Clinical trial NCT04426851
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2020-07-13; Completion date: 2020-10-12
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of Part 1 of this trial is to investigate the absolute bioavailability of BI 1358894 with an intravenous microdose formulation containing labelled \[C-14\] BI 1358894 and an unlabelled oral tablet formulation of BI 1358894 in healthy male subjects.

The main objective of Part 2 of this trial is to investigate the relative bioavailability of BI 1358894 administered as an oral suspension.

Detailed description:

Arms: arm 1: BI 1358894 arm 2: BI 1358894
Interventions: intervention 1: BI 1358894 intervention 2: BI 1358894 (C-14) intravenous solution intervention 3: BI 1358894
Intervention descriptions: intervention 1: Tablet intervention 2: BI 1358894 mixed with \[carbon labelled (C-14)\] BI 1358894 intervention 3: Oral suspension

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c29880107-02
EudraCT No.
2020-000351-13
BI Trial No.
1402-0016
BI Investigational
Medicinal Product
BI 1358894
Title
Investigation of pharmacokinetics and absolute bioavailability of 
BI 1358894 administered orally as tablet co-administered with an 
intravenous microtracer dose of [C-14]-BI 1358894 in healthy 
male volunteers via a non-randomised, open-label, fixed-sequence
trial (part 1) followed by a randomised, open-label, single-
dose, two-period, two-sequence cross-over relative bioavailability 
trial in BI 1358894 oral suspension (part 2)
Lay Title
A study in healthy men to test how BI 1358894 is taken up in the 
body and how food influences the amount of BI 1358894 in the 
blood
Clinical Phase
I
Trial Clinical 
Monitor
Phone: 
Fax: 
Principal 
Investigator
Phone: 
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date
Version: 2.0
Date: 26 Jun 2020
Page 1 of 84
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
20 May 2020
Revision date
26 Jun 2020
BI trial number
1402-0016
Title of trial
Investigation of pharmacokinetics and absolute bioavailability of BI 
1358894 administered orally as tablet co-administered with an 
intravenous microtracer dose of [C-14]-BI 1358894 in healthy male 
volunteers via a non-randomised, open-label, fixed-sequence trial 
(part 1) followed by a randomised, open-label, single-dose, two-
period, two-sequence cross-over relative bioavailability trial in BI 
1358894 oral suspension (part 2)
Principal 
Investigator
Trial site
Clinical phase
I
Trial rationale
This trial is intended to examine the absolute oral bioavailability of BI 
1358894 as tablet formulation for oral administration and the relative 
bioavailability of BI 1358894 administered as an oral suspension. The 
data are considered necessary to further support the understanding of 
the pharmacokinetics of BI 1358894.
Trial objectives
To determine the absolute oral bioavailability of BI 1358894.
To investigate the relative bioavailability of an oral suspension of BI 
1358894.
Trial design
Part 1:
Period 1: non-randomized, open-label, single period, single arm
Part 2:
Period 2 and 3: randomized, open label, two-period, two-sequence 
cross-over
Part 1 and 2 are designed in a fixed sequence.


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Trial endpoints:
Part 1: 
Primary endpoints:
AUC0-∞of [C-14]-BI 1358894 i.v.
AUC0-∞of BI 1358894 p.o.
Secondary endpoints:
Oral route: Cmax of BI 1358894 p.o.
Part 2:
Primary endpoints:
AUC0-312 of BI 1358894 p.o 
Secondary endpoints:
Cmax of BI 1358894 p.o.
AUC0-∞of BI 1358894 p.o 
Number of subjects 
total entered
12* (all on active drug)
*Screening may include more than 12 healthy subjects who will be 
exposed to BI 1358894
each treatment
12 (all to receive active treatment in period 1-3)
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 55 years (inclusive), body mass 
index (BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Trial product 1 
Part 1 (Period 1)
BI 1358894 film-coated tablet (Treatment Test (T1))
dose
100 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Trial product 2 
Part 1 (Period 1)
BI 1358894 (C-14) as intravenous solution (Treatment Reference 
(R1))
dose
100 μg BI 1358894 consisting of 90 μg unlabelled BI 1358894 mixed 
with 10 μg labelled [C-14]-BI 1358894 in 10 mL intravenous solution 
(10 μg BI 1358894 [C-14] /mL)
The radioactive dose per infusion will be ~0.039 MBq.


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mode of admin.
Intravenous infusion of 15 min at ~ tmax (5 h) 
Trial product 3 
Part 2 (Period 2/3)
       dose
       mode of admin.
BI 1358894 oral suspension under fasted (Treatment Reference (R2)) 
or fed (Treatment Test (T2)) conditions 
100 mg
Oral with 240 mL of water following a high fat, high calorie breakfast 
when fed (T2) or after an overnight fast of at least 10 h when fasted 
(R2).
Duration of 
treatment
Part 1:
Oral dose (Treatment T1): Single oral dose, Day 1
Intravenous dose (Treatment R1): Single intravenous infusion of 
microtracer over 15 min, Day 1
Part 2:
Oral dose (Treatment T2, R2) : Single oral dose, Day 1 of each Period
(separated by a washout period of at least 17 days between drug 
administrations)


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Statistical methods
Part 1:
Absolute bioavailability (F) will be estimated by the ratios of the 
geometric means (test/reference) for the primary endpoints AUC0-∞ 
(dose normalized). Additionally, their two-sided 90% confidence 
intervals (CIs) will be provided. This method corresponds to the two 
one-sided t-tests procedure, each at the 5% significance level. Since 
the main focus is on estimation and not testing, an acceptance range is 
not specified. The statistical model will be an analysis of variance 
(ANOVA) on the logarithmic scale including the fixed effect for 
‘formulation’ and ‘subject’ as a random effect. CIs will be calculated 
based on the residual error from ANOVA.
Part 2:
Relative bioavailability will be estimated by the ratios of the 
geometric means (test/reference) for the primary and secondary 
endpoints. Additionally, their two-sided 90% confidence intervals 
(CIs) will be provided. This method corresponds to the two one-sided 
t-test procedure, each at a 5% significance level. Since the main focus 
is on estimation and not testing, a formal hypothesis test and 
associated acceptance range is not specified. The statistical model 
will be an ANOVA on the logarithmic scale including effects for 
sequence, subjects nested within sequences, period and treatment. CIs 
will be calculated based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART (PART 1)
Period
Visit
Day
Planned time (relative to drug 
administration) [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK plasma
7
PK plasma [C-14] BI 1358894
Suicidality assessment (C-SSRS)9
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 5
SCR
1
-21 to -2
Screening (SCR)1
x
x
x
x
2
-1
-22:00
10:00
Admission to trial site11
x
4, 13
-14:00
18:00
Dinner
-10:30
21:30
Light voluntary snack12
1
-1:00
07:00
x2
x2, 6
x2
0:00
08:00
Drug administration
(BI 1358894, 100 mg tablet, oral)
0:15
08:15
x
0:30
08:30
x
x
1:00
09:00
x
x8
x
1:30
09:30
x
x
2:00
10:00
240 mL fluid intake
x
3:00
11:00
x
x
4:00
12:00
Light snack3
x
x
x8
x
5:00
13:00
Start of IV infusion containing
[C-14]-BI 1358894
240 ml fluid intake
x
x
5:05
13:05
x
x
5:10
13:10
x
x
5:15
13:15
Stop of IV infusion containing
[C-14]-BI 1358894
x
x
5:30
13:30
x
x
5:45
13:45
x
x
6:00
14:00
240 mL fluid intake, thereafter 
lunch3
x
x
x
6:30
14:30
x
x
7:00
15:00
x
x
8:00
16:00
x
x
x8
x
10:00
18:00
Dinner3
x
x
12:00
20:00
x
x
x8
x
2
24:00
08:00
Breakfast3
x13
x
x
x8
x
34:00
18:00
x
x
x
3
48:00
08:00
Breakfast3
x
x
x
x
4
72:00
08:00
Breakfast3
x
x
x
5
96:00
08:00
Breakfast (voluntary)3, Discharge 
from trial site10
x
x
x
x
x
7
144:00
08:00
Ambulatory visit
x
x
x
x
9
192:00
08:00
Ambulatory visit
x
x
x
11
240:00
08:00
Ambulatory visit
x
x
x
x
14
312:00
08:00
Ambulatory visit
x
x
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, check of vital signs, ECG, safety laboratory (including drug screening, urine 
alcohol test, hepatitis serology and HIV antibodies), demographics (including determination of body height and weight, 
smoking status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion 
criteria, neurological examination and suicidality assessment (C-SSRS). 
2.
The time is approximate; the procedure is to be performed and completed within the 2 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
Safety laboratory including urine drug screening and urine alcohol test will be done at this time point.
5. 
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for twice daily
during in-house days.
6.
Prior to BI drug administration 3 triplicate ECGs will be recorded within approximately one hour. The recordings 
should be separated by at least 15 minutes.
7.
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.
8.
ECGs taken at these time points should be performed as triplicate and will be sent out for external evaluation.
9.
Suicidality assessment will be performed at screening, at discharge from trial site for each period and at end of trial.
10. Confirmation of fitness includes physical and neurological examination, vital signs, ECG, suicidality assessment (C-
SSRS), recordings of AEs and concomitant therapies assessed on Day 5 as well as evaluation of safety laboratory 
assessed on Day 2.
11. All subjects will be admitted to the trial site after an overnight fast of at least 10 h for all treatments.
12. Light voluntary snack to be consumed within 30 min to allow 10 h fasting prior to oral drug administration.
13. A PCR testing for SARS-CoV-2/COVID-19 will be performed at admission on Day – 1 and on Day 2.


