Clinical trial NCT03927209
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2019-06-06; Completion date: 2019-11-22
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this trial is to investigate the effect of multiple oral dosing of high dose BI 1467335 over 28 days and multiple oral dosing of low dose BI 1467335 over 42 days on MAO-B occupancy in the brain compared to baseline using \[11C\]-L-deprenyl-D2 PET tracer in healthy male subjects.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 1467335
Intervention descriptions: intervention 1: tablet

Protocol documents:
Prot_002.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c25939630-02
EudraCT No.
2018-003745-41
BI Trial No.
1386-0022
BI Investigational
Medicinal Product
BI 1467335
Title
A Phase I, open-label, Positron Emission Tomography study in 
healthy male subjects to explore the inhibition of monoamine 
oxidase B in the brain after multiple oral doses of BI 1467335
(non-randomized, open-label, parallel-group study)
Lay Title
A study in healthy men to test the effects of different doses of BI 
1467335 on MAO-B activity in the brain.
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Principal 
Investigator
Phone: 
Status
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date
Version: 2.0
Date: 24 Jun 2019
Page 1 of 71
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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BI Trial No.: 1386-0022
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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
07 January 2019
Revision date
24 June 2019
BI trial number
1386-0022
Title of trial
A Phase I, open-label, Positron Emission Tomography study in healthy male 
subjects to explore the inhibition of monoamine oxidase B in the brain after 
multiple oral doses of BI 1467335 (non-randomized, open-label, parallel-group 
study).
Principal Investigator:
Trial sites
 
Clinical phase
I
Trial rationale
In vitro data suggests an irreversible MAO-B inhibition in humans by BI 1467335. 
This trial is intended to identify and quantify MAO-B inhibition in the brain 
following multiple oral administration of BI 1467335 in healthy male subjects to 
exclude a potential clinical relevance. 
Trial objective
To investigate the effect of multiple oral dosing of 10 mg BI 1467335 over 28 days
and 3 mg BI 1467335 over 42 days compared to baseline on MAO-B inhibition in 
the brain using [11C]-L-deprenyl-D2 PET tracer.
Trial design
Non-randomised, open-label, parallel-group, multiple-dose design.
Trial endpoints:
Primary endpoint: 
-
% reduction in MAO-B availability upon treatment with BI 1467335 on 
the last treatment day (Day 28 for the 10 mg dose group and Day 42 for the 
3 mg dose group) compared to baseline.
Secondary endpoints:
-
% reduction in MAO-B availability upon treatment with 10 mg BI 
1467335 on Day 14 compared to baseline.
-
% reduction in MAO-B availability upon treatment with 3 mg BI 1467335 
on Day 28 compared to baseline.
-
MAO-B inhibition in platelet rich plasma at Day 14 (10 mg dose group 
only), Day 28, and Day 42 (3 mg dose group only) compared to baseline. 
-
Cmax,N, and AUC0-24, N on Day 14 (10 mg dose group only), Day 28 and 
Day 42 (3 mg dose group only).


Boehringer Ingelheim
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Number of subjects 
total entered
10
each treatment
5
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 21 to 55 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive), non-smoker 
Test products
BI 1467335 film-coated tablet formulation (dose strengths 5 mg and 1 mg)
dose
Dose group 1: 10 mg of free base (2 x 5 mg)
Dose group 2: 3 mg of free base (3 x 1 mg)
mode of admin.
Oral with 240 mL of water
Diagnostic tracer
[11C]-L-deprenyl-D2
dose
≤ 100 µg
mode of admin.
Intravenous bolus injection
Duration of treatment
10 mg BI 1467335: Once daily for twenty-eight days.
3 mg BI 1467335: Once daily for forty-two days.
[11C]-L-deprenyl-D2: One single intravenous bolus injection before each PET scan, 
between Day -14 to Day -2 for a predose assessment, on Day 28 for both dose 
groups and additionally on Day 14 for the 10 mg dose group only and on Day 42 for 
the 3 mg dose group only.
Statistical methods
 will conduct image analysis to generate the outcome parameter for the PET 
data (proportional to the target availability at each PET scan), using the PET 
emission and the metabolite corrected arterial plasma input function, within an 
appropriate kinetic model. Tissue time-activity curves (TACs) for each region of 
interest (ROI) will be analysed together with arterial blood data, processed to 
generate metabolite-corrected arterial plasma input function curves. Kinetic 
modelling techniques will then be applied to the input function and TAC data to 
estimate parameters relating to the level of target availability for each PET scan. 
For scans following 14 or 28 days of dosing with 10 mg BI 1467335 and 28 or 42 
days of dosing with 3 mg BI 1467335, fractional occupancy values will be 
generated for each post-dose PET scan by comparing the outcome parameters for 
baseline and post-dose scans for a subject (primary and secondary MAO-B 
inhibition endpoints). The occupancy data will be related to the plasma 
concentration of BI 1467335 at the time of the PET scan.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
DOSE GROUP 3 mg BI 1467335
Visit
Day
Planned time (relative to 
first oral drug 
administration [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK plasma
15
PET procedure8
Platelet-enriched plasma
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy10
1
-28 to 
-2
Screening (SCR)1
x
x
x
-14 to 
-2
Predose PET scan13
x
2
-1
-14:00
18:00
Admission to clinical trial site9
x5
1
-2:00
07:00
x2, 4
x2
x
x2
x2
0:00
09:00
Drug administration
2 to 6
24:00 to 
120:00
09:00
Drug administration
7
144:00
09:00
Drug administration
x5
x2
x2
8 to 12
168:00 to 
264:00
09:00
Drug administration
13
288:00
09:00
Drug administration
14
312:00
09:00
Drug administration
x2, 4, 5
x2
x2
15 to 
20
336:00 to 
456:00
09:00
Drug administration
21
480:00
09:00
Drug administration
x2
x2
22 to 
27
504:00 to 
624:00
09:00
Drug administration
24
552:00
09:00
Drug administration
25
576:00
09:00
Drug administration
26
600:00
09:00
Drug administration
27
624:00
09:00
Drug administration
28
648:00
09:00
Drug administration
x2, 4, 11
x2
x2
x2
648:20
09:20
x
648:45
09:45
x
649:00
10:00
x
649:30
10:30
x
x
x
651:00
12:00
x
652:00
13:00
Lunch, 240 mL water intake3
x
655:00
16:00
Snack3
x
657:00
18:00
Dinner3
x
x
659:00
20:00
x
29
672:00
09:00
Drug administration
x2
30
696:00
09:00
Drug administration
31
720:00
09:00
Drug administration
32
744:00
09:00
Drug administration
33
768:00
09:00
Drug administration


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Visit
Day
Planned time (relative to 
first oral drug 
administration [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK plasma
15
PET procedure8
Platelet-enriched plasma
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy10
2
34
792:00
09:00
Drug administration
35
816:00
09:00
Drug administration
x2
x2
36
840:00
09:00
Drug administration
37
864:00
09:00
Drug administration
38
888:00
09:00
Drug administration
39
912:00
09:00
Drug administration
40
936:00
09:00
Drug administration
41
960:00
09:00
Drug administration
x2
x2
42
984:00
09:00
Drug administration
x2, 4, 11
x2
x2
x2
984:20
09:20
x
984:45
09:45
x
985:00
10:00
x
985:30
10:30
x
x
x
987:00
12:00
x
988:00
13:00
Lunch, 240 mL water intake3
x
991:00
16:00
Snack3
x
993:00
18:00
Dinner3
x
x
995:00
20:00
x
43
1008:00
09:00
Discharge from trial site and 
confirmation of fitness12
x
x
x
3
47-50
End of trial (EoTrial) 
examination6, 7
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, alcohol, nicotine
and virus screening), demographics (including determination of body height and weight, BMI, smoking status and 
alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. In case subject 
is considered eligible for study participation, an MRI will be conducted as part of the screening procedures.
2.
The time is approximate; the procedure is to be performed and completed within a time window of 3 h prior to drug 
administration. After start of treatment on Day 1, further predose PK blood sampling should be performed within 30 
minutes before next scheduled dosing.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
Subjects are to be fasted for at least 10 h before sample is taken.
5.
Only urine drug, alcohol screening and assessment of urine cotinine to confirm no smoking will be done on Day -1. On 
Day 7 and Day 14, these assessments will only be performed upon re-admission, in case the subject leaves the unit for 
the afternoon.
6.
End-of-trial (EoTrial) examination to be performed on Day 47-50, EoTrial examination includes physical examination,
vital signs, ECG, safety laboratory, recording of AEs and concomitant therapies.
7.
For definition of the individual subject’s end of trial see Section 6.2.3.
8.
Dynamic PET scan will be acquired from 0 to 90 minutes after injection of the PET ligand [11C]-L-deprenyl-D2. In 
parallel arterial blood samples will be collected continuously for 15 min using an automated blood sampling system at a 
speed of 5 mL/min. In addition, arterial blood will be drawn manually at several time points during the PET scan.


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9.
Subjects will be hospitalized at the clinical trial site from admission on Day -1 to Day 43. On Day 7 and Day 14, 
subjects will be allowed to leave the unit in the afternoon.
10. AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
11. On trial days 28 and 42 subjects will be allowed a light breakfast after safety assessments have been completed.
12. Discharge from trial site after completion of all assessments, including physical examination for confirmation of fitness.
13. Predose PET scan will only take place once subjects have completed all screening procedures (including MRI) and they 
are considered eligible for study participation.
15. On the days of the PET scans, any PK samples that would need to be taken during the PET scan, can be taken earlier or 
later, if required. Actual sampling times will be recorded in the CRF.


