Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: yes

Brief summary:
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics (PK) of BI 1358894 in healthy male subjects following oral administration of single rising doses.

Detailed description:

Arms:
arm 1: For each dose group a placebo group was given matching placebo tablets, participants were randomized within each dose group in a 3:1 ratio (active drug:placebo), tablets taken orally with \~240 milliliter of water 30 minutes after a standard high-fat, high-calorie meal (after an overnight fast of 10 hours). arm 2: 2 film-coated tablets of 25 milligram (mg) BI 1358894 taken orally with \~240 milliliter of water 30 minutes after a standard high-fat, high-calorie meal (after an overnight fast of 10 hours). arm 3: 1 film-coated tablet of 100 milligram BI 1358894 taken orally with \~240 milliliter of water 30 minutes after a standard high-fat, high-calorie meal (after an overnight fast of 10 hours). arm 4: 2 film-coated tablets of 100 milligram BI 1358894 taken orally with \~240 milliliter of water 30 minutes after a standard high-fat, high-calorie meal (after an overnight fast of 10 hours).

Interventions: intervention 1: Placebo intervention 2: Dose group 1 - 50 mg BI 1358894 intervention 3: Dose group 2 - 100 mg BI 1358894 intervention 4: Dose group 3 - 200 mg BI 1358894
Intervention descriptions: intervention 1: For each dose group a placebo group was given matching placebo tablets, participants were randomized within each dose group in a 3:1 ratio (active drug:placebo), tablets taken orally with \~240 milliliter of water 30 minutes after a standard high-fat, high-calorie meal (after an overnight fast of 10 hours). intervention 2: 2 film-coated tablets of 25 milligram (mg) BI 1358894 taken orally with \~240 milliliter of water 30 minutes after a standard high-fat, high-calorie meal (after an overnight fast of 10 hours). intervention 3: 1 film-coated tablet of 100 milligram BI 1358894 taken orally with \~240 milliliter of water 30 minutes after a standard high-fat, high-calorie meal (after an overnight fast of 10 hours). intervention 4: 2 film-coated tablets of 100 milligram BI 1358894 taken orally with \~240 milliliter of water 30 minutes after a standard high-fat, high-calorie meal (after an overnight fast of 10 hours).

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c25765859-01
BI Trial No.
1402-0008
BI Investigational
Medicinal Product
BI 1358894
Title
Safety, tolerability and pharmacokinetics of single rising oral 
doses of BI 1358894 in healthy Japanese male subjects (double-
blind, randomised, placebo-controlled parallel dose group design)
Lay Title
A study about how different doses of BI 1358894 are taken up in 
the body and how well they are tolerated in healthy Japanese men
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Principal 
Investigator
Phone:
Fax:
Status
Final Protocol
Version and Date
Version: 1.0 
Date: 17 Jan 2019
Page 1 of 79
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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
17 Jan 2019
Revision date
Not applicable
BI trial number
1402-0008
Title of trial
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 1358894 
in healthy Japanese male subjects (double-blind, randomised, placebo-controlled 
parallel dose group design)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
The objective of this trial is to investigate the safety, tolerability, and 
pharmacokinetics of BI 1358894 in healthy Japanese male subjects. The chosen 
population of healthy male volunteers using single rising oral doses is considered 
adequate to provide the basis for the clinical development program of BI 1358894 
in Japan.
Trial objectives
To investigate safety, tolerability and pharmacokinetics following single rising 
doses of BI 1358894
Trial endpoints
Primary endpoint
The number [N(%)] of subjects with drug related adverse events
Secondary endpoints:
AUC0-tz, Cmax, AUC0-∞(if evaluable) of BI 1358894
Trial design
Double-blind, randomised, placebo-controlled within parallel dose groups
Number of subjects 
total entered
24
each treatment
8 per dose group (6 on BI 1358894 and 2 on placebo) 
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy Japanese male subjects, age of 20 to 45 years (inclusive), body mass index 
(BMI) of 18.5 to 25.0 kg/m2 (inclusive)
Test product(s)
BI 1358894 film-coated tablet (25 mg, 100 mg)


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dose
50 mg, 100 mg, and 200 mg
mode of admin.
Oral with 240 mL of water after a high-calorie, high-fat breakfast
Comparator product(s)
Matching placebo(s)
dose
Not applicable
mode of admin.
Oral with 240 mL of water after a high-calorie, high-fat breakfast 
Duration of treatment
Single dose
Statistical methods
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Dose Group 1 and 2 (50 mg and 100 mg)
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory13
PK blood 
PK urine
9
Orthostatic testing
Visual analogue scale
C-SSRS
12-lead ECG
Continuous ECG 
monitoring
Vital signs (BP, PR, RR)
Questioning for AEs and 
concomitant therapy 6
1
-28 to 
-1
Screening (SCR)1
x
x
x
x
x
x
2
-1
-24:007
09:00
Ambulatory visit
x7
x
-12:00
21:00
Admission to trial site
x5
1
-1:00
08:00
Allocation to treatment2
x2
x2
x12
x2
x2
x2,8
x2
x2
-0:30
08:30
High-calorie, high-fat
breakfast
0:00
09:00
Drug administration10
▲
▲
0:10
09:10
x
│
│
0:20
09:20
x
│
│
0:30
09:30
x
│
x8
│
x
x
1:00
10:00
x
│
x8
│
x
x
1:30
10:30
x
│
x8
│
x
x
2:00
11:00
240 mL fluid intake
x
│
x
x8
│
x
x
2:30
11:30
x
│
│
3:00
12:00
x
│
x
x8
│
x
x
4:00
13:00
240 mL fluid intake, 
thereafter lunch3
x
x
┼
x
x8
▼
x
x
5:00
14:00
x
│
x8
x
x
6:00
15:00
x
│
x8
x
x
7:00
16:00
x
│
8:00
17:00
x
┼
x
x8
x
x
10:00
19:00
Dinner3
x
│
12:00
21:00
x
┼
x8
x
x 
2
16:00
01:00
x
│
x8
x
24:00
09:00
Breakfast3
x
x
┼
x
x8
x
x
34:00
19:00
x
│
x
x8
x
x
3
48:00
09:00
Breakfast3
x
┼
x
x8
x
x
4
72:00
09:00
Breakfast3
x
┼
x
x
x
5
96:00
09:00
Breakfast3, confirmation of 
fitness11, Discharge from 
trial site
x
│
▼
x
x
x
x
x
6
120:00
09:00
Ambulatory visit
x
x
x
7
144:00
09:00
Ambulatory visit
x
x
x
8
168:00
09:00
Ambulatory visit
x
x
x
9
192:00
09:00
Ambulatory visit
x
x
x
3
10 to 
14
End of trial (EOT) 
examination4
x
x
x
x
x
x
PK: pharmacokinetics, ECG: electrocardiogram, AE: adverse event


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs (including orthostatic testing), ECG, safety laboratory 
(including drug screening, hepatitis serology, HIV antibodies and syphilis), demographics (including determination of 
body height and weight, smoking status and alcohol history), relevant medical history, concomitant therapy and review 
of inclusion/exclusion criteria, Bowdle visual analogue scales and suicidality assessment (C-SSRS).
2.
The time is approximate; the respective procedure is to be performed and completed within 2 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies, Bowdle visual analogue scales and suicidality assessment (C-SSRS).
5.
Only urine drug screening and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.    Safety laboratory to be taken and to be medically evaluated on Day -1; this safety laboratory can be omitted, if the 
screening examination is performed on Days -3, -2 or -1. 
8.
The ECG recording has to be performed as triple at this time point
9.
A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24, 24-48, 48-72 and 72-96 h.
10. One blood sample for pharmacogenomics analyses will be taken at any time after administration on Day 1.
11. Confirmation of fitness includes physical examination, vital signs, ECG, recording of AEs and concomitant therapies,
Bowdle visual analogue scales and suicidality assessment (C-SSRS).
12.  A blank urine sample for PK is to be obtained within 3 h prior to drug administration.
13.  Safety laboratory samples will be collected after the subjects have fasted for at least 10 h except 4h on Day 1.


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Dose Group 3 (200 mg)
Visit
Day
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory13
PK blood 
PK urine
9
Orthostatic testing
Visual analogue scale
C-SSRS
Neurological Examination
12-lead ECG
Continuous ECG 
monitoring
Vital signs (BP, PR, RR)
Questioning for AEs and 
concomitant therapy 6
1
-28 to 
-1
Screening (SCR)1
x
x
x
x
x
x
x
2
-1
-24:007
09:00
Ambulatory visit
x7
x
-12:00
21:00
Admission to trial site
x5
1
-1:00
08:00
Allocation to treatment2
x2
x2
x12
x2
x2
x2,8
x2
x2
-0:30
08:30
High-calorie, high-fat
breakfast
0:00
09:00
Drug administration10
▲
▲
0:10
09:10
x
│
│
0:20
09:20
x
│
│
0:30
09:30
x
│
x8
│
x
x
1:00
10:00
x
│
x8
│
x
x
1:30
10:30
x
│
x8
│
x
x
2:00
11:00
240 mL fluid intake
x
│
x
x8
│
x
x
2:30
11:30
x
│
│
3:00
12:00
x
│
x
x8
│
x
x
4:00
13:00
240 mL fluid intake, 
thereafter lunch3
x
x
┼
x
x8
▼
x
x
5:00
14:00
x
│
x8
x
x
6:00
15:00
x
│
x8
x
x
7:00
16:00
x
│
8:00
17:00
x
┼
x
x8
x
x
10:00
19:00
Dinner3
x
│
12:00
21:00
x
┼
x8
x
x 
2
16:00
01:00
x
│
x8
x
24:00
09:00
Breakfast3
x
x
┼
x
x8
x
x
34:00
19:00
x
│
x
x8
x
x
3
48:00
09:00
Breakfast3
x
┼
x
x8
x
x
4
72:00
09:00
Breakfast3
x
┼
x8
x
x
5
96:00
09:00
Breakfast3
x
x
│
▼
x8
x
x
6
120:00
09:00
Breakfast3
x
x8
x
x
7
144:00
09:00
Breakfast3, confirmation 
of fitness11, Discharge 
from trial site
x
x
x
x
x8
x
x
9
192:00
09:00
Ambulatory visit
x
x
x
11
240:00
09:00
Ambulatory visit
x
x
x
15
336:00
09:00
Ambulatory visit
x
x
x
22
504:00
09:00
Ambulatory visit
x
x
x
29
672:00
09:00
Ambulatory visit
x
x
x
3
29 to 
33
End of trial (EOT) 
examination4
x
x
x
x
x
x
x
PK: pharmacokinetics, ECG: electrocardiogram, AE: adverse event


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, neurological examination, check of vital signs (including orthostatic testing), 
ECG, safety laboratory (including drug screening, hepatitis serology, HIV antibodies, and syphilis), demographics 
(including determination of body height and weight, smoking status and alcohol history), relevant medical history, 
concomitant therapy and review of inclusion/exclusion criteria, Bowdle visual analogue scales and suicidality 
assessment (C-SSRS).
2.
The time is approximate; the respective procedure is to be performed and completed within 2 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, neurological examination, body weight, vital signs, ECG, safety 
laboratory, recording of AEs and concomitant therapies, Bowdle visual analogue scales and suicidality assessment (C-
SSRS).
5.
Only urine drug screening and alcohol breath test will be done at this time point. 
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated on Day -1; this safety laboratory can be omitted, if the 
screening examination is performed on Days -3, -2 or -1. 
8.
The ECG recording has to be performed as triple at this time point
9.
A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24, 24-48, 48-72 and 72-96 h.
10. One blood sample for pharmacogenomics analyses will be taken at any time after administration on Day 1.
11. Confirmation of fitness includes physical examination, neurological examination, vital signs, ECG, recording of AEs 
concomitant therapies and Bowdle visual analogue scales and suicidality assessment (C-SSRS).
12.  A blank urine sample for PK is to be obtained within 3 h prior to drug administration.
13.  Safety laboratory samples will be collected after the subjects have fasted for at least 10 h except 4h on Day 1.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................16
Nonclinical pharmacology....................................................................16
1.2.1
Safety pharmacology ............................................................................16
1.2.2
Toxicology..............................................................................................17
1.2.3
Nonclinical pharmacokinetics..............................................................20
1.2.4
Clinical experience in humans.............................................................21
1.2.5
Residual Effect Period..........................................................................22
1.2.6
Drug product.........................................................................................22
1.2.7
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
1.4
BENEFIT - RISK ASSESSMENT ...................................................................23
Procedure-related risks ........................................................................23
1.4.1
Drug-related risks and safety measures..............................................24
1.4.2
Overall assessment................................................................................26
1.4.3
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 endpoint ..............................................................................27
2.1.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 30
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................32
Main diagnosis for trial entry..............................................................32
3.3.1
Inclusion criteria...................................................................................33
3.3.2


