Conditions: Healthy
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 16
Healthy volunteers: yes

Brief summary:
The main objective of this trial is to investigate the relative bioavailability of BI 1358894 in plasma when given as oral single dose together with multiple oral doses of itraconazole (Test, T) as compared to when given alone as oral single dose (Reference, R).

Detailed description:

Arms:
arm 1: Treatment period 1 (Reference (R)): Oral administration of single dose of 10 milligram (mg) BI 1358894 (2 tablets of 5 mg) with 240 milliliter (mL) of water after an high-fat, high-calorie breakfast on Day 1 of Treatment Period 1.

Treatment period 2 (Test (T)): Oral administration of 200 mg itraconazole (20 mL of 10 mg/mL solution) with 240 mL of water after an overnight fast for at least 10 h once daily for 14 days on Days -3 to 11 combined with a single dose of 10 mg BI 1358894 (2 tablets of 5 mg) on Day 1 of Treatment Period 2, 1.5 hours after administration of itraconazole.

Administrations of BI 1358894 were separated by a washout interval of at least 17 days.

Interventions: intervention 1: BI 1358894 intervention 2: Itraconazole
Intervention descriptions: intervention 1: Oral administration of single dose of 10 milligram (mg) BI 1358894 (2 tablets of 5 mg) with 240 milliliter (mL) of water after an high-fat, high-calorie breakfast on Day 1 of Treatment Period 1. intervention 2: Oral administration of 200 mg itraconazole (20 mL of 10 mg/mL solution) with 240 mL of water after an overnight fast for at least 10 h once daily for 14 days on Days -3 to 11 combined with a single dose of 10 mg BI 1358894 (2 tablets of 5 mg) on Day 1 of Treatment Period 2, 1.5 hours after administration of itraconazole.

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c25796375-03
EudraCT No.
2018-004274-10
BI Trial No.
1402-0007
BI Investigational
Medicinal Product
BI 1358894
Title
Relative bioavailability of a single oral dose of BI 1358894 when 
administered alone or in combination with multiple oral doses of 
itraconazole in healthy male subjects (an open-label, fixed 
sequence study)
Lay Title
A study in healthy men to test how itraconazole influences the 
amount of BI 1358894 in the blood
Clinical Phase
I
Clinical Trial Lead
Phone:
Fax: 
Principal 
Investigator
 
Phone: 
Fax:
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 27 Mar 2019
Page 1 of 91
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
18 December 2018
Revision date
27 March 2019
BI trial number
1402-0007
Title of trial
Relative bioavailability of a single oral dose of BI 1358894 when administered 
alone or in combination with multiple oral doses of itraconazole in healthy male 
subjects (an open-label, fixed sequence study)
Principal Investigator:
Trial site(s)
 
Clinical phase
I
Trial rationale
This clinical trial will be performed to investigate the effect of multiple doses of 
itraconazole on the pharmacokinetics of a single dose of BI 1358894 in order to 
assess if and to which extent the pharmacokinetics of BI 1358894 are affected by 
co-administration of a drug that inhibits cytochrome P450 3A4 (CYP3A4) and P-
glycoprotein.
Trial objective(s)
The main objective of this trial is to investigate the relative bioavailability of BI 
1358894 in plasma when given as oral single dose together with multiple oral doses 
of itraconazole (Test, T) as compared to when given alone as oral single dose
(Reference, R).
Trial design
Open-label, two-treatment, two-period, fixed sequence design
Trial endpoints:
Primary endpoints: AUC0-∞and Cmax of BI 1358894
Secondary endpoints: AUC0-tz of BI 1358894
Number of subjects 
total entered
16
each treatment
16
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 45 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product 1
BI 1358894 film-coated tablets
dose
10 mg
mode of admin.
Oral with 240 mL of water after an high-fat, high-caloric breakfast


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Test product 2 (probe)
Itraconazole oral solution (Sempera® 10 mg/ml oral solution)
dose
200 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment
Treatment “Reference” (R, in treatment period 1):
-
One single dose of 10 mg BI 1358894 on Day 1
Treatment “Test” (T; in treatment period 2):
-
200 mg itraconazole once daily (QD) for 14 days on Days -3 to 11
-
One single dose of 10 mg BI 1358894 on Day 1 
Wash-out interval
Administrations of BI 1358894 will be separated by a wash-out interval of at least 
17 days
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means
(test/reference) for the primary and secondary endpoints. Additionally, their 
two-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at a 5% significance level. 
Since the main focus is on estimation and not testing, a formal hypothesis test and 
associated acceptance range is not specified. The statistical model will be an 
analysis of variance (ANOVA) on the logarithmic scale including effects for 
‘subjects’ and ‘treatment’. CIs will be calculated based on the residual error from 
the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to first 
drug administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory9
PK blood BI 1358894 and 
metabolite
PK blood itraconazole
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Physical and neurological 
examination
C-SSRS
SCR
1
-21 to 
-1
Screening (SCR)1
A 9
x
x
x
x
Period 1: Treatment R (BI 1358894 alone) 7
2
-1
-12:00
20:00
Admission to trial site
x5
x
-11:30
20:30
Snack (voluntary)
1
-0:30
07:30
High-fat, high caloric 
breakfast
A2, 9, 
10
x2
x2
x2
x2
0:00
08:00
BI 1358894 
administration
0:30
08:30
x
x
x
1:00
09:00
x
x
x
x
1:30
09:30
x
x
x
2:00
10:00
240 mL fluid intake
x
x
x
2:30
10:30
x
3:00
11:00
x
x
x
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x
x
x
6:00
14:00
x
x
x
7:00
15:00
x
x
x
8:00
16:00
Snack (voluntary)3
x
x
x
10:00
18:00
Dinner
x
12:00
20:00
x
x
x
x 
16:00
24:00
x
x
2
24:00
08:00
B9
x
x
x
x
34:00
18:00
x
x
x
3
48:00
08:00
x
x
x
x
4
72:00
08:00
Breakfast (voluntary),
discharge from trial 
site8
B9
x
x
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
x
6
120:00
08:00
Ambulatory visit
x
x
x
7
144:00
08:00
Ambulatory visit
x
x
x
8
168:00
08:00
Ambulatory visit
x
x
x
9
192:00
08:00
Ambulatory visit
B9
x
x
x
11
240:00
08:00
Ambulatory visit
x
x
x
14
312:00
08:00
Ambulatory visit
B9
x
x
x


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FLOW CHART (continued)
Period
Visit
Day
Planned time (relative to first 
BI 1358894 administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory9
PK blood BI 1358894 and 
metabolite
PK blood itraconazole
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Physical and neurological 
examination
C-SSRS
Period 2: Treatment T (BI 1358894  + itraconazole) 7
3
-3
-72:00
08:00
Ambulatory visit,
itraconazole administration
-2
-48:00
08:00
Ambulatory visit,
itraconazole administration
-1
24:00
08:00
Ambulatory visit,
itraconazole administration
-12:00
20:00
Admission to trial site
x5
x
-11:30
20:30
Snack (voluntary)
1
-2:30
05:30
B2, 9
x2
x2
x2
x2
x2
-1:30
06:30
Itraconazole administration
-0:30
07:30
High-fat, high-caloric breakfast
0:00
08:00
BI 1358894 administration
0:30
08:30
x
x
x
1:00
09:00
x
x
x
x
1:30
09:30
x
x
x
2:00
10:00
240 mL fluid intake
x
x
x
2:30
10:30
x
3:00
11:00
x
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x
x
6:00
14:00
x
x
x
7:00
15:00
x
x
x
8:00
16:00
Snack (voluntary)3
x
x
x
10:00
18:00
Dinner
x
12:00
20:00
x
x
x
x 
16:00
24:00
x
x
2
24:00
08:00
itraconazole administration
B9
x
x2
x
x
x
34:00
18:00
x
x
x
3
48:00
08:00
itraconazole administration
x
x
x
x
4
72:00
08:00
itraconazole administration
Breakfast (voluntary)
discharge from trial site8
B9
x
x
x
x
x
x
5
96:00
08:00
Ambulatory visit,
itraconazole administration
x
x
x
x
6
120:00
08:00
Ambulatory visit,
itraconazole administration
x
x2
x
x
7
144:00
08:00
Ambulatory visit,
itraconazole administration
x
x
x
8
168:00
08:00
Ambulatory visit,
itraconazole administration
x
x
x


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Period
Visit
Day
Planned time (relative to first 
BI 1358894 administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory9
PK blood BI 1358894 and 
metabolite
PK blood itraconazole
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Physical and neurological 
examination
C-SSRS
9
192:00
08:00
Ambulatory visit,
itraconazole administration
B9
x
x
x
10
216:00
08:00
Ambulatory visit,
itraconazole administration
x
x
x
11
240:00
08:00
Ambulatory visit,
itraconazole administration
x
x2
x
x
14
312:00
08:00
Ambulatory visit
B9
x
x
x
21
480:00
08:00
Ambulatory visit
x
x
x
F
U
4
22 - 28
End of trial (EoTrial) examination4
C
x
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. 
Screening procedures include: physical examination, neurological examination, check of vital signs, ECG, safety 
laboratory (including drug screening, hepatitis serology and HIV antibodies), demographics (including determination of 
body height and weight, smoking status and alcohol history), relevant medical history, concomitant therapy and review 
of inclusion/exclusion criteria, and suicidality assessment (C-SSRS).
2.
The time is approximate; the procedure is to be performed and completed within the 2 h prior to drug administration
(Period 1) / within 2.5 h prior to BI 1358894 administration (Period 2).
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
End of trial examination (performed 11 to 17 days after last itraconazole and 21 to 27 days after last BI 1358894 
administration) includes: physical examination, neurological examination, body weight, vital signs, ECG, safety 
laboratory, recording of AEs and concomitant therapies, and suicidality assessment (C-SSRS).
5.
Only urine drug screening and alcohol breath test will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above. Headaches will be recorded with the data given in Section 6.2.2.
7.
Treatments R and T are to be separated by a wash-out interval of at least 17 days between administrations of BI 
1358894.
8.
Discharge from trial site fitness assessment includes: physical examination, neurological examination, ECG, vital signs, 
recording of AEs, suicidality assessment (C-SSRS), and concomitant therapies. 
9.
Letters A, B, and C define different sets of safety laboratory examinations (see Section 5.2.3). Safety laboratory 
examination A to be taken and medically evaluated within 3 days before first administration of BI 1358894. This can be 
omitted if screening examination is performed on Days -3, -2 or -1 of treatment period 1.
10. Blood sample for pharmacogenetic assessment.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 16
DRUG PROFILE...............................................................................................17
1.2
1.2.1
BI 1358894 .............................................................................................17
1.2.1.1
Nonclinical pharmacology.......................................................17
1.2.1.2
Safety pharmacology ...............................................................17
1.2.1.3
Toxicology...............................................................................18
Single dose toxicity ...................................................18
1.2.1.3.1
Repeat-dose toxicity studies......................................19
1.2.1.3.2
Genotoxicity ..............................................................20
1.2.1.3.3
Reproductive and developmental toxicity.................20
1.2.1.3.4
Phototoxicity..............................................................21
1.2.1.3.5
1.2.1.4
Nonclinical pharmacokinetics..................................................21
1.2.1.5
Clinical experience in humans.................................................23
1.2.1.6
Drug product ............................................................................30
1.2.2
Itraconazole ...........................................................................................30
1.2.3
Residual effect period ...........................................................................31
RATIONALE FOR PERFORMING THE TRIAL........................................31
1.3
BENEFIT - RISK ASSESSMENT ...................................................................31
1.4
1.4.1
Procedure-related risks ........................................................................32
1.4.2
Drug-related risks and safety measures..............................................32
1.4.2.1
Risks related to BI 1358894.....................................................32
1.4.2.2
Risks related to itraconazole....................................................33
1.4.2.3
Risks related to the potential drug-drug interaction between 
itraconazole and BI 1358894 ...................................................33
1.4.2.4
Risk minimisation (safety precautions) ...................................33
1.4.2.5
Drug-induced liver injury ........................................................34
1.4.3
Overall assessment of benefit-risk ratio..............................................34
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 36
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......36
2.1
2.1.1
Main objectives......................................................................................36
2.1.2
Primary endpoints ................................................................................36
2.1.3
Secondary endpoint ..............................................................................36


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2.2.2.2
Safety and tolerability..............................................................37
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 38
OVERALL TRIAL DESIGN AND PLAN ......................................................38
3.1
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S).....................................................................................38
SELECTION OF TRIAL POPULATION ......................................................39
3.3
3.3.1
Main diagnosis for trial entry..............................................................39
3.3.2
Inclusion criteria...................................................................................39
3.3.3
Exclusion criteria ..................................................................................40
3.3.4
Withdrawal of subjects from treatment or assessments ...................41
3.3.4.1
Discontinuation of trial treatment............................................42
3.3.4.2
Withdrawal of consent to trial participation ............................42
3.3.4.3
Discontinuation of the trial by the sponsor..............................42
3.3.5
Replacement of subjects .......................................................................43
4.
TREATMENTS........................................................................................ 44
INVESTIGATIONAL TREATMENTS ..........................................................44
4.1
4.1.1
Identity of the Investigational Medicinal Products ...........................44
4.1.2
Selection of doses in the trial and dose modifications........................44
4.1.3
Method of assigning subjects to treatment groups ............................45
4.1.4
Drug assignment and administration of doses for each subject .......45
4.1.5
Blinding and procedures for unblinding ............................................46
4.1.6
Packaging, labelling, and re-supply ....................................................46
4.1.7
Storage conditions.................................................................................47
4.1.8
Drug accountability ..............................................................................47
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ...............................................................................................47
4.2.1
Other treatments and emergency procedures....................................47
4.2.2
Restrictions............................................................................................48
4.2.2.1
Restrictions regarding concomitant treatment .........................48
4.2.2.2
Restrictions on diet and life style.............................................48
TREATMENT COMPLIANCE.......................................................................49
4.3
5.
ASSESSMENTS....................................................................................... 50
ASSESSMENT OF EFFICACY.......................................................................50
5.1
ASSESSMENT OF SAFETY............................................................................50
5.2
5.2.1
Physical examination ............................................................................50
5.2.2
Vital signs...............................................................................................50
5.2.3
Safety laboratory parameters..............................................................50