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DOSE GROUP 10 mg BI 1467335
Visit
Day
Planned time (relative to 
first oral drug 
administration [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK plasma
15
PET procedure8
Platelet-enriched plasma
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy10
1
-28 to 
-2
Screening (SCR)1
x
x
x
-14 to 
-2
Predose PET scan13
x
2
-1
-14:00
18:00
Admission to clinical 
trial site9
x5
1
-2:00
07:00
x2, 4, 
x2
x
x2
x2
0:00
09:00
Drug administration
2
24:00
09:00
Drug administration
3
48:00
09:00
Drug administration
4
72:00
09:00
Drug administration
x2
x2
5
96:00
09:00
Drug administration
6
120:00
09:00
Drug administration
7
144:00
09:00
Drug administration
x2
x2
8
168:00
09:00
Drug administration
9
192:00
09:00
Drug administration
10
216:00
09:00
Drug administration
11
240:00
09:00
Drug administration
12
264:00
09:00
Drug administration
13
288:00
09:00
Drug administration
14
312:00
09:00
Drug administration
x2, 4
x2
x2
x2
312:20
09:20
x
312:45
09:45
x
313:00
10:00
x
313:30
10:30
x
x
x
315:00
12:00
x
316:00
13:00
Lunch, 240 mL water 
intake3
x
319:00
16:00
Snack3
x
321:00
18:00
Dinner3
x
x
323:00
20:00
x
15
336:00
09:00
Drug administration
x2
16
360:00
09:00
Drug administration
17
384:00
09:00
Drug administration
18
408:00
09:00
Drug administration
19
432:00
09:00
Drug administration
20
456:00
09:00
Drug administration
21
480:00
09:00
Drug administration
x2
x2
22
504:00
09:00
Drug administration


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Visit
Day
Planned time (relative to 
first oral drug 
administration [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK plasma
PET procedure8
Platelet-enriched plasma
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy10
2
23
528:00
09:00
Drug administration
24
552:00
09:00
Drug administration
25
576:00
09:00
Drug administration
26
600:00
09:00
Drug administration
27
624:00
09:00
Drug administration
28
648:00
09:00
Drug administration
x2, 
4
x2
x2
x2
648:20
09:20
x
648:45
09:45
x
649:00
10:00
x
649:30
10:30
x
x
x
651:00
12:00
x
652:00
13:00
Lunch, 240 mL water 
intake3
x
655:00
16:00
Snack3
x
657:00
18:00
Dinner3
x
x
659:00
20:00
x
29
672:00
09:00
Discharge from trial 
site and confirmation 
of fitness12
x
x
x
3
33-
36
End of trial (EoTrial) 
examination6, 7
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, alcohol, nicotine
and virus screening), demographics (including determination of body height and weight, BMI, smoking status and 
alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. In case subject 
is considered eligible for study participation, an MRI will be conducted as part of the screening procedures.
2.
The time is approximate; the procedure is to be performed and completed within a time window of 3 h prior to drug 
administration. After start of treatment on Day 1, further predose PK blood sampling should be performed within 30 
minutes before next scheduled dosing.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
Subjects are to be fasted for at least 10 h before sample is taken.
5.
Only urine drug, alcohol screening and assessment of urine cotinine to confirm no smoking will be done at this time 
point.
6.
End-of-trial (EoTrial) examination to be performed on Day 33-36, EoTrial examination includes physical examination,
vital signs, ECG, safety laboratory, recording of AEs and concomitant therapies.
7.
For definition of the individual subject’s end of trial see Section 6.2.3.
8.
Dynamic PET scan will be acquired from 0 to 90 minutes after injection of the PET ligand [11C]-L-deprenyl-D2. In 
parallel arterial blood samples will be collected continuously for 15 min using an automated blood sampling system at a 
speed of 5 mL/min. In addition, arterial blood will be drawn manually at several time points during the PET scan
9.
Subjects will be hospitalized from admission on Day -1 up to Day 29.
10. AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
11. On trial days 14 and 28, subjects will be allowed a light breakfast after safety assessments have been completed. 


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12. Discharge from trial site after completion of all assessments, including physical examination for confirmation of fitness.
13. Predose PET scan will only take place once subjects have completed all screening procedures (including MRI) and they 
are considered eligible for study participation. 
15. On the days of the PET scans, any PK samples that would need to be taken during the PET scan, can be taken earlier or 
later, if required. Actual sampling times will be recorded in the CRF.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................18
BI 1467335 .............................................................................................18
1.2.1
Residual Effect Period..........................................................................23
1.2.2
[11C]-L-deprenyl- D2.............................................................................23
1.2.3
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................23
1.4
BENEFIT - RISK ASSESSMENT ...................................................................23
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......27
Main objectives......................................................................................27
2.1.1
Primary endpoint..................................................................................27
2.1.2
Secondary endpoints.............................................................................27
2.1.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................29
3.3
SELECTION OF TRIAL POPULATION ......................................................30
Main diagnosis for trial entry ..............................................................30
3.3.1
Inclusion criteria...................................................................................30
3.3.2
Exclusion criteria ..................................................................................31
3.3.3
Withdrawal of subjects from treatment or assessments ...................33
3.3.4
3.3.4.1
Discontinuation of trial treatment ............................................33
3.3.4.2
Withdrawal of consent to trial participation ............................33
3.3.4.3
Discontinuation of the trial by the sponsor..............................34
Replacement of subjects .......................................................................34
3.3.5
4.
TREATMENTS........................................................................................ 35


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4.1
INVESTIGATIONAL TREATMENTS ..........................................................35
Identity of the Investigational Medicinal Product .............................35
4.1.1
Identity of the Non Investigational Medicinal Product.....................35
4.1.2
Selection of doses in the trial................................................................35
4.1.3
Method of assigning subjects to treatment groups ............................35
4.1.4
Drug assignment and administration of doses for each subject .......36
4.1.5
Blinding and procedures for unblinding ............................................36
4.1.6
Packaging, labelling, and re-supply ....................................................37
4.1.7
Storage conditions.................................................................................37
4.1.8
Drug accountability ..............................................................................37
4.1.9
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................38
Other treatments and emergency procedures....................................38
4.2.1
Restrictions............................................................................................38
4.2.2
4.2.2.1
Restrictions regarding concomitant treatment .........................38
4.2.2.2
Restrictions on diet and life style.............................................38
4.3
TREATMENT COMPLIANCE.......................................................................39
5.
ASSESSMENTS....................................................................................... 40
5.1
ASSESSMENT OF EFFICACY.......................................................................40
5.2
ASSESSMENT OF SAFETY............................................................................40
Physical examination ............................................................................40
5.2.1
Vital signs...............................................................................................40
5.2.2
Safety laboratory parameters ..............................................................40
5.2.3
Electrocardiogram................................................................................43
5.2.4
Other safety parameters.......................................................................44
5.2.5
Assessment of adverse events...............................................................44
5.2.6
5.2.6.1
Definitions of adverse events...................................................44
Adverse event ............................................................44
5.2.6.1.1
Serious adverse event ................................................44
5.2.6.1.2
AEs considered ‘Always Serious’.............................45
5.2.6.1.3
Adverse events of special interest .............................45
5.2.6.1.4
Intensity (severity) of AEs.........................................46
5.2.6.1.5
Causal relationship of AEs ........................................46
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................47
AE collection.............................................................47
5.2.6.2.1
AE reporting to the sponsor and timelines ................48
5.2.6.2.2
Information required..................................................48
5.2.6.2.3
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................48
Assessment of pharmacokinetics .........................................................48
5.3.1
Methods of sample collection ...............................................................48
5.3.2
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................48
Analytical determinations ....................................................................49
5.3.3


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5.3.3.1
Analytical determination of BI 1467335, 
 
 plasma concentrations ...............................................49
5.4
ASSESSMENT OF BIOMARKER..................................................................49
Platelet-enriched plasma ......................................................................49
5.4.1
5.4.1.1
Assessment...............................................................................49
5.4.1.2
Method of sample collection....................................................49
5.5
MRI AND PET PROCEDURE.........................................................................49
MRI and PET Scan...............................................................................49
5.5.1
Arterial blood sampling........................................................................50
5.5.2
5.6
BIOBANKING ...................................................................................................50
5.8
APPROPRIATENESS OF MEASUREMENTS.............................................51
6.
INVESTIGATIONAL PLAN.................................................................. 52
6.1
VISIT SCHEDULE............................................................................................52
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................52
Screening period....................................................................................52
6.2.1
Treatment period ..................................................................................52
6.2.2
Follow-up period and trial completion ...............................................53
6.2.3
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 54
7.1
STATISTICAL DESIGN – MODEL ...............................................................54
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................54
7.3
PLANNED ANALYSES....................................................................................54
Primary endpoint analyses...................................................................55
7.3.1
Secondary endpoint analyses ...............................................................56
7.3.2
Safety analyses.......................................................................................56
7.3.4
7.4
INTERIM ANALYSES .....................................................................................57
7.5
HANDLING OF MISSING DATA ..................................................................57
Safety......................................................................................................57
7.5.1
Pharmacokinetics..................................................................................58
7.5.2
7.6
RANDOMISATION ..........................................................................................58
7.7
DETERMINATION OF SAMPLE SIZE ........................................................58
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 59


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8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................59
8.2
DATA QUALITY ASSURANCE .....................................................................60
8.3
RECORDS..........................................................................................................60
Source documents .................................................................................60
8.3.1
Direct access to source data and documents.......................................61
8.3.2
Storage period of records.....................................................................61
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................61
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......61
Collection, storage and future use of biological samples and 
8.5.1
corresponding data ...............................................................................62
8.6
TRIAL MILESTONES .....................................................................................62
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................63
9.
REFERENCES......................................................................................... 64
9.1
PUBLISHED REFERENCES...........................................................................64
9.2
UNPUBLISHED REFERENCES.....................................................................65
10. APPENDICES .......................................................................................... 67
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 68
11.1
GLOBAL AMENDMENT 1 .............................................................................68
11.2
GLOBAL AMENDMENT 2 .............................................................................71


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALCOA
Attributable, legible, contemporaneous, original, accurate
ALT
Alanine amino transferase
AOC3
Amine oxidase copper-containing 3
AST
Aspartate amino transferase
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the time 24 h
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BMS
Biomarker treated set (TS)
BP
Blood pressure
CA
Competent authority
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,N
maximum measured concentration of the analyte
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTM
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
EC
Ethics committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 


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EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EU
European Union 
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HCL
Hydrochloride
HPLC
High performance liquid chromatography 
HR
Heart rate
IB
Investigator’s brochure
IC50
Half maximal inhibitory concentration
ICRP
International Commission on Radiological Protection
IEC
Independent Ethics Committee
iPD
Important protocol deviations
IQRMP
integrated risk management plan
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MAO-A/B
Monoamine oxidase A/B
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
MRI
Magnetic Resonance Imaging
NAFLD
Non-alcoholic fatty liver disease
NASH
Non-alcoholic steatohepatitis
NIMP
Non Investigational Medicinal Product
NOAEL
No observed adverse effect level
PD
Pharmacodynamic(s)
PET
Positron emission tomography
PETS
PET set 
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
q.d.
Quaque die, once daily


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QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
REP
Residual effect period
ROI
region of interest 
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
SSAO
Semi-carbazide-sensitive amine oxidase
TAC (s)
time-activity curve (s)
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
TSAP
Trial statistical analysis plan
UK
United Kingdom
ULN
Upper limit of normal
VAP-1
Vascular adhesion protein-1