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Exclusion criteria ..................................................................................33
3.3.3
Withdrawal of subjects from treatment or assessments ...................35
3.3.4
Discontinuation of trial treatment............................................35
3.3.4.1
Withdrawal of consent to trial participation ............................36
3.3.4.2
Discontinuation of the trial by the sponsor..............................36
3.3.4.3
Replacement of subjects .......................................................................36
3.3.5
4.
TREATMENTS........................................................................................ 37
4.1
INVESTIGATIONAL TREATMENTS ..........................................................37
Identity of the Investigational Medicinal Products ...........................37
4.1.1
Selection of doses in the trial................................................................37
4.1.2
Method of assigning subjects to treatment groups ............................37
4.1.3
Drug assignment and administration of doses for each subject .......38
4.1.4
Blinding and procedures for unblinding ............................................39
4.1.5
Blinding ...................................................................................39
4.1.5.1
Unblinding and breaking the code...........................................39
4.1.5.2
Packaging, labelling, and re-supply ....................................................40
4.1.6
Storage conditions.................................................................................40
4.1.7
Drug accountability ..............................................................................40
4.1.8
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................41
Other treatments and emergency procedures....................................41
4.2.1
Restrictions............................................................................................41
4.2.2
Restrictions regarding concomitant treatment .........................41
4.2.2.1
Restrictions on diet and life style.............................................41
4.2.2.2
4.3
TREATMENT COMPLIANCE.......................................................................42
5.
ASSESSMENTS....................................................................................... 43
5.1
ASSESSMENT OF EFFICACY.......................................................................43
5.2
ASSESSMENT OF SAFETY............................................................................43
Medical examination.............................................................................43
5.2.1
Vital signs...............................................................................................43
5.2.2
Safety laboratory parameters..............................................................43
5.2.3
Electrocardiogram................................................................................46
5.2.4
12-lead resting ECG.................................................................46
5.2.4.1
Continuous ECG monitoring ...................................................47
5.2.4.2
Other safety parameters.......................................................................47
5.2.5
Visual Analogue Scale (VAS) .................................................47
5.2.5.1
Suicidality assessment .............................................................48
5.2.5.2
Neurological examinations ......................................................48
5.2.5.3
Assessment of adverse events...............................................................49
5.2.6
Definitions of adverse events...................................................49
5.2.6.1


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Adverse event ............................................................49
5.2.6.1.1
Serious adverse event ................................................49
5.2.6.1.2
AEs considered ‘Always Serious’.............................50
5.2.6.1.3
Suicidal risk assessed by the C-SSRS .......................50
5.2.6.1.4
Adverse events of special interest .............................51
5.2.6.1.5
Intensity (severity) of AEs.........................................51
5.2.6.1.6
Causal relationship of AEs ........................................51
5.2.6.1.7
Adverse event collection and reporting ...................................52
5.2.6.2
AE collection.............................................................52
5.2.6.2.1
AE reporting to the sponsor and timelines ................53
5.2.6.2.2
Information required..................................................53
5.2.6.2.3
Pregnancy ..................................................................53
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................54
Assessment of pharmacokinetics .........................................................54
5.3.1
Methods of sample collection...............................................................54
5.3.2
Blood sampling for pharmacokinetic analysis.........................54
5.3.2.1
Urine sampling for pharmacokinetic analysis..........................54
5.3.2.2
Analytical determinations ....................................................................55
5.3.3
Analytical determination of analyte plasma concentration......55
5.3.3.1
Analytical determination of analyte urine concentration.........55
5.3.3.2
5.4
OTHER ASSESSMENTS .................................................................................55
Pharmacogenomic evaluation..............................................................55
5.4.1
Methods and timing of sample collection................................56
5.4.1.1
Analytical determinations........................................................56
5.4.1.2
5.5
APPROPRIATENESS OF MEASUREMENTS.............................................56
6.
INVESTIGATIONAL PLAN.................................................................. 57
6.1
VISIT SCHEDULE............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................57
Screening period....................................................................................57
6.2.1
Treatment period ..................................................................................57
6.2.2
End of Trial period ...............................................................................58
6.2.3
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 59
7.1
STATISTICAL DESIGN – MODEL ...............................................................59
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................59
7.3
PLANNED ANALYSES....................................................................................59
Primary endpoint analyses...................................................................60
7.3.1
Secondary endpoint analyses ...............................................................60
7.3.2
Safety analyses.......................................................................................61
7.3.4
7.4
INTERIM ANALYSES .....................................................................................62


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7.5
HANDLING OF MISSING DATA ..................................................................62
Safety......................................................................................................62
7.5.1
Pharmacokinetics..................................................................................62
7.5.2
7.6
RANDOMISATION ..........................................................................................62
7.7
DETERMINATION OF SAMPLE SIZE ........................................................63
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 64
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................64
8.2
DATA QUALITY ASSURANCE .....................................................................65
8.3
RECORDS..........................................................................................................65
Source documents .................................................................................65
8.3.1
Direct access to source data and documents.......................................66
8.3.2
Storage period of records.....................................................................66
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................67
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......67
8.6
TRIAL MILESTONES .....................................................................................67
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................67
9.
REFERENCES......................................................................................... 69
9.1
PUBLISHED REFERENCES...........................................................................69
9.2
UNPUBLISHED REFERENCES.....................................................................70
10. APPENDICES .......................................................................................... 72
10.1
VISUAL ANALOGUE SCALE (VAS) ............................................................72
10.2
COLUMBA-SUICIDE SEVERITY RATING SCALE..................................73
11. DESCRIPTION OF GLOBAL AMENDMENT................................... 79
11.1
GLOBAL AMENDMENT 1 .............................................................................79


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2
Amount of analyte eliminated in urine over the time interval t1 to t2
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC
Area under the concentration-time curve of the analyte in plasma
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24h
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
%AUCtz-∞
The percentage of AUC0-∞obtained by extrapolation
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
borderline personality disorder
C16h
Concentration of the analyte in plasma at 16h after dosing
CA
Competent authority
CI
Confidence interval
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
CLR, t1-t2
Renal clearance of the analyte in plasma from the time point t1 to t2
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central Nervous System
CRF
Case report form
CRO
Contract Research Organization
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Cardiovascular
DMET
“drug metabolizing enzymes and transporters
DILI
Drug induced liver injury
DMET
drug metabolizing enzymes and transporters
DRF
Dose Range Finding
ECG
Electrocardiogram


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eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
FDA
Food and Drug Administration
FE
Food Effect
fet1-t2
Fraction of administered drug excreted unchanged in urine over the time 
interval from t1 to t2
FIH
First in human
GCP
Good Clinical Practice
hERG
human ether-a-go-go related gene
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
LVSP
left ventricular pressure parameters 
MDD
major depressive disorder 
MedDRA
Medical Dictionary for Regulatory Activities
MRTpo
Mean residence time of the analyte in the body after oral administration
nM
Nanomolar 
NOAEL
No observed adverse effect level
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QD
once daily
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)
RAUCt1-t2,M/P
Ratio of the AUC value of the metabolite versus AUC value of the mother 
compound over time interval t1-t2
RCmax,t1-t2,M/P
Ratio of the Cmax value of the metabolite versus Cmax value of the 
mother compound after single dose
REP
Residual effect period
RR
Respiratory rate
SAE
Serious adverse event
SCR
Screening


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SRD
Single-rising dose
SOP
Standard Operating Procedure
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TRPC
transient receptor potential cation channel
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VAS
Visual analogue scale
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WBC
White blood cells


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Boehringer Ingelheim (BI) is developing BI 1358894, an oral,
 
 adjunct 
 for the 
treatment 
 is a debilitating disease characterised by 
 and often by 
 
 and
. It can strongly impact a person’s life and health, including 
significantly increased risk of suicidality, and is difficult to treat, even with systematic 
antidepressant strategies. In the 
 
trial of
 patients with
, about 
 of the patients did not reach 
 different medications 
and continued to experience residuals 
symptoms
which significantly impacted the patients’ quality of life 
 
When 
 is insufficient, clinicians employ different 
 strategies 
including add-on treatment with 
 or 
 When 
 
strategies also fail,
 therapies such as 
 may be 
used.
 with an estimated prevalence of around 
 in the general 
community 
 and severe impaired quality of life 
. The main symptom 
clusters of
 
 Patients with
 have 
 
 and a rate of 
 that is 5
 higher than in the 
general population 
Even the presence of a single diagnostic feature of 
 is 
predictive for poor functioning and psychiatric illness burden 
 Treatment 
guidelines recommend 
 as the mainstay of treatment, but pharmacotherapy is 
commonly used as an adjunctive, symptom-targeted component of treatment. However, no 
drug is approved for the treatment of 
 are involved in the regulation of 
 
They are most highly expressed in 
 and 
 which are involved in modulation and processing of 
 Pre-clinically, treatment with BI 1358894 has shown diminished 
 and 
 and increased 
without impairing other brain functions such as 
 
It is hypothesized that in patients with 
 disorders, an 
 is a major 
contributor to 
 and there is growing evidence supporting the role of 
in the emotion 
processing 
observed in patients with 
 Therefore, treatment 
with BI 1358894 has the potential to improve 
in 
patients with 


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1.2
DRUG PROFILE
Nonclinical pharmacology
1.2.1
channels are 
 
 channels implicated in diverse physiological functions, including 
 
 
Safety pharmacology
1.2.2


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Toxicology
1.2.3


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Nonclinical pharmacokinetics
1.2.4
e 
p
ll 
 


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Clinical experience in humans
1.2.5
A FIH (first-in-human) trial [Trial 1402-0001; c13880029] is currently being conducted to 
explore the safety, tolerability and pharmacokinetics (PK) of single rising oral doses of 
BI 1358894 in healthy male subjects (single-blind, partially randomised, placebo-controlled 
parallel group design) and to evaluate the effect of food on the relative bioavailability of  
BI 1358894 (open-label, randomised, two-way cross-over design). 
In accordance with the trial protocol, the study continued with the food effect (FE) part at a 
dose level of 50 mg and 100 mg of BI 1358894 administered under fasted and fed conditions, 
according to an open-label, two-period crossover design. Twenty healthy male subjects 
aligned to the FE part have completed the study. 


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Residual Effect Period
1.2.6
The Residual Effect Period (REP) of BI 1358894, the time interval when measurable drug 
levels or pharmacodynamics (PD) effects are still likely to be present after the last 
administration, 
.
Drug product
1.2.7
Please refer to Section 4.1. For a more detailed description of the BI 1358894 profile, please 
refer to the current IB
1.3
RATIONALE FOR PERFORMING THE TRIAL
 form ion channels that are involved in the regulation of 
 
. They are highly expressed in 
 
involved in modulation and processing of 
 It is hypothesized 
that in patients with 
 disorders, an 
 is a major contributor to 
 
 BI 1358894 may therefore have the potential to improve 
 symptoms and 
 in patients with 
The objective of this trial is to investigate the safety, tolerability, and pharmacokinetics of 
BI 1358894 in healthy Japanese male subjects. The chosen population of healthy male 
volunteers using single rising oral doses is considered adequate to provide the basis for the 
clinical development program of BI 1358894 in Japan.
The pharmacokinetic and safety data obtained in the current study will help to define 
appropriate doses for further studies with this compound.


