Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: yes

Brief summary:
The primary objective of the trial is to investigate the safety and tolerability of BI 1358894 in healthy male subjects following oral administration of multiple rising doses over 14 days.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: BI 1358894 intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet intervention 3: Solution for injection

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c21808436-05
EudraCT No.:
BI Trial No.:
2018-000389-12
1402-0002
BI Investigational
Product:
BI 1358894
Title:
Safety, tolerability, and pharmacokinetics of multiple rising oral doses 
of BI 1358894 (double-blind, randomised, placebo-controlled, 
parallel-group design) and evaluation of midazolam interaction 
(nested, open, fixed-sequence, intra-individual comparison) in healthy 
male subjects
Lay Title:
This study in healthy men tests how different doses of BI 1358894 are 
taken up in the body and how well they are tolerated. The study also 
tests how BI 1358894 affects the way the body breaks down 
midazolam.
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax: 
Principal Investigator:
Phone:
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendment 4))
Version and Date:
Version: 5.0
Date: 03 April 2019
Page 1 of 105
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
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:
03 April 2019
29 May 2018
1402-0002
Title of trial:
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of BI 1358894 
(double-blind, randomised, placebo-controlled, parallel-group design) and evaluation 
of midazolam interaction (nested, open, fixed-sequence, intra-individual comparison) 
in healthy male subjects
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
(1) To investigate safety, tolerability, and pharmacokinetics following multiple rising 
doses of BI 1358894
(2) To investigate the effect of BI 1358894 on the pharmacokinetics of midazolam 
given as oral microdose
Methodology:
(1) Double-blind, randomised (within dose groups), placebo-controlled, parallel-group 
comparison
(2) Nested, open, fixed-sequence, intra-individual comparison
No. of subjects: 
total entered:
50*
each treatment:
10 per dose group (8 on active drug and 2 on placebo) 
* 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 50, but will not exceed 80 subjects entered.
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
Test product 1:
BI 1358894 film-coated tablets
dose:
10 mg, 25 mg, 50 mg, 100mg, 200 mg q.d.
mode of admin.:
Oral with 240 mL of water after a standard continental breakfast
Test product 2 (probe): Midazolam for injection used as oral solution
dose:
75 µg q.d.
mode of admin.:
Oral with 240 mL of water after a standard continental breakfast


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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:
03 April 2019
29 May 2018
1402-0002
Comparator product to 
test product 1:
Matching placebo
Dose:
Not applicable
Mode of admin.:
Oral with 240 mL of water after a standard continental breakfast
Duration of treatment: (1) BI 1358894 or placebo: 14 days with q.d. multiple doses
(2) Midazolam: 3 single doses (Days -1, 1, and 14)
Criteria for
pharmacokinetics:
Secondary endpoints:
(1) BI 1358894
After the first dose:
AUC0-24 and Cmax
After the last dose:
AUCτ,ss and Cmax,ss
(2) Midazolam
After single doses:
AUC0-tz and Cmax
Further criteria of interest
(1) BI 1358894
After the first dose:
AUC0-tz, AUCt1-t2, tmax  
After the last dose:
Cmin,ss, Cavg,ss, Cpre,ss, AUCt1-t2,ss , tmax,ss, λz,ss, t1/2,ss, 
MRTex,ss, CL/Fss, Vz/Fss, PTF
After the first and last dose:
Aet1-t2(,ss), fet1-t2(,ss), CLRt1-t2(,ss)
Before doses on at least 3 days:
Cpre,N
Accumulation ratios:
RA,AUC, RA,Cmax
(2) Midazolam
After each single dose:
AUC0-∞, AUCt1-t2, tmax, λz, t1/2, % AUCtz-∞
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 (including testing for faecal occult blood and faecal calprotectin), 
12-lead electrocardiogram (ECG), vital signs (blood pressure [BP], pulse rate [PR], 
respiratory rate [RR]), orthostatic tests, Bond & Lader and Bowdle visual analogue 
scales, and suicidality assessment (C-SSRS).


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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:
03 April 2019
29 May 2018
1402-0002
Statistical methods:
(1) BI 1358894
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 1358894 will be explored using a regression model. A 
95% confidence interval (CI) for the slope will be computed.
Attainment of steady state will be analysed by a repeated measures linear model for 
trough concentrations (Cpre) of BI 1358894 with dose as an additional covariate if 
permissible.
(2) Midazolam
Descriptive statistics will be calculated for all endpoints.
Relative bioavailability will be estimated by the ratios of the geometric means (test/
reference) for the secondary endpoints of midazolam. Additionally, their two-sided 
90% 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 is not specified. The statistical model will be an 
ANOVA on the logarithmic scale including effects for ‘subjects’, and ‘treatment’. CIs 
will be calculated based on the residual error from ANOVA.


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FLOW CHART
Visit
Day
Planned time (relative to first 
BI 1358894 administration
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9 BI 1358894
PK blood MDZ9
PK urine
9, 10
Faecal laboratory test14
Visual analogue scales
Orthostatic testing
12-lead ECG16
Vital signs (BP, PR, RR)
Questioning for AEs & 
concomitant therapy5
1 -21 to -2
Screening (SCR)1,11
x
x
x
x
x
x
x
2
-4 to -2
-72:00
08:00
Ambulatory visit
x6
x
x
-1
-25:30
06:30
Admission to trial site
x2,12
x2,7
x2
x
x2
x2
x2
-24:30
07:30
Standardized continental breakfast
-24:00
08:00
Midazolam administration
-23:50
08:10
x
-23:30
08:30
x
-23:00
09:00
x
x
x
-22:00
10:00
240 mL fluid intake
x
x
x
x
-21:30
10:30
x
-21:00
11:00
x
-20:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
x
x
-18:00
14:00
x
-16:00
16:00
Snack (voluntary)3
x
x
x
-14:00
18:00
Dinner3
1
-1:00
07:00
Allocation to treatment: BI 1358894 
or placebo
x2,15 x2
x2
x2
x2
x2,13
x2
x2
-0:30
07:30
Standardized continental breakfast
0:00
08:00
BI 1358894 or placebo administration 
& midazolam
▲
│
0:10
08:10
x
x
│
0:20
08:20
x
│
0:30
08:30
x
x
│
1:00
09:00
x
x
│
x8
x
2:00
10:00
240 mL fluid intake
x
x
│
x
x
x
x
2:30
10:30
x
│
3:00
11:00
x
x
│
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
┼
x
x
x
x
6:00
14:00
x
x
│
8:00
16:00
Snack (voluntary)3
x
x
┼
x
x
x
10:00
18:00
Dinner3
│
12:00
20:00
x
┼
x
x
x
x 
2
24:00
08:00
BI 1358894 or placebo administration19
x
x2
▼
x2,17
x
x
x
27:00
11:00
x
x
3
48:00
08:00
BI 1358894 or placebo administration19
x2
x
x
x
4
72:00
08:00
BI 1358894 or placebo administration19
x18
x2
x
x
x8
x
x
75:00
11:00
x
x
76:00
12:00
x
x
x
80:00
16:00
x
x
x
x
5
96:00
08:00
BI 1358894 or placebo administration19
x2
x
x
x
6
120:00
08:00
BI 1358894 or placebo administration19
x2
x
x
x
123:00
11:00
x
x


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, neurological examination; check of vital signs, ECG, safety laboratory 
(including drug screening and alcohol breath test), faecal laboratory tests, demographics (including determination of 
body height and weight, smoking status and alcohol history), relevant medical history, concomitant therapy and review 
of inclusion/exclusion criteria, orthostatic testing, Bond & Lader and Bowdle visual analogue scales and suicidality 
assessment (C-SSRS).
2.
Time is approximate. The respective procedure is to be performed and completed within 2 h (3 h on day -1) prior to 
drug administration. 
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
Visit
Day
Planned time (relative to first 
drug administration
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9 BI 1358894
PK blood MID9
PK urine
9, 10
Faecal  laboratory tests14
Visual analogue scale
Orthostatic testing
12-lead ECG
Vital signs (BP, PR, RR)
Questioning for AEs & 
concomitant therapy 5
2
7
144:00
08:00
BI 1358894 or placebo administration19
x18
x2
x
x
x8
x
x
148:00
12:00
x
x
x
152:00
16:00
x
x
x
x
8
168:00
08:00
BI 1358894 or placebo administration19
x
x
x
9
192:00
08:00
BI 1358894 or placebo administration19
x2
x
x
x
195:00
11:00
x
x
10
216:00
08:00
BI 1358894 or placebo administration19
x
x
x
x
x
11
240:00
08:00
BI 1358894 or placebo administration19
x2
x2,17
x
x
x
243:00
11:00
x
x
12
264:00
08:00
BI 1358894 or placebo administration19
x
x
x
13
288:00
08:00
BI 1358894 or placebo administration19
x2
x
x
x
14
311:00
07:00
x2
x7,2
x
x
x
x8
x2
x2
311:30
07:30
Standardized breakfast
312:00
08:00
Last BI 1358894 or placebo
administration & midazolam
▲
│
x22
312:10
08:10
x7
x
│
312:20
08:20
x7
│
312:30
08:30
x7
x
│
313:00
09:00
x7
x
│
x
x
314:00
10:00
240 mL fluid intake 
x
x7
x
│
x
x
x
x
314:30
10:30
x
│
315:00
11:00
x7
x
│
x
316:00
12:00
240 mL fluid intake, thereafter lunch3
x7
x
┼
x
x8
x
x
318:00
14:00
x7
x
│
320:00
16:00
Snack (voluntary)3
x7
x
┼
x8
x
x
322:00
18:00
Dinner3
│
324:00
20:00
x7
┼
x8
x
x
15
336:00
08:00
x
x7
▼
x8
x
x
16
360:00
08:00
x7
x
x
x
17
384:00
08:00
x7
x8
x
x
18
408:00
08:00
x
x7
x
x
19
432:00
08:00
x
x8
x
x
20
456:00
08:00
Breakfast3 (voluntary),
discharge from trial site11, 20
x7
x
x
x8
x
x
22
504:00
08:00
Ambulatory visit
x7
x
x
3
28 to 32
End of trial (EOT) examination4,11
x
x
x
x
x
x


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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.
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.
6.
Safety laboratory to be taken and to be medically evaluated within 4 days prior to first administration of BI 1358894. 
This safety laboratory can be omitted, if the screening examination is performed on Days -4, -3 or -2.
7.
At these time points, additional blood samples for metabolite identification will be taken (refer to Section 5.5.2.2). 
A blank sample is to be taken prior to any medication intake (Day -1).
8.
The ECG recording has to be performed as triple at this time point.
9.
Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject.
10.
A blank urine sample (x) is to be obtained on Day 1 prior to administration of BI trial medication. Other urine samples 
are to be collected on Day 1 over the post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12 and 12-24 h and on Day 14 
over the post-dose intervals (◄––│––│––►)312-316, 316-320, 320-324, and 324-336 h.
11.
Suicidality assessment only at screening, discharge from trial site and end of trial.
12.
Only drug screening and alcohol breath test.
13.
Prior to BI drug administration 3 triplicate ECGs are recorded within approximately one hour. The recordings should 
be separated by at least 15 minutes.
14.
Faecal laboratory testing (faecal occult blood and faecal calprotectin) will be done at screening, within 4 days prior to 
first dosing of BI 1358894 (i.e. Day -4 to Day -2), in the first stool released after 12 hours after administration on Days 
1, 4, 7, 10, and 14, on Day 16, and at EOT.
15.
Additionally, one blood sample will be taken for pharmacogenomic analyses.
16.
ECGs performed on Days 1 through 20 will be transferred to the central ECG lab for evaluation.
17.
At these time points, visual analogue scale assessments will be done at 08:00, 10:00 and 12:00.
18.
Only CRP.
19.
Trial drug will be administered after a standardized continental breakfast.
20.
Confirmation of fitness includes physical examination, neurological examination, Bond & Lader and Bowdle visual 
analogue scale, vital signs, ECG, recording of AEs and concomitant therapies. Evaluation of safety lab assessed on 
Day 15 and 18.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................16
1.2.1
BI 1358894 .............................................................................................16
1.2.1.1
Nonclinical pharmacology.......................................................16
1.2.1.2
Safety pharmacology ...............................................................16
1.2.1.3
Toxicology...............................................................................17
1.2.1.3.1 Single dose toxicity..................................................17
1.2.1.3.2 Repeat-dose toxicity studies.....................................17
1.2.1.3.3 Genotoxicity.............................................................19
1.2.1.3.4 Reproductive and developmental toxicity................19
1.2.1.3.5 Phototoxicity............................................................20
1.2.1.4
Nonclinical pharmacokinetics..................................................20
1.2.1.5
Clinical experience in humans.................................................21
1.2.1.6
Drug product ............................................................................28
1.2.2
Midazolam .............................................................................................28
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 29
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................29
2.2
TRIAL OBJECTIVES.......................................................................................30
2.3
BENEFIT - RISK ASSESSMENT ...................................................................31
2.3.1
Procedure-related risks ........................................................................31
2.3.2
Risks related to the intake of BI 1358894 and safety measures........31
2.3.2.1
Drug-related risks.....................................................................31
2.3.2.2
Risk minimization (safety precautions and stopping rules).....32
2.3.2.3
Drug induced liver injury.........................................................33
2.3.3
Overall assessment................................................................................33
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 35
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................35
3.1.1
Administrative structure of the trial...................................................37
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................38
3.3
SELECTION OF TRIAL POPULATION ......................................................38


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3.3.1
Main diagnosis for study entry............................................................39
3.3.2
Inclusion criteria...................................................................................39
3.3.3
Exclusion criteria ..................................................................................39
3.3.4
Removal of subjects from therapy or assessments.............................41
3.3.4.1
Removal of individual subjects................................................41
3.3.4.2
Discontinuation of the trial by the sponsor..............................41
3.3.5
Replacement of subjects .......................................................................42
4.
TREATMENTS........................................................................................ 43
4.1
TREATMENTS TO BE ADMINISTERED....................................................43
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................43
4.1.2
Method of assigning subjects to treatment groups ............................43
4.1.3
Selection of doses in the trial................................................................44
4.1.4
Drug assignment and administration of doses for each subject .......44
4.1.5
Blinding and procedures for unblinding ............................................46
4.1.5.1
Blinding ..................................................................................46
4.1.5.2
Procedures for emergency unblinding .....................................46
4.1.6
Packaging, labelling, and re-supply ....................................................47
4.1.7
Storage conditions.................................................................................47
4.1.8
Drug accountability ..............................................................................48
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................48
4.2.1
Other treatments and emergency procedures....................................48
4.2.2
Restrictions............................................................................................49
4.2.2.1
Restrictions regarding concomitant treatment .........................49
4.2.2.2
Restrictions on diet and life style.............................................49
4.3
TREATMENT COMPLIANCE.......................................................................49
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 51
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................51
5.1.1
Endpoints of efficacy.............................................................................51
5.1.2
Assessment of efficacy...........................................................................51
5.2
SAFETY..............................................................................................................51
5.2.1
Endpoints of safety................................................................................51
5.2.2
Assessment of adverse events...............................................................51
5.2.2.1
Definitions of adverse events...................................................51
5.2.2.2
Adverse event collection and reporting ...................................55
5.2.3
Assessment of safety laboratory parameters......................................56
5.2.4
Electrocardiogram................................................................................59
5.2.4.1
12-lead resting ECG.................................................................59
5.2.5
Assessment of other safety parameters...............................................61
5.2.5.1
Vital signs ................................................................................61
5.2.5.2
Orthostatic tests........................................................................61


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5.2.5.3
Visual Analogue Scale (VAS) .................................................62
5.2.5.4
Medical examinations..............................................................62
5.2.5.5
Suicidality assessment .............................................................62
5.2.5.6
Neurological examinations ......................................................62
5.3
OTHER...............................................................................................................63
5.3.1
Pharmacogenomic evaluation..............................................................63
5.3.1.1
Methods and timing of sample collection................................63
5.3.1.2
Analytical determinations........................................................63
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................64
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................64
5.5.1
Pharmacokinetic endpoints..................................................................64
5.5.1.1
Secondary endpoints................................................................64
5.5.2
Methods of sample collection...............................................................66
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................66
5.5.2.2
Plasma sampling for metabolism analysis ...............................67
5.5.2.3
Urine sampling for pharmacokinetic analysis..........................67
5.5.3
Analytical determinations ....................................................................68
5.5.3.1
Analytical determination of BI 1358894 plasma     
concentration............................................................................68
5.5.3.2
Analytical determination of BI 1358894 urine concentration .68
5.5.3.3
Analytical determination of midazolam plasma concentration68
6.
INVESTIGATIONAL PLAN.................................................................. 69
6.1
VISIT SCHEDULE............................................................................................69
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................69
6.2.1
Screening period....................................................................................69
6.2.2
Treatment period ..................................................................................69
6.2.3
End of trial period.................................................................................70
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 72
7.1
STATISTICAL DESIGN – MODEL ...............................................................72
7.1.1
Objectives...............................................................................................72
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................72
7.3
PLANNED ANALYSES....................................................................................72
7.3.1
Primary analyses...................................................................................73
7.3.2
Secondary analyses ...............................................................................73
7.3.3
Safety analyses.......................................................................................76
7.3.4
Preliminary PK analyses......................................................................77
7.3.5
Pharmacokinetic analyses ....................................................................78
7.4
HANDLING OF MISSING DATA ..................................................................78
7.4.1
Safety......................................................................................................78


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7.4.2
Plasma/urine drug concentration - time profiles ...............................78
7.4.3
Pharmacokinetic parameters...............................................................78
7.5
RANDOMISATION ..........................................................................................78
7.6
DETERMINATION OF SAMPLE SIZE ........................................................79
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 80
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................80
8.2
DATA QUALITY ASSURANCE .....................................................................80
8.3
RECORDS..........................................................................................................81
8.3.1
Source documents .................................................................................81
8.3.2
Direct access to source data and documents.......................................81
8.3.3
Storage period of records.....................................................................81
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................81
8.5
STATEMENT OF CONFIDENTIALITY.......................................................82
8.6
COMPLETION OF TRIAL..............................................................................82
9.
REFERENCES......................................................................................... 83
9.1
PUBLISHED REFERENCES...........................................................................83
9.2
UNPUBLISHED REFERENCES.....................................................................84
10. APPENDICES .......................................................................................... 86
10.1
DRUG SUPPLIES USED FOR DILUTION AND ANALYTICAL 
TESTING............................................................................................................86
10.1.1 Drug supplies overview.........................................................................86
10.1.2 Required equipment and dosing aids – overview...............................87
10.1.3 Dilution procedure................................................................................88
10.1.4 In-use stability.......................................................................................89
10.1.5 Mode of application ..............................................................................89
10.2
VISUAL ANALOGUE SCALE (VAS) ............................................................90
10.3
BOWDLE VAS-SCORE ...................................................................................91
10.4
COLUMBA-SUICIDE SEVERITY RATING SCALE..................................92
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 98


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2
Amount of analyte eliminated in urine over the time interval t1 to t2
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24h
%AUCtz-∞
the percentage of AUC0-∞obtained by extrapolation
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
Borderline personality disorder
CA
Competent authority
CI
Confidence interval
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
Cmin
Minimum measured concentration of the analyte in plasma
CML
Local clinical monitors
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
CRA
Clinical research associate
CRF
Case report form
CRO
Clinical Research Organization
C-SSRS
Columbia Suicidal Severity Rating scale
CTP
Clinical trial protocol
CTR
Clinical trial report


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CV
Arithmetic coefficient of variation
DDI
Drug-drug interaction
DG
Dose group
DILI
Drug induced liver injury
ECG
Electrocardiogram
ECT
Electro-convulsive therapy
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
FDA
Food and Drug Administration
fet1-t2
Fraction of administered drug excreted unchanged in urine over the time 
interval from t1 to t2
FIH
First in human
FST
Forced swim test
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GLP
Good laboratory practice
gMean
Geometric mean
GMP
Good Manufacturing Practice
hERG
human ether-a-go-go related gene
HR
Heart rate
IB
Investigator’s brochure
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LVSP
left ventricular pressure parameters 
MDD
Major depressive disorder
MDZ
Midazolam
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
MRTex
Mean residence time of the analyte in the body after extravascular/oral 
administration
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available


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PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
PR
Pulse rate
q.d.
Quaque die, 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
RA
Accumulation ratio of the analyte in plasma after multiple dose 
administration over a uniform dosing interval τ
RR
Respiratory rate
SAE
Serious adverse event
SCR
Screening
SRD
Single-rising dose
SOP
Standard Operating Procedure
ss
(at) steady state
T
Test product or treatment
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
tz
Time of last measurable concentration of the analyte in plasma
TDMAP
Trial Data Management and Analysis Plan
TRPC
transient receptor potential cation channel
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VAS
Visual Analogue Scale
Vz/F,ss
Apparent volume of distribution during the terminal phase at steady state
after extravascular administration


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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).
MDD is a debilitating disease characterised by low mood and often by low self-esteem, low
energy, and a loss of interest. It can strongly impact a person’s life and health, including 
significantly increased risk of suicidality, and is difficult to treat, even with systematic 
antidepressant strategies. In the 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 residual 
symptoms [R16-5475] that 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 severely impaired 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, 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, treatment 
with BI 1358894 has the potential to improve affective symptoms and emotion control in
patients with MDD and BPD.


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1.2
DRUG PROFILE
1.2.1
BI 1358894
1.2.1.1
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. 
BI 1358894 was profiled using patch clamp electrophysiology and was shown to be a highly 
potent inhibitor of TRPC4 and TRPC5 without species selectivity. In cells expressing human 
TRPC4 and TRPC5 and stimulated with carbachol, the IC50 was 1.2 nM (hTRPC4) and 
0.2 nM (hTRPC5), respectively. 
BI 1358894 was investigated in several standard behavioural tests in rodents, such as Forced 
Swim Test (FST) [n00252903], Marble Burying Test [n00252207] and Elevated Plus Maze 
Test [n00252277]. The in vivo pharmacology studies demonstrated consistent 
pharmacological effects in line with anxiolytic and/or antidepressant efficacy. In the FST, 
half maximal efficacy was demonstrated at a plasma exposure of 77 nM, indicating that at
this plasma exposure, free brain levels are in the range of the in vitro IC50 [n00253628].
BI 1358894 is highly selective against more than 10 ion channels (including other TRPs, 
potassium channels, calcium channels and sodium channels) with more than 1000-fold 
selectivity for TRPC4 and at least 200-fold selectivity for TRPC5 [n00248384]. The effect of 
BI 1358894 on more than 120 targets was evaluated at 1 µM [n00252179]. BI 1358894 was 
shown to be highly selective.
1.2.1.2
Safety pharmacology
General and safety pharmacology studies have been conducted with BI 1358894 to address 
the core battery of CNS [n00253725], cardiovascular [n00253723, n00253727, n00253734], 
renal and hepatic [n00253732], respiratory [n00253732], and GI function [n00253729]. The 
results demonstrated an acceptable profile for clinical trials in healthy volunteers.
BI 1358894-related effects on the central nervous system (CNS) of rats were limited to an 
early and transient increase of motility at dose levels of 10, 30, and 100 mg/kg (nocturnal 
motility test). This was considered to reflect an increased arousal or decreased anxiety in a
novel environment associated with the intended efficacy (anti-depressive and anxiolytic 
effect). The absence of detectable locomotor effects in the two Modified Irwin studies might 
be due to differences in the study design.
In the cardiovascular (CV) rat study, long-lasting decreases in arterial blood pressure 
(10 mm Hg) were present at 10 mg/kg. Additionally, BI 1358894 induced dose-dependent 
and long-lasting increases in heart rate (15 – 20 b.p.m.) in rat and dog at 30 mg/kg after 
single oral dose in the general pharmacology studies. However, increase in heart rate was no 
longer detectable after 4-day repeat-dosing in rats at 30 mg/kg. In rat telemetry at 100 mg/kg, 
transient increases in PR duration and body temperature were noted. None of the


