Relative Bioavailability of Batch 1 and Batch 2 of the Intended Commercial Formulation of BI 425809 Compared to Each Other and to TF 2 Formulation of BI 425809 Following Oral Administration in Healthy Male and Female Subjects (Randomized, Open-label, Single-dose, Three-treatment, Three-period, Six-sequence Crossover Study)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

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Clinical Trial Protocol
TITLE PAGE
Document Number:
c23832649-03
EudraCT No.
2018-003625-29
BI Trial No.
1346-0019
BI Investigational
Medicinal Product
BI 425809
Title
Relative bioavailability of batch 1 and batch 2 of the intended 
commercial formulation of BI 425809 compared to each other and to 
TF 2 formulation of BI 425809 following oral administration in healthy 
male and female subjects (Randomized, open-label, single-dose, 
three-treatment, three-period, six-sequence crossover study)
Lay Title
A study in healthy people to test if taking different formulations of 
BI 425809 tablets influences the amount of BI 425809 in the blood
Clinical Phase
I
Clinical Trial Leader
Phone: 
Fax:     
Principal Investigator
Phone
Fax:   
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0 
Date: 04 June 2019
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© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
04 June 2019
Revision date
Not applicable
BI trial number
1346-0019
Title of trial
Relative bioavailability of batch 1 and batch 2 of the intended commercial 
formulation of BI 425809 compared to each other and to TF 2 formulation of BI 
425809 following oral administration in healthy male and female subjects 
(Randomized, open-label, single-dose, three-treatment, three-period, six-sequence 
crossover study)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
To define the relative bioavailability of the tablet formulation TF2 used in Phase 2 
trials and of the newly developed intended commercial formulation for Phase 3 in 
order to bridge PK and safety data between the formulations and secure Phase 3 
dosing 
Trial objective
To investigate the relative bioavailability of batch 1 of the intended commercial
tablet formulation (iCF1) of BI 425809 vs batch 2 of the intended commercial
tablet formulation (iCF2) of BI 425809 vs BI 425809 TF2 formulation
Trial design
Randomised, open-label, single-dose, three-treatment, three-period, six-sequence 
crossover study
Trial endpoints:
Primary endpoints: AUC0-72 and Cmax of BI 425809
Number of subjects 
total entered
18
each treatment
18
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male/female subjects, age of 18 to 55 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Test product 1
BI 425809 intended commercial formulation batch 1 (iCF1) (Treatment T1)
Dose
25 mg
Mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h 
Test product 2
BI 425809 intended commercial formulation batch 2 (iCF2) (Treatment T2)
Dose
25 mg
Mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h 
Reference product
BI 425809 tablet formulation 2 (TF2) (Treatment R)
Dose
25 mg

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Mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment
One day (single dose) for each treatment
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(T1/T2, T1/R and T2/R) for the primary endpoints. Additionally, their two-sided 
90% confidence intervals (CIs) will be provided. This method corresponds to the 
two one-sided t-tests procedure, each at the 5% significance level. Since the main 
focus is on estimation and not testing, an acceptance range is not specified. The 
statistical model will be an 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 ANOVA.
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART
Period
Visit
Day
Planned time (relative to first 
drug administration [h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
x
x
x
1/2/3 (three identical periods with a wash-out of at least 14 days
2/3/4
-1
-12:00
20:00
Admission to trial site7
x5
x
1
-3:00
05:00
Allocation to treatment2 (visit 2 only)
x2
x2
x2
x2
0:00
08:00
Drug administration
0:30
08:30
x
1:00
09:00
x
2:00
10:00
240 mL fluid intake
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
5:00
13:00
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
x
x
x
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
4
72:00
08:00
Ambulatory visit
x
x
EOT
5
12 to 20
End of trial (EoTrial) examination4
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening 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 3 h prior to drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial 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 time points 
indicated in the Flow Chart above.
7.
The time is approximate; admission is to be performed no later than 10 h prior to scheduled drug administration.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................12
1.2.1
Non-clinical pharmacokinetics ............................................................12
1.2.2
Non-clinical safety pharmacology and toxicology..............................13
1.2.3
Residual Effect Period..........................................................................13
1.2.4
Clinical experience in humans.............................................................13
1.2.5
Clinical pharmacokinetics....................................................................14
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................15
1.4
BENEFIT - RISK ASSESSMENT ...................................................................15
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 17
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......17
2.1.1
Main objectives......................................................................................17
2.1.2
Primary endpoints ................................................................................17
2.1.3
Secondary endpoint ..............................................................................17
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS .........................17
2.2.2
Further endpoints .................................................................................17
2.2.2.2
Safety and tolerability..............................................................17
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 18
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................18
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................18
3.3
SELECTION OF TRIAL POPULATION ......................................................18
3.3.1
Main diagnosis for trial entry..............................................................19
3.3.2
Inclusion criteria...................................................................................19
3.3.3
Exclusion criteria ..................................................................................19
3.3.4
Withdrawal of subjects from treatment or assessments ...................20
3.3.4.1
Discontinuation of trial treatment............................................21
3.3.4.2
Withdrawal of consent to trial participation ............................21
3.3.4.3
Discontinuation of the trial by the sponsor..............................22