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5.2.4
Electrocardiogram................................................................................53
5.2.5
Other safety parameters.......................................................................54
5.2.5.1
Suicidality assessment .............................................................54
5.2.5.2
Medical examinations..............................................................54
5.2.5.3
Neurological examinations ......................................................54
5.2.6
Assessment of adverse events...............................................................55
5.2.6.1
Definitions of adverse events...................................................55
Adverse event ............................................................55
5.2.6.1.1
Serious adverse event ................................................55
5.2.6.1.2
AEs considered ‘Always Serious’.............................56
5.2.6.1.3
Adverse events of special interest .............................56
5.2.6.1.4
Intensity (severity) of AEs.........................................57
5.2.6.1.5
Causal relationship of AEs ........................................57
5.2.6.1.6
5.2.7
Suicidal risk assessed by the C-SSRS (paper version): .....................58
5.2.7.1
Adverse event collection and reporting ...................................59
AE collection.............................................................59
5.2.7.1.1
AE reporting to the sponsor and timelines ................60
5.2.7.1.2
Information required..................................................60
5.2.7.1.3
Pregnancy ..................................................................60
5.2.7.1.4
DRUG CONCENTRATION MEASUREMENTS AND 
5.3
PHARMACOKINETICS..................................................................................60
5.3.1
Assessment of pharmacokinetics .........................................................60
5.3.2
Methods of sample collection...............................................................61
5.3.2.1
Blood sampling for pharmacokinetic analysis of BI 1358894 
and 
61
5.3.2.2
Blood sampling for determination of itraconazole ..................61
5.3.3
Analytical determinations ....................................................................62
5.3.3.1
Analytical determination of analyte in plasma concentration..62
BIOBANKING ...................................................................................................62
5.4
OTHER ASSESSMENTS .................................................................................62
5.5
5.5.1
Pharmacogenomic evaluation..............................................................62
5.5.1.1
Analytical determinations........................................................63
APPROPRIATENESS OF MEASUREMENTS.............................................63
5.6
6.
INVESTIGATIONAL PLAN.................................................................. 64
VISIT SCHEDULE............................................................................................64
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................64
6.2
6.2.1
Screening and run-in period(s)............................................................64
6.2.2
Treatment period(s)..............................................................................65
6.2.3
Follow-up period and trial completion ...............................................65
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 67
STATISTICAL DESIGN – MODEL ...............................................................67
7.1


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NULL AND ALTERNATIVE HYPOTHESES ..............................................67
7.2
PLANNED ANALYSES....................................................................................67
7.3
7.3.1
Primary endpoint analyses...................................................................69
7.3.2
Secondary endpoint analyses ...............................................................70
7.3.4
Safety analyses.......................................................................................70
INTERIM ANALYSES .....................................................................................71
7.4
HANDLING OF MISSING DATA ..................................................................71
7.5
7.5.1
Safety......................................................................................................71
7.5.2
Pharmacokinetics..................................................................................71
RANDOMISATION ..........................................................................................72
7.6
DETERMINATION OF SAMPLE SIZE ........................................................72
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 74
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
8.1
CONSENT ..........................................................................................................74
DATA QUALITY ASSURANCE .....................................................................75
8.2
RECORDS..........................................................................................................75
8.3
8.3.1
Source documents .................................................................................75
8.3.2
Direct access to source data and documents.......................................76
8.3.3
Storage period of records.....................................................................76
EXPEDITED REPORTING OF ADVERSE EVENTS .................................76
8.4
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......77
8.5
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................77
TRIAL MILESTONES .....................................................................................77
8.6
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................78
8.7
9.
REFERENCES......................................................................................... 79
PUBLISHED REFERENCES...........................................................................79
9.1
UNPUBLISHED REFERENCES.....................................................................81
9.2
10. APPENDICES .......................................................................................... 84
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) ...............84
10.1
10.1.1 Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening ................................................................................84
10.1.2 Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last 
Visit
..................................................................................................87
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 90
GLOBAL AMENDMENT 1 .............................................................................90
11.1


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GLOBAL AMENDMENT 2 .............................................................................91
11.2


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ABBREVIATIONS

Bioequivalence margin
ADH
Alcohol dehydrogenase
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
 
AUC0-∞
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
 
b.p.m.
Beats per minute
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
Borderline personality disorder
CA
Competent authority
CHO
Chinese hamster ovary
CI
Confidence interval
CL
Confidence limit
 
Cmax
Maximum measured concentration of the analyte in plasma
CML
Clinical Monitor Local
CNS
Central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CRP
C-reactive protein
C-SSRS
Columbia Suicide Severity Rating Scale


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CTL
Clinical Trial Lead
CTM
Clinical Trial Monitor
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
CYP
Cytochrome P450
DILI
Drug induced liver injury
DNA
Desoxyribonucleic acid
DRF
Dose-range finding
e.g.
exempli gratia (for example)
ECG
Electrocardiogram
eCRF
Electronic case report form
ECT
Electro-convulsive therapy
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EMA
European Medicines Agency
EoTrial
End of trial
ES
Entered Set
ESR
Erythrocyte sedimentation rate
EU
European Union
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FDA
Food and Drug Administration
FE
Food effect
FIH
First-in-human
FST
Forced Swim Test
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GLP
Good Laboratory Practice
gMean
Geometric mean
GMP
Good Manufacturing Practice
hERG
Human ether-a-go-go related gene
HIV
Human immunodeficiency virus
HPLC-MS/MS
High performance liquid chromatography tandem mass spectrometry
i.d.
Intradermal
i.v.
Intravenous


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IB
Investigator’s brochure
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonisation of technical requirements for 
registration of pharmaceuticals for human use
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
IUD
Intrauterine device
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDD
Major depressive disorder
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MIST
Metabolites in safety testing
NIMH
National Institute of Mental Health
NOAEL
No observed adverse event level
p.o.
Oral
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PR
Pulse rate
PT
Preferred Term
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)
R
Reference treatment
 
 
REP
Residual effect period
SAE
Serious adverse event


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SCR
Screening
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SOP
Standard operating procedure
SRD
Single-rising dose
T
Test product or treatment
 
TCPK
Trial Pharmacokineticist
 
TRP
Transient receptor potential
TRPC 4/5
Transient receptor potential cation channel, subfamily C, members 4 and 5
TS
Treated set
TSAP
Trial statistical analysis plan
TSTAT
Trial Statistician
ULN
Upper limit of normal
VAS
Visual analogue scale
 
WBC
White blood cell count


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1.
INTRODUCTION


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DRUG PROFILE
1.2
1.2.1
BI 1358894
1.2.1.1
Nonclinical pharmacology
Transient receptor potential cation (TRPC) channels are Ca2+-permeable nonselective cation 
channels implicated in diverse physiological functions, including smooth muscle contractility 
and synaptic transmission.
The compound inhibits La3+ activated hTRPC5-channels with an IC50 of 0.2 nM. In 
addition the compound inhibits TRPC5 and TRPC4, respectively, after activation by 
Carbachol, with an the half maximal inhibitory concentration (IC50) of 0.8 nM (hTRPC5) and 
0.2 nM (hTRPC4).
BI 1358894 was investigated in several standard behavioural tests in rodents, such as Forced 
Swim Test (FST) [n00252903], Marble Burying Test [n00252207] and Elevated Plus Maze 
Test [n00252277]. The in vivo pharmacology studies demonstrated consistent 
pharmacological effects in line with anxiolytic and/or antidepressant efficacy. In the FST, 
half maximal efficacy was demonstrated at a plasma exposure of 77 nM, indicating that at 
this plasma exposure, free brain levels are in the range of the in vitro IC50 [n00253628].
BI 1358894 is highly selective against more than 10 ion channels (including other TRPs, 
potassium channels, calcium channels and sodium channels) with more than 1000-fold 
selectivity for TRPC4 and at least 200-fold selectivity for TRPC5 [n00248384]. The effect of 
BI 1358894 on more than 120 targets was evaluated at 1 μM [n00252179]. BI 1358894 was
shown to be highly selective.
1.2.1.2
Safety pharmacology
General and safety pharmacology studies have been conducted with BI 1358894 to address 
the core battery of central nervous system (CNS) [n00253725], cardiovascular [n00253723], 
[n00253727], [n00253734], renal and hepatic [n00253732], respiratory [n00253732], and 
gastrointestinal function [n00253729]. The results demonstrated an acceptable profile for 
clinical trials in healthy volunteers.
BI 1358894-related effects on the CNS of rats were limited to an early and transient increase 
of motility at dose levels of 10, 30, and 100 mg/kg (nocturnal motility test). This was 
considered to reflect an increased arousal or decreased anxiety in a novel environment 
associated with the intended efficacy (anti-depressive and anxiolytic effect). The absence of 
detectable locomotor effects in the two Modified Irwin studies might be due to differences in 
the study design.
In the cardiovascular rat study, long-lasting decreases in arterial blood pressure (10 mm Hg) 
were present at ≥10 mg/kg. Additionally, BI 1358894 induced dose-dependent and long-
lasting increases in heart rate (15 – 20 b.p.m.) in rat and dog at ≥30 mg/kg after single oral 


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dose in the general pharmacology studies. However, increase in heart rate was no longer 
detectable after 4-day repeat-dosing in rats at 30 mg/kg. In rat telemetry at 100 mg/kg, 
transient increases in PR duration and body temperature were noted. None of the 
cardiovascular findings could be confirmed in dog safety pharmacology or toxicity studies. 
Other ECG parameters, including QT and QTc intervals, and left ventricular pressure 
parameters (LVSP and dP/dtmax) were not affected by BI 1358894.
Transient effects of BI 1358894 on the respiratory function (increases in respiratory rate and 
minute volume) were seen in male rats treated with 1000 mg/kg. Altered electrolyte (Cl-, Na+, 
Ca2+) and urea urinary excretion at ≥10 mg/kg was regarded to be indicative of a change in 
rat renal function. Increases in total and conjugated bilirubin levels were not reproduced after 
repeated dosing for 4 weeks. Rat kidney and liver injury biomarkers were not altered. No 
structural degenerative correlates were present in the microscopic examination in toxicity 
studies.
Dose-dependent decreased gastric emptying was noted at 30 mg/kg (-22%) and 100 mg/kg 
(-29%). No effects on consistency of intestinal contents and intestinal transit were noted at 
any dose level. 
The influence of BI 1358894 on human ether-a-go-go related gene (hERG)-mediated 
potassium current in stably transfected Chinese hamster ovary (CHO) cells was determined to 
evaluate the potential proarrhythmic risk [n00253752]. The IC50 for tail current inhibition
was 1.15 μM, suggesting a selectivity ratio of about 200 against hERG-encoded channel
[hTRCP 1/5 = 5 nM]. These preclinical data do not suggest a proarrhythmic risk.
1.2.1.3
Toxicology
The nonclinical safety program investigating the in vivo toxicological profile of BI 1358894 
comprised repeat-dose studies up to 4 weeks of once daily oral (gavage) treatment and a 
complete battery of in vitro and in vivo studies assessing the genotoxic potential of the 
compound. Additionally, a 4-week oral repeat-dose (non-GLP) study in mice was performed. 
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.
Single dose toxicity
1.2.1.3.1
No single dose toxicity assessments have been conducted with BI 1358894. Relevant 
information was obtained from the repeat-dose toxicity studies in mice, rats, and dogs. The 
maximum tolerated dose was considered to be above 2000 mg/kg in rodents, the highest 
tested dose. In dogs, oral administration of 500 mg/kg was discontinued after 11 days due to 
prominent clinical signs. Systemic drug exposure at that dose level was 385-fold for Cmax and 
596-fold for AUC0-24h compared to predicted therapeutic exposure (please see Section 5.3.9 
of the Investigator's Brochure [c10354149].