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cardiovascular findings could be confirmed in dog safety pharmacology or toxicity studies. 
Other ECG parameters, including QT and QTc intervals, and left ventricular pressure 
parameters (LVSP and dP/dtmax) were not affected by BI 1358894.
Transient effects of BI 1358894 on the respiratory function (increases in respiratory rate and 
minute volume) were seen in male rats treated with 1000 mg/kg.
Altered electrolyte (Cl-, Na+, Ca2+) and urea urinary excretion at 10 mg/kg was regarded to 
be indicative of a change in rat renal function. Increases in total and conjugated bilirubin 
levels were not reproduced after repeated dosing for 4 weeks. Rat kidney and liver injury 
biomarkers were not altered. No structural degenerative correlates were present in the 
microscopic examination in toxicity studies.
Dose-dependent decreased gastric emptying was noted at 30 mg/kg (-22%) and 100 mg/kg 
(-29%). No effects on consistency of intestinal contents and intestinal transit were noted at 
any dose level.
The influence of BI 1358894 on human ether-a-go-go related gene (hERG)-mediated 
potassium current in stably transfected CHO cells (Chinese hamster ovary) was determined to 
evaluate the potential proarrhythmic risk [n00253752]. The IC50 for tail current inhibition 
was 1.15 µM, suggesting a selectivity ratio of about 200 against hERG-encoded channel 
[hTRCP 1/5 = 5 nM]. These preclinical data do not suggest a proarrhythmic risk.
1.2.1.3
Toxicology
The nonclinical safety program investigating the in vivo toxicological profile of BI 1358894 
comprised repeat-dose studies up to 4 weeks of once daily oral (gavage) treatment and a 
complete battery of in vitro and in vivo studies assessing the genotoxic potential of the 
compound. Additionally, a 4-week oral repeat-dose (non-GLP) study in mice was performed.
Rats and dogs were employed as the animal species for general toxicology investigations on 
BI 1358894, because in vitro and in vivo profiling supported the suitability of both species 
for nonclinical safety profiling of BI 1358894. 
1.2.1.3.1
Single dose toxicity
No single dose toxicity assessments have been conducted with BI 1358894. Relevant 
information was obtained from the repeat-dose toxicity studies in mice, rats, and dogs. The 
maximum tolerated dose was considered to be above 2000 mg/kg in rodents, the highest 
tested dose. In dogs, oral administration of 500 mg/kg was discontinued after 11 days due to 
prominent clinical signs. Systemic drug exposure at that dose level was 385-fold for Cmax and 
596-fold for AUC0-24h compared to predicted therapeutic exposure (please see Section 5.3.9 
of the Investigator's Brochure [c10354149].
1.2.1.3.2
Repeat-dose toxicity studies 
Repeat dose non-GLP toxicity study in mice, rats and dogs revealed toxicologically relevant 
effects on the skin, Harderian glands, and hepatic function in mice, the vascular system in 


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rats, the CNS function in dogs, and the digestive tract in all three species. In addition, 
haematology evaluation revealed increases of WBC counts in all species.
A 4-week toxicity testing in mice identified skin, Harderian glands, and gastrointestinal tract 
as main target organs in this species at doses 500 mg/kg QD. Clinical pathology evaluation 
indicated a slight to moderate increase in plasma total bilirubin, but without any microscopic 
degenerative correlate. Administration of BI 1358894 was clinically well tolerated up to 
1500 mg/kg. Minimal to slight epidermal hyperplasia was observed in the skin. In the 
Harderian glands, crystal deposits (mainly a carboxylic acid metabolite of BI 1358894) 
induced minimal to severe degeneration and necrosis of the glandular tissue. A metabolite of 
BI 1358894 was the major compound-related constituent as shown by mass spectrometry 
analysis. Due to the species-specific metabolism, this mouse finding was considered to be of 
limited toxicological relevance. Multifocal erosion/ulceration, graded minimal to slight in 
severity, affected the mucosa of the stomach and the intestine and minimal to moderate 
epithelial vacuolation of the villi and minimal villous atrophy were present in the duodenum. 
Other BI 1358894-related pathological findings in the hematopoietic and lymphoid organs (at 
7 mg/kg) associated with increased reticulocyte and WBC counts in blood, the liver (at 
30 mg/kg), and the heart (at 1500 mg/kg) were regarded as non-adverse due to their 
adaptive character. 
Repeat-dose toxicity testing in rats revealed no serious clinical signs of toxicity, no 
toxicologically relevant effects on body weight and food and water consumption, and no 
ophthalmology findings were noted. The main findings in clinical pathology were indicative 
of a minimal inflammatory response starting at 200 mg/kg, characterised by leukocytosis, 
hyperproteinaemia, and hyperglobulinemia. On Day 5 after the start of treatment, minimal to 
moderate periarterial inflammation was present in the mesentery, pancreas, and/or liver at 
30 mg/kg, with dose-related increases in incidence and severity. In a few animals given 
200 mg/kg, arterial inflammation and necrosis focally affected the pancreas and the serosa 
of the intestine. In a 4-week DRF 'reversibility' study where animals were sacrificed and 
microscopically examined on Day 5 and at the end of the treatment period (Day 28), 
perivascular/mesenteric inflammation induced by BI 1358894 occurred early after start of 
dosing and resolved over 4 weeks despite continued treatment, indicating the transient 
character of the inflammation. Other BI 1358894-related pathological findings in the kidneys 
(at 7.5 mg/kg), the heart and the liver (at 30 mg/kg), and the mandibular glands (at 
1000 mg/kg) were considered to be non-adverse due to their adaptive character, low 
magnitude, and/or absence of pathological correlates. All changes were fully reversible or 
greatly ameliorated over a 4-week off-treatment recovery period. 
In repeat-dose toxicity testing in dogs, no spontaneous deaths occurred up to 1000 mg/kg, the 
highest tested dose, administered for 11 days. Decreased body weight, reduced food 
consumption and faecal alterations occurred at 150 mg/kg. Distinct clinical signs of toxicity 
were present at 500 mg/kg, starting on the 3rd day of treatment (gait abnormalities, 
decreased motor activity, one episode of convulsions, trembling). In addition, a territorial 
behaviour was shown by dogs administered 150 mg/kg over 4 weeks. Pathology and clinical 
pathology investigations did not reveal any pertinent findings which could have explained the 
clinical signs. Administration of BI 1358894 did not result in any pertinent changes in 
ophthalmology and cardiovascular investigation. Clinical pathology evaluation revealed a 


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limited number of changes at 500 mg/kg: moderate decreases in reticulocyte counts, 
minimal increases in WBC and neutrophil counts, slight increases in phosphate and minimal 
decreases in calcium levels in the blood, and slightly to moderately reduced urinary sodium 
and chloride excretion. Few relevant BI 1358894-related histopathological findings were 
noted at 500 mg/kg, namely (multi)focal minimal to slight erosion/ulceration in the oral 
cavity, esophagus and duodenum. Changes observed in the thymus (decreased weight, 
reduced size, lymphoid depletion), the spleen (decreased weight), the liver (decreased 
glycogen content), and the salivary glands (secretory depletion) were regarded as unspecific 
response to stress or secondary to reduced food consumption. No BI 1358894-related 
findings were observed during a 4-week recovery period.
An overview of estimated safety margins (exposure multiples) is presented in 
Table: 1.2.1.3.2: 1 below. The comparison revealed safety margins of ≥9 for Cmax and for 
AUC0-24h.
Table 1.2.1.3.2: 1
Overview of estimated safety margins (exposure multiples) for 
BI 1358894 based on the NOAELs of the 4-week oral toxicity studies 
in rats and dogs and the 4-week oral DRF study in mice
Species
NOAEL
[mg/kg]
Mean Cmax
at NOAEL [nM] 
in m/f
Mean AUC0-24h
at NOAEL 
[nM∙h] in m/f
Human to Animal Safety 
Margin in m/f
Based on 
multiples of 
Cmax 
Based on 
multiples of 
AUC0-24h
Rat
30
1960 / 3600
26300 / 53900
9 / 17
9 / 19
Dog
30
7190 / 4240
137000 / 57300
34 / 20
49 / 20
Mouse
30
7750 / 6270
89400 / 101000
37 / 30
32 / 36
m: male; f: female; safety margins related to predicted human exposure at therapeutic dose (35 mg QD)
1.2.1.3.3
Genotoxicity
The genotoxic potential of BI 1358894 was investigated in an ICH-compliant test battery of 
in vitro and in vivo studies (for details see Section 5.3.9 of the Investigator's Brochure, 
[c10354149]. There was no evidence that BI 1358894 is associated with genotoxic activity.
1.2.1.3.4
Reproductive and developmental toxicity
Dose range finding studies for effects of BI 1358894 on embryofetal development have not 
been conducted. There was no indication from the pivotal (GLP) 4-week toxicity studies in 
rats and dogs that oral administration of BI 1358894 was associated with morphological 
changes in reproductive organs of both sexes.


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1.2.1.3.5
Phototoxicity
BI 1358894 is unlikely to cause phototoxicity. For a more detailed description of the 
BI 1358894 profile please refer to the current Investigator’s Brochure [c10354149].
1.2.1.4
Nonclinical pharmacokinetics
Drug Absorption and Disposition
The disposition of BI 1358894 is characterized in rats by low clearance and moderate volume 
of distribution. High oral bioavailability (81.9 %) in rats suggests an at least moderate 
bioavailability in humans. The plasma protein binding of BI 1358894 was high in all 
investigated species, with unbound fractions of 0.26 % (mouse), 0.42 % (rat), 0.31 % (dog),
and 0.25 % (human). 
In a quantitative whole body autoradiography study, the extent of distribution of 
[14C]BI 1358894 from plasma into tissues was considered to be moderate [n00252628]. 
Highest concentrations of radioactivity were found in the Harderian gland (up to 27 times 
higher than in plasma), the liver (up to 14 times), and the walls of the gastrointestinal tract 
(up to 9.4 times higher than in plasma). Lowest tissue-to-plasma ratios were found in total 
eyeball (1% of plasma level), nasal mucosa (3%), and CNS (11% to 23%).
While the total eyeball was exposed to drug-related radioactivity throughout the entire time-
frame of investigation, drug-related radioactivity in the skin was below the limit of 
quantification. Qualitative evaluation of the autoradiograms, however, revealed discernible 
photo-luminescence signals in lipid-rich parts of the skin until the last time-point of 
investigation. 
The terminal half-lives for BI 1358894 in rats were 6.21 h (male) and 7.91 h (female) and 
longer for [14C] BI 1358894 – related radioactivity with 14.0 h (male) and 14.2 h (female). 
The fraction of total exposure for BI 1358894 ([14C]BI 1358894 – related radioactivity) was 
31% (males) and 49% (females). Similar proportions of parent compound and drug-related 
radioactivity after oral and intravenous administration indicated a low first pass effect.
After intravenous (short term infusion) administration, 0.8% of the total administered 
radioactive dose was excreted in the urine within 24 h. In faeces, 55.7% (males) or 45.4% 
(females) of the total dose was recovered within 24 h. Excretion was slow, with a faecal
excretion of 81.4% (mean of males and females) within 168 h. The biliary excretion in 
anesthetized rats was 12.4% (males) or 16.5% (females) of the dose within 6 h.
Potential pharmacokinetic interactions
The inhibition potential of BI 1358894 was investigated for human CYP enzymes 
CYP1A1/2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 [n00253492]. BI 1358894 was a 
competitive in vitro inhibitor of CYP2C9, 2C8, 2D6, 2C19 and 2B6 with Ki values of 
3.71 μM (CYP2C9), 4.82 μM (CYP2C8), 5.51 μM (CYP2D6), 10.1 μM (CYP2C19) and 
13.6 μM (CYP2B6). Due to binding of BI 1358894 to plastic surfaces and microsomal 
protein, the actual concentrations of BI 1358894 in incubations were lower than the nominal 
concentrations. Therefore, it has to be taken into account that the actual Ki data could be 


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slightly lower than the measured values. Irreversible inhibition by BI 1358894 was not 
observed for any of the CYP enzymes under investigation. Depending on the level of 
exposure during drug therapy, in vivo inhibition of multiple CYP enzymes by BI 1358894 
may be possible.
The in vitro potential of BI 1358894 and the metabolite BI 1361608 to induce rat CYP 
enzymes (CYP1A1, 2B1, 2C7, 2C11, 2D1, 2E1, 3A1/2, 4A) in rat hepatocytes was 
investigated [n00253490]. An induction potential towards CYP3A1 mRNA was seen with 
BI 1358894 concentration-dependent at high concentrations of ≥5 μM, and to a lesser extent 
with BI 1361608 at 20 μM.
The potential for BI 1358894 to induce human CYP enzymes was investigated in vitro at 
BI 1358894 concentrations up to 100 µM using sandwich cultured human hepatocytes 
prepared from three donors. BI 1358894 was not an inducer of CYP1A2 but might be a weak 
inducer for both CYP2B6 and CYP2C8. BI 1358894 was an inducer of CYP3A4 mRNA and 
enzyme activity up to 25 μM [n00256526].
1.2.1.5
Clinical experience in humans
An FIH (first-in-human) trial [Trial 1402.1; c13880029] is currently being conducted to 
explore the safety, tolerability, and pharmacokinetics (PK) of single rising oral doses of 
BI 1358894 in healthy male subjects (single-blind, partially randomised, placebo-controlled 
parallel group design) and to evaluate the effect of food on the relative bioavailability of  
BI 1358894 (open-label, randomised, two-way cross-over design). The SRD part of the study 
has been completed involving 55 subjects in 7 dose groups with single oral doses of 3 mg, 
6 mg, 10 mg, 25 mg, 50 mg, 100 mg or 200 mg of BI 1358894 administered under fasted 
conditions. In each of the 7 dose groups 6 subjects were assigned to BI 1358894 and 2 
subjects to placebo. At a dose level of 200 mg, the SRD part was stopped because of a less 
than dose proportional increase in exposure (Cmax and AUC0-24), which was considered to be 
possibly related to a reduced solubility of the film-coated tablets under fasting conditions. 
The further dose escalation in the SRD part was not stopped because of safety issues. Up to a 
single dose of 200 mg administered under fasting conditions, BI 1358894 was safe and well 
tolerated in all doses. There were no SAEs or dose limiting AEs. In accordance with the trial 
protocol, the study continued with the FE food effect (FE) part at a dose level of 50 mg and 
100 mg of BI 1358894 administered under fasted and fed conditions, according to an open-
label, two-period crossover design. Since in this dose group no dose limiting no safety signals 
precluding a further dose escalation of BI 1358894.
With 100 mg of BI 1358894 tested under fed conditions, a geometric mean exposure of 
AUC0-24 of 6780 nmol*h/L and Cmax of 517 nmol/L was observed, i.e. close to the exposure 
limit (AUC0-24 = 9500 nmol*h/L, Cmax = 980 nmol/L) specified in the former trial protocol. A 
further dose escalation such as 200 mg of BI 1358894 administered under fed conditions was 
expected to exceed the former exposure limit. Based on the available clinical safety data of 
trial 1402-0001 presented herein, BI considered it justified to further increase the maximum 
acceptable exposure limit and to included also a dose group receiving 200 mg under fed 
conditions.


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Safety evaluations of Trial 1402.1 included physical examination, vital signs, ECG, 
laboratory tests, and adverse events. Data analysis from this study is currently on-going. In 
the tested dose range, BI 1358894 was well tolerated with a low frequency of AEs in all dose 
groups. There were no AEs considered to be dose limiting and no SAEs; all subjects 
completed the study per protocol.
Adverse Events
There were no AEs considered to be dose limiting and no SAEs. All subjects completed the 
study per protocol. All AEs were of mild to moderate intensity; no AE of severe intensity was 
reported. 
The following results were observed (see also Table 1.2.1.5: 1 and Table 1.2.1.5: 2 for a more 
detailed overview of AEs):

In the SRD part, 22 of 42 subjects on BI 1358894 and 3 of 13 subjects on placebo 
reported at least one AE.

In the FE part, 16 of 20 subjects (all on BI 1358894) reported at least one AE. The 
higher prevalence of AEs in the FE part compared to the SRD part might be related to 
the two treatment periods and the longer period of safety monitoring.

SRD: The frequency of subjects with at least one AE in the highest dose group 
(200 mg fasted) was comparable to the 50 mg and 100 mg fasted dose groups.

Food Effect: The frequency of subjects with at least one AE in the 50 mg dose group 
(fasted and fed period) was higher compared to the SRD part. In contrast, the 
frequency of subjects with at least one AE in the dose group 100 mg (fasted and fed 
period) was similar to the SRD part. The subjects with the highest exposure (100 mg 
fed period) had a slightly lower frequency of adverse events compared to the fasted 
period.

At the System Organ Class (SOC) level, the most frequently reported AEs were 
nervous system disorders, reported in 21 subjects in the SRD part (19 of 42 subjects 
on BI 1358894 and 2 of 13 subjects on placebo) and 16 of 20 subjects in the FE part 
(all on active). 

At the Preferred Term (PT) level, the following AEs were observed in more than one 
subject:
Headache in 18 subjects in the SRD part (17 of 42 subjects on active and 1 of 
13 subjects on placebo) and in 15 of 20 subjects in the FE part (all on active),

Dizziness in 3 subjects in the SRD part (2 of 42 subjects on active and 1 of 
13 subjects on placebo) and 7 of 20 subjects in the FE part (all active),

Fatigue in 3 subjects in the FE part (all on active), and

Disturbance in attention in 2 subjects in the FE part (all on active).

No dose dependent increase in frequency was observed for any of these AEs.


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
AEs of moderate intensity were mainly observed in subjects on BI 1358894:

Injury due to a cycling accident in one subject 6 days after dosing (6 mg 
SRD);

Syncope because of a vasovagal reaction during blood drawing in one subject 
on placebo (25 mg dose group, SRD);

Back pain in one subject 2 days after dosing, resolved in 11 hours (50 mg 
SRD);

Nasopharyngitis in one subject 4 days after dosing (100 mg, FE, fasted).

Headache in 10 subjects (2 SRD, 8 FE, all on active) with an onset mostly 
4-7 hours after dosing and resolved mainly within a few hours.
There were no protocol-specified AEs of special interest (AESI) and no other significant AEs 
according to ICH E3. Per protocol AESI was hepatic injury, as defined by AST and/or ALT ≥
3-fold ULN combined with total bilirubin ≥2-fold ULN, and/or aminotransferase elevations ≥
10 fold ULN.
There were isolated events of apathy, auditory disorder and abnormal dreams in 3 subjects 
treated with either 3 mg or 6 mg of BI 1358894. Since no comparable events were reported 
for the remaining dose groups up to a single dose of 200 mg of BI 1358894 and due to the 
lack of a temporal relationship between dosing and event, these events are considered as 
chance findings and not drug related. Further, no changes in the Bowdle-VAS were seen for 
these subjects.
Additional Safety Assessments
There were no clinically relevant changes of lab values. In particular there were no changes 
of ESR or CRP suggesting an inflammatory event.
Explorative analysis of the Bowdle-VAS scores showed a comparable pattern between 
subjects across all dose groups. There were in particular no abnormalities for the score 
‘feeling high’ and ‘changes of perception’, which may indicate psychedelic effects. The 
occasional occurrence of ‘drowsy’ was evenly distributed between active and placebo.
The suicidality assessment based on C-SSRS did not reveal an individual subject who 
developed suicidal ideation by end of the study.
ECGs recorded from Day 1 pre-dose until Day 2 /34h post-dose were analyzed centrally. 
After each dose group absolute values and changes in ECG parameters were reported by the 
ECG core lab to the sponsor and CRO. No dose dependent trend of a possible QTcF 
prolongation was observed (the maximum individual QTcF interval across all dose groups of 
the SRD part was 432 ms, and for the FE part 450 ms). 
Based on the prespecified criteria of the trial protocol orthostatic testing did not reveal a 
subject with a positive test after dosing, i.e. no reduction in systolic BP of ≥20 mm Hg or in 
diastolic BP of ≥10 mm Hg within 3 minutes of standing , no orthostatic symptoms and no 
increase of heart rate > 100/min during orthostatic testing. Monitoring of vital signs and 
adverse events conducted in the further course of the study did also not reveal findings 


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suggesting orthostatic effects of BI 1358894. The data on treatment emerging adverse events 
in the SRD part covering dose groups 1 to 7 are displayed in Table 1.2.1.5: 1 as well as the 
adverse events in the FE part are depicted in Table 1.2.1.5: 2.
Table 1.2.1.5: 1
Preliminary frequency [N (%)] of subjects with adverse events treated 
with BI 1358894 or placebo - FIH Trial 1402-0001
System Organ Class,
Preferred Term
Placebo
(N=13)
BI 3mg 
(DG1)
(N=6)
BI 6mg 
(DG2)
(N=6)
BI 10mg 
(DG3)
(N=6)
BI 25mg
(DG4)
(N=6)
BI 50mg 
(DG5)
(N=6)
BI 100mg 
(DG6)
(N=6)
BI 200mg 
(DG7)
(N=6)
Total with adverse 
events
3 (23.1)
3 (50.0)
6 (100.0)
0 (0.0)
2 (33.3)
4 (66.7)
4 (66.7)
3 (50.0)
Nervous system 
disorders
2 (15.4)
2 (33.3)
5 (83.3)
0 (0.0)
2 (33.3)
3 (50.0)
4 (66.7)
3 (50.0)
Headache
1 (7.7)
2 (33.3)
4 (66.7)
0 (0.0)
2 (33.3)
3 (50.0)
3 (50.0)
3 (50.0)
Dizziness
1 (7.7)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Head discomfort
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Syncope
1 (7.7)
0 (0.0)
0 (0.0%)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Musculoskeletal and 
connective tissue 
disorders
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
2 (33.3)
0 (0.0)
0 (0.0)
Back pain
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Pain in extremity
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Ear and labyrinth 
disorders
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Auditory disorder
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Gastrointestinal 
disorders
2 (15.4)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Oral discomfort
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Abdominal pain
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Abdominal pain upper
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Nausea
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
General disorders and 
administration site 
conditions
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Fatigue
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Injury, poisoning and 
procedural 
complications
1 (7.7)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Limb injury
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Road traffic accident
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Vascular procedure 
complication
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Psychiatric disorders
0 (0.0)
1 (16.7)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Abnormal dreams
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Apathy
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Metabolism and 
nutrition disorders
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Decreased appetite
1 (7.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)


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Table 1.2.1.5: 2
Frequency [N (%)] of subjects with adverse events treated with 
BI 1358894– FE part
System Organ Class,
Preferred Term
BI 50mg 
(fast)
(N=8)
BI 50mg 
(fed)
(N=8)
BI 100mg 
(fast)
(N=12)
BI 100mg 
(fed)
(N=12)
Total with adverse events
7 (87.5)
7 (87.5)
8 (66.7)
6 (50.0)
Nervous system disorders
7 (87.5)
7 (87.5)
8 (66.7)
5 (41.7)
Headache
7 (87.5)
6 (75.0)
7 (58.3)
4 (33.3)
Dizziness
3 (37.5)
2 (25.0)
3 (25.0)
2 (16.7)
Disturbance in attention
2 (25.0)
0 (0.0)
0 (0.0)
0 (0.0)
Head discomfort
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Paraesthesia
1 (12.5)
0 (0.0)
0 (0.0)
0 (0.0)
Skin and subcutaneous tissue 
disorders 
0 (0.0)
2 (25.0)
0 (0.0)
1 (8.3)
Pruritus generalised
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Rash macular
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Skin reaction
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Acne
0 (0.0)
0 (0.0)
0 (0.0)
1 (8.3)
General disorders and 
administration site conditions
1 (12.5)
0 (0.0)
0 (0.0)
2 (16.7)
Fatigue
1 (12.5)
0 (0.0)
0 (0.0)
2 (16.7)
Musculoskeletal and connective 
tissue disorders
0 (0.0)
1 (12.5)
2 (16.7)
0 (0.0)
Musculoskeletal chest pain
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Arthralgia
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Back pain
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Gastrointestinal disorders
1 (12.5)
1 (12.5)
0 (0.0)
0 (0.0)
Flatulence
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Nausea
1 (12.5)
0 (0.0)
0 (0.0)
0 (0.0)
Infections and infestations
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Nasopharyngitis
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Dose Groups 2, 3 and 6 already have sample results available up to 192 h and, therefore, were 
used to calculate PK parameters dependent on the terminal rate constant (lambda z). Half-life 
as calculated from these 3 DGs is around 45 to 52h (gMean) and appears to be independent of 
dose.


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


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Table 1.2.1.5: 4
Summary of gMean (gCV %) PK parameters of 50 mg and 100 mg 
BI 1358894 administered under fasted conditions and after a high 
calorie, high fat meal [relative BA food effect part; clinical trial 
1402-0001]
Dose [mg]/
condition
50 mg
Fasted
(N=8)
50 mg
Fed
(N=8)
100 mg
Fasted
(N=12)
100 mg
Fed
(N=12)
AUC0-24 [nmol*h/L]
1570 (36.7)
2980 (25.1)
2350 (40.6)
6780 (12.2)
AUC0-24/D 
[nmol*h/L/mg]
31.4 (36.7)
59.6 (25.1)
23.5 (40.6)
67.8 (12.2)
AUC0-72 [nmol*h/L]
3120 (20.9)
5110 (28.9)
4600 (49.2)
11600 (14.8)
AUC0-72/D 
[nmol*h/L/mg]
62.4 (20.9)
102 (28.9)
46.0 (49.2)
116 (14.8)
AUC0-∞[nmol*h/L]
5060 (29.3)
7900 (42.9)
6930 (54.6)*
17200 (21.8)
AUC0-∞/D 
[nmol*h/L/mg]
101 (29.3)
158 (42.9)
69.3 (54.6)*
172 (21.8)
Cmax [nmol/L]
149 (59.4)
237 (24.9)
210 (38.8)
517 (8.61)
Cmax/D [nmol/L/mg]
2.99 (59.4)
4.74 (24.9)
2.10 (38.8)
5.17 (8.61)
tmax [h]1
5 (1-5)
5 (2.98-6)
2.5 (1-6)
6 (0.5-7)
t1/2
71.2 (24.7)
74.4 (27.7)
68.9 (34.6)*
66.7 (25.8)
MRTpo
82.5 (24.1)
76.7 (35.9)
78.8 (30.8)*
70.1 (29.4)
*N=11 due to drop out of subject #
 PK samples of this subject up to 96 hours available only
Table 1.2.1.5: 5
Summary of preliminary statistical evaluation of food effect [FE part] 
– adjusted by-treatment geometric means and relative bioavailability
Dose
PK 
Parameter
Fasted 
adjusted 
gMean
Fed adjusted 
gMean
Ratio 
fed/fasted
90 % Confidence Interval
50 mg 
(n = 8)
Cmax
149 nmol/L
237 nmol/L
1.59 
1.14
2.21
AUC0-24
1570 nmol*h/L
2982 nmol*h/L
1.90
1.46
2.47
AUC0-72
3121 nmol*h/L
5112 nmol*h/L
1.64
1.38
1.94
AUC0-C
5059 nmol*h/L
7904 nmol*h/L
1.56
1.32
1.85
100 mg 
(n = 12)
Cmax
210 nmol/L
517 nmol/L
2.46
2.03
2.98
AUC0-24
2353 nmol*h/L
6777 nmol*h/L
2.88
2.36
3.51
AUC0-72
4601 nmol*h/L
11598 nmol*h/L
2.52
2.04
3.12
AUC0-C
6966 nmol*h/L
17232 nmol*h/L
2.47
2.00
3.06


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1.2.1.6
Drug product
Please refer to Section 4.1. For a more detailed description of the BI 1358894 profile, please 
refer to the current IB [c10354149].
Residual Effect Period 
The Residual Effect Period (REP) of BI 1358894 is approximately 14 days. This is the period 
after the last dose where measurable drug levels and/or pharmacodynamic effects are still likely 
to be present.
1.2.2
Midazolam
Midazolam is a sensitive substrate of CYP3A4, used both in vitro and in vivo as a probe drug 
for CYP3A4 drug interactions. Absorption is rapid, with maximum concentrations reached 
around 15 to 30 min. Clearance is also rapid, with an elimination half-life of 1.5 to 2.5 hours. 
The PK of midazolam is dose proportional over a range of at least 0.1 µg to 3 mg 
[R17-3022]. For further information, refer to the summary of product characteristics 
[R17-3087].


