metabolic profiling, and mass balance assessments, refer to 
Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial 
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.2.2
Treatment periods in part B (absolute BA part)
Each subject is expected to participate in one treatment period. On Day -1 of the treatment 
period, trial participants will be admitted to the trial site and kept under close medical 
surveillance until at least the morning of Day 8. The subjects will then be allowed to leave the 
trial site after formal assessment and confirmation of their fitness.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoS Visit must be followed 

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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
This is a phase I, non-randomised, open-label study to investigate human ADME and 
absolute bioavailability of BI 1810631 administered to healthy male subjects. No
confirmatory analysis will be conducted for this study. 
For Part A data will be reported with descriptive statistics only. 
For Part B, the absolute bioavailability of 
 BI 1810631 administered 
 
 (test treatment T2) compared with 
 BI 1810631 (C-14) (reference treatment R) 
administered as intravenous microtracer will be estimated by the ratio of the geometric means 
(test/reference) for primary and secondary dose-normalized PK endpoints, and their 
corresponding 2-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at the 5% significance level. Since the 
main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the IPD categories will be updated as needed.

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7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for BI 1810631 and 
[14C]BI 1810631 and [14C]-radioactivity will be calculated according to the relevant BI 
internal procedures. 
Plasma, urine and faeces 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, urine and faeces 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, urine and faeces 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
Part A:
The primary endpoints (refer to Section 2.1.2) will be calculated according to the relevant BI 
internal procedures. The analysis will be descriptive in nature. To avoid underestimation of 
the total recovery of [14C], the excretion during the non-sampling phase of the study will be 
estimated using linear interpolation between the observed 24-h sampling periods before and 
after the non-sampling period for urine and faeces respectively.

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Part B:
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: subjects and treatment. The effect 
'subjects' will be considered as random, whereas the other effect 'treatment' will be considered 
as fixed. The model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response measured on subject m receiving treatment k,
= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., 7
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received treatment k,
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the dose-normalized
primary endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will 
be provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
‘subjects’ considered as fixed effect.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.2.3
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the relevant 
BI internal procedures and will be assessed statistically using the same methods as described 
for the primary endpoints.

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7.2.4
Further endpoint analyses
7.2.4.1
Pharmacokinetic analyses
Further PK endpoints will be analysed descriptively.
7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.6. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the assigned treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between first trial medication intake and end of REP 
(see Section 1.2.3) will be assigned to the treatment period. Events occurring after the REP 
but prior to end of trial termination date will be assigned to ’follow-up’. In case of two or 
more treatments, the follow-up will be summarized according to the previous treatment. 
These assignments including the corresponding time intervals will be defined in detail in the 
TSAP. Note that AEs occurring after the last per protocol contact but entered before
unblinding of the trial will be reported to Pharmacovigilance only and will not be captured in 
the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.

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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
The trial will not be randomised, thus this Section is not applicable.
7.5
DETERMINATION OF SAMPLE SIZE
For this exploratory study, no prospective calculations of statistical power have been made.
The sample size of 8 subjects in Part A and 7 subjects in Part B has been selected to provide 
at least 6 evaluable subjects per trial part, which are considered sufficient information to 
assess the main objectives of this trial.

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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 
webpage: 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.
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. 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: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.

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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a participant identification number instead of the trial 
participant’s name. The code is only available at the site and must not be forwarded to the 
sponsor. In case participant’s records will be forwarded e.g. for SAE processing or 
adjudication committees, personal data that can identify the trial participant will be redacted 
by the site prior to forwarding. Access to the participant files and clinical data is strictly 
limited: personalised treatment data may be given to the trial participant’s personal physician 
or to other appropriate medical personnel responsible for the trial participant’s welfare. Data 
generated at the site as a result of the trial need to be available for inspection on request by 
the participating physicians, the sponsor’s representatives, by the IRB/IEC and the regulatory 
authorities.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs/IECs and trial 
participants will be informed as appropriate.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF

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8.6
TRIAL MILESTONES
The first act of recruitment represents the start of the trial and is defined as the date when the 
first trial participant (subject) in the whole trial signs informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at
 under the supervision of the Principal Investigator. Relevant documentation on 
the participating (Principal) Investigators (e.g. their curricula vitae) will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required trial activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local Clinical Trial Managers
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites
The trial medication will be provided by:

BI 1810631 film-coated tablets (part B): provided by 
 

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
BI 1810631 (C-14) oral solution (part A): provided by

BI 1810631 (C-14)
(part B): provided by
Safety laboratory tests and haematocrit measurements will be performed by the local 
laboratory of the trial site 
Bioanalytical analyses will be performed at:

For BI 1810631 in plasma (parts A and B): 
 

For BI 1810631 in urine (part A): 

For [14C]-radioactivity in whole blood, plasma, urine, and faeces (part A): 

For metabolic profiling of BI 1810631 and its metabolites in plasma, urine, and faeces 
(part A):
o
Mass spectrometry analyses (plasma, urine, and faeces):
 
o
Radioprofiling:

For [14C]BI 1810631 in plasma (part B): 
 

For total [14C]radioactivity in plasma (part B): 
  
