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

BI-VQD-11906_40-106_AD-13 (8.0)
Clinical Trial Protocol
TITLE PAGE
Document Number:
c40561285-03
EUCT No.
2022-503046-50-00
BI Trial No.
1479-0011 (CRS trial number: 140/22)
BI Investigational
Medicinal Product
BI 1810631
Title
The effect of multiple doses of carbamazepine on the 
pharmacokinetics of a single oral dose of BI 1810631 in healthy 
male subjects (an open-label, two-period, fixed-sequence trial)
Lay Title
A study in healthy men to test whether carbamazepine 
influences the amount of BI 1810631 in the blood
Clinical Phase
I
Clinical Trial Leader
Phone: +
, Fax: +
 Investigator
Phone: +
 Fax: 
Current Version, Date
Version 3.0, 14 Sep 2023
Original Protocol Date
31 Mar 2023
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Boehringer 
\J1lll1v lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
31 March 2023
Revision date
14 Sep 2023
BI trial number
1479-0011
Title of trial
The effect of multiple doses of carbamazepine on the pharmacokinetics of a single 
oral dose of BI 1810631 in healthy male subjects (an open-label, two-period, fixed-
sequence trial)
 Investigator
Trial site
Clinical phase
I
Trial rationale
BI 1810631 is a substrate for CYP3A in vitro. The in vivo effect of induction of 
CYP3A on BI 1810631 pharmacokinetics is not known. It needs to be investigated 
to inform concomitant treatment recommendations. 
Trial objective
To investigate the effect of multiple oral doses of the strong CYP3A inducer 
carbamazepine on the pharmacokinetics of a single dose of BI 1810631 in plasma.
Trial endpoints
Primary endpoints: AUC0-and Cmax of BI 1810631
Secondary endpoint: AUC0-tz of BI 1810631
Trial design
Open-label, two-period, fixed-sequence crossover design 
Number of subjects 
total entered
16
on each treatment
16
Diagnosis
Not applicable
Main inclusion criteria
Healthy male subjects, age of 18 to 55 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product 1
BI 1810631 60 mg film-coated tablets
dose
60 mg
mode of 
administration
Oral with 240 mL of water after an overnight fast of at least 10 h

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Test products 2 and 3
Test product 2: Carbamazepin-neuraxpharm® 400 mg retard tablets
Test product 3: Carbamazepin-neuraxpharm® 600 mg retard tablets
Dose
Titration, starting with low dose 200 mg q.d., to mid dose 400 mg q.d., followed by 
the maximal dose 600 mg q.d.
mode of admin.
Oral with 240 mL of water after a dinner
Duration of treatment
Period 1:
-
BI 1810631 60 mg: 1 single dose in the morning of Day 1
Period 2:
-
Carbamazepine 
o
Day -18 to -15: 200 mg q.d. in the evening
o
Day -14 to -8: 400 mg q.d. in the evening
o
Day -7 to +6: 600 mg q.d. in the evening
-
BI 1810631 60 mg: 1 single dose in the morning of Day 1
Statistical methods
The extent of the drug-drug interaction will be estimated by the ratios of the 
geometric means (test/reference) for the primary and secondary endpoints. 
Additionally, their two-sided 90% confidence intervals (CIs) will be provided. This 
method corresponds to the two one-sided t-test procedure, each at a 5% significance 
level. Since the main focus is on estimation and not testing, a formal hypothesis test 
and associated acceptance range is not specified. The statistical model will be an 
analysis of variance (ANOVA) on the logarithmic scale including effects for subject
and treatment. CIs will be calculated based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART
Period
Visit
Day
Planned time (relative to BI 1810631 
administration) [h:min]
Approximate clock time of actual day 
[h:min]
Event and comment 12
Safety laboratory 10
PK BI 1810631 (plasma)
PK carbamazepine (plasma)
4β-OH Cholesterol (plasma)
6β-OH Cortisol / cortisol ratio (urine)7
12-lead ECG and vital signs (BP, PR)
Neurological examination, C-SSRS13
Skin inspection14
Questioning for AEs and concomitant 
therapy 6
SCR
1
-21 to -1
Screening (SCR)1
A
x
x
x
Period 1 (Treatment R = BI 1810631 alone)
2
-1
-14:00
18:00
Admission to site
x5
x
-13:00
19:00
Dinner3
1
-1:00
07:00
B2
x2
x2
x2
0:00
08:00
Administration: 
BI 1810631 60 mg
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
x
11:00
19:00
Dinner3
12:00
20:00
x
x 
2
24:00
08:00
B
x
x
x
36:00
20:00
x
x
3
48:00
08:00
Discharge from site
x
x
4
72:00
08:00
Ambulatory visit
x
x
6
120:00
08:00
Ambulatory visit
x
x
811
168:00
08:00
Ambulatory visit
B
x
x
Period 2 (Treatment T = carbamazepine + 
BI 1810631)
3
-1911
-446:00
18:00
Admission to site
x5
x
-444:00
20:00
▲
-18
-432:00
08:00
│
x
x
x
x
-421:00
19:00
Dinner3
│
x
-420:00
20:00
Administration: 
Carbamazepine 200 mg
x9
x9
▼
-17
-408:00
08:00
x
-397:00
19:00
Dinner3
x
-396:00
20:00
Administration: 
Carbamazepine 200 mg
-16
-384:00
08:00
x
-373:00
19:00
Dinner3
x
-372:00
20:00
Administration: 
Carbamazepine 200 mg
-15
-360:00
08:00
C
x
x
-349:00
19:00
Dinner3
x
-348:00
20:00
Administration: 
Carbamazepine 200 mg
-14
-336:00
08:00
x
x

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Period
Visit
Day
Planned time (relative to BI 1810631 
administration) [h:min]
Approximate clock time of actual day 
[h:min]
Event and comment 12
Safety laboratory 10
PK BI 1810631 (plasma)
PK carbamazepine (plasma)
4β-OH Cholesterol (plasma)
6β-OH Cortisol / cortisol ratio (urine)7
12-lead ECG and vital signs (BP, PR)
Neurological examination, C-SSRS13
Skin inspection14
Questioning for AEs and concomitant 
therapy 6
-325:00
19:00
Dinner3
x
-324:00
20:00
Administration: 
Carbamazepine 400 mg
-13
-312:00
08:00
x
-301:00
19:00
Dinner3
x
-300:00
20:00
Administration: 
Carbamazepine 400 mg
▲
-12
-288:00
08:00
B
│
x
x
-277:00
19:00
Dinner3
│
x
-276:00
20:00
Administration: 
Carbamazepine 400 mg
x9
x9
▼
-11
-264:00
08:00
x
x
-253:00
19:00
Dinner3
x
-252:00
20:00
Administration: 
Carbamazepine 400 mg
-10
-240:00
08:00
x
-229:00
19:00
Dinner3
x
-228:00
20:00
Administration: 
Carbamazepine 400 mg
-9
-216:00
08:00
C
x
-205:00
19:00
Dinner3
x
-204:00
20:00
Administration: 
Carbamazepine 400 mg
-8
-192:00
08:00
x
-181:00
19:00
Dinner3
x
-180:00
20:00
Administration: 
Carbamazepine 400 mg
▲
-7
-168:00
08:00
│
x
x
x
x
-157:00
19:00
Dinner3
│
x
-156:00
20:00
Administration: 
Carbamazepine 600 mg
x9
x9
▼
-6
-144:00
08:00
B
x
-133:00
19:00
Dinner3
x
-132:00
20:00
Administration: 
Carbamazepine 600 mg
▲
-5
-120:00
08:00
│
x
-109:00
19:00
Dinner3
│
x
-108:00
20:00
Administration: 
Carbamazepine 600 mg
x9
x9
▼
-4
-96:00
08:00
x
-85:00
19:00
Dinner3
x
-84:00
20:00
Administration: 
Carbamazepine 600 mg
▲
-3
-72:00
08:00
C
│
x
x
-61:00
19:00
Dinner3
│
x

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Period
Visit
Day
Planned time (relative to BI 1810631 
administration) [h:min]
Approximate clock time of actual day 
[h:min]
Event and comment 12
Safety laboratory 10
PK BI 1810631 (plasma)
PK carbamazepine (plasma)
4β-OH Cholesterol (plasma)
6β-OH Cortisol / cortisol ratio (urine)7
12-lead ECG and vital signs (BP, PR)
Neurological examination, C-SSRS13
Skin inspection14
Questioning for AEs and concomitant 
therapy 6
-60:00
20:00
Administration: 
Carbamazepine 600 mg
x9
x9
▼
-2
-48:00
08:00
x
-37:00
19:00
Dinner3
x
-36:00
20:00
Administration: 
Carbamazepine 600 mg
▲
-1
-24:00
08:00
│
x
x
x
-13:00
19:00
Dinner3
│
x
-12:00
20:00
Administration: 
Carbamazepine 600 mg
x9
x9
▼
1
-1:00
07:00
B2
x2
x2
x2
0:00
08:00
Administration: 
BI 1810631 60 mg
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
x
11:00
19:00
Dinner3
12:00
20:00
Administration: 
Carbamazepine 600 mg
x8
▲
x 
2
24:00
08:00
B
x
│
x
x
35:00
19:00
Dinner3
│
x
36:00
20:00
Administration: 
Carbamazepine 600 mg
x9
x9
x9
▼
3
48:00
08:00
x
x
59:00
19:00
Dinner3
x
60:00
20:00
Administration: 
Carbamazepine 600 mg
▲
4
72:00
08:00
x
│
x
x
x
83:00
19:00
Dinner3
│
x
84:00
20:00
Administration: 
Carbamazepine 600 mg
x9
x9
▼
5
96:00
08:00
C
x
107:00
19:00
Dinner3
x
108:00
20:00
Administration: 
Carbamazepine 600 mg
6
120:00
08:00
x
x
131:00
19:00
Dinner3
x
132:00
20:00
Administration: 
Carbamazepine 600 mg
▲