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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] 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
This is the second trial with BI 1358894 and the first with multiple dose administration. The 
objective of this trial is to investigate the safety, tolerability, and pharmacokinetics of 
BI 1358894 in healthy male subjects. The chosen population of healthy male volunteers using 
multiple rising oral doses is considered adequate to provide the basis for the clinical 
development program of BI 1358894. This trial will provide pharmacokinetic information in 
healthy volunteers at steady state exposure.
The FIH trial is currently on-going (see Section 1.2.1.5) to explore the safety, tolerability, and 
pharmacokinetics of BI 1358894 following single oral doses up. The originally planned 
maximum dose was 600 mg of BI 1358894, but dose escalation was stopped at the 200 mg 
dose level because of a less than dose proportional increase in exposure. The study will 
continue with exploring the food effect in the already tested dose range. At the time of 
preparation of this protocol, the dose levels up to 200 mg (fasted) had been completed. 
According to preliminary data, BI 1358894 was safe and well tolerated up to the maximum 
tested dose of 200 mg of BI 1358894 administered under fasted conditions. There were no 
dose-limiting AEs and no SAEs.
Based on in vitro screening data, BI 1358894 is an inducer of CYP3A4 (for details, refer to 
Section 1.2.1.4). To exclude a clinically relevant CYP 3A4 modulation with BI 1358894 as 
perpetrator, effect of BI 1358894 on midazolam metabolism will be assessed. Therefore, 
subjects will receive a microdose of midazolam at the start, during, and at the end of 
treatment with BI 1358894.
The pharmacokinetic and safety data obtained in this study will help to define appropriate 
doses for further studies with this compound.
Dose Selection
As stated above, it is intended to investigate the safety and tolerability of 10 mg, 25 mg, 
50 mg, 100 mg, and 200 mg q.d. over 14 days. The background for this dose selection is 
described in the following. The EC50 of 77 nM derived from PK/PD modelling of data 
derived from the mouse Forced Swim Test was set as pharmacologically threshold target 
concentration in humans at 16 hours after dosing (beginning of sleeping phase). The current 
assumption is that this will translate to an effective exposure of a Cmax,ss of 210 nM and an 
AUCss of 2830 nM·h in humans. 


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Starting dose
Based on preliminary PK results of the ongoing SRD study, the intended starting dose of 
10 mg q.d. Cmax (59.7 nM) and AUC0-24 (399.7 nM·h) is expected to be significantly lower 
than the predicted therapeutic exposure in humans. These data were obtained under fasting 
conditions. Because of a less than dose proportional increase of Cmax under fasting 
conditions, the planned MRD study will be conducted under fed conditions (assuming a 
positive food effect for the poorly soluble compound, evaluation in SRD study ongoing). A 
low starting dose of 10 mg of BI 1358894 is considered to assure that the exposure will 
remain below the predicted effective exposure in humans, even in case of a relevant food 
effect or an accumulation after repeated dosing because of the observed long terminal half-
life of about 40 h (see Section 1.2.1). Thus, it is considered unlikely that a multiple dose of 
10 mg q.d. of BI 1358894 will exceed the already tested maximum exposure of the ongoing 
SRD study. At the time of first dosing of the MRD study, food effect data obtained with a 
single dose of 50 mg and 100 mg of BI 1358894 will become available. These upcoming data 
are expected to further justify the planned starting dose of 10 mg q.d.. In addition, the 
planned MRD study will only include doses already tested in the SRD study under fed 
conditions. 
Maximum dose and dose escalation
Based on current human PK data, a dose of 50 mg to 100 mg q.d. of BI 1358894 may be 
required as a therapeutic dose. However, higher than therapeutic doses are typically explored 
in MRD studies to provide a safety margin for studies such as drug-drug-interaction studies, 
or patients with impaired excretion function, where substantial increases in exposure may be 
observed. Furthermore, studies in patients may demonstrate that an EC50 is insufficient to 
show a clinical effect and higher doses of BI 1358894 may be required to obtain efficacy. To 
adequately address all these aspects, a dose of 200 mg of BI 1358894 has been selected as the 
maximum dose. Based on the currently available data, even multiple doses of 200 mg q.d. are 
still expected not to exceed the exposure at NOAEL in the most sensitive species (rat with a 
Cmax of 1960 nM and AUC0-24 of 26 300 nM/h).
Dose escalation will be in the range of factor 2.5 from 10 mg to 25 mg and no more than 
2-fold for the subsequent dose levels. This dose escalation scheme is considered to be 
adequate and safe. However, it should be highlighted that any dose escalation beyond 10 mg 
q.d. will be only conducted if the already tested dose levels were shown to be safe and well 
tolerated, in particular with no noteworthy safety signal regarding blood pressure and heart 
rate or inflammatory markers (CRP, ESR, calprotectin).
2.2
TRIAL OBJECTIVES
The primary objective of the trial is to investigate the safety and tolerability of BI 1358894 in 
healthy male subjects following oral administration of multiple rising doses of 10 mg, 25 mg, 
50 mg, 100 mg, 200 mg q.d. over 14 days.
Secondary objectives are the exploration of PK, including dose proportionality and 
investigation of steady state attainment of BI 1358894 after multiple dosing. 


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In addition, the effect of BI 1358894 on the pharmacokinetics of midazolam, given as an oral 
microdose, will be explored.
A description of the endpoints to be determined and the observations, along with specific 
information as how to collect the data for that information, is provided in Section 5. 
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of 
BI 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.
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 and safety measures
2.3.2.1
Drug-related risks
Risk factors were derived from (1) observations in nonclinical studies, (2) the mode of action 
and nature of the target, and (3) the relevance of animal models. 
Risks derived from observations in non-clinical studies
Rats and dogs were employed as the animal species for general toxicology investigations on 
BI 1358894, because in vitro and in vivo profiling supported the suitability of both species 
for nonclinical safety profiling of BI 1358894. 
As summarised in Section 1.2.1, potential risks observed in non-clinical studies are a long 
lasting decrease in the blood pressure in rats, an increase in heart rate in rats and dogs, and 
signs of a short lasting episode of arterial/ perivascular inflammation in rats. All findings 
were observed within 5 days after the start of treatment. The 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 the start of dosing and 
resolved despite continued treatment, indicating its transient character. The non-clinical 
safety data support clinical Phase I trials in non-childbearing humans with daily oral 
administration for up to 4 weeks.


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Mode of action and nature of the target
The TRP family members are ion channels considered to play a crucial role in physiological 
processes such as to act as a cellular sensor or to support signal transmission [R18-0249]. The
subtypes TRPC4 and TRPC5 form ion channels that are involved in the regulation of 
neuronal excitability. They are highly expressed in the amygdala, in the frontal cortex, 
hippocampus, and hypothalamus [R15-3888, R16-5350], which are involved in modulation 
and processing of emotion and affect. Preclinically, inhibition of these receptors by 
BI 1358894 has resulted in diminished fear and anxiety and increased social interaction 
without impairing other brain functions such as learning and memory behaviours. In 
accordance with these findings, TRPC5 deficient mice display an anxiolytic-like phenotype 
[R15-3888]. This supports the assumption that CNS effects in healthy subjects due to an 
inhibition of TRPC 4/5 are limited to a reduced anxiety.  However, clinical data with 
compounds inhibiting this target have yet to be published.
Relevance of animal models
Human TRPC4 and TRPC5 proteins show high homology with the rat, mouse, and dog 
proteins and the potency of BI 1358894 to the target is comparable across species. In 
addition, expression at the protein level is similar across different species, including human. 
Rat and dog had good oral bioavailability, significant systemic exposure, and good 
tolerability after oral dosing of a nanosuspension of BI 1358894. Finally, all known 
metabolites formed after incubation of human hepatocytes with BI 1358894 were covered 
with the combination of rat and dog. Overall, pharmacodynamic activity, pharmacokinetics, 
and metabolism all indicate that rat and dog were suitable species for nonclinical safety 
profiling of BI 1358894.
It should be highlighted that toxicity study in rats [n00250347] did not reveal any 
toxicologically relevant effects of BI 1358894 on the immune system up to the highest tested 
dose of 2000 mg/kg (1000 mg/kg twice daily). Furthermore, the pharmacological effects of 
BI 1358894 are dose dependent and no evidence for irreversible effects has been observed. 
Therefore, despite the novelty of the target, BI 1358894 is not considered a high-risk 
compound. 
2.3.2.2
Risk minimization (safety precautions and stopping rules)
The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers: 

Careful dose selection

Shallow dose escalation using a factor ≤2.5 for all rising steps 

For safety reasons, each dose group will be divided into 2 cohorts of 5 subjects each 
(4 on active drug, 1 on placebo). Each drug administration will be separated by at 
least 10 minutes and the dosing of the cohorts will be separated by at least 48h. 

Interim measurements of BI 1358894 plasma concentrations will be performed. Dose 
escalation will be stopped if the mean Cmax or AUC of a dose group exceeds the 
exposure thresholds (either following a single dose or multiple doses) of 1960 nM for 
Cmax or 26 300 nM·h for AUC0-24, or if the mean of the above parameters for the next 


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higher dose group is expected to exceed these values. Estimations will be based on 
preliminary PK results of the preceding dose groups (see Section 7.3.4)

If one dose level was safe and showed acceptable tolerability and if no stopping 
criterion was met (see Section 3.3.4.2), the next higher dose will be given, 
maintaining a time interval of at least 6 days (referring to the first subject of each dose 
group)

An extensive safety laboratory will be performed with special focus on full blood 
exam (see Flow Chart)

Repeated triplet 12-lead ECGs are scheduled throughout the study 

In this study, blood pressure and heart rate will be closely monitored (see Flow 
Chart). Dose escalation will be stopped if at least 2 subjects at one dose level show a 
sustained decrease in systolic blood pressure of ≥20 mmHg for at least 2 hours after 
drug administration compared to baseline (Day 1, predose). Orthostatic testing will be 
performed to detect whether potential hemodynamic effects of BI 1358894 might 
interfere with daily life activities. Dose escalation will be stopped if orthostatic 
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 blood 
pressure, pulse rate, respiratory rate), orthostatic tests, ECGs, safety laboratory tests 
including CRP, ESR, hormone parameters, faecal occult blood and faecal calprotectin 
tests, visual analogue scales, suicidality, and assessment of adverse events) 

Subjects will be hospitalised throughout the study from Day -1 (treatment with oral
microdose of midazolam) to Day 17 and will be discharged only after a formal 
assessment and confirmation of fitness by an investigator or qualified designee. 
During the in-house stay, the subjects will be under medical observation and 
thoroughly monitored for both expected and unexpected adverse events

As reproductive toxicity studies have not yet been conducted, only male subjects will 
be enrolled in this study
2.3.2.3
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, adverse events of special interest).
2.3.3
Overall assessment
In summary, although not therapeutically tested in humans to date, BI 1358894 has the 
potential to become an oral treatment for major depressive disorder as an adjunct to 
antidepressant therapy and for the treatment of borderline personality disorder. Based upon 
preclinical data for BI 1358894, the preliminary clinical data from the on-going FIH study, as 
well as the implemented safety measures described above, healthy subjects will not be 
exposed to undue risks in relation to the important information expected from this trial as a 
basis for further clinical development of this compound. Healthy volunteers are not expected 


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to have any direct benefit from participation in the clinical trial with BI 1358894, as is the 
usual case in such Phase I trials. Considering the medical need for the development of a safer 
and more effective treatment for patients with 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
Overall, 50 subjects are planned to participate in this Phase I trial, according to 5 sequential 
dose groups, comprising 10 subjects per group. 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 50, but will not exceed 80 subjects 
entered. If required for the further evaluation of pharmacokinetics such changes may be 
implemented via non-substantial CTP amendments. However, the addition of further dose 
groups for the evaluation of safety findings is subject to a substantial CTP amendment 
requiring approval.
The trial design is depicted in Figure 3.1: 1. 
Figure 3.1: 1 
Overview of trial design
Arrows: trial drug administration (red: BI 1358894, blue: midazolam); triangles: PK blood sampling (red: BI 1358894, 
blue: midazolam)
BI 1358894
This multiple-rising dose segment is double-blind, randomised within dose groups, and 
placebo-controlled within dose groups. 
Within each dose group, 8 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group. For safety reasons, the dose groups are each 
divided into 2 cohorts (per cohort: 4 subjects on active and 1 subject on placebo, treated in 
parallel). Both cohorts will be dosed in a randomised fashion. Each drug administration will 
be separated by at least 10 minutes and the dosing of the cohorts will be separated by at least 
48 h.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.


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Table 3.1: 1
Dose groups
Dose Group
1
2
3
4
5
Dose (mg)
10
25
50
100
200
Number of subjects
10
10
10
10
10
Subjects receiving placebo
2
2
2
2
2
Subjects receiving active drug
8
8
8
8
8
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 6 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 PK data of the 
preceding dose groups. The next 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).
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

Results from 12-lead ECG in the current and preceding dose groups

Vital signs and results from orthostatic tests in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups

Preliminary PK data with availability as per 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 trial clinical monitor is responsible for 
organisation 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. 


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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.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
Midazolam 
This segment is designed as a nested, open, fixed-sequence, intra-individual comparison.
The potential interaction of BI 1358894 with a CYP3A4 substrate will be assessed separately 
in dose groups 1 to 5 and in the subjects receiving placebo. This will be conducted in parallel 
to the multiple dose assessments, using a microdose of midazolam (a sensitive CYP3A4 
substrate) administered at 3 different time points (Days -1, 1, and 14).
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 the participating trial site
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 by 
 
under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
The analyses of BI 1358894 and midazolam 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. 
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for post-study evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.


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Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
For multiple-rising dose trials, the design described in Section 3.1 is viewed favourably under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 1358894.
With the rising dose design, double-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, 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 the 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 and tolerability. Each dose group consists of 10 subjects with 8 on 
active treatment, and 2 on placebo. The placebo control group includes all subjects of all dose 
groups treated with placebo. Eight subjects per active treatment group are in general 
considered as sufficient for the exploratory evaluation of pharmacokinetics.
The evaluation of a potential CYP3A4 interaction with BI 1358894 using a microdose of 
midazolam is considered to be acceptable. A microdose of midazolam is not expected to have 
any pharmacological effects. Therefore, subjects are not exposed to undue risks. Also, the 
evaluation of the investigational drug should not be influenced. This assessment will allow 
for better judgement regarding acceptable co-medications in a Proof of Clinical Concept 
study and later in the Phase III development.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 50 healthy males will enter the study. The actual number of subjects entered 
may exceed the total of 50 if additional intermediate doses will be tested (see Section 3.1). 
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.
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.


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3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the investigator’s assessment, based on a complete 
medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and 
clinical laboratory tests
2. Age of 18 to 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 adequate contraception with their female partner 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 (with medical assessment of 
the surgical success) or

Surgical sterilisation (including bilateral tubal occlusion, hysterectomy or bilateral 
oophorectomy) of the subject's female partner or

The use of condoms, if the female partner uses an adequate contraception method in 
addition, e.g., intrauterine device (IUD), hormonal contraception (e.g. implants, 
injectables, combined oral or vaginal contraceptives) that started at least 2 months 
prior to first drug administration, or barrier method (e.g. diaphragm with spermicide)
Unprotected sexual intercourse with a 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 and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. C-Reactive Protein > upper limit of normal (ULN), erythrocyte sedimentation rate (ESR) 
≥15 millimeters/h, liver or kidney parameter above ULN, or any other laboratory value 
outside the reference range that the investigator considers to be of clinical relevance
4. Positive or missing faecal occult blood test (retest allowed)
5. Positive testing for faecal calprotectin (retest allowed)


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6. Any evidence of a concomitant disease judged as clinically relevant by the investigator
7. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
8. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
9. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
10. History of relevant orthostatic hypotension, fainting spells, or blackouts
11. Chronic or relevant acute infections
12. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
13. Use of drugs within 30 days prior to administration of trial medication that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
14. 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
15. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
16. Inability to refrain from smoking during in-house confinement
17. Alcohol abuse (consumption of more than 30 g per day)
18. Drug abuse or positive drug screening
19. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
20. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
21. Inability to comply with dietary regimen of trial site
22. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
23. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome) 
24. 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:
25. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
26. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
For study restrictions, refer to Section 4.2.2.


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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, 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 a raised CRP level of >3.00 mg/dL or an ESR of ≥20 millimeters/hour 
7. The subject experiences a serious’ adverse reaction which is considered at least possibly 
related to the IMP administration
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).
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. These discontinuations will be discussed in the 
CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:


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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 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 if the Cmax or AUC0-24 of at least 1 subject of one dose 
group increases above the following exposure thresholds or if the estimated systemic 
exposure (group gMean values) of the next dose level is expected to exceed a Cmax of 
1,960 nM or an AUC0-24 of 26,300 nM*h (see Section 7.3.4).
6. Dose escalation will be stopped if at least 2 subjects at one dose level show relevant 
individual QT prolongation (absolute QT or QTc greater than 500 ms), which has been 
confirmed by a repeat ECG recording.
7. Dose escalation will be stopped if at least 2 subjects at one dose level show a sustained 
decrease in systolic blood pressure of ≥20 mmHg for at least 2 hours after drug 
administration compared to baseline (Day 1, predose), which will be measured after 
15 min in a supine position (to avoid false positive signals because of the required 
prolonged resting period after drug intake) 
8. Severe non-serious adverse reactions (i.e. severe non-serious adverse events considered 
as, at least, possibly related to the IMP administration) in two subjects in the same cohort, 
independent of within or not within the same system-organ-class.
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
If 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 or treatment sequence 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.
4.1.1
Identity of BI investigational product and comparator products
The characteristics of the investigational products are given below.
Table 4.1.1: 1
Characteristics of investigational products
Test product 
Reference product 
Probe product
Substance
BI 1358894
Matching placebo
Midazolam 
(Midazolam-
ratiopharm®)
Pharmaceutical 
formulation
Film-coated tablet
Film-coated tablet
Solution for injection
Source
BI Pharma GmbH & 
Co. KG, Germany
BI Pharma GmbH & 
Co. KG, Germany
Ratiopharm GmbH, 
Germany
Unit strength
5 mg, 25 mg, 100 mg
n.a.
5 mg/5 mL diluted to 
50 μg/mL•1.5 mL 
(75 μg)
Posology
2-0-0 (10 mg), 1-0-0 
(25 mg), 2-0-0 (50 mg), 
1-0-0 (100 mg), 2-0-0 
(200 mg)
2-0-0 (10 mg), 1-0-0 
(25 mg), 2-0-0 (50 mg), 
1-0-0 (100 mg), 2-0-0 
(200 mg)
1-0-0 
Route of 
administration
p.o.
p.o.
p.o.
Duration of use
14 days q.d.
14 days q.d.
3 single doses (Days -1, 
1, and 14) 
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 10 dose cohorts (2 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 list of subject and medication numbers 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 


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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
The doses selected for this trial are intended to cover the sub-therapeutic as well as the 
estimated therapeutic and supra-therapeutic range and include a safety margin. For details, 
refer to Section 1.2.
BI 1358894
The dose range of BI 1358894 for this trial was selected on the basis of the data obtained in 
the ongoing FIH SRD Trial 1402.1. So far, dose levels up to 200 mg were well tolerated.
Midazolam
The dose of midazolam used for the DDI evaluation was chosen to be 75 μg, within the 
definition of a microdose, i.e. a 1/100th of the therapeutic dose (in case of midazolam 7.5 mg) 
or 100 μg whichever is smaller. Since midazolam PK is dose proportional ranging from the 
microdose to the therapeutic dose, the microdose should still accurately predict CYP3A4 DDI 
liability, while remaining below a pharmacologically active concentration. A solution for 
injection was chosen for administration as an oral solution, as a solution for injection is meant 
to be diluted and, thus, there is data available regarding the stability and compatibility of a 
diluted solution. Furthermore, the solution for injection contains midazolam in isotonic saline 
solution, while the oral solution has added excipients, making it less than ideal for such a 
dilution. Finally, the IV solution has been successfully diluted and administered orally as a 
microdose in previous clinical studies without any reports of AEs [R17-3022, R17-3023].
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 (BI 1358894) and Table 4.1.4: 2
(midazolam). The number of units for placebo corresponds to the number of units of the 
respective dose level.
Table 4.1.4: 1
BI 1358894 and placebo treatments, oral administration
Dose
Substance
Pharmaceutical 
form
Unit strength
Number of units 
per administration
Total daily 
dose
1
BI 1358894
Film-coated tablet
5 mg
2 tablets q.d. for 14 days
10 mg
2
BI 1358894
Film-coated tablet
25 mg
1 tablet q.d. for 14 days
25 mg
3
BI 1358894
Film-coated tablet
25 mg
2 tablets q.d. for 14 days
50 mg
4
BI 1358894
Film-coated tablet
100 mg
1 tablet q.d. for 14 days
100 mg
5
BI 1358894
Film-coated tablet
100 mg
2 tablets q.d. for 14 days
200 mg
1-5
Placebo*
Film-coated tablet
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups 


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Table 4.1.4: 2
Midazolam treatments, oral administration
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Number of units 
per administration
Total daily 
dose
1 to 5
Midazolam
Solution for 
injection
5 mg/5 mL diluted to 
50 μg/mL
1.5 mL 
75 µg
The oral solutions for dosing midazolam will be prepared according to the instruction given 
in Appendix 10.1. Trial medication will be prepared by pharmacists or qualified pharmacy 
staff members or qualified medical study personnel at the trial site under the responsibility of 
the investigator.
Trial medications will be administered orally to the subjects, while in a sitting or standing 
position, together with about 240 mL of water under supervision of the investigating 
physician or an authorised designee. The so-called four-eye principle (two-person rule) 
should be applied for administration of trial medication and its preparation. To ensure a 
dosing interval of 24 h, the administration of trial medication should take place at the same 
time every day. On Days 1 and 14, BI 1358894 will be administered immediately prior to 
midazolam.
In each treatment, a standard continental breakfast will be served 30 min before drug
administration. The meal must be completely consumed prior to drug administration. The 
composition of the standard continental breakfast is detailed in Table 4.1.4: 3.
Table 4.1.4: 3
Composition of the standard continental breakfast
Ingredients
kcal
1 bread roll
164
15 g butter
113
1 slice of Gouda cheese (approximately 40g)
146
1 slice of meat (approximately 20g)
33
1 cup of decaffeinated coffee or tea (without sugar)
2
Sum1
458
1
The total caloric content was supplied approximately as following: 88 kcal as protein, 133 kcal 
as carbohydrate, and 237 kcal as fat.
Subjects will be hospitalised and kept under close medical surveillance throughout the study 
from Day -1 (microdose of midazolam) until Day 20 (72 h following drug administration on 
Day 14). During the first 2 h after drug administration on all application days, subjects are not 
allowed to lie down (i.e. no declination of the upper body of more than 45 degrees from 
upright posture except for medical examination), or to sleep. For restrictions with regard to 
diet, see Section 4.2.2.2.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
BI 1358894
This segment of the trial will be double-blind with regard to subjects and investigators (as 
well as the research staff at the trial site) in order to eliminate observer or performance bias. 
This means avoiding systematic differences in assessments regarding the subject’s treatment 
(active drug or placebo). According to the rising dose design, the current dose level will be 
known to the subjects and investigator.
At the trial site, access to the randomisation schedule is restricted to unblinded pharmacists 
and pharmacy staff members. Access to the codes will be controlled and documented by a 
signed confidentiality statement, which will be stored in the TMF. Persons directly involved 
in the clinical conduct of the trial will not have access to the treatment allocation prior to 
database lock.
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, 
statistician, bioanalyst, pharmacokineticist, pharmacokinetic analyst, pharmacometrician, 
drug metabolism scientist as well as dedicated CRO personnel). The objective of the trial is 
not expected to be affected.
Within the ECG laboratory, the staff involved with interval measurements and assessments 
will be blinded with respect to the treatment and also with regard to the recording date and 
time as well as the time points of the ECGs. The interval measurements for a given subject 
will be performed in a random and blinded sequence by a single technician. No more than 
two different blinded readers will evaluate the ECGs of the study. If an interim safety 
analysis of ECG data is required, a part of the staff of the ECG laboratory may be unblinded. 
This part of the staff will be strictly separated from the staff that is involved with interval 
measurements and assessments of single ECGs (blinded).
Midazolam 
Midazolam treatment 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
BI 1358894
For the blinded treatment of this trial, the investigator will be supplied with a set of sealed 
envelopes containing the medication codes for each subject according to the randomisation 
scheme. The envelopes will be kept unopened at the trial site until the end of data collection. 
An envelope may only be opened in emergency situations when the identity of the trial drug 
must be known to the investigator in order to provide appropriate medical treatment or to 


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assure safety of trial participants. If the envelope for a subject is opened, the sponsor must be 
informed immediately. The reason for opening the code break must be documented on the 
envelope or appropriate CRF page along with the date and the initials of the person who 
broke the code. At the close-out visit, all envelopes are collected.
Midazolam
As midazolam treatment will be conducted in an open fashion, the treatment information will 
be known. 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, with the exception of 
midazolam, which will be purchased by the trial site.
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 or medication number

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 
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.