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Repeat-dose toxicity studies
1.2.1.3.2
Repeat dose non-GLP toxicity study in mice, rats and dogs revealed toxicologically relevant 
effects on the skin, Harderian glands, and hepatic function in mice, the vascular system in 
rats, the CNS function in dogs, and the digestive tract in all three species. In addition, 
haematology evaluation revealed increases of white blood cell count (WBC) counts in all
species. 
A 4-week toxicity testing in mice identified skin, Harderian glands, and gastrointestinal tract 
as main target organs in this species at doses ≥500 mg/kg QD. Clinical pathology evaluation 
indicated a slight to moderate increase in plasma total bilirubin, but without any microscopic 
degenerative correlate. Administration of BI 1358894 was clinically well tolerated up to 
1500 mg/kg. Minimal to slight epidermal hyperplasia was observed in the skin. In the 
Harderian glands, crystal deposits (mainly a carboxylic acid metabolite of BI 1358894) 
induced minimal to severe degeneration and necrosis of the glandular tissue. A metabolite of 
BI 1358894 was the major compound-related constituent as shown by mass spectrometry 
analysis. Due to the species-specific metabolism, this mouse finding was considered to be of 
limited toxicological relevance. Multifocal erosion/ulceration, graded minimal to slight in 
severity, affected the mucosa of the stomach and the intestine and minimal to moderate 
epithelial vacuolation of the villi and minimal villous atrophy were present in the duodenum. 
Other BI 1358894-related pathological findings in the hematopoietic and lymphoid organs (at 
≥7 mg/kg) associated with increased reticulocyte and WBC counts in blood, the liver (at 
≥30 mg/kg), and the heart (at 1500 mg/kg) were regarded as non-adverse due to their 
adaptive character. 
Repeat-dose toxicity testing in rats revealed no serious clinical signs of toxicity, no 
toxicologically relevant effects on body weight and food and water consumption, and no 
ophthalmology findings were noted. The main findings in clinical pathology were indicative 
of a minimal inflammatory response starting at 200 mg/kg, characterised by leukocytosis, 
hyperproteinaemia, and hyperglobulinemia. On Day 5 after the start of treatment, minimal to 
moderate periarterial inflammation was present in the mesentery, pancreas, and/or liver at 
≥30 mg/kg, with dose-related increases in incidence and severity. In a few animals given 
≥200 mg/kg, arterial inflammation and necrosis focally affected the pancreas and the serosa 
of the intestine. In a 4-week dose-range finding (DRF) 'reversibility' study where animals
were sacrificed and microscopically examined on Day 5 and at the end of the treatment 
period (Day 28), perivascular/mesenteric inflammation induced by BI 1358894 occurred 
early after start of dosing and resolved over 4 weeks despite continued treatment, indicating 
the transient character of the inflammation. Other BI 1358894-related pathological findings in 
the kidneys (at ≥7.5 mg/kg), the heart and the liver (at ≥30 mg/kg), and the mandibular 
glands (at ≥1000 mg/kg) were considered to be non-adverse due to their adaptive character, 
low magnitude, and/or absence of pathological correlates. All changes were fully reversible 
or greatly ameliorated over a 4-week off-treatment recovery period.
In repeat-dose toxicity testing in dogs, no spontaneous deaths occurred up to 1000 mg/kg, the 
highest tested dose, administered for 11 days. Decreased body weight, reduced food 
consumption and faecal alterations occurred at ≥150 mg/kg. Distinct clinical signs of toxicity 
were present at ≥500 mg/kg, starting on the 3rd day of treatment (gait abnormalities, 


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decreased motor activity, one episode of convulsions, trembling). In addition, a territorial 
behaviour was shown by dogs administered 150 mg/kg over 4 weeks. Pathology and clinical 
pathology investigations did not reveal any pertinent findings which could have explained the 
clinical signs. 
Administration of BI 1358894 did not result in any pertinent changes in ophthalmology and 
cardiovascular investigation. 
Clinical pathology evaluation revealed a limited number of changes at ≥500 mg/kg: moderate 
decreases in reticulocyte counts, minimal increases in WBC and neutrophil counts, slight 
increases in phosphate and minimal decreases in calcium levels in the blood, and slightly to 
moderately reduced urinary sodium and chloride excretion. Few relevant BI 1358894-related 
histopathological findings were noted at ≥500 mg/kg, namely (multi)focal minimal to slight 
erosion/ulceration in the oral cavity, esophagus and duodenum. Changes observed in the 
thymus (decreased weight, reduced size, lymphoid depletion), the spleen (decreased weight), 
the liver (decreased glycogen content), and the salivary glands (secretory depletion) were 
regarded as unspecific response to stress or secondary to reduced food consumption. No BI 
1358894-related findings were observed during a 4-week recovery period. 
An overview of estimated safety margins (exposure multiples) is presented in
Table: 1.2.1.3.2: 1 below. The comparison revealed safety margins of ≥9 for Cmax and for 
AUC0-24h.
Table: 1.2.1.3.2: 1 
Overview of estimated safety margins (exposure multiples) for BI
1358894 based on the NOAELs of the 4-week oral toxicity studies in 
rats and dogs and the 4-week oral DRF study in mice
Species
NOAEL
[mg/kg]
Mean Cmax at 
NOAEL [nM]
in m/f
Mean AUC0-24h
at NOAEL 
[nM×h] in m/f
Human to Animal Safety 
Margin in m/f
Based on 
multiples of 
Cmax
Based on 
multiples of 
AUC0-24h
Rat
30
1960 / 3600
26300 / 53900
9 / 17
9 / 19
Rat
7.5
913 / 1440
9439 / 13600
4 / 7
3 / 5
Dog
30
7190 / 4240
137000 / 57300
34 / 20
49 / 20
Predicted human Cmax: 210 nM, predicted human AUC0-24: 2800 nM.h
Genotoxicity
1.2.1.3.3
The genotoxic potential of BI 1358894 was investigated in an ICH-compliant test battery of 
in vitro and in vivo studies (for details see Section 5.3.9 of the Investigator's Brochure, 
[c10354149]. There was no evidence that BI 1358894 is associated with genotoxic activity.
Reproductive and developmental toxicity
1.2.1.3.4
In preliminary studies on embryofoetal development, BI 1358894 was well tolerated in 
pregnant rats and had no effect on embryofoetal viability, but caused overt maternal toxicity 


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and embryofoetal lethality at all dose levels tested in rabbits. These effects in rabbits occurred 
at BI 1358894 plasma levels in the range or at low multiples of estimated efficacious human 
levels. The poor tolerability of BI 1358894 in rabbits is considered to be related to their 
known sensitivity to disturbances of the alimentary tract and the embryofoetal lethality as a 
sequel thereof.
There was no indication from the pivotal (GLP) 4-week toxicity studies in rats and dogs that 
oral administration of BI 1358894 was associated with morphological changes in 
reproductive organs of both sexes.
Phototoxicity
1.2.1.3.5
BI 1358894 is unlikely to cause phototoxicity. BI 1358894 did not induce any cytotoxic 
effect in the in vitro 3T3 NRU phototoxicity test.
1.2.1.4
Nonclinical pharmacokinetics
Drug Absorption and Disposition
The disposition of BI 1358894 is characterized in rats by low clearance and moderate volume 
of distribution. High oral bioavailability (81.9%) in rats suggests an at least moderate 
bioavailability in humans. The plasma protein binding of BI 1358894 was high in all 
investigated species, with unbound fractions of 0.26 % (mouse), 0.42% (rat), 0.31% (dog), 
and 0.25% (human).
In a quantitative whole body autoradiography study, the extent of distribution of 
[14C]BI 1358894 from plasma into tissues was considered to be moderate [n00252628].
Highest concentrations of radioactivity were found in the Harderian gland (up to 27 times 
higher than in plasma), the liver (up to 14 times), and the walls of the gastrointestinal tract 
(up to 9.4 times higher than in plasma). Lowest tissue-to-plasma ratios were found in total 
eyeball (1% of plasma level), nasal mucosa (3%), and CNS (11% to 23%).
While the total eyeball was exposed to drug-related radioactivity throughout the entire 
timeframe of investigation, drug-related radioactivity in the skin was below the limit of 
quantification. Qualitative evaluation of the autoradiograms, however, revealed discernible 
photo-luminescence signals in lipid-rich parts of the skin until the last time-point of 
investigation. The terminal half-lives for BI 1358894 in rats were 6.21 h (male) and 7.91 h 
(female) and longer for [14C] BI 1358894 – related radioactivity with 14.0 h (male) and 
14.2 h (female). The fraction of total exposure for BI 1358894 ([14C]BI 1358894 – related 
radioactivity) was 31% (males) and 49% (females). Similar proportions of parent compound 
and drug-related radioactivity after oral and intravenous administration indicated a low first 
pass effect. After intravenous (short term infusion) administration, 0.8% of the total 
administered radioactive dose was excreted in the urine within 24 h. In faeces, 55.7% (males) 
or 45.4% (females) of the total dose was recovered within 24 h. Excretion was slow, with a 
faecal excretion of 81.4% (mean of males and females) within 168 h. The biliary excretion in 
anesthetized rats was 12.4% (males) or 16.5% (females) of the dose within 6 h. 
Metabolism


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The in vitro metabolism of [14C]BI 1358894 was investigated by the use of human liver 
microsomes, S9 supernatant, cytosol, expressed CYP, UDP-glucuronosyl transferase, 
aldehyde oxidase, and alcohol dehydrogenase (ADH) enzymes and human hepatocytes
[n00258719]. Metabolites were identified by HPLC-MS/MS analysis.
Metabolite M700(1) (BI 1358894-glucuronide) and metabolite M538(1) (BI 1361608) were
the predominant metabolites formed in human hepatocytes. Only low amounts of additional
metabolites M540(2) and M538(2) were observed. These metabolites were formed at
amounts close to the lower limit of the linear detection range. The aldehyde structured
intermediate metabolite M522(1) (BI 1361575) was not observed in experiments with human
hepatocytes but was found only during in vitro incubations in the absence of cytosolic
enzyme sources.
Metabolites in safety testing (MIST) relevant metabolites found in human hepatocytes were
also found in rat in vivo, therefore the potential for disproportionate human metabolites was 
considered to be low [R17-0660].
In order to obtain in vivo information on the metabolic pathways and the routes of excretion
the metabolism of BI 1358894 was investigated at a dose of 0.5 mg/kg (i.v.) and 1 mg/kg
(p.o./i.d.) in male and female Sprague Dawley rats [n00261794].
After intravenous (i.v.) and oral (p.o.) administration of [14C]BI 1358894, 0.8% and 0.6% of
drug-related radioactivity was excreted with urine within 0 – 24 h and the bulk of the
radioactivity (about 80%-90%) was excreted with faeces within 0 - 168 h.
Neither BI 1358894 nor a metabolite was excreted > 0.5% of dose in urine. In faeces, the 
most abundant metabolite was generated by oxidation of the alcohol group to carboxylic acid
M538(1) (BI 1361608) which is also present in bile. Great amount of radioactivity was
eliminated via faeces as the hydroxylated metabolite M540(1) and N-demethylated M510(1).
Lower amounts, about 5% in faeces, were eliminated as parent compound, the hydrogenated
and twofold hydroxylated metabolite M558(1) and the both N-methylated metabolites
M524(2) and M686(1) which were also detected in bile samples. M542(2) was further
oxidated to the carboxylic acid and M686(1) was a glucuronide conjugate. Metabolites which 
were exclusively found in bile samples were the glucuronide of the parent compound 
M700(1) and the hydroxylated and further glucuronidated conjugate M716(1). First 
hydroxylated followed by a glutathione conjugation was the metabolite M847(1) and two 
additionally metabolites were M689(1) (+C4H11O2N3S) and M647(1) (+CH5O2N3S).
The main metabolite in plasma, in addition to parent compound, was M538(1) (BI 1361608).
In smaller amounts present were the N-demethylated metabolite M510(1), the hydroxylated
metabolite M540(2) and the twofold hydroxylated and hydrogenated metabolite M558(1).
Two radioactive peak fractions of about 1% could not be assigned. Those were defined as m1
and m2.
Relevant differences of metabolite pattern in plasma, urine, faeces and bile related to
application route were not observed. However, the metabolite pattern in faeces and bile
showed a higher prevalence of oxidation to the carboxylic acid M538(1) versus
demethylation to M510(1) in male compared to female rats.


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Potential pharmacokinetic interactions 
The inhibition potential of BI 1358894 was investigated for human CYP enzymes 
CYP1A1/2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 [n00253492]. BI 1358894 was a 
competitive in vitro inhibitor of CYP2C9, 2C8, 2D6, 2C19 and 2B6 with Ki values of 
3.71 μM (CYP2C9), 4.82 μM (CYP2C8), 5.51 μM (CYP2D6), 10.1 μM (CYP2C19) and 
13.6 μM (CYP2B6). Due to binding of BI 1358894 to plastic surfaces and microsomal 
protein, the actual concentrations of BI 1358894 in incubations were lower than the nominal 
concentrations. Therefore, it has to be taken into account that the actual Ki data could be 
slightly lower than the measured values. Irreversible inhibition by BI 1358894 was not 
observed for any of the CYP enzymes under investigation. Depending on the level of 
exposure during drug therapy, in vivo inhibition of multiple CYP enzymes by BI 1358894 
may be possible.
The in vitro potential of BI 1358894 and the metabolite 
 to induce rat CYP 
enzymes (CYP1A1, 2B1, 2C7, 2C11, 2D1, 2E1, 3A1/2, 4A) in rat hepatocytes was 
investigated [n00253490]. An induction potential towards CYP3A1 mRNA was seen with 
BI 1358894 concentration-dependent at high concentrations of ≥5 μM, and to a lesser extent 
with 
at 20 μM.
The potential for BI 1358894 to induce human CYP enzymes was investigated in vitro at BI 
1358894 concentrations up to 100 μM using sandwich cultured human hepatocytes prepared 
from three donors. BI 1358894 was not an inducer of CYP1A2 but might be a weak inducer 
for both CYP2B6 and CYP2C8. BI 1358894 was an inducer of CYP3A4 mRNA and enzyme 
activity up to 25 μM [n00256526].
1.2.1.5
Clinical experience in humans
An 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). 
The single-rising dose (SRD) part of the study has been completed involving 55 subjects in 7
dose groups with single oral doses of 3 mg, 6 mg, 10 mg, 25 mg, 50 mg, 100 mg or 200 mg 
of BI 1358894 administered under fasted conditions. In each of the 7 dose groups 6 subjects 
were assigned to BI 1358894 and 2 subjects to placebo. At a dose level of 200 mg, the SRD 
part was stopped because of a less than dose proportional increase in exposure (Cmax and 
AUC0-24), which was considered to be possibly related to a reduced solubility of the film-
coated tablets under fasting conditions. The further dose escalation in the SRD part was not 
stopped because of safety issues. Up to a single dose of 200 mg administered under fasting 
conditions, BI 1358894 was safe and well tolerated in all doses. There were no SAEs or dose 
limiting AEs. 
Furthermore, BI 1358894 has been tested in 20 subjects with and without a high calorie, high 
fat breakfast to evaluate the effect of food on its relative bioavailability (food effect [FE] part: 
8 subjects at 50 mg, 12 subjects at 100 mg).


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Adverse events
There were no adverse events (AEs) considered to be dose limiting and no serious adverse 
events (SAEs). All subjects completed the study per protocol. All AEs were of mild to
moderate intensity; no AE of severe intensity was reported.
The following results were observed (see also Table 1.2.1.5: 1 and Table 1.2.1.5: 2 for a more
detailed overview of AEs):

In the SRD part, 22 of 42 subjects on BI 1358894 and 3 of 13 subjects on placebo 
reported at least one AE.

