Clinical trial NCT03210272
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-07-18; Completion date: 2019-02-18
Enrollment: 83 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to investigate the safety and tolerability of BI 1358894 in healthy male subjects following oral administration of single rising doses. Secondary objectives are the exploration of the pharmacokinetics (PK), including dose proportionality of BI 1358894 after single dosing.

Detailed description:

Arms: arm 1: Group of healthy male volunteers receive rising single doses of BI 1358894 arm 2: Group of healthy male volunteers receive single doses of BI 1358894 with and without food
Interventions: intervention 1: Placebo intervention 2: BI 1358894 intervention 3: BI 1358894 (Test) intervention 4: BI 1358894 (Reference)
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet intervention 3: Fasting state intervention 4: Fed state

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c13880029-10
EudraCT No.:
BI Trial No.:
2017-000143-40
1402-0001
BI Investigational
Product:
BI 1358894
Title:
Safety, tolerability and pharmacokinetics of single rising oral doses of 
BI 1358894 in healthy male subjects (single-blind, partially 
randomised, placebo-controlled parallel group design) and effect of 
food on the relative bioavailability of BI 1358894 (open-label, 
randomised, two-way cross-over)
Clinical Phase:
I
Trial Clinical Monitor:
Phone
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 9))
Version and Date:
Version: 10.0
Date: 25 September 2018
Page 1 of 108
Proprietary confidential information
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1358894
Protocol date:
Trial number:
Revision date:
25 September 2018
23 February 2017
1402-0001
Title of trial:
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 1358894 in 
healthy male subjects (single-blind, partially randomised, placebo-controlled parallel 
group design)  and effect of food on the relative bioavailability of BI 1358894 (open-
label, randomised, two-way cross-over)
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate safety, tolerability, and pharmacokinetics (PK) following single rising 
doses including food effect of BI 1358894
Methodology:
-
Single rising dose (SRD): single-blind, partially randomised within dose groups, 
placebo-controlled, parallel-group design
-
Food effect (FE): randomised, open label, two-way, two-sequence
cross-over design
No. of subjects: 
total entered:
*88
each treatment:
SRD: 8 per dose group (6 on active drug and 2 on placebo)
FE: 24 (all on active treatment)
* The study will be initially conducted with a tablet formulation and 8 dose groups resulting in 
a planned number of 64 subjects in the SRD part and 24 subjects in the FE part. 
Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 88, but will not exceed 96 subjects entered.
The food effect part will not start before the respective dose has been tested in the SRD part, 
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 45 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1358894
Protocol date:
Trial number:
Revision date:
25 September 2018
23 February 2017
1402-0001
Test product 1:
BI 1358894 film-coated tablet (tablet strength 1 mg, 5mg, 25 mg 100 mg)
dose:
SRD*: 3 mg, 6 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg (fasted q.d.), FE:, 50 mg,
and 100 mg
SRD fed: 200 mg (fed)* q.d. 
* Dose selection based on the assumption to include the potential therapeutic range. In the SRD 
part doses may be decreased or increased based on the knowledge gained during trial conduct 
(e.g. safety, exploratory PK analyses). In any case, the selected dose must not exceed the 
approved dose range. The food effect part will not start before the respective dose has been 
studied in the SRD part.
**The estimated exposure of 200 mg of BI 1358894 administered under fed conditions may 
exceed the current exposure threshold Cmax of 980 nM or an AUC0-24h of 9500 nM*h. Since at 
the time of this 200 mg fed dose group clinical data up to 200 mg fasted and 100 mg fed are
available, the exposure threshold for the dose group of 200 mg administered under fed 
conditions will be further increased to the exposure at NOAEL in rats (i.e. Cmax of 1960 nM and 
an AUC0-24 of 26300 nM*h). The exposure in previous fed dose groups indicates that the 
geometric mean of the AUC0-24 for the 200mg fed group is predicted to be 15400 nM*h and the 
geometric mean of Cmax is predicted to be 1127 nM, i.e. below the new  threshold. Even based 
on the 95% prediction interval the threshold would not be exceeded.
mode of admin.:
SRD: 
Oral with 240 mL of water after an overnight fast of at least 10 h
FE: 
Oral with 240 mL of water after an overnight fast of at least 10 h and after a 
standard high fat breakfast
SRD fed: Oral  after a standardized high fat breakfast
Comparator products: Matching placebo tablets
dose:
Not applicable
mode of admin.:
SRD: Oral with 240 mL of water after an overnight fast of at least 10 h
SRD fed: Oral with 240 mL of water after a standardized high fat breakfast
Duration of treatment: SRD: 1 single dose
FE: 2 single doses [separated by a wash-out period of at least 7 days between drug
administrations] 
Criteria for
pharmacokinetics:
SRD
Secondary endpoints: AUC0-∞(if evaluable), Cmax, AUC0-tz
FE:
Secondary endpoints: AUC0-∞(if evaluable), Cmax, AUC0-tz
 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1358894
Protocol date:
Trial number:
Revision date:
25 September 2018
23 February 2017
1402-0001
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 1358894 is the number 
[N (%)] of subjects with drug related adverse events.
Further criteria of interest:
AEs including clinically relevant findings from the physical examination, safety 
laboratory tests, 12-lead electrocardiogram (ECG), continuous ECG monitoring, vital 
signs (blood pressure [BP], pulse rate [PR], respiratory rate [RR]), orthostatic test and 
Bond & Lader and Bowdle visual analogue scales and suicidality assessment 
(C-SSRS).
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
The PK parameters AUC and Cmax will be explored for dose proportionality of BI 
1358894 using a regression model; a 95% confidence interval (CI) for the slope will
be computed.
The statistical model to assess relative bioavailability in the food effect part will be an 
analysis of variance (ANOVA) on the ln-transformed parameters AUC and Cmax
including effects for "sequence", "subjects nested within sequences", "period" and 
"treatment". Point estimators (geometric means) for the ratios of response under test 
compared to reference treatment and their two-sided 90% confidence intervals will be 
calculated.
Confidence intervals will be based on the residual error from ANOVA


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FLOW CHART
SRD (3 mg – 200 mg fasted)
Visit
Day
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
10, 11
Orthostatic testing
Visual analogue scale15
12-lead ECG
Continuous ECG 
monitoring
Vital signs (BP, PR, RR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to -1
Screening (SCR)1
x
x
x
x
x
2
-3 to -1
-72:007
08:00
Ambulatory visit
x7
x
1
-1:30
06:30
Admission to trial site
x5
x
x
-0:30
07:30
Allocation to treatment2
x13
x2
x2
x2,9
x2
x2
0:00
08:00
Drug administration
▲
0:10
08:10
x
│
0:20
08:20
x
│
0:30
08:30
x
x9
│
x
x
1:00
09:00
x
x9
│
x
x
1:30
09:30
x
x9
│
x
x
2:00
10:00
240 mL fluid intake
x
x
x9
│
x
x
2:30
10:30
x
│
3:00
11:00
x8
x
x9
│
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x
x9
▼
x
x
5:00
13:00
x
x9
x
x
6:00
14:00
x
x9
x
x
7:00
15:00
x
8:00
16:00
Snack (voluntary)3
x
x
x9
x
x
10:00
18:00
Dinner3
x
12:00
20:00
x
x9
x
x 
16:00
24:00
x
x9
x
2
24:00
08:00
Breakfast 
x
x
x
x9
x
x
34:00
18:00
x
x
x9
x
x
3
48:00
08:00
Breakfast, Discharge from trial site16
x
x
x9
x
x
4
72:00
08:00
Ambulatory visit
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
x
6
120:00
08:00
Ambulatory visit
x14
x
x
7
144:00
08:00
Ambulatory visit
x14
x
x
8
168:00
08:00
Ambulatory visit
x14
x
x
9
192:00
08:00
Ambulatory visit
x14
x
x
4
10 to 14
End of trial (EOT) examination4, 14
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, 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, 
Bond & Lader and Bowdle visual analogue scales and suicidality assessment (C-SSRS).


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2.
The time is approximate; the respective procedure is to be performed and completed within 2 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to (first) drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies, Bond & Lader and Bowdle visual analogue scales and suicidality assessment 
(C-SSRS).
5.
Only urine drug screening and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
safety laboratory can be omitted, if the screening examination is performed on Days -3, -2 or -1. 
14. Time points optional, may be modified after availability of PK data of each dose, EOT starts one day after the last 
ambulatory visit
15. Suicidality assessment only at screening and end of trial.
16. Confirmation of fitness includes physical examination, vital signs, ECG, recording of AEs and concomitant therapies. 
Evaluation of safety lab assessed on Day 2.


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Food Effect (FE), 50 mg and 100 mg
Visit
Day
Planned Time [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety Laboratory
Alcohol and drug screening
PK blood
9,12
12-lead ECG
Vital signs  (BP, PR, RR)
AE/CT-Qestioning6
1
-21 to -1
Screening examination 1
x
x
x
x
2 
or
38
-3 
-72:00
8:00
x7
x7
-1
-12:00
20:00
Admission to trial site
x5
1
-1:30
6:30
Treatment allocation10
x2,11
x2
x2
x2
x2
x
-0:30
7:30
Standardized breakfast (only in 
fed state arm)
0:00
8:00
Drug administration
0:10
8:10
x
0:20
8:20
x
0:30
8:30
x
1:00
9:00
x
x
1:30
9:30
x
2:00
10:00
240 mL fluid intake
x
x
x
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, Lunch3  
x
x
x
x
5:00
13:00
x
6:00
14:00
x
x
7:00
15:00
x
8:00
16:00
Snack3 (voluntary)
x
x
x
x
10:00
18:00
Dinner3
x
12:00
20:00
x
x
x
16:00
24:00
x
x
2
24:00
8:00
confirmation of fitness, 
discharge from trial site,
breakfast3
x
x
x
x
x
36:00
20:00
Ambulatory visit
x
x
x
3
48:00
08:00
Ambulatory visit
x
x
x
x
4
72:00
08:00
Ambulatory visit
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
6
120:00
08:00
Ambulatory visit
x13
x
x
7
144:00
08:00
Ambulatory visit
x13
x
x
8
168:00
08:00
Ambulatory visit
x13
x
x
9
192:00
08:00
Ambulatory visit
x13
x
x
4
10 to 14
End-of-trial (EOT)-
examination4,13
x
x
x
x
1
Subject must be informed and written informed consent obtained prior to starting any screening procedures. 
Screening procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug 
screening 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 Bond & Lader and Bowdle visual analogue scales and suicidality assessment 
(C-SSRS).


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2
The time is approximate; the respective procedure is to be performed and completed within 2 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed 
prior to (first) drug administration.
3
If several actions are indicated at the same time point, the intake of meals will be the last action.
4
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies, Bond & Lader and Bowdle visual analogue scales and suicidality 
assessment (C-SSRS).
5
Only urine drug screening and alcohol breath test will be done at this time point.
6
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time 
points indicated in the Flow Chart above
7
AE/CT-Questioning and safety laboratory will take place once, prior to first study drug administration between 
72 h and 24 h.
8
Two identical treatment periods, separated by a wash-out period of at least 7 days between drug administrations; 
based on sequence intake of study drug under fasted or fed conditions. The duration of wash-out period may be 
revised based on the PK exploratory analysis in SRD part of the study. Predose at visit 3 Bond & Lader and 
Bowdle visual analogue scales and suicidality assessment (C-SSRS) will be performed.
9
The sample collection schedule may be altered based on the results of  PK exploratory analyses in the SRD part
10
Treatment allocation only at visit 2
12
Based on preliminary PK evaluations, visit days and blood samples may be modified as long as blood loss will not 
exceed 500 ml
13
Time points optional, may be modified after availability of  PK data of the SRD part, EOT starts one day after the 
last ambulatory visit


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SRD 200 mg fed Dose group
Visit
Day
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9
Orthostatic testing
Visual analogue scale12
12-lead ECG
Continuous ECG 
monitoring
Vital signs (BP, PR, RR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to -1
Screening (SCR)1
x
x
x
x
x
2
-3 to -1
-72:007
08:00
Ambulatory visit
x7
x
1
-1:30
06:30
Admission to trial site
x5
x
x
-0:30
07:30
Allocation to treatment2
x11
x2
x2
x2,8
x2
x2
-0:30
7:30
Standardized breakfast
0:00
08:00
Drug administration
▲
0:10
08:10
x
│
0:20
08:20
x
│
0:30
08:30
x
x8
│
x
x
1:00
09:00
x
x8
│
x
x
1:30
09:30
x
x8
│
x
x
2:00
10:00
240 mL fluid intake
x
x
x8
│
x
x
2:30
10:30
x
│
3:00
11:00
x
x
x8
│
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x
x8
▼
x
x
5:00
13:00
x
X8
x
x
6:00
14:00
x
X8
x
x
7:00
15:00
x
8:00
16:00
Snack (voluntary)3
x
x
X8
x
x
10:00
18:00
Dinner3
x
12:00
20:00
x
X8
x
x 
16:00
24:00
x
X8
x
2
24:00
08:00
Breakfast 
x
x
x
X8
x
x
34:00
18:00
x
x
X8
x
x
3
48:00
08:00
x
x
X8
x
x
4
72:00
08:00
x
X8
x
x
5
96:00
08:00
x
x
X8
x
x
6
120:00
08:00
x
X8
x
x
7
144:00
08:00
Breakfast, confirmation of 
fitness13,12, discharge from trial site
x
X8
x
x
9
192:00
08:00
Ambulatory visit
x
x
x
11
240:00
08:00
Ambulatory visit
x
x
x
15
336:00
08:00
Ambulatory visit
x
x
x
22
504:00
08:00
Ambulatory visit
x
x
x
29
672:00
08:00
Ambulatory visit
x
x
x
4
29 to 33
End of trial (EOT) examination4
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, Bond & Lader and Bowdle visual analogue scales and suicidality assessment (C-SSRS).