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Dose Selection
In this trial it is intended to investigate the safety and tolerability of 50 mg, 100 mg, and 200 
mg single dose under the fed condition. The background for this dose selection is described in 
the following. 
The dose range in this trial is expected to cover the potential highest dose in Phase II. The 
safety, tolerability and pharmacokinetic data will provide further insight on the integration of 
Asian population into global Phase II.
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 BI 1358894. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
Procedure-related risks
1.4.1
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.


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The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (400 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
1.4.2
Risk factors were derived from (1) observations in nonclinical studies, (2) the mode of action 
and nature of the target, and (3) the relevance of animal models. 
Risks derived from observations in non-clinical studies
Rats and dogs were employed as the animal species for general toxicology investigations on 
BI 1358894, because in vitro and in vivo profiling supported the suitability of both species for 
nonclinical safety profiling of BI 1358894. 
As summarised in 
 potential risks observed in non-clinical studies are a long 
lasting 
 in rats, an 
 in rats and dogs, and 
signs of a 
 in rats. All findings 
were observed within 5 days after the start of treatment. The 
 observed in rodents 
and non-rodents can be easily monitored in a Phase I study 
 
 induced by BI 1358894 occurred early after the start of dosing and 
resolved despite continued treatment, indicating its transient character. The non-clinical 
safety data support clinical Phase I trials in non-childbearing humans with daily oral 
administration for up to 4 weeks.
Mode of action and nature of the target
The 
 members are 
 considered to play a crucial role in physiological 
processes such as to act as a cellular sensor or to support signal transmission 
 The 
subtypes 
 form 
 that are involved in the regulation of 
. They are highly expressed in 
 
 which are involved in modulation 
and processing of 
 Preclinically,
 of these receptors by 
BI 1358894 has resulted in diminished 
 and increased 
 
without impairing other brain functions such as 
 and 
. In 
accordance with these findings, 
deficient mice display an 
 phenotype 
 This supports the assumption that 
 in healthy subjects due to an 
inhibition of 
 are limited to a 
.  However, clinical data with 
compounds inhibiting this target have yet to be published.


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Relevance of animal models
Human 
 proteins show high homology with the rat, mouse, and dog 
proteins and the potency of BI 1358894 to the target is comparable across species. In 
addition, expression at the protein level is similar across different species, including human. 
Rat and dog had good oral bioavailability, significant systemic exposure, and good 
tolerability after oral dosing of a nanosuspension of BI 1358894. Finally, all known 
metabolites formed after incubation of human hepatocytes with BI 1358894 were covered 
with the combination of rat and dog. Overall, pharmacodynamic activity, pharmacokinetics, 
and metabolism all indicate that rat and dog were suitable species for nonclinical safety 
profiling of BI 1358894.
It should be highlighted that toxicity study in rats 
 did not reveal any 
toxicologically relevant effects of BI 1358894 on the immune system up to the highest tested 
dose of 
. Furthermore, the pharmacological effects of 
BI 1358894 are dose dependent and no evidence for irreversible effects has been observed. 
Therefore, despite the novelty of the target, BI 1358894 is not considered a high-risk 
compound.
Risk minimization (safety precautions and stopping rules)
The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers: 

Careful dose selection

Shallow dose escalation using a factor 2 for all rising steps 

For safety reasons, Dose Group 3 will be divided into 2 cohorts of 4 subjects each (3
on active drug, 1 on placebo). The dosing of the cohorts will be separated by at least 
48h. 

If one dose level was safe and showed acceptable tolerability and if no stopping 
criterion was met (see Section 3.3.4), the next higher dose will be given, maintaining 
a time interval of at least 6 days (referring to the first subject of each dose group)

An extensive safety laboratory will be performed with special focus on full blood 
exam (see Flow Chart)

A thorough ECG monitoring including continuous ECG monitoring for at least 15 
min pre dose and over 4 hours post dose to cover the anticipated period of highest 
drug exposure and additional repeated, with frequency indicated in the Flowchart,
single 12-lead ECGs over 96 hours for Dose Groups 1 and 2 or over 144 hours for 
Dose Group 3 following drug administration. Dose escalation would be stopped as 
soon as at least 2 subjects at one dose level showed relevant QT prolongation (see 
Section 3.3.4.3 for details).

In this study, blood pressure and heart rate will be closely monitored (see Flow 
Chart). Dose escalation will be stopped if at least 2 subjects at one dose level show a 
sustained decrease in systolic blood pressure of ≥20 mmHg for at least 2 hours after 
drug administration compared to baseline (Day 1, predose). Orthostatic testing will be 
performed to detect whether potential hemodynamic effects of BI 1358894 might 
interfere with daily life activities. Dose escalation will be stopped if orthostatic 


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dysregulation (see Section 5.2.2 for definition) is observed in more than 1 subject 
(severe) or more than 3 subjects (moderate) per dose group

Adequate safety monitoring will be performed (e.g., vital signs including ECGs, 
safety laboratory tests including hormone parameters, adverse events including 
Bowdle visual analogue scales). 

Subjects will be hospitalised throughout the study from Day -1 to Day 5 for Dose 
Groups 1 and 2 or from Day -1 to Day 7 for Dose Group 3 and will be discharged 
only after a formal assessment and confirmation of fitness by an investigator or 
qualified designee. During the in-house stay, the subjects will be under medical 
observation and thoroughly monitored for both expected and unexpected adverse 
events
Drug induced liver injury
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 5.2.6.1.5, adverse events of special interest.
Overall assessment
1.4.3
In summary, although not therapeutically tested in humans to date, BI 1358894 has the 
potential to become an oral treatment for 
 as an adjunct to 
 therapy and for the treatment of 
. Based upon 
preclinical data for BI 1358894, the preliminary clinical data from the on-going FIH study, as 
well as the implemented safety measures described above, healthy subjects will not be 
exposed to undue risks in relation to the important information expected from this trial as a 
basis for further clinical development of this compound. Healthy volunteers are not expected 
to have any direct benefit from participation in the clinical trial with BI 1358894, as is the 
usual case in such Phase I trials. Considering the medical need for the development of a safer 
and more effective treatment for patients with 
 disorders, the 
Sponsor considers that the benefit outweighs the potential risks and justifies exposure of 
healthy human volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics
(PK) of BI 1358894 in healthy male subjects following oral administration of single rising 
doses.
Primary endpoint
2.1.2
The primary endpoint for assessment of safety and tolerability of BI 1358894 is the number 
[N(%)] of subjects with drug related adverse events.
Secondary endpoint
2.1.3
The following pharmacokinetic parameters will be determined for BI 1358894 if feasible:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data time point tz)

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single-rising dose trial is designed as double-blind, randomised, and placebo-controlled 
within parallel dose groups.
It is planned to include a total of 24 healthy male subjects in the trial. The subjects will be 
assigned to 3 groups consisting of 8 subjects per group; the groups will be dosed sequentially
(see Table 3.1: 1).
The trial design is depicted in Figure 3.1: 1. 
Figure 3.1: 1 
Overview of trial design
Within each dose group, 6 subjects will receive BI 1358894 and 2 will receive placebo. Only 
one dose is tested within each dose group.


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The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
Dose (mg)
50
100
200
Number of subjects
8
8
8
Subjects receiving placebo
2
2
2
Subjects receiving active drug
6
6
6
The groups will be dosed consecutively in ascending order, and a time interval of at least 6
days will be maintained between the last drug administration to subjects in the previous dose 
group and the first drug administration to subjects in the subsequent dose group. The decision 
to treat the next dose group will be based upon safety, and tolerability data of all the 
preceding dose groups. The next dose group will only be treated if, in the opinion of the 
investigator, no safety concerns have arisen in the preceding dose groups (i.e. no dose-
limiting events occurred), and if none of the pre-specified trial-specific stopping criteria have 
been met (refer to Section 3.3.4). For safety reasons, Dose Group 3 will be divided into 
2 cohorts (per cohort: 3 subjects on active and 1 subject on placebo, treated in parallel). Both 
cohorts will be dosed in a randomised fashion.
A documented safety review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime by the Principal Investigator (or 
an authorised deputy) or the sponsor of the study (for instance, due to the occurrence of any 
unforeseen adverse events). 
Although no formal Safety Review meeting will take place within a given dose group, safety 
will be continuously monitored during this trial, and an individual will only be dosed in the 
absence of any safety concern (i.e. no dose-limiting events occurred) and if none of the pre-
specified trial-specific stopping criteria have been met (refer to Section 3.3.4).
The minimum data set for review consists of the following:

AEs in the current and preceding dose groups including clinically relevant findings 
from ancillary safety testing listed below (Note: AEs may be ongoing at the time of 
Safety Reviews and AE information may be subject to change prior to Database Lock)

Results from 12-lead ECG in the current and preceding dose groups

Vital signs in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the Clinical Trial Leader (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs, and out-of-range 
laboratory results (if considered clinically significant). Dose escalation will only be permitted 


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if no safety concerns exist neither in the opinion of the Principal Investigator (or an 
authorised deputy) nor the Clinical Trial Leader (or an authorised deputy). 
Safety Reviews can be conducted face-to-face or by video/telephone conference. The Clinical 
Trial Leader is responsible for the organisation and minutes of the reviews. Minutes will be 
signed off by the Principal Investigator (or an authorised deputy) and Clinical Trial Leader
(or an authorised deputy), and will be filed in the investigator site file (ISF) and trial master 
file (TMF).
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single-rising dose trials, the sequential rising dose design described in Section 3.1 is 
viewed favourably under the provision not to expose the subjects involved to undue risks
since the main study objective is to investigate safety and tolerability of BI 1358894.
With the rising dose design, double-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, subjects and investigators will 
be aware of the dose of drug administered. The disadvantage of the trial design is a possible 
observer bias with regard to the dose-dependent effects; in addition, the sequential dosing of 
groups could potentially result in time-related effects. However, as such effects are expected 
to be small relative to the differences between the doses in the broad range investigated, 
unbiased comparisons between treatments can still be expected.
It is standard in single or multiple rising dose trials involving healthy volunteers to include a 
placebo group to control for safety and tolerability of the trial medication. Each dose group 
consists of 8 subjects, with 6 on active treatment, and 2 on placebo. For data analysis 
purposes, the placebo control group will include all subjects of all dose groups treated with 
placebo. Six subjects per active treatment group are generally considered to be sufficient for 
the exploratory evaluation of pharmacokinetics.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 24 healthy male will enter the study. Subjects will be recruited from the 
volunteers' pool of the trial site.
Only male subjects will be included in the trial because no data on reproductive toxicology 
are available at this time.
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.


