Metabolism and Pharmacokinetics of BI 425809 After Administration of BI 425809 (C-14) as Oral Solution in Healthy Male Volunteers
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c11975084-02
EudraCT No.:
BI Trial No.:
2018-001192-21
1346-0016
BI Investigational
Product:
BI 425809
Title:
Metabolism and pharmacokinetics of BI 425809 after administration 
of BI 425809 XX (C-14) as oral solution in healthy male volunteers
Lay Title:
A study in healthy men to find out how BI 425809 is taken up and 
handled by the body
Clinical Phase:
I
Trial Clinical Monitor:
Phone: +
Fax:     +
Principal Investigator:
Phone:       +
Fax:        +
Status:
Final Protocol
Version and Date:
Version: 2.0 
Date: 25 Sep 2018
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© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 425809
Protocol date:
Trial number:
Revision date:
25Sep2018
29 June 2018
1346-0016
Title of trial:
Metabolism and pharmacokinetics of BI 425809 after administration of BI 425809
XX (C-14) as oral solution in healthy male volunteers
Principal Investigator: 
Trial site:
Clinical phase:
I
Objectives:
To determine the basic pharmacokinetics of BI 425809 and [14C]-radioactivity, 
including mass balance, excretion pathways and metabolism following a single oral 
dose of 25 mg BI 425809 XX (C-14) given to healthy male subjects
Methodology:
Non-randomized, open-label, single period, single arm
No. of subjects: 
total entered:
6*
each treatment:
6*
* In case a subject vomits within 8 hours after administration of trial drug on day 1 an additional subject 
may be entered and dosed in order to have 6 evaluable subjects, i.e. the actual number of subjects entered 
may increase up to 8 
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 65 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2
Test product 
BI 425809 XX (C-14) as oral solution 
dose:
25 mg (calculated as free base BI 425809)
in 12.5 mL oral solution (2 mg/mL)
corresponding to 25 mg BI 425809 XX
containing a radioactive dose of 3.7 MBq
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h 
Duration of treatment:
Single dose

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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 425809
Protocol date:
Trial number:
Revision date:
25Sep2018
29 June 2018
1346-0016
Criteria for 
pharmacokinetics:
Primary endpoints:
Mass balance recoveries of total radioactivity in urine and faeces:
Amount of radioactivity excreted as a percentage of the administered dose (fe0-t2) for 
urine and faeces
Secondary endpoints:
Assessment of the oral pharmacokinetics of a solution formulation of BI 425809 XX
(C-14) by calculation of the following parameters for total radioactivity and 
BI 425809 in plasma: Cmax and AUC0-tz
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, safety laboratory tests, 12-lead electrocardiogram (ECG), vital signs 
(blood pressure [BP], pulse rate [PR]) 
Statistical methods:
Descriptive statistics and graphical displays.

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FLOW CHART
Visit
Day
Planned time (relative to 1st 
drug administration
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PKblood/plasma
2
PKurine
6
PKfaeces
7
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy9
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)15
1
-2:00
06:00
x3
x3
x3
x14
x3
x3
x3
0:00
08:00
Drug administration 
┬
┬
0:30
08:30
x
│
│
0:45
08:45
x
│
│
1:00
09:00
x
│
│
1:30
09:30
x
│
│
2:00
10:00
240 mL fluid intake
x
│
│
4:00
12:00
240 mL fluid intake, thereafter lunch4
x8
x
┼
│
x
x
x
6:00
14:00
x
│
│
8:00
16:00
Snack (voluntary)4
x
┼
│
11:00
19:00
Dinner
│
│
12:00
20:00
x
┼
│
x
x
x
13:30
21:30
Snack (voluntary)
│
│
2
24:00
08:00
x
┼
┼
x
x
36:00
20:00
x
│
│
3
48:00
08:00
x8
x
┼
┼
x
4
72:00
08:00
x
┼
┼
x
5
96:00
08:00
x
┼
┼
x
6
120:00
08:00
x
┼
┼
x
7
144:00
08:00
x
┼
┼
x
8
168:00
08:00
x8
x
┼
┼
x
9
192:00
08:00
x
┼
┼
x
10
216:00
08:00
x
┼
┼
x
11
240:00
08:00
x
┼
┼
x
12
264:00
08:00
x
┼
┼
x
13
288:00
08:00
x
┼
┼
x
14
312:00
08:00
x
┼
┼
x
15
336:00
08:00
Discharge from trial centre
x
x
┴
┴
x
x
x
20
461:00
13:00
Start home collection 
┬
21
485:00
13:00
Admission to trial site11,12
x
┬
┼
x
22
509:00
13:00
Discharge from trial site11
┴
┴
x
27
629:00
13:00
Start home collection 
┬
28
653:00
13:00
Admission to trial site11,12
x
┬
┼
x
29
677:00
13:00
Discharge from trial site11
┴
┴
x
34
797:00
13:00
Start home collection 
┬
35
821:00
13:00
Admission to trial site11,12
x
x
┬
┼
x
36
845:00
13:00
Discharge from trial site11
┴
┴
x