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Period
Visit
Day
Planned time (relative to BI 1810631 
administration) [h:min]
Approximate clock time of actual day 
[h:min]
Event and comment 12
Safety laboratory 10
PK BI 1810631 (plasma)
PK carbamazepine (plasma)
4β-OH Cholesterol (plasma)
6β-OH Cortisol / cortisol ratio (urine)7
12-lead ECG and vital signs (BP, PR)
Neurological examination, C-SSRS13
Skin inspection14
Questioning for AEs and concomitant 
therapy 6
7
144:00
08:00
│
x
156:00
20:00
x
x
▼
x
8
168:00
08:00
Discharge from trial site
x
x
FU
4
15-22
End of study (EoS) 
examination4
B
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, neurological examination, skin inspection, check of vital signs, ECG, safety 
laboratory (including drug screening test), demographics (including determination of body height and weight, smoking 
status and alcohol history), relevant medical history, concomitant therapy, review of inclusion/exclusion criteria and 
suicidality assessment (C-SSRS). 
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to the next drug 
administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of study (synonym for end of trial), the EoS examination includes physical examination, neurological 
examination, skin inspection, suicidality assessment (C-SSRS), vital signs, ECG, safety laboratory, recording of AEs
and concomitant therapies, and a determination of body weight. 
5.
Only urine drug screening and alcohol breath test and a nasal/oral swab for SARS-CoV-2 PCR testing (nasal/oral swab 
and Covid-19 test at admission or within 36 h before admission) will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
In period 2, urine samples are to be collected over the stated 24 h intervals (◄––►) -444 to -420, -300 to -276, -180 
to -156, -132 to -108, -84 to -60, -36 to -12, +12 to +36, +60 to +84, and +132 to +156 h.
8.
Blood sample on time, carbamazepine dosing immediately afterwards
9.
Within 15 min before administration of carbamazepine
10. Letters A, B, and C designate different sets of safety laboratory examinations, see Section 5.2.3
11. Day 8 of period 1 is the same day as Day -19 of period 2
12. On Day 1 of both periods, only meals as described in the Flow Chart will be served. On the other days with in-house 
stays, food will be served as per the CRO’s SOPs. Of note, a dinner will be served before all carbamazepine 
administrations as indicated by the Flow Chart.
13. For content of neurological examination see Section 5.2.5.1. Suicidality assessment using the Columbia-Suicide 
Severity Rating Scale (C-SSRS): ‘Screening/Baseline’ version at Visit 1, and ‘since last visit’ version at Visits 3 and 4 –
see also Sections 5.2.5.3 and Appendix 10.1
14. See Section 5.2.5.2.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS AND DEFINITIONS..................................................... 13
1.
INTRODUCTION.................................................................................... 16
1.1
MEDICAL BACKGROUND............................................................................16
1.2
DRUG PROFILE...............................................................................................17
1.2.1
BI 1810631 .............................................................................................17
1.2.1.1
Mode of action.........................................................................17
1.2.1.2
Potential for drug-drug interactions (DDIs) with CYP3A 
inducers ...................................................................................17
1.2.1.3
Data from studies in humans....................................................17
1.2.1.3.1 Pharmacokinetic data of patient first-in-man trial 
1479-0001 (preliminary data)....................................18
1.2.1.3.2 Pharmacokinetic data of healthy volunteer trial 1479-
0003...........................................................................19
1.2.1.3.3 Safety and tolerability data of patient first-in-man trial 
1479-0001 (preliminary data; data cut 24 Feb 2023) 20
1.2.1.3.4 Safety and tolerability data of healthy volunteer trial 
1479-0003..................................................................23
1.2.2
Carbamazepine .....................................................................................24
1.2.3
Residual Effect Period..........................................................................24
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................24
1.4
BENEFIT - RISK ASSESSMENT ...................................................................25
1.4.1
Benefits...................................................................................................25
1.4.2
Risks .......................................................................................................25
1.4.3
Discussion...............................................................................................32
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 34
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......34
2.1.1
Main objectives......................................................................................34
2.1.2
Primary endpoints ................................................................................34
2.1.3
Secondary endpoint ..............................................................................34

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 36
3.1
OVERALL TRIAL DESIGN............................................................................36
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................36
3.3
SELECTION OF TRIAL POPULATION ......................................................37
3.3.1
Main diagnosis for trial entry..............................................................37
3.3.2
Inclusion criteria...................................................................................37
3.3.3
Exclusion criteria ..................................................................................38
3.3.4
Withdrawal of subjects from treatment or assessments ...................40
3.3.4.1
Withdrawal from trial treatment ..............................................40
3.3.4.2
Withdrawal of consent to trial participation ............................41
3.3.4.3
Discontinuation of the trial by the sponsor..............................41
3.3.5
Replacement of subjects .......................................................................42
4.
TREATMENTS........................................................................................ 43
4.1
INVESTIGATIONAL TREATMENTS ..........................................................43
4.1.1
Identity of the Investigational Medicinal Products ...........................43
4.1.2
Selection of doses in the trial................................................................44
4.1.3
Method of assigning subjects to treatment groups ............................44
4.1.4
Drug assignment and administration of doses for each subject .......44
4.1.5
Blinding and procedures for unblinding ............................................45
4.1.6
Packaging, labelling, and re-supply ....................................................46
4.1.7
Storage conditions.................................................................................46
4.1.8
Drug accountability ..............................................................................46
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................47
4.2.1
Other treatments and emergency procedures....................................47
4.2.2
Restrictions............................................................................................48
4.2.2.1
Restrictions regarding concomitant treatment .........................48
4.2.2.2
Restrictions on diet and life style.............................................48
4.2.2.3
Contraception requirements.....................................................49
5.
ASSESSMENTS....................................................................................... 50
5.1
ASSESSMENT OF EFFICACY.......................................................................50
5.2
ASSESSMENT OF SAFETY............................................................................50
5.2.1
Physical examination ............................................................................50
5.2.2
Vital signs...............................................................................................50
5.2.3
Safety laboratory parameters..............................................................50
5.2.4
Electrocardiogram................................................................................52
5.2.5
Other safety parameters.......................................................................53
5.2.5.1
Neurological examinations ......................................................53
5.2.5.2
Skin inspection.........................................................................54
5.2.5.3
Suicidality assessment .............................................................54

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5.2.6
Assessment of adverse events...............................................................55
5.2.6.1
Definitions of adverse events...................................................55
5.2.6.1.1 Adverse event ............................................................55
5.2.6.1.2 Serious adverse event ................................................56
5.2.6.1.3 AEs considered ‘Always Serious’.............................56
5.2.6.1.4 Adverse events of special interest .............................57
5.2.6.1.5 Intensity (severity) of AEs.........................................58
5.2.6.1.6 Causal relationship of AEs ........................................58
5.2.6.2
Adverse event collection and reporting ...................................59
5.2.6.2.1 AE collection.............................................................59
5.2.6.2.2 AE reporting to the sponsor and timelines ................59
5.2.6.2.3 Pregnancy ..................................................................60
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................60
5.3.1
Assessment of pharmacokinetics .........................................................60
5.3.2
Methods of sample collection...............................................................60
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................60
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................62
5.4
ASSESSMENT OF BIOMARKERS................................................................62
5.4.1
Drug-Drug Interaction Biomarkers ....................................................62
5.4.1.1
Methods of sample collection..................................................62
5.4.1.1.1 4β-OH cholesterol in plasma.....................................62
5.4.1.1.2 6β-OH cortisol and cortisol in urine..........................63
5.4.2
Pharmacodynamic biomarkers............................................................64
5.4.3
Pharmacogenomic biomarkers............................................................64
5.5
BIOBANKING ...................................................................................................64
5.6
OTHER ASSESSMENTS .................................................................................64
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................64
6.
INVESTIGATIONAL PLAN.................................................................. 65
6.1
VISIT SCHEDULE............................................................................................65
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................65
6.2.1
Screening period....................................................................................65
6.2.2
Treatment periods.................................................................................65

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6.2.3
Follow-up period and trial completion ...............................................66
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 67
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................67
7.2
PLANNED ANALYSES....................................................................................67
7.2.1
General considerations.........................................................................67
7.2.1.1
Analysis sets.............................................................................67
7.2.1.2
Pharmacokinetics.....................................................................67
7.2.1.3
Biomarkers...............................................................................68
7.2.2
Primary endpoint analyses...................................................................68
7.2.3
Secondary endpoint analyses ...............................................................69
7.2.5
Safety analyses.......................................................................................70
7.2.6
Interim analyses ....................................................................................71
7.3
HANDLING OF MISSING DATA ..................................................................71
7.3.1
Safety......................................................................................................71
7.3.2
Pharmacokinetics..................................................................................71
7.4
RANDOMISATION ..........................................................................................71
7.5
DETERMINATION OF SAMPLE SIZE ........................................................71
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 73
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................73
8.2
DATA QUALITY ASSURANCE .....................................................................74
8.3
RECORDS..........................................................................................................74
8.3.1
Source documents .................................................................................74
8.3.2
Direct access to source data and documents.......................................75
8.3.3
Storage period of records.....................................................................75
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................76
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......76
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................76
8.6
TRIAL MILESTONES .....................................................................................77
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................77
9.
REFERENCES......................................................................................... 79
9.1
PUBLISHED REFERENCES...........................................................................79
9.2
UNPUBLISHED REFERENCES.....................................................................80
10. APPENDICES .......................................................................................... 81

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10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE ................................81
10.2
BLOOD SAMPLING OVERVIEW.................................................................87
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 89
11.1
GLOBAL AMENDMENT 1 .............................................................................89
11.2
GLOBAL AMENDMENT 2 .............................................................................90

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ABBREVIATIONS AND DEFINITIONS
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CRO
Clinical Research Organisation
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
CYP3A
Cytochrome P450 family 3 subfamily A
DDI
Drug Drug Interaction
DILI
Drug induced liver injury
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EGFR
Epidermal growth factor receptor
EoS
End of Study (synonym for End of Trial)
EUCT No.
European Clinical Trial Number

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FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRTpo
Mean residence time of the analyte in the body after oral administration
MTD
Month-do-Date
NF
New formulation
NSCLC
Non-small-cell lung cancer
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
RTK
Receptor tyrosine kinases
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
ss
(at) steady state
T
Test product or treatment
TF1
Trial formulation 1
t1/2
Terminal half-life of the analyte in plasma

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tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
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/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WOBC
woman of child-bearing potential

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

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1.2
DRUG PROFILE
1.2.1
BI 1810631
For a comprehensive description of BI 1810631 refer to the IB [c32836122]. Preliminary PK 
and safety data available so far from clinical studies and not included in the IB are described 
below in Section 1.2.1.3.
1.2.1.1
Mode of action
BI 1810631 is an EGFR wild type sparing, selective HER2 inhibitor with potent inhibitory 
activity on all major HER2 mutations including the HER2 YVMA insertion allele. It is 
intended to treat patients with advanced solid tumors with HER2 aberrations.
1.2.1.2
Potential for drug-drug interactions (DDIs) with CYP3A inducers
Based on in vitro data, CYP3A4/5 is primarily responsible for the hepatic oxidative 
metabolism of BI 1810631, 
. Thus, concomitant 
medication with inducers of CYP3A could cause clinically relevant decreases of the plasma 
exposure of BI 1810631. For more details refer to the IB [c32836122].
1.2.1.3
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).
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 
q.d. or b.i.d. dosing schemes. PK and safety data are collected. So far, 42 patients were 
treated in the dose escalation part with BI 1810631 either in one of the b.i.d. cohorts (17 
patients - 15-30-60-100-150 mg) or the q.d. cohorts (25 patients - 60-120-180-240-300 mg). 
Data cut time point for the data described here is 24 Feb 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 30 mg 
BI 1810631 in 4 treatment periods in randomized order, separated by wash-out intervals of at 
least 14 days. The 4 treatments were: 

R: 30 mg BI 1810631 trial formulation 1 (TF1) under fasted conditions

T1: 30 mg BI 1810631 new formulation (NF) under fasted conditions

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
T2: 30 mg BI 1810631 NF after a high-fat, high-calorie breakfast

T3: 30 mg BI 1810631 NF after a 5-day pre-treatment with the proton-pump inhibitor 
rabeprazole.
1.2.1.3.1
Pharmacokinetic data of patient first-in-man trial 1479-0001 (preliminary data)
Table 1.2.1.3.1: 1
Single-dose BI 1810631 PK data of ongoing patient trial 1479-0001 
(preliminary data)
Preliminary PK 
parameters: gMean 
(gCV%)
tmax
[h]1
Cmax
[nM]
AUC0-12
[nM*h]
AUC0-tz
[nM*h]2
AUC0-∞
[nM*h]
t1/2
[h]
Dose group (N) 
15 mg b.i.d. (3)
30 mg b.i.d. (3) 
60 mg b.i.d. (3)
60 mg q.d. (5)
100 mg b.i.d. (4)
120 mg q.d. (4)
150 mg b.i.d. (3)
180 mg q.d. (5)
240 mg q.d. (4)
300 mg q.d. (3)
1 median (min-max)
2

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Table 1.2.1.3.1: 2
Steady-state BI 1810631 PK data of ongoing patient trial 1479-0001 
(preliminary data)
Preliminary PK 
parameters: 
gMean (gCV%)
tmax,ss
[h]1
Cmax
[nM]
AUCτ,ss
[nM*h]
t1/2,ss
[h]
Dose group (N) 
15 mg b.i.d. (3)
30 mg b.i.d. (3) 
60 mg b.i.d. (3)
60 mg q.d. (5)
100 mg b.i.d. (4)
120 mg q.d. (3)
150 mg b.i.d. (2)
180 mg q.d. (4)
240 mg q.d. (4)
300 mg q.d. (2)
1 median (min-max)
1.2.1.3.2
Pharmacokinetic data of healthy volunteer trial 1479-0003
Table 1.2.1.3.2: 1
Single-dose BI 1810631 PK data of healthy volunteer trial 1479-0003
Preliminary PK 
parameters: gMean 
(gCV%)
tmax
[h]1
Cmax
[nM]
AUC0-tz
[nM*h]
AUC0-∞
[nM*h]
t1/2
[h]
Treatment (N)
R = 30 mg TF1 fasted 
(12)
T1 = 30 mg NF fasted 
(12)
T2 = 30 mg NF fed 
(9)
T3 = 30 mg NF fasted + 
rabeprazole (11)
1 median (min-max)