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3.3.5
Replacement of subjects .......................................................................22
4.
TREATMENTS........................................................................................ 23
4.1
INVESTIGATIONAL TREATMENTS ..........................................................23
4.1.1
Identity of the Investigational Medicinal Products ...........................23
4.1.2
Selection of doses in the trial................................................................24
4.1.3
Method of assigning subjects to treatment groups ............................24
4.1.4
Drug assignment and administration of doses for each subject .......24
4.1.5
Blinding and procedures for unblinding ............................................25
4.1.6
Packaging, labelling, and re-supply ....................................................25
4.1.7
Storage conditions.................................................................................25
4.1.8
Drug accountability ..............................................................................25
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................26
4.2.1
Other treatments and emergency procedures....................................26
4.2.2
Restrictions............................................................................................26
4.2.2.1
Restrictions regarding concomitant treatment .........................26
4.2.2.2
Restrictions on diet and life style.............................................26
4.3
TREATMENT COMPLIANCE.......................................................................27
5.
ASSESSMENTS....................................................................................... 28
5.1
ASSESSMENT OF EFFICACY.......................................................................28
5.2
ASSESSMENT OF SAFETY............................................................................28
5.2.1
Physical examination ............................................................................28
5.2.2
Vital signs...............................................................................................28
5.2.3
Safety laboratory parameters..............................................................28
5.2.4
Electrocardiogram................................................................................31
5.2.5
Other safety parameters.......................................................................32
5.2.6
Assessment of adverse events...............................................................32
5.2.6.1
Definitions of adverse events...................................................32
Adverse event ............................................................32
5.2.6.1.1
Serious adverse event ................................................32
5.2.6.1.2
AEs considered ‘Always Serious’.............................33
5.2.6.1.3
Adverse events of special interest .............................33
5.2.6.1.4
Intensity (severity) of AEs.........................................34
5.2.6.1.5
Causal relationship of AEs ........................................34
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................35
AE collection.............................................................35
5.2.6.2.1
AE reporting to the sponsor and timelines ................36
5.2.6.2.2
Information required..................................................36
5.2.6.2.3
Pregnancy ..................................................................36
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................36
5.3.1
Assessment of pharmacokinetics .........................................................36
5.3.2
Methods of sample collection...............................................................37

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5.3.2.1
Blood sampling for pharmacokinetic analysis.........................37
5.3.3
Analytical determinations ....................................................................37
5.3.3.1
Analytical determination of analyte plasma concentration......37
5.4
ASSESSMENT OF BIOMARKER(S) .............................................................37
5.5
BIOBANKING ...................................................................................................37
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................38
6.
INVESTIGATIONAL PLAN.................................................................. 39
6.1
VISIT SCHEDULE............................................................................................39
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................39
6.2.1
Screening period....................................................................................39
6.2.2
Treatment periods.................................................................................39
6.2.3
Follow-up period and trial completion ...............................................40
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 41
7.1
STATISTICAL DESIGN – MODEL ...............................................................41
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................41
7.3
PLANNED ANALYSES....................................................................................41
7.3.1
Primary endpoint analyses...................................................................42
7.3.2
Secondary endpoint analyses ...............................................................44
7.3.4
Safety analyses.......................................................................................44
7.4
INTERIM ANALYSES .....................................................................................45
7.5
HANDLING OF MISSING DATA ..................................................................45
7.5.1
Safety......................................................................................................45
7.5.2
Pharmacokinetics..................................................................................45
7.6
RANDOMISATION ..........................................................................................45
7.7
DETERMINATION OF SAMPLE SIZE ........................................................45
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 48
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................48
8.2
DATA QUALITY ASSURANCE .....................................................................49
8.3
RECORDS..........................................................................................................49
8.3.1
Source documents .................................................................................49
8.3.2
Direct access to source data and documents.......................................50
8.3.3
Storage period of records.....................................................................51
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................51