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Inclusion criteria
3.3.2
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests
2. Japanese ethnicity, according to the following criteria:
-
born in Japan, have lived outside of Japan <10 years, and have parents and 
grandparents who are Japanese
3. Age of 20 to 45 years (inclusive) at screening
4. BMI of 18.5 to 25.0 kg/m2 (inclusive) at screening
5. Signed and dated written informed consent prior to admission to the study, in accordance 
with Good Clinical Practice (GCP) and local legislation
6. Willingness to comply with contraception requirements. Subjects who are sexually active 
must use with their female partner, adequate contraception throughout the study and until 
three months after the last administration of trial medication. Adequate methods are:

A vasectomy performed at least 1 year prior to screening (with medical assessment of 
the surgical success) or

Surgical sterilisation (including bilateral tubal occlusion, hysterectomy or bilateral 
oophorectomy) of the subject’s female partner or

The use of condoms, if the female partner uses an adequate contraception method in 
addition, e.g., intrauterine device (IUD), hormonal contraception (e.g., implants, 
injectables, combined oral or vaginal contraceptives) that started at least 2 months 
prior to first drug administration, or barrier method (e.g., diaphragm with spermicide)
Unprotected sexual intercourse with a pregnant female partner is not allowed throughout 
the study and until three months after the last administration of trial medication.
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. C-Reactive Protein (CRP) > upper limit of normal (ULN),  erythrocyte sedimentation rate 
(ESR) ≥ 15 millimeters/hour, liver and kidney parameter above ULN, other 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)


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7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections including viral hepatitis, human immunodeficiency 
virus (HIV) and/or syphilis. (Subject with positive Hepatitis B core antibody will not be 
allowed to participate in this trial)
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more 30 g per day for males)
16. Drug abuse or positive drug screening
17. Blood donation of more than 400 mL within 12 weeks or 200 mL within 30 days or 
plasma donation within 2 weeks prior to administration or intended blood donation during 
the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
23. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
24. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
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 End of Trial (EOT) visit, the discontinued subject should if possible be questioned for 
AEs and concomitant therapies in order to ensure collection of AEs and concomitant 
therapies until the planned EOT visit date, if not contrary to any consent withdrawal of the 
subject.
Discontinuation of trial treatment
3.3.4.1
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. An AE or clinically significant laboratory change or abnormality occurs that the 
investigator assesses as warranting discontinuation of treatment. This may include cases 
of sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg), clinically relevant changes in ECG requiring intervention, or unexplained 
hepatic enzyme elevations at any time during the trial
6. The subject has an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample), or ALT 
and/or AST elevations ≥10 fold ULN and/or needs to be followed up according to the 
DILI checklist provided in the ISF
7. The subject shows a raised CRP level of >3.00 mg/dL or an Erythrocyte Sedimentation 
Rate (ESR) of ≥ 20 millimeters/hour.
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.


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A subject can also be removed from the trial if eligibility criteria are being violated.
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.
Withdrawal of consent to trial participation
3.3.4.2
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see section 3.3.4.1 above
Discontinuation of the trial by the sponsor
3.3.4.3
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
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk assessment. Dose escalation will be terminated if more 
than 50% of the subjects at one dose level show drug-related and clinically relevant 
adverse events of moderate or severe intensity, or if at least one drug-related serious 
adverse event is reported.
3. Violation of GCP, or the CTP (clinical trial protocol), 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. Dose escalation will be stopped if at least 2 subjects on active treatment at one dose level 
have relevant individual QT prolongations, i.e. a QTc increase of greater than 60 ms from 
baseline in connection with absolute QT or QTc greater than 500 ms, as confirmed by a 
repeat ECG recording
6. Dose escalation will be stopped if at least 2 subjects at one dose level showed a sustained 
decrease in systolic blood pressure of ≥ 20 mmHg for at least 2 hours after drug 
administration compared to baseline (Day 1, predose) which will be measured after 15 
min in supine position (to avoid false positive signals because of the required prolonged 
resting period after drug intake).
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
Replacement of subjects
3.3.5
If some subjects do not complete the trial, the Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. A replacement subject will be assigned a unique trial subject number, and will be 
assigned to the same treatment as the subject 
 replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products have been manufactured by BI Pharma GmbH & Co. KG. 
Identity of the Investigational Medicinal Products
4.1.1
The characteristics of the test product are given below:
Substance:
BI 1358894
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg, 100 mg
Posology:
2-0-0 (50 mg), 1-0-0 (100 mg), and 2-0-0 (200 mg)
Route of administration:
oral
Duration of use:
Single dose
The characteristics of the reference product (placebo) are given below:
Substance:
Matching placebo
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
2-0-0 (50 mg), 1-0-0 (100 mg), and 2-0-0 (200 mg)
Route of administration:
oral
Duration of use:
Single dose
Selection of doses in the trial
4.1.2
The dose range of BI 1358894 for this trial was selected on the basis of the data obtained in 
the ongoing FIH SRD Trial 1402-0001. So far, dose levels up to 200 mg in fasting status and 
100 mg in fed status were well tolerated.
The doses selected for this trial cover the estimated therapeutic range and supra-therapeutic 
range and include a safety margin (see Section 1.2).
Method of assigning subjects to treatment groups
4.1.3
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects are allocated to 1 of the 3


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dose cohorts, the following subjects will be allocated to one of the other dose cohorts. 
Therefore, the allocation of subjects to dose cohorts is not influenced by trial personnel, but 
only by the subjects’ temporal availability. Because the study includes healthy subjects from 
a homogenous population, relevant imbalances between the dose groups are not expected.
Subjects will be assigned to treatments (active treatment or placebo) prior to the first
administration of trial medication. For this purpose, the randomisation list will be provided to 
the trial site in advance. Numbers of the randomization list will be allocated to subjects by the 
method ‘first come first served’. Subjects are then assigned to treatment according to the 
randomisation list. Once a subject number has been assigned, it cannot be reassigned to any 
other subject.
The randomisation procedure is described in Section 7.6.
Drug assignment and administration of doses for each subject
4.1.4
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of units for 
placebo corresponds to the number of units of the corresponding dose level.
Table 4.1.4: 1
BI 1358894 and placebo treatments, oral administration
Dose
Substance
Pharmaceutical form
Unit strength
Number of units 
per administration
Total dose
1
BI 1358894
Film-coated tablet
25mg
2 tablet
50 mg
2
BI 1358894
Film-coated tablet
100 mg
1 tablets
100 mg
3
BI 1358894
Film-coated tablet
100 mg
2 tablet
200 mg
1-3
Placebo*
Film-coated tablet
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups
The trial medication will be administered to the subjects, while in a sitting position, as an oral 
dose together with about 240 mL of water under supervision of the investigating physician or 
an authorised designee in the morning of Day 1. For drug administration, the so-called four-
eye principle (two-person rule) should be applied.
After an overnight fast of at least 10 hours, a high-fat, high-calorie breakfast will be served 
30 min before drug administration. The subjects must completely consume the meal prior to 
drug intake. The composition of the standard high-fat, high-calorie meal is detailed in Table 
4.1.4: 2; this meal is in compliance with the Food and Drug Administration (FDA) guidance
'Food-Effect Bioavailability and Fed Bioequivalence Studies' [R03-2269]. For restrictions 
with regard to diet, see Section 4.2.2.2.


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Table 4.1.4: 2
Composition of the high-fat, high-calorie meal
Ingredients
kcal
102g  roll
322
105g  sausage
337
36g   process cheese
122
50g   boiled egg (whole content)
76
12g   tomato ketchup
14
6g  
mayonnaise
40
150 mL water
0
Sum1
911
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat. 
Subjects will be kept under close medical surveillance until 96 h for Dose Groups 1 and 2 and 
144 h for Dose Group 3 after drug administration. During the first 2 h after drug 
administration, subjects are not allowed to lie down (i.e. no declination of the upper body of 
more than 45 degrees from upright posture except for medical examination) or to sleep. For 
restrictions with regard to diet see Section 4.2.2.2.
Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
The trial is designed double-blind. The treatments administered (active or placebo) will be 
blinded to the subjects and the investigators (outcome assessors) in order to limit the 
occurrence of any bias which the knowledge of treatment may have.
Regarding the sponsor, the database of this trial will be handled open label. This means that 
trial functions of the sponsor are unblinded (including clinical trial leader, data manager, 
statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug metabolism scientist as 
well as dedicated contract research organization (CRO) personnel). The objective of the trial 
is not expected to be affected.
Within the central ECG lab, the staff involved with interval will be blinded with respect to 
the treatment and also with regard to the recording date and time as well as planned time 
points of the ECGs. The interval measurements for a given subject will be performed in a 
random and blinded sequence by a single technician.
Unblinding and breaking the code
4.1.5.2
The investigator or designee will be supplied with a set of sealed envelopes containing the 
medication codes for each subject according to the randomisation scheme. The envelopes will 
be kept unopened at the trial site until the end of data collection. An envelope may only be 
opened in emergency situations when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or otherwise assure safety of 
trial participants. If the envelope for a subject is opened, the sponsor must be informed 


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immediately. The reason for breaking the code must be documented on the envelope and/or 
appropriate CRF page along with the date and the initials of the person who broke the code.
Packaging, labelling, and re-supply
4.1.6
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. Examples of the labels will be available in 
the ISF.
No re-supply is planned.
Storage conditions
4.1.7
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the
correct temperature. If the storage conditions are found to be outside the specified range, the 
clinical trial manager (as provided in the list of contacts) is to be contacted immediately.
Drug accountability
4.1.8
The investigator or designee will receive the investigational drugs from the sponsor when the 
following requirements are fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (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 (CA)

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. Receipt, usage and disposal must be documented on the respective forms. Account must 
be given for any discrepancies.
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 return to the sponsor 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 return to the 


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sponsor, the investigator or designee must verify that no remaining supplies are in the 
investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
Other treatments and emergency procedures
4.2.1
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.
In case of alterations of blood pressure (hypotension) and heart rate (tachycardia), which 
were reported in toxicology studies (see section 1.2.3), physical interventions will be the first 
treatment of symptoms. If unsuccessful, appropriate drug therapy will be initiated according 
to common guidelines and algorithms trained in emergency trainings. Dependent on 
individual symptoms, for the treatment of tachycardia this may include intravenous 
administration of beta blockers or appropriate antiarrhythmic drugs. For the treatment of 
hypotension, in addition to volume substitution, administration of vasopressors may be a 
further step. The entire staff of the trial site assuming medical responsibility during conduct 
of the study is routinely trained in emergency procedures.
Restrictions
4.2.2
Restrictions regarding concomitant treatment
4.2.2.1
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.
Restrictions on diet and life style
4.2.2.2
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the water served with 
breakfast (see Table 4.1.4: 2), the water administered with the drug, and an additional 
240 mL of water served on Day 1 at 2 h and 4 h post-dose (mandatory for all subjects). 
During the days of urine collection, total fluid intake should be at least 1.5 litres and should 
not exceed 3.5 litres.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each study period is collected.
Poppy-seed containing products should not be consumed starting 4 days before first trial drug 
administration until last PK sampling of the trial.


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Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 4 h before until 4 h after each administration of trial 
medication.
Smoking is not allowed during in-house confinement while admitted to the trial site.
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.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion 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). 


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
Medical examination
5.2.1
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history, relevant medical history and concomitant therapy, review of 
inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory 
tests, a physical examination, Bowdle visual analogue scales and suicidality assessment (C-
SSRS). At the end of trial examination, it will include review of vital signs, 12-lead ECG, 
laboratory tests, a physical examination including determination of weight, Bowdle visual 
analogue scales and suicidality assessment (C-SSRS).
Vital signs
5.2.2
Systolic and diastolic BP as well as PR will be measured by a blood pressure device 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. Respiratory rate (RR) will be measured after 5 
minutes of rest in supine position for at least 1 minute.
Orthostatic tests will be performed at the time points indicated in the Flow Chart. Subjects 
should have spent at least 5 min in the supine position before blood pressure and pulse rate 
are measured the first time. A further 2 measurements will be performed immediately after 
standing up and after 3 min in a standing position. The term “Orthostatic dysregulation” will 
be used to describe adverse events that occur during orthostatic testing. Orthostatic 
hypotension is defined as a reduction in systolic BP of ≥20 mm Hg or in diastolic BP of ≥10 
mm Hg within 3 minutes of standing and will be recorded as an AE. Orthostatic hypotension 
may be accompanied by symptoms of dizziness, diaphoresis, a decline in blood pressure, 
tachycardia (PR >100 bpm), or even fainting (which is reflected in the assessment of AE 
intensity).
At the time points given in the Flow Chart, the following sequence of measurements should 
be adhered to: 12 lead-ECG and vital signs will be done before blood sampling; orthostatic 
testing will be done after blood sampling. While standing up, subjects will be accompanied 
by staff.
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
except 4h on Day 1. For retests, at the discretion of the investigator or designee, overnight 


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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. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count and clinically relevant 
in the opinion of the investigator or in the urinalysis, respectively.
Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Erythrocyte Sedimentation Rate (ESR)
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if automatic
differential WBC is abnormal and 
clinically relevant in the opinion of the 
investigator)
Polymorphnuclear neutrophils (segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
Hormones1
Thyroid stimulating hormone (TSH)
fT3, fT4
Substrates1
Plasma glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Protein electrophoresis (only at screening examination)
Albumin 
Alpha-1-Globulin
Alpha-2-Globulin
Beta-Globulin
Gamma-Globulin 
C-Reactive Protein (CRP) 
Uric acid 
Total cholesterol 
Triglycerides


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
Test name 
Electrolytes
Sodium
Potassium
Calcium
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment (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)
1
Protein electrophoresis only at screening. Hormones only at screening and end of trial.
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. Infectious serology is planned at screening only. Drug screening will be performed at 
screening and after admission to the trial site.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody and/or antibody (qualitative)
Syphilis test (RPR, TP antibody method)
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
at screening and upon admission to the trial site, and may be repeated at any time during the 
study at the discretion of an investigator or designee. The results will not be included in the 
CTR
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at the local 
laboratory of the trial site or/and at a CRO designated by the sponsor.