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Of note, the film-coated tablets used in the current trial 1479-0011 are based on the same 
formulation principle as the NF used in trial 1479-0003, i.e. pharmacokinetic data of NF 
(fasted) are expected to be representative for current trial 1479-0011.
1.2.1.3.3
Safety and tolerability data of patient first-in-man trial 1479-0001 (preliminary 
data; data cut 24 Feb 2023)
Among the 42 patients treated with BI 1810631 in either q.d. or b.i.d. dosing schemes, no 
severe expected or serious unexpected safety findings were observed so far at data cut point
(24 Feb 2023). Overall, BI 1810631 was well tolerated, and reported AEs were manageable.
B.i.d. cohorts
For all b.i.d. cohorts (17 patients treated), the most frequent treatment related reported AE 
was diarrhoea in 8 (47.1%) patients with CTCAE Grade 1 severity in 6 (35.3%) cases and 
Grade 2 severity in 2 (11.8%) cases. For 3 (17.6%) patients, anaemia was reported (related, 
two patients Grade 1 and one patient Grade 2). Dry skin, hypertension, rhinitis, and blood 
creatinine increased was reported in 2 (11.8%) patients each, all related, Grade 1. 
There was one patient with related ALT increased Grade 3 during treatment with 150 mg 
BI 1810631. Treatment for this patient was interrupted and restarted at the same dose level. 
Reported AST and ALT levels decreased during continued treatment with BI 1810631.
Otherwise, single events reported of Grades 3, 4, or 5 were all assessed as not related to 
BI 1810631. The two fatal cases were associated to malignant neoplasm progression. No 
serious event was reported as related to BI 1810631. 
 was observed as dose-limiting toxicity (DLT) in dose 
group 60 mg and 
. This event caused a 
 
. 
, 
. For another case (not yet captured in clinical 
database), one related AE of diarrhoea Grade 2 was observed as DLT in dose group 150 mg. 
 
 In dose group 60 mg one 
related AE of stomatitis Grade 1 was observed. No DLTs were reported during Cycle 1 
(MTD period). No AE leading to discontinuation of BI 1810631 was reported.
Q.d. cohorts
For all q.d. cohorts (25 patients treated), the most frequent reported related AEs were
diarrhoea in 5 (20.8%) patients, followed by ALT increased and blood AP increased in 4
(16.7%) patients each, followed by anaemia, AST increased, GGT increased, 
hyperglycaemia, and hypoalbuminaemia, each in 3 (12.5%) patients. Two related ALT
increases were of CTCAE Grade 3 (180 mg, 240 mg), and one each of the related AEs AST
increased (240 mg) and GGT increased (60 mg) were of Grade 3. Moreover, one related 
anaemia, one related lymphocyte count decreased, and one related hypocalcaemia (all at 
60 mg) were of CTCAE Grade 3. Of note, the observed Grade 3 AEs of anaemia, lymphocyte 
count decreased and GGT increased are under re-evaluation for causality.

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All other related AEs were of Grades 1 or 2. Otherwise, single events reported of Grade 3 and 
Grade 5 were assessed as not related to BI 1810631. There were two fatal cases, both related 
to underlying malignancy. 
The five related diarrhoea reports were of CTCAE grade 1. In dose group 240 mg 2 related 
AEs of stomatitis Grade 1 were observed, and in dose group 300 mg one related AE of mouth 
ulceration Grade 1 was observed.
One anaemia Grade 3 (60 mg) (re-evaluation for causality pending) and one ALT / AST
increased, both Grade 3, (240 mg) were reported as drug-related serious adverse events. One 
anaemia Grade 3 (60 mg) (re-evaluation pending) in Cycle 11 and one ALT increased Grade 
3 (180 mg) in Cycle 4 were reported as DLTs. No DLTs were reported during Cycle 1 (MTD 
period). In one patient at 180 mg, one ALT increased Grade 3 led to dose reduction (120 mg). 
The AE was improving. For another patient at 240 mg, one ALT increased Grade 3 and one 
AST increased Grade 3 led to dose reduction (180 mg). Both AEs were improving. Follow-up 
data is pending for both patients who required dose reductions. One anaemia Grade 3 (re-
evaluation pending) at 60 mg and one SARS-CoV-2 test positive Grade 1 at 180 mg led to 
treatment discontinuations.
Table 1.2.1.3.3: 1
Number (%) of patients with drug-related AEs by dose group –
b.i.d. cohorts (preliminary data)
Preferred term
15 mg b.i.d.
[N (%)]
30 mg b.i.d.
[N (%)]
60 mg b.i.d.
[N (%)]
100 mg b.i.d.
[N (%)]
150 mg b.i.d.
[N (%)]
Number of patients
3 (100.0)
3 (100.0)
4 (100.0)
4 (100.0)
3 (100.0)
Total with drug-related AEs
2 (66.7)
2 (66.7)
4 (100.0)
3 (75.0)
2 (66.7)
Diarrhoea
ALT increased
Anaemia
AST increased
Blood AP increased
Blood creatinine increased
Dyspepsia
Dry skin
Fatigue
Hypercholesterolaemia
Hypertension
Hypoalbuminaemia
Hypocalcaemia
Increased upper airway secretion
Oedema
Paronychia
Platelet count decreased
Pruritus
Rash
Rash maculo-papular
Rhinitis
Stomatitis
Taste disorder
Vomiting
0
0
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
1 (33.3)
0
0
0
1 (33.3)
0
0
1 (33.3)
0
0
0
0
0
0
0
0
0
0
3 (75.0)
0
0
0
1 (25.0)
0
0
0
1 (25.0)
0
0
0
0
0
1 (25.0)
0
0
0
0
0
1 (25.0)
1 (25.0)
0
0
2 (50.0)
0
1 (25.0)
0
0 
1 (25.0)
0
1 (25.0)
0
0
1 (25.0)
1 (25.0)
1 (25.0)
0
0
0
0
0
0
1 (25.0)
1 (25.0)
0
0
1 (25.0)
2 (66.7)
1 (33.3)
2 (66.7)
1 (33.3)
0
1 (33.3)
0
1 (33.3)
0
0
0
0
0
0
0
1 (33.3)
1 (33.3)
0
1 (33.3)
0
0
0
1 (33.3)
0

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Table 1.2.1.3.3: 2
Number (%) of patients with drug-related AEs by dose group –
q.d. cohorts (preliminary data)
Preferred term
60 mg q.d.
[N (%)]
120 mg q.d.
[N (%)]
180 mg q.d.
[N (%)]
240 mg q.d.
[N (%)]
300 mg q.d.
[N (%)]
Number of patients
5 (100.0)
4 (100.0)
6 (100.0)
5 (100.0)
4 (100.0)*
Total with drug-related AEs
3 (60.0)
3 (75.0)
4 (66.7)
5 (100.0)
1 (25.0)
Abdominal pain upper
ALT increased
Anaemia
Arthralgia
AST increased
Bilirubin conjugated increased
Blood AP increased
Blood creatinine increased
Blood fibrinogen increased
Blood LDH increased
Blood phosphorus decreased
Bone pain
Chest pain
Decreased appetite
Dermatitis acneiform
Diarrhoea
Dry eye
Dry skin
Dysgeusia
Fatigue
Flatulence
GGT increased
Glucose urine present
Hyperglycaemia
Hypermagnesaemia
Hyperphosphataemia
Hypertriglyceridaemia
Hyperuricaemia
Hypoaesthesia oral
Hypoalbuminaemia
Hypocalcaemia
Hypochloraemia
Hypokalaemia
Hypomagnesaemia
Hyponatraemia
Hypophosphataemia
Hypothyroidism
INR increased
Insomnia
Lymphocyte count decreased
Malaise
Mouth ulceration
Nausea
Paronychia
Peripheral sensory neuropathy
Proteinuria
Prothrombin time prolonged
Pruritus
Rash
SARS-CoV-2 test positive
0
0
1 (20.0)
0
0
1 (20.0)
1 (20.0)
1 (20.0)
1 (20.0)
0
0
1 (20.0)
0
1 (20.0)
0
0
0
1 (20.0)
0
1 (20.0)
0
1 (20.0)
1 (20.0)
1 (20.0)
0
0
1 (20.0)
1 (20.0)
0
1 (20.0)
1 (20.0)
0
1 (20.0)
1 (20.0)
1 (20.0) 
1 (20.0)
0 
1 (20.0)
0
1 (20.0)
1 (20.0)
0
1 (20.0)
1 (20.0)
1 (20.0)
1 (20.0)
1 (20.0)
0
0
0
0
1 (25.0)
1 (25.0)
0
0
0
1 (25.0)
1 (25.0)
0
1 (25.0)
1 (25.0)
0
0
0
0
2 (50.0)
1 (25.0)
0
0
0
0
1 (25.0)
0
1 (25.0)
1 (25.0)
1 (25.0)
1 (25.0)
0
0
1 (25.0)
1 (25.0)
1 (25.0)
1 (25.0)
0
1 (25.0)
0
1 (25.0)
0
0
0
0
0
0
0
0
1 (25.0)
0
1 (25.0)
0
0
1 (16.7)
2 (33.3)
1 (16.7)
0
2 (33.3)
0
1 (16.7)
0
0
0
0
0
0
1 (16.7)
1 (16.7)
0
0
0
1 (16.7)
0
1 (16.7)
1 (16.7)
0
1 (16.7)
0
0
0
0
1 (16.7)
1 (16.7)
0
0
0
0
0
0
0
0
1 (16.7)
0
1 (16.7)
0
0
1 (16.7)
0
0
0
0
1 (16.7)
1 (16.7)
0
1 (20.0)
0
0
1 (20.0)
0
0
0
0
0
0
0
0
0
0
2 (40.0)
0
0
0
0
0
0
0
0
0
0
0
1 (20.0)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (20.0)
0
0
0
1 (25.0)
0
1 (25.0)
1 (25.0)
0
0
0
0
0
1 (25.0)
0
0
1 (25.0)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (25.0)
0
0
0
0
0
0
1 (25.0)
0

