The Effect of Food on the Pharmacokinetics of a BI 425809 Tablet Formulation Administered as a Single Dose With and Without Food to Healthy Subjects (an Open-label, Randomised, Two-period, Two-sequence Crossover Trial)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim



Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 2 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
28 FEB 2022
Revision date
Not applicable
BI trial number
1346-0053
Title of trial
The effect of food on the pharmacokinetics of a BI 425809 tablet formulation 
administered as a single dose with and without food to healthy subjects (an open-
label, randomised, two-period, two-sequence crossover trial)
 Investigator
Trial site
Clinical phase
I
Trial rationale
The aim of this pivotal trial is to compare bioavailability and pharmacokinetic
parameters of BI 425809 following administration of the intended commercial 
tablet formulation of 10 mg BI 425809 with and without food. The resulting data 
are required for marketing of BI 425809.
Trial objective
To investigate the potential effect of food on the pharmacokinetics of BI 425809 
following administration of the intended Commercial Formulation (iCF) with food 
(Test treatment, T) and without food (Reference treatment, R).    
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of BI 425809
Secondary endpoints: AUC0-! of BI 425809
Trial design
Randomised, open-label, single-dose, two-period, two-sequence crossover design
Number of subjects 
total entered
16
on each treatment
16
Diagnosis
Not applicable
Main inclusion criteria
Healthy male/female subjects, age of 18 to 55 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Trial product
BI 425809, 10 mg film-coated tablets, intended commercial formulation (iCF)
dose
10 mg (1 tablet) in treatment T and treatment R
mode of 
administration
Oral intake with 240 mL of water in fasted state after overnight fast of at least 10h 
(treatment R) and in fed state after high fat, high calorie breakfast (treatment T)
Duration of treatment
One day (single dose) for each treatment

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 3 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
Statistical methods
Relative bioavailability 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 
sequence, subjects nested within sequences, period and treatment. CIs will be 
calculated based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 4 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
FLOW CHART
Period
Visit
Day
Planned time (relative to
drug administration)
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory 7
PK blood (BI 425809)
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to
-1
Screening (SCR)1
A
x
x
1/2 (two identical periods separated by a wash-out phase
)
2/3
-1
-12:00
20:00
Admission to trial site8
x5,8
x8
1
-1:00
07:00
Allocation to treatment2 (visit 2 only)
B2
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast
(treatment T only)
0:00
08:00
Drug administration
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x
2:30
10:30
x
3:00
11:00
x
3:30
11:30
x
4:00
12:00
240 mL fluid intake
x
4:30
12:30
x
5:00
13:00
Lunch3
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x 
2
24:00
08:00
Breakfast (voluntary)3, discharge from trial site
B
x
x
x
3
47:00
07:00
Ambulatory visit
x
x
4
71:00
07:00
Ambulatory visit
x
x
6
119:00
07:00
Ambulatory visit
x
x
8
167:00
07:00
Ambulatory visit
x
x
10
215:00
07:00
Ambulatory visit
x
x
FU
4
15 to 
22
End of study (EoS) examination4
C
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening in all 
subjects and pregnancy test in women), demographics (including determination of body height and weight, smoking 
status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
Pharmacogenetic samples will be collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 2 h prior to 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, vital signs, ECG, 
safety laboratory (including pregnancy test in women), recording of AEs and concomitant therapies.
5.
Only urine drug screening and alcohol breath test as well as pregnancy test in women will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Letters A, B and C below define different sets of safety laboratory examinations (for details refer to Section 5.2.3).
8. 
The time is approximate; the procedure is to be completed no later than 10 hours prior to drug administration