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Visit
Day
Planned time (relative to 1st 
drug administration
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PKblood/plasma
2
PKurine
6
PKfaeces
7
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy9
2
41
965:00
13:00
Start home collection 
┬
42
989:00
13:00
Admission to trial site11,12
x
┬
┼
x
43
1013:00
13:00
Discharge from trial site11
┴
┴
x
48
1133:00
13:00
Start home collection 
┬
49
1157:00
13:00
Admission to trial site11,12
x
┬
┼
x
50
1181:00
13:00
Discharge from trial site11
┴
┴
x
3
15-50 
End of trial (EOT) examination10,13
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening procedures 
include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 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.    Pharmacokinetics (PK): BI 425809 and metabolites in plasma; [14C]-radioactivity in whole blood and plasma (see Section 5.5.2.1).
       Blood sampling for an individual subject can be stopped if [14C]-radioactivity in plasma is below limit of detection
      (< LLOQ 10 dpm/mL) at two consecutive sampling time points for this subject (earliest stop on day 15).
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.
Safety lab including urine drug screening and alcohol test.
6.    Urine collection intervals (for PK/[14C]-radioactivity assessment and metabolic profiling; planned  time): on Day -1 or Day 1 predose 
(blank) sample within 2 h before drug administration, on Day 1 prior to start of urine collection voiding of the bladder, 0-4 , 4-8, 8-12, 
12-24; 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264, 264-288, 288-312 and 312-336 hours 
after drug administration. Thereafter, if warranted, 24 h collections are to be performed every 7 days starting on day 21.When the 
release criteria for radioactivity recovery have been met then urine sampling for PK will be stopped (earliest stop on day 15).
7.   All stools (for PK and metabolic profiling) will be collected quantitatively in portions up to 336 hours (sampling intervals of 0-24, 24-
48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264, 264-288, 288-312 and 312-336 hours) after drug 
administration. Thereafter, if warranted, 24 h collections are to be performed every 7 days starting on day 20. A blank sample will be 
collected before drug administration on Day -1 or Day 1. Collection of the predose faeces sample will start from approximately -48 h 
before admission (see Section 5.5.2.3). When the release criteria for radioactivity recovery have been met then faeces sampling for PK 
will be stopped (earliest stop on day 15).
8.    Only measurement of haematocrit
9.    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.
10. End-of-trial (EOT) examination to be performed within 1 to 7 days after last discharge from the study centre, or, if all once-weekly 24 h 
sampling periods are needed, prior to discharge on Day 50. End of trial examination includes physical examination, vital signs, ECG, 
safety laboratory, recording of AEs and concomitant therapies. 
11. The planned times for admission, discharge, start and end of the urine and faeces collection intervals are approximate. The procedures 
are to be performed within a time window of +/- 4 h to the planned time.
12. Subjects are to collect faeces at home within 24 h intervals before admission to once-weekly in-house collection intervals. Home 
collection intervals: Day 20-21, 27-28, 34-35, 41-42, and 48-49. If faeces are collected in the subsequent in-house collection interval, 
faeces collected at home will be discarded. If no faeces is collected in the subsequent in-house collection interval (no defecation), faeces 
collected at home will be used instead for analysis.
13.  For definition of the individual subject’s end of trial see Section 6.2.3
14.  Subjects will collect a predose faeces sample at home in specific containers provided by 
15. To be consumed within 30 min to allow 10h fast prior drug administration

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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
1.2.3
Residual Effect Period..........................................................................15
1.2.4
Clinical experience in humans.............................................................15
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 17
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................17
2.2
TRIAL OBJECTIVES.......................................................................................17
2.3
BENEFIT - RISK ASSESSMENT ...................................................................18
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 21
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................21
3.1.1
Administrative structure of the trial...................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................23
3.3
SELECTION OF TRIAL POPULATION ......................................................23
3.3.1
Main diagnosis for study entry............................................................23
3.3.2
Inclusion criteria...................................................................................23
3.3.3
Exclusion criteria ..................................................................................24
3.3.4
Removal of subjects from therapy or assessments.............................25
3.3.4.1
Removal of individual subjects................................................25
3.3.4.2
Discontinuation of the trial by the sponsor..............................26
3.3.5
Replacement of subjects .......................................................................27
4.
TREATMENTS........................................................................................ 28
4.1
TREATMENTS TO BE ADMINISTERED....................................................28
4.1.1
Identity of BI investigational product.................................................28
4.1.2
Method of assigning subjects to treatment groups ............................28
4.1.3
Selection of doses in the trial................................................................29
4.1.4
Drug assignment and administration of doses for each subject .......29
4.1.5
Blinding and procedures for unblinding ............................................29

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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.
VARIABLES AND THEIR ASSESSMENT ......................................... 33
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................33
5.1.1
Endpoints of efficacy.............................................................................33
5.1.2
Assessment of efficacy...........................................................................33
5.2
SAFETY..............................................................................................................33
5.2.1
Endpoints of safety................................................................................33
5.2.2
Assessment of adverse events...............................................................33
5.2.2.1
Definitions of adverse events...................................................33
5.2.2.2
Adverse event collection and reporting ...................................36
5.2.3
Assessment of safety laboratory parameters......................................37
5.2.4
Electrocardiogram................................................................................40
5.2.5
Assessment of other safety parameters...............................................40
5.2.5.1
Vital signs ................................................................................40
5.2.5.2
Medical examinations..............................................................40
5.3
OTHER...............................................................................................................40
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................40
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................41
5.5.1
Pharmacokinetic endpoints..................................................................41
5.5.1.1
Primary endpoints....................................................................41
5.5.1.2
Secondary endpoints................................................................41
5.5.2
Methods of sample collection...............................................................44
5.5.2.1
Sampling of whole blood and plasma......................................44
5.5.2.2
Sampling of whole blood and plasma for [14C]-radioactivity 
analysis in whole blood and plasma and quantification of 
BI 425809 and its metabolites in plasma.................................44
5.5.2.5
Urine sampling.........................................................................45
5.5.2.6
Faeces sampling.......................................................................45
5.5.2.7
Collection of vomit ..................................................................46

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5.5.3
Analytical determinations ....................................................................46
5.5.3.1
Analytical determination of BI 425809 and its metabolites 
plasma and urine concentrations..............................................46
5.5.3.3
Radiokinetic and Excretion Balance........................................47
5.6
BIOMARKER....................................................................................................47
5.7
PHARMACODYNAMICS................................................................................47
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....47
6.
INVESTIGATIONAL PLAN.................................................................. 48
6.1
VISIT SCHEDULE............................................................................................48
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................48
6.2.1
Screening period....................................................................................48
6.2.2
Treatment period ..................................................................................48
6.2.3
End of trial period.................................................................................49
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 50
7.1
STATISTICAL DESIGN – MODEL ...............................................................50
7.1.1
Objectives...............................................................................................50
7.1.2
Endpoints...............................................................................................50
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................50
7.3
PLANNED ANALYSES....................................................................................50
7.3.1
Primary analyses...................................................................................51
7.3.2
Secondary analyses ...............................................................................51
7.3.3
Safety analyses.......................................................................................51
7.3.4
Interim analyses ....................................................................................52
7.3.5
Pharmacokinetic analyses ....................................................................52
7.4
HANDLING OF MISSING DATA ..................................................................53
7.4.1
Safety......................................................................................................53
7.4.2
Blood/Plasma/urine/faeces drug concentration - time profiles.........53
7.4.3
Pharmacokinetic parameters...............................................................53
7.5
RANDOMISATION ..........................................................................................53
7.6
DETERMINATION OF SAMPLE SIZE ........................................................53
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 54
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................54
8.2
DATA QUALITY ASSURANCE .....................................................................54
8.3
RECORDS..........................................................................................................55
8.3.1
Source documents .................................................................................55
8.3.2
Direct access to source data and documents.......................................55