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Table 1.2.1.3.3: 2 
Number (%) of patients with drug-related AEs by dose group –
q.d. cohorts (preliminary data) – cont.
Preferred term
60 mg q.d.
[N (%)]
120 mg q.d.
[N (%)]
180 mg q.d.
[N (%)]
240 mg q.d.
[N (%)]
300 mg q.d.
[N (%)]
Number of patients
5 (100.0)
4 (100.0)
6 (100.0)
5 (100.0)
4 (100.0)*
Total with drug-related AEs
3 (60.0)
3 (75.0)
4 (66.7)
5 (100.0)
1 (25.0)
Sinus bradycardia
Stomatitis
Vomiting
Weight increased
White blood cells urine positive
0
0
1 (20.0)
1 (20.0)
0
0
0
0
0
1 (25.0)
0
0
0
0
0
0
2 (40.0)
0
0
0
1 (25.0)
0
0
0
0
* 1 additional patient in 300 mg dose group not yet captured in clinical database
1.2.1.3.4
Safety and tolerability data of healthy volunteer trial 1479-0003 
Table 1.2.1.3.4: 1
Frequency [N (%)] of healthy subjects with on-treatment adverse 
events by treatment, primary system organ class and preferred term in 
trial 1479-0003
System organ class /
  Preferred term
R –
TF1 fasted
[N (%)]
T1 –
NF fasted
[N (%)]
T2 –
NF fed
[N (%)]
T3 partial –
Rabeprazole 
alone
[N (%)]
T3 partial –
NF fasted + 
rabeprazole
[N (%)]
Total
Number of subjects
12 (100.0)
12 (100.0)
9 (100.0)
11 (100.0)
11 (100.0)
13 (100.0)
Total with AEs
4 (33.3)
1 (8.3)
4 (44.4)
2 (18.2)
4 (36.4)
8 (61.5)
Gastrointestinal disorders
  Haemorrhoids
  Nausea
  Diarrhoea
  Abdominal pain upper
0
  0
  0
  0
  0
1 (8.3)
  0
  0
  0
  1 (8.3)
2 (22.2)
  1 (11.1)
  1 (11.1)
  0
  0
0
  0
  0
  0
  0
1 (9.1)
  0
  0
  1 (9.1)
  0 (0.0)
4 (30.8)
  1 (7.7)
  1 (7.7)
  1 (7.7)
  1 (7.7)
Infections and 
infestations
  COVID-19
  Furuncle
  Hordeolum
  Pharyngitis
3 (25.0)
  2 (16.7)
  0
  0
  1 (8.3)
1 (8.3)
  1 (8.3)
  0
  0
  0
0
  0
  0
  0
  0
2 (18.2)
  0
  1 (9.1)
  1 (9.1)
  0
0
  0
  0
  0
  0 
6 (46.2)
  3 (23.1)
  1 (7.7)
  1 (7.7)
  1 (7.7)
Injury, poisoning and 
procedural complications
  Sunburn
  Contusion
0
  0
  0
0 
  0
  0
1 (11.1)
  1 (11.1)
  0
0
  0
  0
1 (9.1)
  0
  1 (9.1)
1 (7.7)
  1 (7.7)
  1 (7.7)
Musculoskeletal and 
connective tissue 
disorders
  Arthralgia
  Myalgia
0
  0
  0
0
  0
  0
0
  0
  0 
0
  0
  0 
2 (18.2)
  1 (9.1)
  1 (9.1)
2 (15.4)
  1 (7.7)
  1 (7.7)
Nervous system 
disorders
  Headache
1 (8.3)
  1 (8.3)
0
  0
0
  0
0
  0
0
  0
1 (7.7)
  1 (7.7)
Psychiatric disorders
  Insomnia
0 
  0 
0 
  0 
0 
  0 
0 
  0 
1 (9.1)
  1 (9.1)
1 (7.7)
  1 (7.7)
Skin and subcutaneous 
tissue disorders
  Rash
  Petechiae
0 
  0 
  0 
0 
  0 
  0 
1 (11.1)
  1 (11.1)
  0 
0 
  0
  0 
1 (9.1)
  0 
  1 (9.1)
2 (15.4)
  1 (7.7)
  1 (7.7)

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In trial 1479-0003, in which oral single doses of 30 mg BI 1810631 were administered to 
healthy volunteers, there were no SAEs, no AESIs, and no other significant AEs. All AEs 
were of CTCAE grade 1 or 2 severity, and none of the AEs were assessed as drug-related. 
Available safety data including AEs, ECGs, VS, and safety laboratory indicate that single 
doses of 30 mg BI 1810631 were safe and well tolerated in trial 1479-0003. 
1.2.2
Carbamazepine
Carbamazepine is an anticonvulsant medication indicated, amongst other indications, for the 
treatment of epilepsy and neuropathic pain. After oral administration, carbamazepine is 
slowly and nearly completely absorbed. Pharmacokinetic steady state is reached after 2 to 8 
days. Plasma protein binding is between 70 and 80%. Carbamazepine is oxidated, 
desaminated, hydroxylated and esterified with glucuronic acid in the liver. After a single 
dose, carbamazepine t1/2 is approximately 36 hours. After multiple doses, t1/2 is reduced due 
to enzyme induction by about 50%. [R23-1121]
Therapeutic doses are usually given once (q.d.) or twice (b.i.d.) daily and range between 400 
and 1200 mg per day. A maximal daily dose of 1600 mg should usually not be exceeded as 
higher doses are associated with a higher risk for side effects. It is recommended to take the 
extended release tablets together with or after a meal. [R23-1121]
FDA recommends carbamazepine as strong index inducer of CYP3A for clinical trials
(https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers; accessed on 23 Jan 2023). 
Stockis A et al. reported from a trial in healthy volunteers that a carbamazepine dosing 
regime of 200 mg/day for 4 days, followed by 400 mg/day for 7 days, followed by 
600 mg/day for 21 days resulted in a maximal induction of CYP3A (based on 
6β-OH cortisol/cortisol ratio) on Day 18 of this regime [R23-0228]. 
For a more detailed description of carbamazepine, please refer to the SmPCs for 
Carbamazepin-neuraxpharm® 200 mg retard / 400 mg retard [R23-1120] and Carbamazepin-
neuraxpharm® 300 mg retard / 600 mg retard [R23-1121].
1.2.3
Residual Effect Period
The Residual Effect Period (REP) of single doses of BI 1810631 is conservatively estimated 
as 14 days. This is the period after the last dose during which measurable drug levels and/or 
pharmacodynamic effects are still likely to be present.
The REP of carbamazepine is defined as 8 days.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Based on in vitro data, CYP3A4/5 is primarily responsible for the hepatic oxidative 
metabolism of BI 1810631, 
 [c32836122]. Thus, 
concomitant medication with inducers of CYP3A could cause clinically relevant decreases of 
the plasma exposure of BI 1810631. It is therefore necessary to investigate the effect of an 
inducer of CYP3A on the pharmacokinetics of BI 1810631 in plasma to inform concomitant 
treatment recommendations. 

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Carbamazepine is selected because the FDA recommends carbamazepine as strong index 
inducer of CYP3A for clinical trials (https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers; 
accessed on 23 Jan 2023). 
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 1810631 for 
treatment of patients with advanced solid tumours with HER2 aberrations.
1.4.2
Risks
Subjects are exposed to risks of trial procedures and risks related to the exposure to the trial 
medication. An overview of trial-related risks is given in Table 1.4.2: 1.
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
Mucositis

Lesions of oral mucosa 
observed in dog 
toxicology and general 
pharmacology studies 
[c32836122]

Stomatitis / mouth 
ulceration observed in 
patients in trial 
1479-0001 (Section
1.2.1.3.3)

AE questioning (see 
Flow Chart)

Instruction of subjects to report 
AEs spontaneously

Protection of subjects by 
administration of only two 
single doses with appropriate 
wash-out

For recommendations for 
mucositis treatment see 
Section 4.2.1
QT prolongation

Preclinical data indicate a 
low proarrhythmic 
potential of BI 1810631

So far no QTc 
prolongations reported 
from patient trial 1479-
0001
Subjects with a marked QTc 
prolongation at baseline are 
excluded from participation in this 
trial (see exclusion criterion 20)
Subjects with a history of risk 
factors for Torsade de Pointes are 
excluded from participation in this 
trial (see exclusion criterion 21)
ECGs will be performed as
defined in the Flow Chart

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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 from 
other tyrosine kinase 
inhibitors
Subjects are protected from this 
finding by administration of only 
two single doses with appropriate 
wash-out
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Subjects with pre-existing 
ILD/pneumonitis or other 
respiratory disorder are excluded 
from trial participation (see 
exclusion criteria 4 and 5)
Hair discoloration

Yellow hair discoloration 
with indication for 
reversibility in rats and 
dogs [c32836122]

So far no hair 
discoloration reported 
from patients after 
multiple-dose treatment 
up to 150 mg b.i.d. / 
300 mg q.d. BI 1810631 
over at least 21 days (see 
Section 1.2.1.3.3)
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Physical examination of subjects 
at end-of-study visit 
Protection of subjects by 
administration of only two single 
doses
Toxicity to adrenal glands

Reversible changes to 
adrenal glands in rats 
after multiple dosing 
(increased organ weights, 
vacuolation, minimal 
single cell necrosis, 
hypertrophy of zona 
fasciculata/ reticularis) 
[c32836122]

Reversible changes to 
adrenal glands in dogs 
after multiple dosing 
(hyperplasia of zona 
glomerulosa) 
[c32836122]
Safety laboratory (see 
Section 5.2.3) includes serum
electrolytes
Protection of subjects by 
administration of only two single 
doses with appropriate wash-out

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Intestinal toxicity

Reversible intestinal 
effects in dogs after 
multiple dosing (fecal 
alterations, Goblet cell 
hyperplasia) [c32836122]

Diarrhoea observed in 
patients in trial 
1479-0001 (see Section 
1.2.1.3.3)
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Protection of subjects by 
administration of only two single 
doses with appropriate wash-out
Reproductive and 
developmental toxicity

Developmental and 
reproductive toxicity 
studies have not been 
conducted. Teratogenicity 
cannot be excluded. 

Through the ejaculate, 
BI 1810631 could 
potentially be transferred 
to a female partner of the 
male participant, be 
vaginally absorbed and 
could thus theoretically 
harm the fetus
Only male subjects are included 
into this trial
Volunteers will, together with 
their WOCBP (woman of child-
bearing potential) partner, use 
highly effective contraception 
from first dosing of BI 1810631 
until 30 days after the last dosing 
with BI 1810631 (see also 
exclusion criterion 28 in 
Section 3.3.3)
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 1.2.1.3.3)
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Following administration of 
BI 1810631, subjects will be in-
house under close observation for 
at least 48 hours 
Protection of subjects by 
administration of only two single 
doses with appropriate wash-out

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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
Uncertainties due to the 
early stage of 
development

Comparatively very high 
plasma exposures were 
explored in humans (see 
Section 1.2.1.3.1) and 
were associated to well 
tolerable and manageable 
safety profile so far (see 
Section 1.2.1.3.3). 
However, the stage of 
development is still early 
and there may still be 
some yet unknown risks 
of treatment with 
BI 1810631
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Following administration of 
BI 1810631, subjects will be in-
house under close observation for 
at least 48 hours 
VS and ECGs after dosing (see 
Flow Chart)
Protection of subjects by 
administration of only two single 
doses with appropriate wash-out
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.
Investigational Medicinal Product: Carbamazepine
Skin reactions

Life-threatening skin 
reactions (e.g., Stephens-
Johnson syndrome, Toxic 
Epidermal Necrolysis) are 
very rare side effects of 
carbamazepine. The 
incidence of life-
threatening skin reactions 
is increased in subjects of 
han-Chinese or Thai
ancestry [R23-1121]
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Skin examinations at pre-defined 
time points (see Flow Chart and 
Section 5.2.5.2)
During the entire phase of 
carbamazepine dosings, subjects 
are in-house at the trial site under 
close medical observation (see 
Flow Chart)
Exclusion of subjects of Asian 
ancestry (see exclusion criterion 
25)
Withdrawal of subjects who 
experience clinical signs of a 
drug-induced Stevens-Johnson 
syndrome or Toxic Epidermal 
Necrolysis (see Section 3.3.4.1
criterion 8)

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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
Disorders of the 
haematopoietic system

During treatment with 
carbamazepine, several 
disorders of the 
haematopoietic systems 
are observed, such as 
anemia, leukopenia or 
thrombocytopenia. 
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Exclusion of subjects with 
relevant deviations in the safety 
laboratory at screening (see 
Section 3.3.3, exclusion criterion 
3)
Exclusion of subjects with 
haemoglobin, leukocytes, or 
platelets below lower level of 
normal at screening (Section 3.3.3, 
exclusion criterion 29)
Withdrawal of subjects who, 
during carbamazepine treatment, 
develop a relevant disorder of the 
haematopoietic system (see 
Section 3.3.4.1, criterion 7)
Frequent safety laboratory during 
carbamazepine dosing phase (see 
Flow Chart)
Hypersensitivity reactions

Various hypersensitivity 
reactions are reported 
during therapy with 
carbamazepine