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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  
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 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 authorise symptomatic 
therapy.
In case of alterations of blood pressure (hypotension) and heart rate (tachycardia), which 
were reported in nonclinical toxicology studies (see Section 1.2.2), first physical 
interventions will be the treatment of symptoms. If unsuccessful, appropriate drug therapy 
will be initiated according to common guidelines and algorithms of emergency trainings. 
Dependent on individual symptoms, for the treatment of tachycardia this may include 
intravenous administration of beta blockers or appropriate antiarrhythmic drugs. For the 
treatment of hypotension, in addition to volume substitution, administration of vasopressors 
may be a further step. The entire staff of the trial site assuming medical responsibility during 
the conduct of the study is routinely trained in emergency procedures. 


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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. On PK profile days (Days -1, 1, and 14), no food is allowed for 
at least 4 hours after drug intake. On the remaining days (Days 2 to 13), food is not allowed 
for at least 2 h after drug intake. 
From 1 hour before drug intake until lunch, liquid intake is restricted to the water 
administered with the drug, and an additional 240 mL of water served on Days -1, 1, and 14 
at 2 h and 4 h post-dose (mandatory for all subjects).  
During urine collection periods (Days 1 and 14), total fluid intake should be at least 1 L but 
should not exceed 3.5 L within 24 hours.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements including St. John's wort (Hypericum perforatum) are not permitted 
starting 7 days before the first trial drug administration until last PK sampling of the trial.
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 foods or drinks (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. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and urinary excretion will provide additional confirmation of compliance.


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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
A continuous safety evaluation, including results of safety laboratories, ECG readings,
recordings of vital signs and adverse events will be performed before the individual subject
and the subsequent cohort is dosed.
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 events.
Further criteria of interest:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

Faecal occult blood and faecal calprotectin tests

12-lead ECG

Vital signs (blood pressure, pulse rate, respiratory rate) and orthostatic tests

Visual analogue scales (Bond & Lader and Bowdle)

Suicidality assessment (C-SSRS)
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.


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The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if 
they are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 

is life-threatening, which refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation, 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect, 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the subject and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.


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Adverse events of special interest 
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.2.2.
The AESI for this trial is hepatic injury, as defined by the following alterations of hepatic 
laboratory parameters:

an elevation of aspartate transaminase (AST) and/or alanine aminotransferase
(ALT)≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN 
measured in the same blood sample, or

aminotransferase (ALT and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure that these parameters 
are analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).


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
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
Suicidal risk assessed by the C-SSRS (paper version)
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the screening visit (using the ‘screening / baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and behavior 
will also be recorded.
After the baseline visit the assessment ‘since last visit’ will be performed at each clinic or 
phone visit (‘since last visit’ version). The investigator is to review positive and negative 
reports for plausibility and clinical relevance. Doubtful reports may be repeated or reports 
may be validated by a consulting psychiatrist. If there is a confirmed positive report of 
suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to 
immediately interview the subject during the clinic visit, and/or is to consult a psychiatrist. 


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If the positive report is confirmed, appropriate actions for the subject’s safety have to be 
initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behaviour must 
be reported as separate SAEs by the investigator.
For ‘Self-injurious behaviour, no suicidal intent’ (Type 11) standard AE / SAE reporting 
rules are to be applied.
For each negative report (suicidal ideation type 1, 2 or 3) after start of the trial, the 
investigator is to decide based on clinical judgment whether it represents an adverse event 
(AE) as defined in the protocol, and if it is considered an AE then it must be reported 
accordingly.
5.2.2.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as 'How do you feel?'. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.


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AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events,  a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timelines apply as for the initial 
information.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
Pregnancy
Once a male subject has been enrolled in the clinical trial and has taken trial medication, and 
if a partner of the male trial participant becomes pregnant, the investigator must report any 
drug exposure during pregnancy in a partner of the male trial participant immediately (within 
24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s unique 
entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood, urine, and stool 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. In addition, faecal occult blood and faecal 
calprotectin will be assessed.
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis,
respectively. 


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
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 
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment (microscopic 
examination if erythrocytes, leukocytes 
nitrite or protein are abnormal in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1
Protein electrophoresis only at screening. Hormones only at screening and end of trial.
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and after admission to the trial site.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qual)
Hepatitis B core antibody (qual)
Hepatitis C antibodies (qual)
HIV-1 and HIV-2 antibody (qual), HIV-1 p24-antigen
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed at screening and upon admission to the trial 
site and may be repeated at any time during the study at the discretion of an investigator or 
designee. The results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at Medizinisches 
Versorgungszentrum Dr. Klein Dr. Schmitt & Partner, Kaiserslautern, Germany with the 
exception of the drug screening tests. These tests will be performed at the trial site using 
Multidrogen Pipettiertest (Diagnostik Nord GmbH, Schwerin).


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Faecal calprotectin testing will be performed at Medizinisches Versorgungszentrum Dr. Klein 
Dr. Schmitt & Partner, Kaiserslautern, Germany. Faecal occult blood testing will be 
performed at the trial site using a test kit (e.g. PreventID CC test by Preventis GmbH or 
similar). These tests will be clinically performed at screening, within 4 days prior to the first 
dosing of BI 1358894 (i.e. Day -4 to Day -2), in the first stool released after 12 hours after 
administration, on Days 1, 4, 7, 10, and 14, on Day 16, and at EOT. As subjects may not be 
able to defecate at the trial site in the morning of Visit 1 (screening), they may collect the 
specimen at home and bring the test specimen to the trial site within the screening period. In 
case of gastrointestinal AEs (e.g. diarrhoea, constipation), additional testing for faecal occult 
blood and faecal calprotectin may be carried out at the discretion of the investigator. If a 
subject tests positive for occult blood in faeces, further tests will be performed and the subject 
will be monitored closely.
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
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the time points given in the Flow Chart. 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.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all subjects are at 
complete rest. All ECGs will be recorded for a 10 sec duration after subjects have rested for 
at least 5 min in a supine position. ECG recording will always precede all other study 
procedures scheduled for the same time (except for blood drawing from an intravenous 
cannula that is already in place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database. 
Storing
All ECGs will be stored electronically on the Muse Cardiology Information System (GE 
Medical Systems, Freiburg, Germany).


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Data transfer
For time points specified in the Flow Chart, ECGs will be transferred electronically to the 
central ECG lab
 for evaluation.
In case of repeat ECGs due to quality reasons, all recordings will be transferred to the central 
ECG lab and the repeated ECGs will be flagged in the database. 
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab and 
evaluated but will not be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a) Central ECG lab
Central ECG lab evaluation (of Visit 2 Days 1 to 20 ECGs only) will be performed for 
the first of three replicate ECGs per time point given in the Flow Chart. The 
remaining second and third replicate ECGs will be stored for additional analyses, if 
required, e.g. by authorities at a later time point. For baseline, where 3 triplicate ECGs 
are recorded, only the first of the triplicate ECGs (i.e. 3 single ECGs) will be 
evaluated. 
The analysis will include the determination of cardiac axis as well as the intervals RR, 
PR, QRS and QT measured semi-automatically.
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will 
be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR.
For automatic interval measurements no lead will be provided.
For blinding arrangements see Section 4.1.5.1. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader. For quality assurance and control of the measurements, all ECGs of a 
subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and, to detect 
accidental switching of leads and/or false subject assignments of the ECGs. After 
quality control, the fiducial point markings will be reviewed by the cardiologist 
assigned to the study. 
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements [R07-4722, R16-0366] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].


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b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
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 
computerised ECG system or their manual corrections by the investigators will be 
used. 
In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data transfer) for 
cardiologic assessment by the central lab. In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator. Any ECG abnormalities will be monitored carefully 
and, if necessary, the subject will be removed from the trial and will receive the appropriate 
medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap, GE Medical Systems, Freiburg, Germany) at the times indicated in the Flow 
Chart, after subjects have rested for at least 5 min in a supine position. All recordings should 
be made using the same type of blood pressure recording instrument on the same arm if 
possible. 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. 
Orthostatic hypotension is defined as a reduction in systolic BP of ≥20 mm Hg or in diastolic 
BP of ≥10 mm Hg within 3 minutes of standing and will be recorded as an AE. Orthostatic 
hypotension may be accompanied by symptoms of dizziness, diaphoresis, a decline in blood 
pressure, tachycardia (PR >100 bpm), or even fainting (which is reflected in the assessment 
of AE intensity). At the time points given in the Flow Chart, the following sequence of 
measurements should be adhered to: 12 lead-ECG and vital signs will be done before blood 
sampling; orthostatic testing will be done after blood sampling. While standing up, subjects 
will be accompanied by staff. 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.


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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 conducted about 2 hours before drug administration on Day 1 will be 
considered as baseline. At each measuring time point indicated in the Flow Chart, the 
subjects will assess their subjective impression of themselves by means of visual analogue 
scales. The subjects will be asked to mark an adequate position on a line between the two 
limits of the characteristic to be measured. The length of the line will be exactly 100 mm, and 
will ascertain a score number (values between 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 10.2.
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 with 
determination of weight.
5.2.5.5
Suicidality assessment
Suicidality assessment to further evaluate the psychological status of the subject will be 
performed at screening using the Columbia Suicidal Severity Rating scale (C-SSRS). The 
C-SSRS is a brief measure which is designed to assess severity and change of suicidality by 
integrating both behaviour and ideation. The C-SSRS was designed to address the need for a 
summary measure to track change in the severity of suicidality across both clinical settings 
and treatment trials.
The original C-SSRS is shown in Appendix 10.4.
5.2.5.6
Neurological examinations
As a general additional safety measure in the planned dose groups 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


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- Pupil size and pupil reactivity
- Reflexes
- Assessment of muscle strength
- Gait
- Romberg test
- Tremor
- Point-to-point movements
- Sensitivity
Documentation, Assessment, and Reporting
Results will be documented in source data at the clinical trial site and assessed for clinical
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant
findings of the neurological examination will be reported as Adverse Events (during the trial)
or as baseline conditions (at screening). Case narratives may be written if necessary.
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
Pharmacogenomics investigates genetic variations to explain and to predict an individual’s 
response to drugs. Therefore, a blood sample for pharmacogenomic testing will be taken
predose on day 1 from each subject. In case of unexplainable variability in pharmacokinetic 
parameters, DNA might be extracted from these samples and used for exploratory analysis of 
variants of genes involved in Absorption, Distribution, Metabolism and Excretion (ADME) 
of drugs. It is not intended to include these data in the final report. However, the data may be 
part of the report if necessary. All remaining samples will be destroyed no later than three 
years after the end of the trial.
5.3.1.1
Methods and timing of sample collection
One blood sample of at most 10 mL will be taken from an arm vein in a PAXgene blood 
DNA drawing tube prior to the first study drug administration (Visit 2, Day 1). The blood 
sample has to be stored at a temperature of approximately -20°C or below. Once frozen, 
thawing of the samples should be avoided.
Frozen blood samples should be shipped on dry ice to:
5.3.1.2
Analytical determinations
Genomic DNA will be extracted from blood samples according to standard molecular 
genetics methods and analysed by DMET analysis or other standard genotyping technologies.


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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 
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
Date and 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
BI 1358894
After the first dose:

AUC0-24 (area under the concentration-time curve of the analyte in plasma over a time 
interval 0 to 24 hours after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma)
After the last dose:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)
Midazolam
After each of the three doses:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)


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
Cmax


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
BI 1358894
For quantification of BI 1358894 plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into a K-EDTA (potassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will be 
withdrawn by means of either an indwelling venous catheter or by 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. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the final study 
report has been signed.


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Midazolam
For quantification of midazolam plasma concentrations, 4 mL of blood will be taken from an 
antecubital or forearm vein into a K-EDTA-anticoagulant blood drawing tube at the times 
indicated in the Flow Chart. Blood will be withdrawn by means of either an indwelling 
venous catheter or by venipuncture with a metal needle.
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, 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.
After completion of the trial, the plasma samples may be used for further methodological 
investigations, e.g., for stability testing, assessment of metabolites. However, only data 
related to the analyte and/ or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the final study 
report has been signed.
5.5.2.2
Plasma sampling for metabolism analysis
Additional K-EDTA plasma samples for the identification of drug metabolites will be 
investigated in the 50 mg dose group. Based on the knowledge gained during the trial 
conduct, e.g. from preliminary PK results, the dose group may be changed to a different one. 
The change will be implemented via a non-substantial CTP Amendment.
The blood samples will be drawn in parallel to PK samples according to the times indicated 
in the Flow Chart. At each of these time points, 3.4 mL blood will be needed for metabolite 
analysis. Sample handling will be described in detail in a separate lab manual. Samples will 
be stored at about -70°C or below until transfer to the metabolism laboratory.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, planned sampling time, and 'MIST'. Further information such as matrix 
and analyte may also be provided. 
Sample handling will be described in detail in a separate lab manual. 
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
the drug metabolism will be reported separately but not included in the CTR of this trial. The 
study samples will be discarded after completion of the experiments but not later than 5 years 
after the final study report has been signed. 
5.5.2.3
Urine sampling for pharmacokinetic analysis
A blank urine sample will be collected before administration of BI trial medication on Day 1
(within the 2 h before drug dosing) and two 1 mL aliquots will be retained to check for 
analytical interference by concomitant or rescue medication. 


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All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
2 L polyethylene (PE) containers and stored at room temperature. Subjects are told to empty 
their bladders at the end of each sampling interval. 
The handling of urine sampling is described in a lab manual.
At minimum, the sample tube labels should list at least the following information: BI trial 
number, subject number, visit, and planned collection time. Further information such as 
matrix and analyte may also be provided. 
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
about -20°C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory the 
urine samples will be stored at about -20°C or below until analysis.
After completion of the trial, the urine samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) will be generated by these additional investigations. 
The study samples will be discarded after completion of the additional investigations but not 
later than 5 years after the final study report has been signed.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 1358894 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.
5.5.3.2
Analytical determination of BI 1358894 urine concentration
BI 1358894 concentrations in urine will be determined by a validated LC-MS/MS assay. All 
details of the analytical method will be available prior to the start of sample analysis.
5.5.3.3
Analytical determination of midazolam plasma concentration
Midazolam concentrations in plasma will be determined by a validated LC-MS/MS assay. All 
details of the analytical methods will be available prior to the start of sample analysis.


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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).
For the first 4h after trial drug administration, the acceptable deviation from the scheduled 
time will be ±10 min for vital signs, ECG, and orthostatic testing and ±30 min for laboratory 
tests. Thereafter, the acceptable deviation will be ±30 min. 
The tolerance for drug administration will be ±1 min on Days -1, 1, and 14. On all other 
treatment days it will be ±10 min.
If several activities are scheduled at the same time point in the Flow Chart, ECG should be 
the first and meal the last activity. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements, except for the orthostatic testing, due to its inconvenience to the subject and 
possible influence on physiological parameters.
For planned individual plasma concentration sampling times and urine collection intervals 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
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), faecal 
laboratory tests, ECG, vital signs, orthostatic tests, visual analogue scales, suicidality 
assessment, and physical examination, refer to Sections 5.2.3 to 5.2.5. 
Pharmacogenomic genotyping will be performed (for details see Section 5.3).
6.2.2
Treatment period
Each subject will receive a single daily dose of BI 1358894 or placebo for 14 days during 
Visit 2 on Days 1 to 14. A single midazolam microdose will be administered on Days -1, 1, 
and 14.


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Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
Study participants will be admitted to the trial site in the morning of Day -1 at which point 
the first midazolam microdose will be administered. Subjects will be kept under close 
medical surveillance for at least further 144 h following last drug administration on Day 14. 
The subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness by the investigator or 
 designee at Day 20, refer to Flow 
Chart. On Day 22, the study will be performed in an ambulatory fashion.
If the subject reports headaches during the treatment period the following information and 
data should be collected daily until the headache is resolved:

Onset after medication intake (hhh:min)

Headache severity on a Numeric Ranking Scale (NRS) ranging from 0 - 10

Quality of headache (New type of headache vs. similar to previous experienced 
episodes of known headaches)

Headache characteristics (pressing or tightening vs. burning vs. pulsating vs. 
aggravated by routine physical activity (such as walking or climbing stairs))

Location (all of the following that apply: unilateral, bilateral, holocephal, frontal, 
temporal, occipital, facial)

Any acompanying symptoms like (all of the following that apply: nausea and/or 
vomiting, photophobia, phonophobia, lacrimation, other)

If Headache is resolved: Overall duration of headache episode (start time and end 
time)
For details on time points and procedures for collection of plasma and urine 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.
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.


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All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
BI 1358894
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 are 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 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. Trough concentration values will be analysed regarding attainment of 
steady state as a pre-requisite for calculation of steady state parameters.
Midazolam
The relative bioavailability of midazolam in the presence and absence of BI 1358894 will be 
evaluated separately within each dose group and separately for all subjects receiving placebo. 
As a sensitivity analysis, the relative bioavailability will be investigated for all dose groups 
together. For details, refer to 7.3.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 5 different dose groups of BI 1358894 are to be determined on the 
basis of the investigated parameters in comparison to 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.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
All individual data will be listed.
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 secondary 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). Analyses will be 
performed for parent drug.
Plasma and urine concentration data and parameters of a subject will be included in the 
statistical 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.
Plasma and urine concentrations and/ or parameters of a subject will be considered as non-
evaluable if, for example:

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 
5.5.1.1.
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







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. 


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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, …, 5, 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.
Attainment of steady state
Attainment of steady state will be explored by using the trough concentrations of BI 1358894
Cpre,9, Cpre,11, Cpre,13, Cpre,14 and the concentrations taken directly at the end of the first and the 
last dosing interval (C 24, C24,14) for each dose level. Pairwise comparisons of concentrations 
are performed using 2-sided 95% CIs based on the t-distribution. The calculation is based on 
a repeated measures linear model on the logarithmic scale.
 =  + 
 + s + e , where

logarithm of the concentrations for subject j at time i, i = 1, 2, …, 5 and
j=1, 2,…, 8

the overall mean,


the effect associated with time point i (repeated effect),
s
(random) effect of subject j, j=1, 2, ..., 8
e
random error associated with subject j at time i (assumed to be independent
and identically normally distributed).
Dose can be included as an additional covariate if there is evidence that the trough 
concentration profiles are comparable across dose levels.


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The model will be used to explore the time to steady state by pairwise comparing 
concentrations from different time points: log-transformed differences between all 
subsequent time points (log(Cpre,i/Cpre,j) = log(Cpre,i) - log(Cpre,j), where j>i) will be compared 
and adjusted means (Least Squares Means) as well as 2-sided 95% CIs will be calculated. 
Thereafter, these quantities will be back-transformed by exponentiation to give the 
corresponding (adjusted) ratio and CI.
Comparisons which reveal CIs (for the adjusted ratio) not including 100% will be inspected 
to determine if the differences between time points are resulting from not yet attaining 
steady-state. 
For further details, refer to the TSAP (such as selection of covariance structure and 
comparison of time points).
Graphical displays
To support the analyses of dose proportionality and attainment of steady state, graphical 
representations of the data might be created. These might include (but are not limited to) 
individual time-courses of trough plasma concentrations and the (geometric) mean plasma 
concentration time profiles.
Midazolam:
Endpoints defined for Midazolam will be compared separately between the last dose of 
midazolam and the first dose of midazolam and between the second dose of midazolam and 
the first dose of midazolam. The statistical analysis will be performed separately for each 
dose group and, separately for the group of subjects receiving placebo. Analyses will be 
conducted for the placebo group to better account for variability in plasma concentrations 
seen between midazolam treatment periods. The statistical model used for the analysis of the 
secondary endpoints will be an ANOVA model on the logarithmic scale. This model will 
include effects accounting for the following sources of variation: ‘subjects’, and ‘treatment’. 
The effect ‘subjects’ will be considered as random, whereas the other effects will be 
considered as fixed. The model is described by the following equation:
 =  + 
 + s + e , where

logarithm of the endpoint for subject j (j=1, 2,…, 8) at Day -1 (first dose of 
midazolam, i=1), Day 1 (second dose of midazolam) or at Day 14 (last dose of 
midazolam, i=2) respectively,

the overall mean,


the effect associated with time point i (Day -1 i=1 , Day 1 or Day 14, i=2),
s
(random) effect of subject j, j=1, 2, ..., 8, and 
e
random error associated with subject j at time i (assumed to be independent
and identically normally distributed).


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The effect of BI 1358894 on midazolam will be estimated by the ratios of geometric means 
(with the second and the last doses of midazolam respectively as the test and the first dose of 
midazolam as the reference) and their two-sided 90% confidence intervals (CIs) for Cmax and 
AUC0-tz. CIs will be calculated based on the residual error from ANOVA. These quantities 
will then be back transformed to the original scale to provide the point estimate and 90% CIs 
for each secondary endpoint.
As a sensitivity analyses, these analyses will also be performed together for all subjects 
receiving BI 1358894. An ANCOVA with a random effect for ‘subject’ and fixed effects for 
‘treatment’ and ‘dose’ (on a logarithmic scale) will be used. More details will be provided in 
the TSAP. 
Further endpoints will be summarized per dose group and per time period (first dose of 
midazolam, second dose of midazolam and last dose of midazolam) and will be compared 
between last dose of midazolam and first dose of midazolam and between the second dose of 
midazolam and the first dose of midazolam.
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.
The analyses will be done by ‘randomised treatment’. 
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' and those between first trial medication intake and 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. 


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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.
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the ECG variables QT, HR, QTcF, QTcB, PR, QRS, RR, and further derived ECG 
parameters. The baseline value of an ECG variable is defined as the mean of the triplicate
ECG measurements prior to drug administration. The derivation of the quantitative and 
qualitative ECG parameters and their analyses will be described in the TSAP.
7.3.4
Preliminary PK analyses
A preliminary analysis of PK parameters (e.g. AUC0-24 and Cmax, both following a single dose 
and at steady state), provided as individual values and geometric means of the first cohort per 
dose level, will be performed for dose levels 1, 2, 3 and 4 (n) before proceeding to dose level 
2, 3, 4, and 5 (n + 1).
(Note: Data from the first cohorts of the above mentioned dose levels will be sufficient as 
long as the data for BI 1358894 from at least 4 subjects on active medication for single and 
multiple doses are available).
The pharmacokinetic parameters AUC0-24, AUCτ,ss and Cmax for BI 1358894 will be 
calculated using a validated software, such as Phoenix WinNonlinTM software (version 6.3 
or higher, Certara USA Inc., Princeton, NJ, USA) or SAS® Version 9.4 (or later version) by 
means of noncompartmental analysis. A quality check of the preliminary analysis will be 
performed. Further PK parameters might be calculated if reasonable.
In contrast to the final PK calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows or not. Therefore, minor deviations of preliminary and final results may occur. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification. The preliminary 
results will be distributed to the Investigator and the trial team. 
Depending on the results of available preliminary PK analyses, the tolerability and safety of 
the compound, and changes of dosing schedule (e.g. additional intermediate doses),
additional PK preliminary analysis may be performed based on the request of the trial clinical 
monitor, the investigator, or trial clinical pharmacokineticist. No formal preliminary PK 
report will be written.
No inferential statistical interim analysis is planned. However, after each dose group the 
investigator (or 
 deputy) is allowed to postpone further dose progression until a 
preliminary analysis of the data already obtained has been performed.


