Investigation of Pharmacokinetics and Absolute Oral Bioavailability of BI 425809 Administered as an Oral Dose With an Intravenous Microtracer Dose of [C-14]-BI 425809 in Healthy Male Volunteers
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

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Clinical Trial Protocol
TITLE PAGE
Document Number:
c21363182-03
EudraCT No.
2018-001194-24
BI Trial No.
1346-0015
BI Investigational
Medicinal Product
BI 425809
Title
Investigation of pharmacokinetics and absolute oral bioavailability of BI 
425809 administered as an oral dose with an intravenous microtracer 
dose of [C-14]-BI 425809 in healthy male volunteers
Lay Title
A study in healthy men to measure the amount of BI 425809 in the 
blood when taken as a tablet
Clinical Phase
I
Clinical Trial Leader
Phone: 
Fax:      
Principal Investigator
Phone:
Fax: 
Status
Final Protocol
Version and Date
Version: 2.0
Date: 07 Jan 2019
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
26Nov2018
Revision date
07Jan2019
BI trial number
1346-0015
Title of trial
Investigation of pharmacokinetics and absolute oral bioavailability of BI 425809 
administered as an oral dose with an intravenous microtracer dose of [C-14]-BI 
425809 in healthy male volunteers
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
This trial is intended to examine the absolute oral bioavailability of BI 425809 as 
tablet formulation for oral administration. The data are considered necessary to 
further support the understanding of the pharmacokinetics of BI 425809.
Trial objective
To determine the absolute oral bioavailability of BI 425809
Trial design
Non-randomized, open-label, single period, single arm
Trial endpoints:
Primary endpoints:
AUC0-∞of [14C]-BI 425809 i.v. 
AUC0-∞of BI 425809 p.o. 
Secondary endpoints:
Oral route:  Cmax of BI 425809 p.o.
Number of subjects 
total entered
6
each treatment
6
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 65 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Trial product 1
BI 425809 film-coated tablet (Treatment Test (T))
dose
25 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Trial product 2
BI 425809 (C-14) as intravenous solution (Treatment Reference (R))
dose
30 µg BI 425809 consisting of 27 µg unlabelled BI 425809 mixed with 3 µg
labelled [C-14]-BI 425809 in 10 mL intravenous solution (3 µg BI 425809 (C-14) 
/mL)
The radioactive dose per infusion will be ~0.011 MBq
mode of admin.
Intravenous infusion of 15 min at ~ tmax (4 h) of 25 mg tablet after an overnight fast 
of at least 10 h 

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Duration of treatment
Intravenous dose (Treatment R): 
Single intravenous infusion of microtracer over 15 min, Day 1
Oral dose (Treatment T): 
Single oral dose, Day 1
Statistical methods
Absolute bioavailability (F) will be estimated by the ratios of the geometric means 
(test/reference) for the primary endpoints AUC0-∞(dose normalized). 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 the fixed effect for ‘formulation’ and ‘subject’ as a random effect. CIs 
will be calculated based on the residual error from ANOVA.
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART
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 plasma BI 425809
PK plasma [ C-14 ]-BI 425809
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and concomitant 
therapy2
1
-21 to -2
Screening (SCR)1
x
x
x
2
-1
-18:00
14:00
Admission to trial site
x5
x
-14:00
18:00
Dinner
-10:30
21:30
Snack (voluntary)
1
-2:00
06:00
x3
x3
x3
x3
0:00
08:00
Drug administration
(BI 425809, 25 mg tablet, oral)
1:00
09:00
x
x
2:00
10:00
240 mL fluid intake
x
x
3:00
11:00
x
x
x
4:00
12:00
Start of IV infusion containing
[C-14]-BI 425809
240 mL fluid intake
4:05
12:05
x
x
4:10
12:10
x
4:15
12:15
Stop of IV infusion containing
[C-14]-BI 425809
x
4:30
12:30
Lunch4
x
5:00
13:00
x
6:00
14:00
x
x
7:00
15:00
x
8:00
16:00
Snack (voluntary)4
x
x
x
x
x
11:00
19:00
Dinner
12:00
20:00
x
x
x
16:00
24:00
x
2
24:00
08:00
Breakfast (voluntary)4,
discharge from trial site
x
x
x
x
x
x
4
72:00
08:00
Ambulatory visit
x
x
x
6
120:00
08:00
Ambulatory visit
x
x
x
x
8
168:00
08:00
Ambulatory visit
x
x
x
3
12 to 15
End of trial (EOT) examination6
x
x
x
x

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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), demographics (including 
determination of body height and weight, smoking status and alcohol history), relevant medical history, concomitant therapy, and 
review of inclusion/exclusion criteria.
2.
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.
3.
The time is approximate; the procedure is to be performed and completed within 2 h prior to drug administration.
4.
If several actions are indicated at the same time point, the intake of meals will be the last action.
5.
Including urine drug screening and alcohol test.
6.
End of trial examination includes physical examination, vital signs, ECG, safety laboratory, recording of AEs and concomitant 
therapies. 