SRD: The frequency of subjects with at least one AE in the highest dose group 
(200 mg fasted) was comparable to the 50 mg and 100 mg fasted dose groups.

In the FE part, 16 of 20 subjects (all on BI 1358894) reported at least one AE. The 
higher prevalence of AEs in the FE part compared to the SRD part might be related to 
the two treatment periods and the longer period of safety monitoring.

Food Effect: The frequency of subjects with at least one AE in the 50 mg dose group 
(fasted and fed period) was higher compared to the SRD part. In contrast, the 
frequency of subjects with at least one AE in the dose group 100 mg (fasted and fed 
period) was similar to the SRD part. The subjects with the highest exposure (100 mg 
fed period) had a slightly lower frequency of adverse events compared to the fasted 
period.

At the System Organ Class (SOC) level, the most frequently reported AEs were 
nervous system disorders, reported in 21 subjects in the SRD part (19 of 42 subjects 
on BI 1358894 and 2 of 13 subjects on placebo) and 16 of 20 subjects in the FE part 
(all on active).

At the Preferred Term (PT) level, the following AEs were observed in more than one 
subject:

Headache in 18 subjects in the SRD part (17 of 42 subjects on active and 1 of 13 
subjects on placebo) and in 15 of 20 subjects in the FE part (all on active),

Dizziness in 3 subjects in the SRD part (2 of 42 subjects on active and 1 of 13 
subjects on placebo) and 7 of 20 subjects in the FE part (all active),

Fatigue in 3 subjects in the FE part (all on active), and 

Disturbance in attention in 2 subjects in the FE part (all on active).

AEs of moderate intensity were mainly observed in subjects on BI 1358894:

Injury due to a cycling accident in one subject 6 days after dosing (6 mg SRD);

Syncope because of a vasovagal reaction during blood drawing in one subject on 
placebo (25 mg dose group, SRD);

Back pain in one subject 2 days after dosing, resolved in 11 hours (50 mg SRD);

Nasopharyngitis in one subject 4 days after dosing (100 mg, FE, fasted).


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
Headache in 10 subjects (2 SRD, 8 FE, all on active) with an onset mostly 4-
7 hours after dosing and resolved mainly within a few hours.
There were no protocol-specified AEs of special interest (AESI) and no other significant AEs 
according to ICH E3. Per protocol AESI was hepatic injury, as defined by aspartate 
aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥3-fold upper limit of normal 
(ULN) combined with total bilirubin ≥2-fold ULN, and/or aminotransferase elevations 
≥10 fold ULN.
There were isolated events of apathy, auditory disorder and abnormal dreams in 3 subjects 
treated with either 3 mg or 6 mg of BI 1358894. Since no comparable events were reported 
for the remaining dose groups up to a single dose of 200 mg of BI 1358894 and due to the 
lack of a temporal relationship between dosing and event, these events were considered as 
chance findings and not drug related.
Additional Safety Assessments
There were no clinically relevant changes of lab values. In particular there were no changes 
of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) suggesting an 
inflammatory event. 
Explorative analysis of the Bowdle-Visual Analogue Scale (VAS) scores showed a 
comparable pattern between subjects across all dose groups. There were in particular no 
abnormalities for the score ‘feeling high’ and ‘changes of perception’, which may indicate 
psychedelic effects. The occasional occurrence of ‘drowsy’ was evenly distributed between 
active and placebo.
The suicidality assessment based on Columbia suicide severity rating scale (C-SSRS) did not 
reveal an individual subject who developed suicidal ideation by end of the study.
ECGs recorded from Day 1 pre-dose until Day 2 / 34 h post-dose were analyzed centrally. 
After each dose group absolute values and changes in ECG parameters were reported by the 
ECG core lab to the sponsor and study site. No dose dependent trend of a possible QTcF 
prolongation was observed (the maximum individual QTcF interval across all dose groups of 
the SRD part was 432 ms, and for the FE part 450 ms).
Based on the pre-specified criteria of the trial protocol orthostatic testing did not reveal a 
subject with a positive test after dosing, i.e. no reduction in systolic BP of ≥20 mm Hg or in 
diastolic BP of ≥10 mm Hg within 3 minutes of standing, no orthostatic symptoms and no 
increase of heart rate > 100/min during orthostatic testing. Monitoring of vital signs and 
adverse events conducted in the further course of the study did also not reveal findings 
suggesting orthostatic effects of BI 1358894. The data on treatment emerging adverse events 
in the SRD part covering dose groups 1 to 7 are displayed in Table 1.2.1.5: 1 as well as the
adverse events in the FE part are depicted in Table 1.2.1.5: 2.


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Table 1.2.1.5: 1
Preliminary frequency [N (%)] of subjects with adverse events treated 
with BI 1358894 or placebo - FIH Trial 1402-0001
System Organ Class, 
Preferred Term
Placebo
(N=13)
BI 3mg 
(DG1)
(N=6)
BI 6mg 
(DG2)
(N=6)
BI 10mg 
(DG3)
(N=6)
BI 25mg
(DG4)
(N=6)
BI 50mg 
(DG5)
(N=6)
BI 100mg 
(DG6)
(N=6)
BI 200mg 
(DG7)
(N=6)
Total with adverse 
events
3 (23.1)
3 (50.0)
6 (100.0)
0 (0.0)
2 (33.3)
4 (66.7)
4 (66.7)
3 (50.0)
Nervous system 
disorders
2 (15.4)
2 (33.3)
5 (83.3)
0 (0.0)
2 (33.3)
3 (50.0)
4 (66.7)
3 (50.0)
Headache
1 (7.7)
2 (33.3)
4 (66.7)
0 (0.0)
2 (33.3)
3 (50.0)
3 (50.0)
3 (50.0)
Dizziness
1 (7.7)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Head discomfort
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Syncope
1 (7.7)
0 (0.0)
0 (0.0%)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Musculoskeletal and 
connective tissue 
disorders
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
2 (33.3)
0 (0.0)
0 (0.0)
Back pain
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Pain in extremity
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Ear and labyrinth 
disorders
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Auditory disorder
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Gastrointestinal 
disorders
2 (15.4)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Oral discomfort
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Abdominal pain
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Abdominal pain upper
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Nausea
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
General disorders and 
administration site 
conditions
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Fatigue
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Injury, poisoning and 
procedural 
complications
1 (7.7)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Limb injury
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Road traffic accident
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Vascular procedure 
complication
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Psychiatric disorders
0 (0.0)
1 (16.7)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Abnormal dreams
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Apathy
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Metabolism and 
nutrition disorders
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Decreased appetite
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)


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Table 1.2.1.5: 2
Frequency [N (%)] of subjects with adverse events treated with 
BI 1358894– FE part
System Organ Class,
Preferred Term
BI 50mg 
(fast)
(N=8)
BI 50mg 
(fed)
(N=8)
BI 100mg 
(fast)
(N=12)
BI 100mg 
(fed)
(N=12)
Total with adverse events
7 (87.5)
7 (87.5)
8 (66.7)
6 (50.0)
Nervous system disorders
7 (87.5)
7 (87.5)
8 (66.7)
5 (41.7)
Headache
7 (87.5)
6 (75.0)
7 (58.3)
4 (33.3)
Dizziness
3 (37.5)
2 (25.0)
3 (25.0)
2 (16.7)
Disturbance in attention
2 (25.0)
0 (0.0)
0 (0.0)
0 (0.0)
Head discomfort
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Paraesthesia
1 (12.5)
0 (0.0)
0 (0.0)
0 (0.0)
Skin and subcutaneous tissue 
disorders 
0 (0.0)
2 (25.0)
0 (0.0)
1 (8.3)
Pruritus generalised
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Rash macular
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Skin reaction
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Acne
0 (0.0)
0 (0.0)
0 (0.0)
1 (8.3)
General disorders and 
administration site conditions
1 (12.5)
0 (0.0)
0 (0.0)
2 (16.7)
Fatigue
1 (12.5)
0 (0.0)
0 (0.0)
2 (16.7)
Musculoskeletal and connective 
tissue disorders
0 (0.0)
1 (12.5)
2 (16.7)
0 (0.0)
Musculoskeletal chest pain
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Arthralgia
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Back pain
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Gastrointestinal disorders
1 (12.5)
1 (12.5)
0 (0.0)
0 (0.0)
Flatulence
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Nausea
1 (12.5)
0 (0.0)
0 (0.0)
0 (0.0)
Infections and infestations
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Nasopharyngitis
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)


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Pharmacokinetics
Following oral administration of film coated tablets in fasted state (SRD part, doses 3 mg to 
200 mg), BI 1358894 reached maximum plasma concentrations between 1 and 5 hours 
(median tmax). Cmax, AUC0-24, AUC0-72 and AUC0-∞increased dependent on dose. However, 
preliminary statistical analysis of dose proportionality indicates a less than dose-proportional 
increase in exposure of BI 1358894 formulated as tablet and administered in fasted state over 
the tested dose range from 3 mg to 200 mg.
Within the Food Effect part of the study, BI 1358894 was administered under fasted 
conditions and after a high-fat, high-caloric breakfast in a 2-way-crossover design. 
A positive food effect (based on AUC and Cmax, see Table 1.2.1.5: 4) was observed when BI 
1358894 was administered as tablet after a high calorie, high fat breakfast in comparison to 
fasted state. An increase of about a factor of 1.6 was observed at the 50 mg dose whereas an 
increase of a factor of about 2.5 was observed after 100 mg between fasted and fed state.
After reaching Cmax, BI 1358894 plasma concentrations declined in a multiphasic fashion 
implying multicompartmental distribution and exhibited a long terminal phase, which seems 
to be dose-independent.
The apparent terminal half-life (t1/2) after oral dosing was calculated based on available data 
until 192 h after administration. Considering the last 3 time points for determination of z
(and dependent parameters) and extrapolation (96 h to 192 h planned sampling times, all 
doses apart from 3 mg DG), the percentage of extrapolation beyond the last measured time 
point was between 2.75% and 26.0% (only 4 subjects above 20%). The resulting t1/2 (gMean) 
was between 50.2 and 74.4 hours. The gMean of mean residence time after oral dosing 
(MRTpo) was between 54.8 and 82.5 hours. t1/2 and MRTpo appear to be independent of dose 
based on PK data of BI 1358894 after a single dose oral administration (Table 1.2.1.5: 3 and
Table 1.2.1.5: 4).


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Table 1.2.1.5: 3
Summary of gMean (gCV %) PK parameters of 3, 6, 10, 25, 50, 100 
and 200 mg BI 1358894 administered under fasted conditions [SRD 
part; clinical trial 1402-0001]
Dose Group:
DG1
DG2
DG3
DG4
DG5
DG6
DG7
Dose [mg], 
formulation
3 mg, 
tablet
6 mg, 
tablet
10 mg, 
tablet
25 mg, 
tablet
50 mg, 
tablet
100 mg, 
tablet
100 mg, 
tablet
200 mg, 
tablet
fasted
fasted
fasted
fasted
fasted
fasted
fasted
fasted
N=6
N=6
N=6
N=6
N=6
N=6
Without 
#1352
N=5
N=6
AUC0-24
[nmol*h/L]
166
(15.7)
269 
(28.9)
400 
(13.9)
937 
(43.4)
1670 
(32.8)
919 
(1130)
2210 
(58.4)
4130 
(30.4)
AUC0-24/D 
[nmol*h/L/mg]
55.5 
(15.7)
44.8 
(28.9)
40.0 
(13.9)
37.5 
(43.4)
33.4 
(32.8)
9.19 
(1130)
22.1 
(58.4)
20.7 
(30.4)
AUC0-72 
[nmol*h/L]
261 
(17.9)
445 
(31.6)
651 
(14.5)
1780 
(31.1)
3040 
(27.7)
2000 
(1320)
5010 
(40.4)
8720 
(32.1)
AUC0-72/D 
[nmol*h/L/mg]
87.1 
(17.9)
74.1 
(31.6)
65.1 
(14.5)
71.2 
(31.1)
60.9 
(27.7)
20.0 
(1320)
50.1 
(40.4)
43.6 
(32.1)
AUC0-∞
[nmol*h/L]
353* 
(25.1)
603 
(33.6)
930 
(20.4)
2580 
(30.2)
4530 
(24.5)
3000 
(1570)
7730 
(39.8)
13900 
(44.8)
AUC0-∞/D 
[nmol*h/L/mg]
118* 
(25.1)
100 
(33.6)
93.0 
(20.4)
103 
(30.2)
90.6 
(24.5)
30.0 
(1570)
77.3 
(39.8)
69.7 
(44.8)
Cmax [nmol/L]
27.6 
(30.0)
35.9 
(33.8)
59.7 
(13.4)
84.2 
(44.2)
183 
(56.3)
94.3 
(735)
206 
(72.8)
385 
(26.8)
Cmax/D 
[nmol/L/mg]
9.20 
(30.0)
5.99 
(33.8)
5.97 
(13.4)
3.37 
(44.2)
3.66 
(56.3)
0.943 
(735)
2.06 
(72.8)
1.92 
(26.8)
tmax [h]1
2.0 
(1-4)
2.5 
(1-5)
1
(1-3)
5
(1-6)
1
(0.5-2.5)
2.25 
(1-6)
3
(1-6)
5
(1-8)
t1/2
46.6* 
(31.9)
53.1 
(14.4)
58.5 
(11.5)
60.6 
(18.7)
58.4 
(13.3)
50.2 
(28.0)
54.0 
(23.7)
60.2 
(39.6)
MRTpo
51.5* 
(33.1)
54.8 
(21.2)
61.2 
(24.0)
66.9 
(16.0)
67.3 
(15.1)
66.3 
(26.7)
71.3 
(21.7)
76.4 
(23.8)
1tmax median (range), D Dose-normalized, DG dose group, 
2sensitivity analysis without subject 
 who had substantially lower BI 1358894 plasma concentrations
* values are based on planned sampling time points up to 96 h only