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7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for BI 1358894 will be calculated 
according to the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma / urine concentrations and/or individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma / urine concentrations, 
pharmacokinetic parameters or other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format as provided in the bioanalytical 
report, (that is, to the same number of decimal places provided in the bioanalytical report).
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma/urine drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), or BLQ (below the lower limit of quantification) will 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).
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
Subjects will be randomised within each dose cohort in a 4:1 ratio, which reflects the ratio of 
subjects receiving active drug to placebo.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 


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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
BI 1358894
It is planned to include a total of 50 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 10 subjects per dose group (8 on active treatment, and 2
on placebo) is commonly used in multiple-rising dose studies of the present type and is in 
general considered as sufficient for the exploratory evaluation of multiple dose safety and 
pharmacokinetics.
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 50, but will not exceed 80 subjects entered.
Midazolam
It is planned to enter a total of 50 subjects in this part of the trial. The planned sample size is 
not based on a power calculation, but is judged to be adequate to attain reliable results and to 
fulfil the objectives and requirements of this exploratory investigation.


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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, et al. 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.
R98-0752
Bond A, Lader M. The use analogue scales in rating subjective feelings. Br 
J Med Psychol 1974;47:211-218.
R06-2872
Trivedi MH, Rush AJ, Wisniewski SR, et al. Factors associated with health-
related quality of life among outpatients with major depressive disorder: a 
STAR*D report. J Clin Psychiatry 2006;67(2):185-195.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005)
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R15-3888
Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao 
GL, Tsvetkov E, Rodig SJ, Veer A van't, Meloni EG, Carlezon WA, 
Bolshakov VY, Clapham DE. Essential role for TRPC5 in amygdala 
function and fear-related behavior. Cell 2009;137(4):761-772.
R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
website:ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Effic
acy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015)
R16-5350
Fowler MA, Sidiropoulou K, Ozkan ED, Phillips CW, Cooper DC. 
Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent 
brain. Plos One 2007;2(6):e573.
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):82-9.
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.


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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.
R17-3022
Halama B, Hohmann N, Burhenne J, Weiss J, Mikus G, Haefeli WE, et al. 
A nanogram dose of the CYP3A probe substrate midazolam to evaluate 
drug interactions. Clin Pharmacol Ther 2013;93(6):564-571
R17-3023
Hohmann N, Kocheise F, Carls A, Burhenne J, Haefeli WE, Mikus G. 
Midazolam microdose to determine systemic and pre-systemic metabolic 
CYP3A activity in humans. Br J Clin Pharmacol 2014;79(2):278-285
R17-3087
Midazolam-ratiopharm 5 mg/1 ml Injektionsloesung, Midazolam-
ratiopharm 5 mg/5 ml Injektionsloesung, Midazolam-ratiopharm 15 mg/3 
ml Injektionsloesung (ratiopharm), verschreibungspflichtig 
(Fachinformation, Stand der Information: Januar 2014).
R18-0249
Minke B. The history of the Drosophila TRP channel: The birth of a new 
channel superfamily. 2010;24(4):216-233.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c10354149
Investigator's brochure BI 1358894 in Major Depressive Disorder and 
Borderline Personality Disorder. 16 Feb 2017.
c13880029
Safety, tolerability and pharmacokinetics of single rising oral doses of 
BI 1358894 in healthy male subjects (single-blind, partially randomised, 
placebo-controlled parallel group design) and effect of food on the relative 
bioavailability of  BI 1358894 (open-label, randomised, two-way cross-
over. Trial 1402.1. 21 Dec 2017.
n00248384
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. 


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n00252179
Safety Pharmacology of HC-122608. Report #: 154. 06 September 2012.
n00252207
Effects of HC-122608 on mouse marble burying. Report #: 213. 18 June 
2013.
n00252277
Effect of HC-122608 in the mouse elevated plus maze. Report #: 168. 16 
January 2013.
n00252628
[14C]BI 1358894: Distribution Study in the Male Pigmented Rat.
n00252903
Effect of BI 1358894 in the mouse forced swimming test. Draft Report. 2 
December 2016.
n00253490
Cytochrome P450 Inducibility in SD rat hepatocytes – Effect on in vitro 
clearance. 18 November 2016.
n00253492
BI 1358894: In vitro inhibition studies on cytochrome P450 dependent 
metabolic reactions. 8 November 2016.
n00253628
Prediction of BI 1358894 Pharmacokinetics and Therapeutic Dose in 
Human. 6 December 2016.
n00253723
Influence of BI 1358894 (10, 30 and 100 mg/kg PO) on cardiovascular 
function (systolic and diastolic arterial pressure, heart rate and ECG) and 
body temperature in conscious rats. GP2014/0251/PH5. 29 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.
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.
n00256526
Evaluation of Induction Potential of Cytochrome P450 Isoforms by 
BI 1358894 in Cultured Human Hepatocytes. 19 July 2017.


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10.
APPENDICES
10.1
DRUG SUPPLIES USED FOR DILUTION AND ANALYTICAL TESTING
10.1.1
Drug supplies overview
a) Midazolam-ratiopharm® 5mg/5mL Injektionslösung; 5 mL-ampoules
b) Isotone Kochsalz-Lösung 0.9% Fresenius Kabi® Infusionslösung, 100 ml bottles 
c) Empty, appropriately labeled glass container, preferably with lid 


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10.1.2
Required equipment and dosing aids – overview
Dosing and diluting syringes:

Henke Sass Wolf 2-part disposable HSW NORM-JECT® Syringes 3 mL

Henke Sass Wolf 2-part disposable HSW NORM-JECT® Syringes 24 mL

Needle tip
Only CE certified syringes WITHOUT rubber stoppers are to be used!


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10.1.3
Dilution procedure
Solution for use with up to 13 subjects
Step 1: 
Open the commercial isotonic saline solution (0.9% NaCl).
Step 2: 
Attach a needle tip to the 3 mL syringe and withdraw a bit more than 1 mL of 
the midazolam solution [concentration: 1 mg/mL] from the originator 
ampoule using a 3 mL syringe.
Step 3:
Remove any air bubbles in syringe (turn upside down and gently push out air 
by depressing the plunger); ensure that exactly 1 mL midazolam solution 
remains in the 3 mL syringe.
Step 4:
Remove and dispose of needle tip; transfer the full 1 mL of midazolam 
solution into an appropriate glass container (with cap) by completely 
depressing the plunger on the 3 mL syringe.
Step 5: 
Attach a needle tip to the 24 mL syringe and withdraw a bit more than 19 mL 
isotonic saline solution into the 24 mL syringe; remove air bubbles (see 
Step 3) and ensure exactly 19 mL isotonic saline solution remains in the 24 ml 
syringe.
Step 6:
Remove and dispose of needle tip; transfer the full 19 mL of isotonic saline 
solution into the same glass container with the midazolam solution by 
completely depressing the plunger on the 24 mL syringe.
Step 7:
Following addition of the midazolam and saline solutions into the glass 
container, ensure the glass container is closed using the corresponding cap. 
The content of the glass container should be mixed thoroughly by swirling 
gently for approximately 1 minute.
Step 8:
Extract a little more than 1.5 mL of the dilution solution using a needle tip 
and a new 3 mL syringe; remove bubbles (see Step 3) and ensure that exactly 
1.5 mL of the diluted midazolam solution (final concentration: 50 µg/mL) 
remains in the 3 mL syringe. Remove and dispose of the needle tip and close 
the syringe with a cap; the solution is now ready for oral administration. 
The final midazolam microdose Oral Solution concentration is 50 µg/mL, for 
administration of 1.5 mL (75 µg), which can be administered per os directly from the 
syringe.


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10.1.4
In-use stability
The chemical in-use stability of the dilution solution is 24 h after its preparation, incl. storage 
at room temperature (15-25°C) in Henke Sass Wolf 2-part disposable HSW NORM-JECT®
syringes until administration.
10.1.5
Mode of application
Microdoses of Midazolam will be administered orally as specified in the Clinical Trial 
Protocol (refer to Flow Chart for dosing schedule). 1.5 ml of diluted midazolam solution 
(concentration 50 µg/mL) will be administered from a syringe, as described above.
Please note that it is the responsibility of the TCM to assure that appropriate supplies are used 
for administration of a dose and dosing is limited to the allowed dosing range for a specific 
dose formulation as stated in this Dilution Instruction.


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10.2
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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10.3
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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10.4
COLUMBA-SUICIDE SEVERITY RATING SCALE


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
12 September 2018
EudraCT number
2018-000389-12
BI Trial number
1402-0002
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1358894 (double-
blind, randomised, placebo-controlled, parallel-
group design) and evaluation of midazolam 
interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects
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
- 1.2.1.5
Clinical experience in humans
- 3.1
Overall trial design and plan
- 3.3.4.1
Removal of individual subjects
- 3.3.4.2
Discontinuation of the trial by the
sponsor
- 5.2.5.6
Neurological examinations
- 6.2.2
Treatment period
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 Flow Chart
- Prolongation of the house confinement to 


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Number of global amendment
1
Day 20 instead of Day 15 due to the halftime of 
BI 1358894
- Additional examinations to confirm the fitness 
of the subjects at discharge Day 20 after breakfast 
(Bond & Lader and Bowdle VAS scores, 
C-SSRS, evaluation of safety lab assessed on 
Day 15 and 18 and a neurological examination).
- Inclusion of neurological examinations at 
discharge and EOT
Section 1.2.1.5
- Safety and tolerability data as well as PK data 
analysed and described from dose groups 3 mg-
200 mg fasted from the SRD part and 50 mg as 
well as 100 mg fed vs. fasted from the FE part. 
Section 3.1
- The respective section of the study has been 
revised to assure that interim doses because of 
safety signals will require a substantial 
amendment
Section 3.3.4.1
- The respective section has been revised to assure 
that a subject who experiences a serious’ adverse 
reaction which is considered at least possibly 
related to the IMP administration will be removed
Section 3.3.4.2
- The respective section has been revised to assure 
that dose escalation will be stopped if the Cmax or 
AUC0-24 of at least 1 subject of one dose group 
increases above the following exposure thresholds 
or if the estimated systemic exposure (group 
gMean values) of the next dose level is expected 
to exceed a Cmax of 1,960 nM or an AUC0-24 of 
26,300 nM*h. 
- As well as severe non-serious adverse reactions 
(i.e. severe non-serious adverse events considered 
as, at least, possibly related to the IMP 
administration) in two subjects in the same 
cohort, independent of within or not within the 
same system-organ-class are leading to a 
discontinuation of the trial by the sponsor.
Section 5.2.5.6
- The addition of the neurological examinations 
has been revised to increase the safety of the 
subjects at discharge and end of trial.


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Number of global amendment
1
Section 6.2.2
- Headache assessment has been included to
classify possibly occurrent headaches
Rationale for change
Based on PK results obtained in the preceding 
SRD study 1402-0001 the mean half-life of 
BI 1358894 is about 50 to 70 h. For this reason 
inhouse confinement will be prolonged by 
additional 3 days (i.e. Day 20). Furthermore, a 
standardized neurological assessment will be 
included at discharge from the unit, in 
combination with suicidality assessment (CSSR) 
and VAS scores (Bowdle, Bond and Lader). This 
enlarged panel of investigations is considered to 
improve the detection of long-lasting CNS effects 
after cessation of treatment if present, thus further 
mitigating safety risks for participating subjects. 
To comply with current guidelines additional 
discontinuation criteria were to be included.
Based on recent comments by competent 
authorities the validated tools used for PK 
analysis have been further specified in the 
respective protocol sections.
Since headache of mild to moderate intensity was 
the most frequent AE of the preceding FIH study, 
a standardized assessment of this specific event 
has been included in the protocol.
The theoretical maximum dose of the MRD study 
was increased to 200 mg QD (Dose Group 5), 
taking into consideration, that this theoretical 
dose level will only be conducted in case safety 
and PK data of preceding dose levels do not 
prevent this.
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
13 November 2018
EudraCT number
2018-000389-12
BI Trial number
1402-0002
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1358894 (double-
blind, randomised, placebo-controlled, parallel-
group design) and evaluation of midazolam 
interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects
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
5.2.4.1
12-lead resting ECG
5.5.2.2
Plasma sampling for metabolism 
analysis
Description of change
Section 5.2.4.1
Duration of ECG Evaluation has been corrected 
according to the Flow Chart. (Day 1 to 20)
Section 5.5.2.2
Duration of sampling has been corrected 
according to the Flow Chart
Rationale for change
Inconsistencies between Flow Chart and Section 
have been corrected.


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Number of global amendment
3
Date of CTP revision
28 February 2019
EudraCT number
2018-000389-12
BI Trial number
1402-0002
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1358894 (double-
blind, randomised, placebo-controlled, parallel-
group design) and evaluation of midazolam 
interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects
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. Footnote
2. Flow Chart
3. Footnote
4. Footnote
5. Exclusion Criteria 16
6. Section 4.1.4
7. Section 5.5.2.3
8. Section 5.2.3
9. Section 10.4
Description of change
1. In Footnote 1 neurological examination added
to Screening Procedures
2. Footnote 2 added on Day 2 in Flow Chart
3. Footnote 2: 3 h added on Day -1
4. Footnote 14: Days 1 + 4 added as described in 
the Flow Chart


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Number of global amendment
3
5. Inability to refrain from smoking on specified 
trial days changed to specified during in-house 
confinement.
6. DG 5 instead of DG 4 entered in Table 4.1.4:2
7. 0.5 ml aliquot changed to 1 ml aliquot
8. Days 1 + 4 added to text regarding to faecal 
blood tests
9. C-SSRS Questionnaire for Screening has been 
corrected
Rationale for change
Correct C-SSRS Questionnaire for Screening 
Visit entered in CTP. In context with this change 
other inconsistencies between Flow Chart and 
Sections and within the CTP have been corrected.


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Number of global amendment
4
Date of CTP revision
03 April 2019
EudraCT number
2018-000389-12
BI Trial number
1402-0002
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1358894 (double-
blind, randomised, placebo-controlled, parallel-
group design) and evaluation of midazolam 
interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Flow Chart
2. Section 6.2.2
Description of change
1. Additional PK samples were inserted at 
days 2, 4, 6, 9 and 11 3 hour after 
administration of BI 1358894 (time of tmax
in previous dose groups)
2. Insertion of the intensity measurement for
headaches


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Number of global amendment
4
Rationale for change
In the 25 mg dose group, 2 subjects showed 
unusual profiles, one with a particularly high 
Cmax, followed by unusual trough values and one 
with lower accumulation (based on trough values) 
than that seen in other subjects. Given the 
peculiar nature of the profiles, it was decided to 
take additional samples at the expected Cmax in 
the case that other subjects show similar profiles. 
In this way, we can identify if it is a consistent 
phenomenon and may better understand 
differences in the PK of the drug. The additional 
amount of blood will not exceed 500 ml per 
subject.
In context with these changes, a few remaining
inconsistencies were also corrected.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21808436
5.0
clinical-trial-protocol-revision-04
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of BI 1358894
(double-blind, randomised, placebo-controlled, parallel-group design) and evaluation
of midazolam interaction (nested, open, fixed-sequence, intra-individual comparison)
in healthy male subjects
Approval-Therapeutic Area 
03 Apr 2019 17:59 CEST
Author-Trial Clinical
Pharmacokineticist
04 Apr 2019 08:44 CEST
Author-Trial Statistician
04 Apr 2019 10:41 CEST
Author-Clinical Trial Leader
04 Apr 2019 14:26 CEST
Verification-Paper Signature
Completion
05 Apr 2019 09:51 CEST
Approval-Team Member Medicine
06 Apr 2019 12:00 CEST


Boehringer Ingelheim 
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Clinical Trial Protocol
TITLE PAGE
Document Number:
c21808436-05
EudraCT No.:
BI Trial No.:
2018-000389-12
1402-0002
BI Investigational
Product:
BI 1358894
Title:
Safety, tolerability, and pharmacokinetics of multiple rising oral doses 
of BI 1358894 (double-blind, randomised, placebo-controlled, 
parallel-group design) and evaluation of midazolam interaction 
(nested, open, fixed-sequence, intra-individual comparison) in healthy 
male subjects
Lay Title:
This study in healthy men tests how different doses of BI 1358894 are 
taken up in the body and how well they are tolerated. The study also 
tests how BI 1358894 affects the way the body breaks down 
midazolam.
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax: 
Principal Investigator:
Phone:
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendment 4))
Version and Date:
Version: 5.0
Date: 03 April 2019
Page 1 of 105
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© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
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:
03 April 2019
29 May 2018
1402-0002
Title of trial:
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of BI 1358894 
(double-blind, randomised, placebo-controlled, parallel-group design) and evaluation 
of midazolam interaction (nested, open, fixed-sequence, intra-individual comparison) 
in healthy male subjects
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
(1) To investigate safety, tolerability, and pharmacokinetics following multiple rising 
doses of BI 1358894
(2) To investigate the effect of BI 1358894 on the pharmacokinetics of midazolam 
given as oral microdose
Methodology:
(1) Double-blind, randomised (within dose groups), placebo-controlled, parallel-group 
comparison
(2) Nested, open, fixed-sequence, intra-individual comparison
No. of subjects: 
total entered:
50*
each treatment:
10 per dose group (8 on active drug and 2 on placebo) 
* 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 50, but will not exceed 80 subjects entered.
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
Test product 1:
BI 1358894 film-coated tablets
dose:
10 mg, 25 mg, 50 mg, 100mg, 200 mg q.d.
mode of admin.:
Oral with 240 mL of water after a standard continental breakfast
Test product 2 (probe): Midazolam for injection used as oral solution
dose:
75 µg q.d.
mode of admin.:
Oral with 240 mL of water after a standard continental breakfast


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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:
03 April 2019
29 May 2018
1402-0002
Comparator product to 
test product 1:
Matching placebo
Dose:
Not applicable
Mode of admin.:
Oral with 240 mL of water after a standard continental breakfast
Duration of treatment: (1) BI 1358894 or placebo: 14 days with q.d. multiple doses
(2) Midazolam: 3 single doses (Days -1, 1, and 14)
Criteria for
pharmacokinetics:
Secondary endpoints:
(1) BI 1358894
After the first dose:
AUC0-24 and Cmax
After the last dose:
AUCτ,ss and Cmax,ss
(2) Midazolam
After single doses:
AUC0-tz and Cmax
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 1358894 is the number 
[N (%)] of subjects with drug-related adverse events.


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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:
03 April 2019
29 May 2018
1402-0002
Statistical methods:
(1) BI 1358894
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 1358894 will be explored using a regression model. A 
95% confidence interval (CI) for the slope will be computed.
Attainment of steady state will be analysed by a repeated measures linear model for 
trough concentrations (Cpre) of BI 1358894 with dose as an additional covariate if 
permissible.
(2) Midazolam
Descriptive statistics will be calculated for all endpoints.
Relative bioavailability will be estimated by the ratios of the geometric means (test/
reference) for the secondary endpoints of midazolam. Additionally, their two-sided 
90% 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 is not specified. The statistical model will be an 
ANOVA on the logarithmic scale including effects for ‘subjects’, and ‘treatment’. CIs 
will be calculated based on the residual error from ANOVA.


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FLOW CHART
Visit
Day
Planned time (relative to first 
BI 1358894 administration
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9 BI 1358894
PK blood MDZ9
PK urine
9, 10
Faecal laboratory test14
Visual analogue scales
Orthostatic testing
12-lead ECG16
Vital signs (BP, PR, RR)
Questioning for AEs & 
concomitant therapy5
1 -21 to -2
Screening (SCR)1,11
x
x
x
x
x
x
x
2
-4 to -2
-72:00
08:00
Ambulatory visit
x6
x
x
-1
-25:30
06:30
Admission to trial site
x2,12
x2,7
x2
x
x2
x2
x2
-24:30
07:30
Standardized continental breakfast
-24:00
08:00
Midazolam administration
-23:50
08:10
x
-23:30
08:30
x
-23:00
09:00
x
x
x
-22:00
10:00
240 mL fluid intake
x
x
x
x
-21:30
10:30
x
-21:00
11:00
x
-20:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
x
x
-18:00
14:00
x
-16:00
16:00
Snack (voluntary)3
x
x
x
-14:00
18:00
Dinner3
1
-1:00
07:00
Allocation to treatment: BI 1358894 
or placebo
x2,15 x2
x2
x2
x2
x2,13
x2
x2
-0:30
07:30
Standardized continental breakfast
0:00
08:00
BI 1358894 or placebo administration 
& midazolam
▲
│
0:10
08:10
x
x
│
0:20
08:20
x
│
0:30
08:30
x
x
│
1:00
09:00
x
x
│
x8
x
2:00
10:00
240 mL fluid intake
x
x
│
x
x
x
x
2:30
10:30
x
│
3:00
11:00
x
x
│
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
┼
x
x
x
x
6:00
14:00
x
x
│
8:00
16:00
Snack (voluntary)3
x
x
┼
x
x
x
10:00
18:00
Dinner3
│
12:00
20:00
x
┼
x
x
x
x 
2
24:00
08:00
BI 1358894 or placebo administration19
x
x2
▼
x2,17
x
x
x
27:00
11:00
x
x
3
48:00
08:00
BI 1358894 or placebo administration19
x2
x
x
x
4
72:00
08:00
BI 1358894 or placebo administration19
x18
x2
x
x
x8
x
x
75:00
11:00
x
x
76:00
12:00
x
x
x
80:00
16:00
x
x
x
x
5
96:00
08:00
BI 1358894 or placebo administration19
x2
x
x
x
6
120:00
08:00
BI 1358894 or placebo administration19
x2
x
x
x
123:00
11:00
x
x


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, neurological examination; check of vital signs, ECG, safety laboratory 
(including drug screening and alcohol breath test), faecal laboratory tests, demographics (including determination of 
body height and weight, smoking status and alcohol history), relevant medical history, concomitant therapy and review 
of inclusion/exclusion criteria, orthostatic testing, Bond & Lader and Bowdle visual analogue scales and suicidality 
assessment (C-SSRS).
2.
Time is approximate. The respective procedure is to be performed and completed within 2 h (3 h on day -1) prior to 
drug administration. 
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
Visit
Day
Planned time (relative to first 
drug administration
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9 BI 1358894
PK blood MID9
PK urine
9, 10
Faecal  laboratory tests14
Visual analogue scale
Orthostatic testing
12-lead ECG
Vital signs (BP, PR, RR)
Questioning for AEs & 
concomitant therapy 5
2
7
144:00
08:00
BI 1358894 or placebo administration19
x18
x2
x
x
x8
x
x
148:00
12:00
x
x
x
152:00
16:00
x
x
x
x
8
168:00
08:00
BI 1358894 or placebo administration19
x
x
x
9
192:00
08:00
BI 1358894 or placebo administration19
x2
x
x
x
195:00
11:00
x
x
10
216:00
08:00
BI 1358894 or placebo administration19
x
x
x
x
x
11
240:00
08:00
BI 1358894 or placebo administration19
x2
x2,17
x
x
x
243:00
11:00
x
x
12
264:00
08:00
BI 1358894 or placebo administration19
x
x
x
13
288:00
08:00
BI 1358894 or placebo administration19
x2
x
x
x
14
311:00
07:00
x2
x7,2
x
x
x
x8
x2
x2
311:30
07:30
Standardized breakfast
312:00
08:00
Last BI 1358894 or placebo
administration & midazolam
▲
│
x22
312:10
08:10
x7
x
│
312:20
08:20
x7
│
312:30
08:30
x7
x
│
313:00
09:00
x7
x
│
x
x
314:00
10:00
240 mL fluid intake 
x
x7
x
│
x
x
x
x
314:30
10:30
x
│
315:00
11:00
x7
x
│
x
316:00
12:00
240 mL fluid intake, thereafter lunch3
x7
x
┼
x
x8
x
x
318:00
14:00
x7
x
│
320:00
16:00
Snack (voluntary)3
x7
x
┼
x8
x
x
322:00
18:00
Dinner3
│
324:00
20:00
x7
┼
x8
x
x
15
336:00
08:00
x
x7
▼
x8
x
x
16
360:00
08:00
x7
x
x
x
17
384:00
08:00
x7
x8
x
x
18
408:00
08:00
x
x7
x
x
19
432:00
08:00
x
x8
x
x
20
456:00
08:00
Breakfast3 (voluntary),
discharge from trial site11, 20
x7
x
x
x8
x
x
22
504:00
08:00
Ambulatory visit
x7
x
x
3
28 to 32
End of trial (EOT) examination4,11
x
x
x
x
x
x