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8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......51
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................51
8.6
TRIAL MILESTONES .....................................................................................52
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................52
9.
REFERENCES......................................................................................... 53
9.1
PUBLISHED REFERENCES...........................................................................53
9.2
UNPUBLISHED REFERENCES.....................................................................53
10. APPENDICES .......................................................................................... 55
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 56
11.1
GLOBAL AMENDMENT 1 .............................................................................56
11.2
GLOBAL AMENDMENT 2 .............................................................................57

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ABBREVIATIONS
AD
Alzheimer’s Disease
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-72
AUC0-72 Area under the concentration-time curve of the analyte in plasma 
over the time interval from 0 to 72 h
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CIAS
Cognitive impairment associated with schizophrenia
CL
Confidence limit
Cmax
Maximum measured concentration of the analyte in plasma
CNS
central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTL
Clinical Trial Leader
CTM
Clinical Trial Monitor
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FSH
Follicle stimulating hormone

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GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
GlyT1
Glycine transporter 1
IB
Investigator’s brochure
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
iCF1
Intended commercial formulation batch 1
iCF2
Intended commercial formulation batch 2
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
NMDA
N-methyl-D-aspartate
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analaysis set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
ss
(at) steady state
T
Test product or treatment
T1
Test product 1
T2
Test product 2
TF2
Tablet formulation 2
TMF
Trial master file
tmax
Time from (last) dosing to the maximum measured concentration of the 

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analyte in plasma
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WHO
World Health Organization
XTC
Ecstasy 

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1.
INTRODUCTION
BI 425809 is a glycine transporter 1 (GlyT1) inhibitor that is being developed for 
symptomatic treatment of Alzheimer’s Disease (AD) and cognitive impairment associated 
with schizophrenia (CIAS).
1.1
MEDICAL BACKGROUND
Schizophrenia and AD are chronic, severe, and disabling brain disorders affecting both men 
and women. Both disorders are characterized by abnormalities in glutamatergic pathways 
related to N-methyl-D-aspartate (NMDA) receptor hypofunction in cortical and hippocampal 
brain areas. These abnormalities are hypothesized to lead to negative symptoms and cognitive 
impairment in schizophrenia and cognitive impairment in AD. Inhibition of GlyT1 aims at 
improving NMDA receptor hypoactivation in patients with schizophrenia and AD by 
increasing the concentration of the NMDA receptor co-activator glycine in the synaptic cleft, 
thereby leading to improvement of negative and cognitive symptoms in patients with 
schizophrenia (as add-on therapy to antipsychotics) as well as to cognitive improvement in 
AD patients (as add-on therapy to acetylcholinesterase inhibitors).
BI 425809 has been administered to healthy volunteers in so far 7 Phase 1 trials and 2 Phase 
2 trials in patients are currently ongoing.  In addition, BI 425809 is not a first in class 
compound. Other GLYT1 inhibitors (e.g. Bitopertin and sarcosine) have been tested in 
clinical trials before (R13-4447, R13-4508).
1.2
DRUG PROFILE
1.2.1
Non-clinical pharmacokinetics

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1.2.2
Non-clinical safety pharmacology and toxicology
For a more detailed description of the BI 425809 profile, please refer to the current 
Investigator’s Brochure (IB) [c02155957-08].
1.2.3
Residual Effect Period
1.2.4
Clinical experience in humans
At the time of preparation of this clinical trial protocol, BI 425809 has been investigated in 
seven Phase 1 trials. Two Phase 2 trials (1346-0009 and 1346-0023) and one Phase 1 trial 
(1346-0016) are ongoing.

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For a more detailed list of observed AEs and safety measures please refer to the current 
Investigator’s Brochure, section 6 [c02155957-08]. 
1.2.5
Clinical pharmacokinetics
For a more detailed description of the BI 425809 profile please refer to the current 
Investigator’s Brochure [c02155957-08].