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
1.2.1
Non-clinical pharmacokinetics ............................................................13
1.2.2
Non-clinical safety pharmacology and toxicology..............................14
1.2.3
Residual Effect Period..........................................................................14
1.2.4
Clinical experience in humans.............................................................14
1.2.5
Clinical pharmacokinetics....................................................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................16
1.4
BENEFIT - RISK ASSESSMENT ...................................................................16
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 19
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......19
2.1.1
Main objectives......................................................................................19
2.1.2
Primary endpoints ................................................................................19
2.1.3
Secondary endpoint ..............................................................................19
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS .........................19
2.2.2
Further endpoints .................................................................................19
2.2.2.2
Safety and tolerability..............................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 22
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................22
3.3
SELECTION OF TRIAL POPULATION ......................................................23
3.3.1
Main diagnosis for trial entry..............................................................23
3.3.2
Inclusion criteria...................................................................................23
3.3.3
Exclusion criteria ..................................................................................24
3.3.4
Withdrawal of subjects from treatment or assessments ...................25
3.3.4.1
Discontinuation of trial treatment............................................25
3.3.4.2
Withdrawal of consent to trial participation ............................26

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3.3.4.3
Discontinuation of the trial by the sponsor..............................26
3.3.5
Replacement of subjects .......................................................................26
4.
TREATMENTS........................................................................................ 27
4.1
INVESTIGATIONAL TREATMENTS ..........................................................27
4.1.1
Identity of the Investigational Medicinal Products ...........................27
4.1.2
Selection of doses in the trial................................................................28
4.1.3
Method of assigning subjects to treatment groups ............................28
4.1.4
Drug assignment and administration of doses for each subject .......28
4.1.5
Blinding and procedures for unblinding ............................................29
4.1.6
Packaging, labelling, and re-supply ....................................................29
4.1.7
Storage conditions.................................................................................30
4.1.8
Drug accountability ..............................................................................30
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................31
4.2.1
Other treatments and emergency procedures....................................31
4.2.2
Restrictions............................................................................................31
4.2.2.1
Restrictions regarding concomitant treatment .........................31
4.2.2.2
Restrictions on diet and life style.............................................31
4.3
TREATMENT COMPLIANCE.......................................................................32
5.
ASSESSMENTS....................................................................................... 33
5.1
ASSESSMENT OF EFFICACY.......................................................................33
5.2
ASSESSMENT OF SAFETY............................................................................33
5.2.1
Physical examination ............................................................................33
5.2.2
Vital signs...............................................................................................33
5.2.3
Safety laboratory parameters..............................................................33
5.2.4
Electrocardiogram................................................................................36
5.2.5
Other safety parameters.......................................................................37
5.2.5.1
Local tolerability......................................................................37
5.2.6
Assessment of adverse events...............................................................37
5.2.6.1
Definitions of adverse events...................................................37
Adverse event ............................................................37
5.2.6.1.1
Serious adverse event ................................................37
5.2.6.1.2
AEs considered ‘Always Serious’.............................38
5.2.6.1.3
Adverse events of special interest .............................38
5.2.6.1.4
Intensity (severity) of AEs.........................................39
5.2.6.1.5
Causal relationship of AEs ........................................39
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................40
AE collection.............................................................40
5.2.6.2.1
AE reporting to the sponsor and timelines ................41
5.2.6.2.2
Information required..................................................41
5.2.6.2.3
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................41
5.3.1
Assessment of pharmacokinetics .........................................................41

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5.3.2
Methods of sample collection...............................................................41
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................41
5.3.3
Analytical determinations ....................................................................42
5.3.3.1
Analytical determination of analyte plasma concentrations....42
5.4
BIOBANKING ...................................................................................................42
5.5
OTHER ASSESSMENTS .................................................................................42
5.6
APPROPRIATENESS OF MEASUREMENTS.............................................42
6.
INVESTIGATIONAL PLAN.................................................................. 44
6.1
VISIT SCHEDULE............................................................................................44
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................44
6.2.1
Screening period....................................................................................44
6.2.2
Treatment period ..................................................................................44
6.2.3
Follow-up period and trial completion ...............................................45
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 46
7.1
STATISTICAL DESIGN – MODEL ...............................................................46
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................46
7.3
PLANNED ANALYSES....................................................................................46
7.3.1
Primary endpoint analyses...................................................................47
7.3.2
Secondary endpoint analyses ...............................................................48
7.3.4
Safety analyses.......................................................................................49
7.4
INTERIM ANALYSES .....................................................................................50
7.5
HANDLING OF MISSING DATA ..................................................................50
7.5.1
Safety......................................................................................................50
7.5.2
Pharmacokinetics..................................................................................50
7.6
RANDOMISATION ..........................................................................................50
7.7
DETERMINATION OF SAMPLE SIZE ........................................................50
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 51
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................51
8.2
DATA QUALITY ASSURANCE .....................................................................52
8.3
RECORDS..........................................................................................................52
8.3.1
Source documents .................................................................................52
8.3.2
Direct access to source data and documents.......................................53
8.3.3
Storage period of records.....................................................................53
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................53
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......53