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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.
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.
6.
Safety laboratory to be taken and to be medically evaluated within 4 days prior to first administration of BI 1358894. 
This safety laboratory can be omitted, if the screening examination is performed on Days -4, -3 or -2.
7.
At these time points, additional blood samples for metabolite identification will be taken (refer to Section 5.5.2.2). 
A blank sample is to be taken prior to any medication intake (Day -1).
8.
The ECG recording has to be performed as triple at this time point.
9.
Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject.
10.
A blank urine sample (x) is to be obtained on Day 1 prior to administration of BI trial medication. Other urine samples 
are to be collected on Day 1 over the post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12 and 12-24 h and on Day 14 
over the post-dose intervals (◄––│––│––►)312-316, 316-320, 320-324, and 324-336 h.
11.
Suicidality assessment only at screening, discharge from trial site and end of trial.
12.
Only drug screening and alcohol breath test.
13.
Prior to BI drug administration 3 triplicate ECGs are recorded within approximately one hour. The recordings should 
be separated by at least 15 minutes.
14.
Faecal laboratory testing (faecal occult blood and faecal calprotectin) will be done at screening, within 4 days prior to 
first dosing of BI 1358894 (i.e. Day -4 to Day -2), in the first stool released after 12 hours after administration on Days 
1, 4, 7, 10, and 14, on Day 16, and at EOT.
15.
Additionally, one blood sample will be taken for pharmacogenomic analyses.
16.
ECGs performed on Days 1 through 20 will be transferred to the central ECG lab for evaluation.
17.
At these time points, visual analogue scale assessments will be done at 08:00, 10:00 and 12:00.
18.
Only CRP.
19.
Trial drug will be administered after a standardized continental breakfast.
20.
Confirmation of fitness includes physical examination, neurological examination, Bond & Lader and Bowdle visual 
analogue scale, vital signs, ECG, recording of AEs and concomitant therapies. Evaluation of safety lab assessed on 
Day 15 and 18.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................16
1.2.1
...................................................................16
1.2.1.1
Nonclinical pharmacology.......................................................16
1.2.1.2
Safety pharmacology ...............................................................16
1.2.1.3
Toxicology...............................................................................17
1.2.2
Midazolam .............................................................................................28
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 29
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................29
2.2
TRIAL OBJECTIVES.......................................................................................30
2.3
BENEFIT - RISK ASSESSMENT ...................................................................31
2.3.1
Procedure-related risks ........................................................................31
2.3.2
Risks related to the intake of BI 1358894 and safety measures........31
2.3.2.1
Drug-related risks.....................................................................31
2.3.2.2
Risk minimization (safety precautions and stopping rules).....32
2.3.2.3
Drug induced liver injury.........................................................33
2.3.3
Overall assessment................................................................................33
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 35
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................35
3.1.1
Administrative structure of the trial...................................................37
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................38
3.3
SELECTION OF TRIAL POPULATION ......................................................38


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3.3.1
Main diagnosis for study entry............................................................39
3.3.2
Inclusion criteria...................................................................................39
3.3.3
Exclusion criteria ..................................................................................39
3.3.4
Removal of subjects from therapy or assessments.............................41
3.3.4.1
Removal of individual subjects................................................41
3.3.4.2
Discontinuation of the trial by the sponsor..............................41
3.3.5
Replacement of subjects .......................................................................42
4.
TREATMENTS........................................................................................ 43
4.1
TREATMENTS TO BE ADMINISTERED....................................................43
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................43
4.1.2
Method of assigning subjects to treatment groups ............................43
4.1.3
Selection of doses in the trial................................................................44
4.1.4
Drug assignment and administration of doses for each subject .......44
4.1.5
Blinding and procedures for unblinding ............................................46
4.1.5.1
Blinding ..................................................................................46
4.1.5.2
Procedures for emergency unblinding .....................................46
4.1.6
Packaging, labelling, and re-supply ....................................................47
4.1.7
Storage conditions.................................................................................47
4.1.8
Drug accountability ..............................................................................48
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................48
4.2.1
Other treatments and emergency procedures....................................48
4.2.2
Restrictions............................................................................................49
4.2.2.1
Restrictions regarding concomitant treatment .........................49
4.2.2.2
Restrictions on diet and life style.............................................49
4.3
TREATMENT COMPLIANCE.......................................................................49
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 51
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................51
5.1.1
Endpoints of efficacy.............................................................................51
5.1.2
Assessment of efficacy...........................................................................51
5.2
SAFETY..............................................................................................................51
5.2.1
Endpoints of safety................................................................................51
5.2.2
Assessment of adverse events...............................................................51
5.2.2.1
Definitions of adverse events...................................................51
5.2.2.2
Adverse event collection and reporting ...................................55
5.2.3
Assessment of safety laboratory parameters......................................56
5.2.4
Electrocardiogram................................................................................59
5.2.4.1
12-lead resting ECG.................................................................59


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5.3
OTHER...............................................................................................................63
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................64
5.5
 
..................................................................................64
5.5.1
..................................................................64
5.5.1.1
Secondary endpoints................................................................64
5.5.2
Methods of sample collection...............................................................66
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................66
5.5.2.2
Plasma sampling for metabolism analysis ...............................67
5.5.2.3
Urine sampling for pharmacokinetic analysis..........................67
5.5.3
Analytical determinations ....................................................................68
5.5.3.1
Analytical determination of BI 1358894 plasma     
concentration............................................................................68
5.5.3.2
Analytical determination of BI 1358894 urine concentration .68
5.5.3.3
Analytical determination of midazolam plasma concentration68
6.
INVESTIGATIONAL PLAN.................................................................. 69
6.1
VISIT SCHEDULE............................................................................................69
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................69
6.2.1
Screening period....................................................................................69
6.2.2
Treatment period ..................................................................................69
6.2.3
End of trial period.................................................................................70
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 72
7.1
STATISTICAL DESIGN – MODEL ...............................................................72
7.1.1
Objectives...............................................................................................72
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................72
7.3
PLANNED ANALYSES....................................................................................72
7.3.1
Primary analyses...................................................................................73
7.3.2
Secondary analyses ...............................................................................73
7.3.3
Safety analyses.......................................................................................76
7.4
HANDLING OF MISSING DATA ..................................................................78
7.4.1
Safety......................................................................................................78


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7.4.2
Plasma/urine drug concentration - time profiles ...............................78
7.4.3
Pharmacokinetic parameters...............................................................78
7.5
RANDOMISATION ..........................................................................................78
7.6
DETERMINATION OF SAMPLE SIZE ........................................................79
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 80
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................80
8.2
DATA QUALITY ASSURANCE .....................................................................80
8.3
RECORDS..........................................................................................................81
8.3.1
Source documents .................................................................................81
8.3.2
Direct access to source data and documents.......................................81
8.3.3
Storage period of records.....................................................................81
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................81
8.5
STATEMENT OF CONFIDENTIALITY.......................................................82
8.6
COMPLETION OF TRIAL..............................................................................82
9.
REFERENCES......................................................................................... 83
9.1
PUBLISHED REFERENCES...........................................................................83
9.2
UNPUBLISHED REFERENCES.....................................................................84
10. APPENDICES .......................................................................................... 86
10.1
DRUG SUPPLIES USED FOR DILUTION AND ANALYTICAL 
TESTING............................................................................................................86
10.1.1 Drug supplies overview.........................................................................86
10.1.2 Required equipment and dosing aids – overview...............................87
10.1.3 Dilution procedure................................................................................88
10.1.4 In-use stability.......................................................................................89
10.1.5 Mode of application ..............................................................................89
10.2
VISUAL ANALOGUE SCALE (VAS) ............................................................90
10.3
BOWDLE VAS-SCORE ...................................................................................91
10.4
COLUMBA-SUICIDE SEVERITY RATING SCALE..................................92
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 98


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2
Amount of analyte eliminated in urine over the time interval t1 to t2
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24h
%AUCtz-∞
the percentage of AUC0-∞obtained by extrapolation
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
Cmin
Minimum measured concentration of the analyte in plasma
CML
Local clinical monitors
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
CRA
Clinical research associate
CRF
Case report form
CRO
Clinical Research Organization
C-SSRS
Columbia Suicidal Severity Rating scale
CTP
Clinical trial protocol
CTR
Clinical trial report


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CV
Arithmetic coefficient of variation
DDI
Drug-drug interaction
DG
Dose group
DILI
Drug induced liver injury
ECG
Electrocardiogram
ECT
Electro-convulsive therapy
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
FDA
Food and Drug Administration
fet1-t2
Fraction of administered drug excreted unchanged in urine over the time 
interval from t1 to t2
FIH
First in human
FST
Forced swim test
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GLP
Good laboratory practice
gMean
Geometric mean
GMP
Good Manufacturing Practice
hERG
human ether-a-go-go related gene
HR
Heart rate
IB
Investigator’s brochure
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LVSP
left ventricular pressure parameters 
MDZ
Midazolam
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
MRTex
Mean residence time of the analyte in the body after extravascular/oral 
administration
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available


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PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
PR
Pulse rate
q.d.
Quaque die, 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
RA
Accumulation ratio of the analyte in plasma after multiple dose 
administration over a uniform dosing interval τ
RR
Respiratory rate
SAE
Serious adverse event
SCR
Screening
SRD
Single-rising dose
SOP
Standard Operating Procedure
ss
(at) steady state
T
Test product or treatment
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
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
Vz/F,ss
Apparent volume of distribution during the terminal phase at steady state
after extravascular administration


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND


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1.2
DRUG PROFILE
1.2.1
1.2.1.1
Nonclinical pharmacology
1.2.1.2
Safety pharmacology


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1.2.1.3
Toxicology


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1.2.2
Midazolam
Midazolam is a sensitive substrate of CYP3A4, used both in vitro and in vivo as a probe drug 
for CYP3A4 drug interactions. Absorption is rapid, with maximum concentrations reached 
around 15 to 30 min. Clearance is also rapid, with an elimination half-life of 1.5 to 2.5 hours. 
The PK of midazolam is dose proportional over a range of at least 0.1 µg to 3 mg 
[R17-3022]. For further information, refer to the summary of product characteristics 
[R17-3087].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Dose Selection


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2.2
TRIAL OBJECTIVES
The primary objective of the trial is to investigate the safety and tolerability of BI 1358894 in 
healthy male subjects following oral administration of multiple rising doses of 10 mg, 25 mg, 
50 mg, 100 mg, 200 mg q.d. over 14 days.
Secondary objectives are the exploration of PK, including dose proportionality and 
investigation of steady state attainment of BI 1358894 after multiple dosing. 


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In addition, the effect of BI 1358894 on the pharmacokinetics of midazolam, given as an oral 
microdose, will be explored.
A description of the endpoints to be determined and the observations, along with specific 
information as how to collect the data for that information, is provided in Section 5. 
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of 
BI 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.
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 and safety measures
2.3.2.1
Drug-related risks
Risk factors were derived from (1) observations in nonclinical studies, (2) the mode of action 
and nature of the target, and (3) the relevance of animal models. 
Risks derived from observations in non-clinical studies
Rats and dogs were employed as the animal species for general toxicology investigations on 
BI 1358894, because in vitro and in vivo profiling supported the suitability of both species 
for nonclinical safety profiling of BI 1358894. 
As summarised in Section 1.2.1, potential risks observed in non-clinical studies are a long 
lasting decrease in the blood pressure in rats, an increase in heart rate in rats and dogs, and 
signs of a short lasting episode of arterial/ perivascular inflammation in rats. All findings 
were observed within 5 days after the start of treatment. The 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 the start of dosing and 
resolved despite continued treatment, indicating its transient character. The non-clinical 
safety data support clinical Phase I trials in non-childbearing humans with daily oral 
administration for up to 4 weeks.


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2.3.2.2
Risk minimization (safety precautions and stopping rules)
The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers: 

Careful dose selection

Shallow dose escalation using a factor ≤2.5 for all rising steps 

For safety reasons, each dose group will be divided into 2 cohorts of 5 subjects each 
(4 on active drug, 1 on placebo). Each drug administration will be separated by at 
least 10 minutes and the dosing of the cohorts will be separated by at least 48h. 

Interim measurements of BI 1358894 plasma concentrations will be performed. Dose 
escalation will be stopped if the mean Cmax or AUC of a dose group exceeds the 
exposure thresholds (either following a single dose or multiple doses) of 1960 nM for 
Cmax or 26 300 nM·h for AUC0-24, or if the mean of the above parameters for the next 


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higher dose group is expected to exceed these values. Estimations will be based on 
preliminary PK results of the preceding dose groups (see Section 7.3.4)

If one dose level was safe and showed acceptable tolerability and if no stopping 
criterion was met (see Section 3.3.4.2), the next higher dose will be given, 
maintaining a time interval of at least 6 days (referring to the first subject of each dose 
group)

An extensive safety laboratory will be performed with special focus on full blood 
exam (see Flow Chart)

Repeated triplet 12-lead ECGs are scheduled throughout the study 

In this study, blood pressure and heart rate will be closely monitored (see Flow 
Chart). Dose escalation will be stopped if at least 2 subjects at one dose level show a 
sustained decrease in systolic blood pressure of ≥20 mmHg for at least 2 hours after 
drug administration compared to baseline (Day 1, predose). Orthostatic testing will be 
performed to detect whether potential hemodynamic effects of BI 1358894 might 
interfere with daily life activities. Dose escalation will be stopped if orthostatic 
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 blood 
pressure, pulse rate, respiratory rate), orthostatic tests, ECGs, safety laboratory tests 
including CRP, ESR, hormone parameters, faecal occult blood and faecal calprotectin 
tests, visual analogue scales, suicidality, and assessment of adverse events) 

Subjects will be hospitalised throughout the study from Day -1 (treatment with oral
microdose of midazolam) to Day 17 and will be discharged only after a formal 
assessment and confirmation of fitness by an investigator or qualified designee. 
During the in-house stay, the subjects will be under medical observation and 
thoroughly monitored for both expected and unexpected adverse events

As reproductive toxicity studies have not yet been conducted, only male subjects will 
be enrolled in this study
2.3.2.3
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, adverse events of special interest).
2.3.3
Overall assessment


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
Overall, 50 subjects are planned to participate in this Phase I trial, according to 5 sequential 
dose groups, comprising 10 subjects per group. 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 50, but will not exceed 80 subjects 
entered. If required for the further evaluation of pharmacokinetics such changes may be 
implemented via non-substantial CTP amendments. However, the addition of further dose 
groups for the evaluation of safety findings is subject to a substantial CTP amendment 
requiring approval.
The trial design is depicted in Figure 3.1: 1. 
Figure 3.1: 1 
Overview of trial design
Arrows: trial drug administration (red: BI 1358894, blue: midazolam); triangles: PK blood sampling (red: BI 1358894, 
blue: midazolam)
BI 1358894
This multiple-rising dose segment is double-blind, randomised within dose groups, and 
placebo-controlled within dose groups. 
Within each dose group, 8 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group. For safety reasons, the dose groups are each 
divided into 2 cohorts (per cohort: 4 subjects on active and 1 subject on placebo, treated in 
parallel). Both cohorts will be dosed in a randomised fashion. Each drug administration will 
be separated by at least 10 minutes and the dosing of the cohorts will be separated by at least 
48 h.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.


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Table 3.1: 1
Dose groups
Dose Group
1
2
3
4
5
Dose (mg)
10
25
50
100
200
Number of subjects
10
10
10
10
10
Subjects receiving placebo
2
2
2
2
2
Subjects receiving active drug
8
8
8
8
8
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 6 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 PK data of the 
preceding dose groups. The next 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).
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

Results from 12-lead ECG in the current and preceding dose groups

Vital signs and results from orthostatic tests in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups

Preliminary PK data with availability as per 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 trial clinical monitor is responsible for 
organisation 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. 


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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.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
Midazolam 
This segment is designed as a nested, open, fixed-sequence, intra-individual comparison.
The potential interaction of BI 1358894 with a CYP3A4 substrate will be assessed separately 
in dose groups 1 to 5 and in the subjects receiving placebo. This will be conducted in parallel 
to the multiple dose assessments, using a microdose of midazolam (a sensitive CYP3A4 
substrate) administered at 3 different time points (Days -1, 1, and 14).
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 the participating trial site
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 by 
 
under the supervision of the Principal Investigator.
Safety laboratory tests will be performed 
 
The analyses of BI 1358894 and midazolam 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. 
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for post-study evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.


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Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
For multiple-rising dose trials, the design described in Section 3.1 is viewed favourably under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 1358894.
With the rising dose design, double-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, 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 the 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 and tolerability. Each dose group consists of 10 subjects with 8 on 
active treatment, and 2 on placebo. The placebo control group includes all subjects of all dose 
groups treated with placebo. Eight subjects per active treatment group are in general 
considered as sufficient for the exploratory evaluation of pharmacokinetics.
The evaluation of a potential CYP3A4 interaction with BI 1358894 using a microdose of 
midazolam is considered to be acceptable. A microdose of midazolam is not expected to have 
any pharmacological effects. Therefore, subjects are not exposed to undue risks. Also, the 
evaluation of the investigational drug should not be influenced. This assessment will allow 
for better judgement regarding acceptable co-medications in a Proof of Clinical Concept 
study and later in the Phase III development.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 50 healthy males will enter the study. The actual number of subjects entered 
may exceed the total of 50 if additional intermediate doses will be tested (see Section 3.1). 
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.
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.


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3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the investigator’s assessment, based on a complete 
medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and 
clinical laboratory tests
2. Age of 18 to 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 adequate contraception with their female partner 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 (with medical assessment of 
the surgical success) or

Surgical sterilisation (including bilateral tubal occlusion, hysterectomy or bilateral 
oophorectomy) of the subject's female partner or

The use of condoms, if the female partner uses an adequate contraception method in 
addition, e.g., intrauterine device (IUD), hormonal contraception (e.g. implants, 
injectables, combined oral or vaginal contraceptives) that started at least 2 months 
prior to first drug administration, or barrier method (e.g. diaphragm with spermicide)
Unprotected sexual intercourse with a 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 and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. C-Reactive Protein > upper limit of normal (ULN), erythrocyte sedimentation rate (ESR) 
≥15 millimeters/h, liver or kidney parameter above ULN, or any other laboratory value 
outside the reference range that the investigator considers to be of clinical relevance
4. Positive or missing faecal occult blood test (retest allowed)
5. Positive testing for faecal calprotectin (retest allowed)


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6. Any evidence of a concomitant disease judged as clinically relevant by the investigator
7. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
8. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
9. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
10. History of relevant orthostatic hypotension, fainting spells, or blackouts
11. Chronic or relevant acute infections
12. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
13. Use of drugs within 30 days prior to administration of trial medication that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
14. 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
15. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
16. Inability to refrain from smoking during in-house confinement
17. Alcohol abuse (consumption of more than 30 g per day)
18. Drug abuse or positive drug screening
19. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
20. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
21. Inability to comply with dietary regimen of trial site
22. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
23. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome) 
24. 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:
25. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
26. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
For study restrictions, refer to Section 4.2.2.


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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, 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 a raised CRP level of >3.00 mg/dL or an ESR of ≥20 millimeters/hour 
7. The subject experiences a serious’ adverse reaction which is considered at least possibly 
related to the IMP administration
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).
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. These discontinuations will be discussed in the 
CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:


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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 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 if the Cmax or AUC0-24 of at least 1 subject of one dose 
group increases above the following exposure thresholds or if the estimated systemic 
exposure (group gMean values) of the next dose level is expected to exceed a Cmax of 
1,960 nM or an AUC0-24 of 26,300 nM*h (see Section 7.3.4).
6. Dose escalation will be stopped if at least 2 subjects at one dose level show relevant 
individual QT prolongation (absolute QT or QTc greater than 500 ms), which has been 
confirmed by a repeat ECG recording.
7. Dose escalation will be stopped if at least 2 subjects at one dose level show a sustained 
decrease in systolic blood pressure of ≥20 mmHg for at least 2 hours after drug 
administration compared to baseline (Day 1, predose), which will be measured after 
15 min in a supine position (to avoid false positive signals because of the required 
prolonged resting period after drug intake) 
8. Severe non-serious adverse reactions (i.e. severe non-serious adverse events considered 
as, at least, possibly related to the IMP administration) in two subjects in the same cohort, 
independent of within or not within the same system-organ-class.
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
If 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 or treatment sequence 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.
4.1.1
Identity of BI investigational product and comparator products
The characteristics of the investigational products are given below.
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 10 dose cohorts (2 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 list of subject and medication numbers 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 


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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
The doses selected for this trial are intended to cover the sub-therapeutic as well as the 
estimated therapeutic and supra-therapeutic range and include a safety margin. For details, 
refer to Section 1.2.
BI 1358894
The dose range of BI 1358894 for this trial was selected on the basis of the data obtained in 
the ongoing FIH SRD Trial 1402.1. So far, dose levels up to 200 mg were well tolerated.
Midazolam
The dose of midazolam used for the DDI evaluation was chosen to be 75 μg, within the 
definition of a microdose, i.e. a 1/100th of the therapeutic dose (in case of midazolam 7.5 mg) 
or 100 μg whichever is smaller. Since midazolam PK is dose proportional ranging from the 
microdose to the therapeutic dose, the microdose should still accurately predict CYP3A4 DDI 
liability, while remaining below a pharmacologically active concentration. A solution for 
injection was chosen for administration as an oral solution, as a solution for injection is meant 
to be diluted and, thus, there is data available regarding the stability and compatibility of a 
diluted solution. Furthermore, the solution for injection contains midazolam in isotonic saline 
solution, while the oral solution has added excipients, making it less than ideal for such a 
dilution. Finally, the IV solution has been successfully diluted and administered orally as a 
microdose in previous clinical studies without any reports of AEs [R17-3022, R17-3023].
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 (BI 1358894) and Table 4.1.4: 2
(midazolam). The number of units for placebo corresponds to the number of units of the 
respective dose level.


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Table 4.1.4: 2
Midazolam treatments, oral administration
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Number of units 
per administration
Total daily 
dose
1 to 5
Midazolam
Solution for 
injection
5 mg/5 mL diluted to 
50 μg/mL
1.5 mL 
75 µg
The oral solutions for dosing midazolam will be prepared according to the instruction given 
in Appendix 10.1. Trial medication will be prepared by pharmacists or qualified pharmacy 
staff members or qualified medical study personnel at the trial site under the responsibility of 
the investigator.
Trial medications will be administered orally to the subjects, while in a sitting or standing 
position, together with about 240 mL of water under supervision of the investigating 
physician or an authorised designee. The so-called four-eye principle (two-person rule) 
should be applied for administration of trial medication and its preparation. To ensure a 
dosing interval of 24 h, the administration of trial medication should take place at the same 
time every day. On Days 1 and 14, BI 1358894 will be administered immediately prior to 
midazolam.
In each treatment, a standard continental breakfast will be served 30 min before drug
administration. The meal must be completely consumed prior to drug administration. The 
composition of the standard continental breakfast is detailed in Table 4.1.4: 3.
Table 4.1.4: 3
Composition of the standard continental breakfast
Ingredients
kcal
1 bread roll
164
15 g butter
113
1 slice of Gouda cheese (approximately 40g)
146
1 slice of meat (approximately 20g)
33
1 cup of decaffeinated coffee or tea (without sugar)
2
Sum1
458
1
The total caloric content was supplied approximately as following: 88 kcal as protein, 133 kcal 
as carbohydrate, and 237 kcal as fat.
Subjects will be hospitalised and kept under close medical surveillance throughout the study 
from Day -1 (microdose of midazolam) until Day 20 (72 h following drug administration on 
Day 14). During the first 2 h after drug administration on all application days, subjects are not 
allowed to lie down (i.e. no declination of the upper body of more than 45 degrees from 
upright posture except for medical examination), or to sleep. For restrictions with regard to 
diet, see Section 4.2.2.2.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
BI 1358894
This segment of the trial will be double-blind with regard to subjects and investigators (as 
well as the research staff at the trial site) in order to eliminate observer or performance bias. 
This means avoiding systematic differences in assessments regarding the subject’s treatment 
(active drug or placebo). According to the rising dose design, the current dose level will be 
known to the subjects and investigator.
At the trial site, access to the randomisation schedule is restricted to unblinded pharmacists 
and pharmacy staff members. Access to the codes will be controlled and documented by a 
signed confidentiality statement, which will be stored in the TMF. Persons directly involved 
in the clinical conduct of the trial will not have access to the treatment allocation prior to 
database lock.
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, 
statistician, bioanalyst, pharmacokineticist, pharmacokinetic analyst, pharmacometrician, 
drug metabolism scientist as well as dedicated CRO personnel). The objective of the trial is 
not expected to be affected.
Within the ECG laboratory, the staff involved with interval measurements and assessments 
will be blinded with respect to the treatment and also with regard to the recording date and 
time as well as the time points of the ECGs. The interval measurements for a given subject 
will be performed in a random and blinded sequence by a single technician. No more than 
two different blinded readers will evaluate the ECGs of the study. If an interim safety 
analysis of ECG data is required, a part of the staff of the ECG laboratory may be unblinded. 
This part of the staff will be strictly separated from the staff that is involved with interval 
measurements and assessments of single ECGs (blinded).
Midazolam 
Midazolam treatment 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
BI 1358894
For the blinded treatment of this trial, the investigator will be supplied with a set of sealed 
envelopes containing the medication codes for each subject according to the randomisation 
scheme. The envelopes will be kept unopened at the trial site until the end of data collection. 
An envelope may only be opened in emergency situations when the identity of the trial drug 
must be known to the investigator in order to provide appropriate medical treatment or to 


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assure safety of trial participants. If the envelope for a subject is opened, the sponsor must be 
informed immediately. The reason for opening the code break must be documented on the 
envelope or appropriate CRF page along with the date and the initials of the person who 
broke the code. At the close-out visit, all envelopes are collected.
Midazolam
As midazolam treatment will be conducted in an open fashion, the treatment information will 
be known. 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, with the exception of 
midazolam, which will be purchased by the trial site.
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 or medication number

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 
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.