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 6 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
3.3.3
Exclusion criteria ..................................................................................24
3.3.4
Withdrawal of subjects from treatment or assessments ...................25
3.3.4.1
Withdrawal from trial treatment ..............................................26
3.3.4.2
Withdrawal of consent to trial participation ............................26
3.3.4.3
Discontinuation of the trial by the sponsor..............................27
3.3.5
Replacement of subjects .......................................................................27
4.
TREATMENTS........................................................................................ 28
4.1
INVESTIGATIONAL TREATMENTS ..........................................................28
4.1.1
Identity of the Investigational Medicinal Products ...........................28
4.1.2
Selection of doses in the trial................................................................28
4.1.3
Method of assigning subjects to treatment groups ............................28
4.1.4
Drug assignment and administration of doses for each subject .......28
4.1.5
Blinding and procedures for unblinding ............................................30
4.1.6
Packaging, labelling, and re-supply ....................................................30
4.1.7
Storage conditions.................................................................................30
4.1.8
Drug accountability ..............................................................................31
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................31
4.2.1
Other treatments and emergency procedures....................................31
4.2.2
Restrictions............................................................................................32
4.2.2.1
Restrictions regarding concomitant treatment .........................32
4.2.2.2
Restrictions on diet and life style.............................................32
4.2.2.3
Contraception requirements.....................................................32
4.3
TREATMENT COMPLIANCE.......................................................................32
5.
ASSESSMENTS....................................................................................... 34
5.1
ASSESSMENT OF EFFICACY.......................................................................34
5.2
ASSESSMENT OF SAFETY............................................................................34
5.2.1
Physical examination ............................................................................34
5.2.2
Vital signs...............................................................................................34
5.2.3
Safety laboratory parameters..............................................................34
5.2.4
Electrocardiogram................................................................................36
5.2.5
Other safety parameters.......................................................................37
5.2.6
Assessment of adverse events...............................................................37
5.2.6.1
Definitions of adverse events...................................................37
5.2.6.1.1 Adverse event ............................................................37
5.2.6.1.2 Serious adverse event ................................................38
5.2.6.1.3 AEs considered ‘Always Serious’.............................38
5.2.6.1.4 Adverse events of special interest .............................38
5.2.6.1.5 Intensity (severity) of AEs.........................................39
5.2.6.1.6 Causal relationship of AEs ........................................39
5.2.6.2
Adverse event collection and reporting ...................................40

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 7 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
5.2.6.2.1 AE collection.............................................................40
5.2.6.2.2 AE reporting to the sponsor and timelines ................41
5.2.6.2.3 Pregnancy ..................................................................41
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................41
5.3.1
Assessment of pharmacokinetics .........................................................41
5.3.2
Methods of sample collection...............................................................42
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................42
5.4
ASSESSMENT OF BIOMARKERS................................................................42
5.5
BIOBANKING ...................................................................................................43
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................43
6.
INVESTIGATIONAL PLAN.................................................................. 44
6.1
VISIT SCHEDULE............................................................................................44
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................44
6.2.1
Screening................................................................................................44
6.2.2
Treatment periods.................................................................................44
6.2.3
Follow-up period and trial completion ...............................................45
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 46
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................46
7.2
PLANNED ANALYSES....................................................................................46
7.2.1
General considerations.........................................................................46
7.2.1.1
Analysis sets.............................................................................46
7.2.1.2
Pharmacokinetics.....................................................................46
7.2.2
Primary endpoint analyses...................................................................47
7.2.3
Secondary endpoint analyses ...............................................................48
7.2.5
Safety analyses.......................................................................................48
7.2.6
Interim analyses ....................................................................................49
7.3
HANDLING OF MISSING DATA ..................................................................50
7.3.1
Safety......................................................................................................50
7.3.2
Pharmacokinetics..................................................................................50
7.4
RANDOMISATION ..........................................................................................50
7.5
DETERMINATION OF SAMPLE SIZE ........................................................50

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 8 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 52
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................52
8.2
DATA QUALITY ASSURANCE .....................................................................53
8.3
RECORDS..........................................................................................................53
8.3.1
Source documents .................................................................................53
8.3.2
Direct access to source data and documents.......................................54
8.3.3
Storage period of records.....................................................................55
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................55
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......55
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................55
8.6
TRIAL MILESTONES .....................................................................................56
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................56
9.
REFERENCES......................................................................................... 58
9.1
PUBLISHED REFERENCES...........................................................................58
9.2
UNPUBLISHED REFERENCES.....................................................................59
10. APPENDICES .......................................................................................... 60
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 61