Boehringer Ingelheim
25 September 2018
BI Trial No.: 1402-0001
c13880029-10
Trial Protocol
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2.
The time is approximate; the respective procedure is to be performed and completed within 2 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to (first) drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, neurological examination, body weight, vital signs, ECG, safety 
laboratory, recording of AEs and concomitant therapies, Bond & Lader and Bowdle visual analogue scales and
suicidality assessment (C-SSRS).
5.
Only urine drug screening and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
safety laboratory can be omitted, if the screening examination is performed on Days -3, -2 or -1. 
12. Suicidality assessment at screening, discharge from CPU and end of trial.
13. Confirmation of fitness includes physical examination, neurological examination, vital signs, ECG,  recording of AEs 
and concomitant therapies. Evaluation of safety lab assessed on Day 2 and 5.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ................................................................................ 11
ABBREVIATIONS.......................................................................................... 15
1.
INTRODUCTION.................................................................................... 18
1.1
MEDICAL BACKGROUND .......................................................................................18
1.2
DRUG PROFILE ..........................................................................................................19
1.2.1
Nonclinical pharmacology....................................................................19
1.2.2
Safety pharmacology ............................................................................19
1.2.3
Toxicology..............................................................................................20
1.2.3.1
Single dose toxicity..................................................................20
1.2.3.2
Repeat-dose toxicity studies ....................................................20
1.2.3.3
Genotoxicity.............................................................................22
1.2.3.4
Reproductive and developmental toxicity ...............................22
1.2.3.5
Phototoxicity............................................................................22
1.2.4
Nonclinical pharmacokinetics..............................................................23
1.2.5
Clinical experience in humans.............................................................23
1.2.6
Drug product.........................................................................................23
1.2.7
Prediction of human pharmacokinetics..............................................24
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 25
2.1
RATIONALE FOR PERFORMING THE TRIAL....................................................25
2.2
TRIAL OBJECTIVES..................................................................................................27
2.3
BENEFIT - RISK ASSESSMENT...............................................................................27
2.3.1
Procedure-related risks ........................................................................27
2.3.2
Risks related to the intake of BI 1358894 ...........................................28
2.3.2.1
Risks derived from observations in non-clinical studies .........28
2.3.2.2
Drug-related risks and safety measures ...................................28
2.3.2.3
Risk minimization (safety precautions and stopping rules).....29
2.3.2.4
Drug induced liver injury.........................................................30
2.3.3
Overall assessment................................................................................30
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 32
3.1
OVERALL TRIAL DESIGN AND PLAN..................................................................32
3.1.1
Administrative structure of the trial...................................................34
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS...................................................................................................35
3.3
SELECTION OF TRIAL POPULATION..................................................................35


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3.3.1
Main diagnosis for study entry............................................................36
3.3.2
Inclusion criteria...................................................................................36
3.3.3
Exclusion criteria ..................................................................................36
3.3.4
Removal of subjects from therapy or assessments.............................38
3.3.4.1
Removal of individual subjects................................................38
3.3.4.2
Discontinuation of the trial by the sponsor..............................39
3.3.5
Replacement of subjects .......................................................................39
4.
TREATMENTS........................................................................................ 40
4.1
TREATMENTS TO BE ADMINISTERED ...............................................................40
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................40
4.1.2
Method of assigning subjects to treatment groups ............................41
4.1.3
Selection of doses in the trial................................................................41
4.1.4
Drug assignment and administration of doses for each subject .......41
4.1.5
Blinding and procedures for unblinding ............................................43
4.1.5.1
Blinding....................................................................................43
4.1.5.2
Procedures for emergency unblinding .....................................44
4.1.6
Packaging, labelling, and re-supply ....................................................44
4.1.7
Storage conditions.................................................................................44
4.1.8
Drug accountability ..............................................................................45
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES, RESTRICTIONS....45
4.2.1
Other treatments and emergency procedures....................................45
4.2.2
Restrictions............................................................................................46
4.2.2.1
Restrictions regarding concomitant treatment .........................46
4.2.2.2
Restrictions on diet and life style.............................................46
4.3
TREATMENT COMPLIANCE ..................................................................................47
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 48
5.1
EFFICACY - CLINICAL PHARMACOLOGY ........................................................48
5.1.1
Endpoints of efficacy.............................................................................48
5.1.2
Assessment of efficacy...........................................................................48
5.2
SAFETY.........................................................................................................................48
5.2.1
Endpoints of safety................................................................................48
5.2.2
Assessment of adverse events...............................................................48
5.2.2.1
Definitions of adverse events...................................................48
5.2.2.2
Adverse event collection and reporting ...................................51
5.2.3
Assessment of safety laboratory parameters......................................53
5.2.4
Electrocardiogram................................................................................56
5.2.4.1
12-lead resting ECG.................................................................56
5.2.4.2
Continuous ECG monitoring ...................................................57
5.2.5
Assessment of other safety parameters...............................................58
5.2.5.1
Vital signs ................................................................................58
5.2.5.2
Orthostatic tests........................................................................58


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5.2.5.3
Visual Analogue Scale (VAS) .................................................58
5.2.5.4
Medical examinations..............................................................59
5.2.5.5
Suicidality assessment .............................................................59
5.2.5.6
Neurological examinations ......................................................59
5.4
APPROPRIATENESS OF MEASUREMENTS ........................................................60
5.5
DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS61
5.5.1
Pharmacokinetic endpoints..................................................................61
5.5.1.1
Secondary endpoints................................................................61
5.5.2
Methods of sample collection...............................................................62
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................62
5.5.3
Analytical determinations ....................................................................64
5.5.3.1
Analytical determination of analyte plasma concentration......64
5.6
BIOMARKER ...............................................................................................................65
6.
INVESTIGATIONAL PLAN.................................................................. 66
6.1
VISIT SCHEDULE.......................................................................................................66
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS............................66
6.2.1
Screening period....................................................................................66
6.2.2
Treatment periods.................................................................................67
6.2.3
End of trial period.................................................................................67
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 69
7.1
STATISTICAL DESIGN – MODEL...........................................................................69
7.1.1
Objectives...............................................................................................69
7.2
NULL AND ALTERNATIVE HYPOTHESES..........................................................69
7.3
PLANNED ANALYSES ...............................................................................................69
7.3.1
Primary analyses...................................................................................70
7.3.2
Secondary analyses ...............................................................................70
7.3.3
Safety analyses.......................................................................................72
7.3.5
Pharmacokinetic analyses ....................................................................74
7.4
HANDLING OF MISSING DATA..............................................................................74
7.4.1
Safety......................................................................................................74


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7.4.2
Plasma
drug concentration - time profiles ...............................75
7.4.3
Pharmacokinetic parameters...............................................................75
7.5
RANDOMISATION......................................................................................................75
7.6
DETERMINATION OF SAMPLE SIZE....................................................................75
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 78
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT......................................................................................................................78
8.2
DATA QUALITY ASSURANCE.................................................................................78
8.3
RECORDS .....................................................................................................................79
8.3.1
Source documents .................................................................................79
8.3.2
Direct access to source data and documents.......................................79
8.3.3
Storage period of records.....................................................................79
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS.............................................79
8.5
STATEMENT OF CONFIDENTIALITY..................................................................80
8.6
COMPLETION OF TRIAL.........................................................................................80
9.
REFERENCES......................................................................................... 81
9.1
PUBLISHED REFERENCES......................................................................................81
9.2
UNPUBLISHED REFERENCES ................................................................................83
10. APPENDICES .......................................................................................... 85
10.1
VISUAL ANALOGUE SCALE (VAS)........................................................................85
10.2
BOWDLE VAS-SCORE...............................................................................................86
10.3
COLUMBA-SUICIDE SEVERITY RATING SCALE .............................................87
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 93


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine amino transferase
ANOVA
Analysis of variance
AST
Aspartate amino transferase
AUC
Area under the curve
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
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BW
Body weight
BPD
borderline personality disorder
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central Nervous System
Cpre,N
Predose concentration of the analyte in plasma immediately before 
administration of the Nth dose after N-1 doses were administered
CRF
Case report form
CRO
Clinical Research Organization
CT
Concomitant Therapy


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CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
DRF
Dose Range Finding
ECG
Electrocardiogram
EDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
FDA
Food and Drug Administration
FE
Food Effect
FIH
First in Human
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
GMP
Good Manufacturing Practice
hERG
human ether-a-go-go related gene
HIV
Human Immunodeficiency Virus
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
LVSP
left ventricular pressure parameters 
MDD
major depressive disorder 
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple rising dose
nM
Nanomolar 
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate


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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
RR
Respiratory rate
SAE
Serious adverse event
SCR
Screening
SRD
Single-rising dose
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test product or treatment
TMF
Trial master file
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
tmax(,N)
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma (after administration of N doses)
TRPC
transient receptor potential cation channel
tz
Time of last measurable concentration of the analyte in plasma
TDMAP
Trial Data Management and Analysis Plan
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VAS
Visual Analogue Scale
WBC
White Blood Cells


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Boehringer Ingelheim (BI) is developing BI 1358894, an oral, small-molecule inhibitor of a 
transient receptor potential cation channel, subfamily C,  members 4 and 5 (TRPC 4/5) for 
major depressive disorder (MDD) as an adjunct to antidepressant therapy and for the
treatment of borderline personality disorder (BPD), that has not yet been tested in humans.
MDD is a debilitating disease that is difficult to treat, even when using systematic 
antidepressant strategies. In the National Institute of Mental Health (NIMH) funded STAR*D 
trial of > 4000 patients with nonpsychotic depression, about 30% of the patients did not reach 
remission after 4 different medications [P06-11895] and continued to experience residuals 
symptoms [R16-5475] which significantly impacted the patients’ quality of life [R06-2872]. 
When monotherapy is insufficient, clinicians employ different augmentation strategies 
including add-on treatment with lithium or atypical antipsychotics. When augmentation 
strategies also fail, convulsive therapies such as electro-convulsive therapy (ECT) may be 
used.
Borderline personality disorder (BPD) is a chronic mental disorder with an estimated
prevalence of around 2% in the general community [R16-5476] and severe impairment of
quality of life [R16-5474]. The main symptom clusters of BPD include impulsive-
behavioural dyscontrol, cognitive-perceptual symptoms, disturbed interpersonal relations and 
affective instability. Patients with BPD have high rates of deliberate self-harm and a rate of 
completed suicide that is 50 times higher than in the general population [R16-5477]. Even the 
presence of a single diagnostic feature of BPD is predictive for poor functioning and 
psychiatric illness burden [R16-5483]. Treatment guidelines recommend psychotherapy as 
the mainstay of treatment, but pharmacotherapy is commonly used as an adjunctive, 
symptom-targeted component of treatment. However, no drug is approved for the treatment 
of BPD.
TRPC4 and TRPC5 form ion channels that are involved in the regulation of neuronal
excitability. They are most 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. Pre-clinically, treatment with BI 1358894 has shown
diminished fear and anxiety and increased social interaction without impairing other brain
functions such as learning and memory behaviours.
It is hypothesized that in patients with affective disorders, an overactive amygdala is a major
contributor to attentional bias to negative stimuli, pessimistic thoughts and anxiety [R16-
5473] and there is growing evidence supporting the role of amygdala in the emotion  
processing disturbances observed in patients with BPD [R16-5472]. Therefore, it is expected
that treatment with BI 1358894 has the potential to improve affective symptoms and emotion
control in patients with MDD and BPD.
The clinical development program will first explore the clinical pharmacology of BI 1358894
in healthy volunteers and subsequently in patients with MDD and BPD. 


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1.2
DRUG PROFILE
1.2.1
Nonclinical pharmacology
Transient receptor potential canonical (TRPC) channels are Ca2+-permeable nonselective 
cation channels implicated in diverse physiological functions, including smooth muscle 
contractility and synaptic transmission. 
1.2.2
Safety pharmacology


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1.2.3
Toxicology


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1.2.4
Nonclinical pharmacokinetics
1.2.5
Clinical experience in humans
This is the first-in-man study. No clinical data are available to date for BI 1358894. Inhibition 
of TRPC4/5 is a novel mechanism of action, with no precedent published clinical data for 
other drug candidates. 
1.2.6
Drug product
Please refer to Section 4.1. For a more detailed description of the BI 1358894 profile please 
refer to the current Investigator’s Brochure [c10354149-01].


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1.2.7
Prediction of human pharmacokinetics


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
TRPC4 and TRPC5 form ion channels that are involved in the regulation of neuronal
excitability. They are highly expressed in the amygdala and other CNS regions [R15-3888; 
R16-5350] which are involved in modulation and processing of emotion and affect. It is 
hypothesized that in patients with affective disorders, an overactive amygdala is a major
contributor to attentional bias to negative stimuli, pessimistic thoughts and anxiety [R16-
5473] . Inhibition of TRPC4/5 ion channels by BI 1358894 may therefore have the potential 
to improve affective symptoms and emotion control in patients with affective disorders.
As a transition from preclinical investigations to clinical development in this first-in-man 
trial, safety, tolerability, and pharmacokinetics of BI 1358894 will be assessed in healthy 
male volunteers using single rising oral doses. The study will provide the basis for potential 
further clinical development of BI 1358894 in patients with MDD and BPD.
Healthy male subjects aged 18 - 45 years will be recruited for this study. They provide a 
relatively stable physiological and biochemical basis for studying drug effects, they show no 
disease-related variation and they are not taking concomitant medication. 
In the single rising dose (SRD) part, within each dose group, all actively treated individuals 
will receive the same BI 1358894 dose. The next higher dose will only be administered (to 
the next group) if the treatment in the preceding dose groups was safe and showed acceptable 
tolerability.
In the relative bioavailability (BA) part, up to 3 dose groups may be studied in a two-way-
crossover fashion. This will help gain information about the effect of food on the exposure of 
BI 1358894 and will support upcoming clinical studies with respect to better trial designs, 
and to help if needed in the optimization for future trial-formulation development.
Dose selection
It is intended to investigate the following dose levels of BI 1358894 in the SRD part of this 
trial: 3 mg, 6 mg, 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg. The background for this dose 
selection is described in the following paragraphs.


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In order to cover the anticipated dose range, a stepwise and careful dose increase has been 
selected for this trial. The escalation schedule has been chosen in a way that a shallow 
escalation will be applied for the higher dose levels with a factor not greater than 2.5. This 
dose escalation is considered to be adequate and safe.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 1358894 in 
healthy male subjects following oral administration of single rising doses of 3 mg, 6 mg, 
10 mg, 25 mg, 50 mg, 100 mg, and 200 mg.
Secondary objectives are the exploration of the pharmacokinetics (PK), including dose 
proportionality of BI 1358894 after single dosing.
The objective of the FE part will be to explore the influence of food on the relative 
bioavailability of BI 1358894.
A description of the endpoints to be determined and the observations to be performed, along
with specific information as how to collect the data for that information, is provided in 
Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of BI 
1358894. The subjects are exposed to the risks of the study procedures and the risks related to 
the exposure to the trial medication.
2.3.1
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.