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Electrocardiogram
5.2.4
12-lead resting ECG
5.2.4.1
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (MAC 2000 ECG machines, GE Healthcare) at the time 
points given in the Flow Chart.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for a 10-second duration after the 
subjects have rested for at least 5 minutes in a supine position. The site personnel will be 
instructed to assure a relaxed and quiet environment so that all subjects are at complete rest 
during the recordings. ECG assessment will always precede all other study procedures of the 
same time point (except blood drawing from an intravenous cannula which is already in 
place) to avoid impact of sampling on the ECG quality.
Electrode placement will be performed according to the method of Wilson, Goldberger and 
Einthoven modified by Mason and Likar (hips and shoulders instead of ankles and wrists). 
Precise electrode placement will be marked with an indelible mark on the skin to allow 
reproducible placement throughout the study.
Triple ECGs will be recorded (within 180 sec) at all-time points on Day 1 to Day 3 (48 h) for 
Dose Groups 1 and 2 or on Day 1 to Day 7 (144h) for Dose Group 3. At all remaining time 
points, single ECGs will be recorded.
All locally printed ECGs will be evaluated by the investigator or a designee.
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle 
movements, electrode dislocation). For time points with triple ECGs, all three single ECGs 
will be repeated. For the repeats due to quality reasons, only the repeated ECG recordings 
will be sent to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. Unscheduled ECGs will not be 
included into the statistical analysis of interval lengths.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of cardiac 
safety during the study, the QT and QTcF values generated by the ECG machines or their 
manual corrections by the investigators will be used. In doubtful cases, ECGs may be sent 
upfront for centralised evaluation (see below). In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening), if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.
A centralised evaluation (during study or post study) of all 12-lead ECGs recorded on Day 1
to Day 3 (48h) for Dose Groups 1 and 2 or on Day 1 to Day 7 (144h) for Dose Group 3 will 
be performed by an independent ECG laboratory. This analysis will include the determination 
of cardiac axis (automatic evaluation based on a validated GE-12-SL-algorithm or 
equivalent) as well as the intervals RR, PR, QRS and QT measured semi-automatically.


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With the exception of the first triple ECG (used as baseline before the drug administration), 
only the first of the three replicate ECGs at a single assessment time will be evaluated. The 
remaining second and third replicate ECGs will be stored for additional analyses if required, 
e.g., by authorities at a later time point.
For each QT interval, the RR interval preceding the QT will be measured to calculate the 
respective frequency corrected QTc intervals ‘QTcF’ according to Fridericia’s formula 
(QTcF = QT/ RR1/3) and ‘QTcB’ according to Bazett’s formula (QTcB = QT/ RR1/2). The 
QTcF correction will be used for evaluation and reporting. Abnormalities detected during 
centralised ECG evaluation will not necessarily qualify as AE. All interval measurements in 
one subject will be performed on the same lead. The intervals will be measured from four 
cardiac cycles (beats) in lead II. If lead II shows a flat T wave or is not measurable for any 
reason, lead V5 will be used, or if that lead is not measurable, then lead I will be used. The 
lead actually used will be reported in the CTR.
For blinding arrangements see Section 4.1.5.
Evaluation of ECGs will comply with the ICH E14 guidance document and supplements 
[R07-4722, R16-0366] as well as the FDA requirements for annotated digital ECGs [R09-
4830].
Continuous ECG monitoring
5.2.4.2
Cardiac rhythm (including heart rate) will be monitored by means of continuous 3-lead ECG 
recording for at least 15 min before drug administration (for baseline assessment) and for 4 h 
following drug administration). This continuous ECG monitoring supports the early detection 
of adverse events such as clinically relevant bradycardia, tachycardia, or arrhythmia at the 
trial site. Beyond this clinical evaluation at the trial site, no further data collection or analyses 
are performed based on continuous ECG monitoring.
ECG data from continuous ECG monitoring will not be transferred to the clinical trial 
database. Abnormal findings during continuous ECG monitoring will be recorded as AEs if 
judged clinically relevant by the Investigator.
Other safety parameters
5.2.5
Visual Analogue Scale (VAS)
5.2.5.1
Possible psychedelic effects will be monitored and evaluated as safety measurement by 
analogue scales developed by Bowdle along with PK sampling. From these measurements, 
following factors are derived - external and internal perception, alertness, mood and
calmness. 
The VAS assessments 2 hours before drug administration will be considered as baseline. At 
each measuring time point indicated in the Flow Chart, the subjects will assess their 
subjective impression by themselves by means of a visual analogue scales. The subjects will 
be asked to mark an adequate position on a line between the two limits characteristics. The 
length of the line will be exactly 100 mm, and will ascertain a score number (values between 


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0 and 100) by measuring the distance in mm from the beginning of the line to the position 
marked by the subject. The score will be documented in the electronic case report form. 
The original English version is shown in Appendix 10.1.
Suicidality assessment
5.2.5.2
Suicidality assessment to further evaluate the psychological status of the subject will be 
performed at screening using the Columbia Suicidal Severity Rating scale C-SSRS.
The C-SSRS is a brief measure which is designed to assess severity and change of suicidality 
by integrating both, behaviour and ideation. The C-SSRS was designed to address the need 
for a summary measure to track change in the severity of suicidality across both clinical 
settings and treatment trials.
The original Columbia Suicidal Severity Rating scale is shown in Appendix 10.2.
Neurological examinations
5.2.5.3
As a general additional safety measure in the Dose Group 3, a physical neurological 
examination will be performed at the time points specified in the respective Flow Chart.
The neurological examination will include the following assessments:
-
General level of arousal
-
Orientation
-
Eye movement
-
Pupil size and pupil reactivity
-
Reflexes 
-
Assessment of muscle strength
-
Gait
-
Romberg test
-
Tremor
-
Point-to-point movements
-
Sensitivity
Documentation, Assessment, and Reporting
Results will be documented in source data at the clinical trial site and assessed for clinical 
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant 
findings of the neurological examination will be reported as Adverse Events (during the trial) 
or as baseline conditions (at screening). Case narratives may be written if necessary.


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Assessment of adverse events
5.2.6
Definitions of adverse events
5.2.6.1
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 subject 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 subject and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
The following events will be handled as ‘deemed serious for any other reason’. An AE which 
possibly leads to disability will be reported as an SAE.


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AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC (electronic Data Capture)
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.
Suicidal risk assessed by the C-SSRS
5.2.6.1.4
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the screening visit (using the ‘screening / baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and behavior 
will also be recorded.
After the baseline visit the assessment ‘since last visit’ will be performed (‘since last visit’ 
version). The investigator is to review positive and negative reports for plausibility and 
clinical relevance. Doubtful reports may be repeated or reports may be validated by a 
consulting psychiatrist. If there is a confirmed positive report of suicidal behavior or suicidal 
ideation type 4 or 5 after start of trial, the investigator is to immediately interview the subject 
during the clinic visit, and/or is to consult a psychiatrist. If the positive report is confirmed, 
appropriate actions for the subject’s safety have to be initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.
For ‘Self-injurious behaviour, no suicidal intent’ (Type 11) standard AE / SAE reporting 
rules are to be applied.


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For each negative report (suicidal ideation type 1, 2 or 3) after start of the trial, the 
investigator is to decide based on clinical judgment whether it represents an adverse event 
(AE) as defined in the protocol, and if it is considered an AE then it must be reported 
accordingly.
Adverse events of special interest
5.2.6.1.5
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 AESI for this trial is hepatic injury, as defined by the following alterations of hepatic
laboratory parameters 

An elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, or

Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure that these parameters 
are analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
5.2.6.1.6
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
5.2.6.1.7
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


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
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)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
Adverse event collection and reporting
5.2.6.2
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: 


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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 new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF
AE reporting to 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 assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
Pregnancy
5.2.6.2.4
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.


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As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
5.3.1
Blood and urine samples will be collected for the purpose of pharmacokinetic analysis. 
Further information about sampling is provided in Section 5.3.2.
Date and clock times of drug administration and pharmacokinetic sampling will be recorded
in the CRFs.
Methods of sample collection
5.3.2
Blood sampling for pharmacokinetic analysis
5.3.2.1
For quantification of BI 1358894 and BI 1361608 concentrations in plasma, 3 mL of blood 
will be drawn from an antecubital or forearm vein into a K-EDTA (potassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle.
Sample handling will be described in detail in a separate lab manual.
Until transfer on dry ice to the analytical laboratory, all sample will be stored upright at 
approximately -20°C or below at the trial site.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. Further information such as matrix and analyte may also be provided. 
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.
Urine sampling for pharmacokinetic analysis
5.3.2.2
A blank urine sample will be collected before administration of trial medication (within 
3 hours before drug dosing) and two 0.5 mL aliquots will be retained to check for analytical 
interference by concomitant or rescue medication. 
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
polypropylene (PP) containers and stored in the refrigerator at 4-8°C. Subjects are told to 
empty their bladders at the end of each sampling interval. To avoid adsorption effects of BI 


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1358894, suitable volume of 10% Tween 20 solution will be added to the collection 
container before sampling. 
The handling of urine sampling is described in a lab manual.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned collection time. Further information, such as matrix and analyte may also be 
provided. 
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
approximately -20°C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory, the 
urine samples will be stored at approximately -20°C or below until analysis.
After completion of the trial, the urine 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) 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 has been archived.
Analytical determinations
5.3.3
Analytical determination of analyte plasma concentration
5.3.3.1
BI 1358894 and BI 1361608 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.
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.
Analytical determination of analyte urine concentration
5.3.3.2
BI 1358894 concentrations in urine will be determined by a validated LC-MS/MS assay. All 
details of the analytical method will be available prior to the start of sample analysis.
5.4
OTHER ASSESSMENTS
Pharmacogenomic evaluation
5.4.1
Pharmacogenomics investigates genetic variations to explain and to predict an individual’s
response to drugs. Therefore, a blood sample for pharmacogenomic testing will be taken from
each subject. In case of unexplainable variability in pharmacokinetic parameters, DNA might
be extracted from these samples and used for exploratory analysis of variants of genes
involved in Absorption, Distribution, Metabolism and Excretion (ADME) of drugs. It is not 
intended to include these data in the final report. However, the data may be part of the report 
if necessary. All remaining samples will be destroyed no later than three years after the end 
of the trial.