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 10 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
EudraCT
European Clinical Trials Database
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
 
gMean
Geometric mean
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
NMDA
N-methyl-D-aspartate 
MRT,ex
Mean residence time of the analyte in the body, extravascular
NOAEL
No observed adverse event level
NSFS
Negative Symptom Factor Score 
PANSS
Positive and Negative Syndrome Scale 
PfOS
Powder for (reconstitution of an) oral solution
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
PT
Preferred term 
qd
quaque die (i.e. one daily)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOC
System organ class 
SOP
Standard operating procedure
SRD
Single-rising dose
T
Test treatment

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 13 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 14 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 15 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
1.2.2
Residual Effect Period
The Residual Effect Period (REP) of BI 425809 is
. This is the period after the last 
dose during which measurable drug levels and/or pharmacodynamic effects are still likely to 
be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
The aim of this pivotal trial is to compare bioavailability and pharmacokinetic parameters of 
BI 425809 following administration of the intended commercial tablet formulation of 10 mg 
BI 425809 with food (Test, T) and without food (Reference, R) in healthy subjects. The 
resulting data are required for marketing of BI 425809.
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 425809 which 
may help to treat patients suffering from CIAS.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 16 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
1.4.2
Risks
1.4.2.1
Risks related to BI 425809 and trial procedures
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 425809
CNS-related effects
#
CNS depressant effects 
indicated by nonclinical 
data, and also observed in 
clinical trials with other 
compounds of the same 
pharmacological class  
[R13-4450]
#
In trials with healthy 
volunteers, headache, 
dizziness and fatigue were 
the most frequently 
reported AEs following 
BI 425809 administration
#
For details, refer to Section 
1.2.1.1 and IB [c02155957]
#
In case of headache, the 
investigator may initiate 
symptomatic therapy if deemed 
necessary
#
Subjects will be asked to use 
public transport instead of 
driving cars and not to operate 
machines if they experience 
CNS-related effects that might 
impair ability to drive or operate 
machines
#
Neurological tests and testing of 
driving ability (using e.g., Vistec 
Corporal Plus®) will be initiated 
in conspicuous cases by the 
investigator prior to discharge.
In-house stay may be prolonged 
at the discretion of the 
investigator
#
Alcohol consumption will not be 
allowed from 48 h before first 
trial drug administration until last 
PK sampling of the trial
#
Subjects will be advised not to
use stairs during in-house period 
(i.e., during the first 24 hours 
after dosing of BI 425809)
Gastrointestinal effects
#
In healthy volunteers, 
nausea, vomiting and 
diarrhoea were among the 
most frequently reported 
AEs after BI 425809 intake 
#
For details, refer to Section 
1.2.1.1 and IB [c02155957]
#
Gastrointestinal symptoms will 
be monitored carefully. 
Symptomatic therapy may be 
initiated by the investigator if 
deemed necessary (e.g., fluid 
replacement in case of diarrhoea)

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 17 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Ophthalmological 
effects
#
In the SRD trial using oral 
solutions (1346.1), dose-
related increases in VAS 
scores and visual 
disturbances (photopsia, 
chromatopsia, blurred 
vision) were observed 
around tmax [c02820512] 
#
Subjects will be advised not to 
drive cars or operate machines if 
they experience blurred vision
#
In conspicuous cases, in-house 
stay may be prolonged at the 
discretion of the investigator
#
Subjects will be advised not to 
use stairs during in-house period 
(i.e., the first 24 hours after 
dosing of BI 425809)
Haematological 
changes
#
Changes in red blood cell 
parameters (reductions in 
haemoglobin, haematocrit, 
etc.) indicated by non-
clinical data
#
In trials with healthy 
volunteers, no notable 
decrease in haemoglobin or 
haematocrit was noted 
compared with placebo
#
For details, refer to 
Sections 1.2.1.1 and the 
current IB [c02155957]
#
Subjects will regularly undergo 
clinical laboratory testing to 
monitor potential BI 425809-
induced alterations
Drug-induced liver 
injury (DILI)
#
Rare but severe event, thus 
under constant surveillance 
by sponsors and regulators.
#
Timely detection, evaluation, and 
follow-up of laboratory 
alterations in selected liver 
laboratory parameters to ensure 
subjects´ safety.
Trial procedures
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 
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
1.4.2.2
Risk in the context of SARS-CoV-2 pandemic
This Phase I study is planned to be conducted in healthy volunteers, aged 18-55 years. This 
population is not at higher risk of severe COVID-19 infection, and trial participation would 