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8.3.3
Storage period of records.....................................................................55
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................55
8.5
STATEMENT OF CONFIDENTIALITY.......................................................55
8.6
COMPLETION OF TRIAL..............................................................................56
9.
REFERENCES......................................................................................... 57
9.1
PUBLISHED REFERENCES...........................................................................57
9.2
UNPUBLISHED REFERENCES.....................................................................57
10. APPENDICES .......................................................................................... 58
10.1
RADIO BURDEN CALCULATION ...............................................................58
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 61

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ABBREVIATIONS
AD
Alzheimer’s disease
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine amino transferase
AST
Aspartate amino transferase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CIAS
Cognitive impairment associated with schizophrenia
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CLR, t1-t2
Renal clearance of the analyte from the time point t1 to t2
CML
Clinical Monitor Local
CNS
Central nervous system
CRA
Clinical Research Associate
CRO
Clinical Research Organization
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
ENTS
Entered set
EOT
End of trial

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EU
European Union
FDA
Food and Drug Administration
fefaeces, 0-t2
Fraction excreted in faeces as percentage of the administered dose over the 
time interval from 0 to the last quantifiable time point
feurine, 0-t2
Fraction excreted in urine as percentage of the administered dose over the 
time interval from 0 to the last quantifiable time point
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GLYT1
Glycine transporter 1
gMean
Geometric mean
GMP
Good Manufacturing Practice
HR
Heart rate
IB
Investigator’s brochure
ICH
International Conference of Harmonization
ICRP
International Commission on Radiological Protection
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
IPV
Important protocol violation
z
Terminal rate constant of the analyte in plasma
LLOQ
Lower limit of quantification
LC-MS/MS
Liquid chromatography tandem mass spectrometry
MBq
MegaBequerel
MedDRA
Medical Dictionary for Regulatory Activities
MRTpo
Mean residence time of the analyte in the body after oral administration
NMDA
N-methyl-D-aspartate
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram

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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
Summary of Product Characteristics
SRD
Single-rising dose
SUSAR
Suspected Unexpected Serious Adverse Reaction
TMF
Trial master file
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TDMAP
Trial Data Management and Analysis Plan
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VAS
Visual Analog Scale

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1.
INTRODUCTION
BI 425809 is a glycine transporter 1 (GlyT1) inhibitor in development 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
BI 425809 is a potent and selective inhibitor of GlyT1 and does not show species selectivity 
regarding inhibition of human, rat and pig GlyT1. In vivo proof-of-mechanism (i.e. target 
engagement in brain) is demonstrated by a dose dependent increase of glycine in rat 
cerebrospinal fluid. Results from pre-clinical studies with BI 425809 have demonstrated pro-
cognitive properties in relevant animal models of learning and memory impairment. 
Therefore it is expected that treatment with BI 425809 has the potential to improve cognitive 
functioning in patients with AD and CIAS.
BI 425809 has been administered to healthy volunteers in so far 7 Phase 1 trials and 2 Phase 
2 trials in patients are currently ongoing.  In addition, BI 425809 is not a first in class 
compound. Other GLYT1 inhibitors (e.g. Bitopertin and sarcosine) have been tested in 
clinical trials before [R13-4447], [R13-4508].

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1.2.3
Residual Effect Period
The Residual Effect Period (REP) of BI 425809 is 11 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
1.2.4
Clinical experience in humans
At the time of preparation of this clinical trial protocol, BI 425809 has been investigated in 
seven Phase 1 trials. Two Phase 2 trials (1346-0009 and 1346-0023) have been re-initiated 
recently and are ongoing.
A total of 245 healthy subjects have received one or more doses of BI 425809 (single doses 
of 0.5 mg to 150 mg and multiple doses of 5 mg to 75 mg bid (150 mg/day)), including 18 
subjects aged 65 years or older (for details please refer to Investigator’s Brochure
[c02155957-08], Table 6.1:1).
Altogether, BI 425809 was generally well tolerated in young and elderly healthy male and 
female volunteers. No deaths or serious adverse events (SAEs) and no AEs of special interest 
(AESI) were reported. Across all BI 425809 treatment groups, there were 3 subjects with 
severe, but self-limiting AEs. Overall, drug-related AEs have been seen more frequently in 
the subjects treated with BI 425809 (33.5% vs 26.9% on placebo). Across all BI 425809 
treatment groups, 3 subjects discontinued treatment due to an AE (2x nausea and vomiting, 
1x procedural headache), all subjects recovered (for details please refer to
Investigator’s Brochure [c02155957-08], Table 6.3.1.1:3). 
The most frequent AEs for BI 425809 were nervous system disorders (25.3%), with headache 
being the most common (18.0%). These AEs appear to be dose-related, with a tendency for 
greater frequency at higher doses and can be clinically monitored.
In addition, transient visual disturbances (at doses ≥ 25 mg BI 425809 qd, mainly blurred 
vision) and somnolence (drowsiness) were observed. These effects are mostly mild to 
moderate and transient.
In general, there were no clinically relevant findings in the clinical laboratory evaluation, 12-
lead ECG, vital signs. No suicidal ideation or behaviour was observed. No notable decrease
in haemoglobin or haematocrit was noted in the BI 425809 treatment groups compared with
placebo.
For a more detailed list of observed AEs and safety measures please refer to the current 
Investigator’s Brochure, section 6 [c02155957-08].