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8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................54
8.6
TRIAL MILESTONES .....................................................................................54
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................55
9.
REFERENCES......................................................................................... 56
9.1
PUBLISHED REFERENCES...........................................................................56
9.2
UNPUBLISHED REFERENCES.....................................................................56
10. APPENDICES .......................................................................................... 58
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 59
11.1
GLOBAL AMENDMENT 1 .............................................................................59

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ABBREVIATIONS
AD
Alzheimer’s Disease
AE
Adverse event
AESI
Adverse events of special interest
ALCOA
Attributable, legible, contemporaneous, original, accurate
AMS
Accelerator mass spectometry
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
aVR
Augmented Voltage Right
aVL
Augmented Voltage Left
aVF
Augmented Voltage Foot
BA
BCS
Bioavailability
Biopharmaceutics Classification System
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CI
Confidence interval
CIAS
Congnitive impairment associated with schizophrenia
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
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’)
CRO
Contract Research Organisation
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical Trial Supplies Unit
DILI
Drug induced liver injury

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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
FDA
Food and Drug Administration
Fp.o.(%)
Absolute bioavailability after oral administration
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GlyT1
Glycine transporter 1
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
ICRP
International Commission on Radiological Protection
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IQRM
Integrated Quality and Risk Management Process
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
MBq
MegaBequerel
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRT
Mean residence time of the analyte in the body after intravenous bolus 
administration
MRT,ex
Mean residence time of the analyte in the body, extravascular
NMDA
N-methyl-D-aspartate
PEG
PolyEthylene Glycol
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
qd
quaque die

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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
SUSAR
Suspected unexpected serious adverse reaction
T
Test product or treatment
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vdss
Volume of distribution at steady state after single intravenous 
administration
Vdz
Volume of distribution after single intravenous administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
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).
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

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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

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For a more detailed description of the BI 425809 profile please refer to the current 
Investigator’s Brochure [c02155957-08].
1.3
RATIONALE FOR PERFORMING THE TRIAL
This trial is intended to examine the absolute oral bioavailability of BI 425809 using an 
intravenous [C-14]-microtracer approach. The data are considered necessary to further 
support the understanding of the pharmacokinetics of BI 425809.
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 solvent for the intravenous infusion containing a mixture of labelled and unlabelled 
BI 425809 is 20% PEG 400 in saline. Therefore, in case of inadvertent paravenous drug 
administration apart from local swelling no tissue damage is expected.
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 

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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.
Risks related to oral 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 M232 (BI 761036) and M530
The major human metabolites of BI 425809, M530 and M232, 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.
Risks related to intravenous administration of BI 425809(C-14) solution
No therapeutic intravenous use is planned for BI 425809. Therefore, in accordance to the 
guideline on non-clinical safety studies ICH-M3(R2) [R15-0594], the intravenous microtracer 
dose of 30 µg BI 425809 (C-14) is considered adequately qualified by the existing oral 
toxicity studies and investigation of intravenous local tolerance of the drug substance is not 
recommended in this situation because the administered dose is very low (< 100 μg) and no 
novel solvent is used.
BI 425809 is labelled with the isotope [14C] which is necessary for the purposes of this 
microtracer trial to distinguish the intravenously administered labelled drug from the 
unlabelled oral drug. The radioactive dose per infusion will be approx. 0.011 MBq and 
thereby falls into the ICRP 1 category (trivial level of risk) based on the calculated ICRP 
Category I limit for administration of [14C]-BI 425809 of 0.9 MBq [c25192159][R15-3219].
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 

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trial, healthy male volunteers will receive a single oral dose of 25 mg BI 425809 and an 
intravenous microtracer dose of 30 µg BI 425809 (C-14). Each participating subject will 
receive only one infusion containing a radioactive dose <0.9 MBq (ICRP 1 category, trivial 
level of risk).
The trial design is optimized to collect as much relevant information as possible on the 
pharmacokinetics 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 investigation of the absolute bioavailability of this BCS class 2 compound contributes 
substantially to a better understanding of its pharmacokinetics. The results of this trial are 
necessary for the further development of BI 425809. Successful development of BI 425809 is 
expected to provide a new valuable treatment to improve cognitive functioning in patients 
with AD and CIAS.
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 primary objective of this trial is to investigate the absolute oral bioavailability of 25 mg 
BI 425809 administered as tablet (Test, T) compared to 3 µg of [C-14]-BI 425809 
administered as intravenous microtracer (the total dose administered iv is a mixture of 3 µg 
labelled [C-14]-BI 425809 and 27 µg unlabelled BI 425809) (Reference, R).
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined in plasma for [14C]-
BI 425809 after intravenous administration as well as for BI 425809 after oral 
administration:

AUC0-(area under the concentration-time curve of the analyte over the time interval 
from 0 to infinity)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for BI 425809 after oral 
administration:
o
Cmax (maximum measured concentration of the analyte in plasma)
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS
2.2.2
Further endpoints

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2.2.2.2
Safety and tolerability
Safety and tolerability of the investigational drug 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 non-randomised, open-label, single period and single arm 
trial in healthy male subjects in order to compare the test treatment (T) to the reference 
treatment (R). The test treatment (T) will be one oral tablet of 25 mg BI 425809 (intended 
clinical formulation (ICF)) and the reference treatment (R) will be an intravenous microtracer 
infusion of 30 µg BI 425809 (14-C) (consisting of 27 µg unlabelled BI 425809 mixed with 3 
µg labelled [C-14]-BI 425809 in 10 mL intravenous solution (3 µg BI 425809 (C-14)/mL)). 
Both treatments will be given in the fasted state. For details refer to Section 4.1.
Drug administration in Treatment R will start 4 h 00 min after drug administration in 
Treatment T, i.e. at the time of expected Tmax of treatment T.
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 Section 6.2, 
respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
To investigate the absolute bioavailability, a single arm, single period trial design using a 
microtracer approach* was considered to be the favourable design also in comparison to the 
traditional cross-over design used for absolute bioavailability studies for the following 
reasons: 
•
As in a traditional cross-over design each subject serves as his own control removing 
inter-subject variability. However, additionally day to day variability within a subject is 
also eliminated as potential confounding variable as each subject is exposed to the two 
treatments in parallel, i.e. treatment R will be administered at Tmax of Treatment T
•
Expected favourable safety due to very low exposures after an intravenous microdose 
•
The radioactive dose per infusion has been calculated to be 0.011 MBq thereby not 
exceeding the ICRP 1 limit for administration of [14C]-BI 425809 of 0.9 MBq, i.e. trivial 
level of risk [c25192159].
•
Reduced duration of the clinical trial
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte.
*In this context ‘microtracer’ is defined as an intravenous dose of an isotopically labelled drug in an absolute bioavailability 
study administered as 1% of the pharmacologic dose or 0.1 mg, whichever is the lower. [R17-1799]

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3.3
SELECTION OF TRIAL POPULATION
It is planned that 6 healthy male subjects will enter the study. They will be recruited from the 
volunteers' pool of the trial site or, if necessary, via advertisement. 
The current trial is designed to investigate the absolute oral bioavailability of BI 425809. 
Healthy male subjects are an ideal population for the objectives of this trial, since they 
provide relatively stable physiological, biochemical and hormonal conditions, i.e. the absence 
of disease-related variations and relevant concomitant medications.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The 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 subjects according to the assessment of the investigator, 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 65 years (incl.) 
3. BMI of 18.5 to 29.9 kg/m2 (incl.) 
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
5. Subjects who are sexually active must use, with their partner, highly effective 
contraception from the time of administration of trial medication until 4 months after 
administration of trial medication. Adequate methods are:
-
Condoms plus use of hormonal contraception by the female partner that started at 
least 2 months prior to administration of trial medication (e.g., implants, injectables, 
combined oral or vaginal contraceptives, intrauterine device) or
-
Condoms plus surgical sterilization (vasectomy at least 1 year prior to enrolment) or
-
Condoms plus surgically sterilised partner (including hysterectomy) or
-
Condoms plus intrauterine device or
-
Condoms plus partner of non-childbearing potential (including homosexual men)
Subjects are required to use condoms to prevent unintended exposure of the partner to 
the study drug via seminal fluid.
Alternatively, true abstinence is acceptable when it is in line with the subject’s 
preferred and usual lifestyle. If a subject is usually not sexually active but becomes 

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active, with their partner, they must comply with the contraceptive requirements 
detailed above.
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) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 139 mmHg, 
diastolic blood pressure outside the range of 45 to 89 mmHg, or pulse rate outside the 
range of 40 to 100 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Clinically significant gastrointestinal, hepatic, renal, respiratory (including but not limited 
to interstitial lung disease), cardiovascular, metabolic, immunological or hormonal 
disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. 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 prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation). Use of 
CYP3A4 inhibitors and inducers 1 week prior to administration of trial medication
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
13. Smoker (more than 5 cigarettes or 1 cigar or 1 pipe per day)
14. Inability to refrain from smoking on specified trial days
15. Average intake of more than 24 units of alcohol per week (1 unit of alcohol equals 
approximately 250 mL of beer, 100 mL of wine or 35 ml of spirits)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within 4 days prior to administration of 
trial medication or during the trial
19. Inability to comply with dietary regimen of trial site

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20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome) 
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
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 Section 3.3.4.1 and 
Section 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, 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.
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 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.