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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  
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 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 authorise symptomatic 
therapy.
In case of alterations of blood pressure (hypotension) and heart rate (tachycardia), which 
were reported in nonclinical toxicology studies (see Section 1.2.2), first physical 
interventions will be the treatment of symptoms. If unsuccessful, appropriate drug therapy 
will be initiated according to common guidelines and algorithms of emergency trainings. 
Dependent on individual symptoms, for the treatment of tachycardia this may include 
intravenous administration of beta blockers or appropriate antiarrhythmic drugs. For the 
treatment of hypotension, in addition to volume substitution, administration of vasopressors 
may be a further step. The entire staff of the trial site assuming medical responsibility during 
the conduct of the study is routinely trained in emergency procedures. 


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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. On PK profile days (Days -1, 1, and 14), no food is allowed for 
at least 4 hours after drug intake. On the remaining days (Days 2 to 13), food is not allowed 
for at least 2 h after drug intake. 
From 1 hour before drug intake until lunch, liquid intake is restricted to the water 
administered with the drug, and an additional 240 mL of water served on Days -1, 1, and 14 
at 2 h and 4 h post-dose (mandatory for all subjects).  
During urine collection periods (Days 1 and 14), total fluid intake should be at least 1 L but 
should not exceed 3.5 L within 24 hours.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements including St. John's wort (Hypericum perforatum) are not permitted 
starting 7 days before the first trial drug administration until last PK sampling of the trial.
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 foods or drinks (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. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and urinary excretion will provide additional confirmation of compliance.


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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
A continuous safety evaluation, including results of safety laboratories, ECG readings,
recordings of vital signs and adverse events will be performed before the individual subject
and the subsequent cohort is dosed.
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 events.
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.


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The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if 
they are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 

is life-threatening, which refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation, 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect, 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the subject and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.


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Adverse events of special interest 
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.2.2.
The AESI for this trial is hepatic injury, as defined by the following alterations of hepatic 
laboratory parameters:

an elevation of aspartate transaminase (AST) and/or alanine aminotransferase
(ALT)≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN 
measured in the same blood sample, or

aminotransferase (ALT and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure that these parameters 
are analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).


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
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
Suicidal risk assessed by the C-SSRS (paper version)
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the screening visit (using the ‘screening / baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and behavior 
will also be recorded.
After the baseline visit the assessment ‘since last visit’ will be performed at each clinic or 
phone visit (‘since last visit’ version). The investigator is to review positive and negative 
reports for plausibility and clinical relevance. Doubtful reports may be repeated or reports 
may be validated by a consulting psychiatrist. If there is a confirmed positive report of 
suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to 
immediately interview the subject during the clinic visit, and/or is to consult a psychiatrist. 


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If the positive report is confirmed, appropriate actions for the subject’s safety have to be 
initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behaviour must 
be reported as separate SAEs by the investigator.
For ‘Self-injurious behaviour, no suicidal intent’ (Type 11) standard AE / SAE reporting 
rules are to be applied.
For each negative report (suicidal ideation type 1, 2 or 3) after start of the trial, the 
investigator is to decide based on clinical judgment whether it represents an adverse event 
(AE) as defined in the protocol, and if it is considered an AE then it must be reported 
accordingly.
5.2.2.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as 'How do you feel?'. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.


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AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events,  a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timelines apply as for the initial 
information.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
Pregnancy
Once a male subject has been enrolled in the clinical trial and has taken trial medication, and 
if a partner of the male trial participant becomes pregnant, the investigator must report any 
drug exposure during pregnancy in a partner of the male trial participant immediately (within 
24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s unique 
entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood, urine, and stool 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. In addition, faecal occult blood and faecal 
calprotectin will be assessed.
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis,
respectively. 


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
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 
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment (microscopic 
examination if erythrocytes, leukocytes 
nitrite or protein are abnormal in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1
Protein electrophoresis only at screening. Hormones only at screening and end of trial.
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and after admission to the trial site.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qual)
Hepatitis B core antibody (qual)
Hepatitis C antibodies (qual)
HIV-1 and HIV-2 antibody (qual), HIV-1 p24-antigen
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed at screening and upon admission to the trial 
site and may be repeated at any time during the study at the discretion of an investigator or 
designee. The results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at Medizinisches 
Versorgungszentrum Dr. Klein Dr. Schmitt & Partner, Kaiserslautern, Germany with the 
exception of the drug screening tests. These tests will be performed at the trial site using 
Multidrogen Pipettiertest (Diagnostik Nord GmbH, Schwerin).


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Faecal calprotectin testing will be performed at Medizinisches Versorgungszentrum Dr. Klein 
Dr. Schmitt & Partner, Kaiserslautern, Germany. Faecal occult blood testing will be 
performed at the trial site using a test kit (e.g. PreventID CC test by Preventis GmbH or 
similar). These tests will be clinically performed at screening, within 4 days prior to the first 
dosing of BI 1358894 (i.e. Day -4 to Day -2), in the first stool released after 12 hours after 
administration, on Days 1, 4, 7, 10, and 14, on Day 16, and at EOT. As subjects may not be 
able to defecate at the trial site in the morning of Visit 1 (screening), they may collect the 
specimen at home and bring the test specimen to the trial site within the screening period. In 
case of gastrointestinal AEs (e.g. diarrhoea, constipation), additional testing for faecal occult 
blood and faecal calprotectin may be carried out at the discretion of the investigator. If a 
subject tests positive for occult blood in faeces, further tests will be performed and the subject 
will be monitored closely.
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
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the time points given in the Flow Chart. 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.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all subjects are at 
complete rest. All ECGs will be recorded for a 10 sec duration after subjects have rested for 
at least 5 min in a supine position. ECG recording will always precede all other study 
procedures scheduled for the same time (except for blood drawing from an intravenous 
cannula that is already in place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database. 
Storing
All ECGs will be stored electronically on the 
 


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Data transfer
For time points specified in the Flow Chart, ECGs will be transferred electronically to the 
central ECG lab
 for evaluation.
In case of repeat ECGs due to quality reasons, all recordings will be transferred to the central 
ECG lab and the repeated ECGs will be flagged in the database. 
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab and 
evaluated but will not be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a) Central ECG lab
Central ECG lab evaluation (of Visit 2 Days 1 to 20 ECGs only) will be performed for 
the first of three replicate ECGs per time point given in the Flow Chart. The 
remaining second and third replicate ECGs will be stored for additional analyses, if 
required, e.g. by authorities at a later time point. For baseline, where 3 triplicate ECGs 
are recorded, only the first of the triplicate ECGs (i.e. 3 single ECGs) will be 
evaluated. 
The analysis will include the determination of cardiac axis as well as the intervals RR, 
PR, QRS and QT measured semi-automatically.
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will 
be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR.
For automatic interval measurements no lead will be provided.
For blinding arrangements see Section 4.1.5.1. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader. For quality assurance and control of the measurements, all ECGs of a 
subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and, to detect 
accidental switching of leads and/or false subject assignments of the ECGs. After 
quality control, the fiducial point markings will be reviewed by the cardiologist 
assigned to the study. 
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements [R07-4722, R16-0366] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].


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b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
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 
computerised ECG system or their manual corrections by the investigators will be 
used. 
In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data transfer) for 
cardiologic assessment by the central lab. In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
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. 


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5.3
OTHER


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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 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 are 
generally used assessments of drug exposure.
5.5
5.5.1
5.5.1.1
Secondary endpoints
BI 1358894
After the first dose:

AUC0-24 (area under the concentration-time curve of the analyte in plasma over a time 
interval 0 to 24 hours after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma)
After the last dose:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)
Midazolam
After each of the three doses:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)


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
Cmax


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
BI 1358894
For quantification of BI 1358894 plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into a K-EDTA (potassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will be 
withdrawn by means of either an indwelling venous catheter or by 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. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the final study 
report has been signed.


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Midazolam
For quantification of midazolam plasma concentrations, 4 mL of blood will be taken from an 
antecubital or forearm vein into a K-EDTA-anticoagulant blood drawing tube at the times 
indicated in the Flow Chart. Blood will be withdrawn by means of either an indwelling 
venous catheter or by venipuncture with a metal needle.
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, 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.
After completion of the trial, the plasma samples may be used for further methodological 
investigations, e.g., for stability testing, assessment of metabolites. However, only data 
related to the analyte and/ or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the final study 
report has been signed.
5.5.2.2
Plasma sampling for metabolism analysis
Additional K-EDTA plasma samples for the identification of drug metabolites will be 
investigated in the 50 mg dose group. Based on the knowledge gained during the trial 
conduct, e.g. from preliminary PK results, the dose group may be changed to a different one. 
The change will be implemented via a non-substantial CTP Amendment.
The blood samples will be drawn in parallel to PK samples according to the times indicated 
in the Flow Chart. At each of these time points, 3.4 mL blood will be needed for metabolite 
analysis. Sample handling will be described in detail in a separate lab manual. Samples will 
be stored at about -70°C or below until transfer to the metabolism laboratory.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, planned sampling time, and 'MIST'. Further information such as matrix 
and analyte may also be provided. 
Sample handling will be described in detail in a separate lab manual. 
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
the drug metabolism will be reported separately but not included in the CTR of this trial. The 
study samples will be discarded after completion of the experiments but not later than 5 years 
after the final study report has been signed. 
5.5.2.3
Urine sampling for pharmacokinetic analysis
A blank urine sample will be collected before administration of BI trial medication on Day 1
(within the 2 h before drug dosing) and two 1 mL aliquots will be retained to check for 
analytical interference by concomitant or rescue medication. 


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All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
2 L polyethylene (PE) containers and stored at room temperature. Subjects are told to empty 
their bladders at the end of each sampling interval. 
The handling of urine sampling is described in a lab manual.
At minimum, the sample tube labels should list at least the following information: BI trial 
number, subject number, visit, and planned collection time. Further information such as 
matrix and analyte may also be provided. 
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
about -20°C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory the 
urine samples will be stored at about -20°C or below until analysis.
After completion of the trial, the urine samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) will be generated by these additional investigations. 
The study samples will be discarded after completion of the additional investigations but not 
later than 5 years after the final study report has been signed.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 1358894 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.
5.5.3.2
Analytical determination of BI 1358894 urine concentration
BI 1358894 concentrations in urine will be determined by a validated LC-MS/MS assay. All 
details of the analytical method will be available prior to the start of sample analysis.
5.5.3.3
Analytical determination of midazolam plasma concentration
Midazolam concentrations in plasma will be determined by a validated LC-MS/MS assay. All 
details of the analytical methods will be available prior to the start of sample analysis.


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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).
For the first 4h after trial drug administration, the acceptable deviation from the scheduled 
time will be ±10 min for vital signs, ECG, and orthostatic testing and ±30 min for laboratory 
tests. Thereafter, the acceptable deviation will be ±30 min. 
The tolerance for drug administration will be ±1 min on Days -1, 1, and 14. On all other 
treatment days it will be ±10 min.
If several activities are scheduled at the same time point in the Flow Chart, ECG should be 
the first and meal the last activity. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements, except for the orthostatic testing, due to its inconvenience to the subject and 
possible influence on physiological parameters.
For planned individual plasma concentration sampling times and urine collection intervals 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
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), faecal 
laboratory tests, ECG, vital signs, orthostatic tests, visual analogue scales, suicidality 
assessment, and physical examination, refer to Sections 5.2.3 to 5.2.5. 
Pharmacogenomic genotyping will be performed (for details see Section 5.3).
6.2.2
Treatment period
Each subject will receive a single daily dose of BI 1358894 or placebo for 14 days during 
Visit 2 on Days 1 to 14. A single midazolam microdose will be administered on Days -1, 1, 
and 14.


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Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
Study participants will be admitted to the trial site in the morning of Day -1 at which point 
the first midazolam microdose will be administered. Subjects will be kept under close 
medical surveillance for at least further 144 h following last drug administration on Day 14. 
The subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness by the investigator or 
 designee at Day 20, refer to Flow 
Chart. On Day 22, the study will be performed in an ambulatory fashion.
If the subject reports headaches during the treatment period the following information and 
data should be collected daily until the headache is resolved:

Onset after medication intake (hhh:min)

Headache severity on a Numeric Ranking Scale (NRS) ranging from 0 - 10

Quality of headache (New type of headache vs. similar to previous experienced 
episodes of known headaches)

Headache characteristics (pressing or tightening vs. burning vs. pulsating vs. 
aggravated by routine physical activity (such as walking or climbing stairs))

Location (all of the following that apply: unilateral, bilateral, holocephal, frontal, 
temporal, occipital, facial)

Any acompanying symptoms like (all of the following that apply: nausea and/or 
vomiting, photophobia, phonophobia, lacrimation, other)

If Headache is resolved: Overall duration of headache episode (start time and end 
time)
For details on time points and procedures for collection of plasma and urine 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.
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.


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All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
BI 1358894
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 are 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 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. Trough concentration values will be analysed regarding attainment of 
steady state as a pre-requisite for calculation of steady state parameters.
Midazolam
The relative bioavailability of midazolam in the presence and absence of BI 1358894 will be 
evaluated separately within each dose group and separately for all subjects receiving placebo. 
As a sensitivity analysis, the relative bioavailability will be investigated for all dose groups 
together. For details, refer to 7.3.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 5 different dose groups of BI 1358894 are to be determined on the 
basis of the investigated parameters in comparison to 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.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
All individual data will be listed.
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 secondary 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). Analyses will be 
performed for parent drug.
Plasma and urine concentration data and parameters of a subject will be included in the 
statistical 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.
Plasma and urine concentrations and/ or parameters of a subject will be considered as non-
evaluable if, for example:

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 
5.5.1.1.
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







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. 


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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, …, 5, 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.
Attainment of steady state
Attainment of steady state will be explored by using the trough concentrations of BI 1358894
Cpre,9, Cpre,11, Cpre,13, Cpre,14 and the concentrations taken directly at the end of the first and the 
last dosing interval (C 24, C24,14) for each dose level. Pairwise comparisons of concentrations 
are performed using 2-sided 95% CIs based on the t-distribution. The calculation is based on 
a repeated measures linear model on the logarithmic scale.
 =  + 
 + s + e , where

logarithm of the concentrations for subject j at time i, i = 1, 2, …, 5 and
j=1, 2,…, 8

the overall mean,


the effect associated with time point i (repeated effect),
s
(random) effect of subject j, j=1, 2, ..., 8
e
random error associated with subject j at time i (assumed to be independent
and identically normally distributed).
Dose can be included as an additional covariate if there is evidence that the trough 
concentration profiles are comparable across dose levels.


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The model will be used to explore the time to steady state by pairwise comparing 
concentrations from different time points: log-transformed differences between all 
subsequent time points (log(Cpre,i/Cpre,j) = log(Cpre,i) - log(Cpre,j), where j>i) will be compared 
and adjusted means (Least Squares Means) as well as 2-sided 95% CIs will be calculated. 
Thereafter, these quantities will be back-transformed by exponentiation to give the 
corresponding (adjusted) ratio and CI.
Comparisons which reveal CIs (for the adjusted ratio) not including 100% will be inspected 
to determine if the differences between time points are resulting from not yet attaining 
steady-state. 
For further details, refer to the TSAP (such as selection of covariance structure and 
comparison of time points).
Graphical displays
To support the analyses of dose proportionality and attainment of steady state, graphical 
representations of the data might be created. These might include (but are not limited to) 
individual time-courses of trough plasma concentrations and the (geometric) mean plasma 
concentration time profiles.
Midazolam:
Endpoints defined for Midazolam will be compared separately between the last dose of 
midazolam and the first dose of midazolam and between the second dose of midazolam and 
the first dose of midazolam. The statistical analysis will be performed separately for each 
dose group and, separately for the group of subjects receiving placebo. Analyses will be 
conducted for the placebo group to better account for variability in plasma concentrations 
seen between midazolam treatment periods. The statistical model used for the analysis of the 
secondary endpoints will be an ANOVA model on the logarithmic scale. This model will 
include effects accounting for the following sources of variation: ‘subjects’, and ‘treatment’. 
The effect ‘subjects’ will be considered as random, whereas the other effects will be 
considered as fixed. The model is described by the following equation:
 =  + 
 + s + e , where

logarithm of the endpoint for subject j (j=1, 2,…, 8) at Day -1 (first dose of 
midazolam, i=1), Day 1 (second dose of midazolam) or at Day 14 (last dose of 
midazolam, i=2) respectively,

the overall mean,


the effect associated with time point i (Day -1 i=1 , Day 1 or Day 14, i=2),
s
(random) effect of subject j, j=1, 2, ..., 8, and 
e
random error associated with subject j at time i (assumed to be independent
and identically normally distributed).


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The effect of BI 1358894 on midazolam will be estimated by the ratios of geometric means 
(with the second and the last doses of midazolam respectively as the test and the first dose of 
midazolam as the reference) and their two-sided 90% confidence intervals (CIs) for Cmax and 
AUC0-tz. CIs will be calculated based on the residual error from ANOVA. These quantities 
will then be back transformed to the original scale to provide the point estimate and 90% CIs 
for each secondary endpoint.
As a sensitivity analyses, these analyses will also be performed together for all subjects 
receiving BI 1358894. An ANCOVA with a random effect for ‘subject’ and fixed effects for 
‘treatment’ and ‘dose’ (on a logarithmic scale) will be used. More details will be provided in 
the TSAP. 
Further endpoints will be summarized per dose group and per time period (first dose of 
midazolam, second dose of midazolam and last dose of midazolam) and will be compared 
between last dose of midazolam and first dose of midazolam and between the second dose of 
midazolam and the first dose of midazolam.
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.
The analyses will be done by ‘randomised treatment’. 
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' and those between first trial medication intake and 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. 


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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.
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the ECG variables QT, HR, QTcF, QTcB, PR, QRS, RR, and further derived ECG 
parameters. The baseline value of an ECG variable is defined as the mean of the triplicate
ECG measurements prior to drug administration. The derivation of the quantitative and 
qualitative ECG parameters and their analyses will be described in the TSAP.


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7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma/urine drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), or BLQ (below the lower limit of quantification) will 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).
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
Subjects will be randomised within each dose cohort in a 4:1 ratio, which reflects the ratio of 
subjects receiving active drug to placebo.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 


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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
BI 1358894
It is planned to include a total of 50 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 10 subjects per dose group (8 on active treatment, and 2
on placebo) is commonly used in multiple-rising dose studies of the present type and is in 
general considered as sufficient for the exploratory evaluation of multiple dose safety and 
pharmacokinetics.
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 50, but will not exceed 80 subjects entered.
Midazolam
It is planned to enter a total of 50 subjects in this part of the trial. The planned sample size is 
not based on a power calculation, but is judged to be adequate to attain reliable results and to 
fulfil the objectives and requirements of this exploratory investigation.


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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


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9.2
UNPUBLISHED REFERENCES


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10.
APPENDICES
10.1
DRUG SUPPLIES USED FOR DILUTION AND ANALYTICAL TESTING
10.1.1
Drug supplies overview
a) Midazolam-ratiopharm® 5mg/5mL Injektionslösung; 5 mL-ampoules
b) Isotone Kochsalz-Lösung 0.9% Fresenius Kabi® Infusionslösung, 100 ml bottles 
c) Empty, appropriately labeled glass container, preferably with lid 


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10.1.2
Required equipment and dosing aids – overview
Dosing and diluting syringes:

Henke Sass Wolf 2-part disposable HSW NORM-JECT® Syringes 3 mL

Henke Sass Wolf 2-part disposable HSW NORM-JECT® Syringes 24 mL

Needle tip
Only CE certified syringes WITHOUT rubber stoppers are to be used!


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10.1.3
Dilution procedure
Solution for use with up to 13 subjects
Step 1: 
Open the commercial isotonic saline solution (0.9% NaCl).
Step 2: 
Attach a needle tip to the 3 mL syringe and withdraw a bit more than 1 mL of 
the midazolam solution [concentration: 1 mg/mL] from the originator 
ampoule using a 3 mL syringe.
Step 3:
Remove any air bubbles in syringe (turn upside down and gently push out air 
by depressing the plunger); ensure that exactly 1 mL midazolam solution 
remains in the 3 mL syringe.
Step 4:
Remove and dispose of needle tip; transfer the full 1 mL of midazolam 
solution into an appropriate glass container (with cap) by completely 
depressing the plunger on the 3 mL syringe.
Step 5: 
Attach a needle tip to the 24 mL syringe and withdraw a bit more than 19 mL 
isotonic saline solution into the 24 mL syringe; remove air bubbles (see 
Step 3) and ensure exactly 19 mL isotonic saline solution remains in the 24 ml 
syringe.
Step 6:
Remove and dispose of needle tip; transfer the full 19 mL of isotonic saline 
solution into the same glass container with the midazolam solution by 
completely depressing the plunger on the 24 mL syringe.
Step 7:
Following addition of the midazolam and saline solutions into the glass 
container, ensure the glass container is closed using the corresponding cap. 
The content of the glass container should be mixed thoroughly by swirling 
gently for approximately 1 minute.
Step 8:
Extract a little more than 1.5 mL of the dilution solution using a needle tip 
and a new 3 mL syringe; remove bubbles (see Step 3) and ensure that exactly 
1.5 mL of the diluted midazolam solution (final concentration: 50 µg/mL) 
remains in the 3 mL syringe. Remove and dispose of the needle tip and close 
the syringe with a cap; the solution is now ready for oral administration. 
The final midazolam microdose Oral Solution concentration is 50 µg/mL, for 
administration of 1.5 mL (75 µg), which can be administered per os directly from the 
syringe.


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10.1.4
In-use stability
The chemical in-use stability of the dilution solution is 24 h after its preparation, incl. storage 
at room temperature (15-25°C) in Henke Sass Wolf 2-part disposable HSW NORM-JECT®
syringes until administration.
10.1.5
Mode of application
Microdoses of Midazolam will be administered orally as specified in the Clinical Trial 
Protocol (refer to Flow Chart for dosing schedule). 1.5 ml of diluted midazolam solution 
(concentration 50 µg/mL) will be administered from a syringe, as described above.
Please note that it is the responsibility of the TCM to assure that appropriate supplies are used 
for administration of a dose and dosing is limited to the allowed dosing range for a specific 
dose formulation as stated in this Dilution Instruction.


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10.2
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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10.3
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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10.4
COLUMBA-SUICIDE SEVERITY RATING SCALE


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
12 September 2018
EudraCT number
2018-000389-12
BI Trial number
1402-0002
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1358894 (double-
blind, randomised, placebo-controlled, parallel-
group design) and evaluation of midazolam 
interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects
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
- 1.2.1.5
Clinical experience in humans
- 3.1
Overall trial design and plan
- 3.3.4.1
Removal of individual subjects
- 3.3.4.2
Discontinuation of the trial by the
sponsor
- 5.2.5.6
Neurological examinations
- 6.2.2
Treatment period
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 Flow Chart
- Prolongation of the house confinement to 


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Number of global amendment
1
Day 20 instead of Day 15 due to the halftime of 
BI 1358894
- Additional examinations to confirm the fitness 
of the subjects at discharge Day 20 after breakfast 
(Bond & Lader and Bowdle VAS scores, 
C-SSRS, evaluation of safety lab assessed on 
Day 15 and 18 and a neurological examination).
- Inclusion of neurological examinations at 
discharge and EOT
Section 1.2.1.5
- Safety and tolerability data as well as PK data 
analysed and described from dose groups 3 mg-
200 mg fasted from the SRD part and 50 mg as 
well as 100 mg fed vs. fasted from the FE part. 
Section 3.1
- The respective section of the study has been 
revised to assure that interim doses because of 
safety signals will require a substantial 
amendment
Section 3.3.4.1
- The respective section has been revised to assure 
that a subject who experiences a serious’ adverse 
reaction which is considered at least possibly 
related to the IMP administration will be removed
Section 3.3.4.2
- The respective section has been revised to assure 
that dose escalation will be stopped if the Cmax or 
AUC0-24 of at least 1 subject of one dose group 
increases above the following exposure thresholds 
or if the estimated systemic exposure (group 
gMean values) of the next dose level is expected 
to exceed a Cmax of 1,960 nM or an AUC0-24 of 
26,300 nM*h. 
- As well as severe non-serious adverse reactions 
(i.e. severe non-serious adverse events considered 
as, at least, possibly related to the IMP 
administration) in two subjects in the same 
cohort, independent of within or not within the 
same system-organ-class are leading to a 
discontinuation of the trial by the sponsor.
Section 5.2.5.6
- The addition of the neurological examinations 
has been revised to increase the safety of the 
subjects at discharge and end of trial.