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1.3
RATIONALE FOR PERFORMING THE TRIAL
This trial is designed to investigate the relative bioavailability of two batches of a newly 
developed tablet formulation (iCF batch 1 and batch 2) of 25 mg of BI 425809 compared to 
each other and to TF2 formulation of 25 mg of BI 425809 following oral administration in 
healthy male and female subjects. 
TF2 has already been administered and investigated in previous clinical trials. iCF is the 
anticipated formulation for phase 3 and, if applicable, later in clinical practice. To allow the 
prediction of safety and pharmacokinetics in phase 3 and clinical practice, comparable 
pharmacokinetic data between TF2 and iCF are considered essential. 
Two batches of iCF have been selected for the assessment of bioavailability that differ in 
their in vitro dissolution profile. iCF batch 1 (iCF1) is the target batch that fulfils the 
specifications in regard to the in vitro dissolution profile at its best. iCF batch 2 (iCF2) is a 
side batch of iCF1 with a slower in vitro dissolution. Based on PBPK modelling this 
difference in their dissolution profile is not expected to relevantly affect the bioavailability; 
i.e. comparable bioavailability of iCF1 and iCF2 is anticipated. However, clinical 
confirmation of the modelling results is needed to define appropriate drug substance 
specifications for the future.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of BI 425809. 
The subjects are exposed to the risks of the study procedures and the risks related to the 
exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling or intravenous 
infusion may be accompanied by mild bruising and also, in rare cases, by transient 
inflammation of the wall of the vein. In addition, in rare cases a nerve might be injured while 
inserting the venous catheter, potentially resulting in paraesthesia, reduced sensibility, and/or 
pain for an indefinite period. The same risks apply to venepuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also section 5.2.6.1.4, adverse events of special interest.

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Risks related to BI 425809 administration
The currently available data from 7 phase I trials in healthy young and elderly subjects with 
single oral administration of up to 150 mg BI 425809 and multiple doses of up to 75 mg BI 
425809 twice daily (150 mg/d), indicate that BI 425809 has a broad safety margin and is 
generally well tolerated. The most frequent AEs were adverse CNS symptoms, most 
commonly headaches that showed a trend for dose dependency, were reversible and can be 
clinically monitored. In addition, BI 425809 may be associated with visual disturbances, and 
somnolence (drowsiness). These effects are understood to be mostly mild to moderate and 
transient. Decreased haemoglobin is a potential risk based on preclinical data and class effect; 
however, no clear decrease in haemoglobin was seen in BI 425809 treated subjects compared 
to placebo in phase I trials so far.
Risks related to BI 761036 and BI 758790
The major human metabolites of BI 425809, BI 758790 and BI 761036, have been evaluated 
in nonclinical studies with no evidence of pharmacological activity, genotoxicity, effects on 
embryo-foetal development, or adverse effects in repeat-dose toxicity in studies of 13 – 15 
weeks duration.
Furthermore, available clinical data with multiple doses of up to 75 mg twice daily (150 
mg/d), were well tolerated, and suggest that there is no metabolite-mediated safety concern 
after single oral dose administration of 25 mg BI 425809 in the present trial.
Summary of benefit-risk assessment
In previous trials in healthy subjects, single oral doses up to 150 mg BI 425809 and multiple 
oral doses up to 75 mg BI 425809 once or twice daily were safely administered. In the current 
trial, healthy volunteers will receive three single oral doses of 25 mg BI 425809.
The trial design is optimized to collect as much relevant information as possible on the 
pharmacokinetics of the newly developed tablet formulation of BI 425809 without exposing 
participating volunteers to undue risk. However, there is always the potential of serious 
adverse events (SAEs) occurring with intake of trial medication. Risks to subjects will be 
minimized and addressed by eligibility criteria, safety laboratory examinations, ECG and 
vital sign measurements, in-house observation periods and verbal communication concerning 
AEs. 
If the investigator should have any clinical concern, the safety of the subjects will be of 
paramount importance. The investigator has the discretion to remove subjects from the study 
should there be any safety concerns or if the subject’s wellbeing is at jeopardy.
The risks of the participating volunteers are minimized and justified when compared to the 
potential benefits of a successful clinical development of BI 425809 for patients with AD, 
and CIAS.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of batch 1 of the 
intended commercial tablet formulation (iCF1) of BI 425809 vs batch 2 of the intended 
commercial tablet formulation (iCF2) of BI 425809 vs BI 425809 TF2 formulation.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 425809:

AUC0-72 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 72 h)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
Not applicable.
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS
2.2.2
Further endpoints
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)

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, three-treatment, three-period, six-
sequence crossover trial in healthy male and female subjects in order to compare the test 
treatments (T1 and T2) to each other and to the reference treatment (R). The treatments will 
be:

Test treatment 1 (Treatment T1):
One 25 mg BI 425809 intended commercial formulation tablet from batch 1 (iCF1)

Test treatment 2 (Treatment T2): 
One 25 mg BI 425809 intended commercial formulation tablet from batch 2 (iCF2)

Reference treatment (Treatment R): 
One 25 mg BI 425809 trial formulation 2 tablet (TF2)
All treatments will be administered to subjects in the fasting state. The subjects will be 
randomly allocated to the six treatment sequences (T1-T2-R, T1-R-T2, T2-T1-R, T2-R-T1, 
R-T1-T2 or R-T2-T1). For details, refer to Section 4.1.
There will be a washout period of at least 14 days between the treatments.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his/her own control, the comparison between treatments is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 18 healthy male and female subjects (at least 1/3 of each sex) will enter the 
study. 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.