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Methods and timing of sample collection
5.4.1.1
One blood sample of about 8.5 mL will be taken from an arm vein in a PAXgene blood DNA 
drawing tube after the study drug administration on Day 1. The blood sample has to be stored 
at a temperature of approximately -20°C or below. Once frozen, thawing of the samples 
should be avoided. Further details of sample processing will be described in a study-specific 
laboratory manual.
Analytical determinations
5.4.1.2
Genomic DNA will be extracted from blood samples according to standard molecular
genetics methods and analysed by drug metabolizing enzymes and transporters (DMET)
analysis or other standard genotyping technologies.
5.5
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration except PK urine sample. A blank urine sample for PK will be 
collected within 3 h before drug administration.
The acceptable deviation from the scheduled time for vital signs, orthostatic testing and ECG
will be ± 10 min and laboratory tests will be ± 30 min for the first 4 h after trial drug 
administration and ± 30 min thereafter.
If several activities are scheduled at the same time point in the Flow chart, ECG should be the 
first and meal the last activity. Furthermore, if several measurements including venipuncture 
are scheduled for the same time, venipuncture should be the last of the measurements due to 
its inconvenience to the subject and possible influence on physiological parameters except for 
the orthostatic testing.
The acceptable deviation from the scheduled time for standardized neurological tests
(conducted in Dose Group 3) is ± 90 min on Day 7.
For planned individual plasma concentration sampling times and urine collection intervals,
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for the determination of 
pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Screening period
6.2.1
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. If the subject 
has not fasted for at least 10 h at screening visit, laboratory test will be done another day after 
the subject has fasted for at least 10 h. For information regarding laboratory tests (including 
drug and virus screening), ECG, vital signs including orthostatic testing, physical 
examination, Bowdle visual analogue scales and suicidality assessment (C-SSRS), refer to 
Sections 5.2.1 to 5.2.5. 
Treatment period
6.2.2
Each subject will receive one dose of trial medication (BI 1358894 or placebo) at Visit 2.


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Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
Study participants will be admitted to the trial site in the evening of Day -1 and kept under 
close medical surveillance for at least 96 h for Dose Groups 1 and 2 and 144 h for Dose 
Group 3 following the drug administration. The subjects will then be allowed to leave the 
trial site after formal assessment and confirmation of their fitness by the investigator or 
 
designee. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma and urine samples for PK 
analysis, refer to Flow Chart and Section 5.3.2. 
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
End of Trial period
6.2.3
For AE assessment, laboratory tests, recording of ECG and vital signs, physical examination, 
Bowdle visual analogue scales and suicidality assessment (C-SSRS) during the end of trial
period, see Sections 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the End of Trial Visit.
All abnormal values (including laboratory parameters) that are 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 End of Trial 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 objectives of this trial will be assessed by calculating descriptive statistics for 
safety as well as for PK parameters, which will be compared between the treatment groups. 
Further analyses of these endpoints comprise the power model for assessment of dose 
proportionality.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in this study.
Any confidence intervals (CIs) computed are to be interpreted in the perspective of the 
exploratory character of the study; i.e., CIs are considered as interval estimates for effects.
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 treatment assignment will be 
determined based on the first treatment the subjects received. The treated set will be 
used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was not excluded due to a 
protocol deviation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviations
(IPD) categories will be specified in the IQRMP, IPDs will be identified no later than in the
Report Planning Meeting, and the IPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2 for BI 1358894 and BI 1361608
will be calculated according to the relevant Standard Operating Procedure (SOP) of the 
Sponsor (001-MCS-36-472). Pharmacokinetic analyses will be performed using validated 
software programs, normally. Phoenix Winnonlin (Pharsight®) with applications validated for 
the respective purpose. Graphs and tables will be generated using validated customised SAS®


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macros or appropriate graphic software. A reference to the software used, e.g., name, will be 
indicated in the CTR.
Plasma and urine 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 and urine 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/urine 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.
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 as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report).
Primary endpoint analyses
7.3.1
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards.
The analysis will be based on the treated set (TS) and will be descriptive in nature.
Secondary endpoint analyses
7.3.2
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively.
Further exploratory analyses
Dose proportionality will be explored via graphical checks and if applicable via the power 
model stated below. The analysis will be performed for the pharmacokinetic endpoints 
(AUC0-tz, AUC0-∞and Cmax) specified in Section 2.1.3.
The power model describes the functional relationship between the dose level and PK 
endpoint on the log scale via
 =  log (xkm) = μ +    ∙ log (Dk) +  ekm ,


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where 
ykm
logarithm of response (PK parameter) measured on subject m receiving dose k,
μ
the overall mean,
β
slope parameter of linear regression line,
D
level of dose k, k=1,…,3,
ekm
the random error associated with the mth subject who was administered dose k 
(e~(0, ) iid).
The slope parameter β together with its two-sided 90% confidence interval will be estimated. 
Safety analyses
7.3.4
Safety will be assessed as defined by the endpoints listed in Section 2.1.2 and 2.2.2 based on 
the treated set (TS). Safety analyses will be descriptive in nature and will be based on BI 
standards. 
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. The placebo group in the safety evaluation 
will consist of all subjects treated with placebo, regardless of the dose group in which they 
were treated. The test treatment groups will be compared to the placebo group in a descriptive 
way. Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Measurements (such as ECGs, vital signs, or laboratory parameters) or AEs will be assigned 
to treatments (see Section 5.2) 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 intake of trial medication will be 
assigned to the screening period, those between trial medication intake until the trial 
termination date will be assigned to the treatment period. These assignments including the 
corresponding time intervals will be defined in detail in the trial statistical analysis plan
(TSAP). Note that AEs occurring after the last per protocol contact but entered before 
database lock will be reported to Pharmacovigilance only and will not be captured in the trial 
database.
Additionally, further treatment intervals (called analysing treatments) may be defined in the 
TSAP in order to provide summary statistics for other than above periods, such as combined 
treatments, on-treatment totals, or periods without treatment effects (such as screening and 
post-study 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 


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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 possibly clinically 
significant values 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. 
The ECG variables QT, HR, QTcF, QTcB, PR, QRS, and RR obtained from the centralised 
evaluation of 12-lead ECG recordings will be the basis for the derivation of quantitative and 
categorical ECG endpoints. These endpoints and their analyses will be described in the 
TSAP.
7.4
INTERIM ANALYSES
No formal interim analysis is planned. If considered necessary, an exploratory PK analyses 
will be performed based on planned sampling times.
7.5
HANDLING OF MISSING DATA
Safety
7.5.1
It is not planned to impute missing values for safety parameters.
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
Subjects will be randomised within each dose group in a 3:1 ratio (test treatment to placebo).
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).


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7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 24 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group (6 on active treatment, and 2 on 
placebo) is commonly used in single-rising dose studies of the present type and is in general 
considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics.


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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 GCP, relevant BI SOPs, the 
Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 
1997) 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 and the Japanese GCP regulations.
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 responsible IRB / Independent Ethics Committee (IEC) and competent 
authority (CA) according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The investigator or delegate must give a full explanation to trial subjects based on the subject 
information form. A language understandable to the subject should be chosen and technical 
terms and expressions avoided, if possible.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. 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.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
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:


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
Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including 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.


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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 below. 
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the ‘date of the last visit of the last subject in 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.
When the trial is completed, the investigator should inform the head of the trial site in writing 
of the completion of the trial, and the head of the trial site should promptly inform the IRB 
and sponsor in writing of the completion.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by 
The trial will be conducted at 
, under the supervision 
of the Principal Investigator. Relevant documentation on the participating (Principal) 
Investigators (e.g. their curricula vitae) will be filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs


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
Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of Clinical Trial Managers, Clinical 
Research Associates, and investigators of participating trial sites
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany.
Safety laboratory tests will be performed by the local laboratory of the trial site.
Analyses of BI 1358894 and BI 1361608 concentrations in plasma and BI 1358894
concentrations in urine will be performed at the Department of Drug Metabolism and 
Pharmacokinetics, BI Pharma GmbH & Co. KG, Biberach, Germany or by a specialised 
contract research organisation appointed by BI.
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation during the trial or post trial.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a CRO appointed by BI
according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P06-11895
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, 
Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath 
PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and 
longer-term outcomes in depressed outpatients requiring one or several 
treatment steps: a STAR*D report. Am J Psychiatry 2006;163(11):1905-
1917.
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2002:1-
9.
R06-2872
Trivedi MH, Rush AJ, Wisniewski SR, Warden D, McKinney W, Downing 
M, Berman SR, Farabaugh A, Luther JF, Nierenberg AA, Callan JA, 
Sackeim HA. Factors associated with health-related quality of life among 
outpatients with major depressive disorder: a STAR*D report. J Clin 
Psychiatry 2006;67(2):185-195.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005)
R09-4830 
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R15-3888
Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao 
GL, Tsvetkov E, Rodig SJ, Veer A van't, Meloni EG, Carlezon WA, 
Bolshakov VY, Clapham DE. Essential role for TRPC5 in amygdala 
function and fear-related behavior. Cell 2009;137(4):761-772.
R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015)
R16-5350
Fowler MA, Sidiropoulou K, Ozkan ED, Phillips CW, Cooper DC. 
Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent 
brain. Plos One 2007;2(6):e573


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R16-5472
Koenigsberg HW, Denny BT, Fan J, Liu X, Guerreri S, Mayson SJ, et al. 
The neural correlates of anomalous habituation to negative emotional 
pictures in borderline and avoidant personality disorder patients. Am J 
Psychiatry 2014; 171(1):82-90.
R16-5473
Mandell D, Siegle G, Shutt L, Feldmiller J, Thase ME. Neural substrates of 
trait ruminations in depression. J Abnorm Psychol 2014;123(1):35-48.
R16-5474
IsHak WW, Elbau I, Ismail A, Delaloye S, Ha K, Bolotaulo NI, et al. 
Quality of life in borderline personality disorder. Harvard Rev Psychiatry 
2013;21(3): 138-150.
R16-5475
McClintock SM, Husain MM, Wisniewski SR, Nierenberg AA, Stewart 
JW, Trivedi MH, et al. Residual symptoms in depressed outpatients who 
respond by 50 % but do not remit to antidepressant medication. J Clin 
Psychopharmacol 2011;31(2): 180-186.
R16-5476
Links PS, Heslegrave R, Reekum R van. Prospective follow-up study of 
borderline personality disorder: prognosis, prediction of outcome, and axis 
II comorbidity. Can J Psychiatry 1998;43(3):265-270.
R16-5477
Skodol AE, Siever LJ, Livesley WJ, Gunderson JG, Pfohl B, Widiger TA. 
The borderline diagnosis II: biology, genetics, and clinical course. Biol 
Psychiatry 2002;51(12):951-963.
R16-5483
Ellison WD, Rosenstein L, Chelminski I, Dalrymple K, Zimmerman M. 
The clinical significance of single features of borderline personality 
disorder: anger, affective instability, impulsivity, and chronic emptiness in 
psychiatric outpatients. J Personal Disord 2016;30(2):261-270.
R18-0249
Minke B. The history of the Drosophila TRP channel: The birth of a new 
channel superfamily. 2010;24(4):216-233
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c10354149
Investigator's brochure BI 1358894 in Major Depressive Disorder and 
Borderline Personality Disorder. Current version
c13880029
Safety, tolerability and pharmacokinetics of single rising oral doses of 
BI 1358894 in healthy male subjects (single-blind, partially randomised, 
placebo-controlled parallel group design) and effect of food on the relative 
bioavailability of  BI 1358894 (open-label, randomised, two-way cross-
over. Trial 1402-0001. 25-Sep-2018.
n00248384 
 Selectivity Test of BI 1358894 on TRPV1, TRPV3, 
TRPM8,TRPC6, TRPA1, hERG, Kv1.3, Cav1.2, Nav1.2, Nav1.7 and 
Nav1.5. Report #: 155. 20 January 2016.