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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.
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, or the contract with BI impairing the appropriate conduct 
of the trial
4. The sponsor decides to discontinue the further development of the investigational product
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case 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 
 replaces.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational unlabelled product (Trial product 1) has been manufactured by BI Pharma 
GmbH & Co. KG. BI 425809 XX is a neutral molecule exhibiting no ionizing centre. 
Therefore 25 mg BI 425809 equal to 25 mg BI 425809 XX.
Radiolabelled BI 425809 (C-14) is administered as an intravenous solution. The powder used 
for intravenous solution contains [C-14] BI 425809 and unlabelled BI 425809 are both 
manufactured by BI Pharma GmbH & Co. KG. The mixture of [C-14] BI 425809 and 
unlabelled BI 425809 and the solution from this mixture are made by 
 
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of Trial Product 1 (Treatment T) are given below:
Name:
BI 425809 intended Commercial Form (iCF)
Substance:
BI 425809
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
single dose
The characteristics of Trial Product 2 (Treatment R) are given below:
Name:
BI 425809 (C-14) intravenous solution
Substance:
BI 425809 mixed with [C-14]-BI 425809
Pharmaceutical formulation: intravenous solution
Source:
Unit strength:
30 µg BI 425809
-
consisting of 3 µg [14C]-labelled BI 425809 mixed with 27
µg unlabelled BI 425809 
-
in 20% PEG 400 in saline solution of 10 mL volume
(Concentration of BI 425809 (C-14): 3 µg/mL)
Posology:
1-0-0
Route of administration:
i.v.
Duration of use:
single infusion over 15 min

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4.1.2
Selection of doses in the trial
The dose of 25 mg BI 425809 is below the already tested highest doses (single doses up to
150 mg, multiple doses up to 75 mg bid (150 mg/d)) of BI 425809 in healthy subjects. In
healthy volunteers, a single dose of 25 mg was safe and well-tolerated (Section 1.2.4). A dose
of 25 mg corresponds to the maximum dose tested in the ongoing phase II studies 1346-0023
[c03632269-05], 1346.9 [c03559983-03] and is considered adequate for the objectives of the
current trial. 
Using the microtracer approach to investigate the absolute bioavailability the intravenously 
administered dose is not expected to significantly add to the systemic drug concentrations 
arising from the oral administration [R17-1799].The oral dose (25 mg BI 425809) is more 
than 800 fold higher than the intravenously infused dose (0.03 mg BI 425809 (C-14)). 
Therefore the exposure of BI 425809 (C-14) originating from the infused microtracer is 
considered negligible (see Section 1.4).
4.1.3
Method of assigning subjects to treatment groups
This is an open-label, phase I, single-dose study. All subjects receive the same treatment. 
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 non-randomised, open-label, single period, single arm trial. All subjects will 
receive the same treatment. 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
Dosage
Total dose of
BI 425809
T (Test)
BI 425809
Tablet
25 mg
1 tablet as single dose on d1
25 mg
R (Reference)
BI 425809 (C-14)
i.v. solution
3 µg /mL
i.v. infusion of 10 ml over 15 min on d1
0.03 mg
The oral medication (Treatment T) will be administered as a single oral dose together with 
about 240 mL of water to a subject in the sitting/standing position under supervision of the 
investigating physician or an authorised designee. 
After drug administration until the start of the intravenous infusion of BI 425809 (C-14), 
subjects are not allowed to lie down (i.e. no declination of the upper body of more than 45 
degrees from upright posture).
The microtracer (Treatment R) will be administered as a constant intravenous infusion over 
15 min to a subject in the semi supine position under supervision of the investigating 
physician or an authorised designee. Start and end time of the infusion will be recorded. For 

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the microtracer intravenous an indwelling catheter is placed into an arm vein of the subject 
and will be kept patent with a saline infusion. A second indwelling catheter used for 
collection of blood samples will be placed on the contralateral arm.
The so-called four-eye principle (two-person rule) should be applied for administration of 
trial medication and – if applicable – its preparation (e.g. reconstitution), if correct dosage 
cannot be ensured otherwise. Administration will be performed following an overnight fast 
starting no later than 10 h before scheduled dosing. 
Subjects will be kept under close medical surveillance until 24 h following drug 
administration. The in-house stay can be extended in case considered medically necessary by 
the investigator.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the Local Drug Law as well as 
Annex 13/EU GMP Guideline will be provided on the containers.
Radiolabelled drug product manufacturing is done by 
 The final container used for 
administration of the radiolabelled drug product will be a syringe for intravenous infusions 
and will be labelled according to GMP Annex 13 / EU GMP Guideline and local drug law.
BI 425809 tablets are provided in blisters within the clinical trial supply containers and will 
be labelled according to GMP Annex 13 / EU GMP Guideline and local drug law.
The EudraCT number is indicated on the title page of this protocol as well as on the subject 
information and informed consent forms. Examples of the labels will be available in the ISF.
No re-supply is planned.