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 18 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
not increase the risk of becoming infected with SARS-CoV-2 beyond the potential risk 
associated with any need for the trial participant to leave his home for trial-related activities 
[adapted from current IB, c02155957].
Risk mitigation SARS-CoV-2 pandemic
#
A risk management plan has been set up at the clinical site that details specific 
precautionary measures (e.g., hygienic rules, wearing of face masks, physical 
distancing), which will be filed in the ISF. These measures were implemented per 
local requirements in Baden-Württemberg and recommendation by the 
 
 The local requirements may be subject to change and the trial procedures 
will be adapted accordingly, if applicable
#
AEs will be closely monitored and guidance pertaining to treatment and management 
of acute infections occurring during the trial will be provided 
#
Trial participants will be screened for SARS-CoV-2, e.g., via polymerase chain 
reaction (PCR) test, prior to screening (see also exclusion criterion #25) and at various 
time points during the trial 
#
During the ambulatory visits, subjects are allowed to enter the site only after it was 
confirmed that subjects do not have any signs or symptoms of infection (e.g., fever)
#
In case SARS-CoV-2 infection is suspected in a subject during trial participation, 
PCR testing will be initiated without delay to enable the investigator to take decisions 
about the next steps (e.g., according to Section 3.3.4.1)
#
Any subject with suspected or diagnosed COVID-19 will be referred to health care 
professionals in charge to receive treatment according to standard of care
SARS-CoV-2 vaccination
Diminished response to the vaccine in subjects receiving BI 425809 is unlikely as there is no 
immunocompromised condition or immunosuppressant treatment present in healthy 
volunteers. It is not expected that there would be any interaction between vaccinations and 
the use of BI 425809 [‘bi-425809-cias-sars-cov-2-vaccination-statement-letter-for-sites’, 
document on file]. However, potential side effects of a vaccination may be hard to distinguish 
from adverse events induced by BI 425809. Therefore, exclusion criterion #12 includes a 
statement to avoid SARS-CoV-2 vaccination during this rather short trial.
1.4.3
Discussion
BI 425809 
 has been adequately characterized 
in non-clinical trials. Non-clinical safety data of BI 425809 support clinical trials in adult 
men and women of childbearing potential. Human exposure to BI 425809 up to the NOAEL 
exposure in the most sensitive species, i.e., minipig, is considered safe [c02155957]. 
The exposures expected in this trial for BI 425809 when given with or without food are 
predicted to stay well below the NOAEL established in the most sensitive species and well 
below exposures of BI 425809 reached so far in phase 1 trials with healthy volunteers (see 
Section 1.2.1.2 and the IB for details).

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 20 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
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 potential effect of food on the 
pharmacokinetics of BI 425809 following administration of the intended Commercial 
Formulation (iCF) with food (Test treatment, T) and without food (Reference treatment, R).
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 425809:
#
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)
#
Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for BI 425809:
#
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 21 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
2.2.2.2
Safety and tolerability
Safety and tolerability of BI 425809 will be assessed based on:
#
Adverse events (including clinically relevant findings from the physical examination)
#
Safety laboratory tests
#
12-lead ECG
#
Vital signs (blood pressure, pulse rate)

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 23 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy male and female subjects (if feasible, at least 5 of each sex) will
enter the trial. They will be recruited from the volunteers' pool of the trial site.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male or female subjects according to the assessment of the investigator, as based 
on a complete medical history including a physical examination, vital signs (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
5. Either male subject, or female subject who meets any of the following criteria for a highly 
effective contraception from at least 30 days before the first administration of trial 
medication until 30 days after trial completion:
-
Use of combined (estrogen and progestogen containing) hormonal contraception that 
prevents ovulation (oral, intravaginal or transdermal), plus condom
-
Use of progestogen-only hormonal contraception that inhibits ovulation (only 
injectables or implants), plus condom
-
Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
-
Sexually abstinent
-
A vasectomised sexual partner who received medical assessment of the surgical 
success (documented absence of sperm) and provided that partner is the sole sexual 
partner of the trial participant
-
Surgically sterilised (including hysterectomy)
-
Postmenopausal, defined as no menses for 1 year without an alternative medical cause
(in questionable cases a blood sample with levels of FSH above 40 U/L and estradiol 
below 30 ng/L is confirmatory)