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3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
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 prior to admission to the study, in accordance 
with GCP and local legislation
5. Male subjects, or female subjects who meet any of the following criteria from at least 30 
days before the first administration of trial medication until 30 days after trial completion:
-
Use of adequate contraception, e.g. any of the following methods plus condom:
implants, injectables, combined oral or vaginal contraceptives, intrauterine device
-
Sexually abstinent
-
A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)
-
Surgically sterilised (including hysterectomy)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in
questionable cases a blood sample with levels of FSH above 40 U/L and estradiol 
below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 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 

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8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. 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)
12. 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
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for
males)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline 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
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
23. Female subjects, only: Positive pregnancy test, pregnancy, or plans to become pregnant 
within 30 days after study completion
24. Female subjects, only: Lactation
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or 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 

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documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.3), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
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 
5.2.6.2.4.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
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, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as pregnancy, 
surgery, adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and section 6.2.3.
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

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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:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least 1 drug-related serious adverse event is 
reported
3. Violation of GCP, or the CTP impairing the appropriate conduct of the trial-
4. The sponsor decides to discontinue the further development of the investigational product
3.3.5
Replacement of subjects
In case more than 2 subjects do not complete the trial the Clinical Trial Leader together with 
the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects 
will be replaced. A replacement subject will be assigned a unique trial subject number, and 
will be assigned to the same treatment as the subject he or she replaces.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products have been manufactured by BI Pharma GmbH & Co. KG. 
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product 1 are given below:
Substance:
BI 425809
Pharmaceutical formulation: intended commercial formulation tablet (film-coated), batch 1 
(iCF1)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
single dose 
The characteristics of the test product 2 are given below:
Substance:
BI 425809
Pharmaceutical formulation: intended commercial formulation tablet (film-coated), batch 2 
(iCF2)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
single dose 
The characteristics of the reference product are given below:
Substance:
BI 425809
Pharmaceutical formulation: tablet formulation (TF2)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
single dose 

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4.1.2
Selection of doses in the trial
The dose of 25 mg BI 425809 that was selected for this trial is the maximum dose used in the 
currently ongoing Phase 2 trials 
4.1.3
Method of assigning subjects to treatment groups
The randomisation list 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 
list will be allocated to the subjects by drawing lots. Subjects are then assigned to a treatment
sequence according to the randomisation list.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a three-treatment, three-period, six-sequence crossover study. All subjects will 
receive the 3 treatments in randomised order, either

T1-T2-R,

T1-R-T2,

T2-T1-R,

T2-R-T1,

R-T1-T2 or

R-T2-T1.
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Total dose
T 1 (Test 1)
BI 425809
Tablet iCF 1
25 mg
25 mg
T 2 (Test 2)
BI 425809
Tablet iCF 2
25 mg
25 mg
R (Reference)
BI 425809
Tablet TF2
25 mg
25 mg
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. The investigator (or 
authorised designee) will administer the trial medication as an oral dose together with about 
240 mL of water to subjects who are in a standing position. For drug administration, the so-
called four-eye principle (two-person rule) should be applied. For this, one authorised 
employee of the trial site should witness the administration of trial medication, and – if 
applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.

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Subjects will be kept under close medical surveillance until 24 h after drug administration. 
During the first 4 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture).
The treatments will be separated by a wash-out phase of at least 14 days.
4.1.5
Blinding and procedures for unblinding
Blinding is not possible in this Phase 1 trial as the treatments are distinguishable. The trial 
will be handled in an open fashion throughout (that is, during the conduct, including data 
cleaning and preparation of the analysis). This is considered acceptable because the potential 
for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
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 
Clinical Trial Monitor (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
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  

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Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
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.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. However, in case of adverse events in need 
of treatment, a concomitant therapy will be permitted. The use of weak, moderate or strong
CYP3A4 inhibitors and inducers is not permitted. CYP3A4 sensitive drugs with narrow 
therapeutic range are not permitted during the trial period. All concomitant or rescue 
therapies will be recorded (including time of intake on study days) on the appropriate pages 
of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
subjects).