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Boehringer Ingelheim (BI) is developing BI 1467335 (formerly Pharmaxis PXS-4728A), an 
oral, small-molecule inhibitor of semi-carbazide-sensitive amine oxidase (SSAO), also 
known as vascular adhesion protein-1 (VAP-1) or amine oxidase copper-containing 3 
(AOC3), in the indication of non-alcoholic steatohepatitis (NASH).
NASH is characterised histologically by a high level of steatosis, ballooning of hepatocytes, 
and necroinflammation. NASH often leads to fibrosis which can progress to cirrhosis with a 
high risk of liver failure. AOC3 in liver sinusoidal endothelial cells is responsible for the firm 
adhesion and transmigration of leukocytes into the tissue and for the propagation of the 
inflammatory environment in steatohepatitis. Fibrotic regions of NASH liver sections are 
strongly positive for AOC3 immune reactivity [R15-5697]. The associated generation of 
peroxide during the course of amine oxidation is known to activate quiescent stellate cells 
supporting the differentiation into myofibroblasts, and fibrotic tissue generation. Therefore, 
targeting the inhibition of AOC3 enzymatic activity might be beneficial for patients with 
steatohepatitis and fibrosis in order to reduce the recruitment of leukocytes into the liver and 
reduce cytokine and oxygen stress dependent hepatocyte damage and activation of hepatic 
stellate cells.
With a prevalence of about 20 - 30% in the general population of Western countries, non-
alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease 
worldwide [R15-5365]. While simple hepatic steatosis can have a benign, non-progressive 
course, about 40% of patients with NAFLD progress to NASH. As the disease progresses, 
significant fibrosis develops in 37 - 41% of subjects within 15 years. In the United States, 
NASH is believed to be the most common cause of liver cirrhosis [R15-6070] which is 
estimated to be the 12th leading cause of death [R15-6057]. Patients with NASH are also at 
increased risk of hepatocellular carcinoma, even in the absence of cirrhosis [R15-5365]. By 
2023, about 13 million patients are projected to have NASH with advanced stages (i.e. ≥ 
stage 3) of fibrosis (of those, 2.9 million in the US, 3.5 million in EU, 5 million in China). 
Individuals with advanced fibrosis are estimated to progress with a 4% annual event rate to 
cirrhosis. The risk of liver-related death in Western patients with NASH ranges from 10% 
over 13.7 years to 18% over 18.5 years [P13-02280].
To date, no approved therapy for liver fibrosis or effective disease modifying regimen for 
NASH is available, despite the strong interface with metabolic syndrome, obesity and Type 2 
diabetes mellitus. The current standard of care for NASH is weight loss through diet and 
exercise to improve insulin resistance and lower fat mass which is a clinically challenging 
goal to achieve and shows minimal impact on disease progression [R15-6044].
For a more detailed description of the BI 1467335 profile please refer to the current 
Investigator’s Brochure (IB) [c04751792]. 


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It should be noted that there are not only ongoing activities to evaluate the potential 
therapeutic effect of BI 1467335 in patients with NASH [c08980589] but also in patients with 
non-proliferative diabetic retinopathy [c14141887].
1.2
DRUG PROFILE
BI 1467335
1.2.1
BI 1467335 is a small molecule AOC3 inhibitor that exhibits both anti-inflammatory and 
anti-fibrotic characteristics in various animal models. AOC3 is a membrane bound adhesion 
protein that facilitates the binding of leukocytes to endothelial cells and the subsequent 
transmigration to sites of inflammation. 
For a more detailed description of the BI 1467335 profile please refer to the current
Investigator’s Brochure (IB) [c04751792].


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For a more detailed description of the BI 1467335 profile, please refer to the current 
Investigator’s Brochure (IB) [c04751792].
Residual Effect Period
1.2.2
The Residual Effect Period (REP) is the period after the last dose with measurable drug levels 
and/or pharmacodynamics effects still likely to be present. The REP of BI 1467335 is not 
known for this clinical trial. Therefore all AEs reported until the end of trial examination (last 
per protocol contact) will be considered on treatment. 
[11C]-L-deprenyl- D2
1.2.3
[11C]-L-deprenyl-D2 is the PET ligand that will be used for the study and is considered a Non 
Investigational Medicinal Product (NIMP). [11C]-L-deprenyl-D2 is a well-established PET 
radioligand used over the past 25 years to evaluate MAO-B status in multiple human studies 
in healthy volunteers and patients with a variety of disorders including epilepsy, traumatic 
brain injury and Parkinson’s disease [R18-2789], [R18-3939], [R18-3940], [R18-3941], 
[R18-3942], [R18-3943], [R18-3950]. In drug development studies [11C]-L-deprenyl-D2 has
been demonstrated to provide reliable information on the occupancy of MAO-B by novel 
pharmaceutical agents. [11C]-L-deprenyl-D2 has been well tolerated in human studies with no 
reports of adverse events related to its administration. The total mass of L-deprenyl-D2 
administered in this study will not exceed 10 µg at each of the PET scans (as per CHMP 
guideline of <100 μg (CHMP/ICH/286/95). A qualified physician will be present during 
radiotracer administration and scanning.
1.3
RATIONALE FOR PERFORMING THE TRIAL
In vitro data for BI 1467335 indicate an irreversible inhibition of MAO-B activity (see 
Section 1.2). Currently, there is no clinical information regarding brain penetration of BI 
1467335 in humans, therefore the clinical relevance of this finding remains open and will be 
explored with the planned study.
This trial is intended to identify and quantify MAO-B inhibition in the brain in healthy male 
subjects following multiple oral administration of BI 1467335. MAO-B inhibition will be 
assessed by PET imaging using [11C]-L-deprenyl-D2 as an established PET ligand. PET 
imaging will be conducted on predose, Day 14 and Day 28 during a 4-week treatment period 
with oral doses of once daily 10 mg of BI 1467335 and on predose, Day 28 and Day 42 
during a 6-week treatment period with oral doses of once daily 3 mg of BI 1467335. The 
10 mg dose group will be investigated first and, in the event no MAO-B inhibition is seen in 
this dose group, the study will be considered complete and no further investigation with a 
lower dose (3 mg dose group) will be conducted.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of the compound. 


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Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
Subjects will have three PET-CT scans each, with up to 300 MBq [11C]-L-Deprenyl-D2 
administered at each of these scans. Each PET-CT scan results in an effective dose of up to 
2.0 mSv (PET) + 0.36 mSv (CT) = 2.36 mSv, so the total dose to each subject is up to a 
maximum of 3 x 2.36 = 7.1 mSv. All of this is over and above standard practice. This is 
equivalent to 3 times the average yearly exposure (2.3 mSv) from naturally occurring 
background radiation in the United Kingdom. For an adult in good health, this exposure 
would result in a risk of around 1 in 2800 of contracting a fatal cancer.
The total exposure falls into category IIb (upper limit 10 mSv) of the guidance published by 
the International Commission on Radiological Protection (ICRP). There is no dose limit for 
research purposes in the UK, but like many EU member states, the UK follows the ICRP 62 
guidance that recommends 10 mSv (or less) per study where research subjects are not 
expected to benefit personally.
To mitigate this risk, the study will exclude subjects who have had previous exposure to 
ionising radiation such that their effective dose resulting from research studies (including this 
one) would exceed 10 mSv in the previous year.
[11C]-L-Deprenyl-D2 will be injected intravenously as a bolus. The intravenous deprenyl 
dose will be ≤100 μg, and thus ≥50–100-fold lower than the typical administered dose of 5–
10 mg deprenyl to patients with Parkinson’s disease [R18-3964]. This low dose of [11C]-L-
Deprenyl-D2 is therefore considered to have no noteworthy pharmacological effect in healthy 
subjects.
The PET investigation includes collection of arterial blood samples to determine the arterial 
concentration of total radioactivity in plasma and whole blood as well as to analyse arterial 
plasma concentration of metabolites. This requires the cannulation of the radial artery, with 
principally similar risks as described for venous sampling. Subjects will receive a local
anaesthetic around the anticipated arterial puncture site, using e.g. 1-2 mL of 1% lidocaine. 
Although the risk associated to the s.c. injection of a local anaesthetic is considered low, rare 
occurrence of hypersensitivity reactions have been reported. Since the radial artery is not an 
‘end’ artery the ulnar artery can completely supply the hand in isolation. The radial artery 
cannulation is considered a safe procedure. However, temporary occlusion, isolated cases of 
permanent ischaemic damage or the development of a pseudoaneurysm have been described.
For mitigation of such risks the arterial puncture will be only conducted by highly skilled 
medical staff, confirmation of adequate collateral circulation with the Allen’s test, and close 
monitoring of the injection site. 


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There is minimal risk to subjects associated with MRI scanning, provided subjects have no 
contraindications to MRI as listed in the exclusion criteria. Some participants may find the 
PET and MRI scanning environments claustrophobic. Participants with severe anxiety of 
confined spaces will be excluded from the study. The potential risks associated with metallic 
implants will be eliminated by a careful screening of the subject during study enrolment 
procedure and by a qualified MR operator on the day of the scan.
Drug-related risks and safety measures
The human safety and tolerability profile in male and female healthy subjects was 
satisfactory for multiple doses given over 28 consecutive days of up to 20 mg of BI 1467335 
in study 1386.8 (see Section 1.2). There were no deaths or other serious adverse events. 
Adverse events, mostly reported as mild (CTCAE grade 1), had no apparent dose or exposure 
relationship. In view of the non-proportional increase of exposure there is an about 10-fold 
safety margin between the highest exposure observed in preceding phase I studies and the 
exposure at the maximum dose of 10 mg of BI 1467335 q.d. in the planned study. 
Drug-induced liver injury (DILI)
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.6.1.4, adverse events of special interest.
Summary of benefit-risk assessment
In a previous trial in healthy subjects, multiple oral doses of up to 20 mg BI 1467335 were 
safe and well-tolerated. Due to the non-proportional increase of the exposure this results in a 
large safety margin between the exposure at the already tested maximum doses and the 
maximum dose of 10 mg of BI 1467335 in the planned study. Each participating subject will 
receive on 3 occasions 14 days apart a single intravenous bolus of [11C]-L-deprenyl-D2, at a 
low dose which is not expected to have a noteworthy pharmacological effect. Furthermore, 
the low dose should result in a negligible radioburden per infusion (ICRP 1 category).
The trial design is optimized to collect as much relevant information as possible on the 
inhibition of MAO-B in the brain upon treatment with BI 1467335 without exposing 
participating volunteers to undue risk. However, there is always the potential of serious 
adverse events (SAEs) occurring with intake of trial medication. Risks to subjects will be 
minimized and addressed by eligibility criteria, safety laboratory examinations, ECG and 
vital sign measurements, in-house observation periods, and verbal communication concerning 
AEs. 