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The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
2.3.2
Risks related to the intake of BI 1358894
2.3.2.1
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 summarized in Section 1.2.3, potential risks observed in non-clinical studies are a long 
lasting decrease of 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 start of treatment. The CV effects observed in rodents and non-
rodents can be easily monitored in a Phase I study (CV effects). Perivascular/mesenteric
inflammation induced by BI 1358894 occurred early after 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.
2.3.2.2
Drug-related risks and safety measures
Mode of action and nature of the target
The TRP family 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 (Minke 2010). 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. Pre-clinically, inhibition of these receptors by BI 
1358894 has shown 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 (Riccio, 2009).  
This is considered to support the assumption that CNS effects in 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 potency of BI 1358894 to the target is comparable across species. In addition, 
expression at the protein level is similar across different species including human. Rat and 
dog had good oral bioavailability, significant systemic exposure and good tolerability after 
oral dosing of a nanosuspension of BI 1358894. Finally, all known metabolites formed after 
incubation of human hepatocytes with BI 1358894 were covered with the combination of rat 
and dog. Overall, pharmacodynamic activity, pharmacokinetics and metabolism all indicated 
that rat and dog were suitable species for nonclinical safety profiling of BI1358894.


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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 m/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. 
2.3.2.3
Risk minimization (safety precautions and stopping rules)
The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers:

Careful dose selection as described in Section 2.1.

Preliminary measurement of BI 1358894 plasma concentrations and preliminary 
determination of PK parameters (Cmax, AUC0-24; see Section 7.3.4). For precautionary 
reasons, drug plasma concentrations of healthy volunteers in this trial should not 
exceed the mean Cmax of 980 nM or mean AUC0-24 of 9500 nM*h, which will be 
considered a preliminary threshold (see Section 2.1). Further dose progression would 
only be allowed after a safety interim analysis and filing and approval of a substantial 
CTP amendment. For subjects receiving 200 mg of BI 1358894 under fed conditions  
that the geometric mean of the AUC0-24 is predicted to be 15400 nM*h and the 
geometric mean of Cmax is predicted to be 1127 nM. Based on the 95% prediction 
interval the threshold (NOAEL in rats: Cmax of 1960 nM or mean AUC0-24 of 26300 
nM*h) would not be exceeded.

An extensive safety laboratory will be performed with special focus on full blood 
exam (see Flow Chart).

For safety reasons, during the single rising dose part each dose group of 8 subjects 
(6 on active, 2 on placebo) will be divided into three cohorts: on the first study day of 
each dose level, only 2 subjects will be treated: one will receive active treatment, the 
other subject will receive placebo. If BI 1358894 treatment is safe and tolerated in this 
first cohort, 2 subjects on active will be treated in the second cohort no sooner than on 
the next day and could be dosed as close as 2 h apart. The remaining 4 subjects (either 
active or placebo) are the third cohort and will be treated no sooner than after 2 days 
following the first cohort. This design ensures that between first and second active 
dose of each dose level there is a time interval of at least 1 day, which covers the 
Tmax of BI 1358894 and the period of highest risk / peak effect. If BI 1358894 was 
safe and showed acceptable tolerability in the first two cohorts, the remaining third 
cohort of the respective dose level could be dosed as close as 10 minutes apart.
During the single rising dose part, a thorough ECG monitoring including continuous 
ECG measurement over 4 hours post dose to cover the anticipated period of highest 
drug exposure and additional repeated single 12-lead ECGs over 96 hours (for Dose 
Group 200 mg fed up to 144 h) following drug administration. Dose escalation would 
be stopped as soon as at least 2 subjects at one dose level showed relevant QT 
prolongation (see Section 3.3.4.2 for details).


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
In this study, blood pressure and heart rate will be closely monitored (see Flow 
Chart). Orthostatic testing will be performed to detect whether potential 
hemodynamic effects of BI 1358894 might interfere with daily life activities. Dose 
escalation will be stopped if orthostatic dysregulation (see Section 5.2.5.2 for 
definition) is observed in more than 1 subject (severe) or more than 3 subjects 
(moderate) per dose group.

Adequate safety monitoring will be performed (e.g. vital signs including ECGs, safety 
laboratory tests including hormone parameters, adverse events including Bond & 
Lader visual analogue scales and suicidality assessment by C-SSR).

The subjects will stay at the trial site for at least 48 hours after study drug 
administration at each dose level. Based on the initially anticipated terminal half-life 
for BI 1358894 of approximately 15 hours, this is expected to cover the period of 
highest risk / peak effect.

The subjects assigned to Dose Group 200 mg fed will stay at the trial site for at least 
144 hours after study drug administration. For a period of at least 24 hours after intake 
of study drugs which is expected to cover the period of highest risk / peak effect, a 
physician will stay at the study site to allow, if needed, immediate emergency 
intervention and rescue measures.

During in house-confinement, the subjects will be under medical observation and 
thoroughly monitored for both expected and unexpected adverse events.

Only if the respective dose of BI 1358894 is safe, shows acceptable tolerability, and 
no stopping criterion are met (refer to Section 3.3.4.2), the next higher dose will be 
given (at least 6 days later, referring to the 1st subject of each dose group).

The food effect part with 50 mg will only start after the completed SRD part.  Further 
dose levels may be tested based on safety and tolerability of the completed SRD part, 
as long as predicted exposure will remain below the predefined thresholds (mean Cmax
of 980 nM or mean AUC0-24 of 9500 nM*h).As reproductive toxicity studies have not 
yet been conducted, women of child-bearing potential will not be enrolled in this 
study.
2.3.2.4
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 5.2.2.1).
2.3.3
Overall assessment
In summary, although not 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,
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 


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basis for further clinical development of this compound. Healthy volunteers are not expected 
to have any direct benefit from participation in this FIM clinical trial with BI 1358894, as is 
the usual case in such Phase I trials. Considering the medical need of the development of a 
safer and more effective treatment for patients with 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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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This FIH study consists of an SRD and an FE part. The SRD part is designed as single-blind, 
partially randomised, and placebo-controlled within parallel dose groups, while the FE part 
will be conducted according to an open-label, randomised, two-way crossover design.
SRD:
The SRD part will start with a tablet formulation. In case the tablet formulation will be used 
up to the final dose group, 64 healthy male subjects will be included, according to 8 
sequential groups comprising 8 subjects per group. However, based on in vitro data, there is a 
possibility that due to the low solubility of the drug substance and tablet, the exposure in 
subjects will be limited and increase may be less than dose proportional (see Section 7.3.4). 
Further subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number may exceed 64, but 
will not exceed 72 subjects entered. Such changes may be implemented via non-substantial 
CTP Amendments.
Within each dose group, 6 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group. Each dose group will consist of 3 cohorts 
which will be treated consecutively for safety reasons.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups (SRD part)
Test product 1: BI 1358894 tablets (1 mg, 5mg, 25 mg 100 mg)
Trial part
SRD
Dose Group
1
2
3
4
5
6
7
8*
Dose (mg)
3
6
10
25
50
100
200
200
Number of subjects
8
8
8
8
8
8
8
8
Subjects receiving placebo
2
2
2
2
2
2
2
2
Subjects receiving active drug
6
6
6
6
6
6
6
6
*Administration under fed conditions
The dose groups of the SRD part will be investigated sequentially in ascending order of 
doses, maintaining a time interval of at least 5 days between the last drug administration in 
the previous dose group and the first drug administration of the subsequent dose group. The 
decision to proceed to the next dose group will be based upon the safety, tolerability, and 
exploratory pharmacokinetic data (see Section 7.3.4) of the preceding dose groups. The next 


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dose will only be given if, in the opinion of the investigator, no safety concerns arose in the 
preceding dose group (i.e. no dose-limiting events occurred) and if none of the pre-specified 
trial-specific stopping criteria were met (refer to Section 3.3.4.2).
FE part
The food effect part will be performed as a randomised, open label, single-dose, two -
sequence, two-way cross-over trial in healthy male subjects in order to compare the test 
treatment (T) to the reference treatment (R). The subjects will be randomly allocated to the 
two treatment sequences (T-R or R-T). The 4 treatments will be two 25 mg tablets and one 
100 mg tablet in the fasting state (R) and two 25 mg tablets and one 100 mg tablet after a 
standardised high fat breakfast (T). The dose strengths to be tested (lowest and maximum 
dose) will be re-evaluated after explorative safety and PK analysis.  For details, refer to 
Section 4.1. There will be a washout period of at least 7 days between the treatments. A total 
of 24 healthy male subjects are planned to participate in the FE part. 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.
The possible dose groups to be evaluated are outlined in Table 3.1: 2 below.
Table 3.1: 2
Dose groups (FE part)
Test product 1: BI 1358894 (film-coated tablets)
Trial part
FE
Dose Group
Dose (mg)
50
100
Number of subjects
12
12
Subjects receiving placebo
--
--
Subjects receiving active drug
12
12
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime for any reasonable cause by the 
Principal Investigator (or an authorised deputy) or the sponsor of the study, e.g. because of 
any unforeseen adverse events, etc. Dose escalation will only be permitted if no safety 
concerns exist in the opinion of the Principal Investigator (or an authorised deputy) and the 
trial clinical monitor (or an authorised deputy).
The minimum data set for review consists of the following data:

AEs in the current and preceding dose groups (including clinically relevant findings 
from ancillary safety testing listed below) (Note: AEs may be ongoing at the time of 
Safety Reviews and AE information may be subject to change prior to Database Lock)


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
Results from 12-lead ECG and continuous ECG monitoring (SRD only) in the current 
and preceding dose groups.

Vital signs and results from the orthostatic test in the current and preceding dose
groups

Clinical laboratory tests in the current and preceding dose groups

Preliminary PK data for selected groups as defined in Section 7.3.4. 

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the trial clinical monitor (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs and out-of-range 
laboratory results (if considered clinically significant). Safety Reviews can be conducted 
face-to-face or by video/telephone conference. The Principal Investigator is responsible for 
organization and minutes of the reviews. Minutes will be signed off by the Principal 
Investigator (or an authorised deputy) and filed in the ISF and TMF.
The investigator (after consultation with the sponsor) is allowed to alter the scheduled dose 
levels (e.g. add low and/or intermediate dose levels) on the basis of experience gained during 
the study, provided the planned and approved highest dose is not exceeded. In this case, the 
total number of subjects in this trial might increase. The investigator and/or the sponsor 
should stop dose escalation in case the safety evaluation leads to concerns that would not 
allow higher dosing.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany.
The trial will be conducted 
,
under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 


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The analyses of BI 1358894 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 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.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
For single-rising dose trials, the design described in Section 3.1 is considered favourably
under the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 1358894.
With the rising dose design, single-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects and investigators. The disadvantage of this trial design is a possible 
observer bias with regard to potential dose-dependent effects, as well as time effects, but it 
has the virtue of minimizing subject risk by sequentially studying ascending doses. As time-
effects are expected to be small relative to the differences between the doses in the broad 
range investigated, unbiased comparisons between treatments can still be expected.
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety, tolerability and pharmacodynamic effects. Each dose group consists 
of 8 subjects with 6 on active treatment, and 2 on placebo. The placebo control group 
includes all subjects of all dose groups treated with placebo. Six subjects per active treatment 
group are in general considered as sufficient for the exploratory evaluation of 
pharmacokinetics. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that up to 64 healthy male subjects will enter the SRD part (8 per dose group, 6 
on active and 2 on placebo) and 24 healthy males will enter the FE part (12 per dose group, 
all on active) of the study. The actual number of subjects entered may exceed the total of 88 
if additional intermediate doses will be tested (see Section 3.1), but will not exceed 96
subjects. Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available.


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A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male according to the investigator’s assessment, based on a complete medical 
history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical 
laboratory tests 
2. Age of 18 to 45 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
5. Willingness to comply with contraception requirements. Subjects who are sexually active, 
must use, with their female partner, adequate contraception throughout the study and until 
one month after the last administration of trial medication. Adequate methods are:

Sexual abstinence or

A vasectomy performed at least 1 year prior to screening in combination with a 
barrier method (condom) or

Surgical sterilisation (including bilateral tubal occlusion, hysterectomy or bilateral 
oophorectomy) of the subjects female partner or

The use of condoms, if the female partner uses in addition an adequate contraception 
method, e.g., intrauterine device (IUD), hormonal contraception (e.g. implants, 
injectables, combined oral or vaginal contraceptives) that started at least 2 months 
prior to first drug administration, or barrier method (e.g. diaphragm with spermicide)
Unprotected sexual intercourse with a pregnant female partner is not allowed throughout 
the study and until one 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) is deviating from 
normal 
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


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3. C-Reactive Protein > ULN,  erythrocyte sedimentation rate (ESR) ≥ 15 millimeters/hour, 
liver and kidney parameter above ULN, other laboratory values outside the reference 
range the investigator considers to be of clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
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 30 g per day for males)
16. Drug abuse as per investigator judgment or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
23. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
24. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)


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For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)
4. 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.
5. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
6.
The subject shows at one dose level a raised CRP level of >3.00 mg/dL or an baseline 
Erythrocyte Sedimentation Rate (ESR) of ≥ 20 millimeters/hour.
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments). This is in particular to be checked before second 
dosing of the FE part.
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.