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI 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
P15-01211
Arteaga CL Engelman JA. ERBB receptors: from oncogene discovery to 
basic science to mechanism-based cancer therapeutics. Cancer Cell; 25(3), 
p. 282-303; 2014#
P19-00456
Wang Y Jiang T Qin Z Jiang J Wang Q Yang S et al. HER2 exon 20 
insertions in non-small-cell lung cancer are sensitive to the irreversible 
pan-HER receptor tyrosine kinase inhibitor pyrotinib. Ann Oncol; 30(3), 
p. 447-455; 2019
P19-10412
Connell CM Doherty GJ. Activating HER2 mutations as emerging targets 
in multiple solid cancers. ESMO Open; 2, p. e000279; 2017
P20-09250
Jebbink M Langen AJ de Boelens MC Monkhorst K Smit EF. The force of 
HER2 - a druggable target in NSCLC? Cancer Treat Rev; 86, p. 101996; 
2020
R09-6185
Hynes NE MacDonald G. ErbB receptors and signaling pathways in 
cancer. Curr Opin Cell Biol; 21, p. 177-184; 2009.
R18-1357
U.S. Department of Health and Human Services. Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published: November 27, 
2017). Website: 
ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCA
E_v 5_Quick_Reference_8.5x11.pdf#search=%22CTCAE%22 (access 
date: 2017-04-09); 2017
R18-1836
Valentin J editor. The 2007 recommendations of the International 
Commission on Radiological Protection: ICRP publication 103. Ann 
ICRP; 37(2 - 4), p. 1-332; 2007.
R18-1905
International Commission on Radiological Protection (ICRP). Factors 
related to project evaluation. Ann ICRP; 22(3), p. 11-13; 1992.
R20-1872
Citri A Yarden Y. EGF-ERBB signalling: towards the systems level. Nat 
Rev Mol Cell Biol; 7, p. 505-516; 2006.
R20-1990
Wang Z. ErbB receptors and cancer. Methods Mol Biol; 1652, p. 3-35; 
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R22-3641
Food and Drug Administration. Guidance for industry: clinical 
pharmacology considerations for human radiolabeled mass balance 
studies: draft guidance (this guidance document is being distributed for 
comment purposes only.) (clinical pharmacology, May 2022). Website: 
fda.gov/media/158178/download (access date: 2022-10-21); 2022
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
c32836122
 Investigator's Brochure BI 1810631 1479-P01. 
Current version.

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10.
APPENDICES
10.1
BLOOD VOLUMES FOR PART A (ADME PART)
Table 10.1: 1
Blood volumes for PK in part A
Visit 2, 
planned 
time 
point [h]
Blood volume for 
[14C]-radioactivity in 
whole blood –
 [mL]
Blood volume for 
[14C]-radioactivity 
in plasma –
[mL]
Blood volume for 
BI 1810631 in plasma 
–
 [mL]
Blood volume for 
metabolic profiling in 
plasma –
[mL]
-2:00
0:30
1:00
1:30
--
2:00
2:30
--
3:00
--
4:00
5:00
--
6:00
--
8:00
10:00
--
12:00
24:00
36:00
--
48:00
72:00
--
96:00
120:00
--
168:00
216:00
--
264:00
--
336:00
--
TOTAL
Table 10.1: 2
Blood volumes for safety assessments in part A
Assessment
Maximum 
# Samples
Volume of Blood per 
Sample (mL)
Total Volume of 
Blood (mL)
Clinical chemistry
5
3.5 
17.5
Hematology 
9
3 
27
Coagulation 
5
2.7
13.5
Serology
1
5
5
Total volume of blood drawn
63
The total blood volume to be collected from each subject in part A of trial 
1479-0006 is
mL.

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10.2
BLOOD VOLUMES FOR PART B (ABSOLUTE BA PART)
For analysis of BI 1810631 in plasma, 
 blood 
 is collected per time point, i.e. 
blood in total
For analysis of [14C]BI 1810631 in plasma, 
 blood
is collected per time 
point, i.e.
blood in total.
For analysis of total [14C]-radioactivity in plasma, 
 blood
is collected per 
time point (only at baseline:
of blood), i.e. 
blood in total.
Table 10.2: 1
Blood volumes for safety assessments in part B
Assessment
Maximum 
# Samples
Volume of Blood 
per Sample (mL)
Total Volume of 
Blood (mL)
Clinical chemistry
5
3.5 
17.5
Hematology 
5
3 
15
Coagulation 
5
2.7
13.5
Serology
1
5
5
Total volume of blood drawn
51
The total blood volume to be collected from each subject in part B of trial 
1479-0006 is 

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10.3
RADIOACTIVE BURDEN CALCULATION FOR PART A (ADME PART)

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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) 
 
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c38775190
1.0
clincial-trial-protocol-version-01
A phase I, open-label trial in two parallel parts to investigate mass balance,
metabolism, and basic pharmacokinetics of BI 1810631 (C-14) administered as oral
solution (part A) and to investigate absolute bioavailability of BI 1810631
administered as film-coated tablet together with an intravenous microtracer dose of
BI 1810631 (C-14) (part B) in healthy male volunteers
Author-Clinical Trial Leader
24 Apr 2023 13:25 CEST
Approval-Clinical Program 
24 Apr 2023 14:52 CEST
Author-Trial Statistician
24 Apr 2023 18:10 CEST
Verification-Paper Signature
Completion
27 Apr 2023 08:47 CEST

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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c38775190
1.0