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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This trial is intended to examine the metabolism in humans, the mass-balance of excretion, 
plasma and urinary concentrations of BI 425809 and its metabolites (as appropriate), the 
resulting PK parameters, and [14C]-radioactivity in blood, plasma, urine and faeces after a 
single oral dose of  25 mg BI 425809 XX (C-14). Major tasks involve metabolite profiling 
and structure elucidation. This study will also help to determine the metabolic pathways 
following oral administration of BI 425809 XX (C-14) in healthy volunteers.
The data are necessary for in-depth understanding of the pharmacokinetics of BI 425809 
including quantitative determination of elimination pathways and drug metabolites and are 
required for submission to regulatory authorities.
2.2
TRIAL OBJECTIVES
This trial intends to investigate the basic pharmacokinetics of BI 425809 and [14C]-
radioactivity, including mass balance, excretion pathways and metabolism following a single 
oral dose of 25 mg BI 425809 XX (C-14) given to healthy male subjects
The primary objective is:

To assess the mass balance recovery of [14C]-radioactivity from urine and faeces after 
a single oral dose of 25 mg BI 425809 XX (C-14) given to healthy male subjects
The secondary objective is:

To assess Cmax and AUC0-tz for total [14C]-radioactivity and BI 425809 in plasma

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A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
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 and the intake of BI 425809 XX (C-14).
Procedure-related risks
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.
The use of an indwelling venous catheter for the purpose of blood sampling 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.
Drug-related risks and safety measures
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also Section 5.2.2.1, adverse events of special interest.
Risks related to BI 425809 administration
The currently available data from 7 phase I trials in healthy young and elderly subjects with 
single oral administration of up to 150 mg BI 425809 and multiple doses of up to 75 mg BI 
425809 twice daily (150 mg/d) indicate that BI 425809 has a broad safety margin and is 
generally well tolerated. The most frequent AEs were adverse CNS symptoms, most 
commonly headaches but also somnolence (drowsiness) that showed a trend for dose 
dependency, were reversible and can be clinically monitored. In addition, BI 425809 may be 

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associated with visual disturbances. 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 (BI 758790)
The major human metabolites of BI 425809, M530 (BI 758790) and M232 (BI 761036), 
have been evaluated in nonclinical studies with no evidence of pharmacological activity, 
genotoxicity, effects on embryo-foetal development, or adverse effects in repeat-dose toxicity 
in studies of 13 – 15 weeks duration.
Furthermore, multiple doses of up to 75 mg twice daily (150 mg/d) were well tolerated in 
previous clinical trials. Based on this human data there is no indication of a metabolite-
mediated safety concern for a single dose administration of 25 mg BI 425809 in the present 
trial.
Risks related to administration of BI 425809XX (C-14)
BI 425809 XX (C-14) is labelled with the isotope [14C] which is necessary for the purposes of 
this mass balance trial. Therefore, subjects will be exposed to ionizing radiation. The 
effective dose that each subject receives from one administration of 3.7 MBq is approx. 0.41
mSv. 
The radioactive dose proposed for administration in the planned human ADME study, 0.41 
mSv, is lower than the limit specified by:
WHO Category 1, (<0.5mSv – within variations of natural background radioactivity)
And lower than the limit proposed by:
ICRP Category 2a, (<1 mSv – risk defined as minor)
For details on the radiation burden calculation please refer to Appendix 10.1.
For clinical investigations to study the disposition, metabolism and excretion of new 
pharmaceutical compounds in man an effective dose of 0.1 – 1.0 mSv is considered 
acceptable [R15-3219].
Summary of benefit-risk assessment
In previous trials in healthy subjects, administration of single oral doses up to 150 mg BI 
425809 and multiple oral doses up to 75 mg BI 425809 once or twice daily was safe and well 
tolerated (Section 1.2.4). In the current trial, healthy male volunteers will receive a single oral 
dose of 25 mg BI 425809. Each participating subject will receive only one radioactive dose.
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 for subjects receiving medication to experience 

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adverse events (AEs), and rarely also serious adverse events (SAEs). 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 risk associated with the expected maximal radiation burden falls in ICRP category 2a 
with minor level risk and in WHO Category 1, i.e. within variations of natural background 
radioactivity. This is considered to be acceptable.
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 this trial.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial will be performed as a non-randomized, open-label, single period, single arm trial
in healthy male volunteers to investigate the basic pharmacokinetics of BI 425809 and [14C]-
radioactivity, including mass balance, excretion pathways and metabolism following a single 
oral dose of  25 mg BI 425809 XX (C-14). 
The planned radioactive dose per subject is 3.7 MBq (0.41 mSv). This is equivalent to 0.111 
mSv/MBq (reference: Appendix 10.1).
On Day 1, subjects will receive the [14C]-labelled drug substance, i.e. 25 mg BI 425809 XX 
(C-14) and will then stay in the study centre up to the morning of Day 15 for collection of 
samples of blood, urine, and faeces. Subjects will be readmitted to the study centre for 24 h 
collection intervals of urine and faeces on Days 21, 28, 35, 42, and 49, if release criteria as 
specified below have not been met on Day 15. Within 24 h before each of these once-weekly 
in-house collection intervals, subjects are to collect faeces at home. This 24 h interval home 
collection faeces will be used for analysis in case no defecation occurs in the subsequent 24 h 
in-house collection interval. Otherwise it will be discarded.
For determination of whether release criteria have been reached for individual subjects, 
[14C]-radioactivity will be measured in excreta (urine and faeces). The actual recovery results 
will be reported as a percentage of the administered dose. 
If one of the following release criteria is true (i.e., release criteria have been met), 
24 h collection intervals after Day 15 will not be performed / will be stopped:
-
Greater than or equal to 90% of the administered dose has been recovered in urine and 
faeces combined over the investigational period, or
-
If <1% of the dose administered has been collected in urine and faeces within 2 
separate, consecutive 24 h intervals, and
-
Concentration of total radioactivity in plasma and in blood <5% of Cmax of total 
radioactivity in plasma
If a subject is unable to attend one of these visits, they may be allowed to reschedule the visit 
if needed.
Irrespective of whether release criteria have been met or not after collection interval Day 
49-50, no further collections are planned.
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.

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3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to

Manage the trial in accordance with applicable regulations and internal SOPs,

Direct the clinical trial team in the preparation, conduct, and reporting of the trial,