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FLOW CHART (PART 2)
Period
Visit
Day
Planned time (relative to drug 
administration) [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK plasma
8
Suicidality assessment (C-SSRS)9
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Period 2/3 (two periods separated by a wash-out of at least 17 days)
3/4
-1
-22:00
10:00
Admission to trial site11
x5, 12
-12:00
18:00
Dinner
1
-1:00
07:00
Allocation to treatment sequence 
x2
x2, 7
x2
-0:30
07:30
High fat, high calorie breakfast or 
overnight fast (for T2 only)
0:00
08:00
Drug administration
0:15
08:15
x
0:30
08:30
x
x
1:00
09:00
x
x1
x
1:30
09:30
x
x
2:00
10:00
240 mL fluid intake
x
3:00
11:00
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x1
x
5:00
13:00
x
x
6:00
14:00
x
x
7:00
15:00
x
8:00
16:00
Snack (voluntary)3
x
x
10:00
18:00
Dinner3
x
12:00
20:00
x
x1
x
2
24:00
08:00
Breakfast3
x12
x
x1
x
34:00
18:00
x
x
3
48:00
08:00
Breakfast3
x
x
x
4
72:00
08:00
Breakfast3
x
x
x
5
96:00
08:00
Breakfast (voluntary)3, Discharge
from trial site10
x
x
x
x
7
144:00
08:00
Ambulatory visit
x
x
x
9
192:00
08:00
Ambulatory visit
x
x
11
240:00
08:00
Ambulatory visit
x
x
x
14
312:00
08:00
Ambulatory visit
x
x
x
FU
5
52 to 57
End of trial (EOT) examination4
x12
x
x
x
x
1.
ECGs taken at these time points should be performed as triplicate and will be sent out for external evaluation
2.
The time is approximate; the procedure is to be performed and completed within the 2 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, body weight, vital signs, ECG, safety 
laboratory, recording of AEs, concomitant therapies, neurological examination and suicidality assessment (C-SSRS). 
5.
Safety laboratory including urine drug screening and urine alcohol test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for twice daily 
during in-house days.
7.
Prior to BI drug administration 3 triplicate ECGs will be recorded within approximately one hour. The recordings 
should be separated by at least 15 minutes.


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8.
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. 
9.
Suicidality assessment will be performed at screening, at discharge from trial site for each period and at end of trial.
10. Confirmation of fitness includes physical and neurological examination, vital signs, ECG, suicidality assessment 
(C-SSRS), and recordings of AEs and concomitant therapies assessed on Day 5 as well as evaluation of safety 
laboratory assessed on Day 2.
11. All subjects will be admitted to the trial site after an overnight fast of at least 10 h for all treatments.
12. A PCR testing for SARS-CoV-2/COVID-19 will be performed at admission on Day – 1, on Day 2 and at Follow-up.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART (PART 1) .................................................................................6
FLOW CHART (PART 2) .................................................................................8
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE...............................................................................................19
1.2.1
BI 1358894 .............................................................................................19
1.2.2
Residual Effect Period..........................................................................21
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
1.4
BENEFIT - RISK ASSESSMENT ...................................................................22
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 24
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......24
2.1.1
Main objectives......................................................................................24
2.1.2
Primary endpoints ................................................................................24
2.1.3
Secondary endpoints.............................................................................24
2.2.2.2
Safety and tolerability..............................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 27
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................27
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................27
3.3
SELECTION OF TRIAL POPULATION ......................................................28
3.3.1
Main diagnosis for trial entry..............................................................28
3.3.2
Inclusion criteria...................................................................................28
3.3.3
Exclusion criteria ..................................................................................28
3.3.4
Withdrawal of subjects from treatment or assessments ...................30
3.3.4.1
Discontinuation of trial treatment............................................30
3.3.4.2
Withdrawal of consent to trial participation ............................31
3.3.4.3
Discontinuation of the trial by the sponsor..............................31
3.3.5
Replacement of subjects .......................................................................31
4.
TREATMENTS........................................................................................ 32


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4.1
INVESTIGATIONAL TREATMENTS ..........................................................32
4.1.1
Identity of the Investigational Medicinal Products ...........................32
4.1.2
Selection of doses in the trial................................................................33
4.1.3
Method of assigning subjects to treatment groups ............................33
4.1.4
Drug assignment and administration of doses for each subject .......34
4.1.5
Blinding and procedures for unblinding ............................................35
4.1.6
Packaging, labelling, and re-supply ....................................................35
4.1.7
Storage conditions.................................................................................36
4.1.8
Drug accountability ..............................................................................36
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................36
4.2.1
Other treatments and emergency procedures....................................36
4.2.2
Restrictions............................................................................................37
4.2.2.1
Restrictions regarding concomitant treatment .........................37
4.2.2.2
Restrictions on diet and life style.............................................37
4.3
TREATMENT COMPLIANCE.......................................................................37
5.
ASSESSMENTS....................................................................................... 38
5.1
ASSESSMENT OF EFFICACY.......................................................................38
5.2
ASSESSMENT OF SAFETY............................................................................38
5.2.1
Physical examination ............................................................................38
5.2.2
Vital signs...............................................................................................38
5.2.3
Safety laboratory parameters..............................................................38
5.2.4
Electrocardiogram................................................................................41
5.2.5
Other safety parameters.......................................................................43
5.2.5.1
Suicidality assessment using the C-SSRS (paper version) ......43
5.2.5.2
Neurological examination........................................................44
5.2.6
Assessment of adverse events...............................................................45
5.2.6.1
Definitions of adverse events...................................................45
Adverse event ............................................................45
5.2.6.1.1
Serious adverse event ................................................45
5.2.6.1.2
AEs considered ‘Always Serious’.............................45
5.2.6.1.3
Adverse events of special interest .............................46
5.2.6.1.4
Intensity (severity) of AEs.........................................47
5.2.6.1.5
Causal relationship of AEs ........................................47
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................48
AE collection.............................................................48
5.2.6.2.1
AE reporting to the sponsor and timelines ................48
5.2.6.2.2
Information required..................................................49
5.2.6.2.3
Pregnancy ..................................................................49
5.2.6.2.4
5.2.6.3
Collection and reporting of the adverse event headache .........49
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................50
5.3.1
Assessment of pharmacokinetics .........................................................50


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5.3.2
Methods of sample collection...............................................................50
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................50
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................51
5.4
ASSESSMENT OF BIOMARKER(S) .............................................................51
5.5
BIOBANKING ...................................................................................................51
5.6
APPROPRIATENESS OF MEASUREMENTS.............................................51
6.
INVESTIGATIONAL PLAN.................................................................. 52
6.1
VISIT SCHEDULE............................................................................................52
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................52
6.2.1
Screening period....................................................................................52
6.2.2
Treatment periods.................................................................................52
6.2.3
Follow-up period and trial completion ...............................................53
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 54
7.1
STATISTICAL DESIGN – MODEL ...............................................................54
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................54
7.3
PLANNED ANALYSES....................................................................................55
7.3.1
Primary endpoint analyses...................................................................56
7.3.2
Secondary endpoint analyses ...............................................................58
7.3.4
Safety analyses.......................................................................................58
7.4
INTERIM ANALYSES .....................................................................................59
7.5
HANDLING OF MISSING DATA ..................................................................59
7.5.1
Safety......................................................................................................59
7.5.2
Pharmacokinetics..................................................................................59
7.6
RANDOMISATION ..........................................................................................60
7.7
DETERMINATION OF SAMPLE SIZE ........................................................60
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 65
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................65
8.2
DATA QUALITY ASSURANCE .....................................................................66
8.3
RECORDS..........................................................................................................66
8.3.1
Source documents .................................................................................66
8.3.2
Direct access to source data and documents.......................................67
8.3.3
Storage period of records.....................................................................67
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................67


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8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......67
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................68
8.6
TRIAL MILESTONES .....................................................................................68
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................69
9.
REFERENCES......................................................................................... 70
9.1
PUBLISHED REFERENCES...........................................................................70
9.2
UNPUBLISHED REFERENCES.....................................................................71
10. APPENDICES .......................................................................................... 72
10.1
C-SSRS (ENGLISH VERSION).......................................................................72
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 82
11.1
GLOBAL AMENDMENT 1 .............................................................................82
11.2
GLOBAL AMENDMENT 2 .............................................................................84


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-312
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 312 h
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
Borderline personality disorder
bpm
Beats per minute
CA
Competent authority
CCK-4
Cholecystokinin tetrapeptid
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
COVID-19
Coronavirus Disease 2019
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CRP
C-reactive protein
C-SSRS
Columbia Suicide Severity Rating Scale
CTM 
Clinical Trial Manager


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CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
CYP3A4
Cytochrome P450 3A4
DG
Dose group
DILI
Drug induced liver injury
DNA
Desoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
e.g.
exempli gratia (for example)
EoTrial
End of trial
EU
European Union
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FDA
Food and Drug Administration
fMRI
Functional magnetic resonance imaging
FIM
First in man
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s brochure
ICH
International Conference on Harmonisation of technical requirements for
registration of pharmaceuticals for human use
ICRP
International commission on radiological protection
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IPV
Important protocol violation
IRB
Institutional Review Board
ISF
Investigator site file
i.v.
Intravenous


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LLOQ
Lower limit of quantification
MDA
Methylenedioxyamphetamine
MDD
Major depressive disorder
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
p.o.
Oral
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory disease Coronavirus 2
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
T
Test product or treatment
TMF
Trial master file
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal


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XTC
Ecstasy 


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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). 
Major depressive disorder 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 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 
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
For a detailed description of the BI 1358894 profile, please refer to the current Investigator’s 
Brochure (IB) [c10354149].
Pharmacokinetics in Humans
Human PK data are currently available from the FIM study 1402-0001, which consisted of an 
SRD part (tested doses: 3 mg – 200 mg BI 1358894) and a food effect part (tested doses: 50 
mg and 100 mg BI 1358894 under fasted and fed conditions) [report in preparation].
Following oral administration of film-coated tablets in fasted state BI 1358894 reached 
maximum plasma concentrations after 1 to 5 hours. Thereafter BI 1358894 plasma 
concentrations declined in a multiphasic fashion implying multi-compartmental distribution 
and exhibited a long terminal phase, which seems to be dose-independent. 
Cmax, AUC0-72 and AUC0-∞of BI 1358894 increased in a dose dependent way. Preliminary 
statistical evaluation showed that the increase in Cmax and AUC0-72 was less than dose 
proportional. AUC0-∞increased slightly less than dose proportional when given without food. 
Also the food effect was dependent on the administered dose. While the exposure of BI 
1358894 increased by factor 1.6 for the 50 mg dose, a food effect of factor 2.5 was observed 
for the 100 mg dose.
After completion of the food effect assessment, a dose of 200 mg BI 1358894 has been given 
after a high-calorie, high-fat meal in the SRD part of 1402-0001. Compared to the cohort 
receiving 200 mg under fasted conditions, food increased exposure by about 2.4-fold 
(exposure of 200 mg BI 1358894, fed conditions: Cmax = 857 nM, AUC0-24 = 11640 nM*h). 
Based on PK data of previous dose groups (DGs) in the 200 mg fed DG PK blood sampling 
was extended to 672 h. Sampling from 240 h to 672 h revealed another phase with low 
plasma concentrations and long terminal half-life of about 200 h. The proportion of AUC 
beyond 192 h is less than 20% of total AUC. Hence, it is not expected that this phase 
markedly contributes to accumulation or steady state attainment. 
Preliminary PK data from the ongoing MRD study 1402-0002 support this observation. In the 
first dose groups (10 mg and 25 mg), an accumulation ratio (based on AUC0-24) of 2.5 was 
observed. Steady state seems to be achieved after about a week. Both accumulation ratio and 
approximation of steady state attainment are in line with an effective half-life of ~33h.
Safety and tolerability in healthy subjects
At the time of preparing this trial protocol, four Phase I trials with administration of BI 
1358894 to approximately 140 healthy subjects have been conducted. Preliminary data on 
safety and tolerability observed in these trials are given below:
1402-0001, SRD part: In the SRD part of 1402-0001 study safety, tolerability, PK and PD of 
rising single doses of BI 1358894 has been investigated in 8 DGs (3 mg – 6 mg – 10 mg – 25 
mg – 50 mg – 100 mg – 200 mg fasted – 200 mg fed) with planned 8 subjects (6 on active, 2 


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on placebo). The most frequent drug related AE was headache, which has been reported by 
18 of 48 subjects on active treatment. While headache occurred in 50% of subjects on active 
treatment in DG 2 and in DG 5-8, it was reported by only 1 subject in DG 1 and by 2 subjects 
in DG 4. The intensity of headache was mild (16 x) to moderate (2 x). The two cases of 
moderate headache have been observed in DG 5 and 7. 
Beyond headache the following drug-related AEs have been observed (each in 1 subject 
only): delayed auditive perception, dizziness, head pressure, back pain, lightheadedness, 
tiredness and loss of concentration. These AEs were of mild to moderate intensity. 
1402-0001, food effect part: This part of the 1402-0001 study investigated the effect of food 
on the kinetics of 50 mg (N=8) and 100 mg (N=12) BI 1358894, given as a single dose in two 
trial periods. The most frequent drug related AE was headache, which has been reported by 
15 of 20 subjects (in nine subjects drug related headache occurred in both trial periods). 
Beyond headache the following drug-related AEs have been observed: dizziness (5 subjects), 
tiredness (3 subjects), lightheadedness (2 subjects), loss of concentration (2 subjects), and 
meteorism, back pain, intermittent hip pain, head pressure, exacerbation of face acne and skin 
irritation with itching at the whole body (1 subject each). All drug related AEs were of mild 
or moderate intensity. 
1402-0002, MRD-study: Trial 1402-0002 investigates safety, tolerability, PK and PD of 
rising multiple doses BI 1358894 (administered over 14 days) in a double-blinded fashion. At 
the time point this protocol is written, the clinical performance of four DGs (10 mg, 25 mg, 
50 mg and 100 mg) with a total of 40 subjects (32 on active, 8 on placebo) has been already 
finished. The highest dose group of 200 mg is currently ongoing.
In course of the first four dose groups the most frequent drug related AE is headache which 
has been reported by 16 of 40 subjects. Frequency of drug related headache was not dose-
dependent. With three and two affected subjects it was even less frequent in the higher DGs 
(50 mg, 100 mg). Drug related headache was mainly of mild intensity. Moderate intensity has 
been reported only for three subjects in DG 2 (2 x) and DG 4 (1 x). 
In the 25 mg DG seven from ten subjects reported drug related headache. In four cases the 
affected subjects suffered from intermittent headache that lasted over 9-12 days. In one 
subject this was accompanied by drug related nausea on Day 6 and 9. Due to this continuous 
impairment the subject withdrew informed consent prior to dosing on Day 10.
Beyond headache the following drug-related AEs have been observed: orthostatic 
dysregulation (8 subjects), dizziness (4 subjects), tiredness (3 subjects), heartburn (2 subjects) 
and stomach cramps, blurred vision, acneiform skin (face), nausea, loose stool, flatulence, 
decreased concentration, head pressure, fasciculation (finger), and pressure on both eyes (1 
subject each). These AEs were of mild intensity and did not follow a specific pattern of 
distribution. 
1402-0003: Trial 1402-0003 investigated the effect of a single dose of BI 1358894 compared 
to placebo on BOLD responses in modulation brain processing of emotional and cognitive 
stimuli on the amygdala and related brain structure using fMRI in unmedicated patients with 
depression in a randomized, placebo-controlled, parallel-group study.


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Overall, 73 patients with MDD (males and females) were treated either with BI 1358894 (25 
patients), with citalopram (24 patients) used as a positive control, or placebo (24 patients). 
The overall summary showed that there were no deaths and SAEs. There were also no reports 
of AESIs, severe AEs, AEs leading to discontinuation of trial drug, or other significant AEs. 
The frequency of patients with any AEs was higher in the BI 1358894 treatment group (23 
patients) than in the citalopram (15 patients) and placebo (14 patients) groups. The most 
common AE was headache. In the BI 1358894 treatment group, headache was reported by 17 
patients compared with 13 patients in the citalopram and 10 patients in the placebo groups. 
Overall safety results from trial 1402-0003 are in line with the safety results of Phase I trials.
1402-0005: Trial 1402-0005 investigated the pharmacodynamic effects of a single dose of BI 
1358894 on CCK-4 induced anxiogenic/panic-like symptoms using the Panic Symptom Scale 
(PSS) in preselected CCK-4 sensitive healthy volunteers in a double-blind, randomized, 
placebo-controlled, crossover study. In this trial, 20 patients were treated with a single dose 
of 100 mg BI 1358894 and placebo (10 patients in the sequence BI 1358894, placebo; 10 
patients in the sequence placebo, BI 1358894). 
The overall summary showed that there were no deaths and SAEs. There were also no reports
of AESIs, AEs leading to discontinuation of trial drug, or other significant AEs. The most 
common AE was headache and was most frequently reported in the BI 1358894 treatment 
group (10 subjects) than in the placebo group (1 subject). Overall, the results of Trial 1402-
0005 are in line with the pooled safety analysis of Phase I trials.
1402-0007: Trial 1402-0007 investigated the effect of the CYP3A4 inhibitor itraconazole on 
the kinetics of the CYP3A4 substrate BI 1358894 in 16 healthy subjects. A single dose of 
10 mg BI 1358894 has been given alone and together with multiple doses of itraconazole. 
The most frequent drug related AE was headache reported by five subjects. In one case 
headache was of severe intensity. All subjects completed the trial.
1402-0009: Trial 1402-0009 investigated the relative bioavailability of rosuvastatin (Part 1) 
and dabigatran (Part 2) given alone and together with BI 1358894 in 28 healthy male subjects 
(14 in each part). Final results are not yet available at the time of CTA, however no safety 
findings in conflict with previous observations were reported.
1402-0010: Trial 1402-0010 investigated the relative bioavailability of different trial 
formulations of BI 1358894. The 24 participating subjects had to undergo three treatment 
periods. In each trial period a single dose of 100 mg BI 1358894 has been administered. The 
most frequent drug related adverse event was headache, that has been reported by about 50% 
of subjects. Drug related dizziness and tiredness was reported by two subjects each. All drug 
related adverse events were of mild or moderate intensity. 
1.2.2
Residual Effect Period
Based on an effective half-life of 33 h the Residual Effect Period (REP) of BI 1358894 is 11
days. This is the period after the last dose with measurable drug levels and/or 
pharmacodynamic effects is still likely to be present.