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n00250347 
 
. BI 1358894: 4-week oral (gavage) 
toxicity study in Sprague Dawley rats
n00252179 
 Selectivity/ Safety Pharmacology of HC-122608. Report #: 154. 
06 September 2012.
n00252207 
 Effects of HC-122608 on mouse marble burying. Report #: 
213. 18 June 2013.
n00252277 
 Effect of HC-122608 in the mouse elevated plus maze. Report #: 
168. 16 January 2013.
n00252628 
 [14C]BI 1358894: Distribution Study in the Male Pigmented Rat.
n00252903 
 Effect of BI 1358894 in the mouse forced swimming test. Draft 
Report. 2 December 2016
n00253490
Cytochrome P450 Inducibility in SD rat hepatocytes – Effect on in vitro 
clearance. 18 November 2016.
n00253492
BI 1358894: In vitro inhibition studies on cytochrome P450 dependent 
metabolic reactions. 8 November 2016.
n00253628 
 Prediction of BI 1358894 Pharmacokinetics and Therapeutic Dose
in Human. Draft Report.
n00253723
 Influence of BI 1358894 (10, 30 and 100 mg/kg PO) on
cardiovascular function (systolic and diastolic arterial pressure, heart rate
and ECG) and body temperature in conscious rats. GP2014/0251/PH5. 29
Novembre 2016.
n00253725
 Effects of BI 1358894 on behavior assessed by observation of
nocturnal activity or in a modified IRWIN-test after oral administration of
10, 30 and 100 mg/kg. GP2014/0271/0272/PH3. 29 November 2016.
n00253727
 Influence of BI 1358894 (10, 30 and 100 mg/kg PO)
on hemodynamic and electrocardiographic parameters in conscious dogs.
GP2014/0269/PH5. 29 November 2016.
n00253729 
 Effects of BI 1358894 (10, 30 and 100 mg/kg
p.o.) on gastrointestinal function in the conscious rat. GP2014/0277/PH4.
12 December 2016.
n00253732
 Effects of BI 1358894 (10, 30 and 100 mg/kg
p.o.) on urine- and serum-derived parameters in conscious rats.
GP2014/0274/PH4. 29 November 2016.
n00253752 
 Selectivity test of HC-122608 on TRPV1, TRPV3, TRPM8,
TRPC6, TRPA1, hERG, Kv1.3, Cav1.2, Nav1.2, Nav1.7 and Nav1.5. 
Report #: 155. 11 January 2013.
n00256526
Evaluation of Induction Potential of Cytochrome P450 Isoforms by 
BI 1358894 in Cultured Human Hepatocytes. 19 July 2017


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10.
APPENDICES
10.1
VISUAL ANALOGUE SCALE (VAS)
Bowdle VAS-score (English version):
My body or body parts seemed to change their shape or position
Not at all
__________________________________________________
Extremely
My surroundings seemed to change in size, depth, or shape
Not at all
__________________________________________________
Extremely
The passing of time was altered
Not at all
__________________________________________________
Extremely
I had feelings of unreality
Not at all
__________________________________________________
Extremely
It was difficult to control my thoughts
Not at all
__________________________________________________
Extremely
The intensity of colors changed
Not at all
__________________________________________________
Extremely
The intensity of sound changes
Not at all
__________________________________________________
Extremely
I heard voices or sounds that were not real
Not at all
__________________________________________________
Extremely
I had the idea that events, objects, or other people had particular meaning that was specific for me
Not at all
__________________________________________________
Extremely
I had suspicious ideas or the belief that others were against me
Not at all
__________________________________________________
Extremely
I felt high
Not at all
__________________________________________________
Extremely
I felt drowsy
Not at all
__________________________________________________
Extremely
I felt anxious
Not at all
__________________________________________________
Extremely


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10.2
COLUMBA-SUICIDE SEVERITY RATING SCALE


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11.
DESCRIPTION OF GLOBAL AMENDMENT
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25765859
1.0
clinical-trial-protocol-version-01
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 1358894 in
healthy Japanese male subjects (double-blind, randomised, placebo-controlled
parallel dose group design)
Author-Clinical Trial Leader
17 Jan 2019 12:11 CET
Author-Trial Statistician
17 Jan 2019 12:27 CET
Approval-Therapeutic Area 
17 Jan 2019 17:56 CET
Approval-Team Member Medicine
18 Jan 2019 11:11 CET
Author-Trial Clinical
Pharmacokineticist
18 Jan 2019 14:41 CET
Verification-Paper Signature
Completion
21 Jan 2019 15:35 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25765859
1.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c28958859-01
BI Trial No.:
1402-0008
Title:
Safety, tolerability and pharmacokinetics of single rising oral doses 
of BI 1358894 in healthy Japanese male subjects (double-blind,
randomised, placebo-controlled parallel dose group design)
Investigational
Product:
BI 1358894
Responsible trial 
statisticians:
Phone: 
Fax: 
Date of statistical 
analysis plan:
14 AUG 2019 SIGNED
Version:
Final
Page 1 of 35
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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
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......................................................................................20
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........22
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................22
7.3
TREATMENT COMPLIANCE........................................................................22
7.4
PRIMARY ENDPOINTS...................................................................................23
7.5
SECONDARY ENDPOINTS.............................................................................23
7.5.1
Key secondary endpoints....................................................................................23
7.5.2
Secondary endpoints...........................................................................................23
7.7
EXTENT OF EXPOSURE.................................................................................24
7.8
SAFETY ANALYSIS..........................................................................................24
7.8.1
Adverse events.....................................................................................................25
7.8.2
Laboratory data ..................................................................................................26
7.8.3
Vital signs.............................................................................................................27
7.8.4
ECG......................................................................................................................27
7.8.5
Others...................................................................................................................29
7.8.5.1 
Physical examination ............................................................................................29
7.8.5.2 
Visual Analogue Scale (VAS) - Bowdle...............................................................29
7.8.5.3 
Suicidality assessment - Columbia Suicidal Severity Rating scale (C-SSRS) .....29
8.
REFERENCES....................................................................................................30


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10.
HISTORY TABLE..............................................................................................35


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR .........................................................12
Table 6.3: 1
Analysis sets for endpoints/data description ....................................................15
Table 6.7: 1
Time schedule of 12-lead ECG recordings ......................................................18
Table 10: 1
History table .....................................................................................................35


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
website: glossary
Term
Definition / description
ALT
Alanine Aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate Aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BMI
Body mass index
BP 
Blood pressure
CARE
Clinical Analysis and Reporting Environment
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CV
Arithmetic Coefficient of Variation
DB
Dose Proportionality, Between-Subject Design
DILI
Drug induced liver injury
ECGPCS
ECG Pharmacokinetic Concentration Set
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
HR
Heart rate
IQRMP
Integrated Quality and Risk Management Plan
LLT
Lower Level Term
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PKS
Pharmacokinetic parameter analysis set


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Term
Definition / description
PR
Pulse rate
Q1
1st quartile
Q3
3rd quartile
QD
Quaque die, once daily
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RR
Respiratory rate
SAS®
Statistical Analysis System
SD
Standard Deviation
SOC
System Organ Class
TS
Treated Set
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary


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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 
endpoints and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP). 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, randomisation.
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).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SAS® (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 adverse event (AE) data or laboratory 
data; Report Appendix Generator system (RAGe) for compilation/formatting of the CTR 
appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in the TSAP are outlined in the CTP. The following changes 
compared to the protocol will be made:
In the protocol, it is stated that the medical examination at screening will include alcohol 
history. However, alcohol history is not captured in the eCRF, and thus, will neither be listed 
nor included in tables.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Section 2.1.2 of the CTP:
The primary endpoint for assessment of safety and tolerability of BI 1358894 is the number 
[N (%)] of subjects with drug related adverse events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP: 
The following pharmacokinetic parameters will be determined for BI 1358894 if feasible:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data time point tz)

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
It is planned that in total 24 Japanese healthy male subjects participate in this study, 
according to 3 sequential dose groups comprising 8 subjects per group. Within each dose 
group, 6 subjects will receive BI 1358894 and 2 will receive placebo.
For details of dosage and formulation see Table 6.1: 1 below.
Table 6.1: 1
Labels for treatments for use in the CTR 
Dose 
group
Treatment
Short label
1-3
P*
Placebo, tablet, qd
Placebo 
1
A
BI 1358894, 2*25 mg tablet, po, qd
BI 50mg 
2
B
BI 1358894, 1*100 mg tablet, po, qd
BI 100mg 
3
D
BI 1358894, 2*100 mg tablet, po, qd
BI 200mg 
‘qd’ means here a single drug administration, not a regular drug administration per day.
*: The placebo group in the safety evaluation will consist of all placebo treated subjects, 
regardless of the dose group in which they were treated.
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00h (midnight) on day of informed consent until 
administration time of study drug (BI or Placebo))

On treatment
o
BI/Placebo treatment (separately for each treatment, ranging from the time of 
administration of BI 1358894 or Placebo until 0:00h (midnight) on the day after 
trial termination date)
Please note that all AEs reported between start of trial drug administration and the trial 
termination date will be considered on treatment (i.e. no follow-up period is considered in 
this trial).
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov) of the CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening will not be included in this analysis. 
The following totals will be provided in addition:

a total over all BI treated phases (“BI Total”)


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
a total over all on treatment phases included in this analysis ("Total on treatment") 
(Section 15.3 only)
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov) of the CTR 
displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all BI treated phases (“BI Total”)

a total over all study phases ("Total")
Tables of vital signs, ECG and laboratory values will present results by the above mentioned 
on treatment phase.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewer`s guide. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects.
Section 7.3 of the CTP: Important protocol deviations (iPDs) categories will be specified in 
the IQRMP, iPDs will be identified no later than in the Report Planning Meeting, and the iPD
categories will be updated as needed.
Consistency check listings (for identification of deviations of 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 (RPM). At this meeting, all 
manual deviations identified at the sites by the CRAs and deviations too complex to program 
will be reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "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 RPM minutes 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 RPM.
The iPDs will be summarised and listed.


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6.3
SUBJECT SETS ANALYSED

Treated set (TS): 
This subject set includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for 
demographics, baseline characteristics, and safety analyses.
The ECG analyses are performed on the TS, except for the exposure-response analyses, 
which are performed on the ECGPCS defined below.
Section 7.3 of the CTP: 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/urine 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.

Pharmacokinetic parameter analysis set (PKS):
The pharmacokinetic parameter analysis set (PKS) includes all subjects from the TS 
receiving BI 1358894 who provide at least one PK endpoint that was not excluded 
according to the description above.
It is used for assessment of dose proportionality and the descriptive analyses of PK 
parameters.


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The descriptive analysis of PK concentrations will be based on the ADS ADPC. The 
descriptive and model based analysis of PK parameters will be based on the ADS ADPP.

ECG Pharmacokinetic Concentration Set (ECGPCS):
This subject set includes all subjects from the TS for whom at least one pair of a valid 
drug plasma concentration of BI 1358894 and a corresponding (i.e. time-matched) ECG 
endpoint to be used in the exposure-response analyses was provided. For placebo 
subjects, the plasma concentration is set to zero and hence always considered as valid. 
The decision whether a time deviation between PK blood sampling and ECG recording is 
acceptable (and thus whether the pair of values will be used) is to be made no later than 
at the RPM before data-base lock.
Table 6.3: 1
Analysis sets for endpoints/data description
Endpoint/data description
Analysis set
TS
PKS
ECGPCS
Primary and further safety endpoints (incl. ECG) 
X
ECG endpoints and plasma concentrations used in 
exposure-response analysis
X
Secondary PK endpoints
X
Demographic/baseline data
X
Important protocol deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards.