AE questioning (see 
Flow Chart)

Instruction of subjects to report 
AEs spontaneously

During the entire phase of 
carbamazepine dosings, subjects 
are in-house at the trial site 
under close medical observation 
(see Flow Chart)

Exclusion of subjects with 
relevant allergy or 
hypersensitivity including 
allergy to the trial medication 
and including allergy to drugs 
structurally related to 
carbamazepine (see 
Section 3.3.3 exclusion criterion 
11)

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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
Hepatic side effects

Rarely / very rarely, 
several hepatic side 
effects, e.g. hepatitis, can 
occur [R23-1121]

Frequent safety laboratory 
during carbamazepine dosing 
phase (see Flow Chart)

Withdrawal of subjects with 
ALT/ AST increase ≥3x ULN 
during carbamazepine dosings 
from treatment (see 
Section 3.3.4.1, criterion 6)
Hyponatremia

Carbamazepine 
frequently causes 
hyponatremia 
[R23-1121]

Frequent safety laboratory 
during carbamazepine dosing 
phase (see Flow Chart)

Withdrawal in case of CTCAE 
grade 3 hyponatremia (see 
Section 3.3.4.1 criterion 9)
Suicidality

Treatment with 
anticonvulsant 
medication has been 
associated with suicidal 
ideation and suicidal 
behaviour [R23-1121]

Suicidality questionnaire 
implemented at screening and 
during the study

During the entire phase of 
carbamazepine dosings, subjects 
are in-house at the trial site 
under close medical observation 
(see Flow Chart)

Exclusion criterion (Section 3.3, 
criteria 26 and 27) and 
withdrawal criterion 
(Section 3.3.4.1, criterion 10) 
defined
Phototoxicity

Photosensitivity is a very
rare side effect of 
carbamazepine 
[R23-1121]

Direct exposure to the sun or 
exposure to solarium radiation 
should be avoided starting from 
first carbamazepine dosing and 
until the end-of-trial 
examination (see 
Section 4.2.2.2)

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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
Risk of subjects falling

Treatment with 
carbamazepine can cause 
ataxia, dizziness, 
somnolence, hypotension, 
confusion, and sedation. 
This could cause subjects 
to fall. [R23-1121]

During the entire phase of 
carbamazepine dosings, subjects 
are in-house at the trial site 
under close medical observation 
(see Flow Chart)

Subjects who experience 
adverse events like dizziness or 
ataxia are allowed to use the lift 
instead of stairs during the in-
house period of Visit 3

Neurological examination at 
pre-defined time points (see 
Section 5.2.5.1 and Flow Chart)
Cardial rhythm disorders

Carbamazepine can cause 
cardial conduction and 
rhythm disorders 
[R23-1121]

Subjects with AV block, QTc 
prolongation or other relevant 
ECG finding are excluded from 
trial participation (see 
Section 3.3.3 criterion 20)

During the entire phase of 
carbamazepine dosings, subjects 
are in-house at the trial site 
under close medical observation 
(see Flow Chart)

ECGs will be done during the 
study as per Flow Chart

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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
Other side effects of 
carbamazepine

See [R23-1121]

Stringent in- and exclusion and 
individual withdrawal criteria 
(see Sections 3.3.2, 3.3.3 and 
3.3.4.1)

During the entire phase of 
carbamazepine dosings, subjects 
are in-house at the trial site 
under close medical observation 
(see Flow Chart)

Neurological examination at 
pre-defined time points (see 
Section 5.2.5.1 and Flow Chart)

Frequent safety laboratory 
during carbamazepine dosing 
phase (see Flow Chart)

AE questioning (see 
Flow Chart)

Instruction of subjects to report 
AEs spontaneously
Trial procedures
Bruising and, in rare 
cases, phlebitis, or nerve 
injury, potentially 
resulting in paraesthesia, 
reduced sensibility, and/or 
pain 
General risk by venipuncture
for blood sampling,
acceptable in the framework 
of trial participation.
Medical expertise of the trial site 
ECG recording: Skin 
irritation, redness, itching
General risk by ECG 
electrodes, acceptable in the 
framework of trial 
participation
Exclusion of subjects from trial 
participation with known clinically 
relevant hypersensitivity reactions to 
adhesive tapes (see Section 3.3.3, 
criterion 11
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 Appendix 10.2 for exact blood volume). No 
health-related risk to healthy subjects is expected from withdrawal of this volume of blood.
1.4.3
Discussion
There is significant medical need in cancer patients harbouring HER2 mutations for effective, 
safe and well-tolerated therapies. BI 1810631 is an EGFR wild-type sparing selective HER2 
inhibitor with potent inhibitory activity on all major HER2 mutations.

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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, preliminary 
data from two clinical trials are available (see Section 1.2.1.3) that support the two single 
doses of BI 1810631 (with or without carbamazepine) planned for the current trial. In 
particular, BI 1810631 has been given at multiple doses of up to 300 mg q.d. and of up to 
150 mg b.i.d. over at least 21 days to patients in first-in-man trial 1479-0001, and in that 
study, BI 1810631 showed so far good safety and tolerability. The observed plasma 
exposures of BI 1810631 in trial 1479-0001 provide a large safety window for the expected 
exposures in the current trial.
The current study is necessary to support the development of BI 1810631: As BI 1810631 is a 
substrate for CYP3A, a DDI study with a CYP3A inducer is required to inform management 
of concomitant medications in the BI 1810631 label and for future clinical trials.
Carbamazepine is a recommended index inducer of CYP3A that has successfully been used 
in previous DDI studies in healthy volunteers (e.g., [R23-0228]). Relevant risks of 
carbamazepine are addressed by appropriate safety measures (see Section 1.4.2).
Considering the medical need for an effective and safe treatment of solid tumours with HER2 
mutations, the benefit of this trial is assessed to outweigh the potential risks.

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

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as an open-label, two-treatment, two-period, fixed-sequence 
crossover trial in healthy male subjects in order to compare the test treatment (T) to the
reference treatment (R). The treatments will be:

Treatment R: One oral single dose of 60 mg BI 1810631 administered as film-coated 
tablet alone

Treatment T: One oral single dose of 60 mg BI 1810631 administered as film-coated 
tablet together with multiple oral doses of carbamazepine (doses titrated from 
200 mg q.d. over 400 mg q.d. to 600 mg q.d.)
BI 1810631 is administered in the fasted state, and carbamazepine is administered after a 
dinner. In the first treatment period (Period 1 = Visit 2), all subjects are planned to undergo 
treatment R, and in the second treatment period (Period 2 = Visit 3), all subjects are planned 
to undergo treatment T. For details, refer to Section 4.1.
Visit 3 follows immediately after Visit 2, i.e. Day 8 is the last day of Visit 2, and Day 8 of 
Visit 2 is the same day as Day -19 of Visit 3.
Figure 3.1: 1
Trial Design
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For drug interaction trials, the crossover design is preferred because of its efficiency: since 
each subject serves as his own control, the comparison between treatments is based on an 
intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
Screening
Visit 2
Visit 3
End of 
trial
Carbamazepine
200 mg q.d.
400 mg q.d.
600 mg q.d.
BI 1810631 60 mg
• 
• 
-
11 
11 
I I 
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~4,'b;-,'b 
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l:i 'b 
'(; 
"v"v 
~rti,i 
"~ 
,i 
,i 
,i 

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Because of the potentially long-lasting CYP3A induction mediated by carbamazepine, a 
fixed-sequence design was selected, in which carbamazepine is administered in the second 
trial period only. The fixed-sequence design is not expected to lead to systematic errors in the 
estimation of the treatment effects since non-specific time-effects are unlikely due to the 
short trial duration.
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma and urine concentrations of the analyte, which should not be 
affected by knowledge of treatment administered.
Dosing duration of carbamazepine is expected to be long enough to reliably achieve maximal 
CYP3A induction. However, this expectation is based on one publication only [R23-0228]; 
therefore two biomarkers (4β-OH cholesterol in plasma and 6β-OH cortisol / cortisol ratio in 
urine) are sampled frequently during carbamazepine dosing to investigate the time course of 
induction.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy male subjects will enter the trial. They will be recruited from the 
volunteers' pool of the trial site.
Only male subjects will be included in the trial because a) no data on reproductive toxicology 
are available at this time for BI 1810631 and b) because of the embryotoxicity of 
carbamazepine [R23-1121].
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial

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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, the neurological 
examination, or the skin inspection) deviating from normal and assessed as clinically
relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
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 and including allergy to drugs structurally related to carbamazepine, such as 
tricyclic antidepressants) 
12. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation or any kind of vaccination)
13. Intake of an investigational drug in another clinical trial within 60 days or within five 
half-lives, whichever is longer of planned administration of investigational drug in the 
current trial, or concurrent participation in another clinical trial in which investigational 
drug is administered
14. Smoker (unless the subject quit smoking for at least 3 months prior to first planned 
administration of trial medication)
15. Alcohol abuse (consumption of more than 24 g per day)
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 one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms), atrioventricular block, 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. History of bone marrow depression, haematologic disease, history of medication-induced 
haematologic reactions, or history of hepatic porphyria
24. Hyponatremia, i.e. serum sodium below lower limit of normal at screening
25. Known Asian ancestry 
26. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
27. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought without method, intent or plan; active suicidal thought with method but 
without intent or plan; active suicidal thought with method and intent but without specific 
plan; or active suicidal thought with method, intent and plan)
28. Subjects with WOCBP partner who are unwilling to use highly effective contraception 
from time point of first administration of BI 1810631 until 30 days after the last 
administration of BI 1810631. Highly effective methods of contraception are:
- Subject is sexually abstinent
- Subject is vasectomized (with appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate) and uses condom
- Use of intrauterine device or intrauterine hormone-releasing system by female partner 
plus use of condom
- Use of progestogen-only hormonal contraception by female partner that inhibits 
ovulation (injectables or implants) plus use of condom
- Use of combined (estrogen and progestogen containing) hormonal contraception by 
female partner that prevents ovulation (oral, intravaginal, or transdermal) plus use of 
condom
- Bilateral tubal occlusion in the female partner plus use of condom
Sperm donation is not allowed from the time point of first administration of BI 1810631 
until 30 days after the last administration of BI 1810631
29. White blood cell count, platelets, or blood haemoglobin below lower limit of normal 
(LLN) at screening

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30. ALT and/or AST exceeding 10% above ULN, confirmed by a repeat test 
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Sections 3.3.4.1 and 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR).
If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.3 , 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
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events (AEs), or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
6. The subject, during treatment with carbamazepine, has an elevation of AST and/or ALT 
≥3-fold ULN
7. The subject, during treatment with carbamazepine, experiences petechial or purpura 
bleedings, a reduction of erythrocytes in blood below 4 million/mm3, a reduction of blood 
haematocrit below 32%, a reduction of blood haemoglobin below 11 g/dL, a reduction of 

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leukocytes below 2,000/mm3, a reduction of neutrophil granulocytes below 1,000/mm3, a 
reduction of platelets below 100,000/mm3, or any symptomatic disorder of 
haematopoiesis
8. The subject, during treatment with carbamazepine, experiences signs of a drug-induced
Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis (e.g., a progressive rash)
9. Hyponatremia of CTCAE grade ≥3
10. The subject exhibits serious suicidality, in the clinical judgment of the investigator or 
according to the following criteria:

Any suicidal behaviour (i.e. actual attempt, interrupted attempt, aborted attempt, 
or preparatory acts or behaviour)

Any suicidal ideation of type 2 to 5 in the C-SSRS (i.e. active suicidal thought 
without method, intent or plan; active suicidal thought with method but without 
intent or plan; active suicidal thought with method and intent but without specific 
plan; or active suicidal thought with method, intent and plan)
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
subjects or take any other appropriate action to guarantee the safety of the trial subjects.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reasons 4 and/or 5 are met, the trial should be discontinued 
immediately):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. The sponsor decides to discontinue the further development of the investigational 
products
3. Deviation from GCP, or the CTP, or the contract with BI impairing the appropriate 
conduct of the trial
4. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment (see Section 3.3.4.1)