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 24 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant chronic or acute infections
10. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
12. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation) or vaccination of any kind within 21 days of planned administration of trial 
medication or any vaccination requiring re-vaccination during the course of the trial
13. Intake of an investigational drug in another clinical trial within 60 days of planned
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
15. Inability to refrain from smoking on specified trial days
16. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per day for
males)
17. Drug abuse or positive drug screening
18. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 25 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
19. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms in males or repeatedly greater than 470 ms in females) or any other 
relevant ECG finding at screening
22. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
24. ALT (alanine transaminase) or AST (aspartate transaminase) or serum creatinine above 
upper limit of normal range at screening examination, confirmed by a repeat test
25. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
26. For female subjects: Lactation, pregnancy, or plans to become pregnant during the trial or 
within 30 days after trial completion
27. For female subjects: Positive pregnancy test
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Sections 3.3.4.1 and 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR).
If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.2, the 
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 26 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, the safety of the 
subject cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as pregnancy, 
surgery, adverse events (AEs), or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN
6. 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
7. The subject experiences a drug-related adverse event of severe intensity or a serious 
adverse event
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.6.2.3.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
subjects or take any other appropriate action to guarantee the safety of the trial subjects.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 27 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reasons 4 and/or 5 are met, the trial should be discontinued 
immediately):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. The sponsor decides to discontinue the further development of the investigational 
products
3. Deviation from GCP or the CTP impairing the appropriate conduct of the trial
4. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment (see Section 3.3.4.1)
5. More than 50% of the subjects show drug-related and clinically relevant adverse events of 
moderate or severe intensity, or if at least one drug-related serious adverse event is 
reported
3.3.5
Replacement of subjects
In case more than 4 subjects do not complete the trial (including subjects non-evaluable for 
PK), subjects may be replaced if considered necessary to reach the 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 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. The total number of replacements may not exceed 1/3 of the total number of 
evaluable subjects anticipated to complete the trial. A replacement subject will be assigned a 
unique trial subject number and will be assigned to the same treatment sequence as the 
subject he or she replaces.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 28 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 425809 will be provided by BI Pharma GmbH & Co. KG, Germany.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the trial product used for treatment T and treatment R are given below:
Substance:
BI 425809
Pharmaceutical formulation: Film-coated tablet, intended Commercial Formulation (iCF)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg
Posology:
1-0-0
Mode of administration:
Oral
Duration of use:
Single dose on Day 1 of Visit 2 and Day 1 of Visit 3 
4.1.2
Selection of doses in the trial
The dose selected for this trial is the therapeutic dose that will be used in clinical drug 
development based on Phase II clinical results (see Section 1.2).
4.1.3
Method of assigning subjects to treatment groups
The randomisation scheme will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
scheme will be allocated to the subjects by drawing lots. Subjects are then assigned to a 
treatment sequence according to the randomisation scheme. Once a subject number has been 
assigned, it cannot be reassigned to any other subject.
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. Treatment of all subjects on the same 
calendar day is acceptable (for discussion of trial-associated risks and safety measures, see 
Section 1.4).
The randomisation procedure is described in Section 7.4.
4.1.4
Drug assignment and administration of doses for each subject
This is a 2-way crossover trial. All subjects will receive the 2 treatments in randomised order. 
The treatments to be evaluated are summarised in Table 4.1.4: 1 below.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 30 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
4.1.5
Blinding and procedures for unblinding
The table below summarizes the masking/blinding level of individual functions, roles and 
responsibilities involved in the trial. 
Table 4.1.5: 1
Blinding level of individual functions
Role/function
Timing of Unblinding / receiving access to the treatment information 
Subject/Participant
This open label trial will provide the subject treatment information as 
soon as treatment has been assigned.
Investigator/Site Staff
As requested to prepare trial site prior to first subject entered.
Sponsor trial team 
and data
Unblinded as requested.
Bioanalytical Staff
Persons directly involved in bioanalyses of PK samples will be blinded 
to trial treatments.
Pharmacokineticist/
Pharmacometrician
As requested for analysis.
During the time a role/function is blinded according to the table above, the randomisation 
schemes (i.e. the treatment information) are kept restricted by the global Randomization 
Team per Sponsor SOP.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP). 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 31 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:
#
Approval of the clinical trial protocol by the IRB / ethics committee
#
Approval/notification of the regulatory authority, e.g. competent authority
#
Availability of the curriculum vitae of the Principal Investigator
#
Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. 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.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 33 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 35 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
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 – INR (International Normalization Ratio)
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 
Bilirubin, Total 
Bilirubin, Direct
C-Reactive Protein (Quant)  
X
X
X
X
X
X
X
--
--
--
X
X
X
X
X
Electrolytes
Sodium
Potassium
X
X
X
X
X
X
Urinalysis2 (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
X
X
X
X
X
X
X
X
X
Urine sediment2
(microscopic 
examination)
Only positive findings will be reported (for instance, the presence of 
sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1  
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visits 2 and 3 on Days 1 and 2 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 4 (end of study examination)
2
Microscopic examination if erythrocytes, leukocytes nitrite or protein are abnormal in urine
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy tests and drug screening, it is planned to perform these tests 