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1.3
RATIONALE FOR PERFORMING THE TRIAL
This trial is intended to examine the absolute oral bioavailability of BI 1358894 as tablet 
formulation for oral administration using an intravenous (i.v.) [C-14] microtracer approach
(Part 1) and to investigate the relative bioavailability of the oral suspension (Part 2). The data 
are considered necessary to further support the understanding of the pharmacokinetics of BI 
1358894.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development. Subjects are 
exposed to risks of study procedures and risks related to the exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The solvent for the intravenous infusion containing a mixture of labelled and unlabelled BI 
1358894 is isotonic sodium chloride solution (0.9%). Therefore, in case of inadvertent 
paravenous drug administration apart from local swelling no tissue damage is expected. 
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
The single dose administration of up to 200 mg BI 1358894 under fasted and fed conditions 
has been well tolerated by healthy subjects in the single rising dose trial [c28907328] as well 
as the single dose administration of 100 mg under fasted and fed administration in the relative 
bioavailability trial 1402-0010 [c28907328]. Therefore no undue risk is expected from the
single dose administration of 100 mg BI 1358894 to healthy subjects planned for this trial. A 
more detailed description of BI 1358894 tolerability in healthy subjects can be found in 
Section 1.2.1.
Drug-induced liver injury (DILI):
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.6.1.4, adverse events of special interest.


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Administration of 14C-labelled BI 1358894
BI 1358894 is labelled with the isotope [14C] which is necessary for the purposes of this
microtracer trial to distinguish the i.v. drug from the unlabelled oral drug. The radioactive 
dose per infusion has been calculated to be 0.039 MBq which does not exceed the threshold 
of 0.1 MBq, and thus falls into the ICRP 1 category (negligible radio burden) that is 
considered acceptable.
Overall assessment
In a previous trial, single oral doses up to 200 mg BI 1358894 administered in fed and fasted
state as tablets were safe and well-tolerated. In the current trial, single oral dose of 100 mg BI 
1358894 will be administered to healthy male subjects which will give an appropriate safety 
margin to the highest dose safely tested in the SRD (1402-0001). Each participant will be 
receiving a single i.v. infusion of a microtracer [C-14] BI 1358894 containing a radioactive 
dose <0.1 mSv (ICRP 1 category, negligible radioburden).
The trial design is optimized to collect as much relevant information as possible on the
pharmacokinetics of BI 1358894 without exposing participating volunteers to undue risk.
However, there is always the potential of serious adverse events (SAEs) occurring with intake
of trial medication. Risks to subjects will be minimized and addressed by eligibility criteria,
safety laboratory examinations, ECG and vital sign measurements, in-house observation
periods and verbal communication concerning AEs.
If the investigator should have any clinical concern, the safety of the subjects will be of
paramount importance. The investigator has the discretion to remove subjects from the study 
should there be any safety concerns or if the subject’s wellbeing is at jeopardy.
The risk associated with the expected maximal radiation burden falls in ICRP category 1 with
minor level risk. This is considered to be acceptable.
The risk to participating subjects is minimized and justified when compared to the potential 
benefit that a successful clinical development of BI 1358894 could provide to the treatment 
of major depressive disorder and borderline personality disorder.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
Part 1
The main objective of Part 1 of this trial is:
-
To investigate the absolute bioavailability of 100 mg of BI 1358894 (Test 1, T1) with 
an intravenous microdose formulation containing labelled [C-14] BI 1358894 and an 
unlabelled oral tablet formulation of BI 1358894 in healthy male subjects.
Part 2
The main objective of Part 2 of this trial is:
-
To investigate the relative bioavailability of BI 1358894 administered as an oral 
suspension.
2.1.2
Primary endpoints
Part 1
The following pharmacokinetic parameters will be determined for BI 1358894:

AUC0-(area under the concentration-time curve of the analyte over the time interval 
from 0 to infinity after i.v. administration) for (C-14) BI 1358894 i.v.

AUC0-(area under the concentration-time curve of the analyte over the time interval 
from 0 to infinity after oral administration) for BI 1358894 p.o.
Part 2
The following pharmacokinetic parameter will be determined for BI 1358894:

AUC0-312 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 312 h)
2.1.3
Secondary endpoints
Part 1
The following pharmacokinetic parameter will be determined for BI 1358894:

Cmax (maximum measured concentration of the analyte after oral administration)
Part 2
The following pharmacokinetic parameters will be determined for BI 1358894:


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
Cmax (maximum measured concentration of the analyte after oral administration)

AUC0-(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity after oral administration)


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


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
Part 1 of the study will be performed as a non-randomised, open-label trial in healthy male 
subjects in order to investigate the pharmacokinetics and absolute bioavailability of BI 
1358894 as an oral tablet co-administered with an i.v. microtracer dose of [C-14]-BI 
1358894. The reference treatment in Part 1 (Reference 1 – R1) will be 10 mL intravenous 
infusion of 100 µg BI 1358894 using a mixture of 90 µg unlabelled and 10 µg [C-14] labelled 
BI 1358894. The oral treatment (Test 1 – T1) will consist of two 50 mg BI 1358894 tablets
administered on Day 1 to subjects in the fasting state. The i.v. infusion will start 5 hours after 
oral drug administration, i.e. at the time of the expected tmax.
This will be followed by Part 2 of the study which will be performed as a randomised, open-
label, single-dose, two-period, two-sequence cross-over trial to investigate the relative 
bioavailability of BI 1358894 administered as an oral suspension. In Part 2, the treatments 
will consist of a single dose of 100 mg BI 1358894 administered as an oral suspension either 
in the fasted state (Reference 2 – R2) or in the fed state (Test 2 – T2). In Part 2, the subjects 
will be randomly allocated to the 2 treatment sequences (T2-R2 or R2-T2).
Part 1 and Part 2 are designed in a fixed sequence. 
For details, refer to Section 4.1.
There will be a washout period of at least 17 days between the treatments, i.e. the dosing in 
Part 1 and the dosing in the first treatment period of Part 2, as well as the dosing in the first 
treatment period of Part 2 and the dosing in the second treatment period of Part 2 are 
separated by at least 17 days.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For the absolute bioavailability, the same subject will receive a 14C-labelled microtracer 
infusion on Day 1 after a single oral dose of BI 1358894. Thus the oral bioavailability will be 
calculated for each subject.
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between treatments is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between formulations [R94-1529].
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.


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3.3
SELECTION OF TRIAL POPULATION
It is planned that 12 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
Only healthy male subjects will be included in the study because they are an ideal population 
for the objectives of this trial since they provide relatively stable physiological biochemical 
and hormonal conditions, i.e. in the absence of disease-related variations and relevant 
concomitant medications.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5. Male subjects who meet any of the following criteria from at least 30 days before the first 
administration of trial medication until 90 days after trial completion:
-
Use of adequate contraception of the female partner, e.g. any of the following
methods plus condom: implants, injectables, combined oral or vaginal contraceptives, 
intrauterine device that started at least 2 months prior to first study drug administration or 
barrier method (e.g. diaphragm with spermicide) or,
-
Sexually abstinent or
-
A vasectomy performed at least 1 year prior to screening (with medical assessment of 
the surgical success) or
-
Surgically sterilised female partner (including hysterectomy, bilateral tubal occlusion 
or bilateral oophorectomy) or
-
Postmenopausal female partner, defined as at least 1 year of spontaneous amenorrhea 
(in questionable cases a blood sample with FSH above 40 U/L and estradiol below 
30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:


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1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 40 to 100 bpm
3. C-reactive protein (CRP) > upper limit of normal (ULN), liver or kidney parameter above 
ULN
4. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
5. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
6. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
7. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
8. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
9. History of relevant orthostatic hypotension, fainting spells, or blackouts
10. Chronic or relevant acute infections
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
12. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
13. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
15. Inability to refrain from smoking on specified trial days
16. Alcohol abuse (average consumption of more than 21 units per week)
17. Drug abuse or positive drug screening
18. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
19. Intention to perform excessive physical activities within 4 days prior to the administration 
of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
22. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 


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In addition, the following trial-specific exclusion criteria apply:
24. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
25. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
26. Exposure to radiation for diagnostic reasons (except dental X-rays and plain X-rays of 
thorax and bony skeleton (excluding spinal column) in the period of 1 year prior to 
screening
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF


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6.
The subject shows a raised CRP level of >3.00 mg/dL 
7. 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.
8. The subject experiences a serious adverse reaction which is considered at least possibly 
related to the IMP administration
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least 1 drug-related serious adverse event is 
reported
3. Violation of GCP, or the CTP , or the contract with BI impairing the appropriate conduct 
of the trial-
4. The sponsor decides to discontinue the further development of the investigational product
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case subjects do not complete the trial, the Clinical Trial Leader together with the Principal 
Investigator, the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how 
many subjects will be replaced. A replacement subject will be assigned a unique trial subject 
number, and will be assigned to the same treatment as the subject he or she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Radiolabelled BI 1358894 (C-14) (R1) is administered as an intravenous solution. The 
powder used for intravenous solution containing [C-14] BI 1358894 and unlabelled BI 
1358894 has been manufactured by BI Pharma GmbH & Co. KG. The mixture of [C-14] BI 
1358894 and unlabelled BI 1358894 and the solution from this mixture are made by 
 
 
Tablet formulation and oral suspension of BI 1358894 have been manufactured by BI Pharma 
GmbH & Co. KG. 
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product 1 (T1) are given below:
Substance:
BI 1358894
Pharmaceutical formulation: Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg
Posology:
2-0-0
Route of administration:
oral
Duration of use:
single dose
The characteristics of the reference product 1 (R1) are given below:
Name:
BI 1358894 (C-14) intravenous solution
Substance:
BI 1358894 mixed with [C-14] BI 1358894
Pharmaceutical formulation: Intravenous solution
Source:
Unit strength:
100 μg BI 1358894 consisting of 
o
90 μg unlabelled BI 1358894 mixed with 10 μg labelled 
[C-14] BI 1358894 
o
in 10 mL intravenous solution (10 μg BI 1358894 (C-
14) /mL)
Posology:
1-0-0
Route of administration:
i.v.
Duration of use:
One single infusion on Day 1 of Part 1, infused over 15 minutes
The characteristics of the test product 2 (T2) and reference product 2 (R2) are given below:


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Substance:
BI 1358894
Pharmaceutical formulation: Oral suspension
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg/mL
Posology:
1-0-0
Route of administration:
oral
Duration of use:
single dose on Day 1 of Period 2 and Period 3
4.1.2
Selection of doses in the trial
The dose selected for this trial is one of the standard clinical doses (see Section 1.2).
The oral dose of 100 mg BI 1358894 is below the already tested highest oral dose of 200 mg 
of BI 1358894 in the SRD in healthy subjects. In healthy volunteers, this dose was safe and 
well-tolerated (Section 1.2). An oral dose of 100 mg, administered as single dose, is 
considered adequate for the objectives of the current trial.
The oral dose (100 mg BI 1358894) is ~1000-fold higher than the intravenously infused dose 
(100 μg). Therefore, exposure of BI 1358894 resulting from the infusion is considered 
negligible.
The i.v. dose on Day 1 of Part 1 administered as an infusion will include 14C radiolabelled BI
1358894. The radiolabelled dose has been selected to provide sufficient analytical sensitivity, 
(Accelerator Mass Spectrometry), in this microtracer study while not exceeding the threshold 
of negligible radioactive burden, see Section 1.4.
4.1.3
Method of assigning subjects to treatment groups
Part 1 of the trial is open-labelled, single arm, therefore all subjects will receive the same 
treatments. Each subject will be assigned a subject number prior to dosing on Day 1 of Visit 
2.
Part 1 and Part 2 will be conducted in a fixed-sequence design.
Part 2 of the trial follows a randomized, two-treatment, two-sequence study design. The
randomisation list for Part 2 will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the administration of trial 
medication in the morning of Day 1 (Visit 3). For this purpose, numbers of the randomisation 
list will be allocated to the subjects in order of screening (the subject who was screened and 
approved first will be the first subject on the subject list). Subjects are then assigned to a 
treatment sequence according to the randomisation list.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.6.


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4.1.4
Drug assignment and administration of doses for each subject
Part 1 of the trial follows a non-randomized, open-label, single arm, single period design. Part 
2 of the trial is a randomized, open-label, two-period, two-way crossover study. In Part 2, all 
subjects will receive the 2 treatments in randomised order. Part 1 and Part 2 of the study are 
designed in a fixed sequence. The treatments to be evaluated are outlined in Table 4.1.4: 1
below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T1
(Test 1)
BI 1358894
Tablet
50 mg
2 tablets (50 mg), single dose, 
fasted
100 mg
R1
(Reference 1)
BI 1358894
(C-14)
i.v. infusion
10 µg/mL
10 mL (10 µg), single dose
100 µg
T2 
(Test 2)
BI 1358894
Oral 
suspension
25 mg/mL
100 mg, single dose, fed
100 mg
R2 
(Reference 2)
BI 1358894
Oral 
suspension
25 mg/mL
100 mg, single dose, fasted
100 mg
Administration of trial medication will be performed after subjects have fasted overnight for 
T1 and R2; fasting is to start no later than 10 h before the scheduled dosing. The investigator 
(or authorised designee) will administer the trial medication as an oral dose together with 
about 240 mL of water to subjects who are in a sitting position.
For drug administration, the so-called four-eye principle (two-person rule) should be applied. 
For this, one authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot 
be ensured otherwise.
For T2, a high-fat, high-calorie meal will be served 30 min before drug administration. The 
subjects must completely consume the meal prior to drug intake. The composition of the 
standard high-fat, high-calorie meal is detailed in Table 4.1.4: 2; this meal is in compliance 
with the FDA guidance ‘Food-Effect Bioavailability and Fed Bioequivalence Studies’ 
[R03-2269]. For restrictions with regard to diet, see Section 4.2.2.2.


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Table 4.1.4: 2
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 chicken eggs (whole content) for scrambled eggs
192
15 g butter for frying scrambled eggs
75
40 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat. 
Subjects will be kept under close medical surveillance until 96 h after drug administration. 
During the first 2 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture).
The treatments in Part 1 and Part 2, as well as between Period 2 and Period 3 of Part 2 will be 
separated by a wash-out phase of at least 17 days.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
Unlabelled drug supplies will be provided by BI. Radiolabelled drug supplies manufacturing 
will be provided by
.
The Investigational Medicine products will be packaged and labelled in accordance with local 
law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 


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kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
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 will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after oral drug intake.
From 1 h before oral drug intake until lunch (or light snack for Part 1), fluid intake is 
restricted to the milk served with breakfast if applicable (see Table 4.1.4: 2), the water 
administered with the drug, and an additional 240 mL of water at 2 h (and 4 h, in Part 2) post-
dose (mandatory for all subjects). 
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each study period is collected.
Poppy-seed containing products should not be consumed starting 3 days prior to first trial
drug administration until after the last PK sample of the trial. 
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before until 24 h after each administration of trial 
medication.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 96 h (4 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 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported),
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG, laboratory tests, a physical examination and a 
neurological examination. At the end of trial examination, it will include review of vital 
signs, 12-lead ECG, laboratory tests, a physical examination including determination of 
weight and a neurological examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (e.g. Dinamap WC 150) at the times indicated in the Flow Chart, after 
subjects have rested for at least 5 min in a supine position. All recordings should be made 
using the same type of blood pressure recording instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 4 h 
at the screening and EOT visits, and at least 10 h for all other time points. For retests, at the 
discretion of the investigator or designee, overnight fasting is not required.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
SARS-CoV-2 / COVID-19 specific test will be conducted at admission on Day – 1 and on 
Day 2 for each treatment period, and at Follow-up. For further details refer to Appendix 10.2.
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
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes count
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands; Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
Free T3 - Triiodothyronine
Free T4 – Thyroxine 
X
X
X
--
--
--
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
Albumin (Protein Electrophoresis) 
Alpha-1-Globulin (Protein Electrophoresis)
Alpha-2-Globulin (Protein Electrophoresis)
Beta-Globulin (Protein Electrophoresis) 
Gamma-Globulin (Protein Electrophoresis) 
C-Reactive Protein (Quant)
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined on Day – 1, Day 1, Day 2, Day 7, Day 11 and Day 14 at Visits 2, 3 and 4 (for 
time points refer to Flow Chart)
C: parameters to be determined at Visit 5 (end of trial examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to each treatment period.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Alcohol
Infectious serology (blood)
Hepatitis A antibodies (qualitative)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a urine alcohol and drug test (e.g. 
ADVIA Chemistry XPT system) will be performed prior to each treatment period, and may 
be repeated at any time during the study at the discretion of an investigator or designee. The 
results will not be included in the CTR
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
., with the 
exception of drug screening. Urinalysis stix and drug screening tests will be performed using 
e.g. Clinitek Novus test and ADVIA Chemistry XPT system, respectively, or comparable test 
systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Recording and storing
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (e.g. Mortara Eli 250 C) at the times provided in the 
Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
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.


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All ECGs will be stored electronically. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven.
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons.
Data transfer
For time points specified in the Flow Chart, i.e. time points on Day 1 up to 24 h post-dose, 
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 by the central ECG laboratory
Central ECG lab evaluation will be performed for the first of three replicate ECGs per time 
point with ECG recordings as specified in the Flow Chart (i.e., Day 1 up to 24 h post-dose for 
each Period). 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.
Central evaluation will include the determination of cardiac QRS-axis as assessed by the 
ECG machine’s algorithm as well as the intervals RR, PR, QRS and QT measured semi-
automatically. The remaining second and third replicate ECG will be stored for additional 
analysis if required, e.g. by authorities at a later time point.
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. After quality control, the
fiducial point markings will be reviewed by the cardiologist assigned to the study. For
blinding arrangements see Section 4.1.5. No more than two blinded readers will evaluate all
ECGs of the study. ECGs from a particular subject should be evaluated by single reader.


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For quality assurance and control of 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].
Evaluation by 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 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
Other safety parameters
5.2.5.1
Suicidality assessment using 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


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reports for plausibility and clinical relevance. Doubtful reports may be repeated or reports
may be validated by a consulting psychiatrist. If there is a confirmed positive report of
suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to
immediately interview the subject during the clinic visit, and/or is to consult a psychiatrist.
If the positive report is confirmed, appropriate actions for the subject’s safety have to be
initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal 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 AE as defined in
the protocol, and if it is considered an AE then it must be reported accordingly.
The original English version can be found in Appendix 10.1.
5.2.5.2
Neurological examination
As a general additional safety measure, a physical neurological examination will be
performed at the time points specified in the respective Flow Chart.
The neurological examination will include the following assessments:
- General level of arousal
- Orientation
- Eye movement
- Pupil size and pupil reactivity
- Reflexes
- Assessment of muscle strength
- Gait
- Romberg test
- Tremor
- Point-to-point movements
- Sensitivity
Documentation, Assessment, and Reporting:
Results will be documented in source data at the clinical trial site and assessed for clinical
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant
findings of the neurological examination will be reported as Adverse Events (during the trial)
or as baseline conditions (at screening).


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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
5.2.6.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.2.6.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 


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as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
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.


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


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5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF by the investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.


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Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
5.2.6.2.4
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
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.
5.2.6.3
Collection and reporting of the adverse event headache
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)


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 1358894 concentrations in plasma, a blood sample will be drawn
from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle.
For quantification of [C-14] BI 13588945 plasma concentrations, an additional K2-
EDTA tube needs to be collected as indicated in the Flow Chart. Blood will be withdrawn by
means of either an indwelling venous catheter or by venipuncture with a metal needle.
For detailed description of blood sampling, sample handling, sample preparation, sample
storage, tube labelling and sample shipment please refer to the laboratory manual.
At a minimum, the sample tube labels should list BI trial number, subject number, and 
planned sampling time. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the CTR is 
archived.