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5. More than 50% of the subjects show drug-related and clinically relevant adverse events of 
CTCAE grade 2 or grade 3 severity (except* for benign carbamazepine-induced grade 2
side effects as follows: leukopenia; hyponatremia; neurological adverse effects such as 
dizziness, ataxia or headache; eye accommodation disorders; gastrointestinal disorders; 
and fatigue), or if at least one drug-related serious adverse event is reported
* Given the safety profile of carbamazepine, it is necessary to except certain carbamazepine-
induced side effects of grade 2 severity from discontinuation criterion 5, that are acceptable 
as long as subjects are in-house at the study site under close medical observation, from 
discontinuation criterion 5; otherwise the successful conduct of the study would be 
jeopardized. 
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 4 subjects do not complete the trial (including subjects non-evaluable for 
PK), subjects may be replaced if considered necessary to reach the objective of the trial.
Subjects who withdraw or are withdrawn from treatment or assessments because of a drug-
related adverse event will not be replaced. The Clinical Trial Leader together with the Trial 
Pharmacologist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. The total number of replacements may not exceed 4 subjects. A replacement subject 
will be assigned a unique trial subject number.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Test product 1:
Substance:
BI 1810631
Pharmaceutical formulation: Film-coated tablet (
)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
60 mg
Posology:
1-0-0
Mode of administration:
Oral
Duration of use:
Single dose in treatment R (Visit 2) and T (Visit 3)
Test product 2:
Name:
Carbamazepin-neuraxpharm® 400 mg retard
Substance:
Carbamazepine
Pharmaceutical formulation: Extended release tablet
Source:
Holder of marketing 
authorisation:
Unit strength:
400 mg
Posology:
Visit 3 Days -18 to -15: 200 mg (1/2 tablet) q.d., 
Days -14 to -8: 400 mg (1 tablet) q.d.
Mode of administration:
Oral
Duration of use:
Q.d. for 11 consecutive days in treatment T (Visit 3)
Test product 3:
Name:
Carbamazepin-neuraxpharm® 600 mg retard
Substance:
Carbamazepine
Pharmaceutical formulation: Extended release tablet
Source:
Holder of marketing 
authorisation:
Unit strength:
600 mg
Posology:
Visit 3 Days -7 to +6: 600 mg (1 tablet) q.d.
Mode of administration:
Oral
Duration of use:
Q.d. for 13 consecutive days in treatment T (Visit 3)

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Note: At the time of protocol finalization, carbamazepine 200 mg retard tablets are not 
available on the German drug market. Therefore, a strength of 400 mg (1/2 tablet per dosing) 
is used for the 200 mg dose on days -18 to -15 of Visit 3.
4.1.2
Selection of doses in the trial
The doses of carbamazepine selected for this trial reflect standard clinical doses and are
considered sufficient to yield significant CYP3A induction. The titration scheme has been 
used successfully in a previous study [R23-0228], with the modification that in the current 
study carbamazepine administration is q.d. instead of b.i.d. This is because a) the tolerability 
of carbamazepine is expected to be improved if dosed only in the evening and b) because a 
once-daily dosing regimen may facilitate, in future studies, that subjects are ambulatory and
not in-house during large phases of the trial. This would decrease the burden to the subjects 
in future trials. 
The dose of BI 1810631 selected for this trial, a dose of 60 mg BI 1810631, is expected to 
result in plasma concentrations that are in the range of concentrations that were explored so 
far in trial 1479-0001 and that were associated with good safety and tolerability (see 
Section 1.2.1.3). Moreover it is expected that the results of the study, by using a single dose 
of 60 mg BI 1810631, are meaningful for concomitant treatment recommendations in future 
trials and the label.
4.1.3
Method of assigning subjects to treatment groups
There is only one treatment sequence investigated in this trial, and each subject will be 
allocated to the same treatment sequence (R-T). The subjects will be allocated to a trial
subject number by the principle “first come first serve” prior to first administration of trial 
medication in the morning of Day 1 of Visit 2.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same 
calendar 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. For discussion of trial-associated risks 
and safety measures, see Section 1.4).
4.1.4
Drug assignment and administration of doses for each subject
This is a fixed-sequence crossover trial. All subjects will receive the 2 treatments in fixed
order (R-T). The treatments to be evaluated are summarised in Table 4.1.4: 1 below. 

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Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
R (Reference)
BI 1810631
Film-coated 
tablet
60 mg
1 tablet as single dose on study 
day 1 of period 1
60 mg
T (Test)
BI 1810631
Carbamazepine
Film-coated 
tablet
Extended-
release 
tablet
60 mg
400 mg/ 
600 mg
1 tablet as single dose on study 
day 1 of period 2
Period 2:
Days -18 to -15: 200 mg q.d.a
Days -14 to -8: 400 mg q.d.b
Days -7 to +6: 600 mg q.d.c
60 mg
11,400 mg
a ½ tablet Carbamazepin-neuraxpharm® 400 mg retard per day
b 1 tablet Carbamazepin-neuraxpharm® 400 mg retard per day
c 1 tablet Carbamazepin-neuraxpharm® 600 mg retard per day
Administration of BI 1810631 will be performed after subjects have fasted overnight; fasting 
is to start no later than 10 h before the scheduled dosing. 
Administration of carbamazepine will be performed after a dinner. It is acceptable if the 
dinner is only partly consumed. 
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a standing or sitting position. For 
drug administration, the so-called four-eye principle (two-person rule) should be applied. For 
this, one authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot 
be ensured otherwise.
Subjects will be kept under close medical surveillance:

At Visit 2: until 48 h after administration of BI 1810631

At Visit 3: during the entire phase of carbamazepine dosings, i.e. from the evening of 
Day 8 of Visit 2 to the morning of Day 8 of Visit 3
During the first 4 h after administration of BI 1810631, subjects are not allowed to lie down 
(i.e. no declination of the upper body of more than 45 degrees from upright posture). For 
measurement of vital signs and ECGs a resting time of at least 5 minutes in the supine 
position is permitted.
Day 8 of Visit 2 is the same day as Day -19 of Visit 3.
The administrations of BI 1810631 will be separated by a wash-out phase of 26 days.
4.1.5
Blinding and procedures for unblinding
This non-randomised open-label Phase I trial will be handled in an open fashion throughout. 
The treatment assignment will be available to all involved parties.

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4.1.6
Packaging, labelling, and re-supply
The investigational medicinal product BI 1810631 will be provided by BI. It will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice
(GMP). 
The label will be prepared according to regulation (EU) No 536/2014, Annex 6, omitting
certain particulars with the following justification:
The "keep out of reach of children" statement was omitted from the label because the product 
will remain at the clinical site.
The 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.
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site including the name of the investigator are provided in the subject information form. The 
EU CT number, the Sponsor study number, and the trial site study number are indicated on 
the title page of this protocol as well as on the subject information and informed consent
forms.
Carbamazepine will be obtained by the trial site from a public pharmacy. The drug will be 
dispensed out of the otherwise original, unmodified packages.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
(BI 1810631) 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

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Carbamazepine can be obtained by the trial site at any time.
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
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 the specific event of drug-related lesions of the oral mucosa, supportive treatment 
and symptom control measures are recommended. These may include atraumatic cleansing 
and rinsing with non-alcoholic solutions such as normal saline, diluted salt and baking soda 
solution (e.g. one-half teaspoonful of salt and one teaspoon of baking soda in one quart of 
water every four hours); avoidance of agents containing iodine, thyme derivatives and 
prolonged use of hydrogen peroxide; dietary manoeuvres such as promotion of soft, non-
irritating foods like ice-cream, mashed/cooked vegetables, potatoes and avoidance of spicy, 
acidic or irritating foods such as peppers, curries, chillies, nuts, and alcohol. If the subject is 
unable to swallow food or liquids, parenteral fluid and/or nutritional support may be needed. 
Examples of some of the agents suggested in Table 4.2.1: 1 include: topical analgesics –
viscous lidocaine 2%; mucosal coating agents – topical kaolin/pectin; oral antacids, 
maltodextrin, sucralfate; topical antifungals – nystatin suspension. (Adapted from 
[P11-09424]).

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Table 4.2.1: 1
Grade-specific treatment recommendations of study-drug related 
lesions of the oral mucosa
Severity (CTCAE 
grading)
Description
Treatment recommendations
Mild (Grade 1)
Minimal symptoms; 
normal diet
Oral rinses with agents such as non-
alcoholic mouth wash, normal saline, 
diluted salt and baking soda solution
Moderate (Grade 2)
Symptomatic, but can 
eat and swallow 
modified diet
Addition of topical analgesic mouth 
treatments, topical corticosteroids, antiviral 
therapy if herpetic infection confirmed, 
antifungal therapy preferably topical on a 
case by case basis.
Severe (Grade 3)
Symptomatic and 
unable to adequately 
aliment or hydrate 
orally
Same as for Grade 2; institute additional 
therapy (topical or systemic) as clinically 
indicated
Life-threatening 
(Grade 4)
Symptoms associated 
with life-threatening 
consequences
Same as for Grade 2; institute additional 
symptomatic therapy (topical or systemic) 
as clinically indicated
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 treatment such as headache, short-term use of ibuprofen is 
acceptable.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. On Day 1 of both periods, only meals as described in the 
Flow Chart will be served. On the other days with in-house stays, food will be served as per 
the CRO’s SOPs. Of note, a dinner will be served before all carbamazepine administrations 
as indicated by the Flow Chart. 
No food is allowed for at least 4 h after BI 1810631 intake.

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From 1 h before BI 1810631 intake until lunch, fluid intake is restricted to the water 
administered with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose 
(mandatory for all subjects). From lunch until 24 h post BI 1810631, total fluid intake is 
restricted to 3000 mL.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products containing St. John's wort (Hypericum perforatum) are not permitted from 7 
days before the first administration of BI 1810631 at Visit 2 until after the last PK sample of 
Visit 3 is collected.
Alcoholic beverages are not permitted from 3 days before the first administration of 
BI 1810631 at Visit 2 until after the last PK sample of Visit 3 is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before until 24 h after each administration of 
BI 1810631.
Smoking is not allowed during the trial.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided starting from 
the first carbamazepine dosing until the end-of-trial examination.
4.2.2.3
Contraception requirements
Subjects whose sexual partner is a WOCBP must be sexually abstinent or use highly effective 
contraception starting from the first dose of BI 1810631 and for at least 30 days after the last 
dose of BI 1810631. See Section 3.3.3 for required contraceptive measures.

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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 including a neurological examination and a skin inspection. At the end 
of trial examination, it will include review of vital signs, 12-lead ECG, laboratory tests, and a 
physical examination including a neurological examination and a skin inspection and a 
determination of body weight.
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 
(Dinamap Pro 100,
) at the times indicated in the 
Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm, 
if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.

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

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The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. The exclusionary laboratory tests will be performed according Flow Chart. 
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/Ecstasy
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
SARS-CoV-2 infection test via 
nasal/oral swab
SARS-CoV-2 PCR test
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest® 
6820,
 will be performed prior to each treatment period, and 
may be repeated at any time during the trial at the discretion of an investigator or designee. 
The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
with the 
exception of drug screening tests. These tests will be performed at the trial site using 
SureStepTM Multi-Drug Test
or comparable test systems. The SARS-CoV-2 PCR 
test will be performed at the safety laboratory or at the trial site.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically
relevant abnormal findings as judged by the Investigator are to be reported as adverse events 
(please refer to Section 5.2.6). 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4). 
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
 at the times provided in the Flow Chart. 