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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 results of this trial are considered necessary for the further development of BI 1467335. 
Successful development of BI 1467335 is expected to provide a new valuable treatment for 
patients with NASH and potentially also for non-proliferative diabetic retinopathy.
The risks of the participating volunteers are minimized and justified when compared to the 
potential benefits of this trial.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
The main objective of this trial is to investigate the effect of multiple oral dosing of 10 mg BI
1467335 over 28 days and multiple oral dosing of 3 mg BI 1467335 over 42 days on MAO-B 
occupancy in the brain compared to baseline using [11C]-L-deprenyl-D2 PET tracer in healthy 
male subjects.
Primary endpoint
2.1.2
The following primary endpoint will be determined:

% reduction in MAO-B availability upon treatment with BI 1467335 on the last 
treatment day (Day 28 for the 10 mg dose group and Day 42 for the 3 mg dose group) 
compared to baseline.
Secondary endpoints
2.1.3
The following secondary endpoints will be determined:

% reduction in MAO-B availability upon treatment with 10 mg BI 1467335 on Day 
14 compared to baseline.

% reduction in MAO-B availability upon treatment with 3 mg BI 1467335 on Day 28 
compared to baseline.

MAO-B inhibition in platelet rich plasma at Day 14 (10 mg dose group only), Day 28, 
and Day 42 (3 mg dose group only) compared to baseline. 

Cmax,N (maximum measured concentration of the analyte) and AUC0-24, N (area under 
the concentration-time curve of the analyte over the time interval from 0 to 24 h) on 
Day 14 (10 mg dose group only), Day 28 and Day 42 (3 mg dose group only).


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a non-randomised, open-label, parallel-group, multiple dose
trial in healthy male subjects in order to investigate the effect of multiple oral doses of 10 mg 
BI 1467335 administered once daily over 28 days and of 3 mg BI 1467335 administered once 
daily over 42 days on MAO-B activity in the brain. The MAO-B activity will be assessed by 
means of a dynamic PET scan using [11C]-L-deprenyl-D2 PET as tracer. PET scans will be 
conducted predose and on Day 28 for both dose groups. An additional PET scan will be 
conducted on Day 14 in the 10 mg dose group and on Day 42 in the 3 mg dose group. On 
these days, subjects will be injected with the radiotracer and subsequently undergo dynamic 
PET scans. In addition to PET scan, MAO-B activity will be also measured in platelet rich 
plasma. 
For the 10 mg dose group, subjects will be hospitalised from Day -1 to Day 29.
For the 3 mg dose group, subject will be hospitalised from Day -1 to Day 43. The subjects 
will be allowed to leave the clinical unit in the afternoon on Day 7 and Day 14.
The 10 mg dose group will be investigated first. In case no MAO-B inhibition is seen in this 
dose group, the 3 mg dose group will not be further investigated.
The oral treatments will consist of either two 5 mg or three 1 mg film-coated tablets (dose 
strength based on free base) for subjects dosed with 10 mg and 3 mg BI 1467335, 
respectively. The treatments will be administered once daily for 28 days for the 10 mg dose 
groups and once daily for 42 days for the 3 mg dose groups. The subjects willing to 
participate can choose convenient visit dates on a first-come, first-served basis: as soon as 5 
subjects have been allocated to 1 of the 2 dose groups, the following subjects will be 
allocated to the other dose group. For details, refer to Section 4.1.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The doses selected for this study, 10 mg BI 1467335 q.d. (2 film-coated tablets of 5 mg dose 
strength) and 3 mg BI 1467335 q.d. (3 film-coated tablets of 1 mg dose strength), have been 
used in healthy volunteers and shown to be well tolerated. The predose measurement will be 
used as a baseline, so no placebo dose is required in this study.
The planned dosing duration of 28 days for the 10 mg dose group and 42 days for the 3 mg 
dose group is long enough to reliably achieve steady-state drug exposures and to exclude any 
transient effects.
Due to the time dependent non-linear kinetics of BI 1467335, systemic exposures on Day 28 
and Day 42 cannot be predicted from Day 1 kinetics (IB [c04751792]). Therefore the MAO-
B inhibition in the brain will be determined on Day 28 and Day 42 after start of treatment 


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with 10 mg and 3 mg BI 1467335, respectively, and compared to the individual baseline 
value to investigate the maximum inhibition. The in vitro data suggested an irreversible 
inhibition, which could potentially accumulate over time following multiple dosing and with 
the increase in exposure observed over time which characterizes BI 1467335 kinetics. The 
investigation on Day 14 for the 10 mg dose group and on Day 28 for the 3 mg dose group
will evaluate whether the MAO-B inhibition reaches its maximum over the treatment 
duration and is maintained regardless of the increase in BI 1467335 systemic exposure. The 
10 mg dose group will be investigated first. In the event no MAO-B inhibition is seen
following the administration of 10 mg BI 1467335 daily over 28 days, the study will be 
considered as complete and no further investigation with a lower dose (3 mg) will be 
conducted.
[11C]-L-deprenyl-D2 is a PET radioligand used for measurement of the MAO-B activity in 
the brain. This radioligand has been used for several PET studies to evaluate MAO-B 
inhibition in the brain in healthy subjects and is unlikely to exhibit any detectable isotope 
effects (see Section 1.4).
Because of the exposure with radioligands the study will only include male subjects.
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from medical procedures and laboratory assessments with an unlikely relevant impact by 
subjective factors.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 10 healthy male subjects (5 in each dose group) will enter the study. They 
will be recruited from the volunteers' pool of the trial site.
The current trial is designed to investigate the effect of multiple oral dosing of 10 mg 
BI 1467335 over 28 days and 3 mg BI 1467335 over 42 days on MAO-B inhibition in the 
brain. Healthy male subjects are an ideal population for the objectives of this trial, since they 
provide relatively stable physiological, biochemical and hormonal conditions, i.e. the absence 
of disease-related variations and relevant concomitant medications.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
Main diagnosis for trial entry
3.3.1
The study will be performed in healthy subjects.
Inclusion criteria
3.3.2
Subjects will only be included in the trial if they meet the following criteria:


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1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests
2. Age of 21 to 55 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5. Non-smoker with no history of smoking
6. 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.
Exclusion criteria
3.3.3
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 


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8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients)
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 90 days or within 5 half-
lives, whichever is longer, of planned administration of investigational drug in the current 
trial, or concurrent participation in another clinical trial in which investigational drug is 
administered
13. Alcohol abuse (consumption of more than 30 g per day for males) within the 24 months 
prior to dosing
14. Drug abuse within the 24 months prior to dosing or positive drug screening
15. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
16. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
17. Inability to comply with the dietary regimen of the trial site
18. 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
19. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
20. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
21. Structural brain abnormality has been shown on an MRI
22. Severe anxiety of enclosed spaces
23. Contraindication for arterial cannulation: Allen’s test indicating potential risk in 
placement of the arterial cannula. 
24. Contraindication to MRI as determined by screening and safety questionnaire including 
but not limited to significant tattoos (as determined by the radiographer), cardiac 
pacemakers, aneurysm clips and cochlear implants.
25. Unable to lie flat on the MRI or PET scanner for a prolonged period of time.
26. Prior participation in other research protocols in the past year such that the total effective 
dose including this study would exceed 10 mSv.
For study restrictions, refer to Section 4.2.2.


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Withdrawal of subjects from treatment or assessments
3.3.4
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
6. In addition to these criteria, the investigator may discontinue subjects at any time based 
on his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up 
as outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 


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discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least 1 drug-related serious adverse event is 
reported
3. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate conduct 
of the trial
4. The sponsor decides to discontinue the further development of the investigational product
5. The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
6. Severe non-serious adverse reactions (i.e. severe non-serious adverse events considered
as, at least, possibly related to the IMP administration) in two subjects in the same dose 
group, independent of within or not within the same system-organ-class.
Replacement of subjects
3.3.5
In case a subject does not complete the trial, the Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if this subject will be replaced. 
Replacement of subjects should always be done in mutual agreement with the principal 
investigator. A replacement subject will be assigned a unique trial subject number, and will 
be assigned to the same treatment as the subject 
 replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG. BI 
1467335 doses will be calculated as a free base of the BI 1467335 salt, with 10 mg 
BI 1467335 free base equals to 11.3 mg BI 1467335 HCl salt and 3 mg BI 1467335 free base 
equals to 3.39 mg BI 1467335 HCl salt.
[11C]-L-deprenyl-D2 will be administered as a solution for injection and will be manufactured 
by 
Identity of the Investigational Medicinal Product
4.1.1
The characteristics of the test products are given below:
Substance:
BI 1467335
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg /1 mg 
Posology:
2-0-0 / 3-0-0
Route of administration:
oral
Duration of use:
28 days / 42 days
Identity of the Non Investigational Medicinal Product
4.1.2
The characteristics of the NIMP are given below:
Substance:
[11C]-L-deprenyl-D2
Pharmaceutical formulation: Solution for injection
Source:
Unit strength:
≤100 µg
Route of administration:
i.v.
Duration of use:
A single dose on 3 different days during study conduct
Selection of doses in the trial
4.1.3
The doses of BI 1467335 selected for this trial are the standard clinical doses (see 
Section 1.2).
Method of assigning subjects to treatment groups
4.1.4
This trial is an open-label, non-randomized, parallel-group, multiple dose study.


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Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate can choose convenient visit dates on a 
first-come, first-served basis: as soon as 5 subjects have been allocated to 1 of the 2 dose 
groups, the following subjects will be allocated to the other dose group. Therefore, the 
allocation of subjects to dose groups is not influenced by trial personnel, but only by the 
subjects’ temporal availability. As the study includes healthy male subjects from a 
homogenous population, relevant imbalances between the dose groups are not expected. 
Within the dose group, numbers of the randomization list will be allocated to subjects in their
order of registration for the study (assignment to dose group according to subjects’ temporal 
availability). Once a subject number has been assigned, it cannot be reassigned to any other 
subject.
Drug assignment and administration of doses for each subject
4.1.5
This trial is a parallel-group multiple dose study. All subjects will receive the treatments in an 
open-labelled fashion. The treatments to be evaluated are outlined in Table 4.1.5: 1 below. 
Table 4.1.5: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
T (Test)
BI 1467335
Film-coated 
tablet
10 mg
2 tablets (5 mg) qd for 28 days
T (Test)
BI 1467335
Film-coated 
tablet
3 mg
3 tablets (1 mg) qd for 42 days
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a sitting position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
[11C]-L-Deprenyl-D2 will be administered as an intravenous bolus injection for a predose 
assessment (between Day -14 to Day -2) and about 1,5 h after dosing of BI 1467335 on Day 
14 (10 mg dose group only), Day 28 and Day 42 (3 mg dose group only).
Blinding and procedures for unblinding
4.1.6
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.