Ensure appropriate training and information of local clinical monitors (CML), 
Clinical Research Associates (CRAs), and participating trial sites.
The radiolabelled trial medication (BI 425809 XX (C-14)) will be provided by
The trial will be conducted at
 under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
The analyses of BI 425809 (and its metabolites) concentrations in plasma, the metabolite 
profiling and the identification in urine, plasma, and faeces will be performed at BI and/or at
a suitable Contract Research Organisation (CRO) under the responsibility of the Department 
of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, Biberach, 
Germany . 
Blood, plasma, urine, and faeces (and vomit if applicable) concentrations of [14C]-
radioactivity will be determined at
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be performed by BI according to BI SOPs 
and/or by a suitable CRO under the responsibility of the Department of Biostatistics and Data 
Sciences, BI Pharma GmbH & Co. KG, Biberach, Germany.
Tasks and functions assigned in order to organize, 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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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This is a standard study design for a [14C] human study of absorption, metabolism, and 
excretion including determination of mass balance.
Inclusion of a control group is not required for this investigation. Due to the prolonged half-
life of the metabolite BI 761036 (M232) (~170h), that contains the radioactive [14C] label, it 
cannot be excluded that prolonged sampling is necessary in humans. Therefore, following 14 
days in-house excreta collection after dosing, subjects will return on a weekly basis for in-
house 24-h collection intervals for up to 7 weeks after dosing as long as release criteria are 
not met (Section 3.1).
Blinding is not necessary, because all subjects receive the same treatment.
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. In case a subject vomits 
within 8 h after trial drug administration assuming an incomplete absorption of the 
radiolabelled compound an additional subject may be entered and dosed to assure that 6 
evaluable subjects will complete the study as per protocol. Thereby, the actual number of 
subjects entered may increase up to 8.
The current trial is designed to investigate the basic pharmacokinetics of BI 425809 including 
absorption, metabolism, and elimination and quantitative determination of excretion by mass 
balance. Samples will be generated for additional metabolic profiling and structural 
identification. 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. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the investigator’s assessment, 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.)

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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 
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

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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 cigars or 1 pipes per day)
14. Inability to refrain from smoking on 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
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 
In addition, the following trial-specific exclusion criteria apply:
23. Participation in another ADME study with a radiation burden of >0.1 mSv in the 
period of 1 year prior to screening or 1.1-2.0 mSv in the past 2 years or 2.1-3.0 mSv 
in the past 3 years etc.
24. Exposure to radiation for diagnostic reasons (except dental X-rays and plain X-rays of
thorax and bony skeleton (excluding spinal column)) in the period of 1 year prior to 
screening
25. Irregular defecation pattern (less than a mean of one bowel movement every day)
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:

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1. The subject withdraws consent for trial treatment or trial participation, without the 
need to justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events, or diseases)
4. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with 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 remove individual subjects at any time 
based on his or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database 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 CRFs. 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 ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more 
than 50% of the subjects show drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least one drug-related serious adverse 
event.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP, or the contract with BI by a trial site or 
investigator, disturbing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).

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3.3.5
Replacement of subjects
In case a subject vomits within 8 h after trial drug administration assuming an incomplete 
absorption of the radiolabelled compound an additional subject may be entered and dosed to 
assure that 6 evaluable subjects will complete the study as per protocol. 
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. Replacement of subjects and dosing of additional subjects as described above
should always be done in mutual agreement with the principal investigator. A replacement 
subject will be assigned a unique study subject number, and will be assigned to the same 
treatment as the subject he replaces.

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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
BI 425809 XX is a neutral molecule exhibiting no ionizing centre. Therefore 25 mg BI 
425809 equals to 25 mg BI 425809 XX.
Radiolabelled BI 425809 is administered as oral solution of BI 425809 (C-14). The oral 
solution contains a mixture of [C-14] BI425809 XX and unlabelled BI 425809 XX and is 
manufactured by BI Pharma GmbH & Co. KG. The solution from this mixture is made by 
4.1.1
Identity of BI investigational product
The characteristics of the test product are given below:
Name:
BI 425809 XX (C-14) oral solution 2 mg/mL (12.5 mL; 
3.7MBq)
Substance:
BI 425809 XX mixed with [C-14] BI425809 XX 
Pharmaceutical formulation: Oral Solution
Source:
Unit strength:
25 mg BI 425809 calculated as free base
-
Corresponding to 25 mg BI 425809 XX 
-
Containing [C-14] BI 425809 XX corresponding to a 
radioactive dose of 3.7 MBq (0.41mSv) 
-
In a solution of 12.5 mL volume
(concentration of BI 425809: 2 mg/mL, dissolved in 12.5 mL 
PEG (polyethylene glycol 400) as solvent) 
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
Single dose
4.1.2
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 randomization procedure is described in Section 7.5.

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4.1.3
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). A dose 
of 25 mg corresponds to the maximum dose tested in the ongoing phase II studies 1346-0023
[c03632269-04], 1346.9 [c03559983-03]. A dose of 25 mg is considered adequate for the
objectives of the current trial. 
This dose administered as oral solution will include 3.7 MBq of BI 425809 XX (C-14). The 
radiolabelled dose of 3.7 MBq is required for the objectives of the study providing good 
detection limits for measurement of radioactivity in urine, faeces and plasma. The total 
effective dose (radiation burden) amounts to 0.41 mSv. This is below the limit of ICRP 
Category 2a and considered acceptable. Radiation burden calculations are presented in 
Appendix 10.1. For risk-benefit assessment, see Section 2.3.
4.1.4
Drug assignment and administration of doses for each subject
In the morning of Day 1, following an overnight fast of at least 10 h, all subjects will receive 
one single oral dose of the radiolabelled trial drug (BI 425809 XX (C-14) oral solution 2 
mg/mL (12.5 mL; 3.7 MBq)). 
The radiolabelled medication will be administered as a single oral dose together with 240 ml 
of water to a subject in the sitting position under supervision of the investigator or an 
authorised designee. The amount of administered radiolabelled medication will be calculated 
based on pre- and postdose weight of the syringe used for oral administration.
The so-called four-eye principle (two-person rule) should be applied for administration of 
trial medication. 
During the first 4 h after drug administration, subjects are not allowed to lie down (i.e., no 
declination of the upper body of more than 45 degrees from upright posture) except for 
medical examinations or if necessary for any medical reasons (e.g., adverse events). For 
restrictions with regard to diet and fluid intake see Section 4.2.2.2.
After drug administration subjects will be kept under close medical surveillance until planned 
discharge from the unit on Day 15. In case release criteria for radioactivity recovery have not 
been met on Day 15, subjects will come back to the unit for once-weekly 24 h sampling 
periods until discharge criteria are met or after the last collection interval day 49-50 was 
completed (see Section 3.1).
4.1.5
Blinding and procedures for unblinding
This is an open-label study.
4.1.6
Packaging, labelling, and re-supply
Drug product manufacturing is done by 
. The clinical trial supply consists of containers 
holding the trial medication which are labelled with trial identification. The final container 