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To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other trial procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the subject will be removed from 
the trial and will receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Neurological examinations
At the time points specified in the Flow Chart, a physical neurological examination will be 
performed. 
The neurological examination will include the following assessments:
-
General level of arousal
-
Orientation
-
Eye movement
-
Pupil size and pupil reactivity
-
Reflexes
-
Assessment of muscle strength
-
Gait
-
Romberg test
-
Tremor
-
Point-to-point movements
-
Sensitivity
Documentation, assessment, and reporting
Results will be documented in source data at the clinical trial site and assessed for clinical 
relevance by an investigator, deputy investigator, or sub-investigator. Clinically relevant 
findings of the neurological examination during the trial will be reported as adverse events 
(AEs). Case narratives may be written if necessary. Clinically relevant findings of the 

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neurological examination at screening fulfil exclusion criterion 1 (see Section 3.3.3) and 
should lead to exclusion of the subject from trial participation.
5.2.5.2
Skin inspection
At the time points indicated by the Flow Chart, a visual inspection of the skin (subject should 
be in underwear) will occur to identify carbamazepine-induced skin reactions. See subject 
withdrawal criterion 8 in Section 3.3.4.1.
Documentation, assessment, and reporting
Results will be documented in source data at the clinical trial site and assessed for clinical 
relevance by an investigator, deputy investigator, or sub-investigator. Clinically relevant 
findings of the skin inspection during the trial will be reported as adverse events (AEs). Case 
narratives may be written if necessary. Clinically relevant findings of the skin inspection at 
screening fulfil exclusion criterion 1 (see Section 3.3.3) and should lead to exclusion of the 
subject from trial participation.
5.2.5.3
Suicidality assessment
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behaviour and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behaviour and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsellor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behaviour, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the screening visit (using the ‘screening / baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and 
behaviour will also be recorded. 
For the exclusion criteria related to the C-SSRS ‘screening / baseline’ version result, see 
Section 3.3.3.
After the baseline visit the assessment ‘since last visit’ will be performed at the time points 
indicated in the Flow Chart (‘since last visit’ version). 
For the withdrawal criterion related to the C-SSRS ‘since last visit’, see Section 3.3.4.1.
See Section 10.1 for the original English C-SSRS. For this trial, the paper version of the
respective German translation will be used.

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Positive reports are generated for any of the following findings:
Suicidal ideation

Active suicidal ideation with method and intent but no plan (type 4)

Active suicidal ideation with method, intent, and plan (type 5)
Suicidal behaviour

Completed suicide

Suicide attempt

Interrupted attempt

Aborted attempt

Preparatory actions toward imminent suicidal behaviours
Negative reports of suicidal ideation are defined as reports where there are no indications of 
the above, i.e. suicidal ideation of type 1-3.
The investigator is to review positive and negative reports for plausibility and clinical 
relevance. Doubtful reports may be repeated or reports may be validated by a consulting 
psychiatrist. If there is a confirmed positive report of suicidal behaviour or suicidal ideation 
type 4 or 5 after start of the trial, the investigator is to immediately interview the subject 
during the clinic visit, and/or is to consult a psychiatrist. If the positive report is confirmed, 
appropriate actions for the subject’s safety have to be initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behaviour must 
be reported as SAEs by the investigator.
For each negative report (suicidal ideation type 1, 2, or 3) after start of the trial, the 
investigator is to decide based on clinical judgment whether it represents an AE as defined in 
the protocol, and if it is considered an AE then it must be reported accordingly. Note that BI 
maintains a list of AEs which are defined as “always serious” – this list includes suicidal 
behaviour and suicidal ideation. Consequently, if an AE relating to suicidal ideation or 
behaviour is reported, it will be required to be reported as SAE.
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):

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
Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation, or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in Section 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.

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5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.

Haematologic toxicities (grades refer to CTCAE grading):
o
Grade 5
o
Grade 4 except for lymphopenia (including, but not limited to Grade 4 anaemia, 
Grade 4 thrombocytopenia and Grade 4 neutropenia)
o
Anaemia of any grade requiring blood transfusion
o
Febrile neutropenia
o
Grade 3 neutropenia with documented infection and/or lasting >3 days
o
Neutropenia of any grade requiring treatment with growth factors
o
Grade 3 thrombocytopenia
o
Thrombocytopenia of any grade requiring platelet transfusion

Any ≥Grade 3 non-haematologic toxicity with the following exceptions (grades refer 
to CTCAE grading):
o
Grade 3 vomiting/nausea or diarrhea which persists for less than 48 hours after 
start of adequate treatments
o
Grade 3 fever
o
Grade 3 fatigue that persists <7 days
o
Grade 3 rash that resolves to ≤Grade 1 within 2 weeks
o
Any Grade 3 laboratory abnormality which is not considered clinically relevant by 
the investigator, resolves spontaneously or responds to conventional medical 
intervention

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o
Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of AEs should be classified and recorded in the CRF according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [R18-1357].
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

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

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5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs. In addition, each subject will be 
regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, subjects will be questioned for AEs (and 
concomitant therapies) at the time points indicated in the Flow Chart. Assessment will be 
made using non-specific questions such as ‘How do you feel?’. Specific questions will be 
asked wherever necessary in order to more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial
(the End of Study (EoS) visit): 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.
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 

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information. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
For reporting of safety information to the Agency by the sponsor please refer to section 8.4.
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 drug 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 samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
BI 1810631 in plasma
For quantification of BI 1810631 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venipuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 120 min, with interim storage of blood samples and aliquots at room

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temperature. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.
At a minimum, the sample tube labels should list BI trial number, barcode, subject number, 
visit, planned sampling time, and analyte ‘BI 1810631’. 
Carbamazepine in plasma
For quantification of carbamazepine concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venipuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 60 min, with interim storage of blood samples and aliquots at room 
temperature. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.
At a minimum, the sample tube labels should list BI trial number, barcode, subject number, 
visit, planned sampling time, and analyte ‘carbamazepine’. 
Further use of samples
After analysis, the plasma samples may be used for further methodological investigations 
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte and/or 
its metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.

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5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSESSMENT OF BIOMARKERS 
5.4.1
Drug-Drug Interaction Biomarkers
5.4.1.1
Methods of sample collection
For the assessment of drug-drug interaction biomarkers, blood and urine 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. 
5.4.1.1.1
4β-OH cholesterol in plasma
For quantification of 4β-OH cholesterol concentrations in plasma, 2.7 mL of blood will be 
drawn from an antecubital or forearm vein into a K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 60 min, with interim storage of blood samples and aliquots at room 
temperature. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -70°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -70°C or below 
until analysis.
At a minimum, the sample tube labels should list BI trial number, barcode, subject number, 
visit, planned sampling time, and analyte ‘4β-OH cholesterol’. 
After analysis, the plasma samples may be used for further methodological investigations 
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte and/or 
its metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 

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additional investigations. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.
5.4.1.1.2
6β-OH cortisol and cortisol in urine
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
2 L polyethylene (PE) containers and stored at room temperature. Subjects are told to empty 
their bladders before the start of the sampling interval (urine to be discarded) and at the end 
of each sampling interval (urine to be collected). 
The urine weight for each collection interval will be documented (however, no correction for 
the specific gravity of urine is done, i.e. 1 L is defined to be equal to 1 kg). Two 0.5 mL 
aliquots will be stored in polypropylene (PP) tubes for bioanalytical measurements. If more 
than one collection container is used in an interval, the contents of all containers are to be 
mixed before aliquots are prepared. Mixing should be done by transferring the entire content 
of all collection containers into a single polyethylene (PE)/ polypropylene (PP) or glass 
container, and stirring the mixed fractions for about 1 min (manually or using a stir bar or 
other stirring device made of PE, PP, Teflon, or glass).
At a minimum, the sample tube labels should list BI trial number, barcode, subject number, 
visit, and planned collection time. 
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
approximately -20C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory, the 
urine samples will be stored at approximately -20°C or below until analysis.
After analysis, the urine samples may be used for further methodological investigations (e.g. 
for stability testing, assessment of metabolites) or to address Health Authority questions 
regarding the results/methodology. However, only data related to the analyte and/or its 
metabolite(s) will be generated by these additional investigations. The trial samples will be 
discarded after completion of the additional investigations but not later than 5 years after the 
CTR has been archived.

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5.4.2
Pharmacodynamic biomarkers
Not applicable.
5.4.3
Pharmacogenomic biomarkers
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and DDI 
biomarker parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of orally administered drugs, 
and are widely used in clinical trials. The pharmacokinetic parameters and measurements 
outlined in Section 5.3 are generally used assessments of drug exposure. The biomarkers and 
measurements outlined in Section 5.4 are of exploratory nature only.

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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’ BI 1810631 administration 
on Day 1 are to be performed and completed within a 3 h-period prior to the trial drug 
administration.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs, ECG, and laboratory tests will be ± 60 min.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for neurological examinations and skin inspections will be ± 4 h.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times and urine 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
(including for DDI biomarkers).
For activities in the mornings of Days 4, 6, and 8 of period 1, the acceptable deviation from 
the scheduled time will be ± 120 min.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.5.
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Period 1: Days -1 to 8; 
Period 2: Days -19 to 8). Day 8 of Period 1 is the same day as Day -19 of Period 2. 

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On Day -1 of the first treatment period, trial participants will be admitted to the trial site and 
kept under close medical surveillance for at least 48 h following administration of 
BI 1810631. The subjects will then be allowed to leave the trial site after formal assessment 
and confirmation of their fitness. This is followed by several ambulatory visits (see 
Flow Chart).
On Day 8 of the first treatment period, trial participants will be admitted to the trial site and 
kept under close medical surveillance until at least 36 hours following the last carbamazepine 
dosing in the second treatment period (i.e. planned until the morning of Day 8 of the second 
treatment period). 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 and urine samples for PK 
and DDI biomarker analysis, refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoS Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained. 

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 1810631 in plasma when given as a single oral dose (R) or 
together with multiple dose of carbamazepine (T) will be estimated by the ratios of the 
geometric means (test/reference), and their corresponding 2-sided 90% confidence intervals 
(CIs) will be provided. This method corresponds to the two one-sided t-test procedure, each 
at the 5% significance level. Since the main focus is on estimation and not testing, a formal 
hypothesis test and associated acceptance range is not specified.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.

Biomarker parameter analysis set (BMS): This set includes all subjects in the treated 
set (TS) who provide at least one evaluable measure of at least one of the exploratory 
biomarkers without important protocol deviations (IPD) relevant to the evaluation of 
biomarkers (as specified in the subsection ‘Biomarkers’). Descriptive analysis of the 
biomarkers will be based on the BMS.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the IPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for drug BI 1810631 will be 
calculated according to the relevant BI internal procedures. 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 

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deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Important protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A predose concentration of BI 1810631 is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which are flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.2.1.3
Biomarkers
Exploratory biomarkers measured are outlined in Section 2.2.2.3. 
Biomarker data and parameters of a subject will be included in the statistical biomarker 
analyses if they are not flagged for exclusion due to a protocol deviation relevant to the 
evaluation of biomarkers (to be decided no later than in the Report Planning Meeting) or due 
to non-evaluability (as revealed during data analysis). Important protocol deviations may be
similar to those listed for pharmacokinetics in Section 7.2.1.2.
Exclusion of a subject’s data will be documented in the CTR. Biomarker data and parameters 
of a subject which is flagged for exclusion will be reported with its individual values but will 
not be included in the statistical analyses.
7.2.2
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-

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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 effects 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 in receiving treatment k,
= the overall mean,
sm = the effect associated with the mth subject,
m = 1, 2, ..., 16
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject received
treatment k.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
‘subjects’ considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.2.3
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the relevant 
BI internal procedures and will be assessed statistically using the same methods as described 
for the primary endpoints.

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7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the assigned treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between first trial medication intake and end of REP 
(see Section 1.2.3) will be assigned to the treatment period. Events occurring after the REP 
but prior to next intake or end of trial termination date will be assigned to ’follow-up’. In case 
of two or more treatments, the follow-up will be summarized according to the previous 
treatment. These assignments including the corresponding time intervals will be defined in 
detail in the TSAP. Note that AEs occurring after the last per protocol contact but entered 
before unblinding the trial will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.