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3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP, or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
5. Dose escalation will be stopped as soon as at least 2 subjects at one dose level on active 
drug showed relevant individual QT prolongation, i.e. a QTc increase of greater 60 ms 
from baseline in connection with absolute QT or QTc greater than 500 ms, which has 
been confirmed by a repeat ECG recording.
6. Dose escalation will be stopped if the estimated exposure is expected to exceed a Cmax of 
1960 nM or anAUC0-24h of 26300 nM*h. Estimation will be done based on preliminary
mean values of AUC0-24h and Cmax of preceding dose groups (see Section 7.3.4).
7. Dose escalation will be stopped, as soon as at least 2 subjects at one dose level showed a 
sustained decrease in systolic blood pressure of over ≥ 20 mmHg for at least 2 hours after 
drug administration compared to baseline (Day 1, predose) which will be measured after 
15 min in supine position (to avoid false positive signals because of the required 
prolonged resting period after drug intake).
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique study subject number, and will 
be assigned to the same treatment as the subject 
 replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational products have been manufactured by BI Pharma GmbH & Co. KG and 
. 
4.1.1
Identity of BI investigational product and comparator products
SRD part
The characteristics of the test product 1 for dose group 1-8 are:
Substance:
BI 1358894
Pharmaceutical formulation: film coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
1mg, 5 mg, 25 mg, 100 mg
Posology:
3-0-0 (3 mg), 6-0-0 (6 mg), 2-0-0 (10 mg, 50 mg, 200 mg), 
1-0-0 (25, 100 mg), 
Route of administration:
p.o.
Duration of use:
single dose
The characteristics of the reference product (placebo) for dose groups 1-8 are:
Substance:
matching placebo
Pharmaceutical formulation: film coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
3-0-0 (3 mg), 6-0-0 (6 mg), 2-0-0 (10 mg, 50 mg, 200 mg), 
1-0-0 (25, 100 mg), 
Route of administration:
p.o.
Duration of use:
single dose 
FE part
The characteristics of the test product 1 are given below:
Substance:
BI 1358894
Pharmaceutical formulation: film coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany


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Unit strength:
25 mg and 100 mg
Posology:
2-0-0 (50 mg) 1-0-0 (100 mg), see Flow chart.
Route of administration:
p.o.
Duration of use:
2 single doses
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects have been allocated to 
one of the dose cohorts (3 cohorts per dose group), the following subjects will be allocated to 
one of the other dose cohorts. Therefore, the allocation of subjects to dose cohorts is not 
influenced by trial personnel, but only by the subjects’ temporal availability. As the study 
includes healthy subjects from a homogenous population, relevant imbalances between the 
dose groups are not expected.
The randomisation list with study subject numbers and allocated treatments (SRD part) or 
treatment sequences (FE part) will be provided to the trial site in advance. The allocation of 
subjects to study subject numbers will be performed prior to the first administration of trial 
medication. For this purpose, the subjects will be allocated to a study subject number by the 
method ‘first come first served’. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
For the SRD part, oral doses in the range of 3 mg to 200 mg have been selected in order to 
assess the safety and tolerability of BI 1358894 in healthy male volunteers, and to investigate 
the PK of this novel TRPC 4/5 inhibitor. The doses selected for this trial cover the 
subtherapeutic, as well as the estimated therapeutic range and potentially supra-therapeutic 
doses within the levels determined by toxicological investigations (see Section 1.2).
For the FE part, oral doses may range from 25 mg to 100 mg.. The dose strengths to be tested 
will (lowest and highest dose) be re-evaluated after explorative safety and PK analysis. The 
FE part will assess the intra-individual food effect, tablet fasted versus tablet fed, of BI 
1358894 in healthy male volunteers, with the aim to cover a dose range suitable for the 
subsequent clinical development.
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of units // 
dose volume for placebo corresponds to the number of units // dose volume of the respective
dose level.


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Table 4.1.4: 1
BI 1358894 and placebo treatments, oral administration for SRD part
Dose
Substance
Pharmaceutical 
form
Unit strength
Number of units / dose volume 
per administration
Total daily
dose
1
BI 1358894
Film-coated 
tablet
1 mg
3 tablets
3 mg
2
BI 1358894
Film-coated 
tablet
1 mg
6 tablets
6 mg
3
BI 1358894
Film-coated 
tablet
5 mg
2 tablets
10 mg
4
BI 1358894
Film-coated 
tablet
25mg
1 tablet
25 mg
5
BI 1358894
Film-coated 
tablet
25 mg
2 tablets
50 mg
6
BI 1358894
Film-coated 
tablet
100 mg
1 tablet
100 mg
7
BI 1358894
Film-coated 
tablet
100 mg
2 tablet
200 mg
8*
BI 1358894
Film-coated 
tablet
100 mg
2 tablet
200 mg
1-8
Placebo*
Film-coated 
tablet 
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups, dose group 8 treatment under fed 
conditions
Table 4.1.4: 2
BI 1358894 film-tablets for the FE part 
Treatment
Substance
Pharmaceutical 
form
Unit       
strength
Number of units /    
dose volume per 
administration
Total 
Dose
T1 (tablet fed)
BI 1358894 Film-coated tablet
25 mg
2 tablets
50 mg
R   (tablet fasted)
BI 1358894 Film-coated tablet
25 mg
2 tablets
50 mg
T1 (tablet fed)
BI 1358894 Film-coated tablet
100 mg
1 tablet
100 mg
R   (tablet fasted)
BI 1358894 Film-coated tablet
100 mg
1 tablet
100 mg
The dose strengths to be tested will (lowest and highest dose) be re-evaluated after 
explorative safety and PK analysis.
The trial medication will be administered to the subjects, while they are in a sitting/standing
position, as an oral dose together with about 240 mL of water, under supervision of the 
investigating physician or an authorised designee in the morning of Day 1. The so-called 
four-eye principle (two-person rule) should be applied for administration of trial medication 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 


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otherwise. Administration will be performed following an overnight fast, which is to start no 
later than 10 h before the scheduled dosing. 
In treatment T1, a high-fat, high-calorie breakfast will be served 30 min before drug 
administration. The breakfast must be completely consumed prior to drug administration. The 
composition of the standard high-fat, high-calorie breakfast will be in compliance with the 
FDA guidance ‘Food-Effect Bioavailability and Fed Bioequivalence Studies’ [R03-2269] as 
detailed in Table 4.1.4: 3.
Table 4.1.4: 3
Composition of the high-fat, high-calorie breakfast
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 will be 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 48 h (SRD part) following drug 
administration. During the first 2 h after drug administration, subjects of the SRD are not 
allowed to lie down (i.e. no declination of the upper body of more than 45 degrees from 
upright posture except for medical examination), or to sleep. During the first 4 hours after 
drug administration, subjects of the FE part will only be allowed to lie down if supine 
positioning is required for trial-related measurements (e.g. recording of 12-lead ECG). For 
restrictions with regard to diet, see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
SRD part
The treatments administered (active or placebo) will be single-blind (blinded to subjects 
only). However, the current dose level will be known to the subjects. 
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical monitor, data manager,


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statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug metabolism scientist, as
well as dedicated CRO personnel). The objective of the trial is not expected to be affected.
FE part
The FE part of 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.
4.1.5.2
Procedures for emergency unblinding
As this trial will be conducted single blinded (single rising dose part) and open-label (food 
effect part), the treatment information will be known to the investigator. Therefore, no 
emergency envelopes will be provided.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Smaller bottles/boxes 
within the clinical trial supply containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Subject number (only SRD part)

Batch number
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given 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.
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 


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correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol  

Availability of the Form 1572
Only authorised personnel as 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. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator / pharmacist must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator / pharmacist will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP, and that reconcile all investigational products 
received from the sponsor. At the time of disposal, the investigator / pharmacist 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.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
In case of adverse events in need of treatment, the investigator can authorize symptomatic 
therapy. 
In case of alterations of blood pressure (hypotension) and heart rate (tachycardia), which 
were reported in toxicology studies (see section 1.2.2) physical interventions will be the first 
treatment of symptoms. If not successful, appropriate drug therapy will be initiated according 
to common guidelines and algorithms trained in emergency trainings. Dependent on 
individual symptoms, for the treatment of tachycardia this may include intravenous 


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administration of beta blockers or appropriate antiarrhythmic drugs. For the treatment of 
hypotension, beside volume substitution, administration of vasopressors may be a further 
step. The whole staff of the trial site assuming medical responsibility during conduct of the 
study is routinely trained in emergency procedures.
If required, any subject with an adverse event 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
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. For the SRD, no food is allowed for at least 4 h after drug 
intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (FE part Treatment T, see Table 4.1.4: 2), the water administered with the drug, and 
an additional 240 mL of water served on Day 1 at 2 h and 4 h post-dose (mandatory for all 
subjects). 
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before the first administration of trial medication until after the last 
PK sample of each study period is collected.
Poppy-seed containing products should not be consumed starting 4 days before first trial drug 
administration until last PK sampling of the trial.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 4 h before until 4 h after each administration of trial 
medication.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination. 


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


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 1358894 is the number [N (%)] of 
subjects with drug- related adverse event.
Further criteria of interest:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring 

Vital signs (blood pressure, pulse rate, respiratory rate) and Orthostatic tests (SRD 
part only)

Visual analogue scale (Bond & Lader)
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:


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
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 or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, or 

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’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.2.2, subsections ‘AE collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term 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 above.
The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN


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These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure 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 of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
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. 
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’ Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful 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, and intensity of the event as 
well as 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 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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The REP for BI 1358894, when measurable drug levels or PD effects are still likely to be 
present after the last administration, is not known for this first-in-human trial. Therefore, all 
AEs reported until the end of trial examination (last per protocol contact) will be considered 
on treatment (please see Section 7.3.3).
AE reporting to sponsor and timelines
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 of 
awareness) 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
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication. 
The following should also be recorded as an (S)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 eCRFonly.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been , assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.


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5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee
for retests.
The parameters that will be determined are listed in 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 and clinically relevant 
in the opinion of the investigator or in the urinalysis, respectively.


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


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
Test name 
Urinalysis1 (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment1 (microscopic
examination if erythrocytes, leukocytes 
nitrite or protein are abnormal in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1
Protein electrophoresis only at screening. Hormones only at screening and end of trial.
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except drug screening, it is planned to perform these tests during screening only. Drug 
screening will be performed at screening, after admission to the trial site (SRD part) and prior 
to each treatment period (FE part).
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody/p24-antigen (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
) will be performed at screening and 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 Table 5.2.3: 1 and 5.2.3: 2 will be performed
 
 with the 
exception of the urinalysis stix and drug screening tests. These tests will be performed at the 


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trial site using Combur9 Test, 
 and 
AccuSign® DOA 10 test (
).
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
 
) at the time points given in the Flow Chart.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for a 10-second duration after the 
subjects have rested for at least 5 minutes in a supine position. The site personnel will be 
instructed to assure a relaxed and quiet environment so that all subjects are at complete rest 
during the recordings. ECG assessment will always precede all other study procedures of the 
same time point (except blood drawing from an intravenous cannula which is already in 
place) to avoid impact of sampling on the ECG quality.
Electrode placement will be performed according to the method of Wilson, Goldberger and 
Einthoven modified by Mason and Likar (hips and shoulders instead of ankles and wrists). 
Precise electrode placement will be marked with an indelible mark on the skin to allow 
reproducible placement throughout the study.
Single rising dose part: Triple ECGs will be recorded (within 180 sec) at all-time points as 
specified in the respective Flow Chart. At all remaining time points, single ECGs will be 
recorded.
Food effect part: Single ECGs will be recorded for all time points. However, the number of 
ECGs per time point may be increased to three ECGs based on preliminary ECG results 
obtained during the single rising dose part of the study.
All locally printed ECGs will be evaluated by the investigator or a designee..
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle 
movements, electrode dislocation). For time points with triple ECGs, all three single ECGs 
will be repeated. For the repeats due to quality reasons, only the repeated ECG recordings 
will be sent to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. Unscheduled ECGs will not be 
included into the statistical analysis of interval lengths.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of cardiac 
safety during the study, the QT and QTcB values generated by the ECG machines or their 
manual corrections by the investigators will be used. In doubtful cases, ECGs may be sent 
upfront for centralised evaluation (see below). In this case, these centrally measured results 
would overrule any other results obtained.


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Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening), if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.
Assessed ECGs will comply with the ICH E14 guidance document and supplements 
[R05-2311, R13-0801, R13-4095] as well as the FDA requirements for annotated digital 
ECGs [R09-4830].
5.2.4.2
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored (only during SRD part) by means of 
continuous 3-lead ECG recording for at least 15 min before (for baseline assessment), and 4 h 
following drug administration using patient monitors (e.g. ApexPro Telemetry System).


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Abnormal findings will be recorded as AEs if judged clinically relevant by the Investigator 
but no other data will be transferred to the database. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure device
) at the times 
indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine position. 
All recordings should be made using the same type of blood pressure recording instrument on 
the same arm if possible. Respiratory rate (RR) will be measured after 5 minutes of rest in 
supine position for at least 1 minute.
5.2.5.2
Orthostatic tests
Orthostatic tests will be performed at the time points indicated in the Flow Chart. Subjects 
should have spent at least 5 min in the supine position before blood pressure and pulse rate 
are measured the first time. A further 2 measurements will be performed immediately after 
standing up and after 3 min in a standing position. The measurements will be performed 
using the blood pressure device described in Section 5.2.5.1. The term “Orthostatic 
dysregulation” will be used to describe adverse events that occur during orthostatic testing. 
Typical symptoms (and findings) of orthostatic dysregulation are Orthostatic hypotension is 
defined as a reduction in systolic BP of ≥20 mm Hg or in diastolic BP of ≥10 mm Hg within 
3 minutes of standing and will be recorded as an AE. Orthostatic hypotension may be 
accompanied by symptoms of dizziness, diaphoresis, a decline in blood pressure, tachycardia 
(PR >100 bpm), or even fainting (which is reflected in the assessment of AE intensity). At 
the time points given in the Flow Chart (MRD part), the following sequence of measurements 
should be adhered to: 12 lead-ECG and vital signs will be done before blood sampling; 
orthostatic testing will be done after blood sampling. While standing up, subjects will be 
accompanied by staff. The timing of orthostatic testing may be adapted based on information 
obtained during the trial (e.g. preliminary PK data (tmax), including reducing or adding 
measurements. This would be implemented via a non-substantial CTP amendment.
5.2.5.3
Visual Analogue Scale (VAS)
Possible psychedelic effects will be monitored and evaluated as safety measurement by 
analogue scales developed by Bond and Lader [R98-0752] and Bowdle along with PK 
sampling. From these measurements, following factors are derived - external and internal 
perception, alertness, mood and calmness. 
The VAS assessments 2 hours before drug administration will be considered as baseline. At 
each measuring time point indicated in the Flow Chart, the subjects will assess their 
subjective impression by themselves by means of a visual analogue scales. The subjects will 
be asked to mark an adequate position on a line between the two limits characteristics. The 
length of the line will be exactly 100 mm, and will ascertain a score number (values between 


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0 and 100) by measuring the distance in mm from the beginning of the line to the position 
marked by the subject. The score will be documented in the electronic case report form. 
The original English version is shown in Appendix 10.1.
5.2.5.4
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, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination and body 
weight.
5.2.5.5
Suicidality assessment
Suicidality assessment to further evaluate the psychological status of the subject will be 
performed at screening, as indicated in the Flow Chart using the Columbia Suicidal Severity 
Rating scale C-SSRS.
The C-SSRS is a brief measure which is designed to assess severity and change of suicidality 
by integrating both, behaviour and ideation. The C-SSRS was designed to address the need 
for a summary measure to track change in the severity of suicidality across both clinical 
settings and treatment trials.
The original Columbia Suicidal Severity Rating scale is shown in Appendix 10.3.
5.2.5.6
Neurological examinations
As a general additional safety measure in the planned dose group 200mg fed a physical 
neurological examination will be performed at the time points specified in the respective 
Flow Chart.
The neurological examination will include the following assessments:
-
General level of arousal
-
Orientation
-
Eye movement
-
Pupil size and pupil reactivity
-
Reflexes 
-
Assessment of muscle strength
-
Gait
-
Romberg test
-
Tremor
-
Point-to-point movements
-
Sensitivity


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Documentation, Assessment, and Reporting
Results will be documented in source data at the clinical trial site and assessed for clinical 
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant 
findings of the neurological examination will be reported as Adverse Events (during the trial) 
or as baseline conditions (at screening). Case narratives may be written if necessary.
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
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 


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clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 are 
generally used assessments of drug exposure. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Plasma samples will be collected for the purpose of pharmacokinetic analysis
 
 
 Further information about sampling 
is provided in Section 5.5.2.
Date and exact clock time of drug administration and pharmacokinetic sampling will be 
recorded in the CRFs.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data), including addition of samples and 
visits, as long as the total blood volume taken per subject does not exceed 500 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Secondary endpoints

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data time point tz)

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 1358894 plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into a K3-EDTA (tripotassium 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 venipuncture with a 
metal needle.
Sample handling will be described in detail in a separate lab manual.
All samples will be stored at about -20°C or below until transfer to the analytical laboratory.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information such as matrix and 
analyte may also be provided. 