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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 manager (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
 pharmacy will receive Trial product 1 (25 mg tablet of BI 425809) delivered from the 
sponsor once the below mentioned requirements are fulfilled. 
 pharmacy will deliver 
trial product 1 and 2 to the investigator upon availability of a valid prescription from the 
investigator. The investigator will also not order the investigational drugs from the 
 
pharmacy before these requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of a signed and dated clinical trial protocol

Availability of licence for clinical research using radioactive isotopes
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 all unused or partially used drug supplies have been 
returned by the clinical trial subject and 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.

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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed except for paracetamol. Limited doses of 
paracetamol (up to 2 grams per day) are allowed prior to entry in the clinic and during the 
clinical stay after prescription by a 
 physician to treat aches and pains. However, in case 
of adverse events in need of treatment, a concomitant therapy will be permitted. The use of 
moderate or potent CYP3A4 inhibitors should be avoided. All concomitant or rescue 
therapies will be recorded (including time of intake on study days) on the appropriate pages 
of the CRF.
In the case of AEs the volunteers will be treated as necessary and if required kept under 
constant supervision at the trial centre or transferred to hospital until such time that all the 
results of the evaluations have returned to a medically acceptable level.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4,5 h after intake of BI 425809 as
tablet. On day 1 all subjects will receive the same standardized meals.
From 1 h before intake of BI 425809 as tablet until lunch, fluid intake is restricted to the 
water administered with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose 
(mandatory for all subjects). From lunch until 24 h post-dose, subjects will be advised that
total fluid intake should be within about 1000 to 3000 mL. 
On Day 1 subjects will receive a 15 minutes microtracer infusion starting at 4 h after intake 
of BI 425809 tablets (i.e., tmax for oral dose). The handling instructions will be filed in the 
ISF.
Poppy-seed containing products should not be consumed starting 2 days before first trial drug 
administration until last PK sampling of the trial.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and
chocolate) are not allowed 24 hours before first dose and at the day of in-house confinement.

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Alcoholic beverages are not allowed 48 hours before administration of the compound, before 
each admission and during the clinic period. During the ambulatory phase alcohol 
consumption is restricted to a maximum of 24 units per week.
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary
supplements and products including St. John's wort (Hypericum perforatum) are not
permitted starting 7 days before the administration of trial medication until after the last
PK sample of each study period is collected.
Smoking is not allowed during in-house confinement at the trial site.
Excessive physical activity (such as competitive sport) should be avoided starting 4 days
before the 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
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 CareScape VC150 from GE Healthcare) 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
except for the Screening safety laboratory evaluation where a 4 h fast is sufficient. For 
retests, at the discretion of the investigator or designee, overnight fasting is not required. 
The parameters that will be determined are listed in Table 5.2.3: 1 and Table 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 
Reticulocytes/Erythrocyte
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); 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 
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 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase 
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
Free T3 - Triiodothyronine
Free T4 – Thyroxine 
X
X
X
--
--
--
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

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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab 
group
BI test name [comment/abbreviation]
A
B
C
Electrolytes
Sodium
Potassium
Magnesium
Calcium
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis1 (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine haemoglobin (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine 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 Visit 2 on Day -1, 2, and 6 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (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 drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and on Day-1 prior to the 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
Alcohol
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, an alcohol test in urine will be 
performed at screening and on Day-1 prior to the 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 Table 5.2.3: 1 and Table 5.2.3: 2 will be performed at the safety 
laboratory of 
 
 The drug and alcohol screening tests will be performed using the ADVIA 
Chemistry XPT system.
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 (Mortara ELI 250 Rx) 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. 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 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 

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carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Local tolerability
Local tolerability will be assessed by the investigator on the basis of swelling, induration, 
heat, redness, pain, and other findings and reported as AE in case of clinical relevant 
findings.
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 

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
Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
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 Section 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, 

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etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
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

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
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)

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.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 425809 plasma concentrations, approx. 3 mL of blood will be taken
from an antecubital or forearm vein into a K2-EDTA (tripotassium ethylendiaminetetraacetic
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart
For quantification of [C-14] BI 425809 plasma concentrations, an additional 3 mL K2-
EDTA tube needs to be collected as 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 aliquots 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 plasma samples will be stored frozen 
and in upright position at about –20°C or below at the clinical site and at the analytical 
laboratory until analysis.
For detailed description of blood sampling, sample handling, sample preparation, sample

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storage, tube labelling and sample shipment refer to the laboratory manual.
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 concentrations
Cold BI 425809 concentrations in plasma will be determined by a validated LC-MS/MS 
(liquid chromatography tandem mass spectrometry) assay.
The analysis will be performed at:
[C-14] BI 425809 will be determined by a validated AMS (accelerator mass spectrometry) 
assay.
The analysis will be performed at:
Since this is an open study, the bioanalyst will be unblinded during sample analysis.
5.4
BIOBANKING
Not applicable.
5.5
OTHER ASSESSMENTS
Not applicable.
5.6
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 

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evaluation of safety and tolerability of an orally and intravenously administered drug, and are 
widely used in clinical trials. The pharmacokinetic parameters and measurements outlined in 
Section 5.4 are generally used assessments of drug exposure. 