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Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (4).
If single cardiac cycles of an ECG (out of the generally four) are missing, the arithmetic 
mean for this single ECG will be computed with the reduced (1, 2 or 3) number of cardiac 
cycles.
If replicate ECG recordings are missing, the arithmetic means per time point will be 
computed with the reduced number (1 or 2) of recordings.
For the classification of the on treatment QTc/QT intervals into “no new onset” / “new onset” 
categories, a missing value is obtained only in case that
(i)
all on treatment values are missing and
(ii)
the baseline value is less than or equal to 500 msec, or missing.
If condition (i) is fulfilled but the baseline value is greater than 500 msec, this case will be 
categorized as ‘no new onset’. If baseline is missing and the maximum on treatment 
QTc interval is greater than 450 msec (or 500 msec for QT interval, respectively), this is 
classified as a ‘new onset’ in the respective category. If baseline is missing and the maximum 
QTc interval is less than or equal to 450 msec (or 500 msec for QT interval, respectively), 
this will be categorized as ‘no new onset’. If baseline is missing, a QTc/QT interval 
> 500 msec at any time on treatment will be a notable finding. In case of a missing qualitative 
ECG finding at baseline, a finding observed on treatment will be categorized as ‘new onset’.
For placebo subjects, the missing plasma concentration values will be replaced by 0 for the 
exposure-response analyses. For subjects on active drug, missing plasma concentration values 
with ‘BLQ’ in the comment field will be replaced by ½ LLOQ (post treatment values) or by 0 
(predose values).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before administration of BI 1358894 or 
Placebo.
Section 6.1 of the CTP: 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 CTP Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration except PK
 sample. A blank 
 sample for PK will be 
collected within 3 h before drug administration.
The acceptable deviation from the scheduled time for vital signs, orthostatic testing and ECG
will be ± 10 min and laboratory tests will be ± 30 min for the first 4 h after trial drug 
administration and ± 30 min thereafter.


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[…]
Adherence to time windows will be checked via the consistency check listings at the RPM.
Unscheduled measurements of laboratory data or vital signs 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.
There will be a centralised evaluation of the 12-lead ECG recordings at the time points and 
for the ECG recordings specified in the Table 6.7: 1 below:
Section 5.2.4.1 of the CTP: Triple ECGs will be recorded (within 180 sec) at all-time points 
on Day 1 to Day 3 (48 h) for Dose Groups 1 and 2 or on Day 1 to Day 7 (144h) for Dose 
Group 3. At all remaining time points, single ECGs will be recorded.


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Table 6.7: 1
Time schedule of 12-lead ECG recordings
Visit
Day
Planned time 
[hh:mm] (relative to 
drug administration)
Study phase
Central evaluation
1
-28 to -1
Screening
NA
2
1
-01:00
Baseline
all 3 single ECGs of the 
triplicate
00:30
On treatment
first of three replicate ECG
01:00
first of three replicate ECG
01:30
first of three replicate ECG
02:00
first of three replicate ECG
03:00
first of three replicate ECG
04:00
first of three replicate ECG
05:00
first of three replicate ECG
06:00
first of three replicate ECG
08:00
first of three replicate ECG
12:00
first of three replicate ECG
2
16:00
first of three replicate ECG
24:00
first of three replicate ECG
34:00
first of three replicate ECG
3
48:00
first of three replicate ECG
4
72:00**
first of three replicate 
ECG**
5
96:00**
first of three replicate 
ECG**
6
120:00**
first of three replicate ECG
7
144:00**
first of three replicate ECG
3
10 to 
14*
29 to 
33**
End of trial
examination
NA
*for dose groups 1 and 2
**for dose group 3 
The baseline value of an ECG variable is defined as the mean of the triplicate ECG 
measurements prior to drug administration.
Section 5.2.4.1 of the CTP: A centralised evaluation (during study or post study) of all 12-
lead ECGs recorded on Day 1 to Day 3 (48h) for Dose Groups 1 and 2 or on Day 1 to Day 7 


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(144h) for Dose Group 3 will be performed by an independent ECG laboratory. This analysis 
will include the determination of cardiac axis (automatic evaluation based on a validated 
GE-12-SL-algorithm or equivalent) as well as the intervals RR, PR, QRS and QT measured 
semi-automatically. With the exception of the first triple ECG (used as baseline before the 
drug administration), only the first of the three replicate ECGs at a single assessment time 
will be evaluated. […].
For the exposure response analyses, pairs of ECG variables and corresponding plasma 
concentrations will be built using the same planned time points, e.g. HR change from 
baseline and the plasma concentration measured at planned time 0:30 will build one pair. 
Whether a time deviation between PK blood sampling time and corresponding ECG 
recording is too big and the pair has to be excluded from the analysis will be decided no later 
than at the RPM. This critical time deviation depends on the PK properties. When plasma 
concentrations are expected to change only little around a given time point, the acceptable 
time deviation between ECG recording and PK blood sampling may be bigger.


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7.
PLANNED ANALYSIS
The placebo group in the safety evaluation will consist of all placebo treated subjects, 
regardless of the dose group in which they were treated.
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.5.2) will also be performed 
by 
 and will be presented in Section 15.5 of the CTR and in 
Appendix 16.1.13.3.
Descriptive data analysis of PK parameters and concentrations will be performed by
 
. The individual values of all subjects and 
descriptive statistics will be presented in Appendix 16.1.13.5 and Section 15.6 of the CTR, 
respectively.
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, sorted by treatment group, subject number, 
and visit. 
The listings except PK evaluations will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation


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For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
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 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 (%) for each 
treatment group. Percentages will be rounded to one decimal place and will be based on all 
subjects in the respective subject set whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
The ADS ADPP (PK parameters) contains column variables indicating inclusion/exclusion 
(APEXC) of a PK parameter and an analysis flag comment (APEXCO). All analyses based 
on the PKS will include parameters if they are not flagged for exclusion, that is APEXCO is 
equal to “Included”.


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Exclusion of PK 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 (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (4) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (5).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment group and in total. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the latest version of the coding system of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded 
using the latest version of the World Health Organization Drug Dictionary (WHO-DD). The 
coding version number will be displayed as a footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: 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 
 will provide 
additional confirmation of compliance.


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It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM and described in the CTR.
7.4
PRIMARY ENDPOINTS
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 1358894.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been specified in the CTP.
7.5.2
Secondary endpoints


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by treatment group.
The safety data for treated subjects who failed to complete the study (dropouts or
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.


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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 and will be based on BI standards.
The standard AE analyses 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 electronic case report form (eCRF) will be 
collapsed into an AE provided that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest (AESI))

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence).
Section 5.2.6.1.5 of the CTP: The AESI for this trial is hepatic injury, as defined by the 
following alterations of hepatic laboratory parameters:

An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold 
ULN measured in the same blood sample, or

Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy,
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results
(ALT, AST, total bilirubin) available, the Investigator should make sure that these parameters
are analysed, if necessary in an unscheduled blood test. Should the results meet the criteria
of hepatic injury alert, the procedures described in the DILI checklist should be followed.
The analysis of adverse events will be based on the concept of treatment emergent AEs. 
Section 1.2.6 of the CTP: The residual effect period (REP) for BI 1358894, the time interval 
when measureable drug levels or pharmacodynamics (PD) effects are still likely to be present 
after the last administration, is not known at this early stage of development. 
Section 7.3.4 of the CTP: Therefore, measurements planned or AEs recorded prior to intake 
of trial medication will be assigned to the screening period, those between trial medication
intake until the trial termination date will be assigned to the treatment period. 
For more details see the TSAP ADS plan.


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According to ICH E3 (7), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the investigator or Clinical Trial Leader at the RPM.
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarized by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with other 
significant AEs according to ICH E3 (7), for subjects with serious AEs, for subjects with 
drug-related AEs, for subjects with drug related serious adverse events and for subjects with 
AESIs.
The SOC and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on 
BI standards.
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possible
clinically significant will be flagged in the data listings.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significant 
abnormal or not (at the RPM at the latest).
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).
The mean normalised values and SD over time for all laboratory parameters, except for 
parameters that are measured at a single time point will be displayed graphically. The time 
span is from baseline to post examination.


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7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate), as well as respiratory rate (RR) and orthostatic tests. In 
the listing the difference from baseline will also be displayed.
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).
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
Continuous safety ECG monitoring (by investigator)
Clinically relevant abnormal findings will be reported as AEs.
No separate listing or analysis of continuous ECG monitoring will be prepared.
12-lead ECG
Abnormal findings, irrespective of whether they originate from central or local evaluation,
will be reported as baseline conditions (at screening) or as AEs (during the trial) if judged 
clinically relevant by the investigator. 
All evaluations of ECG data will be based on the TS, except the exposure-response analyses, 
which are based on the ECGPCS.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
For all subjects with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding time profiles will be shown.


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Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time of QTcF, HR, QT, PR and QRS. The time profiles of mean and SD for the 
changes from baseline on treatment will be displayed graphically by treatment.
For QTcF and HR changes from baseline, the relationship to the corresponding plasma 
concentrations will be evaluated using a random coefficient model. For subjects in the 
ECGPCS, all time points with available ECG endpoints and valid time-matched drug plasma 
concentrations will be included. For the handling of missing values, see Section 6.6.
The response variable will be the change from baseline in QTcF (QTcF). The placebo 
subjects will be included in the analysis, setting their plasma concentrations to zero.
As a first step, it is investigated if there is a potential delayed or accelerated (e.g. due to 
metabolites) effect of the drug on QTcF. A general visual impression will be provided by 
overlaying time profiles of plasma concentrations and QTcF changes from baseline (QTcF). 
These figures will be generated for each subject (presented in Statistical Appendix of the 
CTR), as well as for means per active treatment (presented in the End-of-Text part of the 
CTR).
The relationship between BI 1358894 plasma concentrations and QTcF changes from 
baseline will be investigated in an exploratory manner using a random coefficient model to 
estimate the difference in means between BI 1358894 and placebo of QTcF change from 
baseline and its 90% confidence interval at the geometric mean of Cmax for each dose. 
Additionally, the estimated overall slope with its 90% confidence interval will be provided. 
The used random coefficient model is based on a white paper from Garnett et al. (8) with 
QTcF as response variable, centered baseline QTc and plasma concentration as continuous 
covariates, treatment and time as fixed categorical effects, and a random intercept and slope 
for each subject. For more details refer to Section 9.3.
For visualization, a scatterplot of the BI 1358894 plasma concentration against the following 
individual QTcF values will be provided: For each subject on active treatment and each time 
point, subtract the mean value of all individual observed ΔQTcF values from the placebo 
group for this time point from the individual observed ΔQTcF value for this subject and time 
point. This results in estimates for “individual ΔΔQTcF” values, which should only be used 
for plotting purposes. The corresponding regression line and its pointwise confidence bands 
as well as and the geometric mean of Cmax for each dose will additionally be displayed in the 
plot.
To check model assumptions, the conditional residuals will be plotted and presented in the 
Statistical Appendix of the CTR. In case of non-linearity or if there is evidence for a delayed 
effect, further models will be explored in order to better characterise the PK-ECG 
relationship (e.g. effect compartment models, non-linear models, etc.).
All of the above described graphical and statistical analyses will be also performed for HR in 
place of QTcF.


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Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval (values log-transformed using the natural 
logarithm) will be estimated by applying the random coefficient model described in 
Section 9.1 using all time points. A scatterplot of QTcF vs RR including the overall
regression line will be included in the Statistical Appendix of the CTR. The resulting (fixed 
effect) slope together with two-sided 95% confidence intervals will be included in the 
footnote for this plot.
7.8.5
Others
7.8.5.1 
Physical examination 
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e. a condition already existent before intake of study drug) or as AE and will be 
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.
7.8.5.2 
Visual Analogue Scale (VAS) - Bowdle
The VAS will be used at screening and at end of trial examination, as well as at the planned 
times -1:00, 2:00, 4:00, 8:00, 24:00, 34:00, 48:00, 96:00 (only DGs 1-2) and 144:00 (only 
DG3). The last VAS assessments before drug administration will be considered as baseline.
Descriptive statistics of the 13 individual Bowdle scales at screening and post examination 
and for the difference from baseline will be provided. Other assessments will be listed only.
Furthermore, the change from baseline of the individual scales will be presented graphically 
over time (arithmetic means + standard deviation).
7.8.5.3 
Suicidality assessment - Columbia Suicidal Severity Rating scale (C-SSRS)
The C-SSRS will be done at
-
Screening 
-
Treatment period
-
End of trial examination 
The results will be listed only.


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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
8.
Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. J Pharmacokin Pharmacodyn (2017) [R18-0143]
9.
Ring A. Statistical models for heart rate correction of the QT interval. Stat Med (2010)
[R10-2920]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
14-AUG-2019
None
This is the final TSAP without any 
modification