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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
BI 1358894 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. 
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.


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5.6
BIOMARKER
No biomarker will be detected. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
The acceptable deviation from the scheduled time for vital signs, orthostatic testing and ECG 
will be ± 10 min and laboratory tests will be ± 30 min for the first 4 h after trial drug 
administration and ± 30 min thereafter.
If 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 except for the orthostatic testing.
The acceptable deviation from the scheduled time for standardized neurological tests
(conducted in Dose Group 200 mg fed) is ± 45 min on day 1, and ± 90 min from day 2 
onwards.
For planned individual plasma concentration 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 determination of 
pharmacokinetic parameter.
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 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, orthostatic tests and physical examination, refer to Sections 5.2.3 to 5.2.5. 


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6.2.2
Treatment periods
SRD part
Each subject will receive one dose of the respective trial medication (BI 1358894 or placebo) 
at Visit 2.
Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
Study participants will be admitted to the trial site in the morning of Day 1 and kept under 
close medical surveillance for at least48h following the first drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness by the investigator or 
 designee. On all other study days, the study will be 
performed in an ambulatory fashion.
For details on time points and procedures for collection of plasma 
samples for PK 
analysis, refer to Flow Chart and Section 5.5.2. 
The safety measurements performed during the treatment period are specified in Section 5.2. 
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
FE part
In the FE part, each subject is expected to participate in 2 treatment periods. The treatment
periods will be separated by at least 7 days between drug administrations. On Day 1 of each 
treatment period, study participants will be admitted to the trial site and kept under close 
medical surveillance for at least 24 h following drug administration. The subjects will then be 
allowed to leave the trial site after formal assessment and confirmation of their fitness. On 
other study days, the study will be performed in an ambulatory fashion.
Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
6.2.3
End of trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 


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up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 1358894
by using descriptive statistics for all endpoints comparing active dose groups to placebo. The 
primary endpoint is defined in Section 5.2.1. Inferential statistics is not planned (as explained 
in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) of BI 1358894. 
Endpoints as specified in Section 5.5.1 will be analysed by descriptive statistics. Secondary 
endpoints as defined in Section 5.5.1.1 will be subjected to analysis of dose proportionality 
by use of the power model. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
SRD part
Safety and tolerability of the different dose groups of BI 1358894 will be determined on the 
basis of the investigational parameters in comparison with placebo. It is not planned to test 
any statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they 
will be described in their entirety and evaluated by descriptive statistical methods.
For the evaluation of the dose proportionality, a two-sided 95% confidence interval of the
slope will be computed. However, the confidence interval will be interpreted according to the 
exploratory character of the study, i.e. as an interval estimate for effects in the present data.
BA part (Food effect evaluation)
The relative bioavailability of BI 1358894 to evaluate the food effect given as tablets under 
fasted conditions (R) compared to BI 1358894 given as tablets under fed conditions (T1) will 
be estimated by the ratios of the geometric means (T1/R). Additionally, their two-sided 90% 
confidence intervals (CIs) will be provided. This method corresponds to the two one-sided t-
tests procedure, each at the 5% significance level. Since the main focus is on estimation and 
not testing, an acceptance range was not specified, that is, no hypothesis will be tested.
7.3
PLANNED ANALYSES
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.


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7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.3.
7.3.2
Secondary analyses
The PK parameters (refer to Section 5.5.1) will be calculated according to the BI Standard 
Operating Procedure (SOP) ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472], current version. 
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 violation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications 

The subject has a protocol deviation relevant to the evaluation of relative 
bioavailability. (Whether a protocol deviation is relevant, will be decided no later than 
the Report Planning Meeting.) 
Plasma 
concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

the subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

missing samples/concentration data at important phases of PK disposition curve.
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one PK parameter that was not excluded according to the description above.
Assessment of dose proportionality
Dose proportionality will be assessed using the pharmacokinetic endpoints as specified in 
Section 5.5.1.1 (AUC and Cmax). The specific AUC for the analysis will be defined in the 
TSAP.
The basic model for the investigation of dose proportionality will be a power model that 
describes the functional relationship between the dose and PK endpoints.
ij
i
ij
ε
)
X
exp(
)
exp(Y









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The model consists of a regression model applied to log-transformed data. The corresponding 
ANCOVA model includes the logarithm of the dose as a covariate. 
Together with
)
exp(


and
)
exp(
ε
ij
ij



, taking natural logarithms converts this model 
to a linear form as follows:
ij
i
ij
ε
X
β
α
Y




where
ij
Y
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, …, 8, j = 1, 2, …, 8;

intercept parameter;
β
slope parameter;
i
X
logarithm of dose i;
ij
ε
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model.
Based on the estimate for slope parameter (β), a 2-sided 95% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of a 
linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
Dose proportionality will be assessed separately for film-coated tablet after fasted and fed 
conditions..
BA part: Investigation of relative bioavailability (food effect evaluation)
Relative bioavailability is primarily to be determined on the basis of the parameters AUC and 
Cmax (cf. Section 5.5) for the dose levels as specified in Section 3.1 (currently planned for 
50mg, 100mg). The specific AUC for the analysis will be defined in the TSAP. Those 
parameters will be ln-transformed (natural logarithm) prior to fitting the model.
The statistical model used for the analysis of AUC and Cmax will be an ANOVA (analysis of 
variance) model on the logarithmic scale. The specific AUC for the analysis will be defined 
in the TSAP. This model will include effects accounting for the following sources of 
variation: ‘sequence’, ‘subjects within sequences’, ‘period’ and ‘treatment’. The effect 
‘subjects within sequences’ will be considered as random, whereas the other effects will be 
considered as fixed. For tests on subject, period, and treatment effects, the denominator sum 
of squares will be the sum of squares for error; while for tests on sequence effects, the 
denominator will be the sum of squares for subjects. The model is described by the following 
equation


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yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment 
k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., 12
j = the jth period effect, j = 1, 2
k = the kth treatment effect, k = 1, 2
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.
The difference between the expected means for test treatments (tablets under fed conditions 
T1) and reference treatment (tablets under fasted conditions R) log(T1)-log(R), will be 
estimated by the difference in the corresponding Least Square Means (point estimate) and 
two-sided 90% confidence intervals based on the t-distribution will be computed. These 
quantities will then be back-transformed to the original scale to give the point estimator 
(geometric mean) and interval estimates for the ratio between response under test and 
response under reference.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is,
all subjects who received at least one dose of study drug), will be included in the safety 
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
In the SRD part, the active treatment groups will be compared to the placebo control group in 
a descriptive way. In the BA part, the two different treatments will be compared in a
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘randomised treatment’.


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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 'screening', those between first trial medication intake until the end of trial visit 
will be assigned to the treatment period. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP. Please note that AEs occurring after the last 
per protocol contact but entered before database lock will be reported to drug safety only and 
will not be captured in the trial database.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.


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7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 1358894 will be 
calculated according to the BI SOP ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472, current version].
Subjects who are not included in the PKS (refer to Section 7.3.1.) will be reported with their 
individual plasma /
concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma /
concentrations, 
pharmacokinetic parameters or other statistical assessment.
Only concentration values within the validated concentration range will be used for the 
calculation of pharmacokinetic parameters.
 
 
Final PK analyses will use actual sampling times.
 
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).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will not be included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.


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7.4.2
Plasma
drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
[001-MCS-36-472, current version].
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed) or BLQ (below the lower limit of quantificationwill be displayed as such 
and not replaced by zero at any time point (this rule also applies to the lag phase, including
the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
[001-MCS-36-472, current version].
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ will 
be set to zero. All other BLQ values of the profile will be ignored. The lag phase is defined as 
the period between time zero and the first time point with a concentration above the 
quantification limit.
7.5
RANDOMISATION
SRD part
The subjects of the first two cohorts per dose level will not be randomised to maintain a 
treatment sequence of active-placebo-active-active due to safety reasons. In the third cohort 
of each dose level the subjects will be assigned to active or placebo treatment using a 3:1 
allocation ratio. 
BA part (food effect evaluation)
Subjects will be randomized to one of the two treatment sequences R/T1, T1/R in a 1:1 ratio. 
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
SRD part
It is planned to include a total of up to 64 subjects in this trial. The planned sample size is not 
based on a power calculation. The size of 8 subjects per dose group (6 on active treatment, 
and 2 on placebo) is commonly used in single-rising dose studies of the present type and is in 


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general considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics [R95-0013].
Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 64 but will not exceed 72 subjects entered.
BA part (food effect evaluation)
It is planned to enter a maximum of 24 subjects in this part of the trial: 12 subjects receiving
50mg and 100mg of BI 1358894. With this sample size, a certain precision in estimating the 
ratio of geometric means (test/reference) can be expected with 95% probability. Precision is 
defined through the ratio of upper to lower confidence interval limit. Note that the precision 
is independent of the actual ratio of geometric means.
For this first-in-man study, no information on intra-subject variability is available. Therefore,
Table 7.6: 1 provides an overview on the achievable precision for estimating the ratio of 
geometric means (test/reference) when comparing the formulations for two different gCV.
For illustrative purposes, the expected 90% confidence intervals with 95% coverage 
probability are displayed for different values of geometric means ratios T1/R.


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Table 7.6: 1
Precision and illustrative two-sided 90% confidence intervals around 
selected ratios of geometric means (T1/R) for different gCVs in a two
way cross-over design trial (N=12)
N
gCV
gMean Ratio [%]
CI of gMean Ratio
Precision w%
12
15%
100
( 86.13, 116.11)
15%
150
(129.19, 174.16)
200
(172.26, 232.21)
20%
100
( 82.01, 121.93)   
20%
150
(123.02, 182.89)
200
(164.03, 243.86)
25%
100
( 78.15, 127.95)
25%
150
(117.23, 191.93)
200
(156.31, 255.91)
30%
100
( 74.54, 134.16)  
29%
150
(111.80,201.25)
200
(149.07,268.33)
Ratio of the geometric means (test/reference) for a PK endpoint defined by (expµT)/exp(µR)
The expected 90% confidence interval limits in the table were derived by CI limitupper, 
lower = exp(ln(θ) ± ω) with θ being the ratio (T1/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 [R12-0972] using R Version 3.2.2.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 


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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.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.


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8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P06-11895
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, 
Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath 
PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and 
longer-term outcomes in depressed outpatients requiring one or several 
treatment steps: a STAR*D report. Am J Psychiatry 2006;163(11):1905-
1917.
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 
2002: 1 - 9.
R05-2311
ICH E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (ICH harmonised 
tripartite guideline, recommended for adoption at step 4 of the ICH process 
on 12 May 2005 by the ICH Steering Committee). www.emea.eu.int 
2005:1-14.
R06-1037
Guidance for industry: estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. U.S. Department 
of Health and Human Services, Food and Drug administration, Center for 
Drug Evaluation and Research (CDER); 2005.
R06-2872
Trivedi MH, Rush AJ, Wisniewski SR, Warden D, McKinney W, Downing 
M, Berman SR, Farabaugh A, Luther JF, Nierenberg AA, Callan JA, 
Sackeim HA. Factors associated with health-related quality of life among 
outpatients with major depressive disorder: a STAR*D report. J Clin 
Psychiatry 2006;67(2):185-195.
R09-1400
European Medicines Agency (EMEA). ICH topic M3 (R2) non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals: step 4: note for guidance on non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals (June 2009, CPMP/ICH/286/95). 
website.emea.europa.eu; 2009.
R09-4830 
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R12-0972
Kupper LL, Hafner KB. How appropriate are popular sample size 
formulas? Am Stat 1989;43(2):101-105.
R13-0801
E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs - Questions and 
Answers (R1). October 2012. 
website.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/ucm323656.htm


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R13-4095
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): ICH guideline E14 - questions and answers: step 
5 (May 2012, EMA/CHMP/ICH/310133/2008). 
website.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2009/09/WC500002878.pdf
R15-3888
Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao 
GL, Tsvetkov E, Rodig SJ, Veer A van't, Meloni EG, Carlezon WA, 
Bolshakov VY, Clapham DE. Essential role for TRPC5 in amygdala 
function and fear-related behavior. Cell 2009;137(4):761-772.
R16-5350
Fowler MA, Sidiropoulou K, Ozkan ED, Phillips CW, Cooper DC. 
Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent 
brain. Plos One 2007;2(6):e573
R16-5472
Koenigsberg HW, Denny BT, Fan J, Liu X, Guerreri S, Mayson SJ, et al. 
The neural correlates of anomalous habituation to negative emotional 
pictures in borderline and avoidant personality disorder patients. Am J 
Psychiatry 2014; 171(1):82-90.
R16-5473
Mandell D, Siegle G, Shutt L, Feldmiller J, Thase ME. Neural substrates of 
trait ruminations in depression. J Abnorm Psychol 2014;123(1):35-48.
R16-5474
IsHak WW, Elbau I, Ismail A, Delaloye S, Ha K, Bolotaulo NI, et al. 
Quality of life in borderline personality disorder. Harvard Rev Psychiatry 
2013;21(3): 138-150.
R16-5475
McClintock SM, Husain MM, Wisniewski SR, Nierenberg AA, Stewart 
JW, Trivedi MH, et al. Residual symptoms in depressed outpatients who 
respond by 50 % but do not remit to antidepressant medication. J Clin 
Psychopharmacol 2011;31(2): 180-186.
R16-5476
Links PS, Heslegrave R, Reekum R van. Prospective follow-up study of 
borderline personality disorder: prognosis, prediction of outcome, and axis 
II comorbidity. Can J Psychiatry 1998;43(3):265-270.
R16-5477
Skodol AE, Siever LJ, Livesley WJ, Gunderson JG, Pfohl B, Widiger TA. 
The borderline diagnosis II: biology, genetics, and clinical course. Biol 
Psychiatry 2002;51(12):951-963.
R16-5483
Ellison WD, Rosenstein L, Chelminski I, Dalrymple K, Zimmerman M. 
The clinical significance of single features of borderline personality 
disorder: anger, affective instability, impulsivity, and chronic emptiness in 
psychiatric outpatients. J Personal Disord 2016;30(2):261-270.
R95-0013
Broom C. Design of first-administration studies in healthy man. Early 
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
R98-0752
Bond A, Lader M. The use analogue scales in rating subjective feelings. Br 
J Med Psychol 1974;47:211-218.