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Packaging, labelling, and re-supply
4.1.7
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
The PET tracer will be manufactured by
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms.
No re-supply is planned.
Storage conditions
4.1.8
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical trial manager (as provided in the list of contacts) is to be contacted immediately.
Drug accountability
4.1.9
The investigator or designee will receive the IMPs delivered from the sponsor provided that
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that all unused or partially used drug supplies have been 
returned by the clinical trial subject and that no remaining supplies are in the investigator’s 
possession.


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All unused medication will be disposed of locally by the trial site upon written authorisation 
of the clinical trial leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
Other treatments and emergency procedures
4.2.1
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
Restrictions
4.2.2
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
Limited amounts of paracetamol (up to 2 g/day) are allowed when prescribed by a medical 
investigator from the clinical site.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products containing St. John's wort (Hypericum perforatum) are not permitted from 7 
days before the first administration of trial medication until after the last PK sample of each 
dose group is collected.
Alcoholic beverages are not allowed 48 h before administration of the compound, during the 
conduct of the study and up discharge from clinic, as well as 48 h before End of Trial.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed during the in-house period.
Poppy-seed containing products should not be consumed starting 2 days before first trial drug 
administration until last PK sampling of the trial.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.


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4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
Physical examination
5.2.1
At screening, the medical examination will include demographics, height and body weight, 
smoking history (non-smoker mandatory) and alcohol history (results not mandatory to be 
entered into CRF or to be reported), relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination (including Allen’s test to check arterial blood
flow of the hands). At discharge and at the end of trial examination, it will include review of 
vital signs, 12-lead ECG, laboratory tests, and a physical examination including 
determination of weight.
Vital signs
5.2.2
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 (e.g. 
Dinamap Pro 1000) 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.
Safety laboratory parameters
5.2.3
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count and urine light microscopy will only be performed 
if there is an abnormality in the automatic blood cell count or in the urinalysis, respectively.
The results of the manual differential white blood cell and urine light microscopy will only be 
reported in the source data.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab 
group
BI test name [comment/abbreviation]
A
B
C
D
E
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes, absol.
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; 
Basophils/ Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Eosinophils/Leukocytes; Eosinophils, absol.; Basophils/ 
Leukocytes; Basophils, absol.; Monocytes/ Leukocytes; 
Monocytes, absol.; Lymphocytes/Leukocytes; 
Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization 
Ratio)
X
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase (LDH)
Lipase
Amylase (total)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
X
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
Alpha glycoprotein acid
C-Reactive Protein (Quant)
Uric Acid
Urea
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
E
Electrolytes
Sodium
Potassium
Magnesium 
Calcium
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine light 
microscopy
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2 on Day 1 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 2 on Day 14 (for time points refer to Flow Chart)
D: parameters to be determined at Visit 2 on Day 28 (for time points refer to Flow Chart)
E: parameters to be determined at Visit 3 (end of trial examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a urine alcohol test (nal von minden 
DrugScreen®) will be performed prior to first administration, 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. Drug screening also includes a cotinine test to confirm compliance with 
non-smoking. 
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at Safety 
Laboratory –
with the exception of drug screening tests and urinalysis. These tests will be 
performed at the trial site using nal von minden DrugScreen® kits and Siemens Multistix® or 
comparable test system.
Laboratory data will be transmitted electronically to the database.
Electrocardiogram
5.2.4
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10-sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven.
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 


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


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require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in Section 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. 
These events should always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
eDC system. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 


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


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


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AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
5.3.1
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. The sampling scheme is to be adhered to as 
closely as possible, but on the days of the PET scans, any PK samples that would need to be 
taken during the PET scan procedures, may be taken earlier or later, if needed.
Methods of sample collection
5.3.2
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 1467335,
 concentrations in plasma, approx. 
3 mL of blood will be drawn from a vein into an K2-EDTA (dipotassium ethylenediamine-
tetraacetic acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. 
Blood will be withdrawn by means of either an indwelling venous catheter or by 
venepuncture with a metal needle.
For detailed description of blood sampling, sample handling, sample preparation, sample 
storage, tube labelling, and sample shipment refer to the laboratory manual. Until transfer on 
dry ice to the analytical laboratory, the plasma samples will be stored frozen and in upright 
position at about -20°C or below at the clinical site and at the analytical laboratory until 
analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned time point, analyte, and aliquot. 


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After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the CTR is 
archived.
Analytical determinations
5.3.3
5.3.3.1
Analytical determination of BI 1467335, 
plasma 
concentrations
BI 1467335, 
concentrations in plasma will be determined by a 
validated LC-MS/MS (liquid chromatography tandem mass spectrometry) assay.
All details of the analytical method will be available prior to the start of sample analysis. 
5.4
ASSESSMENT OF BIOMARKER
Platelet-enriched plasma
5.4.1
5.4.1.1
Assessment
For the assessment of platelet-enriched plasma, blood samples will be collected at the time 
points indicated in the Flow Chart. The actual sampling times will be recorded.
5.4.1.2
Method of sample collection
Blood will be withdrawn into citrate monovettes. After collection, blood was centrifuged at 
200 g for 10 min at RT. Supernatants (platelet rich plasma) will be aliquoted and stored at -20 
°C ±10 °C. Details regarding the collection of the platelet-enriched plasma will be specified 
in a dedicated laboratory manual.
5.5
MRI AND PET PROCEDURE
MRI and PET Scan
5.5.1
Each subject will report to the PET site on 4 occasions:
-
Screening visit: A screening brain MRI will be performed and interpreted at the PET 
site to determine eligibility of the subjects by ruling out any brain abnormality.
Subject’s brain MR images will be evaluated by a radiologist to exclude incidental 
findings of clinical relevance. In the unlikely event of an unexpected and clinical 
significant finding on structural MRI, which may require further investigation, 


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participants and/or their General Practitioner will be informed, with the participant’s 
consent. In the case of a subject being re-screened, an MRI (without any abnormality) 
obtained at the study’s imaging center made within 90 days prior to Day -1 check-in 
is acceptable for eligibility.
-
Day -14 to Day -2: Subjects will be admitted to the PET site after confirmation of 
eligibility at the clinical site. They will be administered [11C]-L-deprenyl-D2 as PET 
ligand through an i.v. bolus and will undergo dynamic PET scans from 0 to 90 min 
following the administration of the PET ligand. 
-
Day 14 (10 mg dose group only)/Day 28/Day 42 (3 mg dose group only): Subjects 
will be admitted to the PET site in the morning, with intake of the daily drug 
administration at the PET site (to assure start of PET scans 90 minutes after dosing of 
BI 1467335). They will receive an intravenous bolus injection of the tracer ([11C]-L-
deprenyl-D2) and will then undergo dynamic PET scans from 0 to 90 min. After 
completion of the PET scan subjects will be re-admitted to the clinical trial site.
Arterial blood sampling
5.5.2
Arterial blood will be collected continuously for 15 min using an automated blood sampling 
system 
 at a speed of 5 mL/min. Arterial blood will also be drawn 
manually after the ligand injection to measure radioactivity in whole blood and plasma. 
Actual sampling times will be detailed in an Arterial Blood Sampling manual, a possible 
schedule could be 1, 2, 4, 6, 8, 10, 15, 20, 30, 45, and 60 min after ligand injection.
The parent fraction of the ligand will be determined using a reversed-phase HPLC method. 
Sample handling instructions will be included in the arterial blood sampling protocol.
5.6
BIOBANKING
Not applicable.


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5.8
APPROPRIATENESS OF MEASUREMENTS
Measurements performed during this trial are mainly standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The PET scan is an established in-vivo tool to evaluate potential MAO 
B occupancy by drugs, with a large body of evidence regarding the validity of the method. 
The assessment of MAO-B activity in platelet-rich plasma will support the results of the PET 
scan thus further substantiating potential signals on MAO B occupancy.
The safety assessments performed during the study are widely used in clinical trials and will 
allow evaluation of safety and tolerability of the study drugs. 
The pharmacokinetic parameters and measurements outlined in Section 5.4 are generally used 
assessments of drug exposure. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for study drug administration will be ±1 h, 
however dosing time within a subject should be the same.
For PET scans and PK blood sampling planned times, refer to the Flow Chart. The acceptable 
deviation from the scheduled days for PET scans and associated PK blood sampling will be 1 
day before up to 2 days after planned study day on Day 14, Day 28 and Day 42. On PET 
days, the acceptable deviation from the scheduled time for PET scans and associated PK 
blood sampling will be ± 2 h. While the nominal times for PK blood sampling should be 
adhered to as closely as possible, the actual sampling times will be recorded and used for the 
determination of pharmacokinetic parameters.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
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
Screening period
6.2.1
Screening visit is defined as Visit 1.
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Treatment period
6.2.2
Each subject is expected to participate in 1 treatment period.