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 38 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
#
Results in death 
#
Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 
#
Requires inpatient hospitalisation, or prolongation of existing hospitalisation
#
Results in persistent or significant disability or incapacity 
#
Is a congenital anomaly/birth defect 
#
Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
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:

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 39 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
#
Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters:
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
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)

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 40 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
#
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
#
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger
#
There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned
#
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs. In addition, each subject will be 
regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, subjects will be questioned for AEs (and 
concomitant therapies) at the time points indicated in the Flow Chart. Assessment will be 
made using non-specific questions such as ‘How do you feel?’. Specific questions will be 
asked wherever necessary in order to more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
#
From signing the informed consent onwards until an individual subject’s end of trial
(the End of Study (EoS) visit): 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 41 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
#
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 immediately (without undue delay) to the 
sponsor’s unique entry point (the country specific reporting process will be provided in the 
ISF). The same timeline applies if follow-up information becomes available. On specific 
occasions, the Investigator could inform the sponsor upfront via telephone. This does not 
replace the requirement to complete and send the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (without undue delay) 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).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
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. 

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 42 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 425809 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed 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, subject number, visit, and 
planned sampling time. 
After analysis, the plasma samples may be used for further methodological investigations
(e.g., for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte and/or 
its metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 43 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
5.5
BIOBANKING
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 45 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
assessment and confirmation of their fitness. On all other trial days, subjects will be treated in 
an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoS Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained. 

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 46 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 425809 tablets administered with food (Test) versus without 
food (Reference) will be estimated by the ratios of the geometric means (test/reference), and 
their corresponding 2-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at the 5% significance level. Since the 
main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:
#
Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.
# Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be suggested in the iPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the iPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for BI 425809 will be 
calculated according to the relevant BI internal procedures. 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 47 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
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
#
Incorrect intake of meal prior to drug administration in treatment periods under fed
conditions
#
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 425809 is >5% Cmax value of that subject in the 
respective treatment period
#
Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which are flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.2.2
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijkm = ∃+ %i + sim + &j + ∋k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment  
k in period j,
∃= the overall mean,
%i = the ith sequence effect, i = 1, 2,