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Table 1.2.1.5: 4 
Summary of gMean (gCV %) non-compartmental PK parameters of 
50 mg and 100 mg BI 1358894 administered under fasted conditions 
and after a high-calorie, high-fat meal [relative BA food effect part; 
clinical trial 1402.1]
Dose [mg]/ 
condition
50 mg
50 mg
100 mg
100 mg
Fasted
Fed
Fasted
Fed
N=8
N=8
N=12
N=12
AUC0-24
[nmol*h/L]
1570 (36.7)
2980 (25.1)
2350 (40.6)
6780 (12.2)
AUC0-24/D 
[nmol*h/L/mg]
31.4 (36.7)
59.6 (25.1)
23.5 (40.6)
67.8 (12.2)
AUC0-72 
[nmol*h/L]
3120 (20.9)
5110 (28.9)
4600 (49.2)
11600 (14.8)
AUC0-72/D 
[nmol*h/L/mg]
62.4 (20.9)
102 (28.9)
46.0 (49.2)
116 (14.8)
AUC0-∞
[nmol*h/L]
5060 (29.3)
7900 (42.9)
6930 (54.6)*
17200 (21.8)
AUC0-∞/D 
[nmol*h/L/mg]
101 (29.3)
158 (42.9)
69.3 (54.6)*
172 (21.8)
Cmax [nmol/L]
149 (59.4)
237 (24.9)
210 (38.8)
517 (8.61)
Cmax/D 
[nmol/L/mg]
2.99 (59.4)
4.74 (24.9)
2.10 (38.8)
5.17 (8.61)
tmax [h]1
5 (1-5)
5 (2.98-6)
2.5 (1-6)
6 (0.5-7)
t1/2
71.2 (24.7)
74.4 (27.7)
68.9 (34.6)*
66.7 (25.8)
MRTpo
82.5 (24.1)
76.7 (35.9)
78.8 (30.8)*
70.1 (29.4)
1tmax median (range), D Dose-normalized 
* N=11 due to drop out of subject
, PK samples of this subject up to 96 hours available only
1.2.1.6
Drug product
Please refer to Section 4.1. For a more detailed description of the BI 1358894 profile, please 
refer to the current IB [c10354149].
1.2.2
Itraconazole
Absorption of itraconazole solution is fast with maximum plasma concentration being 
reached within 2.5 h after oral administration in fasting condition. Bioavailability of 
itraconazole liquid is increased by 30% when given under fasting condition compared to 
administration together with food [R18-2644]. Mean peak plasma concentrations were 
547.7 ng/mL after a single dose of 200 mg itraconazole solution (fasting) and 1965 ng/mL
after 15 days of daily treatment with 200 mg itraconazole (solution, fasting). Kinetics of 


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itraconazole are non-linear. The half-life of itraconazole after multiple doses of 200 mg once 
daily with solution formulation was about 40 h [R17-3742].
In the liver, itraconazole is metabolised extensively to more than 30 metabolites [R17-3743]. 
Its main metabolite, OH-itraconazole, accounts for about twice the amount of plasma 
itraconazole at trough. It has been shown in vitro that CYP3A4 is mainly responsible for the 
formation of this metabolite [R18-2643]. FDA classifies itraconazole as strong index 
inhibitor of CYP3A and as inhibitor of P-glycoprotein [R18-0241]. However, not only 
itraconazole contributes to the in vivo inhibition of CYP3A observed after itraconazole 
administration but also three of its metabolites (OH-itraconazole, keto-itraconazole and N-
desalkyl-itraconazole) [R10-1102].
For a more detailed description of itraconazole please refer to the SmPC [R18-2643].
1.2.3
Residual effect period
The Residual Effect Period (REP) of BI 1358894 is approximately 14 days. This is the period 
after the last dose where measurable drug levels and/or pharmacodynamic effects are still 
likely to be present.
For the use of itraconazole in this trial, the REP is defined as 6 days.
RATIONALE FOR PERFORMING THE TRIAL
1.3
Results from nonclinical studies indicate that BI 1358894 is metabolized by CYP3A4.
This clinical trial will be performed to investigate the effect of multiple doses of itraconazole 
on the pharmacokinetics (PK) of a single dose of BI 1358894 in order to assess if and to 
which extent the PK of BI 1358894 are affected by co-administration of a drug that inhibits
CYP3A and P-glycoprotein.
Itraconazole is chosen for this trial as perpetrator drug, as this drug is recommended as strong 
inhibitor of CYP3A by EMA [P15-06991], as strong index inhibitor of CYP3A and inhibitor 
of P-glycoprotein by FDA [R18-0241], and as strong inhibitor of CYP3A and typical 
inhibitor of P-glycoprotein by PMDA [P15-06298]. Moreover, safety and tolerability of 
itraconazole were acceptable in previous drug-drug interaction trials [c02336088], 
[c03355329], [c08928447].
BENEFIT - RISK ASSESSMENT
1.4
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.


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1.4.1
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
ECG electrodes may cause local and typically transient skin reactions.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
1.4.2
Drug-related risks and safety measures
1.4.2.1
Risks related to BI 1358894
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 Section 1.2.1, potential risks observed in non-clinical studies are a long 
lasting decrease in the blood pressure in rats, an increase in heart rate in rats and dogs, and 
signs of a short lasting episode of arterial/ perivascular inflammation in rats. All findings 
were observed within 5 days after the start of treatment. The cardiovascular effects observed 
in rodents and non-rodents can be easily monitored in a Phase I study (cardiovascular
effects). Perivascular/ mesenteric inflammation 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 transient receptor potential (TRP) family members are ion channels considered to play a 
crucial role in physiological processes such as to act as a cellular sensor or to support signal 
transmission [R18-0249]. The subtypes TRPC4 and TRPC5 form ion channels that are 
involved in the regulation of neuronal excitability. They are highly expressed in the 
amygdala, in the frontal cortex, hippocampus, and hypothalamus [R15-3888], [R16-5350], 
which are involved in modulation and processing of emotion and affect. Preclinically, 
inhibition of these receptors by BI 1358894 has resulted in diminished fear and anxiety and 
increased social interaction without impairing other brain functions such as learning and 
memory behaviours. In accordance with these findings, TRPC5 deficient mice display an 
anxiolytic-like phenotype [R15-3888]. This supports the assumption that CNS effects in


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healthy subjects due to an inhibition of TRPC 4/5 are limited to a reduced anxiety. However, 
clinical data with compounds inhibiting this target have yet to be published.
Relevance of animal models 
Human TRPC4 and TRPC5 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, PK, 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 [n00250347] did not reveal any 
toxicologically relevant effects of BI 1358894 on the immune system up to the highest tested 
dose of 2000 mg/kg (1000 mg/kg twice daily). 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.
1.4.2.2
Risks related to itraconazole
Multiple dosing of 200 mg itraconazole up to 15 days was of acceptable tolerability in 
healthy subjects [c02336088], [c03355329], [c08928447], [R17-3742].
1.4.2.3
Risks related to the potential drug-drug interaction between itraconazole and BI
1358894
It is likely that concomitant administration of BI 1358894 with itraconazole may cause an 
increase of plasma concentrations and t1/2 of BI 1358894 (see Section 1.2.1.4).
Therefore, a low dose of 10 mg BI 1358894 has been selected for this trial.
Doses of up to 200 mg BI 1358894 in fasted state, and of 50 and 100 mg in fed state had been 
shown to be safe and well-tolerated in the FIH trial 1402-0001. Cmax, AUC0-24, AUC0-72 and 
AUC0-∞increased dependent on dose, and a higher bioavailability of BI 1358894 was 
observed when given together with food. 
Thus, with a dose of 10 mg BI 1358894 administered in fasted or fed state, even in case of 
substantial increases of BI 1358894 plasma concentrations by itraconazole, the safety margin 
was assessed to be sufficient for the current trial.
1.4.2.4
Risk minimisation (safety precautions)
The following safety measures will be applied in this study in order to minimize the risk for
healthy volunteers:


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
Careful dose selection

An extensive safety laboratory will be performed with special focus on full blood 
exam (see Flow Chart).

Repeated triplet 12-lead ECGs are scheduled throughout the study.

Blood pressure and heart rate will be closely monitored (see Flow Chart).

Adequate safety monitoring will be performed (e.g. vital signs including blood 
pressure, pulse rate), ECGs, safety laboratory tests including CRP, ESR, hormone 
parameters, suicidality, and assessment of adverse events).

Subjects will be hospitalised in each treatment period from Day -1 (treatment with 
oral dose of BI 1358894) to Day 4 and will be discharged only after a formal 
assessment and confirmation of fitness by an investigator or qualified designee. The 
hospitalisation may be extended at the investigator’s discretion.

During the in-house stay, the subjects will be under medical observation and 
thoroughly monitored for both expected and unexpected adverse events.

Only male subjects will be enrolled in this study.

In order to address the risk of hepatotoxicity, only subjects with normal liver enzyme 
values will be included into the study (see Section 3.3.3), criterion 3. 

Safety laboratory parameters will be monitored closely. An individual subject will be 
removed from the trial if the subject shows an elevation of AST and/or ALT ≥3-fold 
ULN combined with an elevation of total bilirubin ≥2-fold ULN (measured in the 
same blood sample, (see Section 3.3.4.1). Further, most of the reported cases of 
serious hepatotoxicity during itraconazole treatment occurred in patients that suffered 
from concomitant liver diseases, had other significant diseases, or took concomitant 
hepatotoxic drugs. Subjects with liver diseases or a medical history of drug induced 
liver failure are excluded from trial participation (Section 3.3.3), criteria 5 and 25.
1.4.2.5
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 5.2.6.1.4, adverse events of special interest.
1.4.3
Overall assessment of benefit-risk ratio
In summary, although not therapeutically tested in humans to date, BI 1358894 has the
potential to become an oral treatment for major depressive disorder as an adjunct to
antidepressant therapy and for the treatment of borderline personality disorder. 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 


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mood and borderline personality 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
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of BI 1358894 in 
plasma when given as oral single dose together with multiple oral doses of itraconazole (Test, 
T) as compared to when given alone as oral single dose (Reference, R).
2.1.2
Primary endpoints
The following PK parameters will be determined for BI 1358894:

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)
2.1.3
Secondary endpoint
The following PK parameter will be determined for BI 1358894:

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)


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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 1358894 will be assessed based on:  

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
The study will be performed as an open-label, two-treatment, two-period, fixed sequence trial
in healthy male subjects in order to compare the test treatment (T) to the reference treatment 
(R). The treatments will be one oral single dose of 10 mg BI 1358894 as tablet formulation 
(tablet strength: 5 mg) together with multiple oral doses of 200 mg itraconazole as oral 
solution formulation (concentration: 10 mg/ml) (T) and one oral single dose of 10 mg BI 
1358894 as tablet formulation (tablet strength: 5 mg) given alone (R). 
The trial design is shown in Figure 3.1: 1.
Figure 3.1: 1: Overview of trial design
In both treatments, BI 1358894 is administered after a high-fat, high-caloric breakfast. 
Itraconazole will be administered in the fasted state. 
In the first treatment period (Period 1, Visit 2), all subjects are planned to undergo treatment 
R, and in the second treatment period (Period 2, Visit 3), all subjects are planned to undergo 
treatment T. For details, refer to Section 4.1.
There will be a washout period of at least 17 days between the administrations of 
BI 1358894.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
For relative bioavailability / bioequivalence trials, the crossover design is preferred because
of its efficiency: since each subject serves as his/her own control, the comparison between 
formulations/treatments is based on an intra-subject comparison, thus removing inter-subject 
variability from the comparison between formulations/treatments [R94-1529].


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Because of the long half-life of itraconazole (about 40 hours) and its metabolites and the 
unknown effect of itraconazole on the half-life of BI 1358894 , a fixed sequence design was 
selected, with administration of itraconazole in the second study period only. This design is 
not expected to lead to systematic errors in the estimation of the treatment effects since 
nonspecific time-effects are unlikely due to the short trial duration. For itraconazole studies, 
this design is recommended by the Innovation and Quality in Pharmaceutical Development’s 
Clinical Pharmacology Leadership Group (CPLG) [R17-3744].
For this PK drug-drug interaction trial, open-label treatment is acceptable, because the 
primary and secondary endpoints of this trial are PK endpoints derived from measurement of 
plasma concentrations of BI 135994 and metabolites. These endpoints are not expected to be
affected by knowledge of treatment.
SELECTION OF TRIAL POPULATION
3.3
It is planned that 16 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
Only male subjects will be included into the study because for the purpose of this trial, male 
healthy volunteers are standard.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 45 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5. Willingness to comply with contraception requirements. Subjects who are sexually active 
must use adequate contraception with their female partner throughout the study and until 
1 month after the last administration of trial medication. Adequate methods are:

Sexual abstinence or

A vasectomy performed at least 1 year prior to screening (with medical assessment of 
the surgical success) or


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
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 female partner is not allowed throughout the study and 
until 1 month after the last administration of trial medication.
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. CRP > ULN, ESR ≥15 millimeters/h, liver or kidney parameter above ULN, or any 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)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medications
or their 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. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 30 g per day)
16. Drug abuse or positive drug screening


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17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study
23. Persons who are committed to an institution by way of official or juridical order will not 
be enrolled in the study
In addition, the following trial-specific exclusion criteria apply:
24. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
25. 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)
26. Any history of drug-induced liver failure.
27. History of ventricular dysfunction or congestive heart failure. 
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. 
If the discontinuation occurs before the end of the REP (see Section 1.2.3) the discontinued 
subject should if possible be questioned for AEs and concomitant therapies at or after the end 
of the REP in order to ensure collection of AEs and concomitant therapies throughout the 
REP, if not contrary to any consent withdrawal of the subject.