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c10354149-01
 Investigator's brochure BI 1358894 in Major Depressive 
Disorder and Borderline Personality Disorder. 19 May 2016 
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
n00252179 
 Selectivity/ Safety Pharmacology of HC-122608. Report #: 154. 
06 September 2012.
n00252207 
 Effects of HC-122608 on mouse marble burying. Report #: 
213. 18 June 2013.
n00252277 
 Effect of HC-122608 in the mouse elevated plus maze. Report #: 
168. 16 January 2013.
n00252628 
 [14C]BI 1358894: Distribution Study in the Male Pigmented Rat.
n00252903 
 Effect of BI 1358894 in the mouse forced swimming test. Draft 
Report. 2 December 2016
n00253628 
 Prediction of BI 1358894 Pharmacokinetics and Therapeutic Dose
in Human. Draft Report.
n00253723
 Influence of BI 1358894 (10, 30 and 100 mg/kg PO) on
cardiovascular function (systolic and diastolic arterial pressure, heart rate
and ECG) and body temperature in conscious rats. GP2014/0251/PH5. 29
Novembre 2016.
n00253725
 Effects of BI 1358894 on behavior assessed by observation of
nocturnal activity or in a modified IRWIN-test after oral administration of
10, 30 and 100 mg/kg. GP2014/0271/0272/PH3. 29 November 2016.
n00253727
 Influence of BI 1358894 (10, 30 and 100 mg/kg PO)
on hemodynamic and electrocardiographic parameters in conscious dogs.
GP2014/0269/PH5. 29 November 2016.
n00253729 
 Effects of BI 1358894 (10, 30 and 100 mg/kg
p.o.) on gastrointestinal function in the conscious rat. GP2014/0277/PH4.
12 December 2016.
n00253732
 Effects of BI 1358894 (10, 30 and 100 mg/kg
p.o.) on urine- and serum-derived parameters in conscious rats.
GP2014/0274/PH4. 29 November 2016.


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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. 
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.


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10.
APPENDICES
10.1
VISUAL ANALOGUE SCALE (VAS)
Visual Analogue Scales (Bond & Lader) –English version
(As described in : Bond A, Lader M. The use of analogue scales in rating subjective feelings. 
Br J Med Psychol 1974;47:211-18) [R98-0752]
Please rate the way you feel in terms of the dimensions given below.
Regard the line as representing the full range of each dimension.
Rate your feelings as they are at the moment.
Mark clearly and perpendicularly across each line.
1
Alert
________________________________________________
Drowsy
2
Calm
________________________________________________
Excited
3
Strong
________________________________________________
Feeble
4
Confused
________________________________________________
Clear-headed
5
Well-coordinated________________________________________________
Clumsy
6
Lethargic
________________________________________________
Energetic
7
Contented
________________________________________________
Discontented
8
Troubled
________________________________________________
Tranquil
9
Mentally slow
________________________________________________
Quick-witted
10
Tense
________________________________________________
Relaxed
11
Attentive
________________________________________________
Dreamy
12
Incompetent
________________________________________________
Proficient
13
Happy
________________________________________________
Sad
14
Antagonistic
________________________________________________
Amicable
15
Interested
________________________________________________
Bored
16
Withdrawn
________________________________________________
Gregarious


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10.2
BOWDLE VAS-SCORE
Bowdle VAS-score (English version):
My body or body parts seemed to change their shape or position
Not at all
__________________________________________________
Extremely
My surroundings seemed to change in size, depth, or shape
Not at all
__________________________________________________
Extremely
The passing of time was altered
Not at all
__________________________________________________
Extremely
I had feelings of unreality
Not at all
__________________________________________________
Extremely
It was difficult to control my thoughts
Not at all
__________________________________________________
Extremely
The intensity of colors changed
Not at all
__________________________________________________
Extremely
The intensity of sound changes
Not at all
__________________________________________________
Extremely
I heard voices or sounds that were not real
Not at all
__________________________________________________
Extremely
I had the idea that events, objects, or other people had particular meaning that was specific for me
Not at all
__________________________________________________
Extremely
I had suspicious ideas or the belief that others were against me
Not at all
__________________________________________________
Extremely
I felt high
Not at all
__________________________________________________
Extremely
I felt drowsy
Not at all
__________________________________________________
Extremely
I felt anxious
Not at all
__________________________________________________
Extremely


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10.3
COLUMBA-SUICIDE SEVERITY RATING SCALE


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
16 May 2017
EudraCT number
2017-000143-40
BI Trial number
1402-0001
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1358894 in healthy male 
subjects (single-blind, partially randomised, placebo-
controlled parallel group design) and effect of food on 
the relative bioavailability of  BI 1358894 (open-label,
randomised, two-way cross-over) 
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. Synopsis and flowchart
2. Section 2.3.2.3; Risk minimization (safety 
precautions and stopping rules)
3. Section 3.1;Overall Trial Design and Plan
4. Section 3.3.3, Exclusion criteria
5. Section 3.3.4.2, Discontinuation of the trial by 
the sponsor
6. Section 4.2.1, Other treatments and 
emergency procedure
7. Section 5.2.5.5, Suicidality assessment


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Number of global amendment
1
Description of change
Changes apply to several sections throughout the 
protocol and are described only once and not 
repeated for each section:
1. Synopsis and Flow Chart
To further evaluate the psychological status  
of subjects at screening and during the study a 
further visual analogue scale (Bowdle VAS to 
screen for psychedelic effects) has been 
included.
In addition a suicidality assessment scores 
(Columbia-Suicide Severity Rating Scale) will 
be conducted at screening and at EOT. This 
applies also for the FE part.
2. Section 2.3.2.3, Risk minimization (safety 
precautions and stopping rules)
Deferred inclusion of subjects and 
implementation of three cohorts per dose 
groups taking into account safety, tolerability 
and preliminary PK data.
3. Section 3.1, Overall Trial Design and Plan
The dose strength used in the FE part will be 
selected based on the data of the completed 
SRD part.
4. Section 3.3.3, Exclusion criteria
Exclusion criteria no. 1 and 3 have been 
modified to limit the acceptance of selected 
abnormal values by the investigator as not 
clinically relevant.Exclusion criteria number 
23 and 24 have been added (abnormal 
suicidality assessment score)
5. Section 3.3.4.2, Discontinuation of the trial by 
the sponsor
Drug related SAEs will lead to discontinuation 
of the trial, no drug related SAE will be 
considered.
6. Section 4.2.1, Other treatments and 
emergency procedure
Emergency procedures for cardiovascular 
events have been specified.


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Number of global amendment
1
7. Section 5.2.5.5, Suicidality assessment
Forms of suicidality assessment and Bowdle 
VAS have been added.
Rationale for change
Based on the feedback by BfArM and Ethics 
Committee, the respective recommendations were 
included in a revised protocol. This applies for all 
major changes as summarized in “Section to be 
changed”, such as deferred inclusion of subjects, 
increased efforts for psychological testing and 
modification of exclusion criteria. In context with 
these changes a few remaining inconsistencies 
were also corrected.


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Number of global amendment
2
Date of CTP revision
19 June 2017
EudraCT number
2017-000143-40
BI Trial number
1402-0001
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1358894 in healthy male 
subjects (single-blind, partially randomised, placebo-
controlled parallel group design) and effect of food on 
the relative bioavailability of  BI 1358894 (open-label,
randomised, two-way cross-over) 
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
-
Synopsis and Flow Chart
-
Section 2.1 Rationale for performing thetrial
-
Section 2.3.2.3 Risk minimization (safety 
precautions and stopping rules)
-
Section 3.1 Overall Trial Design and Plan
-
Section 3.1 Table 3.1:1 Dose Groups
-
Section 3.3 Selection of Trial Population
-
Section 3.3.3 Exlusion Criteria
-
Section 3.3.4.1 Removal of individual 
subjects
-
Section 4.1.1 Identity of BI investigational 
product + comparator products
-
Section 4.1.1 Table 4.1.4:1 BI 1358894 and 
placebo treatments, oral administration for 
SRD part
-
Section 5.2.1.1 Routine laboratory tests
-
 


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Number of global amendment
2
Description of change
Changes apply to several sections throughout the 
protocol and are described only once and not 
repeated for each section:
Synopsis and different sections throughout the 
protocol:
The maximum exposure threshold was lowered to 
mean AUC 0-24  of 950 nmol*h/L corresponding  to 
1/10th  of the exposure observed in  male rats at 
7.5 mg/kg/day in the 4-week toxicology study
An additional dose group of 6 mg  
was added. The maximum number of subject 
may increase to 120 in the SRD part.
Section 3.3.3 Exlusion Criteria
C-reactive Protein > ULN and erythrocyte 
sedimentation rate > 15mm/hour are included as 
strict exlusion criteria
Section 3.3.4.1 
C-reactive Protein > 3 mg/dl and erythrocyte 
sedimentation rate > 20mm/hour  are included as 
individual discontinuation criteria
Rationale for change
Based on the feedback by FDA, the respective 
recommendations were included in this revised 
protocol. This applies for most of the changes as 
summarized in “Section to be changed”, such as
lowering of the exposure threshold, modification 
of exclusion criteria and discontinuation criteria
for an individual subject. In context with these 
changes some inconsistencies were also corrected, 
in particular the addition of psychological 
assessments prior to the second dosing of the FE 
part.


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Number of global amendment
3
Date of CTP revision
27 July 2017
EudraCT number
2017-000143-40
BI Trial number
1402-0001
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1358894 in healthy male 
subjects (single-blind, partially randomised, placebo-
controlled parallel group design) and effect of food on 
the relative bioavailability of  BI 1358894 (open-label, 
randomised, two-way cross-over) 
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
-
3.3.4.2 Discontinuation of the trial by the 
sponsor
Description of change
Changes apply only to the section 3.3.4.2
To avoid false positive blood pressure values 
Rationale for change
To avoid false positive signals in blood pressure 
values  because of the required prolonged resting 
period after drug intake. 
In context with these changes some 
inconsistencies were also corrected.


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Number of global amendment
4
Date of CTP revision
21 December 2017
EudraCT number
2017-000143-40
BI Trial number
1402-0001
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1358894 in healthy male 
subjects (single-blind, partially randomised, placebo-
controlled parallel group design) and effect of food on 
the relative bioavailability of  BI 1358894 (open-label, 
randomised, two-way cross-over) 
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. Synopsis 
2. Section 2.1 Rational for performing the 
trial
3. Section 2.3.2.3 Risk minimization
4. Section 3.1 Overall Trial Design and Plan
5. Section  3.3.4.2 Discontinuation of the 
trial by the sponsor


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Number of global amendment
4
Description of change
Changes apply to several sections throughout the 
protocol and are described only once and not 
repeated for each section:
Synopsis and different sections throughout the 
protocol:
The maximum exposure threshold was increased
to geometric mean AUC 0-24  of 9500 nmol*h/L 
corresponding  to the maximum  of the exposure 
observed in  male rats at 7.5 mg/kg/day in the 4-
week toxicology study
Section 3.1 and section 7.3.4
In case of a less than dose proportional increase 
of exposure with a tablet formulation a switch to 
an oral suspension for further dose escalations
may be considered.
Rationale for change
Oral single doses of up to 25 mg were shown to 
be well tolerated. There were no SAEs and no 
AEs considered to be dose limiting. With an oral 
dose of 25 mg we are approaching the predefined 
maximum exposure threshold. Since all currently 
tested dose levels were well tolerated we consider 
it justified to further increase the exposure 
threshold which would allow us to test doses 
beyond 25 mg. We would like to propose an 
increase of the exposure threshold up to the 
NOAEL in rats due to the up to now encouraging 
safety profile in the ongoing Phase I study. We 
would like to highlight that we continue to stop 
dose escalation as soon as safety signal as defined 
in the protocol will be observed. 
In context with these changes a few remaining 
inconsistencies were also corrected.


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Number of global amendment
5
Date of CTP revision
06 February 2018
EudraCT number
2017-000143-40
BI Trial number
1402-0001
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1358894 in healthy male 
subjects (single-blind, partially randomised, placebo-
controlled parallel group design) and effect of food on 
the relative bioavailability of  BI 1358894 (open-label, 
randomised, two-way cross-over) 
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
Synopsis and different sections throughout the 
protocol:
Description of change
Hospitalisation period will be prolonged to 48 h 
instead of 34 hours.
Rationale for change
Based on interim PK-data of the ongoing study 
the preliminary half-life was calculated to be in a 
range of about 40 hours instead of an initially 
predicted human half-life of about 15 hours. 
Because of the longer half-life it is considered 
necessary to extend the observation period to at 
least 48 hours.