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Relevant ECG findings will be reported as AEs.
Results regarding the C-SSRS will only be listed.
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. All subjects will receive
the same treatments in the same order.
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 16 subjects in the trial with the aim of at least 12 evaluable 
subjects in the trial, because this sample size is considered sufficient to achieve the aims of 
this exploratory trial. With this sample size, the following precision in estimating the ratio of 
geometric means (test/reference) can be expected with 95% probability. Precision is defined 
as the ratio of upper CI limit to the relative BA estimate. Note that the precision is 
independent of the actual ratio of geometric means.
The observed intra-individual coefficient of variation (gCV) for BI 1810631 in the previous 
trial 1479-0003 was roughly 31% for Cmax and 9% for AUC for NF fed vs NF fasted, and 
30.5% for Cmax and 14.2% for AUC for NF fasted + rabeprazole vs NF fasted.
For various assumptions around the gCV of 
, Table 7.5:1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (test/reference). For 
illustrative purposes, the expected 90% confidence intervals are displayed for different values 
of the ratios T/R of geometric means.

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

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles. Deviation from the protocol, the principles of ICH GCP or applicable 
regulations will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject according to ICH-GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional subject-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject 
information must be given to each subject.
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 including Clinical Trial Regulation Art. 42.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a participant identification number instead of the trial 
participant’s name. The code is only available at the site and must not be forwarded to the 
sponsor. In case participant’s records will be forwarded e.g. for SAE processing or 
adjudication committees, personal data that can identify the trial participant will be redacted 
by the site prior to forwarding. Access to the participant files and clinical data is strictly 
limited: personalised treatment data may be given to the trial participant’s personal physician 
or to other appropriate medical personnel responsible for the trial participant’s welfare. Data 
generated at the site as a result of the trial need to be available for inspection on request by 
the participating physicians, the sponsor’s representatives, by the IRB/IEC and the regulatory 
authorities.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs/IECs and trial 
participants will be informed as appropriate.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF

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8.6
TRIAL MILESTONES
The first act of recruitment represents the start of the trial and is defined as the date when the 
first trial participant (subject) in the whole trial signs informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at
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 BI 1810631 will be provided by the 
 
The trial medication carbamazepine will be 
obtained by the trial site from a
Safety laboratory tests will be performed by the local laboratory of the trial site 
(
).

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Analyses of BI 1810631 concentrations in plasma will be performed at 
 
 
Analyses of carbamazepine concentrations in plasma will be performed at 
 
Analyses of 4β-OH cholesterol concentrations in plasma will be performed at 
 
Analyses of 6β-OH cortisol and of cortisol concentrations in urine will be performed at 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or by a contract research 
organization appointed by BI.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P11-09424
Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, 
Creel P, Dickow B, Fischer P, Gornell SS, Meloni F, Motzer RJ. 
Management of adverse events associated with the use of everolimus in 
patients with advanced renal cell carcinoma. Eur J Cancer 2011; 47; 1287-
1298.
P15-01211
Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to 
basic science to mechanism-based cancer therapeutics. Cancer Cell; 2014; 
25(3); 282-303. Cancer Cell 25, March 17, 2014 ª2014 Elsevier Inc. 303.
P19-00456 
Wang Y, Jiang T, Qin Z, Jiang J, Wang Q, Yang S, et al. HER2 exon 20
insertions in non-small-cell lung cancer are sensitive to the irreversible pan-
HER receptor tyrosine kinase inhibitor pyrotinib. Annals of Oncology. 31 
December 2018. 447-455.
P19-10412 
Connell CM, Doherty GJ. Activating HER2 mutations as emerging targets
in multiple solid cancers. ESMO Open 2017; 2; e000279.
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 2020 ; 86; 
101996.
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
R09-6185
Hynes NE, MacDonald G. ErbB receptors and signaling pathways in 
cancer. Curr Opin Cell Biol; Current Opinion in Cell Biology 2009, 
21:177–184.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R18-1357
U.S. Department of Health and Human Services. Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published: November 27, 
2017). U.S.Department of Health and Human Services, National Institutes 
of Health, National Cancer Institute; 2017.
R20-1872
Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat 
Rev Mol Cell Biol; 2006; 7; 505-516. JULY 2006.
R20-1990 
Wang Z. ErbB receptors and cancer. Methods in Molecular Biology; 
2017;1652; 3-35. vol. 1652, DOI 10.1007/978-1-4939-7219-7_1, © 
Springer Science+Business Media LLC 2017.
R23-0228
Stockis A Chanteux H Rosa M Rolan P. Brivaracetam and carbamazepine 
interaction in healthy subjects and in vitro. Epilepsy Res; 113, p. 19-27; 
2015.
R23-1120
Carbamazepin-neuraxpharm ® 200 mg retard / 400 mg retard. 
(Fachinformation (Zusammenfassung der Merkmale des 
Arzneimittels/SmPC). https://static.neuraxpharm.com/wp-
content/uploads/sites/6/2021/05/06134749/fach info-carbamazepin-
neuraxpharm-200-400-mg-retard-12-2021.pdf. 12/2021

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R23-1121
Carbamazepin-neuraxpharm ® 300 mg retard / 600 mg retard. 
(Fachinformation (Zusammenfassung der Merkmale des 
Arzneimittels/SmPC). https://s3.eu-central-1.amazonaws.com/prod-cerebro-
ifap/media_all/113537.pdf 12/2021
9.2
UNPUBLISHED REFERENCES
c32836122
. Investigator's 
Brochure BI 1810631 1479-P01. Current version.

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10.
APPENDICES
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Ba · lin~ 
rccnin 
rsi n 
\ "4; i n I 14 09 
Po 11er, K.; {Jr 111 D.; Lucas, .,· Gould, M. • ta11ley B.; Brow11 
. • F'.' lier P. • Zelav ,y J. • 
Burke 
. • Ot111endo, M.; Mtmn, J. 
Disdoimer. 
Th scale Is lnrended 10 be used by lnd'r,/dlJ(lls who h<rve rtcewed uolning ln iu odminlsuol.lon_ The ~estJons coniained In 
lhe Columbio-Suk:ide Severily Roting Scale ore WggtJted probe Ultimately. the determination o(lhe presence of sulddol 
ideation or behavior depends on lhe judgment of the inortiduol administering lhe scole. 
De(,nilions of behavioral sulddot events in lhis scale ore based on !hose used in The Co{umb/q Suicide History Form, 
developed by
In M.8. F"irst 
(Ed.) S 
dardized Evalu lion in Cl nlcal Pr.ictic pp. I 03 • I 30. 2003J 
For reprints o(lhe C.SSRS contoct 
 
; in~iries and 11aining requirements contoa 
 
C 2008 Th Res rch Foundation for Mental Hygiene. Inc. 

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all\ . procudto "~ <1"-1I &hU\tOr~ 
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COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
p, 
II r, K.; Brent, n.,· L,, 
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Boehringer Ingelheim
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V,.,. ,,, 
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Boehringer Ingelheim
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BI-VQD-11906_40-106_AD-13 (8.0)
I ,, .. 
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Boehringer Ingelheim
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10.2
BLOOD SAMPLING OVERVIEW
Table 10.2: 1
Blood Sampling Overview
Trial Period
Day
Number of blood 
samplings
Amount of blood (mL)
Safety blood samplings
Screening
Day -21 to -1
1
14.4
Period 1
Day 1
1
11.8
Day 2
1
11.8
Day 8
1
11.8
Period 2
Day -15
1
7.6
Day -12
1
11.8
Day -9
1
7.6
Day -6
1
11.8
Day -3
1
7.6
Day 1
1
11.8
Day 2
1
11.8
Day 5
1
7.6
End of Trial
Day 15 to 22
1
11.8
Total number of safety blood samplings: 13
Total amount of blood for safety evaluation: 139.2 mL
PK BI 1810631 blood samplings
Period 1
Day 1
11
29.7
Day 2
2
5.4
Day 3
1
2.7
Day 4
1
2.7
Day 6
1
2.7
Day 8
1
2.7
Period 2
Day 1
11
29.7
Day 2
2
5.4
Day 3
1
2.7
Day 4
1
2.7
Day 6
1
2.7
Day 8
1
2.7
Total number of PK BI 1810631 blood samplings: 34
Total amount of blood for PK BI 1810631 blood samplings: 91.8 mL
PK carbamazepine blood samplings
Period 2
Day -18
1
2.7
Day -12
1
2.7
Day -7
1
2.7
Day -5
1
2.7
Day -3
1
2.7
Day -1
1
2.7
Day 2
1
2.7
Day 4
1
2.7
Day 7
1
2.7

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Table 10.2: 1
Blood Sampling Overview (cont)
Trial Period
Day
Number of blood 
samplings
Amount of blood (mL)
Total number of PK carbamazepine blood samplings: 9
Total amount of blood for PK carbamazepine blood samplings: 24.3 mL
4β-OH cholesterol blood samplings
Period 2
Day -18
1
2.7
Day -12
1
2.7
Day -7
1
2.7
Day -5
1
2.7
Day -3
1
2.7
Day -1
1
2.7
Day 2
1
2.7
Day 4
1
2.7
Day 7
1
2.7
Total number of 4β-OH cholesterol blood samplings: 9
Total amount of blood for 4β-OH cholesterol blood samplings: 24.3 mL
TOTAL BLOOD WITHDRAWN IN THE TRIAL: 279.6 mL

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
29 Jun 2023
EUCT No.
2022-503046-50-00
BI Trial number
1479-0011 (CRS trial number: 140/22)
BI Investigational Medicinal 
Product(s)
BI 1810631
Title of protocol
The effect of multiple doses of carbamazepine on 
the pharmacokinetics of a single oral dose of BI 
1810631 in healthy male subjects (an open-label, 
two-period, fixed-sequence trial
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment
Non-substantial Global Amendment
Section to be changed
3.3.3
Description of change
Further specification of exclusion criteria #13
Rationale for change
To exclude intake of investigational drug in another 
trial within 60 days or within five half-lives, 
whichever is longer.
Request from competent authorities.
Section to be changed
5.2.6.2.2 and 8.4
Description of change
Addition of obligation of the sponsor to report 
safety information to the agency.
Rationale for change
Request from competent authorities

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11.2
GLOBAL AMENDMENT 2
Date of amendment
12 Sep 2023
EUCT No.
2022-503046-50-00
BI Trial number
1479-0011 (CRS trial number: 140/22)
BI Investigational Medicinal 
Product(s)
BI 1810631
Title of protocol
The effect of multiple doses of carbamazepine on 
the pharmacokinetics of a single oral dose of BI 
1810631 in healthy male subjects (an open-label, 
two-period, fixed-sequence trial
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment
Non-substantial Global Amendment
Section to be changed
Title Page
Description of change
Clinical Trial Leader changed
Rationale for change
Change in Clinical Trial Leader
Section to be changed
4.1.4
Description of change
Clarification regarding ECG examination during the 
4 h period after dosing
Rationale for change
Correction / Clarification
Section to be changed
5.2.3
Description of change
Changes due to inconsistence between Flow Chart 
and Section 5.2.3
Rationale for change
Correction / Clarification
Section to be changed
8.7
Description of change
Changes due to inconsistence between Flow Chart 
und Section 8.7
Rationale for change
Correction / Clarification

 
 
 
 
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The effect of multiple doses of carbamazepine on the pharmacokinetics of a single
oral dose of BI 1810631 in healthy male subjects (an open-label, two-period,
fixed-sequence trial)
Approval-Clinical Program 
15 Sep 2023 12:14 CEST
Approval
18 Sep 2023 07:40 CEST
Verification-Paper Signature
Completion
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18 Sep 2023 14:20 CEST
Boehringer 
~11111~ lngelhein1 

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