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3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as pregnancy, 
surgery, adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the Investigator Site File (ISF)
6. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg) or of clinically relevant changes in ECG requiring intervention as well as 
unexplained liver enzyme elevations at any time during the trial
7. The subject shows a raised CRP level of >3.00 mg/dL or an ESR of ≥20 mm/h
8. The subject experiences a serious’ adverse reaction which is considered at least possibly 
related to the Investigational Medicinal Product (IMP) administration
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his 
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim (BI) reserves the right to discontinue the trial at any time for any of the
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 


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if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least 1 drug-related SAE is reported
3. Violation of Good Clinical Practice (GCP), or the clinical trial protocol (CTP), or the
contract with BI impairing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational product
5. Occurrence of severe non-serious adverse events considered as drug-related by the 
investigator in 2 subjects
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 4 subjects do not complete the trial, the Clinical Trial Lead (CTL) together 
with the Trial Pharmacokineticist (TCPK) and the Trial Statistician (TSTAT) 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
INVESTIGATIONAL TREATMENTS
4.1
The investigational product BI 1358894 has been manufactured by BI Pharma GmbH & Co. 
KG. Itraconazole oral solution will be obtained from a public pharmacy.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the two test products are given below:
Test product 1
Substance:
BI 1358894
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology:
2-0-0
Route of administration:
oral
Duration of use:
1 day (in treatments R and T)
Test product 2
Name:
Sempera® 10 mg/ml oral solution
Substance:
Itraconazole
Pharmaceutical formulation: Oral solution
Source:
Public pharmacy (obtained by the clinical site)
Holder of marketing authorisation:
Janssen-Cilag GmbH, Neuss, Germany
Unit strength:
10 mg/ml
Posology:
20 ml-0-0
Route of administration:
oral
Duration of use:
14 days (in treatment T only)
4.1.2
Selection of doses in the trial and dose modifications
Perpetrator (itraconazole)
The dose of itraconazole selected for this trial reflects standard clinical doses, is considered
sufficient to yield significant CYP3A inhibition and has been used successfully and safely in
previous drug-drug interaction trials [c02336088], [c03355329], [c08928447].


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4.1.3
Method of assigning subjects to treatment groups
This is an open-label, two-treatment, fixed sequence study. Each subject will be allocated to 
the same treatment sequence (R-T, see Flow Chart). Once a subject number has been 
assigned, it cannot be reassigned to any other subject.
All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same 
calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), the 
group may be split into several cohorts as required. For safety margin to exposure reached in 
previous SRD trial 1402-0001 refer to Section 1.4.2.3 and for discussion of study-associated 
risks and safety measures see Section 1.4.3).
The randomisation procedure is described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a two-treatment, two-period, fixed sequence study. All subjects will receive the 2 
treatments in fixed order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment 
period
Treatment
Substance
Formulation Unit 
strength
Dosage
Total  
dose
1
R (Reference)
BI 1358894
Tablet
5 mg
2 tablets on Day 1
10 mg
2
T (Test)
BI 1358894
Tablet
5 mg
2 tablets on Day 1
10 mg
Itraconazole Oral 
solution
10 mg/ml
20 ml (200 mg) on Days -3 
to 11
2800 mg
Administration of itraconazole will be performed after subjects have fasted overnight; fasting 
is to start no later than 10 h before the scheduled dosing of itraconazole on Day 1 of Period 2 
(coadministration of BI 1358894), and on Days 2 to 11 (itraconazole alone) fasting from at 
least 6 h before until 1 h after intake of itraconazole.
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a sitting position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
In each treatment period, a high-fat, high-calorie meal will be served 30 min before BI 
1358894 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 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
2 chicken eggs (whole content) for scrambled eggs
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
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 72 h after administration of 
BI 1358894. 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 reasons or for recording of 12-lead ECG and vital signs measurements.
The treatments will be separated by a wash-out phase of at least 17 days between BI 1358894 
administrations.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
BI 1358894 tablets will be provided by BI. They will be packaged and labelled in accordance 
with local law and the principles of Good Manufacturing Practice (GMP).
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.
Itraconazole oral solution
Itraconazole oral solution will be obtained by the clinical trial site from a public pharmacy.
The drug will be dispensed out of the original, unmodified packages.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the 
sponsor, if the following requirements are fulfilled:

Approval of the CTP 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

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated CTP  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the IMP 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 IMP received from the sponsor. At the time of disposal 
of remaining trial medication, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial subject and that no 
remaining supplies are in the investigator’s possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
In case of AEs in need of treatment, the investigator can authorise symptomatic therapy.
In case of alterations of blood pressure (hypotension) and heart rate (tachycardia), which
were reported in nonclinical toxicology studies (see Section 1.2.1.2 and Section 1.4.2.1), first
physical interventions will be the treatment of symptoms. If unsuccessful, appropriate drug 


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therapy will be initiated according to common guidelines and algorithms of emergency 
trainings. Dependent on individual symptoms, for the treatment of tachycardia this may 
include i.v. 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 
the conduct of the study is routinely trained in emergency procedures.
If required, any subject with an AE in need of treatment will be kept under supervision at the 
trial site or transferred to a hospital until all medical evaluation results have returned to an 
acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Acetylsalicylic acid or other drugs that may inhibit platelet aggregation or coagulation should 
be avoided during the entire study.
Known inhibitors/inducers of CYP3A and P-glycoprotein activity as well as drugs with a 
known hepatotoxicity profile should be avoided during the entire study.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after BI 1358894 intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 2), the water administered with the drug, and an additional 
240 mL of water at 2 h and 4 h post-dose on PK profile days (mandatory for all subjects).
From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL.
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.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before until 24 h after each administration BI 1358894.
Barbecued meat and broccoli should be avoided during the trial.
Smoking is not allowed from 24 h before until 24 h after each administration of BI 1358894.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.


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


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5.
ASSESSMENTS
ASSESSMENT OF EFFICACY
5.1
No efficacy endpoints will be evaluated in this trial.
ASSESSMENT OF SAFETY
5.2
5.2.1
Physical examination
Physical examination performed at screening and updated at end of trial examination includes 
general condition/psyche, skin, lymph nodes, head (eyes, ears, mouth), neck / thyroid gland, 
lungs, heart, abdomen, kidney, musculoskeletal system, neurological system, and vascular 
system.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(IntelliVue Patients Monitor MP70, Philips GmbH Market DACH, Hamburg, Germany) at 
the times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. 
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes, absol.
Reticulocytes/Erythrocyte
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
Erythrocyte sedimentation rate (ESR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
and absolute
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time (aPTT)
Prothrombin time – International Normalisation Ratio (INR)
Fibrinogen
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
Free T3 - Triiodothyronine  
Free T4 – Thyroxine
X
X
X
--
--
--
X
X
X
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
Albumin (Protein Electrophoresis) 
Alpha-1-Globulin (Protein Electrophoresis)
Alpha-2-Globulin (Protein Electrophoresis)
Beta-Globulin (Protein Electrophoresis) 
Gamma-Globulin (Protein Electrophoresis) 
C-Reactive Protein (CRP) (Quant)  
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
Test name [comment/abbreviation]
A
B
C
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine Erythrocytes/hemoglobin
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine 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)
A: parameters to be determined at Visit 1 (screening examination) and at Visit 2 Day 1 (if screening had been 
earlier than 3 days prior)
B: parameters to be determined at Visit 2 on Days 2, 4, 9, 14 and at Visit 3 on Days 1, 2, 4, 9, 14 (for time 
points refer to Flow-Chart)
C: parameters to be determined at Visit 4 (end of trial examination).
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to each treatment period.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis A antibodies (qualitative)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative) HIV-1 p24 antigen
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
6810 und 6820, Dräger AG, Lübeck, Germany) will be performed prior to each treatment 
period, and may be repeated at any time during the study at the discretion of an investigator 
or designee. The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 with the 
exception of drug screening tests. These tests will be performed at the trial site using
Diagnostika Nord: M10/14PDT-10 test, respectively, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the times provided in the Flow Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. 
ECG assessment will always precede all other study procedures scheduled for the same time 
to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology Information System (GE 
Medical Systems, Freiburg, Germany).
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). 


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Precise electrode placement will be marked with an indelible mark on the skin to allow 
reproducible placement throughout the study. 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Suicidality assessment
Suicidality assessment to further evaluate the psychological status of the subject will be
performed using the 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 C-SSRS questionnaires are shown in Appendix 10.1.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR, RR), 12-lead ECG, 
laboratory tests, suicidality assessment (C-SSRS), and a physical examination including 
neurological examination. 
At the end of trial examination, it will include review of AEs and concomitant therapies, vital
signs, 12-lead ECG, laboratory tests, suicidality assessment (C-SSRS), and a physical 
examination including neurological examination with determination of weight.
5.2.5.3
Neurological examinations
As a general additional safety measure, a physical neurological examination will be 
performed at the time points specified in the Flow Chart.
The neurological examination will include the following assessments:
- General level of arousal
- Orientation
- Eye movement
- Pupil size and pupil reactivity
- Reflexes


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- 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 AEs. Case narratives may be 
written if necessary.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
5.2.6.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical
investigation subject administered a medicinal product and which does not necessarily have
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.2.6.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 


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
Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.7.1, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should
always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.7.1.1.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the
electronic data capture (eDC) system. In case of clinical symptoms of hepatic injury (icterus,


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


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
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.7
Suicidal risk assessed by the C-SSRS (paper version):
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical 
experts in cooperation with the FDA, assessing both suicidal behaviour and suicidal 
ideation. It does not give a global score, but provides some categorical and some severity 
information specifically for behaviour and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, 
clinical social worker, mental health counsellor, 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 behaviour, 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 behaviour will also be recorded.
After the baseline visit the assessment ‘since last visit’ will be performed at each clinic or 
phone visit (‘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 behaviour 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 behaviour 
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.
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.


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5.2.7.1
Adverse event collection and reporting
AE collection
5.2.7.1.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.


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AE reporting to the sponsor and timelines
5.2.7.1.2
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
5.2.7.1.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
5.2.7.1.4
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.
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.
DRUG CONCENTRATION MEASUREMENTS AND 
5.3
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points / 
time intervals indicated in the Flow Chart. The actual sampling times will be recorded and 
used for determination of pharmacokinetic parameters. 


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5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis of BI 1358894 and 
For quantification of analyte concentrations in plasma, 2.7 mL of blood will be drawn from 
an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venepuncture with a 
metal needle.
The K2-EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2,000 g to 4,000 g and at 4 to 8°C. Two plasma aliquots will be obtained and stored in 
polypropylene tubes. The first aliquot should contain at least 0.5 mL plasma, the second 
aliquot will contain the remaining plasma. The process from blood collection until transfer of 
plasma aliquots into the freezer should be completed within 2 h, with interim storage of blood 
samples and aliquots on ice. The time each aliquot was placed in the freezer will be 
documented.
Until transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot.
At the analytical laboratory, the plasma samples will be stored at approximately -20°C or 
below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time, and the analyte “BI 1358894”. Further information, such as matrix,
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.
5.3.2.2
Blood sampling for determination of itraconazole
For quantification of itraconazole concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into a K2-EDTA-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 venipuncture with a metal needle.
The K2-EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 120 min, with interim storage of blood samples and aliquots at room 
temperature. The time each aliquot was placed in the freezer will be documented.


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Until transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time, and the analyte “itra”. Further information, such as matrix, 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.
5.3.3
Analytical determinations
5.3.3.1
Analytical determination of analyte in plasma concentration
BI 1358894, 
and itraconazole 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.
BIOBANKING
5.4
Not applicable.
OTHER ASSESSMENTS
5.5
5.5.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a blood sample for pharmacogenomic testing 
will be taken from each subject. In case of unexplainable variability in pharmacokinetic or 
pharmacodynamic parameters, DNA might be extracted from these samples and used for 
exploratory analysis of variants of genes related to these parameters, such as genes involved 
in Absorption, Distribution, Metabolism and Excretion (ADME). 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.
Methods and timing of sample collection
One blood sample of at most 10 mL will be taken from an arm vein in a PAXgene blood 
DNA drawing tube on Visit 2 (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.
The sampling tubes will be labelled with study number, subject number, visit, time point, 
matrix, and “DNA pre-specified”.


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Frozen blood samples should be shipped on dry ice to:
5.5.1.1
Analytical determinations
Genomic DNA will be extracted from blood samples according to standard molecular
genetics methods and analysed by DMET analysis or other standard genotyping technologies.
APPROPRIATENESS OF MEASUREMENTS
5.6
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
pharmacodynamic 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
VISIT SCHEDULE
6.1
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’ BI 1358894 administration 
on Day 1 of Period 1 are to be performed and completed within a 2 h-period prior to BI 
1358894 administration.
Study measurements and assessments scheduled to occur ‘before’ itraconazole administration 
on Days -3 to -1 and 2 to 11 of Period 2 are to be performed and completed within a 2 h-
period prior to itraconazole administration. Study measurements and assessments scheduled 
to occur ‘before’ BI 1358894 administration on Day 1 of Period 2 are to be performed and 
completed within a 1.0 h-period prior to itraconazole administration.
In visits 2 and 3, the acceptable deviation from the scheduled time for vital signs, ECG, and 
laboratory tests will be ± 45 min on Day 1, ± 60 min on Day 2, and ± 120 min from Day 3 
onwards.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including 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.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters. Starting from 48 hours after BI 1358894
administration (and beyond), a time window of ± 120 min will be allowed for 
pharmacokinetic blood sampling times.
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.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening and run-in period(s)
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.4.