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will be an oral syringe holding the Investigational Drug Products and will be labelled 
according to GMP Annex 13 / EU GMP Guideline and local drug law. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where 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 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
 pharmacy will deliver the investigational drugs to the investigator upon availability of a 
valid prescription from the investigator.
The investigator will not order the drugs from the 
 pharmacy before the following 
requirements are fulfilled:

Approval of the study protocol by the IRB / ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre

Approval/notification of the regulatory authority, e.g. competent authority

Availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol 

Availability of licence for clinical research using radioactive isotopes
Only authorised personnel as documented in the form ‘Site Delegation Log’ may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused trial medication must be returned to the sponsor or disposed 
locally by the trial site upon written authorisation by the clinical monitor. Appropriate 
retention samples will be kept at 
 until finalization of the clinical trial report. Receipt, 
usage and return or disposal must be documented on the respective forms. Account must be 
given for any discrepancies.
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the return to the sponsor or alternative 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 products and trial subjects. The 
investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the CTP, and that reconcile all investigational products received from 
the sponsor. At the time of disposal or return to the sponsor (and/or) appointed CRO, the 
investigator must verify that no remaining supplies are in the investigator’s possession

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4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no specific rescue drugs foreseen for the treatment of AEs. No special emergency 
procedures are to be followed. No additional treatment is planned. However, in case of 
adverse events in need of treatment, the investigator can authorize 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 medical evaluation results have returned to an 
acceptable level.
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.
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. Standardized meals will be served at the time points 
described in the Flow Chart. On Day 1 no food is allowed for at least 4 h after drug intake.
For fasting times before drug administration see Section 4.1.4. For fasting times before safety 
laboratory investigations see Section 5.2.3.
From 1 h before drug intake until lunch, fluid intake is restricted to the 240 ml of 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, total fluid intake should be 
within about 1000 to 3000 mL.
During the days of urine collection, subjects will be advised that total fluid intake should be 
at least 1.5 liters and should not exceed 3.5 liters.
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 at days of in-house confinement.
Alcoholic beverages are not allowed 48 hours before administration of the compound, before 
each admission and during the clinic period. During ambulatory phases alcohol consumption 
is restricted to 24 units a week.

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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 first 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 first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
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 
and urinary and faeces excretion 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.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
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)
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3).
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether 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 exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the CRF only.

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Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 

is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 

requires inpatient hospitalization  

requires prolongation of existing hospitalization,

results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect, 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization or development of dependency or 
abuse.
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.2.2, 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 
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 5.2.2.2.

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The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST (aspartate transaminase) and/or ALT(alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-
fold ULN measured in the same blood sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
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
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
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).

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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
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.

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
After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and 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.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that 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 the initial 
information.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee
for retests.
The parameters that will be determined are listed in Table5.2.3: 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
Test name 
Haematology
Haematocrit 
Haemoglobin 
Red blood cell count (RBC) 
Reticulocyte count
White blood cell count (WBC)
Platelet count  
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if automatic
differential WBC is abnormal)
Polymorphnuclear neutrophils (segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
Hormones1
Thyroid stimulating hormone (TSH)
fT3, fT4
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
C-Reactive Protein (CRP)
Uric acid1
Total cholesterol1
Triglycerides1
Electrolytes
Sodium
Potassium
Magnesium
Calcium
1
Only at screening and end of trial. 

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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
Test name 
Urinalysis1 (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine haemoglobin
Urine leukocytes
Urine pH
Urine sediment1 (microscopic
examination if haemoglobin, 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)
1
Only at screening and end of trial. 
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which 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.
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.

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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 time points given in the 
Flow Chart.
All ECGs will be recorded for a 10-sec duration after the subjects have rested for at least 5
min in a supine position. ECG assessment will always precede all other study procedures of 
the same time point (except blood drawing from an intravenous cannula which is already in 
place) to avoid impact of sampling on the 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. ECGs may be 
repeated for quality reasons (like alternating current artefacts, muscle movements, electrode 
dislocation) and the repeated ECG will be used for analysis. Additional (unscheduled) ECGs 
may be collected by the investigator for safety reasons. 
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
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.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, 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.
5.3
OTHER
5.4
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 

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administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 are
generally used assessments of drug exposure in human mass-balance trials.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the eCRFs.
5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
Primary endpoints will be the mass balance recoveries of [14C]-radioactivity in urine and 
faeces after a single oral dose of 25 mg BI 425809 XX (C-14) given to healthy male subjects:

feurine, 0-t2 (fraction of [14C]-radioactivity excreted in urine as percentage of the 
administered oral dose over the time interval from 0 to the last quantifiable time 
point)

fefaeces, 0-t2 (fraction of [14C]-radioactivity excreted in faeces as percentage of the 
administered oral dose over the time interval from 0 to the last quantifiable time 
point)
Timeframe: The timeframe for determination of these endpoints depends on discharge of 
radioactivity from each individual subject and is predicted to vary between 2-7 weeks after 
drug administration.
5.5.1.2
Secondary endpoints
The following secondary endpoints will be evaluated for [14C]-radioactivity and BI 425809 in 
plasma: 

Cmax (maximum measured concentration of the analyte)

AUC0-tz (area under the concentration-time curve of the analyte over the time interval 
from 0 to the last quantifiable time point)

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5.5.2
Methods of sample collection
5.5.2.1
Sampling of whole blood and plasma
Whole blood and plasma will be collected at time points shown in the Flow Chart:

to determine [14C]-radioactivity concentrations in whole blood and plasma

to determine concentrations of BI 425809 and its metabolites in plasma

to identify the metabolites of BI 425809 in plasma

to determine the blood cell/plasma and blood/plasma ratios of [14C]-radioactivity
5.5.2.2
Sampling of whole blood and plasma for [14C]-radioactivity analysis in whole 
blood and plasma and quantification of BI 425809 and its metabolites in plasma
Blood for pharmacokinetics and metabolite identification purposes will be taken from an 
antecubital or forearm vein into a K2-EDTA (tripotassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times indicated in the Flow Chart.
At each time point listed in the Flow Chart, 5 mL (for time points 0.5h – 240 h (inclusive)) or
8 mL (for the pre-dose sample and from time points 264 h to the last) of whole blood will be 
drawn.
It is planned that aliquots of all time points are prepared for the determination of [14C]-
radioactivity in whole blood and plasma.
Bioanalysis of BI 425809 and its metabolites in plasma are planned to be prepared as long as 
PK blood sample are collected for total radioactivity after 336 h.
Premature stopping of blood sampling
In case [14C]-radioactivity in plasma samples is not detectable (<LLOQ 10 dpm/mL) at two 
consecutive time points for a subject, blood sampling can be stopped for this subject. 
However, all samples until and including the 336 h sample for single dose have to be taken.
Laboratory manual
For detailed description of blood sampling, sample handling, sample preparation, sample 
storage, tube labelling and sample shipment refer to the laboratory manual.