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5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSESSMENT OF BIOMARKER(S) 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
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 5.4 are 
generally used assessments of drug exposure. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 of each treatment period are to be performed and completed within a
2 h-period prior to the trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests 
will be ± 10 min for the first 4 h following the trial drug administration (on Day 1 of each 
treatment period) and ± 30 min thereafter until discharge on Day 5. During the ambulatory 
visits, the acceptable deviation from the scheduled time for vital signs, ECG, and laboratory 
tests will be ± 120 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
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 provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
6.2.2
Treatment periods
Each subject is expected to participate in 3 treatment periods (Part 1 of the trial and Period 2 
and 3 of Part 2). At least 17 days will separate drug administrations in the first and second
Part of the trial as well as in the second and third treatment periods of Part 2 of the trial.
On Day – 1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 96 h following drug administration. The 


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subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
Part 1:
The main objective of this study part 1 is to investigate absolute bioavailability of an 
unlabelled oral tablet formulation of BI 1358894 (Test 1, T1) compared to BI 1358894 [C-
14] as intravenous solution (Reverence 1, R1) in healthy male subjects on the basis of the 
primary and secondary pharmacokinetic endpoints, as listed in Section 2.1.2 and 2.1.3.
Part 2:
The main objective of this study part 2 is to investigate the relative bioavailability of 100 mg 
BI 1358894 administered as an oral suspension in fed healthy male subjects (Test 2, T2) 
compared with 100 mg BI 1358894 administered as an oral suspension in fasted healthy male 
subjects (Reverence 2, R2) on the basis of the primary and secondary pharmacokinetic 
endpoints, as listed in Section 2.1.2 and 2.1.3.
The trial is designed to allow intra-subject comparisons and will be evaluated statistically by 
use of a linear model for logarithmically transformed PK endpoints.
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Part 1:
The absolute bioavailability of 100 mg BI 1358894 with an intravenous microdose 
formulation containing labelled [C-14] BI 1358894 compared with an unlabelled oral tablet 
formulation of BI 1358894 will be estimated by the ratios of the geometric means 
(test/reference), and their corresponding 2-sided 90% confidence intervals (CIs) will be 
provided. This method corresponds to the two one-sided t-test procedure, each at the 5% 
significance level. Since the main focus is on estimation and not testing, a formal hypothesis 
test and associated acceptance range is not specified.


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Part 2:
The relative bioavailability of 100 mg BI 1358894 administered as an oral suspension under 
fed conditions compared with 100 mg BI 1358894 administered as an oral suspension under 
fasted conditions will be estimated by the ratios of the geometric means (test/reference), and 
their corresponding 2-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at the 5% significance level. Since the 
main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
In both parts of the trial, confidence intervals and p-values will be computed, but 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, while p-values are considered as an 
exploratory measure of evidence for effects in the present data.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol violation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment.
Descriptive and model based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol violation 
(IPD) categories will be suggested in the IQRM plan, IPDs will be identified no later than in 
the Report Planning Meeting, and the IPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug BI 1358894 will be calculated 
according to the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
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:


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
Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.3.1
Primary endpoint analyses
Primary analyses
Part 1:
The statistical model of study part 1 used for the analysis of the primary endpoints will be an 
analysis of variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will 
be log-transformed (natural logarithm) prior to fitting the ANOVA model. This model will 
include effects accounting for the following sources of variation: ‘subjects’ and 
‘formulation’. The effect 'subjects' will be considered as random, whereas ’formulation’ will 
be considered as fixed. The model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response measured on subject m receiving formulation k,
= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n
k = the kth formulation effect, k = 1, 2,


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ekm = the random error associated with the mth subject who received
formulation k,
where sm ~ N(0, σ2
B) i.i.d., ekm ~ N(0, σ2
W) i.i.d. and sm, ekm are independent random variables.
Part 2:
The statistical model of study part 2 used for the analysis of the primary endpoints will be an 
analysis of variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will 
be log-transformed (natural logarithm) prior to fitting the ANOVA model. This model will 
include effects accounting for the following sources of variation: sequence or block, subjects 
within sequences, period and treatment. The effect 'subjects within sequences' will be 
considered as random, whereas the other effects will be considered as fixed. The model is 
described by the following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence I receiving treatment 
k in period j,
= the overall mean,
i = the ith sequence or block effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j,
where sim ~ N(0, σ2
B) i.i.d., eijkm ~ N(0, σ2
W) i.i.d. and sim, eijkm are independent random 
variables.
For study part 1 and part 2, point estimates for the ratios of the geometric means 
(test/reference) for the primary endpoints (see Section 2.1) and their two-sided 90% 
confidence intervals (CIs) will be provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.


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7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will be assessed statistically using the same 
methods as described for the primary endpoints.
7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will
be assigned to the screening period, those between first trial medication intake (test


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treatment) and beginning of reference treatment will be assigned to the test treatment period.
Those between the start of infusion until the end of REP (see Section 1.2.2) will be assigned
to the combined test/reference treatment period. Events occurring after the REP but prior to
next intake or end of trial termination date will be assigned to ’follow-up’. These assignments
including the corresponding time intervals will be defined in detail in the TSAP. Note that
AEs occurring after the last per protocol contact but entered before final database lock will be
reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the derivation of further qualitative and quantitative ECG endpoints, including the 
calculation of heart rate corrected QT intervals. The TSAP will provide further details.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.


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7.6
RANDOMISATION
Part 1:
Randomization is not applicable in this open-label and single group clinical study part. All
subjects will receive the same treatment. Consecutive subject numbers will be assigned via
the EDC system.
Part 2:
Subjects will be randomised to one of the 2 treatment sequences in a 1:1 ratio. The block size 
will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 12 subjects in the trial, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratio of geometric means (test/reference) can be expected with 
95% probability. Precision is defined as the ratio of upper CI limit to the relative BA 
estimate. Note that the precision is independent of the actual ratio of geometric means.
Trial 1402-0010 used the same tablet formulation as the tablet formulation that will be used 
in this trial [c28907328]. The observed intra-individual coefficient of variation (gCV) for BI 
1358894 in that trial was roughly 18% for Cmax and 8% for AUC0-.
For various assumptions around the gCV of 18-20%, Tables 7.7: 1, 7.7: 2, 7.7: 3 provide an
overview of the achievable precision for estimating the ratio of geometric means 
(test/reference). For illustrative purposes, the expected 90% confidence intervals are 
displayed for different values of the ratios T/R of geometric means.


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Table 7.7: 1
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R) for different gCVs in a 2x2 crossover trial 
(N=10).
gCV [%]
Precision 
upper CL / 
relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
16.000
1.202
40.000
33.275
48.085
16.000
1.202
50.000
41.593
60.106
16.000
1.202
60.000
49.912
72.127
16.000
1.202
70.000
58.231
84.148
16.000
1.202
80.000
66.549
96.169
16.000
1.202
90.000
74.868
108.190
16.000
1.202
100.000
83.187
120.212
18.000
1.230
40.000
32.529
49.187
18.000
1.230
50.000
40.661
61.484
18.000
1.230
60.000
48.793
73.781
18.000
1.230
70.000
56.926
86.077
18.000
1.230
80.000
65.058
98.374
18.000
1.230
90.000
73.190
110.671
18.000
1.230
100.000
81.322
122.968
20.000
1.258
40.000
31.804
50.309
20.000
1.258
50.000
39.755
62.886
20.000
1.258
60.000
47.705
75.463
20.000
1.258
70.000
55.656
88.040
20.000
1.258
80.000
63.607
100.618
20.000
1.258
90.000
71.558
113.195
20.000
1.258
100.000
79.509
125.772
22.000
1.286
40.000
31.099
51.449
22.000
1.286
50.000
38.873
64.312
22.000
1.286
60.000
46.648
77.174
22.000
1.286
70.000
54.422
90.036
22.000
1.286
80.000
62.197
102.899
22.000
1.286
90.000
69.972
115.761
22.000
1.286
100.000
77.746
128.623
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).


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Table 7.7: 2
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R) for different gCVs in a 2x2 crossover trial 
(N=12).
gCV [%]
Precision 
upper CL / 
relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
16.000
1.173
40.000
34.114
46.902
16.000
1.173
50.000
42.642
58.627
16.000
1.173
60.000
51.171
70.353
16.000
1.173
70.000
59.699
82.078
16.000
1.173
80.000
68.228
93.803
16.000
1.173
90.000
76.756
105.529
16.000
1.173
100.000
85.285
117.254
18.000
1.196
40.000
33.452
47.830
18.000
1.196
50.000
41.815
59.788
18.000
1.196
60.000
50.178
71.745
18.000
1.196
70.000
58.541
83.703
18.000
1.196
80.000
66.904
95.660
18.000
1.196
90.000
75.267
107.618
18.000
1.196
100.000
83.630
119.575
20.000
1.219
40.000
32.806
48.772
20.000
1.219
50.000
41.007
60.965
20.000
1.219
60.000
49.209
73.158
20.000
1.219
70.000
57.410
85.351
20.000
1.219
80.000
65.612
97.543
20.000
1.219
90.000
73.813
109.736
20.000
1.219
100.000
82.015
121.929
22.000
1.243
40.000
32.176
49.726
22.000
1.243
50.000
40.220
62.158
22.000
1.243
60.000
48.264
74.590
22.000
1.243
70.000
56.308
87.021
22.000
1.243
80.000
64.352
99.453
22.000
1.243
90.000
72.396
111.884
22.000
1.243
100.000
80.440
124.316
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).