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6.2.2
Treatment period(s)
Each subject is expected to participate in 2 treatment periods. 
Genotyping will be performed (for details, see Section 5.5.1).
If screening had been earlier than 3 days prior to Day 1 of Visit 2, safety laboratory panel A
will be repeated on that day.
At least 17 days will separate administrations of BI 1358894 in the first and second treatment 
periods.
On Day -1 of each period, study participants will be admitted to the trial site and kept under
close medical surveillance for at least 72 h following drug administration. The subjects will 
then be allowed to leave the trial site after formal assessment and confirmation of their 
fitness. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma 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.
If the subject reports headaches during the treatment periods, the following information and
data should be collected daily until the headache is resolved:

Onset after medication intake (hh:min)

Headache severity on a Numeric Ranking Scale (NRS) ranging from 0 - 10

Quality of headache (New type of headache vs. similar to previous experienced
episodes of known headaches)

Headache characteristics (pressing or tightening vs. burning vs. pulsating vs.
aggravated by routine physical activity (such as walking or climbing stairs))

Location (all of the following that apply: unilateral, bilateral, holocephal, frontal,
temporal, occipital, facial)

Any accompanying symptoms like (all of the following that apply: nausea and/or
vomiting, photophobia, phonophobia, lacrimation, other)

If headache is resolved: Overall duration of headache episode (start time and end
time)
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.2 to 5.2.5.


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Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
STATISTICAL DESIGN – MODEL
7.1
The main objective of this trial is to investigate the relative bioavailability of BI 1358894 in 
plasma when given as oral single dose together with multiple oral doses of itraconazole (Test, 
T) compared to when given alone as oral single dose (Reference, R) on the basis of the 
primary and secondary pharmacokinetic endpoints, as listed in Section 2.1.2 and 2.1.3. The 
trial will be conducted as a two-treatment, two-period, fixed sequence design, which allows
intra-subject comparisons. It will be evaluated statistically by use of a linear model for 
logarithmically transformed primary and secondary PK endpoints. 
 
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The relative bioavailability of BI 1358894 in plasma when given with multiple oral doses of 
itraconazole (T) vs. single oral dose of BI 1358894 alone (R) will be estimated by the ratios 
of the geometric means (T/R), and their corresponding 2-sided 90% confidence intervals 
(CIs) will be provided. This method corresponds to the two one-sided t-test procedure, each 
at the 5% significance level. Since the main focus is on estimation and not testing, a formal 
hypothesis test and associated acceptance range is not specified.
PLANNED ANALYSES
7.3
Analysis sets
Statistical analyses will be based on the following analysis sets:

Entered Set (ES): The Entered Set includes all subjects who entered the trial, i.e. who 
have been assigned to a subject number whether treated or not.

Treated set (TS): The Treated Set includes all subjects of the Entered Set who were 
treated with at least one dose of study drug. The Treated Set will be used for safety 
analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
Treated Set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment.


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Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the Integrated Quality Risk Management Plan
(IQRMP), IPDs will be identified no later than in the Blinded Report Planning Meeting, and 
the IPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Sections 2.1 and 2.2 for drug BI 1358894 or 
will be calculated according to the BI Standard Operating Procedure (SOP) 
‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). Further PK parameters may be 
calculated if considered appropriate.
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A pre-dose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 


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7.3.1
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for ‘subject’ and ‘treatment’. The ‘subject’ effect will be considered as 
random, whereas the ‘treatment’ effect will be considered as fixed. The model is described by 
the following equation:
ykm = + k + sm + ekm, where
ykm = logarithm of response measured on subject m receiving treatment k,
= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received
treatment k.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables. The indices ‘B’ and ‘W’ correspond to ‘between’ and ‘within’ variability, 
respectively.
Point estimates for the ratios of the geometric means (T/R) for the primary endpoints (see 
Section 2.1) and their two-sided 90% confidence intervals (CIs) will be provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.


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7.3.2
Secondary endpoint analyses
The secondary endpoint (refer to Section 2.1.3) will be assessed statistically using the same 
methods as described for the primary endpoints.
7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between first intake of BI 1358894 until end of 
residual effect period (14 days) in period 1 are attributed to the treatment interval “BI 
1358894 alone”. Events after the residual effect period of BI 1358894 but prior to first intake 
of itraconazole will be assigned to “BI 1358894 follow-up”. Events between first intake of
itraconazole in period 2 and administration of BI 1358894 in period 2 are attributed to the 
treatment interval “itraconazole alone” and those occurring between treatment with BI 
1358894 and itraconazole in period 2 and end of residual effect period of itraconazole (6 
days) after last intake of itraconazole or end of residual effect period of BI 1358894 (14 days) 
after BI 1358894 intake, whatever occurs first, are attributed to the treatment interval “BI 
1358894 + itraconazole”. Events after the treatment interval “BI 1358894 + itraconazole” but 
before trial termination date are assigned to “BI 1358894 + itraconazole follow-up”. These
assignments including the corresponding time intervals will be defined in detail in the TSAP. 
Note that AEs occurring after the individual subject’s end of trial but entered before final
database lock will be reported to Pharmacovigilance only and will not be captured in the trial 
database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-


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treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. 
Relevant ECG findings and relevant findings from neurological examinations during the trial 
will be reported as AEs.
INTERIM ANALYSES
7.4
A preliminary, exploratory analysis of the PK parameters (AUC0-tz, AUC0-∞and Cmax of BI 
1358894) may be performed based on all evaluable data after last subject out and prior to data 
base lock. This may be necessary, e. g., in case the information is needed to inform other
activities during the development of BI 1358894 such as concomitant treatment restrictions in
other studies. In contrast to the final pharmacokinetic calculations, the preliminary, 
exploratory analysis will be based on planned sampling times rather than on actual times, 
regardless of whether actual times were within the time windows or not. Therefore, minor 
deviations of preliminary and final results may occur. Results will be provided as individual 
values and geometric means as well as the adjusted gMean ratios determined according to the 
planned primary analysis described in Section 7.3.1. The preliminary, exploratory results will
be distributed to the trial team.
No formal preliminary PK report will be written.
HANDLING OF MISSING DATA
7.5
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.


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RANDOMISATION
7.6
In this trial all subjects receive both treatments in the same order, thus, no randomisation for 
the treatment assignment is performed (see also Section 4.1.3).The sponsor will arrange for 
the packaging and labelling of BI 1358894 trial medication. 
DETERMINATION OF SAMPLE SIZE
7.7
It is planned to enter a total of 16 subjects in the trial, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratio of geometric means (T/R) can be expected with 95% 
tolerance probability. Precision is defined as the ratio of upper CI limit to the relative BA 
estimate. Note that the precision is independent of the actual ratio of geometric means.
The observed intra-individual coefficient of variation (gCV) for BI 1358894 in previous trial
1402-0001 [c10354149] was about 13%-73% for Cmax and 20%-45% for AUC0-∞. Based on
the data obtained in trial 1402-0001 under fasted and fed conditions, sample size estimations 
were performed assuming %CV of 25% to 35%.
For various assumptions around the gCV of 30% and different samples sizes N=12 and 16 
Table 7.7: 1 provides and overview of the achievable precision for estimating the ratio of 
geometric means (T/R). For illustrative purposes, the expected 90% confidence intervals are 
displayed for different values of the ratios of geometric means (T/R).
Table 7.7: 1
Precision that can be expected with 95% tolerance probability and
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R) for different gCVs (N=12 and 16)
N
gCV [%]
Precision 
upper CL / 
relative BA 
estimate
Ratio [%]*
Lower CL 
[%]
Upper CL [%]
12
25.000
1.273
100.000
78.550
127.307
12
25.000
1.273
130.000
102.116
165.499
12
25.000
1.273
150.000
117.826
190.960
12
30.000
1.334
100.000
74.988
133.355
12
30.000
1.334
130.000
97.484
173.362
12
30.000
1.334
150.000
112.481
200.033
12
35.000
1.396
100.000
71.654
139.560
12
35.000
1.396
130.000
93.150
181.428
12
35.000
1.396
150.000
107.481
209.340
16
25.000
1.218
100.000
82.119
121.774


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Table 7.7: 1
Precision that can be expected with 95% tolerance probability and
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R) for different gCVs (N=12 and 16) (cont.)
N
gCV [%]
Precision 
upper CL / 
relative BA 
estimate
Ratio [%]*
Lower CL 
[%]
Upper CL [%]
16
25.000
1.218
130.000
106.755
158.306
16
25.000
1.218
150.000
123.179
182.661
16
30.000
1.265
100.000
79.067
126.475
16
30.000
1.265
130.000
102.787
164.417
16
30.000
1.265
150.000
118.601
189.712
16
35.000
1.313
100.000
76.187
131.256
16
35.000
1.313
130.000
99.043
170.633
16
35.000
1.313
150.000
114.280
196.884
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
Assuming a gCV of 25% and given a sample size of 16 subjects the precision of the two-
sided 90% confidence interval of the geometric mean ratio will be approximately 1.218 If 
only 12 patients will be evaluable in both periods, the precision would still be approximately 
1.273.
The expected 90% confidence interval limits in the tables were derived by
 , =  !"(#($) ± &),
With θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.5.1.


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


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The consent and re-consenting process should be properly documented in the source 
documentation.
DATA QUALITY ASSURANCE
8.2
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.
RECORDS
8.3
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication


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


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STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
8.5
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g, biomarker proposal, analysis plan and 
report) ensures compliant usage

If applicable, a fit for purpose approach will be used for assay/equipment validation 
depending on the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
ICF.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.


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The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
ADMINISTRATIVE STRUCTURE OF THE TRIAL
8.7
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
 
, under the supervision of the Principal Investigator. 
BI has appointed a Clinical Trial Lead, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of Clinical Trial Monitors (CTM), 
Clinical Research Associates, and investigators of participating trial sites
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 
concentrations in plasma 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.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
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PUBLISHED REFERENCES
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Trivedi MH, Rush AJ, Wisniewski SR, et al. Factors associated with health-
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Templeton IE, Thummel KE, Kharasch ED, Kunze KL, Hoffer C, Nelson 
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Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
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psychiatric outpatients. J Personal Disord 2016;30(2):261-270.
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Willems L, Geest R van der, Beule K de. Itraconazole oral solution and 
intravenous formulations: a review of pharmacokinetics and 
pharmacodynamics. J Clin Pharm Ther 26, 159 - 169 (2001).
R17-3744 
Liu L, Bello A, Dresser MJ, Heald D, Komjathy SF, O'Mara E, et al. Best
practices for the use of itraconazole as a replacement for ketoconazole in
drug-drug interaction studies. J Clin Pharmacol 56 (2), 143 - 151 (2016)


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R18-0241
Guidance for industry: clinical drug interaction studies - study design, data 
analysis, and clinical implications (draft guidance, this guidance document 
is being distributed for comment purposes only) (October 2017, clinical 
pharmacology). 
https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf (access 
date: 19 January 2018); Silver Spring: U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER) (2017).
R18-0249
Minke B. The history of the Drosophila TRP channel: The birth of a new 
channel superfamily. 2010;24(4):216-233.
R18-2643
Sporanox 10 mg/ml oral solution (Janssen-Cilag) (summary of product
characteristics, updated 01-Mar-2018).
https://www.medicines.org.uk/emc/product/1522/smpc/print (access date: 
14 August 2018); 2018.
R18-2644
Sempera Liquid 10 mg/ml, Loesung zum Einnehmen (Janssen-Cilag) 
(Fachinformation, Stand der Information: Dezember 2017).
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
UNPUBLISHED REFERENCES
9.2
c02336088
 Relative bioavailability of a
single oral dose of BI 691751 when administered alone or in combination
with multiple oral doses of itraconazole in healthy male subjects (an open-
label, randomised, two-period, two-sequence crossover study). 1334.10. 09
Jan 2015.
c03355329
 Relative bioavailability of a 
single oral dose of BI 425809 when administered alone or in combination 
with multiple oral doses of itraconazole in healthy male subjects (an open-
label, two-period, fixed-sequence trial) 1346.10. 03 Dec 2015.
c08928447
 Effect of multiple doses of
itraconazole on the pharmacokinetics of a single oral dose of BI 1026706 in
healthy male subjects (an open-label, randomised, two-period, two-
sequence crossover study) 1320.20. 29 Sep 2016.
c10354149
Investigator's brochure BI 1358894 in Major Depressive Disorder and
Borderline Personality Disorder. 23 November 2018.


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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 crossover.
Trial 1402.1. 21 Dec 2017.
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.
n00250347
 
 BI 1358894: 4-week oral (gavage) 
toxicity study in Sprague Dawley rats. 16B024. 04 July 2017.
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. 
HG96MB. 27 September 2016.
n00252903
 Effect of BI 1358894 in the mouse forced swimming test. 05 
October 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. 06 December 2016
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 November 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.


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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.
n00253734
 Partial validation of an LC-MS/MS method for the quantification of 
BI 1072668 in rat plasma, calibration range 5.00 - 25000 nmol/L. 16B133.
09 February 2017.
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 May2017.
n00258719
Investigations on the 
in vitro metabolism of [14C]BI 1358894 and assessment of the human 
cytochrome P450 enzymes that are involved. 7 November 2017.
n00261794
 Metabolism of BI 1358894 in rats. 28 May 2018.


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10.
APPENDICES
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS)
10.1
10.1.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening


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10.1.2
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
GLOBAL AMENDMENT 1
11.1
Date of amendment
21 Feb 2019
EudraCT number
2018-004274-10
BI Trial number
1402-0007
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
Relative bioavailability of a single oral dose of BI 
1358894 when administered alone or in combination 
with multiple oral doses of itraconazole in healthy 
male subjects (an open-label, fixed sequence study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Flowchart, Section 1.4.2.4, Section 6.2.2
2. Section 3.3.3
3. Section 3.3.4.3
4. Section 4.2.2.2
5. Flowchart and Section 5.2.3
6. Section 8
Description of change
1. Hospitalisation phase extended to 72 h, safety 
laboratory added
2. Exclusion criteria no. 23 added.
3. Discontinuation criteria added.
4. Smoking restrictions updated due to longer in-
house confinement.
5. Panel B of safety laboratory markers extended by 
additional markers and time points in the 
flowchart.
6. Reference to EU regulation 536/2014 deleted.
Rationale for change
All changes were done based on the request of
regulatory authorities.In addition, typos throughout 
the document were corrected.