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Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of the trial is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before until 24 h after each administration of trial 
medication.
Smoking is not allowed during in-house confinement.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
If female subjects of child-bearing potential are included in the trial, adequate contraception 
is to be maintained throughout the course of the trial (see Section 3.3.2 for the definition of 
adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight,
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported), 
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a physical examination. At 
the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, and a physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) at the times indicated in the 
Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm, 
if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. 
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively. 

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands; Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
X
X
X
X
X
X
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
Protein, Total
C-Reactive Protein (Quant)  
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
X
X
--
--
X
X

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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Urinalysis1 (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment1
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visits 2,3,4 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 5 (end of trial examination)
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 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
each treatment period, and as part of the end of trial examination. Drug screening will be 
performed at screening and prior to each treatment period.

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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410, Dräger AG, Lübeck, Germany) will be performed prior to each treatment period, and 
may be repeated at any time during the study at the discretion of an investigator or designee. 
The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed
 
 with the exception of 
drug screening and pregnancy tests. These tests will be performed at the trial site using M-
10/14-PDT test and HCG-K20 test, respectively, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the times provided in the Flow Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven. 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 

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assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
Not applicable.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
5.2.6.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.2.6.1.2
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  

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

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
Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardize 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
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer 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’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further 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. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
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:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, 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 

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test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
Intensity (severity) of AEs
5.2.6.1.5
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
Causal relationship of AEs
5.2.6.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like 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)

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
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
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 as well as the time of onset, end
time, and intensity of these events. 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: 
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 or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.

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AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax 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.
Information required
5.2.6.2.3
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 assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
5.2.6.2.4
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
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 Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
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 Trials 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 indicated 
in the Flow Chart. The actual sampling times will be recorded and used for determination of 
pharmacokinetic parameters. 

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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 a K2-EDTA (dipotassium ethylenediaminetetraacetic
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venepuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed in less than 60 min, with interim storage of blood samples and aliquots on ice. 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 completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites. 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 study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the CTR is 
archived.
5.3.3
Analytical determinations
5.3.3.1
Analytical determination of analyte plasma concentration
BI 425809 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. 
During sample analysis, the bioanalyst will be blinded to subject allocation and will have no 
access to the randomisation code.
5.4
ASSESSMENT OF BIOMARKER(S) 
Not applicable.
5.5
BIOBANKING
Not applicable.

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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 as assessments of drug exposure.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests 
will be ± 30 min within the first 4 h after drug administration and then ± 60 min for all 
following measurements up to the last measurement before 72 h post dose. Starting from 72 h 
post administration a deviation from scheduled time of +- 70 min is acceptable
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.3).
6.2.2
Treatment periods
Each subject is expected to participate in 3 treatment periods (Days -1 to 4 in each period). At 
least 14 days will separate drug administrations in the first and second treatment periods as 
well as in the second and third treatment periods.
On Day -1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration. The 

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subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study 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. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
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 Sections 5.2.1 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
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 EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the relative bioavailability of 25 mg of 
BI 425809 intended commercial formulation batch 1 (Test 1, T1), compared with 25 mg of 
BI 425809 intended commercial formulation batch 2 (Test 2, T2), compared with 25 mg of 
BI 425809 tablet TF2 (Reference, R) following oral administration on the basis of the 
primary pharmacokinetic endpoints, as listed in Section 2.1.2. The trial is designed to allow 
intra-subject comparisons and will be evaluated statistically by use of a linear model for 
logarithmically transformed PK endpoints. Relative bioavailability of the three treatments 
will be assessed pairwise.
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of T1 compared with T2, T1 compared with R, and T2 compared 
with R will be estimated by the ratios of the geometric means (T1/T2, T1/R, and T2/R), 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.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Randomised set (RS): The randomised set includes all subjects who were randomised, 
i.e., who have been assigned a subject number, whether treated or not.