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Each study participants will receive a once daily administration of BI 1467335 of either 
10 mg (2 x 5 mg film-coated tablets) from Day 1 to Day 28 or 3 mg (1 x 3 mg film-coated 
tablets) from Day 1 to Day 42. 
For the 10 mg dose group, the subjects will be kept at the clinical site from Day -1 up to Day 
29, at which time they will be allowed to leave the trial site after formal assessment and 
confirmation of their fitness.
For the 3 mg dose group, the subjects will be kept at the clinic from Day -1 to Day 43. 
However on Day 7 and Day 14, subjects will be allowed to leave the clinic in the afternoon at 
the discretion of the Investigator. Before subjects are allowed to leave the trial site on Day 43, 
they will undergo formal assessments and confirmation of their fitness.
Between Day -14 and Day -2 and on Day 14 (for the 10 mg dose group only), Day 28 and 
Day 42 (for the 3 mg dose group only), each study participants will be admitted to the PET
site for a PET ligand administration followed by a PET scan. After completion of PET scan
on Day 14, 28 and Day 42, subjects will be re-admitted to the clinical trial site.
For details on time points and procedures for collection of plasma samples for PK analysis
and platelet-enriched plasma analysis, refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
Follow-up period and trial completion
6.2.3
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the effect of multiple oral dosing of 10 mg BI 
1467335 over 28 days and 3 mg BI 1467335 over 42 days on MAO-B occupancy in the brain 
compared to baseline using [11C]-L-deprenyl-D2 PET tracer on the basis of the primary and 
secondary endpoints, as listed in Section 2.1.2 and 2.1.3.
A second objective of this trial is to investigate the MAO-B inhibition in platelet-enriched 
plasma compared to baseline.
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypothesis with regard to the primary and secondary 
endpoints in a confirmatory sense. Instead, they will be described in their entirety and 
evaluated by descriptive statistical methods.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint and was not excluded due to a 
protocol deviation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he/she contributes only one PK parameter value to the 
statistical assessment. Analyses of PK parameters will be based on the PKS.
PET set (PETS): This set includes all subjects in the treated set (TS) who provide at 
least one PET scan at baseline and one on-treatment.
Adherence to the protocol will be assessed by the trial team. Important protocol deviations
(iPD) categories will be suggested in the integrated risk management plan (IQRMP), iPDs
will be identified no later than in the Report Planning Meeting, and the iPD categories will be
updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2 for BI 1467335,
 
will be calculated according to the relevant SOP of the Sponsor [001-MCS-36-472]. 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
Biomarkers
All scans for which good quality PET emission and arterial plasma radioligand concentration 
data will be obtained, will be included in the analysis.
Primary endpoint analyses
7.3.1
Image analysis will be used to generate the outcome parameter for the PET data (proportional 
to the target availability at each PET scan), using the PET emission and the metabolite 
corrected arterial plasma input function, within an appropriate kinetic model. Tissue time-
activity curves (TACs) for each region of interest (ROI) will be analysed together with 
arterial blood data, processed to generate metabolite-corrected arterial plasma input function 
curves. Kinetic modelling techniques will then be applied to the input function and TAC data 
to estimate parameters relating to the level of target availability for each PET scan. For scans 


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following 14, 28 or 42 days of dosing with BI 1467335, fractional occupancy values will be 
generated for each post-dose PET scan by comparing the outcome parameters for baseline 
and post-dose scans for a subject (primary endpoint). In addition to the individual values, 
descriptive statistics per dose group will be provided.
The occupancy data will be related to the plasma concentration of BI 1467335 at the time of 
the PET scan.
Secondary endpoint analyses
7.3.2
Secondary endpoints:

% reduction in MAO-B availability upon treatment with 10 mg BI 1467335 on Day 
14 compared to baseline.

% reduction in MAO-B availability upon treatment with 3 mg BI 1467335 on Day 28 
compared to baseline.

MAO-B inhibition in platelet rich plasma at Day 14 (10 mg dose group only), Day 28 
and Day 42 (3 mg dose group only) compared to baseline. 
Will be analysed similarly to the primary endpoints described in Section 7.3.1 above.
The secondary endpoints Cmax and AUC0-24 of BI 1467335 will be only evaluated 
descriptively. The following descriptive statistics will be calculated: N, arithmetic mean, 
standard deviation, minimum, median, maximum, arithmetic coefficient of variation, 
geometric mean, and geometric coefficient of variation. The data format for descriptive 
statistics of concentrations will be identical with the data format of the respective 
concentrations. The descriptive statistics of PK parameters will be 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 3 
significant digits in the clinical trial report.
Safety analyses
7.3.4
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.


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For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between first trial medication intake and end of 
REP (which corresponds to the patient’s individual end of treatment; see Section 1.2.2) will 
be assigned to the treatment period. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP. Note that AEs occurring after the last per 
protocol contact but entered before final database lock will be reported to Pharmacovigilance
only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No formal interim analysis is planned, however a preliminary analysis of MAO-B inhibition 
after completion of the 10 mg dose group will be performed.
7.5
HANDLING OF MISSING DATA
Safety
7.5.1
It is not planned to impute missing values for safety parameters.


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Pharmacokinetics
7.5.2
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure [001-MCS-36-472].
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Randomisation is not applicable in this open-label, parallel group study. A list of consecutive 
random numbers for each treatment arm (10 mg and 3 mg) will be provided (see 
Section 4.1.3 for details of allocation of random numbers to subjects).
7.7
DETERMINATION OF SAMPLE SIZE
For this exploratory study, no prospective calculations of statistical precision or power have
been made. The planned sample size of 5 subjects per dose group has been selected for
practical reasons and is judged as being adequate to get reliable results regarding the trial
objectives.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract.
As a general rule, no trial results should be published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC), the Administration of Radioactive Substances Advisory Council (ARSAC) and 
competent authority (CA) according to national and international regulations. The same 
applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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


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
Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Direct access to source data and documents
8.3.2
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
Storage period of records
8.3.3
Trial site:
The trial site must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 


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Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
Collection, storage and future use of biological samples and corresponding 
8.5.1
data
Measures are in place to comply with the applicable rules for the collection and future use of 
biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants are 
qualified for the storage of biological samples collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage
Samples and/or data may be transferred to third parties and other countries as specified in the 
ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.


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The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted 
 
 under the supervision of the Principal 
Investigator. Relevant documentation on the participating (Principal) Investigators (e.g. their 
curricula vitae) will be filed in the ISF.
The PET procedure will be conducted at
 under the supervision of 
an Investigator.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

ensure appropriate training and information of local clinical trial manager (CTM), 
Clinical Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
 
Safety laboratory tests will be performed by the local laboratory of the trial site 
.
Analyses of BI 1467335 concentrations in plasma will be performed at
. Analysis of the platelet-enriched plasma will be performed at 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P13-02280
Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment 
of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012; 
10:837-58.
R15-5365
Weston CJ, Shepherd EL, Claridge LC et al. Vascular adhesion protein-1
promotes liver inflammation and drives hepatic fibrosis. Journal of Clinical 
Investigation. 2015; 125:501-520.
R15-5697
Karim S, Liaskou E, Fear J, Garg A, Reynolds G, Claridge L, Adams DH, 
Newsome PN, Lalor PF Dysregulated hepatic expression of glucose 
transporters in chronic disease: contribution of semicarbazide-sensitive 
amine oxidase to hepatic glucose uptake. Am J Physiol 307 (12), G1180 -
G1190 (2014)
R15-6044
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management 
of non-alcoholic fatty liver disease: practice guideline by the American 
Association for the Study of Liver Diseases, American College of 
Gastroenterology, and the American Gastroenterological Association
Hepatology. 2012; 55:2005-2023.
R15-6057
Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital 
Stat Rep 2013;61(4):1-117.
R15-6070
Dharel N, Fuchs M. Nonalcoholic Fatty Liver Disease – A Major Public
Health Challenge for the 21st Century. JSM Gastroenterology and
Hepatology. 2014; 1018.
R18-2789
Logan J, Fowler JS, Volkow ND, Wang G-J, MacGregor RR, Shea C. 
Reproducibility of repeated measures of deuterium substituted [11C]L-
deprenyl ([11C]L-deprenyl-D2) binding in the human brain. Nucl. Med. 
Biol. 2000; 27:43-49.
R18-3939
Fowler JS, Logan J, Volkow ND, Wang G-J. Translational neuroimaging: 
positron emission tomography studies of monoamine oxidase. Mol. 
Imaging Biol. 2005; 7: 377-387.
R18-3940
Lammertsma AA, Bench CJ, Price GW, Cremer JE, Luthra SK, Turton D, 
Wood ND, Frackowiak RSJ. Measurement of Cerebral Monoamine 
Oxidase B Activity Using L-[11C]Deprenyl and Dynamic Positron 
Emission Tomography. J. Cereb. Blood Flow Metab. 1991; 11: 545-556.
R18-3941
Fowler JS, Logan J, Wang G-J, Volkow ND, Telang F, Ding Y-S, Shea C, 
Garza V, Xu Y, Li Z, Alexoff D, Vaska P, Ferrieri R, Schlyer D, Zhu W, 
Gatley SJ. Comparison of the binding of the irreversible monoamine 
oxidase tracers, [11C]clorgyline and [11C]l-deprenyl in brain and 
peripheral organs in humans. Nucl. Med. Biol. 2004; 31: 313-319.


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R18-3942
Fowler JS, Volkow ND, Wang GJ, Logan J, Pappas N, Shea C, MacGregor 
R. Age-related increases in brain monoamine oxidase B in living healthy 
human subjects. Neurobiol Aging 1997; 18: 431-435.
R18-3943
Kumlien E, Nilsson A, Hagberg G, Långström B, Bergström M. PET with 
11C-deuterium-deprenyl and 18F-FDG in focal epilepsy. Acta Neurol. 
Scand 2001; 103: 360-366.
R18-3950
Fowler JS, Volkow ND, Cilento R, Wang G-J, Felder C, Logan J. 
Comparison of brain glucose metabolism and monoamine oxidase B (MAO 
B) in traumatic brain injury. Clin. Pos. Imag. 1999; 2:71-79.
R18-3964
Cephalon (UK) Limited. Zelapar - Summary of Product Characteristics 
(SmPC). 28 September 2015
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c04751792
. Investigator's 
Brochure: BI 1467335 in NASH and NPDR. 29 May 2018.
c08854973
 Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising oral doses of BI 1467335 in healthy 
male and female subjects (double-blind, randomised, placebo-controlled 
within dose groups). 1386.8. 05 Oct 2016.
c08980589
 A multi-centre, double-blind, parallel-group, 
randomised, placebo controlled phase II a study to investigate safety, 
tolerability, pharmacodynamics, and pharmacokinetics of different doses of 
orally administered BI 1467335 during a 12-week treatment period 
compared to placebo in patients with clinical evidence of NASH. 1386.4. 
12 Sep 2018.
c09036683
 Single ascending dose and multiple ascending dose phase 1 
study of PXS-4728A administered orally in healthy adult males. PXS-
4728A-101. 13 Nov 2015.
c14141887
. A Randomized, double-masked, placebo-controlled exploratory 
study to evaluate safety, tolerability, pharmacodynamics and 
pharmacokinetics of Orally administered BI 1467335 for 12 weeks with a 
12 week follow up period in patients with Non-proliferative diabetic 
retinopathy without center-involved diabetic macular edema (ROBIN 
study). 1386.12. 01 Aug 2018.
c16567028
. 8-07-other-preliminary-
analysis_10+15mg-appendix2. 1386.8 . 28 Mar 2017.