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GLOBAL AMENDMENT 2 
11.2
Date of amendment
27 March 2019
EudraCT number
2018-004274-10
BI Trial number
1402-0007
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
Relative bioavailability of a single oral dose of BI 
1358894 when administered alone or in combination 
with multiple oral doses of itraconazole in healthy 
male subjects (an open-label, fixed sequence study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Flowchart, 
2. Section 6.2.2
Description of change
1. Adaptation of planned time at
      Day -3,- 2 and -1
2. Insertion of the intensity measurement for 
headaches
Rationale for change
In addition, typos and inconsistencies throughout the 
document were corrected.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25796375
3.0
clinical-trial-protocol-revision-2
Relative bioavailability of a single oral dose of BI 1358894 when administered alone
or in combination with multiple oral doses of itraconazole in healthy male subjects
(an open-label, fixed sequence study)
Author-Clinical Trial Leader
27 Mar 2019 16:39 CET
Author-Trial Clinical
Pharmacokineticist
27 Mar 2019 17:09 CET
Author-Trial Statistician
28 Mar 2019 09:28 CET
Verification-Paper Signature
Completion
28 Mar 2019 14:32 CET
Approval-Team Member Medicine
28 Mar 2019 22:22 CET
Approval-Therapeutic Area 
01 Apr 2019 10:40 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25796375
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c28521708-01
BI Trial No.:
1402-0007
Title:
Relative bioavailability of a single oral dose of BI 1358894 when
administered alone or in combination with multiple oral doses of
itraconazole in healthy male subjects (an open-label, fixed
sequence study)
(including Protocol Amendments No.1 [c25796375-02] and No. 2 
[c25796375-03])
Investigational
Product:
BI 1358894
Responsible trial 
statisticians:
Phone:
Fax:
Date of statistical 
analysis plan:
12JUL2019 SIGNED
Version:
Final
Page 1 of 28
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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 ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
5.3.2
Safety endpoints ..................................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................19
7.3
TREATMENT COMPLIANCE........................................................................19
7.4
PRIMARY ENDPOINTS...................................................................................19
7.4.1
Primary analysis of the primary endpoints......................................................19
 
7.5
SECONDARY ENDPOINTS.............................................................................21
7.5.1
Key secondary endpoints....................................................................................21
7.5.2
Secondary endpoints...........................................................................................21
7.6.2
Safety endpoints ..................................................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................22
7.8
SAFETY ANALYSIS..........................................................................................22


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7.8.1
Adverse Events ....................................................................................................22
7.8.2
Laboratory data ..................................................................................................24
7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................25
8.
REFERENCES....................................................................................................26


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................11
Table 6.1: 2
Flow chart of analysis phases for statistical analyses of AEs..........................12
Table 6.3: 1
Subject sets analysed........................................................................................15
Table 10: 1
History table .....................................................................................................28


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
website: glossary
Term
Definition / description
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
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
BWU
Bioavailability/Bioequivalence, Within-Subject Design, uncontrolled
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DILI
Drug induced liver injury
gCV
Geometric coefficient of variation
gMean
Geometric mean
ITZ
Itraconazole
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
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile


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Term
Definition / description
R / Ref
Reference treatment
RAGe
Report Appendix Generator system
SD
Standard deviation
SOC
System organ class
T
Test treatment
TS
Treated set
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary
variables and other data.
This 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 SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. The following changes compared to the protocol will be made:
No ‘Entered set’ (ES) will be defined in the TSAP as data of subjects discontinued before 
first administration of trial medication will not be entered in the database. A correct display 
of the ES would not be possible.
To define the study phases for adverse events conservatively, the period ‘BI + ITZ’ will be 
defined as follows:
Section 7.3.4 of the CTP: […] Adverse events occurring between treatment with 
BI 1358894 and itraconazole in period 2 and end of residual effect period of itraconazole (6 
days) after last intake of itraconazole or end of residual effect period of BI 1358894 (14 days) 
after BI 1358894 intake, whatever occurs first last, are attributed to the treatment interval 
“BI 1358894 + itraconazole”.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP: The following PK parameters will be determined for BI 1358894:

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)
The pharmacokinetic parameters listed in Sections 2.1 and 2.2 of the protocol for drug 
BI 1358894 or 
will be calculated according to the BI Standard Operating 
Procedure (SOP) ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472] (7).
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 PK parameter will be determined for BI 1358894:

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)


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5.3.2
Safety endpoints
Section 2.2.2.2 and 5.2.5 of the CTP: Safety and tolerability of BI 1358894 will be assessed 
based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Suicidality assessment (Columbia Suicide Severity Rating Scale (C-SSRS))


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment sequences 
and selection of doses, please see CTP, Sections 3 and 4.
The study will be performed as a randomised, open-label trial with two treatments (T and R) 
and one fixed sequence (R then T). 
In total, it was planned to assign 16 healthy male subjects.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
R
BI 1358894, 2*5 mg tablet, po, qd
BI 
T
BI 1358894, 2*5 mg tablet + Itraconazole 20ml, 10mg/ml, qd
BI + ITZ
Section 1.2.3 of the CTP: The Residual Effect Period (REP) of BI 1358894 is approximately 
14 days. This is the period after the last dose where measurable drug levels and/or 
pharmacodynamic effects are still likely to be present.
For the use of itraconazole in this trial, the REP is defined as 6 days.
The following separate study phases will be defined for the analyses of AEs:


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Table 6.1: 2
Flow chart of analysis phases for statistical analyses of AEs
Study 
analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of BI 1358894
alone in treatment period 1
On-treatment
BI
Date/time of first 
administration of BI 
1358894 alone in treatment 
period 1
Date/time of first 
administration of BI 1358894 
alone in treatment period 1 + 
14 days (336 h) thereafter
On-treatment
ITZ
Date/time of first 
administration of 
Itraconazole alone
Date/time of first 
administration of BI 1358894 
administration in treatment 
period 2
On-treatment
BI+ITZ
Date/time of first 
administration of 
BI 1358894 in treatment 
period 2
Date/time of first 
administration of BI 1358894 
in treatment period 2 + 6 
days (144 h) after last 
administration of 
Itraconazole OR
14 days (336 h) after the BI 
1358894  administration in 
treatment period 2, whatever 
occurs later
Follow-up
F/U BI
Date/time of first 
administration of 
BI 1358894 alone in 
treatment period 1 + 14 
days (336 h) thereafter
Date/time of first 
administration of 
Itraconazole alone OR
0:00h on the day after trial-
termination date in case of no 
further treatment
Follow-up
F/U BI+ITZ
Date/time of first 
administration of 
BI 1358894 in treatment 
period 2 + 6 days (144 h) 
after last administration of 
Itraconazole OR
14 days (336 h) after the BI 
1358894  administration in 
treatment period 2, 
whatever occurs later
0:00h on the day after trial 
termination date


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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 and EudraCT only) 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 and follow-up periods will not be included in 
this analysis. 
The following total will be provided in addition (Section 15.3 only):
a total over all on treatment phases involving BI ("BI Total on treatment")
a total over all on treatment phases included in this analysis ("Total on treatment")
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:
Screening 
On treatment (labelled with the name of the study treatment (short label))
Follow-up BI (labelled "FU BI")
Follow-up BI+ITZ (labelled "FU BI+ITZ")
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:
a total over all on treatment phases involving BI ("Total BI")
a total over all study phases ("Total")
For detailed information on the handling of the treatments refer to Technical TSAP ADS plan
and Analysis Data Reviewers guide. 


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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 deviation (IPD) categories will be suggested in 
the Integrated Quality and Risk Management Plan (IQRMP), IPDs will be identified no later 
than in the Report Planning Meeting, and the IPD categories will be updated as needed.
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 
an accompanying Excel spreadsheet (3). Categories which are considered to be iPDs in this 
trial are defined in the integrated quality and risk management plan (IQRMP). If the data 
show other iPDs, the definition in the IQRMP will be supplemented accordingly by the time 
of the Report Planning Meeting.
The iPDs will be summarised and listed.
6.3
SUBJECT SETS ANALYSED

Treated set (TS): The treated set includes all subjects who were treated with at least one 
dose of study drug. The treated set will be used for safety analyses.
Section 7.3 of the CTP:

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
Treated Set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol 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 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.
[…]
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


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Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if
for example

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

A pre-dose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of PK endpoints 
X
Safety parameters
X
Demographic/baseline parameters
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.


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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 (see 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before administration of BI 1358894 in 
each period.
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’ BI 1358894 administration 
on Day 1 of Period 1 are to be performed and completed within a 2 h-period prior to 
BI 1358894 administration. Study measurements and assessments scheduled to occur 
‘before’ itraconazole administration on Days -3 to -1 and 2 to 11 of Period 2 are to be 
performed and completed within a 2 h-period prior to itraconazole administration. Study
measurements and assessments scheduled to occur ‘before’ BI 1358894 administration on 
Day 1 of Period 2 are to be performed and completed within a 1.0 h-period prior to
itraconazole administration.
In visits 2 and 3, the acceptable deviation from the scheduled time for vital signs, ECG, and
laboratory tests will be ± 45 min on Day 1, ± 60 min on Day 2, and ± 120 min from Day 3
onwards.
[…]
Starting from 48 hours after BI 1358894 administration (and beyond) a time window of 
± 120 min will be allowed for pharmacokinetic blood sampling times.
Adherence to time windows will be checked via the consistency check listings at the RPM.
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement. 


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7.
PLANNED ANALYSIS
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 7.4, Section 7.5.2 and 
Section 7.6) 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 endpoints and concentrations will be performed by the 
department Translational Medicine and Clinical Pharmacology (TMCP) at BI and will be 
presented in Section 15.6 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations (7).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number, visit and actual treatment (if appropriate). 
The listings 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
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


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The data format for descriptive statistics of concentrations will be identical to 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 sequence/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”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and 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” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (11).
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 in total.


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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 coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using 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.
A medication will be considered concomitant, if it

is ongoing at the time of the first administration of the respective treatment

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases)
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 as medication will be administered by the investigator (or authorised 
designee). The measured plasma concentrations of trial medication will provide additional 
confirmation of compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
Relative bioavailability of BI 1358894 in plasma is to be determined on the basis of the 
primary pharmacokinetic endpoints AUC0-∞and Cmax (see Section 5.1). 
7.4.1
Primary analysis of the primary endpoints
Section 7.3.1 of the CTP: The statistical model used for the analysis of the primary
endpoints will be an analysis of variance (ANOVA) model on the logarithmic scale. That is, 
the PK endpoints will be log-transformed (natural logarithm) prior to fitting the ANOVA
model. This model will include effects accounting for ‘subject’ and ‘treatment’. The ‘subject’ 
effect will be considered as random, whereas the ‘treatment’ effect will be considered as 
fixed. The model is described by the following equation:


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ykm = µ + τk + sm + ekm, where
ykm = logarithm of response measured on subject m receiving treatment k,
µ = the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n
τk = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received treatment k.
where sm~ N(0,
) i.i.d., ekm ~ N(0, 
 ) i.i.d. and sm, ekm are independent random variables. 
The indices ‘B’ and ‘W’ correspond to ‘between’ and ‘within’ variability, respectively.
Point estimates for the ratios of the geometric means (T/R) for the primary endpoints (see 
Section 5.1) and their two-sided 90% confidence intervals (CIs) will be provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
The implementation for this analysis will be accomplished by using the XPKISTAT macro, 
based on PKS, and option BWU (Bioavailability/Bioequivalence, within-subject design, 
uncontrolled w.r.t. time).


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
The secondary PK parameter AUC0-tz will be assessed using the same methods as described 
for the primary endpoints.
7.6.2
Safety endpoints
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 1358894.


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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. 
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.
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 as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (8).
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 case report form (CRF) will be collapsed 
into one 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).
For further details on summarization of AE data, please refer to [001-MCG-156] (8).
The analysis of AEs will be based on the concept of treatment-emergent AEs. That means 
that all AEs will be assigned to the screening, treatment or follow-up phases as defined in 
Section 6.1.
Section 5.2.6.1.4 of the CTP: The following are considered as AESIs:


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
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the 'DILI checklist’ provided in the
electronic data capture (eDC) system. In case of clinical symptoms of hepatic injury 
(icterus, unexplained encephalopathy, unexplained coagulopathy, right upper 
quadrant abdominal pain, etc.) without lab results (ALT, AST, total bilirubin) 
available, the investigator should make sure that these parameters are analysed, if 
necessary in an unscheduled blood test. Should the results meet the criteria of hepatic 
injury alert, the procedures described in the DILI checklist should be followed.
Section 7.3.4 of the CTP: Note that AEs occurring after the individual subject’s end of trial 
but entered before final database lock will be reported to Pharmacovigilance only and will 
not be captured in the trial database.
For more detail see the TSAP ADS plan.
According to ICH E3 (9), AEs classified as ‘other significant’ need 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 Clinical Monitor/Investigator at the Report Planning Meeting. 
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarised 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 (9), 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 SOCs 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.


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For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on 
BI standards [001-MCG-157] (10). 
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 possibly
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 significantly 
abnormal or not (at the RPM/DBLM 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).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate). In the listing the difference from baseline will also be 
displayed.
For vital signs, descriptive statistics will be calculated by planned time point based on the last 
value of the subject at that planned time point (or assigned to that planned time point).
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment), and will be analysed as such.


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7.8.5
Others
Suicidality assessment (C-SSRS)
The C-SSRS will be done at
-
Screening 
-
PTM 72:00 (in treatment period 1 and 2) 
-
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, IDEA for CON.
3.
BI-KMED-COPS-TMP-0001: "iPD log", current version; IDEA for GEN.
4.
001-MCG-156_RD-01: “Handling of Missing and Incomplete AE Dates”, current 
version; IDEA for CON.
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies”, current version; IDEA for CON.
6.
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current version; 
IDEA for CON.
7.
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
8.
001-MCG-156: “Analysis and Presentation of Adverse Event Data from Clinical Trials”, 
current version; IDEA for CON.
9.
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.
10. 001-MCG-157: “Handling, Display and Analysis of Laboratory Data”, current version; 
IDEA for CON.
11. 001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.


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