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Number of global amendment
6
Date of CTP revision
12 March 2018
EudraCT number
2017-000143-40
BI Trial number
1402-0001
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1358894 in healthy male 
subjects (single-blind, partially randomised, 
placebo-controlled parallel group design) and 
effect of food on the relative bioavailability of BI 
1358894 (open-label, randomised, two-way cross-
over) 
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flow Chart SRD and FE
Description of change
Additional PK blood samples at 8:10 hour 
(0:10min) and 8:20 (0:20 min) 
Rationale for change
Based on interim PK-data of the ongoing study, 
dose group 5 (50 mg), the increase of plasma 
concentrations before Cmax  should be covered 
adequately by earlier PK sampling.
In context with these changes a few remaining 
inconsistencies were also corrected.


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Number of global amendment
7
Date of CTP revision
12 June 2018
EudraCT number
2017-000143-40
BI Trial number
1402-0001
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1358894 in healthy male 
subjects (single-blind, partially randomised, 
placebo-controlled parallel group design) and 
effect of food on the relative bioavailability of BI 
1358894 (open-label, randomised, two-way cross-
over) 
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
Synopsis
Section 4.1.1 Identity of BI investigational 
product and comparator products
Section 4.1.3 Selection of dose trial
Table 4.1.4:2 BI 1358894 film-tablets for the FE 
part
Description of change
Additional dose group in the food effect part
Rationale for change
The ongoing study has recently completed the 
first dose group of the food effect part, using 50 
mg as the initial dose strength. Since preliminary 
PK and safety assessments did not prevent further 
dose escalation the FE part of the study will 
continue with a dose level of 100 mg. Provided 
that the FE part with 100 mg does still not reveal 
dose limiting findings, a further dose group 
beyond 100 mg may enter the FE part. The 
maximum planned dose of the tentative group 


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7
will not exceed the maximum tested dose of the 
SRD part, i.e. 200 mg, and the predicted exposure 
for this tentative dose group is required to not 
exceed the approved exposure threshold (gMean 
AUC 0-24 of 9500 nmol*h/L).
In context with these changes a few remaining 
inconsistencies were also corrected.


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Number of global amendment
8
Date of CTP revision
17 August 2018
EudraCT number
2017-000143-40
BI Trial number
1402-0001
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1358894 in healthy male 
subjects (single-blind, partially randomised, 
placebo-controlled parallel group design) and 
effect of food on the relative bioavailability of BI 
1358894 (open-label, randomised, two-way cross-
over) 
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
-
Synopsis and Flowchart
-
2.1 Rationale for performing the trial
-
2.2 Trial objectives
-
2.3.2.3 Risk minimization
-
3.1 Overall trial design and plan
-
3.3.4 Removal from therapy or assessments
-
4.1 Treatments to be administered 
-
5.2.4 Electrocardiogram
-
5.2.5.8 Neurological examination
-
6.1 Visit schedule
Description of change
Changes applies to several sections of the CTP,
therefore it will be described once and not 
repeated for each section.
Synopsis and Flowchart, sections 2.2, 3.1, and 
4.1
- Inclusion of a new dose group to receive 200 
mg under fed conditions


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Number of global amendment
8
- Dose group of 400 mg and 600 mg deleted, 
will not be conducted
- Additional flow chart for Dose group 200 mg 
fed, prolongation of in-house period, prolonged 
ECG monitoring, assessment of C-SSRS at 
discharge from CPU, inclusion of standardized 
neurological examination, increase of 
individual exposure threshold to AUC0-24 to 
26300 nM*h and Cmax to 1960 nM.
- Oral suspension will not be applied and 
therefore will be deleted
- 25 mg in the FE part was not conducted and 
therefore will be deleted
Sections 2.3.2.3, 3.3.4
- Dose group 200 mg fed will be only conducted, 
if there is an at least 90% probability that the 
estimated individual exposure based on PK of 
preceding dose groups will not exceed the new 
exposure limit of 26300 nM*h (AUC0-24)
Section 5.2.4 
- For dose group 200 mg fed, triple ECG 
recordings up to 144 h
Section 5.2.5.8
- For dose group 200 mg fed, physical 
examination includes standardized neurological 
assesment
Section 6.1
- Definition of time window for neurological 
examination
Rationale for change
The ongoing study has recently completed the 
second dose group of the food effect part, using 
100 mg as dose strength. Safety assessments from 
all dose groups including the most recent 100 mg 
administered under fed conditions did not reveal 
dose limiting safety findings and the mean 
exposure (AUC0-24) remained below the current 
threshold of 9500 nmol*h. A further increase of 
dose beyond 100 mg administered under fed 
conditions requires an adjustment of the exposure 
threshold to the exposure at NOAEL in rats (i.e. 
Cmax of 1960 nM and an AUC0-24 of 26300 
nM*h), which is considered to be the maximum 
possible threshold for an individual exposure in 
healthy subjects. The safety assessments of this 
final dose group have been intensified and the 


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Number of global amendment
8
hospitalisation phase will be extended to Day 7.
In context with these changes a few remaining 
inconsistencies were also corrected, such as the 
deletion of dose levels beyond 200 mg in the SRD 
part (i.e. 400 mg, 600 mg) and 25 mg fed in the 
FE part as well as the oral suspension which will 
no more be tested in this study to the exposure at 
NOAEL in rats (i.e. Cmax of 1960 nM and an 
AUC0-24 of 26300 nM*h), which is considered 
to be the maximum possible threshold for an 
individual exposure in healthy subjects.


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Number of global amendment
9
Date of CTP revision
25 September 2018
EudraCT number
2017-000143-40
BI Trial number
1402-0001
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1358894 in healthy male 
subjects (single-blind, partially randomised, 
placebo-controlled parallel group design) and 
effect of food on the relative bioavailability of BI 
1358894 (open-label, randomised, two-way cross-
over) 
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
-
2.3.2.3 Risk minimization
Description of change
- For a period of at least 24 hours after intake of 
study medication a physician will stay at the 
study site to allow, if needed, immediate 
emergency intervention and rescue measures.
Rationale for change
BfArm request to assure presence of a physician 
at the study site for at least 24 h after dosing. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13880029
10.0
clinical-trial-protocol-revision-09
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 1358894 in
healthy male subjects (single-blind, partially randomised, placebo-controlled parallel
group design) and effect of food on the relative bioavailability of BI 1358894
(open-label, randomised, two-way cross-over)
Author-Trial Clinical
Pharmacokineticist
27 Sep 2018 08:22 CEST
Author-Trial Statistician
27 Sep 2018 08:51 CEST
Approval-Therapeutic Area 
27 Sep 2018 11:12 CEST
Author-Clinical Trial Leader
27 Sep 2018 14:08 CEST
Verification-Paper Signature
Completion
27 Sep 2018 14:12 CEST
Approval-Team Member Medicine
27 Sep 2018 22:00 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13880029
10.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c26550915-01
BI Trial No.:
1402-0001
Title:
Safety, tolerability and pharmacokinetics of single rising oral doses 
of BI 1358894 in healthy male subjects (single-blind, partially
randomised, placebo-controlled parallel group design) and effect of 
food on the relative bioavailability of BI 1358894 (open-label, 
randomised, two-way cross-over)
Including Protocol Amendment 1 to 9 [c13880029-10]
Investigational
Product:
BI 1358894
Responsible trial 
statisticians:
Phone: 
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
18 MAR 2019 SIGNED
Version:
Final
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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.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................9
5.
ENDPOINTS........................................................................................................10
5.1
PRIMARY ENDPOINT......................................................................................10
5.2
SECONDARY ENDPOINTS .............................................................................10
5.2.1
Key secondary endpoints ....................................................................................10
5.2.2
Secondary endpoints ...........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS...........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................15
6.3
SUBJECT SETS ANALYSED ...........................................................................17
6.5
POOLING OF CENTRES..................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................18
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................20
7.
PLANNED ANALYSIS ......................................................................................23
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........25
7.2
CONCOMITANT DISEASES AND MEDICATION......................................25
7.3
TREATMENT COMPLIANCE ........................................................................25
7.4
PRIMARY ENDPOINT......................................................................................25
7.5
SECONDARY ENDPOINTS .............................................................................25
7.5.1
Key secondary endpoint......................................................................................25
7.5.2
Secondary endpoints ...........................................................................................25
7.7
EXTENT OF EXPOSURE .................................................................................28
7.8
SAFETY ANALYSIS..........................................................................................28
7.8.1
Adverse events .....................................................................................................28
7.8.2
Laboratory data...................................................................................................30
7.8.3
Vital signs.............................................................................................................30
7.8.4
ECG ......................................................................................................................30
7.8.5
Others ...................................................................................................................33
7.8.5.1 Physical examination....................................................................................................33
7.8.5.2 Neurological examination ............................................................................................33
7.8.5.3 Visual Analogue Scale (VAS) - Bond & Lader and Bowdle.......................................33
7.8.5.4 Suicidality assessment - Columbia Suicidal Severity Rating scale (C-SSRS)............35
8.
REFERENCES ....................................................................................................36


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10.
HISTORY TABLE..............................................................................................40


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR (SRD Part).......................................13
Table 6.1: 2
Labels for treatments for use in the CTR (FE Part)..........................................13
Table 6.2: 1
Important protocol deviations...........................................................................16
Table 6.3: 1
Analysis sets for endpoints/data description ....................................................18
Table 6.7: 1
Time schedule of 12-lead ECG recordings (SRD part)....................................21
Table 6.7: 2
Time schedule of 12-lead ECG recordings (FE part).......................................22
Table 7.8.5.3: 1
Factor loadings for Bond and Lader VAS................................................34
Table 10: 1
History table .....................................................................................................40


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis Dataset
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AST
Aspartate Aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data time point tz
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BLQ
Below Limit of Quantification
BMI
Body mass index
BWC
Bioavailability/Bioequivalence, Within-Subject Design, Time-Controlled
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
C-SSRS
Columbia Suicidal Severity Rating scale
CRF
Case Report Form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation
DB
Dose Proportionality, Between-Subject Design
DBLM
Database Lock Meeting
DILI
Drug induced liver injury
ECG
Electrocardiogram


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Term
Definition / description
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FE
Food Effect
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
ICH
International Conference On Harmonisation
iPD
Important Protocol Deviation
ISF
Investigator Site File
LLT
Lower Level Term
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
N
Number non missing observations
O*C
Oracle Clinical
P10
10th percentile
P90
90th percentile
PK
Pharmacokinetic(s)
PKS
PK parameter analysis set
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
SAS®
Statistical Analysis System
SD
Standard Deviation
SOC
System Organ Class
SRD
Single rising dose
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
WHO-DD
World Health Organization Drug Dictionary


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Term
Definition / description
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), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM (O*C) system.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SAS® (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number of 
SASTM-based tools (e.g., macros for the analyses of 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:
According to the Reference Document 3 of the Boehringer Ingelheim (BI) Statistical Position 
Paper on Statistical Methods for PK (13), the 90% confidence intervals (CI) should be 
considered for all described PK analyses. Therefore, the 90% CI will be used instead of the 
95% CI.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Section 5.2.1 of the CTP: Primary endpoint to assess safety and tolerability of BI 1358894 is 
the number [N (%)] of subjects with drug- related adverse events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 5.5.1.1 of the CTP: 

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data time point tz)

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma) 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
It is planned that 64 healthy male subjects will enter the SRD part (8 per dose group, 6 on 
active and 2 on placebo) and 24 healthy males will enter the FE part (12 per dose group, all on 
active) of the study.
For details of dosage and formulation see Tables 6.1:1 and 6.1:2 below.
Table 6.1: 1
Labels for treatments for use in the CTR (SRD Part)
Treatment
Short label
P*
Placebo, tablet, qd
Placebo
AA
BI 1358894, 3*1 mg tablet, po, qd 
BI 3mg 
CA
BI 1358894, 6*1 mg tablet, po, qd
BI 6mg 
AB
BI 1358894, 2*5 mg tablet, po, qd
BI 10mg 
AC
BI 1358894, 1*25 mg tablet, po, qd
BI 25mg 
AD
BI 1358894, 2*25 mg tablet, po, qd
BI 50mg 
AE
BI 1358894, 1*100 mg tablet, po, qd
BI 100mg 
AF
BI 1358894, 2*100 mg tablet, po, qd
BI 200mg 
CD
BI 1358894, 2*100 mg tablet, po, qd, fed
BI 200mg fed
*: The placebo control group in the safety evaluation will consist of all placebo treated 
subjects, regardless of the dose group in which they were treated.
Table 6.1: 2
Labels for treatments for use in the CTR (FE Part) 
Treatment
Short label
W
BI 1358894, 2*25 mg tablet, po, qd, fed
BI 50mg fed
X
BI 1358894, 2*25 mg tablet, po, qd, fasted
BI 50mg fast
Y
BI 1358894, 1*100 mg tablet, po, qd, fed
BI 100mg fed
Z
BI 1358894, 1*100 mg tablet, po, qd, fasted
BI 100mg fast
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00 h on day of informed consent until administration time 
of study drug)


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
On treatment
(SRD part: separately for each treatment, ranging from the time of first administration 
of BI / Placebo until 0:00h on the day after trial termination date;
FE part: separately for each treatment, ranging from the time of first administration of 
BI until administration time of next study drug dose or 0:00h on the day after trial 
termination date)
Please note that all AEs reported between start of trial drug administration and the last per-
protocol contact will be considered on treatment (i.e. no follow-up period is considered in this 
trial).
Displays of AEs will be presented separately for the treatments described in Table 6.1: 1 and 
Table 6.1: 2 above.
Two types of AE displays will be provided in the report:
A) Section 15.3 (separately for SRD and FE part) and Appendix 16.1.13.1.8 (for 
ClinicalTrials.gov and EudraCT only but combined for SRD and FE part) of the CTR 
displays:
In these displays, the on treatment phase will be analysed by dose group (labelled with the 
name of the study treatment (short label)). Screening will not be included in this analysis. 
The following totals will be provided in addition:

a total over all on treatment phases included in this analysis ("Total on treatment")
(Section 15.3 only)

SRD part: a total over all BI treated phases ("BI Total")
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))
In Section 16.1.13.1.8 AE tables (separately for SRD and FE part), the following totals will be 
provided in addition:

a total over all study phases ("Total")

SRD part: a total over all BI treated phases ("BI Total")
Tables of vital signs and laboratory values will present results by the above mentioned 
screening and on treatment phase. Tables of ECG values will present results by the above 
mentioned on treatment phase
For detailed information on the handling of the treatments in the O*C views refer to Technical 
TSAP ADS (analysis data set) 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.
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, all 
manual deviations identified at the sites by the CRAs and deviations too complex to program 
will be reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" 
(2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM minutes via an accompanying Excel spreadsheet (3). The following Table 6.2: 1
contains the categories which are considered to be iPDs in this trial. If the data show other 
iPDs, this table will be supplemented accordingly by the time of the RPM/DBLM at the latest.
Protocol deviations will be summarised and listed.