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 49 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed, or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between trial medication intake and end of REP (see 
Section 1.2.2) will be assigned to the respective treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
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 database 
lock will be reported to Pharmacovigilance only and will not be captured in the trial database
(see Section 5.2.6.2.1).
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
For laboratory data and vital signs baseline is defined as the last measurement prior to trial 
medication intake of respective treatment period.
Relevant ECG findings will be reported as AEs.
7.2.6
Interim analyses
No interim analysis is planned.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 51 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
Table 7.5: 1 Precision that can be expected with 95% probability and illustrative two-sided 
90% confidence intervals around the ratios of geometric means (T/R) for 
different gCVs in a 2x2 crossover trial (N=12, 16)
N
gCV 
[%]
Precision 
upper CL** 
/ relative BA 
estimate
90% CI [%] of respective ratio*
100
125
150
12
15
1.16
(86.13; 116.11)
(107.66; 145.13)
(129.19; 174.16)
12
20
1.22
(82.01; 121.93)
(102.52; 152.41)
(123.02; 182.89)
12
25
1.28
(78.15; 127.95)
(97.69; 159.94)
(117.23; 191.93)
16
15
1.13
(88.62; 112.84)
(110.77; 141.05)
(132.93; 169.26)
16
20
1.17
(85.18; 117.40)
(106.47; 146.75)
(127.77; 176.10)
16
25
1.22
(81.92; 122.07)
(102.40; 152.59)
(122.88; 183.11)
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(∃T)/exp(∃R).
**Confidence interval limit
The calculation was performed as described by Julious [R11-5230] using R Version 4.0.2.
Thus, based on a sample size of N=12 evaluable subjects and assuming a gCV of 20% for the
PK endpoint of BI 425809, the precision of the 90% CI would be 1.22. If the gMean ratio 
would be 125%, then the 90% CI is expected to range approximately from 103 to 152%. 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.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 52 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
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. 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 (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or
delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 53 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
The consent and re-consenting process should be properly documented in the source 
documentation.
For subjects enrolled during the COVID-19 pandemic: In addition to the study-specific 
informed consent, separate written consent will be obtained for testing for SARS-CoV-2 
infection. 
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the 
– the 
validated ClinBase
system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as database. Instead of being entered into CRFs, selected data are directly 
entered into the ClinBaseTM system.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 54 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the subject, documented 
in their medical records, would be acceptable.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:
#
Subject identification: gender, year of birth (in accordance with local laws and 
regulations)
#
Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)
#
Dates of subject’s visits, including dispensing of trial medication
#
Medical history (including trial indication and concomitant diseases, if applicable)
#
Medication history
#
AEs and outcome events (onset date [mandatory], and end date [if available])
#
SAEs (onset date [mandatory], and end date [if available])
#
Concomitant therapy (start date, changes)
#
Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)
#
ECG results (original or copies of printouts)
#
Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)
#
Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 55 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
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 
the local requirements valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular
#
Sample and data usage have to be in accordance with the informed consent
#
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.
#
An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
#
A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 56 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
#
A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
#
Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the
 under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
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