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Table 7.7: 3
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R) for different gCVs in a 2x2 crossover trial 
(N=14).
gCV [%]
Precision 
upper CL / 
relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
16.000
1.152
40.000
34.713
46.093
16.000
1.152
50.000
43.391
57.616
16.000
1.152
60.000
52.069
69.139
16.000
1.152
70.000
60.747
80.662
16.000
1.152
80.000
69.426
92.185
16.000
1.152
90.000
78.104
103.708
16.000
1.152
100.000
86.782
115.231
18.000
1.173
40.000
34.112
46.904
18.000
1.173
50.000
42.640
58.630
18.000
1.173
60.000
51.168
70.356
18.000
1.173
70.000
59.696
82.082
18.000
1.173
80.000
68.224
93.808
18.000
1.173
90.000
76.752
105.534
18.000
1.173
100.000
85.280
117.260
20.000
1.193
40.000
33.525
47.726
20.000
1.193
50.000
41.906
59.657
20.000
1.193
60.000
50.287
71.589
20.000
1.193
70.000
58.668
83.520
20.000
1.193
80.000
67.050
95.452
20.000
1.193
90.000
75.431
107.383
20.000
1.193
100.000
83.812
119.315
22.000
1.214
40.000
32.951
48.557
22.000
1.214
50.000
41.189
60.696
22.000
1.214
60.000
49.426
72.836
22.000
1.214
70.000
57.664
84.975
22.000
1.214
80.000
65.902
97.114
22.000
1.214
90.000
74.140
109.253
22.000
1.214
100.000
82.377
121.393
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).


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The calculation was performed as described by Julious [R11-5230] using R Version 3.5.1.


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


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


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


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


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The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

ensure appropriate training and information of local clinical trial manager (CTM), 
Clinical Research Associates, and investigators of participating trial sites
The non-labelled trial medication will be provided by the 
 
.
The radiolabelled trial medication will be provided by 
Safety laboratory tests will be performed by the local laboratory of the trial site (
).
Analyses of cold BI 1358894 concentrations in plasma will be performed at the 
 
 
.
Analyses of radioactive [C-14] BI 13588945 concentrations in plasma will be conducted
using 
 
 
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P06-11895
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, 
Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath 
PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and 
longer-term outcomes in depressed outpatients requiring one or several 
treatment steps: a STAR*D report. Am J Psychiatry 2006;163(11):1905-
1917
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2002:1-
9.
R06-2872
Trivedi MH, Rush AJ, Wisniewski SR, Warden D, McKinney W, Downing 
M, Berman SR, Farabaugh A, Luther JF, Nierenberg AA, Callan JA, 
Sackeim HA. Factors associated with health-related quality of life among 
outpatients with major depressive disorder: a STAR*D report. J Clin 
Psychiatry 2006;67(2):185-195.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval
prolongation and proarrhythmic potential for non-antiarrhythmic 
drugs.Rockville: U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER), 
Center for Biologics Evaluation and Research (CBER); 2005.
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
2005.
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
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/Gui
delines/Efficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 
2015) ;Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use; 2015.


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R16-5350
Fowler MA, Sidiropoulou K, Ozkan ED, Phillips CW, Cooper DC. 
Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent 
brain. Plos One 2007;2(6):e573
R16-5472
Koenigsberg HW, Denny BT, Fan J, Liu X, Guerreri S, Mayson SJ, et al. 
The neural correlates of anomalous habituation to negative emotional 
pictures in borderline and avoidant personality disorder patients. Am J 
Psychiatry 2014; 171(1):82-90.
R16-5473
Mandell D, Siegle G, Shutt L, Feldmiller J, Thase ME. Neural substrates of 
trait ruminations in depression. J Abnorm Psychol 2014;123(1):35-48.
R16-5474
IsHak WW, Elbau I, Ismail A, Delaloye S, Ha K, Bolotaulo NI, et al. 
Quality of life in borderline personality disorder. Harvard Rev Psychiatry 
2013;21(3): 138-150.
R16-5475
McClintock SM, Husain MM, Wisniewski SR, Nierenberg AA, Stewart 
JW, Trivedi MH, et al. Residual symptoms in depressed outpatients who 
respond by 50 % but do not remit to antidepressant medication. J Clin 
Psychopharmacol 2011;31(2): 180-186.
R16-5476
Links PS, Heslegrave R, Reekum R van. Prospective follow-up study of 
borderline personality disorder: prognosis, prediction of outcome, and axis 
II comorbidity. Can J Psychiatry 1998;43(3):265-270.
R16-5477
Skodol AE, Siever LJ, Livesley WJ, Gunderson JG, Pfohl B, Widiger TA. 
The borderline diagnosis II: biology, genetics, and clinical course. Biol 
Psychiatry 2002;51(12):951-963.
R16-5483
Ellison WD, Rosenstein L, Chelminski I, Dalrymple K, Zimmerman M. 
The clinical significance of single features of borderline personality 
disorder: anger, affective instability, impulsivity, and chronic emptiness in 
psychiatric outpatients. J Personal Disord 2016;30(2):261-270.
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. 31 Jan 2020.
c28907328
 Relative bioavailability and food 
effect of a single dose of different solid formulations of BI 1358894 
compared to a single dose of the reference tablet formulation of BI 1358894 
following oral administration under fed and fasted conditions in healthy 
male subjects (an open-label, single-dose, randomised, incomplete blocks 
crossover design study). 1402-0010. 27 Apr 2020


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10.
APPENDICES
10.1
C-SSRS (ENGLISH VERSION)


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10.2
COVID-19 RELATED ASSESSMENT AND RISK MITIGATION
This section contains a risk assessment for study 1402-0016 with BI 1358894 due to the 
circumstances created by the coronavirus disease-19 (COVID-19) pandemic. In addition, the 
document summarizes the mitigation approaches to be followed to minimize the risk of 
spreading severe acute respiratory syndrome coronavirus 2 (SARS CoV-2).
Risk Assessment
BI 1358894 is a TRPC4/5 inhibitor in development for treatment of Major Depressive 
Disorder and for the treatment of Borderline Personality Disorder (BoPD). It is expected that 
treatment with BI 1358894 has the potential to improve affective symptoms and emotion 
control, especially in patients with MDD who inadequately respond to the current standard of 
care (SSRI; SNRI) and in patients with BoPD, where no approved drug treatment is currently 
available
Relevant information on the product
BI 1358894 is a highly potent and selective TRPC4/5 Inhibitor (transient receptor potential 
cation channel, subfamily C, members 4 and 5). It has the potential to address core symptoms 
of MDD and BoPD as it targets TRPC4/5 ion channels. TRPC4 and TRPC5 are highly 
expressed in pyramidal neurons of the amygdala in the frontal cortex, hippocampus, and 
hypothalamus, brain areas that are involved in circuits contributing to emotional control. BI 
1358894 is thought to decrease neuronal excitability leading to normalization of the 
activation state of limbic circuits, which are known to be important for emotional control. 
BI 1358894 is characterised by high bioavailability after oral intake, moderate volume of 
distribution, low clearance and long terminal half-life. Excretion occurs almost exclusively
via faeces. After administration of BI 1358894 tablets, maximum plasma concentrations of BI 
1358894 occurred around 1 to 5 hours after dosing. The terminal half-life was 41 to 52 hours 
for blood. Steady state was reached after 11 to 14 days of BI 1358894 dosing.
Currently, repeat dose toxicity studies up to 13 weeks revealed toxicologically relevant 
effects on the skin (mice), Harderian glands (mice), hepatic function (mice), the vascular 
system (rats), male genital tract (rats), the Central Nervous System (CNS) function (dogs), 
and the digestive tract, renal function, and white blood cell parameters (mice, rats and dogs).
Minimal to moderate subacute perivascular inflammation was observed in animals dosed at 
≥30 mg/kg/day. The inflammation was centred around arterioles and small- to medium-sized 
muscular arteries of the mesentery and sometimes extended into the serosa of the digestive 
tract. In few animals dosed at 200 or 1000 mg/kg/day, diffuse slight inflammation and 
minimal to moderate focal necrotizing vasculitis were also noted. Vascular findings were no 
longer present after continued dosing at the same dose level for 4 or 13 weeks. 
Minimally to moderately increased extramedullary hematopoiesis (EMH) in the spleen 
correlated with increased spleen weights at all dose levels. At ≥30 mg/kg/day, minimally to 
slightly increased myelopoiesis was present in the bone marrow (sternum) and minimal to 