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c17150058
 Relative bioavailability of a BI 
1467335 tablet compared to a BI 1467335 oral solution and the effect of 
food on the bioavailability of the tablet following oral adminsitartion (a 
randomised, open-label, single dose, three-way crossover trial in helathy 
male subjects). 1386.17. 09 Nov 2017.
n00244592
 BI 1467335: 4-week oral (gavage) 
supplementary toxicity study in Sprague Dawley rats. 15B108. 06 Jul 2016
n00247850
. A Four-Week Oral Repeat Dose Toxicity and Toxicokinetic Study 
of PXS-4728A in Beagle Dogs. 53703-13-825. 04 Nov 2014.
n00252396
. Excretion in urine, faeces and bile after oral and intravenous 
administration of [14C]BI 1467335 to rats. A096/15SMB. 18 Oct 2016.
n00252404
. Pharmacokinetics of radioactivity and BI 1467335 after 
oral and intravenous administration of [14C]BI 1467335 to rats. B5778. 18 
Oct 2016.
n00257993
 In vitro inhibition of MAO-A and MAO-B 
catalyzed kynuramine deamination by BI 1467335. A437/17LU. 31 Aug 
2017.
n00259383
 Irreversible in vitro inhibition of MAO-B 
catalyzed kynuramine deamination by BI 1467335. A442/17LU. 01 
December 2017.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
24 June 2019
EudraCT number
EU number
2018-003745-41
BI Trial number
1386-0022
BI Investigational Medicinal 
Product
BI 1467335
Title of protocol
A Phase I, open-label, Positron Emission 
Tomography study in healthy male subjects to 
explore the inhibition of monoamine oxidase B in 
the brain after multiple oral doses of BI 1467335 
(non-randomized, open-label, parallel-group study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Flow Chart: 3 mg Dose Group
2. Flow Chart: 10 Dose Group
3. Section 1.3: Rationale for performing the trial
4. Section 3.1: Overall trial design and plan
5. Section 3.2: Discussion of trial design, including 
the choice of control group
6. Section 5.3.4: Pharmacokinetic-
pharmacodynamic relationship
7. Section 6.1: Visit Schedule
8. Section 8.7: Administrative structure of the trial
Description of change
1.
Flow Chart 3 mg Dose Group:
Urine drugs, alcohol breath test and urine 
nicotine have been amended to improve 
compliance by performing these tests upon 
readmission to the site on Day 7 and 14 when the 
subjects are allowed to leave the clinic.
In addition, a minor clarification regarding 
footnote 2 has been added, which states that 
predose PK sampling after Day 1 should be 
collected within 30 min before the following 
dose.


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2.
Flow Chart 10 mg Dose Group:
A minor discrepancy regarding the planned PK 
time points and EOT time window was 
corrected. In addition, a minor clarification
regarding footnote 2 has been added, which 
states that predose PK sampling after Day 1
should be collected within 30 min before the 
following dose. 
3.
Section 1.3: Rationale for performing the trial
An additional decision point was included in the 
trial: the 10 mg dose group will be investigated 
first and in case no inhibition of MAO-B is seen 
in this group, further investigation of the 3 mg 
dose group will not be performed and the study 
will be considered as complete.
4.
Section 3.2: Discussion of trial design, including 
the choice of control group
Description of the additional decision point as 
outlined in bullet point 3.
5.
Section 3.2: Discussion of trial design, including 
the choice of control group
Description of the additional decision point as 
outlined in bullet point 3.
6.
Section 5.3.4: Pharmacodynamic-
pharmacodynamic relationship
Description of this section was omitted in the 
previous version, the information that no formal 
analysis of the relationship is planned was 
added.
7.
Section 6.1 Visit schedule
Clarification regarding deviation window 
allowance for ECGs, Vital signs and Safety 
laboratory has been added.
8.
Section 8.7: Administrative structure of the trial
Laboratories for PK analysis and biomarker 
analysis have been corrected.
Rationale for change
Following discussion with the Ethics committee, an 
additional decision point was included in the trial in 
order to ensure that the minimum number of subjects 


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are investigated.
In addition, correction of discrepancies and minor 
changes in administrative structure were amended in 
the context of the amendment.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
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
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25939630
2.0
clinical-trial-protocol-version-02
A Phase I, open-label, Positron Emission Tomography study in healthy male subjects
to explore the inhibition of monoamine oxidase B in the brain after multiple oral
doses of BI 1467335 (non-randomized, open-label, parallel-group study)
Author-Clinical Trial Leader
24 Jun 2019 11:34 CEST
Approval-Therapeutic Area 
24 Jun 2019 13:00 CEST
Approval-Team Member Medicine
24 Jun 2019 13:35 CEST
Author-Trial Statistician
25 Jun 2019 11:01 CEST
Author-Trial Clinical
Pharmacokineticist
26 Jun 2019 15:19 CEST
Verification-Paper Signature
Completion
27 Jun 2019 06:35 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25939630
2.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c30677999-01
BI Trial No.:
1386-0022
Title:
A Phase I, open-label, Positron Emission Tomography study in 
healthy male subjects to explore the inhibition of monoamine 
oxidase B in the brain after multiple oral doses of BI 1467335
(non-randomized, open-label, parallel-group study)
Revised protocol 2.0
Investigational
Product:
BI 1467335
Responsible trial 
statistician:
Phone:  
Fax:    
Date of statistical 
analysis plan:
17 JAN 2020 SIGNED 
Version:
1
Page 1 of 27
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2020 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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
5.3.3
Safety and Tolerability endpoints......................................................................10
5.4.1
Demographic and other baseline characteristics .............................................11
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.4
PRIMARY ENDPOINT .....................................................................................18
7.4.1
Primary analysis of the primary endpoint........................................................18
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoints...............................................................................................19
7.5
SECONDARY ENDPOINTS.............................................................................19
7.5.1
Key secondary endpoint(s).................................................................................19
7.5.2
(Other) Secondary endpoint(s) ..........................................................................20
7.6.1
Safety parameters ...............................................................................................21


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7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse Events ....................................................................................................22
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................24
8.
REFERENCES....................................................................................................25
10.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.1: 1
Dosage and treatment schedule........................................................................12
Table 6.1: 2
Analysis phases for statistical analysis of AEs ................................................12
Table 6.2: 1
Handling of iPDs..............................................................................................14
Table 6.3: 1
Subject sets analyzed........................................................................................15
Table 10: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADME
Absorption, distribution, metabolism, and excretion
ADS
Analysis data set
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-24,N
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to 24 h
BI 
Boehringer Ingelheim
CDR
Clinical Data Repository
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,N
Maximum measured concentration of the analyte
CRF
Case report form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DNA
Desoxyribonucleic acid
ECG
Electrocardiogram
EDC
Electronic data capture
eCRF
Electronic case report form
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
iPD
Important protocol deviation
IQRMP
Integrated quality and risk management plan
MAO-B
Monoamine oxidase B


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Term
Definition / description
MedDRA
Medical Dictionary For Regulatory Activities
NIMP
Non-investigational medicinal product
PD
Pharmacodynamic(s)
PDS
Pharmacodynamic Set
PET
Positron emission tomography
PETS
PET set 
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
RAGe
Report appendix generator
ROI
Region of interest
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class
TAC
Time activity curve
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated by means of noncompartmental analysis using Phoenix 
WinNonlinTM software (current version Phoenix 6.3 or higher, Certara USA Inc., Princeton, 
NJ, USA). Outputs for the CTR will be generated using SASTM (current Version 9.4, by SAS 
Institute Inc., Cary, NC, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. 
In addition, a pharmacodynamic set (PDS) has been introduced for analysis of MAO-B 
inhibition in platelet rich plasma.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is measured by PET scans and is defined in Section 2.1.2 of the CTP:

% reduction in MAO-B availability upon treatment with BI 1467335 on the last 
treatment day (Day 28 for the 10 mg dose group and Day 42 for the 3 mg dose group) 
compared to baseline.
The % reduction in MAO-B availability refers to the whole brain. 
 
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
CTP, Section 2.1.3: 
The following secondary endpoints will be determined:

% reduction in MAO-B availability upon treatment with 10 mg BI 1467335 on Day 14 
compared to baseline.

% reduction in MAO-B availability upon treatment with 3 mg BI 1467335 on Day 28 
compared to baseline.

MAO-B inhibition in platelet rich plasma at Day 14 (10 mg dose group only), Day 28, 
and Day 42 (3 mg dose group only) compared to baseline. 

Cmax,N (maximum measured concentration of the analyte) and AUC0-24, N (area under 
the concentration-time curve of the analyte over the time interval from 0 to 24 h) on 
Day 14 (10 mg dose group only), Day 28 and Day 42 (3 mg dose group only).
The % reduction in MAO-B availability refers to the whole brain. 
 


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5.3.3
Safety and Tolerability endpoints
Safety and tolerability of BI 1467335 will be assessed based on parameters defined in 
Section 2.2.2.2 of the CTP:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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5.4.1
Demographic and other baseline characteristics
The following demographic variables and baseline characteristics will be reported in the 
eCRF: Sex, ethnicity, race, birth year, age, smoking status, alcohol history, height, weight, 
relevant medical history and concomitant therapy.
Body mass index will be calculated as weight [kg] / height [m]2.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment 
groups, and selection of doses, cf. Section 4 of the CTP.
Each subject is planned to be treated daily over a period of 4 or 6 weeks with BI 1467335 
film-coated tablets:
Table 6.1: 1
Dosage and treatment schedule
Substance
Formulation
Unit strength
Dosage
BI 1467335
Film-coated 
tablet
10 mg
2 tablets (5 mg) qd for 28 days
BI 1467335
Film-coated 
tablet
3 mg
3 tablets (1 mg) qd for 42 days
In addition to the two investigational treatments stated above, the following non-
investigational PET tracer will be used:

PET tracer (NIMP)
≤ 100 μg [11C]-L-deprenyl-D2 as solution for injection for a predose assessment and 
about 1,5 h after dosing of BI 1467335 on Day 14 (10 mg dose group only), Day 28 
and Day 42 (3 mg dose group only).
For statistical analyses of AEs, the following separate analysis phases will be defined for 
each subject:
Table 6.1: 2
Analysis phases for statistical analysis of AEs
Study analysis 
phase
Label
Start
End
Screening
Screening
Date of informed consent
Date/time of first administration of BI 
1467335
On treatment
BI 
1467335
Date/time of first administration 
of BI 1467335
12:00 a.m. on day after subject's end of 
study participation date.
In CTR Section 15, AE displays will be presented for the on-treatment phase only.
In CTR Section 15, AE tables, the following totals will be provided in addition: 

"Total on treatment", defined as the total over all on-treatment phases
AEs during the screening phase will be listed in CTR Section 16.2 but not tabulated.