Treated set (TS): The treated set includes all subjects in the randomised set (RS) who 
were treated with at least one dose of study 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 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 

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parameter value for one period to the statistical assessment. Descriptive and model 
based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IQRM plan, IPDs will be identified no later than in 
the - Report Planning Meeting, and the IPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and Section 2.2.2.1 for drug BI 425809
will be calculated according to the relevant SOP of the Sponsor 
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.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is 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). 
7.3.1
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints (see Section 2.1.2) will be 
an analysis of variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints 

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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, ..., 6,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, ..., t,
k = the kth treatment effect, k = 1, ..., t,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables. The primary analysis will be conducted with t=3, i.e., the ANOVA model will be 
based on data from all three treatments (T1, T2, R).
Point estimates for the ratios of the geometric means (T1/T2, T1/R and T2/R) for the primary 
endpoints and their two-sided 90% confidence intervals (CIs) will be provided.
For each endpoint, the difference between the expected means for log(T1)-log(T2), log(T1)-
log(R) and log(T2)-log(R) will be estimated by the difference in the corresponding adjusted 
means (Least Squares Means). Additionally their two-sided 90% confidence intervals will be 
calculated based on the residual error from the ANOVA and quantiles from the t-distribution. 
These quantities will then be back-transformed to the original scale to provide the point 
estimate and 90% CIs for each endpoint.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects , and with t=2 (i.e., estimates for each comparison of two 
treatments will be developed based on an ANOVA model using data from these two 
treatments only).
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.

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7.3.2
Secondary endpoint analyses
Not applicable.
7.3.4
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.3) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the recorded time of the 
measurement or of AE onset (concept of treatment emergent AEs). Therefore, measurements 
planned or AEs recorded prior to first intake of trial medication will be assigned to the 
screening period, those between first trial medication intake and end of REP (see Section 
1.2.3) will be assigned to the treatment period. Events occurring after the REP but prior to 
next intake or end of trial termination date will be assigned to ’follow-up’. The follow-up will 
be summarized according to the previous treatment. These assignments including the 
corresponding time intervals will be defined in detail in the TSAP. Note that AEs occurring 
after the last per protocol contact but entered before final database lock will be reported to 
Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1.4), 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 as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, on-treatment differences from baseline will be evaluated.
Vital signs will be assessed with regard to possible on-treatment changes from baseline.

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Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure 
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Subjects will be randomised to one of the six treatment sequences in a 1:1:1:1:1:1 ratio. The 
block size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 18 subjects in the trial, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratios of geometric means (T1/T2, T1/R and T2/R) can be 
expected with 95% tolerance probability. Precision is defined as the ratio of upper CI limit to 
the relative BA estimate. Note that the precision is independent of the actual ratio of 
geometric means.
The observed intra-individual coefficient of variation (gCV) for BI 425809 in previous trials 
[c18001523-01; c03572014-01] was roughly 21% for Cmax and 16% for AUC.
For various assumptions around the gCV of 25%, Table 7.7: 1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (T1/T2, T1/R and T2/R). For 
illustrative purposes, the expected 90% confidence intervals are displayed for different values 
of the ratios of geometric means.

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Table 7.7: 1
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T1/T2, T1/R and T2/R) for different gCVs in a 
3x6x3 crossover trial (N=18)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
22.5
1.16
70
60.20
81.39
22.5
1.16
80
68.80
93.02
22.5
1.16
90
77.41
104.64
22.5
1.16
100
86.01
116.27
22.5
1.16
110
94.61
127.90
25.0
1.18
70
59.23
82.73
25.0
1.18
80
67.69
94.54
25.0
1.18
90
76.16
106.36
25.0
1.18
100
84.62
118.18
25.0
1.18
110
93.08
130.00
27.5
1.20
70
58.28
84.07
27.5
1.20
80
66.61
96.08
27.5
1.20
90
74.94
108.09
27.5
1.20
100
83.26
120.10
27.5
1.20
110
91.59
132.11
*Ratio of geometric means (test [T]/reference [R]) for a PK endpoint is defined by exp(T)/exp(R).
Assuming a sample size of 16 subjects in the PKS analysis set, Table 7.7: 2 provides an 
overview of the achievable precision for estimating the ratio of geometric means (T1/T2, 
T1/R and T2/R) for various assumptions around the gCV of 25%. For illustrative purposes, 
the expected 90% confidence intervals are displayed for different values of the ratios of 
geometric means. Note that in a 3x6x3 crossover trial, N=16 will result in an unbalanced 
design; 3/3/3/3/2/2 was assumed for this precision estimation.

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Table 7.7: 2
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T1/T2, T1/R and T2/R) for different gCVs in a 
3x6x3 crossover trial (N=16)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
22.5
1.18
70
59.33
82.59
22.5
1.18
80
67.81
94.39
22.5
1.18
90
76.28
106.19
22.5
1.18
100
84.76
117.98
22.5
1.18
110
93.23
129.78
25.0
1.20
70
58.28
84.08
25.0
1.20
80
66.61
96.09
25.0
1.20
90
74.93
108.10
25.0
1.20
100
83.26
120.11
25.0
1.20
110
91.58
132.12
27.5
1.22
70
57.26
85.58
27.5
1.22
80
65.44
97.80
27.5
1.22
90
73.62
110.03
27.5
1.22
100
81.80
122.25
27.5
1.22
110
89.98
134.48
*Ratio of geometric means (test [T]/reference [R]) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit,  = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.3.2

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonised standards for Medical Devices (ISO 14155, current version).
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.
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 archiving 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.