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5.5.2.5
Urine sampling
Urine will be collected during the trial as indicated in the Flow Chart:
• to determine the concentration and amount of BI 425809 and its metabolites M530 
(BI 758790), M232 (BI 761036), and M312 (IN 79211) in urine
• to determine total [C-14] BI 425809 related material in urine
• to investigate the metabolic profile of BI 425809 in urine
A blank urine sample will be collected within approximately 14 hours prior to drug
administration. All urine voided will be collected in containers, according to intervals, given
in the Flow Chart. Addition of Tween 20 resulting in a final concentration of at least 0.05% 
Tween 20 is required. For urine collection, the weight of the empty containers has to be 
determined prior to and at the end of the collection interval. The urine volume (weight will be 
set equal to volume, i.e. 1 kg = 1 L, without correction for specific gravity of urine) for each 
collection interval will be documented. Volunteers will empty their bladders at the end of 
each sampling interval. The exact start and end times of the urine collection intervals will be 
recorded in the CRF.
All samples are planned to be used for determination of [14C]-radioactivity.
Samples until and including the collection interval 312-336 h are planned to be used for 
analysis of BI 425809 and its metabolites.
Samples to be used for metabolic profiling will be selected according to the levels of 
radioactivity in each urine sample.
For a detailed description of urine sampling, preparation of collection containers, sample 
storage, sample handling, labelling, and sample shipment refer to the laboratory manual.
5.5.2.6
Faeces sampling
Faeces will be collected for the analysis of [14C]-radioactivity and for metabolic profiling in 
intervals as indicated in the Flow Chart. A blank faeces sample will be collected prior to drug
administration.
All faeces samples after intake of BI 425809 XX (C-14) are planned to be used for 
determination of [14C]-radioactivity.

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Samples to be used for metabolic profiling will be selected according to the levels of 
radioactivity in each faeces sample interval.
All stools will be collected quantitatively in portions up to 336 hours after drug 
administration. The weight of the faeces and the exact times of faeces collection will be 
recorded in the eCRF. 
Laboratory Manual
For a detailed description of faeces sampling, sample preparation, sample storage, labelling, 
and sample shipment refer to the laboratory manual.
5.5.2.7
Collection of vomit
If vomiting occurs in a volunteer within 12 h after radioactive drug administration, the vomit 
will be collected for determination of weight and [14C]-radioactivity.
For a detailed description of vomit sampling, sample preparation, sample storage, labelling, 
and sample shipment refer to the laboratory manual.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 425809 and its metabolites plasma and urine 
concentrations
BI 425809 concentrations in plasma and urine will be determined by a validated LC-MS/MS
(liquid chromatography tandem mass spectrometry) assay.
The analysis will be performed at:
Since this is an open study, the bioanalyst will be unblinded during sample analysis.

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5.5.3.3
Radiokinetic and Excretion Balance
Determination of [14C]-radioactivity concentrations in plasma, whole blood, urine, and faeces 
(and vomit, if applicable) will be done by means of validated liquid scintillation counting 
methods at 
The blood, plasma, urine and faeces (and vomit, if applicable) concentrations of radioactivity 
will be determined in agreement with relevant 
 Standard Operating Procedures (SOPs).
5.6
BIOMARKER
No biomarker will be determined.
5.7
PHARMACODYNAMICS
No pharmacodynamic sampling will be performed.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.

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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 end of trial examination are given 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, 12-
lead ECG, urine/faeces collection and blood samplings 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 individual plasma concentration sampling times and urine/faeces sampling times/
collection intervals refer to the Flow Chart. While these nominal times should be adhered to
as closely as possible, the actual sampling times will be recorded and used for determination 
of pharmacokinetic parameter. If beginning or end of a urine/faeces collection interval and a 
blood sample are scheduled for the same time point, urine/faeces collection should be done 
first, with withdrawal of the blood sample as closely to the planned time point as possible.
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 give their 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 336 h following drug administration. The subjects will then 
be allowed to leave the trial site after formal assessment and confirmation of their fitness. In 
case release criteria have not been met on the Day 15 (Section 3.1), subjects will return to the
trial site for up to 5 weekly 24-h collection intervals of urine and faeces until release criteria 

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have been reached. For these additional 24-h collection intervals, subjects will be admitted to 
the trial site as indicated in the Flow Chart and discharged after formal assessment and
confirmation of their fitness. 
Within 24 h before each once-weekly in-house collection interval, subjects are to collect 
faeces at home (beginning of home collections on Days 20, 27, 34, 41, and 48). Faeces 
collected in these 24-h home-collection intervals will be used for analysis in case no 
defecation occurs in the subsequent 24-h in-house collection interval. E.g., if no defecation 
occurs in in-house collection interval Day 21-22, faeces of home-collection interval Day 20-
21 will be used for analysis. If however faeces are collected in the subsequent 24-h in-house 
collection interval, faeces collected at home will be discarded. E.g., if defecation occurs in in-
house collection interval Day 21-22, faeces of home-collection interval Day 20-21 will be 
discarded. Once release criteria are reached, home collections will be stopped.
Irrespective of whether release criteria have been met or not after collection interval day 
49-50, no further collections are planned.
For details on time points and procedures for collection of blood, plasma, faeces and urine 
samples for PK analysis and mass balance assessment, refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for 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
End of trial period
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial 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 end of trial visit.
All abnormal values (including laboratory parameters) that are judged 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 subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
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.

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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to examine the metabolism in humans, the mass-balance 
of excretion, plasma and urinary concentrations of BI 425809 and its metabolites (as 
appropriate), the resulting PK parameters, and [14C]-radioactivity in blood, plasma, urine and 
faeces after a single oral dose of  25 mg BI 425809 XX (C-14). The assessment of safety and 
tolerability will be an additional main objective of this trial, and will be evaluated by 
descriptive statistics.
7.1.2
Endpoints
The basic pharmacokinetics of BI 425809, its metabolites, and [14C]-radioactivity, including 
mass balance, excretion pathways and metabolism is to be determined on the basis of the 
primary and secondary pharmacokinetic endpoints (see Section 5.5.1).
Safety and tolerability will be determined on the basis of the 
parameters specified in Section 5.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No confirmatory analysis will be conducted for this study. Data will be reported with
descriptive statistics only.
7.3
PLANNED ANALYSES
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited
concomitant medication, completeness and consistency of data) will be checked. Important
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and
provided in the TSAP.
Plasma/urine/faeces concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol violation 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 violations 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.