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 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 on Day 1 and ± 90 min on the following days of Visit 2.
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 Section 5.2.3 to Section 5.2.5.
6.2.2
Treatment period
Each subject is expected to participate in one treatment period (Visit 2).
On Day -1 of Visit 2 study participants will be admitted to the trial site and kept under close 
medical surveillance for at least 24 h following drug administration. The 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.
If several activities, including 12-lead ECG and meal intake, are scheduled at the same time

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point in the Flow Chart, ECG should be the first and meal intake the last activity.
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.
The safety measurements performed during the treatment period are specified in Section 5.3
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 Section 5.2.2 to Section 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 primary objective of this trial is to investigate the absolute oral bioavailability of 25 mg 
BI 425809 administered as tablet (Test, T) compared to 3 µg of [C-14]-BI 425809 
administered as intravenous microtracer (mixed with 27 µg unlabelled BI 425809)
(Reference, R) on the basis of the primary and secondary pharmacokinetic endpoints, as 
listed in Section 2.1.2 and Section 2.1.3. The trial is designed to allow intra-subject 
comparisons and will be evaluated statistically by use of an appropriate linear model.
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 absolute bioavailability of 25 mg orally administered BI 425809 compared to 3 µg of 
[C-14]-BI 425809 administered as intravenous microtracer (mixed with 27 µg unlabelled BI 
425809) will be estimated by the ratios of the geometric means (test/reference) for the dose 
normalized primary PK endpoints. Additionally, their 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.
Confidence intervals and p-values will be computed, but have to be interpreted in the
perspective of the exploratory character of the study, i.e. confidence intervals are considered
as interval estimates for effects, while p-values are considered as an exploratory measure of
evidence for effects in the present data.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
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 or 
secondary and was not excluded due to a protocol violation 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 

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contributes only one PK parameter value for one period to the statistical assessment.
Descriptive and model based analyses of PK parameters will be based on the PKS.
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 for drug BI 425809 will be calculated 
according to the relevant SOP of the Sponsor [001-MCS-36-472]. 
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% of the 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 will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-

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transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: ‘subjects’ and ‘formulation’. The 
effect 'subjects ' will be considered as random, whereas ‘formulation’ will be considered as 
fixed. The model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response (dose normalized primary endpoint, see Section 7.2 )
measured on subject m receiving formulation k,
= the overall mean,
sm = the effect associated with the mth subject,
m = 1, 2, ..., n
k = the kth formulation effect (either tablet or i.v.), k = 1, 2,
ekm = the random error associated with the mth subject who received
formulation k.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Further exploratory analyses
As a sensitivity analysis, the same statistical model as stated above will be repeated for the 
primary endpoints but with subject as fixed effect instead of random effect. This result will be 
presented in the same manner as for the primary analyses. 
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ [001-MCS-36-472] and will be assessed statistically using the same 
methods as described for the primary endpoints.

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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 ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time 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 (test 
treatment) and beginning of reference treatment will be assigned to the test treatment period.   
Those between the start of infusion until the end of REP (see Section 1.2.3) will be assigned 
to the combined test/reference treatment period. Events occurring after the REP but prior to 
next intake or end of trial termination date will be assigned to ’follow-up’. These assignments 
including the corresponding time intervals will be defined in detail in the TSAP. Note that 
AEs occurring after the last per protocol contact but entered before 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), 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, differences from baseline will be evaluated.

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Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
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 [001-MCS-36-472].
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Randomization is not applicable in this open-label and single group clinical study. All
subjects will receive the same treatment. Consecutive subject numbers will be assigned via
the EDC system.
7.7
DETERMINATION OF SAMPLE SIZE
For this exploratory trial, no prospective calculations of statistical precision or power have
been made. The planned sample size of 6 evaluable subjects has been selected for practical
reasons and is judged as being adequate to get reliable results regarding the trial objectives.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC 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. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to archiving of the CTR.
The terms and conditions of the insurance coverage will be described in the ICF and stored in 
the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.

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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: 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

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

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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, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storing facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

If applicable, a fit for purpose approach will be used for assay/equipment validation 
depending on the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date 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.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.