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Statistical analyses of safety laboratory tests and vital signs will be conducted with clear 
differentiation between baseline (cf. Section 6.7) and on-treatment measurements.
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting. At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an iPD. For definition of iPDs, and for the process of identification of these, 
refer to the BI reference document "Identify and Manage Important Protocol Deviations 
(iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the minutes of the Report Planning Meeting via an accompanying Excel spreadsheet (3). 
Categories which are considered to be iPDs in this trial are defined in the integrated quality 
and risk management plan (IQRMP). If the data show other iPDs, the definition in the 
IQRMP will be supplemented accordingly by the time of the Report Planning Meeting.
iPDs will be summarized and listed. Table 6.2: 1 below specifies which kind of iPDs could 
potentially lead to exclusion from which analysis set. The decision on exclusion of patients 
from analysis sets will be made at the latest at the Report Planning Meeting, after discussion 
of exceptional cases and implications for analyses.


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Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief Description
Excluded from which analysis set
iPD B1 
Informed consent not available/not 
done
All
iPD B2 
Informed consent too late
None
iPD A1
Inclusion Criteria not met
PKS, PDS, PETS
iPD A2
Exclusion Criteria met
PKS, PDS, PETS
iPD C1
Randomisation not followed
Not applicable
iPD C2
Non-compliance
PKS, PDS, PETS
iPD C3
Incorrect intake of trial medication
PKS, PDS, PETS
iPD D1
Prohibited medication use
PKS, PDS, PETS
iPD D2
Improper washout of concomitant 
medication
PKS, PDS, PETS
iPD E1
Certain violations of procedures used 
to measure primary or secondary data
PKS, PDS, PETS
iPD F1
Certain violations of time schedule 
used to measure primary or secondary 
data
PKS, PDS, PETS
iPD G1
PDs affecting safety and rights of 
subjects
PKS, PDS, PETS
6.3
SUBJECT SETS ANALYSED
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of study drug. The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint and was not excluded due to a 
protocol deviation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he/she contributes only one PK parameter value to the 
statistical assessment. Analyses of PK parameters will be based on the PKS.

Pharmacodynamic analysis set (PDS): This set includes all subjects in the treated set 
(TS) who provide at least one post-baseline measurement of MAO-B inhibition in 


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platelet rich plasma which were not excluded due to a protocol deviation relevant to 
the evaluation of PD.
PET set (PETS): This set includes all subjects in the treated set (TS) who provide at 
least one PET scan at baseline and one on-treatment, i.e. the reduction in MAO-B 
availability can be calculated for at least one post-baseline measurement (either 14 or 
28 or 42 days)
The following Table 6.3: 1 contains the information which subject is used for which class of 
endpoint:
Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
PETS
PDS
PKS
Primary endpoint 
X
Secondary MAO-B availability from 
PET scan endpoints
X
Secondary MAO-B inhibition in 
platelet rich plasma endpoint
X
Secondary 
 PK endpoints 
X
Safety parameters & treatment 
exposure
X
Demographic/baseline endpoints
X
Important protocol deviations
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study is performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to first administration of 
investigational study drug will not be reported in the CTR.
Data of subjects who drop out or withdraw from the trial will be reported in the CTR as far as 
their data are available. All withdrawals will be documented and the reason for withdrawal 
reported in the CTR.


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CTP Section 7.5.1: It is not planned to impute missing values for safety parameters.
One exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards.
CTP Section 7.5.2: PK parameters that cannot be reasonably calculated based on the 
available drug concentration-time data will not be imputed.
Missing data and outliers of PK data are handled according to BI standards (4).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
A separate baseline is defined for each study treatment. The baseline is the last available 
value before first administration of BI 1467335.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the Report Planning Meeting.
Unscheduled measurements of laboratory data or vital signs data will be assumed to be repeat 
measurements of the most recent scheduled measurement (e.g. for follow-up or confirmation 
of a particular value). Therefore, unscheduled measurements will be assigned to the planned 
time point of the previous scheduled measurement.
Descriptive statistics of laboratory data will be calculated by planned time point based on the 
worst value of the subject at that planned time point (or assigned to that planned time point).
For vital signs, descriptive statistics will be calculated by planned time point based on the last 
value of the subject at that planned time point (or assigned to that planned time point).


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the standards defined in the BI standards 
with the exception of those generated for PK-calculations (6).
The individual values of all subjects will be listed. Listings will be sorted by treatment, 
subject number and visit (if visit is applicable in the respective listing). AE listings will be 
sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PD parameters the CV (arithmetic coefficient of variation) will additionally be 
calculated.
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be 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 CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.
Only descriptive statistics are planned for this section of the CTR.
7.4
PRIMARY ENDPOINT
CTP Section 7.3.1: Image analysis will be used to generate the outcome parameter for the 
PET data (proportional to the target availability at each PET scan), using the PET emission 
and the metabolite corrected arterial plasma input function, within an appropriate kinetic 
model. Tissue time-activity curves (TACs) for each region of interest (ROI) will be analysed 
together with arterial blood data, processed to generate metabolite-corrected arterial plasma 
input function curves. Kinetic modelling techniques will then be applied to the input function 
and TAC data to estimate parameters relating to the level of target availability for each PET 
scan. For scans following 14, 28 or 42 days of dosing with BI 1467335, fractional occupancy 
values will be generated for each post-dose PET scan by comparing the outcome parameters 
for baseline and post-dose scans for a subject (primary endpoint).
7.4.1
Primary analysis of the primary endpoint
The primary endpoint will be analyzed based on the PETS.
Individual line plots of reduction of MAO-B availability over time by dose group and median 
reduction of MAO-B availability by dose group over time will be created. Descriptive 
statistics will be provided.


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7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoints
An Emax model will be fitted for plasma concentration against % reduction of MAO-B 
availability. The analysis will be performed on the PKS.
The model is defined as follows:
% reduction = E0 + Emax*Concentration**N / (Concentration**N+ED50**N),
with E0 (basal effect) being set to 0. Parameters to be estimated are Emax (maximum effect), 
ED50 (concentration which produces half of Emax) and N (Hill factor).
SAS procedure PROC NLIN will be used for this analysis.
PROC NLIN DATA = indata METHOD = marquardt;
PARAMETERS IMAX = imax.-5 to imax.+5 by 2.5
                            IC50 = ic50.*0.8 to ic50.*1.2 by ic50.*0.1.
    HILL = 1 to 10 by 3;
MODEL reduct = 0+(IMAX*conc**HILL)/(IC50**HILL+conc**HILL);
RUN;
Starting values will use a range for IMAX, IC50 and HILL. The imax starting value will be 
estimated as the maximum value of MAO-B % reduction across all time points and subjects. 
This value will be increased and decreased by an absolute 2.5 twice to both sides to get a 
range of starting values (values above 100 will be set to 100). The HILL factor will be set to 
1, 4, 7, and 10. The ic50 starting value will be estimated as the median plasma concentration 
across all time points and for all subjects. This value will be decreased and increased by a 
relative 10% twice to both sides to come to an adequate starting value range (values less than 
0 will be set to 0).
The Emax model will also be presented graphically.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.


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7.5.2
(Other) Secondary endpoint(s)
The descriptive analysis of all secondary endpoints referring to MAO-B availability will 
follow the principles of analysis of the primary endpoint. Where applicable, all time points 
will be summarized in the same table or figure. 
 
Pharmacodynamic parameters
MAO-B inhibition in platelet rich plasma will be analysed descriptively by department 
Translational Medicine and Clin. Pharmacology at BI according to BI standards (4) [001-
MCS-36-472_RD-01].
Exclusion of measurements of MAO-B inhibition in platelet rich plasma
The ADS ADYC (PD values per time-point or per time-interval) contains column variables 
ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a measurement and an 
analysis flag comment (ACEXCO). Exclusion of a measurement depends on the analysis flag 
comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the value will be 
excluded for all types of analyses based on measurements. If ACEXCO is set to "DESC 
STATS" the value will be excluded from descriptive evaluations per planned time point/time 
interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME DEVIATION", 
the value can be used for further analyses based on actual times.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (5).
Pharmacokinetic parameters
Analysis of BI 1467335 concentrations in plasma will be performed by department 
Translational Medicine and Clin. Pharmacology at BI.
CTR Section 7.3.2: The secondary endpoints Cmax and AUC0-24 of BI 1467335 will be only 
evaluated descriptively. The following descriptive statistics will be calculated: N, arithmetic 
mean, standard deviation, minimum, median, maximum, arithmetic coefficient of variation, 
geometric mean, and geometric coefficient of variation. The data format for descriptive 
statistics of concentrations will be identical with the data format of the respective 
concentrations. The descriptive statistics of PK parameters will be 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 3 
significant digits in the clinical trial report.


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Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the 
value will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (5).
7.6.1
Safety parameters
Safety and tolerability will be analysed as described in Section 7.8 of this TSAP.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to screening or on-treatment phases as defined in Section 6.1. 
AEs will be analysed based on actual treatments, as defined in Table 6.1: 2.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (7) and for the class of 
AESIs.
CTP, Section 5.2.6.1.4: “The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:


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○
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 
○
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN”
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (7), AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately. Separate tables will also be provided for subjects with SAEs, subjects 
with AESIs and subjects with other significant AEs (according to ICH E3 (7)). The frequency 
of subjects with AEs will also be summarised by maximum intensity, primary SOC and 
preferred term.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards.
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.


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Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the Report Planning Meeting at the latest. It is the 
Investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values in an 
automated manner will not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see Section 
6.7) will be provided.
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.4
ECG
Relevant ECG findings will be reported as relevant medical history/baseline condition (if a 
condition already exists before first administration of study treatment) or as AE (if condition 
emerges after first administration of study treatment) and will be summarized as such. No 
separate listing or analysis of ECG findings will be prepared.
7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized as 
such. No separate listing or analysis of physical examination findings will be prepared.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, BIRDS
3.
BI-KMED-COPS-TMP-0001: "iPD log", current version; KMED
4.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies”, current version; IDEA for CON.
5.
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
6.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
7.
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, current 
version


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1
17-JAN-2020
None
This is the final TSAP