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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
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 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 data base. Instead of being entered into CRFs, selected data are directly 
entered into the 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.
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, 

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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: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
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 
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.

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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 (whatever is longer).
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
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
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, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking 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 (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
biobanking ICF

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8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for 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.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted 
 
 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, 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 Clinical Trial Monitors (CTM), 
Clinical Research Associates, and investigators of participating trial sites

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
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 62, 1196 -
1204 (2005)
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) 
9.2
UNPUBLISHED REFERENCES
c02155957-08
Investigator`s Brochure BI 425809 Alzheimers Disease Cognitive 
Impairment Associated with Schizophrenia (CIAS). 06 Jun 2017
c08949593-01
. 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
c18001523-01
 Effects of rifampicin on the 
pharmacokinetics of BI 425809 following oral administration in healthy 
male subjects (an open-label, two-period, fixed-sequence trial) 1346-0018. 
09 Jan 2018
c03572014-01
. 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 

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Trial Protocol
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a single oral dose of BI 425809 after oral administration in the morning 
versus...1346.2. 04 Jul 2016

Boehringer Ingelheim
04 Jun 2019
BI Trial No.: 1346-0019
c23832649-03
Trial Protocol
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10.
APPENDICES
Not applicable.  

Boehringer Ingelheim
04 Jun 2019
BI Trial No.: 1346-0019
c23832649-03
Trial Protocol
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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
22 January 2019
EudraCT number
EU number
2018-003625-29
BI Trial number
1346-0019
BI Investigational Medicinal 
Product(s)
BI 425809
Title of protocol
Relative bioavailability of batch 1 and batch 2 of the 
intended commercial formulation of BI 425809 compared 
to each other and to TF 2 formulation of BI 425809 
following oral administration in healthy male and female 
subjects (Randomized, open-label, single-dose, three-
treatment, three-period, six-sequence crossover 
study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Section 5.2.3: Safety laboratory parameters
Description of change
Footnote B and C of Table 5.2.3.:1  Visits were 
corrected to be in accordance with the Flow Chart
Rationale for change
Due to a typo in footnotes B and C there was a 
discrepancy between the correct Flow Chart and 
these footnotes. These typos were corrected. The 
number of scheduled safety laboratory examinations 
was not changed and also not the amount of blood to 
be taken. 

Boehringer Ingelheim
04 Jun 2019
BI Trial No.: 1346-0019
c23832649-03
Trial Protocol
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11.2
GLOBAL AMENDMENT 2
Date of amendment
04 June 2019
EudraCT number
EU number
2018-003625-29
BI Trial number
1346-0019
BI Investigational Medicinal 
Product(s)
BI 425809
Title of protocol
Relative bioavailability of batch 1 and batch 2 of the 
intended commercial formulation of BI 425809 
compared to each other and to TF 2 formulation of BI 
425809 following oral administration in healthy male 
and female subjects (Randomized, open-label, single-
dose, three-treatment, three-period, six-sequence 
crossover study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Title page
2. Synopsis
Description of change
1.+.2. There was a shift in PI function: 
 
 was replaced by 
 
Rationale for change
As the current Principal Investigator 
 
will take over a new position 
 
 the PI function will 
be handed over to 
 starting 
from 01July2019.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23832649
3.0
clinical-trial-protocol-version-3
Relative bioavailability of batch 1 and batch 2 of the intended commercial
formulation of BI 425809 compared to each other and to TF 2 formulation of BI
425809 following oral administration in healthy male and female subjects
(Randomized, open-label, single-dose, three-treatment, three-period, six-sequence
crossover study)
Approval-Clinical Trial Leader
04 Jun 2019 14:16 CEST
Author-Trial Statistician
04 Jun 2019 14:25 CEST
Approval-Team Member Medicine
04 Jun 2019 15:59 CEST
Approval-Therapeutic Area 
04 Jun 2019 16:27 CEST
Author-Trial Clinical
Pharmacokineticist
04 Jun 2019 20:58 CEST
Approval-Biostatistics
06 Jun 2019 13:58 CEST
Verification-Paper Signature
Completion
17 Jun 2019 08:38 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23832649
3.0