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Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if
for example:

A pre-dose concentration is >5% of the Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve.
The following analysis sets will be defined for this trial:

Treated set (TS)
This subject set includes all subjects from the ENTS who were documented to have
received at least one dose of study drug

Pharmacokinetic set (PKS)
This subject set includes all subjects in the TS who provide at least one primary or 
secondary PK parameter that was not excluded according to the description above. 
Thus, a subject will be included in the PKS, even if he/she contributes only one PK 
parameter value to the statistical assessment.
7.3.1
Primary analyses
Analysis of the primary endpoints (refer to Section 5.5.1.1) is described in Section 7.3.5.
7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI SOP
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ [001-MCS-36-472] and will statistically be assessed using the same 
methods as described for the primary endpoints.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is,
all subjects who received at least one dose of study drug), will be included in the safety
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Tabulations of frequencies/proportions will be used for the evaluation of 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 
the treatment (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 'screening', those between first trial medication intake until
end of the residual effect period (REP) (see Section 1.2) will be assigned to the treatment
period, and all AEs occurring between the end of REP and trial termination date will be 
assigned to 'follow-up'. Additionally, further treatment intervals may be defined in order to 
provide summary statistics for time intervals, such as periods without treatment effects (such 

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as post-study intervals). These assignments including the corresponding time intervals will be 
defined in detail in the TSAP. Please note that AEs occurring after the last per protocol 
contact but entered before database lock will be reported to drug safety only and will not be 
captured in the trial database.
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 5.2.2.1) and
other significant AEs (according to ICH E3) will be listed separately.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
Relevant ECG findings will be reported as AEs.
7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic endpoints listed in Section 5.5.1 will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472, current version].
Subjects who are not included in the PKS (refer to Section 7.3) will be reported with their 
individual plasma/urine/faeces concentrations and individual pharmacokinetic parameters;
however, they will not be included in descriptive statistics for plasma/urine/faeces 
concentrations, pharmacokinetic parameters or other statistical assessment.
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).
Plasma concentrations and whole blood concentrations (when applicable) will be plotted 
graphically versus time for all subjects as listed in the drug plasma concentration-time tables. 
For the presentation of the mean profiles, the arithmetic mean, geometric mean and the 
planned blood sampling times will be used. The primary analysis of primary and secondary 
endpoints will be based on descriptive statistics only.
The following descriptive statistics will be calculated for concentration-time data as well as 
for all pharmacokinetic parameters: number, arithmetic mean, standard deviation, minimum, 
median, maximum, arithmetic coefficient of variation, geometric mean, and geometric 
coefficient of variation. Descriptive statistics of pharmacokinetic parameters will be 

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calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the Clinical Trial Report.
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Blood/Plasma/urine/faeces drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure of the Sponsor [001-MCS-36-472].
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
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.
7.6
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, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND 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 are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, 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.

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The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
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
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.

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Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated 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, i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC / competent authority in each participating EU member state needs to be notified
about the end of the trial (last subject / subject out, unless specified differently in 
Section 6.2.3 of the CTP) or early termination of the trial.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R07-0364
Elashoff JD. nQuery Advisor version 6.0 user's guide. Cork: Statistical 
Solutions 2005
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
R15-3219
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.
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
c02820512-01
 Safety, tolerability, and 
pharmacokinetics of single rising oral doses of BI 425809 in healthy male 
subjects (partially randomised, single-blind, placebo-controlled) and 
investigation of relative bioavailability and food effect of BI 425809 (open-
label, randomised, three-way crossover) 1346.1. 05 May 2015
c03632269-04
. 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 Dec 2017
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

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10.
APPENDICES
10.1
RADIO BURDEN CALCULATION

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global 
amendment
2.0
Date of CTP revision
25 Sep 2018
EudraCT number
2018-001192-21
BI Trial number
1346-0016
BI Investigational Product(s)
BI 425809
Title of protocol
Metabolism and pharmacokinetics of BI 
425809 after administration of BI 425809 
XX (C-14) as oral solution 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
a.Flow Chart
b.4.2.2.2
c.5.2.5.1
d.5.5.2.5
a.
Footnote 6 
b.
Restrictions on diet and lifestyle
c.
Vital signs
d.
Urine sampling
Description of change
a. Flow Chart
b. 4.2.2.2
c. 5.2.5.1
d. 5.5.2.5
a.
Urine predose corrected from 14 to 2h 
b.
Clarified that subjects shall be advised to 
drink the recommended volume 
Deletion of  a doubled “are not allowed”
c.
Changed the monitoring system used for 
blood pressure measurement
d.
Added “at least” in front of Tween “0.05% 
Tween 20”

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Number of global 
amendment
2.0
Rationale for change
a.
Flow Chart
b.
4.2.2.2
c.
5.2.5.1
d.
5.5.2.5
a.
Inconsistency between Flow Chart and 
Footnote corrected
b.
Clarification that on days of urine collection 
the suggested fluid intake is a 
recommendation The “doubling” of “are not 
allowed” was a leftover of the drafting 
process
c.
The site has changed equipment since 
finalization of this protocol
d.
Clarification that the concentration of 
Tween 20 in the urine is allowed to be 
0.05% or higher

 
 
 
 
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clinical-trial-protocol-revision-1
Metabolism and pharmacokinetics of BI 425809 after administration of BI 425809
XX (C-14) as oral solution in healthy male volunteers
Author-Clinical Trial Leader
26 Sep 2018 12:32 CEST
Author-Trial Statistician
26 Sep 2018 12:44 CEST
Approval-Team Member Medicine
26 Sep 2018 13:23 CEST
Approval-Therapeutic Area 
26 Sep 2018 13:39 CEST
Verification-Paper Signature
Completion
27 Sep 2018 10:02 CEST
Author-Trial Clinical
Pharmacokineticist
27 Sep 2018 10:17 CEST

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