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Number of global amendment
1
Section 6.2.2
- Headache assessment has been included to
classify possibly occurrent headaches
Rationale for change
Based on PK results obtained in the preceding 
SRD study 1402-0001 the mean half-life of 
BI 1358894 is about 50 to 70 h. For this reason 
inhouse confinement will be prolonged by 
additional 3 days (i.e. Day 20). Furthermore, a 
standardized neurological assessment will be 
included at discharge from the unit, in 
combination with suicidality assessment (CSSR) 
and VAS scores (Bowdle, Bond and Lader). This 
enlarged panel of investigations is considered to 
improve the detection of long-lasting CNS effects 
after cessation of treatment if present, thus further 
mitigating safety risks for participating subjects. 
To comply with current guidelines additional 
discontinuation criteria were to be included.
Based on recent comments by competent 
authorities the validated tools used for PK 
analysis have been further specified in the 
respective protocol sections.
Since headache of mild to moderate intensity was 
the most frequent AE of the preceding FIH study, 
a standardized assessment of this specific event 
has been included in the protocol.
The theoretical maximum dose of the MRD study 
was increased to 200 mg QD (Dose Group 5), 
taking into consideration, that this theoretical 
dose level will only be conducted in case safety 
and PK data of preceding dose levels do not 
prevent this.
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
13 November 2018
EudraCT number
2018-000389-12
BI Trial number
1402-0002
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1358894 (double-
blind, randomised, placebo-controlled, parallel-
group design) and evaluation of midazolam 
interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects
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
5.2.4.1
12-lead resting ECG
5.5.2.2
Plasma sampling for metabolism 
analysis
Description of change
Section 5.2.4.1
Duration of ECG Evaluation has been corrected 
according to the Flow Chart. (Day 1 to 20)
Section 5.5.2.2
Duration of sampling has been corrected 
according to the Flow Chart
Rationale for change
Inconsistencies between Flow Chart and Section 
have been corrected.


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Number of global amendment
3
Date of CTP revision
28 February 2019
EudraCT number
2018-000389-12
BI Trial number
1402-0002
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1358894 (double-
blind, randomised, placebo-controlled, parallel-
group design) and evaluation of midazolam 
interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects
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. Footnote
2. Flow Chart
3. Footnote
4. Footnote
5. Exclusion Criteria 16
6. Section 4.1.4
7. Section 5.5.2.3
8. Section 5.2.3
9. Section 10.4
Description of change
1. In Footnote 1 neurological examination added
to Screening Procedures
2. Footnote 2 added on Day 2 in Flow Chart
3. Footnote 2: 3 h added on Day -1
4. Footnote 14: Days 1 + 4 added as described in 
the Flow Chart


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Number of global amendment
3
5. Inability to refrain from smoking on specified 
trial days changed to specified during in-house 
confinement.
6. DG 5 instead of DG 4 entered in Table 4.1.4:2
7. 0.5 ml aliquot changed to 1 ml aliquot
8. Days 1 + 4 added to text regarding to faecal 
blood tests
9. C-SSRS Questionnaire for Screening has been 
corrected
Rationale for change
Correct C-SSRS Questionnaire for Screening 
Visit entered in CTP. In context with this change 
other inconsistencies between Flow Chart and 
Sections and within the CTP have been corrected.


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Number of global amendment
4
Date of CTP revision
03 April 2019
EudraCT number
2018-000389-12
BI Trial number
1402-0002
BI Investigational Product(s)
BI 1358894
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1358894 (double-
blind, randomised, placebo-controlled, parallel-
group design) and evaluation of midazolam 
interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Flow Chart
2. Section 6.2.2
Description of change
1. Additional PK samples were inserted at 
days 2, 4, 6, 9 and 11 3 hour after 
administration of BI 1358894 (time of tmax
in previous dose groups)
2. Insertion of the intensity measurement for
headaches


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Number of global amendment
4
Rationale for change
In the 25 mg dose group, 2 subjects showed 
unusual profiles, one with a particularly high 
Cmax, followed by unusual trough values and one 
with lower accumulation (based on trough values) 
than that seen in other subjects. Given the 
peculiar nature of the profiles, it was decided to 
take additional samples at the expected Cmax in 
the case that other subjects show similar profiles. 
In this way, we can identify if it is a consistent 
phenomenon and may better understand 
differences in the PK of the drug. The additional 
amount of blood will not exceed 500 ml per 
subject.
In context with these changes, a few remaining
inconsistencies were also corrected.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21808436
5.0
clinical-trial-protocol-revision-04
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of BI 1358894
(double-blind, randomised, placebo-controlled, parallel-group design) and evaluation
of midazolam interaction (nested, open, fixed-sequence, intra-individual comparison)
in healthy male subjects
Approval-Therapeutic Area 
03 Apr 2019 17:59 CEST
Author-Trial Clinical
Pharmacokineticist
04 Apr 2019 08:44 CEST
Author-Trial Statistician
04 Apr 2019 10:41 CEST
Author-Clinical Trial Leader
04 Apr 2019 14:26 CEST
Verification-Paper Signature
Completion
05 Apr 2019 09:51 CEST
Approval-Team Member Medicine
06 Apr 2019 12:00 CEST


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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c27807278-01
BI Trial No.:
1402-0002
Title:
Safety, tolerability, and pharmacokinetics of multiple rising oral 
doses of BI 1358894 (double-blind, randomised, placebo-
controlled, parallel-group design) and evaluation of midazolam 
interaction (nested, open, fixed-sequence, intra-individual 
comparison) in healthy male subjects
Final protocol (including protocol revision 1 (c21808436-02), 2 
(c21808436-03), 3 (c21808436-04) and 4 (c21808436-05))
Investigational
Product(s):
BI 1358894
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
12 AUG 2019 SIGNED
Version:
“Final” 
Page 1 of 35
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................17
7.
PLANNED ANALYSIS......................................................................................20
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........21
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................21
7.3
TREATMENT COMPLIANCE........................................................................21
7.4
PRIMARY ENDPOINT .....................................................................................21
7.4.1
Primary analysis of the primary endpoint........................................................21
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoint ................................................................................................21
7.5
SECONDARY ENDPOINTS.............................................................................21
7.5.1
Key secondary endpoint .....................................................................................21
7.5.2
Secondary endpoints...........................................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................24


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7.8
SAFETY ANALYSIS..........................................................................................24
7.8.1
Adverse Events ....................................................................................................24
7.8.2
Laboratory data ..................................................................................................26
7.8.3
Vital signs.............................................................................................................26
7.8.4
ECG......................................................................................................................26
7.8.5
Others...................................................................................................................28
8.
REFERENCES....................................................................................................31
10.
HISTORY TABLE..............................................................................................35


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs...........................12
Table 6.1: 2
Flow chart of analysis phases for statistical analysis of safety laboratory, 
vital signs, VAS and ECG – based on dose groups..........................................13
Table 6.2: 1
Handling of iPDs ..............................................................................................14
Table 6.3: 1
Subject sets analysed ........................................................................................16
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation ..........18
Table 7.8.5: 1 Factor loadings for Bond & Lader VAS...........................................................29
Table 10: 1
History table .....................................................................................................35


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24h
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
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a dosing interval τ
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state
CV
Arithmetic coefficient of variation
ECGPCS
ECG plasma concentration set
gCV
geometric coefficient of variation
HR
Heart rate
MedDRA
Medical Dictionary For Regulatory Activities
NOA
Not analysed
NOR
No valid result
NOS
No sample available
PKS
Pharmacokinetic parameter set
PR
Pulse rate
QRS complex
Combination of the Q, R, and S waves
QT interval
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTcB
QT interval, heart rate corrected according to Bazetts formula
QTcF
QT interval, heart rate corrected according to Fridericias formula
RAGe
Report appendix generator
RR interval
ECG interval from the peak of the R wave to the peak of the subsequent R 
wave
SD
Standard Deviation
SOC
System Organ Class
TS
Treated Set
ULN
Upper limit of normal range


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Term
Definition / description
VAS
Visual analogue scale


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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 revised CTP, and to
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its 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 Medidata Rave system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
Certara USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described 
in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint is the number of subjects with drug-related AEs, as defined in Section 5.2.1 
of the CTP.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
Secondary PK endpoints will be as defined in Section 5.5.1.1 of the CTP.
BI 1358894
Secondary endpoints are AUC0-24 and Cmax of BI 1358894 in plasma after the first dose, 
AUCτ,ss and Cmax,ss of BI 1358894 in plasma after the last dose.
Midazolam
Secondary endpoints are AUC0-tz and Cmax of midazolam after each of the three doses.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups, 
and selection of doses, cf. Section 4 of the CTP.
Each subject is planned to be treated with 75 μg q.d. of midazolam (solution for injection) as 
single dose on Day -1, Day 1, and Day 14.
Starting on Day 1, the subjects will receive 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg q.d. of 
BI 1358894 or placebo (orally) as multiple doses every 24 hours over 14 days.
On Day 1 and Day 14, BI 1358894 will be administered immediately prior to midazolam.
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made for placebo subjects).
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first administration 
of Midazolam
On-treatment
MDZ
Date/time of first administration 
of Midazolam
Date/time of first administration 
of BI 1358894/Placebo or 
date/time of first administration 
of midazolam + 1 day (1 * 24 h)
whichever occurs earlier
On-treatment
Pbo+MDZ,
10 mg BI+MDZ,
25 mg BI+MDZ,
50 mg BI+MDZ,
100 mg BI+MDZ
or 200 mg 
BI+MDZ
respectively
Date/time of first administration 
of BI 1358894/Placebo together 
with Midazolam (e.g. planned on 
Day 1 and Day 14)
Date/time of first administration 
of BI 1358894/Placebo together 
with Midazolam (e.g. planned 
administration on Day 1 and 
Day 14) + 1 day (1 * 24 h)
On-treatment
Pbo,
10 mg BI,
25 mg BI,
50 mg BI,
100 mg BI,
or 200 mg BI,
respectively
Date/time of first administration 
of BI 1358894/Placebo together 
with Midazolam (e.g. planned 
administration on Day 1 and 
Day 14) + 1 day (1 * 24 h)
Date/time of last administration 
of BI 1358894/Placebo + REP 
(14 * 24 h) or 12:00 a.m. on day 
after subject's trial termination 
date, whichever occurs earlier
Follow-up
F/U Pbo,
F/U 10 mg BI,
F/U 25 mg BI,
F/U 50 mg BI,
F/U 100 mg BI,
or F/U 200 mg BI,
respectively
Date/time of last administration 
of BI 1358894/Placebo + REP 
(14 * 24 h)
12:00 a.m. on day after subject's 
trial termination date
In addition, follow-up period “F/U MDZ” may be applicable if BI+Midazolam was not administered within 24 h after first 
administration of Midazolam.


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Analysis phases for statistical analysis of AEs are defined for each subject as described in the 
Table 6.1: 1.
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only.
In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 
AE tables), the following totals will be provided in addition:

"Total BI", defined as the total over all on-treatment phases involving BI

"Total on-trt", defined as the total over all on-treatment phases, including placebo
CTR Appendix 16.1.13.1.8.1 displays will present results for the screening, on-treatment and 
follow-up phases.
Additionally to the totals defined above, the following total will be provided in CTR 
Section 16.1.13.1.8.1 AE tables:

"Total", defined as the total over all study phases (screening + on-treatment + follow-up)
Safety laboratory data, vital signs, VAS and ECG will be analysed based on dose groups
(Pbo, 10 mg BI, 25 mg BI, 50 mg BI, 100 mg BI, or 200 mg BI). 
Analysis phases for statistical analysis of safety laboratory data, vital signs, VAS and ECG 
are defined for each subject as described in the table below.
Table 6.1: 2
Flow chart of analysis phases for statistical analysis of safety laboratory, vital 
signs, VAS and ECG – based on dose groups
Study analysis phase
Start (inclusive)
End (exclusive)
Screening
Date of informed consent at 12 a.m.
Date/time of first administration of 
BI 1358894 or Placebo
On-treatment
Date/time of first administration of 
BI 1358894 or Placebo
Date/time of last administration of 
BI 1358894 or Placebo+ REP (14 * 24 h)
Follow-up
Date/time of last administration of 
BI 1358894 or Placebo+ REP (14 * 24 h)
12:00 a.m. on day after subject's trial 
termination date
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects entered and 
randomised who did not fail during screening.
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, it will be 


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decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important protocol deviation (iPD). For definition of iPDs and for the process 
of identification of these refer to BI reference document "Identify and Manage Important 
Protocol Deviations (iPD)" (2). Each decision which was agreed during the RPM will be 
documented in the decision log.
If any iPDs are identified, they are to be summarised into categories and will be captured in
an accompanying excel spreadsheet. Categories which are considered to be iPDs in this trial
are defined in the integrated quality and risk management plan (IQRMP). If the data show 
other iPDs, the definition in the IQRMP will be supplemented accordingly by the time of the 
RPM. Table 6.2: 1 specifies which kind of iPDs should be excluded from which analysis set.
Table 6.2: 1
Handling of iPDs
Category / 
iPD Code
Description
Excluded from which 
analysis set
A
Entrance criteria not met
A1
Inclusion criteria not met
None
A2
Exclusion criteria met
None
B
Informed consent
B1
Informed consent not available/not done
Treated set
B2
Informed consent too late
None
C
Trial medication and randomisation
C2
Randomisation not followed
None
C3
Non-compliance
PKS, ECGPCS
C4
Medication code broken inappropriately
PKS, ECGPCS
C5
Incorrect intake of trial medication
PKS, ECGPCS
D
Concomitant medication
D1
Prohibited medication use
PKS, ECGPCS
E
Missing data
Certain violations of procedures used to measure primary or 
secondary data
None
F
Incorrect timing
F1
Certain violations of time schedule used to measure primary or 
secondary data
PKS, ECGPCS
G
Other trial specific important deviation
G1
Incorrect intake of meal
PKS, ECGPCS
G2
Not conducted CSSRS at discharge and EOT
None
Deviations C1, C2, C5 and G1 can only be detected at the trial site.
1 Missing visits, evaluations, and tests will be considered missing data, not protocol deviations
iPDs will be summarised and listed.


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6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug. 
This is the full analysis set population in the sense of ICH E9 (1). It will be used for 
analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one PK parameter 
that was not excluded due to a protocol deviation relevant to the statistical evaluation 
of PK endpoints or due to PK non-evaluability.
Section 7.3.2 of the CTP: Plasma and urine concentration data and parameters of a 
subject are included in the statistical 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 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
Refer to the CTP Section 7.3.2 for further details.

PKS-Midazolam (PKS-MDZ)
The PKS-Midazolam (PKS-MDZ) includes all subjects from the TS receiving 
BI 1358894 or Placebo and Midazolam who provide at least one secondary PK 
parameter for Midazolam that was not excluded according to the description above. It 
is used for investigation of relative bioavailability.
All ECG analyses are performed on the TS, 
 


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The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at RPM prior to DBL.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
PKS-MDZ
ECGPCS
Disposition
X
Exposure
X
IPDs
X
Demographic/baseline endpoints
X
Primary endpoint
X
Other safety parameters
X
ECG endpoints and plasma concentrations 
 
X
ECG endpoints in other analyses
X
Secondary PK endpoints (BI 1358894)
X
Secondary PK endpoints (Midazolam)
X
Further PK endpoints (BI 1358894)
X
Further PK endpoints (Midazolam)
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
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.
Data of subjects who failed to complete all periods of the study (dropouts or withdrawals) will 
be reported in the CTR as far as their data are available. All withdrawals will be documented 
and the reason for withdrawal recorded in the CTR.
Section 7.4.1 of the CTP: With respect to safety evaluations, it is not planned to impute 
missing values.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).


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No imputation will be done for ECG endpoints. If replicate ECG recordings are missing, the 
arithmetic means per time point will be computed with the reduced (1 or 2) number of 
recordings. If single cardiac cycles (also denoted as beats or waveforms) are missing, the 
arithmetic mean per single ECG will be computed with the reduced (1, 2 or 3) number of 
cardiac cycles.
Missing data and outliers of PK data are handled according to BI standards (4) and (6).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
There will be a centralised evaluation of 12-lead ECG recordings at the time points specified 
in Table 6.7: 1.
Section 5.2.4.1 of the CTP: ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. 
three single ECGs recorded within 180 sec) as indicated in the Flow Chart of the CTP.
At predose (Visit 2, Day 1, planned time point -01:00), three triplicate ECGs (9 single ECGs) 
will be recorded.
All ECGs performed on Days 1 through 20 are transferred to the central ECG lab for 
evaluation.
Section 5.2.4.1 of the CTP: Central ECG lab evaluation (of Visit 2 Days 1 to 20 ECGs only) 
will be performed for the first of three replicate ECGs per time point given in the Flow Chart.
For the 3 predose triplicates, only the first of the 3 replicate ECGs at a single assessment time 
will be evaluated centrally.
For ECGs recorded as triple, only the first single ECG is evaluated and transferred. Therefore, 
for each post-baseline time point only a single ECG record will be analysed, including the 
ones which were measured as triple.
The baseline value of an ECG variable is defined as the mean of the first single ECG 
measurement of each triple ECG prior to first drug administration.


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Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation
Visit
Day
Planned time [hh:mm]
- relative to respective drug administration
Study phase
2
1
-01:00
Baseline 
01:00
On-treatment
02:00
04:00
08:00
12:00
2
24:00
3
48:00
4
72:00
76:00
80:00
5
96:00
6
120:00
7
144:00
148:00
152:00
8
168:00
9
192:00
10
216:00
11
240:00
12
264:00
13
288:00
14
311:00
313:00
314:00
316:00
320:00
324:00
15
336:00
17
384:00
19
432:00
20
456:00
In all other analyses (except for analyses of ECG variables), the last non-missing value 
determined prior to the first dosing of BI 1358894 or Placebo will be defined as baseline.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked via the consistency check listings at the RPM.


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Unscheduled measurements of laboratory data, vital signs or VAS data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement.
Descriptive statistics of laboratory data will be calculated by planned time point based on the 
worst value of the subject at that planned time point (or assigned to that planned time point). 
For vital signs and VAS, descriptive statistics will be calculated by planned time point based 
on the last value of the subject at that planned time point (or assigned to that planned time 
point).


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (5).
The individual values of all subjects will be listed. Listings will generally be sorted by dose 
group, subject number and visit (if visit is applicable in the respective listing). AE listings will 
be sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical to the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the World Health Organisation – Drug 
Dictionary, version March 2018.
Only descriptive statistics are planned for this section of the CTR based on the TS.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of first administration of the respective treatment or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the RPM (cf. Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis of 
the number of subjects with drug related AEs, which is the primary endpoint of this trial.
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint
Not applicable.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
The analysis of secondary endpoints of BI 1358894 will be based on the PKS and the analysis 
of the secondary endpoints of Midazolam will be based on the PKS-MDZ.


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Analysis of secondary endpoints of BI 1358894
Dose proportionality will be evaluated as defined in the CTP, Section 7.3.2, by use of a power 
model for the secondary endpoints AUC0-24 and Cmax of BI 1358894 in plasma after the first 
dose and AUCτ,ss and Cmax,ss of BI 1358894 in plasma after the last dose.
Section 7.3.2 of the CTP: Attainment of steady state will be explored by using the trough 
concentrations of BI 1358894 Cpre,9, Cpre,11, Cpre,13, Cpre,14 and the concentrations taken 
directly at the end of the first and the last dosing interval (C24, C24,14) for each dose level.
[…].
Attainment of steady state of BI 1358894 will be explored as defined in the CTP, 
Section 7.3.2, by use of a repeated measures linear model on the logarithmic scale. The model 
will be estimated using an unstructured covariance matrix. In case convergence criteria are 
not met when using this covariance structure, another structure (Huynh-Feldt, Toeplitz or 
AR(1)) will be used. The information criterion of Akaike (AIC) will be used to select the best 
fitting structure. Results will only be presented for the best fitting structure. A compound 
symmetry structure of the covariance matrix will not be considered, as this structure already 
postulates a steady state.
Section 7.3.2 of the CTP: Comparisons which reveal CIs (for the adjusted ratio) not 
including 100% will be inspected to determine if the differences between time points are 
resulting from not yet attaining steady-state.
Analysis of secondary endpoints of Midazolam
Analysis of relative bioavailability of the secondary endpoints AUC0-tz and Cmax of midazolam 
in plasma on Day 1 and on Day 14 will be performed as defined in Section 7.3.2 of the CTP.
The endpoints will be compared between the second dose of midazolam (Test 1) and third 
dose of midazolam (Test 2) and the first dose of midazolam (Reference). The relative 
bioavailability will be analysed separately for each dose group.
The statistical model for the relative bioavailability analysis defined in the CTP is an ANOVA 
model on the logarithmic scale including "treatment" ("midazolam" and "midazolam + 
Placebo/BI") as fixed effect and "subject" as random effect. The analysis will be performed 
separately for Day 1 and Day 14.
CTP Section 7.3.2: The effect of BI 1358894 on midazolam will be estimated by the ratios of 
geometric means (with the second and the last doses of midazolam respectively as the test and 
the first dose of midazolam as the reference) and their two-sided 90% confidence intervals 
(CIs) for Cmax and AUC0-tz. CIs will be calculated based on the residual error from ANOVA. 
These quantities will then be back transformed to the original scale to provide the point 
estimate and 90% Cis for each secondary endpoint.


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In addition, a sensitivity analysis will be performed for the secondary endpoints AUC0-tz and 
Cmax of midazolam in plasma on Day 1 and on Day 14 including all subjects who were treated 
with BI 1358894. The model will include "subject" as a random effect, "time point" as fixed 
effect and the logarithm (base 2) of the dose (10 mg, 25 mg, 50 mg, 100mg und 200 mg) as 
covariate. The ANCOVA model is described by the following equation:
 =  + 
 +  + β + e , where 
 = logarithm of response measured on subject j at time point i,
= the overall mean,
 = (random) effect associated with the jth subject, j = 1, 2, ..., 40

 = the effect associated with the time point i, i = 1 (Day -1) and i=2 (Day 1 or Day 14)
β = fixed effect regression coefficient for dose effect
 = the logarithm (base 2) of the dose level of subject j
e = the random error associated with the jth subject at time point i
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (6).


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7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the CTR.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS except the exposure response ECG analysis 
which will be based  on the ECGPCS.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3).
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to the screening, on-treatment or follow-up phase as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (8) and for the class of 
AESIs.


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Section 5.2.2.1 of the CTP: The AESI for this trial is hepatic injury, as defined by the 
following alterations of hepatic laboratory parameters: 

an elevation of aspartate transaminase (AST) and/or alanine aminotransferase 
(ALT)≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN 
measured in the same blood sample, or

aminotransferase (ALT and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related (primary 
endpoint) will be summarised separately. Separate tables will also be provided for subjects 
with SAEs, subjects with AESIs and subjects with other significant AEs (according to ICH E3 
(8)). The frequency of subjects with AEs and the frequency of subjects with AEs considered 
by the investigator to be drug related will also be summarised by maximum intensity, primary 
SOC and preferred term.
The system organ classes and preferred terms within system organ classes will be sorted by 
descending frequency overall treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised by dose group.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term. The number of 
subjects included by country and the number of subjects inside (member states) and outside 
the EU (third countries) will also be summarised by dose group.
If the subject reports headaches during the treatment period further information about the 
duration of headache, location, characteristics, and signs and symptoms were recorded. The 
information will be summarized with descriptive statistics.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
"Display and Analysis of Laboratory Data" (9). The assessments will include testing for 
faecal occult blood and faecal calprotectin.
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM prior to DBL at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. Values 
outside the reference range as well as values defined as possible clinically significant will be 
flagged in the data listings. Standard or project-specific rules for flagging clinically significant 
values in an automated manner will not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) and orthostatic tests will be 
descriptive in nature. Descriptive statistics of each parameter over time and for the difference 
from baseline (see Section 6.7) will be provided.
Orthostatic change will be defined as the difference between standing and supine blood 
pressure (calculated as standing minus supine), and will be calculated separately for systolic 
and diastolic blood pressure. Orthostatic change will be summarized in the same way as vital 
signs parameter. 
Clinically relevant findings in vital signs and orthostatic test data will be reported as baseline 
conditions (at screening) or as AEs (during the trial) if judged clinically relevant by the 
investigator, and will be analysed as such.
7.8.4
ECG
12-lead ECG
ECG data will be analysed based on dose groups.
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator. 


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All evaluation of ECG data except of exposure response analysis will be based on the TS. 
 
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2.
Occurrences of notable findings (as defined in Section 5.3.2) will be flagged.
For QTcB and RR, only listings will be provided.
For all subjects with any notable finding in quantitative ECG recordings, a separate listing 
will be created as end-of-text display (based on the same display template as in 
Appendix 16.2), and the corresponding time profiles will be shown.
Comments regarding the ECGs will be listed.
Categorical Endpoints
For the categorical endpoints, frequency tables will be provided.
For subjects with notable findings, the individual time courses of QTcF, QT, HR, PR and 
QRS of these subjects will be presented in figures.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time of QTcF, HR, QT, PR and QRS. The time profiles of mean and SD for the 
changes from baseline on treatment will be displayed graphically by treatment group for PR 
and QRS.
 
No plots are planned for QT.


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Others


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9; 
Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical Trials, 
current version
2
001-MCS-40-413_1.0: "Identify and Manage Important Protocol Deviations (iPD)", 
current version; IDEA for CON
3
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; KMED
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / Pharmacodynamic
Analyses of Clinical Studies", current version; IDEA for CON
5
KM Asset BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project 
Summaries", current version; KMED
6
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD Data 
Files", current version; IDEA for CON
7
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse Event Data 
from Clinical Trials", current version; KMED
8
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
9
KM Asset BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", 
current version; KMED
10 Bond A, Lader M. The use analogue scales in rating subjective feelings. Br J Med 
Psychol. 1974. 47: 211-218. [R98-0752]
11 Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018. 45(3): 383-397.
[R18-0143]


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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
12-AUG-19
None
This is the final TSAP