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Table 6.2: 1
Important protocol deviations
Category/Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomisation not followed
C3
Non-compliance
C4
Incorrect intake of trial medication
C5
Improper washout between treatments
D
Concomitant medication
D1
Concomitant medication with the potential to affect the assessment of the 
trial medication
D2
Improper washout of concomitant medication
E
Missing data 
E1
Certain deviations from procedures used to measure secondary data
F
Incorrect timing1
F1
Certain deviations from time schedule used to measure secondary data
G
Other trial specific important deviations
G1
Incorrect intake of meal before administration of treatment
G2
Protocol deviations affecting safety and rights
1 Time deviations will only be flagged as iPD, when leading to exclusion of the entire subject from an analysis set


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6.3
SUBJECT SETS ANALYSED

Treated set (TS):
This subject set includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for safety 
analysis.
 
Section 7.3.2 of the CTP: Plasma and urine concentration data and parameters of a subject 
will be included in the statistical pharmacokinetic (PK) analyses if they are not flagged for 
exclusion due to a protocol deviation relevant to the evaluation of PK (to be decided no later 
than in the RPM) 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

The subject has a protocol deviation relevant to the evaluation of relative 
bioavailability. (Whether a protocol deviation is relevant, will be decided no later 
than the Report Planning Meeting.)
Plasma and urine concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

the subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

missing samples/concentration data at important phases of PK disposition curve.

PK parameter analysis set (PKS):
The PK parameter analysis set (PKS) includes all subjects from the TS receiving 
BI 1358894 who provide at least one secondary PK parameter (AUC or Cmax) that was 
not excluded according to the description above.
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 (FE part).
It is used for assessment of dose proportionality (SRD part/FE part) and for assessment of 
the food effect (FE part).
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.


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Table 6.3: 1
Analysis sets for endpoints/data description
Analysis set
Endpoint/data description
TS
PKS
Primary endpoint / Safety assessments (incl. ECG)
X
Secondary and further PK endpoints 
X
Demographic/baseline data
X
Important Protocol Deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.4.
The only exception where imputation might be necessary for safety evaluation is 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).


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For placebo subjects the missing plasma concentration values will be replaced by 0 for the
exposure response analysis. For subjects on active drug, missing plasma concentration values 
with ‘BLQ’ in the comment field will be replaced by ½ LLOQ (post treatment values) or by 0 
(pre dose values).


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For the analysis of vital signs and VAS the baseline value is defined as the last measurement 
before trial drug administration (SRD part) / before trial drug administration in each treatment 
period (FE part). 
For laboratory analysis the baseline is defined as the last measurement before trial drug 
administration in the first 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 end of trial examination 
are given in the CTP Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
The acceptable deviation from the scheduled time for vital signs, orthostatic testing and ECG 
will be ± 10 min and laboratory tests will be ± 30 min for the first 4 h after trial drug 
administration and ± 30 min thereafter.
[…] The acceptable deviation from the scheduled time for standardized neurological tests
(conducted in Dose Group 200 mg fed) is ± 45 min on day 1, and ± 90 min from day 2 
onwards.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.


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Section 5.2.4 of the CTP: With the exception of the first triple ECG (used as baseline before 
the first drug administration), only the first of the three replicate ECGs at a single assessment 
time will be evaluated.


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7.
PLANNED ANALYSIS
The SRD and FE part will be evaluated separately.
The placebo group in the safety evaluation of the SRD part will consist of all placebo treated 
subjects, regardless of the dose group in which they were treated.
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.5.2) will also be performed 
by 
 and will be presented in Section 15.5 of the CTR and in 
Appendix 16.1.13.3.
Descriptive data analysis of PK parameters and concentrations will be performed by the 
department of Translational Medicine and Clinical Pharmacology 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.
In the SRD part, the individual values of all subjects will be listed, sorted by treatment group,
subject number, and visit. 
In the FE part, 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


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Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment group/sequence. 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 APEXC and APEXCO 
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 APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO 
is set to ‘HALF LIFE’ the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in “Noncompartmental Pharmacokinetic / Pharmacodynamic
Analyses of Clinical Studies” [001-MCS-36-472_RD-01] (5) and “Description of Analytical 
Transfer Files and PK/PD Data Files” [001-MCS-36-472_RD-03] (7).


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
SRD part: The data will be summarised by treatment group and in total. 
FE part: The data will be summarised by treatment sequence and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the 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.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations and/or urinary excretion 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/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINT
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 1358894.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoints
Assessment of dose proportionality
Dose proportionality of the PK endpoints AUC 0-∞, Cmax, AUC0-tz in plasma of BI 1358894
will be explored using the power model that describes the functional relationship between 
dose and PK endpoints. The basic model consists of a regression model applied to log-


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transformed data (log-transformation refers to using the natural logarithm). The corresponding 
ANCOVA (Analysis of Covariance) model includes the logarithm of the dose as a covariate.
The model is described by the following equation:
Yij = α + β*Xi + εij
where
Yij
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, …,n,  j = 1, 2, …, m, 
α
intercept parameter;
β 
slope parameter;
Xi
logarithm of dose i;
εij
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
Section 7.3.2 of the CTP:  This equation can be fit as a linear regression model.
Based on the estimate for slope parameter (β), a 2-sided 90% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of a 
linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed. 
Dose proportionality will be assessed separately for film-coated tablet after fasted (treatment 
groups of SRD part only) and fed conditions (combination of treatment groups of SRD and 
FE part).
This analysis will be accomplished by using the XPKISTAT macro (design DB), based on the 
PKS.
A regression plot will be performed, where the logarithm of dose is depicted versus logarithm 
of PK endpoint, including the estimated regression line from the power model and reference 
line of perfect proportionality (β=1).
Investigation of relative bioavailability (food effect evaluation – FE part)
Section 7.3.2 of the CTP: Relative bioavailability is primarily to be determined on the basis 
of the parameters AUC (AUC 0-∞, AUC0-tz) and Cmax [...] for the dose levels […] 50mg, 
100mg. […] Those parameters will be ln-transformed (natural logarithm) prior to fitting the 
model.
The statistical model used for the analysis of AUC 0-∞, AUC0-tz and Cmax will be an ANOVA 
(analysis of variance) model on the logarithmic scale. […] This model will include effects 
accounting for the following sources of variation: ‘sequence’, ‘subjects within sequences’, 


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‘period’ and ‘treatment’. The effect ‘subjects within sequences’ will be considered as random, 
whereas the other effects will be considered as fixed. For tests on subject, period, and 
treatment effects, the denominator sum of squares will be the sum of squares for error; while 
for tests on sequence effects, the denominator will be the sum of squares for subjects. The 
model is described by the following equation
yijkm = µ+ ζi + sim + πj + τk + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving 
treatment k in period j,
µ
the overall mean,
ζi
the ith sequence effect, i = 1, 2
sim 
the effect associated with the mth subject in the ith sequence, m =1, 2, ..., pi; 
pi=number of subjects in ith sequence
πj
the jth period effect, j = 1, 2
τk
the kth treatment effect, k = 1, 2
eijkm
the random error associated with the mthsubject in sequence i who received 
treatment k in period j.
The difference between the expected means for test treatments (tablets under fed conditions
T1) and reference treatment (tablets under fasted conditions R) log(T1)-log(R), will be
estimated by the difference in the corresponding Least Square Means (point estimate) and 
two-sided 90% confidence intervals based on the t-distribution will be computed. These 
quantities will then be back-transformed to the original scale to give the point estimator 
(geometric mean) and interval estimates for the ratio between response under test and 
response under reference.
The analysis will be accomplished by using the XPKISTAT macro, based on PKS (design
BWC).
In addition, a sensitivity analysis will be performed by fitting the model described above, but 
using all effects as fixed. This analysis will be done using PROC GLM.


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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, separately for SRD and FE part.
If not stated otherwise, the safety results will be sorted by treatment group (SRD part) or by 
actual treatment (FE part).
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] (9).
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 CRF will be collapsed into an AE provided 
that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, therapy
required, seriousness, reason for seriousness, relationship, outcome, AE of special 
interest)

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)


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For further details on summarization of AE data, please refer to [001-MCG-156] (9).
Section 5.2.2.1 of the CTP: The following are considered as AESI in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory
parameters:
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain,
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should
make sure these parameters are analysed, if necessary in an unscheduled blood test.
Should the results meet the criteria of hepatic injury alert, the procedures described in
the DILI checklist should be followed.
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. 
Section 5.2.2.2 of the CTP: The REP for BI 1358894, when measurable drug levels or PD 
effects are still likely to be present after the last administration, is not known for this first-in-
human trial. Therefore, all AEs reported until the end of trial examination (last per protocol 
contact) will be considered on treatment […].
According to ICH E3 (10), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at the RPM at the latest.
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarized by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with other 
significant AEs according to ICH E3 (10), for subjects with serious AEs, for subjects with 
drug-related AEs, for subjects with drug related serious adverse events and for subjects with 
AESIs.
The SOC and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.


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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] (11).
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possible 
clinically significant will be flagged in the data listings. 
It is the investigator's responsibility to decide whether a lab value is clinically significant 
abnormal or not (at the RPM/DBLM at the latest).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate), as well as respiratory rate (RR) and orthostatic tests
(SRD part only).
7.8.4
ECG
Continuous safety ECG monitoring (by investigator) – (SRD part only)
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.
12-lead ECG (SRD part + FE part)
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator. 
The descriptive evaluation of ECG data will be based on the TS, separately for the SRD part 
and the FE part.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.


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7.8.5
Others
7.8.5.1 Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.
7.8.5.2 Neurological examination 
Neurological examination findings will be reported as relevant medical history/baseline 
condition (i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. 
No separate listing or analysis of neurological examination findings will be prepared.
7.8.5.3 Visual Analogue Scale (VAS) - Bond & Lader and Bowdle
The VAS will be used at screening and at end of trial examination, as well as on predose at 
visit 3 (FE part only) and planned times -1:00 (dose groups 3mg to 50mg), -0:30 (dose groups 
100mg, 200mg and 200mg fed), 2:00, 4:00, 8:00, 24:00, 34:00 and 48:00 (SRD part only). 
The last VAS assessments before drug administration will be considered as baseline.
The results of both VAS will be listed and descriptive statistics over time including change 
from baseline will be performed.
Visual analogue scale – Bond and Lader
For Bond and Lader VAS, three factors will be calculated using the loadings (regression
weights) from the factor analysis in (12), which are shown in Table 7.8.5.3:1 below. The
individual scores on each scale will be multiplied by the scale's factor loading and totaled 
within the three factors. The summed scores will then be divided by the sum of loadings for 
each factor.
Alertness 
= F1 = 1/ Σw1i * Σ(w1i*VASi)
Contentment = F2 = 1/ Σw2i * Σ(w2i*VASi)
Calmness 
= F3 = 1/ Σw3i * Σ(w3i*VASi)
where
VASi measured scale i; where i = 1, ... , 16
wfi factor loading for factor f and scale i; where f = 1, 2, 3 and i = 1, ... , 16,
Since some scales for these loadings are reversed compared to the scales in the questionnaire
the corresponding individual scores have to be reversed (100– measured score value (mm))
before multiplication. Descriptive statistics of the three factors over time and for the
difference from baseline will be provided. Furthermore, for the SRD part, the change from 


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baseline of the three factors will be presented graphically over time (arithmetic means + 
standard deviation).
Table 7.8.5.3: 1
Factor loadings for Bond and Lader VAS
Measured score value
Factor loadings to
Alertness
Contentment
Calmness
Alert / Drowsy
1. Alert
0.827
0.088
0.008
Calm / Excited
2. Calm
0.049
0.029
0.845
Strong / Feeble
3. Strong
0.618
0.142
0.328
Muzzy / Clear-headed *
4. Clear-headed
0.755
0.149
0.080
Well-coordinated / Clumsy
5. Well-
coordinated
0.642
0.122
0.424
Lethargic / Energetic *
6. Energetic
0.776
0.174
-0.019
Contented / Discontented
7. Contented
0.233
0.677
0.278
Troubled / Tranquil *
8. Tranquil
0.133
0.697
0.429
Mentally slow / Quick-
witted *
9. Quick-witted
0.635
0.340
-0.138
Tense / Relaxed *
10. Relaxed
0.031
0.445
0.677
Attentive / Dreamy
11. Attentive
0.792
0.179
0.098
Incompetent / Proficient *
12. Proficient
0.593
0.328
0.027
Happy / Sad
13. Happy
0.270
0.823
0.051
Antagonistic / Amicable *
14. Amicable
0.159
0.738
0.172
Interested / Bored
15. Interested
0.614
0.412
-0.006
Withdrawn / Gregarious *
16. Gregarious
0.343
0.594
-0.217
* Measured score value will be reversed
Visual analogue scale – Bowdle
Descriptive statistics of the 13 individual Bowdle scales at screening and post examination
and for the difference from baseline (=screening) will be provided. Other assessments will be 
listed only.
Furthermore, for the SRD part, the change from baseline of the individual scales will be 
presented graphically over time (arithmetic means + standard deviation).


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7.8.5.4 Suicidality assessment - Columbia Suicidal Severity Rating scale (C-SSRS)
The C-SSRS will be done at
-
screening and PTM 144:00 and end of trial examination in dose group 200mg fed
-
screening and end of trial examination in dose groups 3mg to 200mg
-
screening, predose at visit 3 and end of trial examination in FE part.
The results will be listed only.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, BIRDS
3.
BI-KMED-COPS-TMP-0001: "iPD log", current version; KMED
4.
001-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_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
8.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
9.
001-MCG-156: “Analysis and Presentation of Adverse Event Data from Clinical Trials”, 
Version 8; IDEA for CON.
10. 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
11. 001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
12. Bond A, Lader M. “The use of analogue scales in rating subjective feelings.” Br J Med
Psychol 1974;47:211-218. [R98-0752]
13. Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. J Pharmacokin Pharmacodyn 2017 [R18-0143]
14. BI Statistical Position Paper - Statistical Methods for PK - Reference Document 3: 
Regulatory recommendations for BA/BE trials and implementation instructions in 
clinical trial documents, version 1.0 (2017).


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
18-MAR-19
None
This is the final TSAP without any 
modification