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The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
 
, under the supervision of the Principal Investigator. Relevant documentation 
on the participating (Principal) Investigators (e.g. their curricula vitae) will be filed in the 
ISF.
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 manager (CTM), Clinical 
Research Associates, and investigators of participating trial sites
The non-labelled trial medication (intended final formulation of 25 mg BI 425809, IFF) will 
be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma GmbH & Co. KG, 
Biberach, Germany.
The radiolabelled trial medication (intravenous microtracer solution) will be provided by 
. 
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
.
The analyses of unlabelled BI 425809 concentrations in plasma will be performed at a 
suitable Contract Research Organisation (CRO) under the responsibility of the Department of 
the Department of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany.
The analyses of labelled BI 425809 via Accelerator mass spectrometry (AMS) analysis will 
be conducted at 
.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R13-4447
Lane HY, Chang YC, Liu Y, Chiu CC, Tsai GE. Sarcosine or D-serine add-
on treatment for acute exacerbation of schizophrenia: a randomized, 
double-blind, placebo-controlled study. Arch Gen Psychiatry 
2005;62:1196-1204
R13-4508
Martin-Facklam M, Patat A, Hofmann C, Boetsch C, Banken L, Biedinger 
U, Boutouyrie-Dumont B. Safety, tolerability and pharmacokinetics of 
bitopertin (RG1678), a novel glycine reuptake inhibitor after multiple doses 
in healthy volunteers. 3rd Biennial Conf of the Schizophrenia International 
Research Society (SIRS), Florence, 14 - 18 Apr 2012 (Poster). 2012
R15-0594
European Medicines Agency (EMA). ICH guideline M3(R2) on non-
clinical safety studies for the conduct of human clinical trials and marketing 
authorisation for pharmaceuticals: step 5 (December 2009, 
EMA/CPMP/ICH/286/1995). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidel
ine/2009/09/WC500002720.pdf (access date: 5 February 2015) ; London: 
European Medicines Agency (EMA); 2009.
R15-3219
International Commission on Radiological Protection (ICRP). 2007
Recommendations of the International Commission on Radiological 
Protection (users edition): abstract. 
http://www.icrp.org/publication.asp?id=ICRP%20Publication%20103%20
(Users%20Editi on) (access date: 24 June 2015) ; (ICRP Publication; 103 
(Users Edition)) International Commission on Radiological Protection 
(ICRP); 2007.
R17-1799
Lappin G. Approaches to intravenous clinical pharmacokinetics: recent 
developments with isotopic microtracers. J Clin Pharmacol 2016;56(1):11-
23.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c02155957-08
BI 425809 Investigators Brochure. 06 Jun 2018
c25192159
. Clinical trial protocol radiation burden calculation report. 
1346.16. 14 May 2018
c03632269-05
 A multi-centre, double-blind, parallel-group, randomised 
controlled study to investigate efficacy and safety of orally administered 
BI425809 during a 12-week treatment period compared to placebo in 
patients with cognitive impairment due to Alzheimer’s Disease. 1346.23.
12 Jul 2018

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07 Jan 2019
BI Trial No.: 1346-0015
c21363182-03
Trial Protocol
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c03559983-03
 A phase II randomised, double-blinded, placebo-controlled 
parallel group trial to examine the efficacy and safety of 4 oral doses of BI 
425809 once daily over 12 week treatment period in patients with 
Schizophrenia. 1346.9. 13 Dec 2017 

Boehringer Ingelheim
07 Jan 2019
BI Trial No.: 1346-0015
c21363182-03
Trial Protocol
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10.
APPENDICES
Not applicable.

Boehringer Ingelheim
07 Jan 2019
BI Trial No.: 1346-0015
c21363182-03
Trial Protocol
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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
07 Jan 2019
EudraCT number
EU number
2018-001194-24
BI Trial number
1346-0015
BI Investigational Medicinal 
Product(s)
BI 425809
Title of protocol
Investigation of pharmacokinetics and absolute oral 
bioavailability of BI 425809 administered as an oral 
dose with an intravenous microtracer dose of [C-14]-
BI 425809 in healthy male volunteers
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
Flow Chart
Description of change
240 mL fluid intake corrected from 14:15 to 14:00
Rationale for change
Inconsistency between Flow Chart and Section 
4.2.2.2 Restriction on diet and life style

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21363182
3.0
clinical-trial-protocol
Investigation of pharmacokinetics and absolute oral bioavailability of BI 425809
administered as an oral dose with an intravenous microtracer dose of [C-14]-BI
425809 in healthy male volunteers
Approval-Therapeutic Area 
07 Jan 2019 13:43 CET
Author-Clinical Trial Leader
07 Jan 2019 14:07 CET
Author-Trial Clinical
Pharmacokineticist
07 Jan 2019 14:16 CET
Author-Trial Statistician
07 Jan 2019 15:35 CET
Approval-Team Member Medicine
07 Jan 2019 23:23 CET
Verification-Paper Signature
Completion
14 Jan 2019 08:47 CET

Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21363182
3.0