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 57 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
The trial medication will be provided by the
Safety laboratory tests will be performed by the local laboratory of the trial site (
).
Analyses of BI 425809 concentrations in plasma will be performed at 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or CRO appointed by BI 
according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 58 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2002:
1-9.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R13-4447
Lane HY, Chang YC, Liu Y, Chiu CC, Tsai GE. Sarcosine or D-serine add-
on treatment for acute exacerbation of schizophrenia: a randomized, double-
blind, placebo-controlled study. Arch Gen Psychiatry 2005. 62. 1196-1204.
R13-4450 
Liem-Moolenaar M, Peeters P, Kamerling IMC, Hogg C, Holder G, Kleijn 
HJ, Spaans E, Haes JU de, Kam ML de, Franson KL, Cohen AF, Gerven 
JMA van. Early stage development of the glycine-1 re-uptake inhibitor 
SCH 900435: central nervous system effects compared with placebo in 
healthy men. Br J Clin Pharmacol. 2013. 75(6). 1455-1467.
R13-4451
Ouellet D, Sutherland S, Wang T, Griffini P, Murthy V. First-time-in 
human study with GSK1018921, a selective GlyT1 inhibitor: relationship 
between exposure and dizziness. Clin Pharmacol Ther 2011; 90(4); 597-
604.
R13-4508
Martin-Facklam M, Patat A, Hofmann C, Boetsch C, Banken L, Biedinger 
U, Boutouyrie-Dumont B. Safety, tolerability and pharmacokinetics of 
bitopertin (RG1678), a novel glycine reuptake inhibitor after multiple doses 
in healthy volunteers. 3rd Biennial Conf of the Schizophrenia International 
Research Society (SIRS), Florence, 14 - 18 Apr 2012 (Poster). 2012.
R13-4518 
Hu NW, Ondrejcak T, Rowan MJ. Glutamate receptors in preclinical 
research on Alzheimer's disease: update on recent advances. Pharmacol 
Biochem Behav. 2012. 100. 855-862.
R13-4521
Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology
and therapy of schizophrenia. Pharmacol Biochem Behav. 2012. 100. 
665-677.
R13-4524
Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter 1 
inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the 
treatment of schizophrenia. Biol Psychiatry 2004. 55. 452-456.
R15-0595
Dunlop J, Brandon NJ. Schizophrenia drug discovery and development in 
an evolving era: are new drug targets fulfilling expectations?. J 
Psychopharmacol 2015. 29(2). 230-238.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 59 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
R15-1266
Umbricht D, Alberati D, Martin-Facklam M, Borroni E, Youssef EA, 
Ostland M, Wallace TL, Knoflach F, Dorflinger E, Wettstein JG, Bausch A, 
Garibaldi G, Santarelli L. Effect of bitopertin, a glycine reuptake inhibitor, 
on negative symptoms of schizophrenia: a randomized, double-blind, proof-
of-concept study. JAMA Psychiatry 2014. 71(6). 637-646.
R18-1054
Bugarski-Kirola D, Blaettler T, Arango C, Fleischhacker WW, Garibaldi G, 
Wang A, et al. Bitopertin in negative symptoms of schizophrenia - results 
from the phase III FlashLyte and DayLyte studies. Biol Psychiatry 2017. 
82(1). 8-16.
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
c02155957
Investigator`s Brochure BI 425809 Alzheimers Disease Cognitive 
Impairment Associated with Schizophrenia (CIAS). 20 Jan 2022.
c02820512
 Safety, tolerability, and 
pharmacokinetics of single rising oral doses of BI 425809 in healthy male 
subjects (partially randomised, single-blind, placebo-controlled) and 
investigation of relative bioavailability and food effect of BI 425809 (open-
label, randomised, three-way crossover). 1346.1. 05 May 2015.
c03355329
 Relative bioavailability of a 
single oral dose of BI 425809 when administered alone or in combination 
with multiple oral doses of itraconazole in healthy male subjects (an open-
label, two-period, fixed-sequence trial). 1346.1. 03 December 2015.
c03572014
 Safety, tolerability, and 
pharmacokinetics of multiple rising doses of BI 425809 tablets given orally 
once or twice daily for 12 days to young and elderly healthy male and 
female volunteers (randomised, double-blind, placebo-controlled within 
dose groups Phase I study) (Part 1) and comparison of pharmacokinetics of 
a single oral dose of BI 425809 after oral administration in the morning 
versus.. 1346.2. 04 July 2016.
c03724403
 Non-randomised, open label, 
sequential-group study to assess the pharmacokinetics and 
pharmacodynamic effect of different multiple oral doses of BI 425809 in 
healthy male volunteers. 1346.3. 01 February 2016.
c08949593
 A study to investigate 
the effects of multiple doses of BI 425809 on the single dose 
pharmacokinetics of cytochrome P450 substrates (midazolam, warfarin and 
omeprazole) and a P-glycoprotein substrate (digoxin) administered orally in 
an open-label, one-sequence trial in healthy male subjects. 1346.22. 01 Aug 
2016.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 60 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
10.
APPENDICES
Not applicable.

Boehringer Ingelheim
28 Feb 2022
BI Trial No.: 1346-0053
c37609834-01
Trial Protocol
Page 61 of 61
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106 RD-13 (7 0) / Saved on: 22 Jun 2021
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.

 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F

FOLQLFDOWULDOSURWRFROYHUVLRQ
7KHHIIHFWRIIRRGRQWKHSKDUPDFRNLQHWLFVRID%,WDEOHWIRUPXODWLRQ
DGPLQLVWHUHGDVDVLQJOHGRVHZLWKDQGZLWKRXWIRRGWRKHDOWK\VXEMHFWVDQ
RSHQODEHOUDQGRPLVHGWZRSHULRGWZRVHTXHQFHFURVVRYHUWULDO
$XWKRU7ULDO6WDWLVWLFLDQ
0DU&(7
$XWKRU&OLQLFDO7ULDO/HDGHU
0DU&(7
9HULILFDWLRQ3DSHU6LJQDWXUH
&RPSOHWLRQ
0DU&(7
$SSURYDO7HDP0HPEHU0HGLFLQH
0DU&(7

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F