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slight extramedullary myelopoiesis was also observed in the axillary, mandibular, and 
mesenteric lymph nodes. These findings correlated also with increases in reticulocytes and 
WBC noted in hematology at all dose levels. These findings were considered to be a 
physiologic adaptive response of hematopoietic and lymphoid organs to increased demand in 
context with perivascular inflammation. 
In summary, toxicological investigations for BI 1358894 did not show any relevant effect on 
the function of the cardio-vascular system, the respiratory system or immune system so far. 
At this time point (16 Apr 2020) the toxicological investigation did not show any evidence 
that BI 1358894 may alter the susceptibility for a SARS-CoV2 infection or may facilitate the 
development of severe COVID-19.
Clinical safety was analysed for 7 completed Phase I clinical trials with 217 healthy 
volunteers and 73 patients with MDD so far (DLP 01 April 2020). There were no deaths or 
SAEs in any of these trials. Overall, BI 1358894 was well tolerated in healthy male subjects 
and in male and female patients with MDD.
In general, there were no clinically relevant findings in the clinical laboratory evaluation, 
including no treatment-emergent signs of inflammation based on erythrocyte sedimentation 
rate (ESR), C-reactive proteins (CRP), and faecal laboratory tests (faecal occult blood and 
faecal calprotectin). No evidence of significant changes in blood pressure, heart rate and ECG 
were observed so far.
Considerations around drug-drug-interactions are not included in this benefit-risk assessment 
– for those it should be referred to the protocol, Investigator’s Brochure and the most recent 
label of the respective medication(s) used for treatment of COVID-19.
Benefit and risk conclusions and recommendations
BI 1358894 is a highly specific inhibitor of the TRPC 4/5 channels. TRPC 4/5 channels are 
predominantly located in the CNS. All investigation into distribution and function of TRPC 
4/5 (preclinical and clinical) so far have not identified any interference with the immune 
system, the respiratory system or the cardio-vascular system. A modulatory impact on the
patient’s immune system for TRPC 4/5 inhibitor is so far not expected so that susceptibility 
to vis-à-vis infections should not be affected. Therefore, subjects participating in Phase I 
trials are at this time point not considered to be at a higher risk for a SARS-CoV2 infection 
due to BI 1358894 intake than currently posed by the ordinary environment. 
For the upcoming Phase I trial, the benefit-risk for the trial participants treated with BI 
1358894 remain unchanged in relation to the COVID-19 pandemic since:
-
The mode of action does not appear to have a substantial effect on clinically relevant 
organs (e.g. respiratory or cardiovascular system) critically affected by COVID-19.
-
There is currently no evidence that intake of BI 1358894 leads to immunosuppression.
-
The healthy volunteers are relatively young (18 – 55 years for the current trial) and in 
general without common co-morbidities associated with severe course of COVID-19.


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Since every subject will be assessed thoroughly and individual benefit-risk assessments are 
made prior to study entrance by the investigator also in respect of potential COVID-19, the 
risk for subjects participating in these studies will not differ from the current general risk of 
COVID-19 with all its consequences.
The investigators will take the totality of information related to each single subject and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each subject’s (continued) participation in the planned trials. BI as the sponsor, where 
required, will support the investigator in their decision finding. It is acknowledged that the 
investigator may decide to implement protocol deviations where this protects the safety, well-
being and/or is in the best interest of the patient.  
Study design key points
The study population for this study consists of healthy subjects with minimized COVID 19 
infection risk (free of COVID-19 symptoms, negative PCR test(s) before investigational 
medicinal product [IMP] administration) and with minimized impact of COVID-19, if 
contracted during the study (eg, during the COVID-19 pandemic the upper age is 55 years 
(inclusive), upper body mass index [BMI] ≤29.9 kg/m2).
Subjects will stay in-house from Day – 1 until Day 5 of each treatment period (following a 
single dose administration on Day 1). Subjects will come back for ambulatory visits on Day 
7, 9, 11 and 14. At the time of the follow-up examination (Day 52 – Day 57) BI 1358894 is 
expected to be eliminated.
SARS-CoV-2 containment measures to the CTP
The following SARS-CoV-2 containment measures will be taken during the study:
-
The study will be conducted in accordance with guidance from the Central Committee 
on Research Involving Human Subjects (CCMO [Centrale Commissie Mensgebonden 
Onderzoek]) on conducting Phase 1 trials in Clinical Research Units in The 
Netherlands during the COVID 19 pandemic.
-
During the entire study, the clinical research unit will implement all recommendations 
issued by the Dutch Government, including specific guidelines related to clinical 
research executed in clinical research units with respect to minimizing the risk of 
disease spreading, e.g., social distancing, disinfection, hygiene, and wearing of 
personal protection equipment by study staff. Details on specific procedures are 
described in the Site Specific Manual.
-
Polymerase chain reaction (PCR) testing for SARS-CoV-2 will be performed at the 
following time points:
o
1 nasopharyngeal PCR test directly before admission to the unit on Day - 1 
and 1 additional nasopharyngeal PCRs on Day 2 for confirmatory purpose for 
each treatment period. 


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o
Repeated nasopharyngeal PCR test at follow-up visit. 
-
Physical exams will be limited to the necessary visits (screening, discharge and 
follow-up).
-
In cases where subjects are not able to attend study visits due to the presence of a 
SARS-CoV 2 infection, the Investigator will discuss with the Sponsor potential 
mitigation approaches (including, but not limited to, extending the visit window, 
conducting evaluations via video link or phone call, allowing for safety procedures to 
be conducted at a local facility). The rationale (e.g., the specific limitation imposed by 
the SARS-CoV-2 infection that led to the inability to perform the protocol-specified 
assessment) and outcome of the discussion will be documented in the electronic case 
report form (eCRF).
-
A subject should not be admitted if there was any contact with a COVID-19 patient 
within the last 2 weeks prior to admission to the clinical research unit.
-
If a subject is tested to be SARS-CoV-2 positive on Day -1, the subject will be 
excluded from participation with reference to exclusion criterion #4, and referred for 
treatment.
-
If a subject becomes ill and/or is tested to be SARS-CoV-2 positive after the first 
administration of study treatment, dosing will be stopped. The subject will be isolated 
from other study participants and referred for treatment. The subject will be followed 
up in quarantine in the clinical research unit until complete elimination of the study 
compound or will be asked to quarantine at home according to guidelines of the Dutch 
government.
Conclusion of COVID-19 risk containment
Given the profile of the compound and given the study design, the COVID-19 risk 
minimization strategy as summarized above is considered adequate. The BI trial team and the 
Principal Investigator and supporting staff recommend study continuation as per latest 
version of the protocol and with implementation of the measures detailed in this appendix to 
the protocol.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
26 June 2020
EudraCT number
EU number
2020-000351-13
BI Trial number
1402-0016
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
Investigation of pharmacokinetics and absolute 
bioavailability of BI 1358894 administered orally as 
tablet co-administered with an intravenous 
microtracer dose of [C-14]-BI 1358894 in healthy 
male volunteers via a non-randomised, open-label, 
fixed-sequence trial (part 1) followed by a 
randomised, open-label, single-dose, two-period, 
two-sequence cross-over relative bioavailability trial 
in BI 1358894 oral suspension (part 2)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Flow Chart Part 1
Flow Chart Part 2
Section 5.2.3 Safety laboratory parameters
Appendix 10.2 COVID-19 related assessment and 
risk mitigation
Description of change
1. Flow Chart Part 1/Flow Chart Part 2
Minor inconsistency regarding day of discharge was 
corrected in the footnotes.
PCR testing was added on Day – 1 and Day 2 for 
each treatment period and at Follow-up.
2. Section 5.2.3 Safety laboratory parameters
PCR testing was added on Day – 1 and Day 2 for 
each treatment period and at Follow-up.
3. Appendix 10.2 COVID-19 related 
assessment and risk mitigation
This Appendix was added to provide additional 
information regarding the benefit-risk assessment 
with regards to COVID-19 infection and the risk 
mitigation in the context of this study.


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Rationale for change
The changes were implemented to provide 
information for the trial on benefit-risk and 
mitigation measures with regards to the COVID-19 
global pandemic. In the context of this amendment, 
minor inconsistencies were corrected throughout the 
document.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29880107
2.0
clinical-trial-protocol-version-02
Investigation of pharmacokinetics and absolute bioavailability of BI 1358894
administered orally as tablet co-administered with an intravenous microtracer dose of
[C-14]-BI 1358894 in healthy male volunteers via a non-randomised, open-label,
fixed-sequence trial (part 1) followed by a randomised, open-label, singledose,
Verification-Paper Signature
Completion
26 Jun 2020 11:15 CEST
Author-Trial Clinical
Pharmacokineticist
26 Jun 2020 13:18 CEST
Approval-Team Member Medicine
26 Jun 2020 18:13 CEST
Author-Clinical Trial Leader
29 Jun 2020 07:44 CEST
Author-Trial Statistician
29 Jun 2020 10:30 CEST
Approval-
 Medicine
29 Jun 2020 11:53 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29880107
2.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c34211779-01
BI Trial No.:
1402-0016
Title:
Investigation of pharmacokinetics and absolute bioavailability of 
BI 1358894 administered orally as tablet co-administered with an 
intravenous microtracer dose of [C-14]-BI 1358894 in healthy male 
volunteers via a non-randomised, open-label, fixed-sequence trial 
(part 1) followed by a randomised, open-label, single dose, two-
period, two-sequence cross-over relative bioavailability trial in BI 
1358894 oral suspension (part 2)
Revised Protocol #01
Investigational
Product:
BI 1358894
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
09 FEB 2021 SIGNED
Version:
1
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINTS.....................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoint .......................................................................................8
5.2.2
Secondary endpoints.............................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................13
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................18
7.4
PRIMARY ENDPOINTS...................................................................................18
7.4.1
Primary analysis of the primary endpoints......................................................18
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoints...............................................................................................20
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoint .....................................................................................20
7.5.2
Secondary endpoints...........................................................................................20
7.6.2
Safety parameters ...............................................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21


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7.8.1
Adverse Events ....................................................................................................21
7.8.2
Laboratory data ..................................................................................................22
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................25
8.
REFERENCES....................................................................................................26
10.
HISTORY TABLE..............................................................................................28


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs...........................11
Table 6.1: 2
Overview of treatments for intra-individual comparison .................................12
Table 6.2: 1
Handling of iPDs ..............................................................................................13
Table 6.3: 1
Subject sets analysed ........................................................................................14
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation ..........16
Table 10: 1
History table .....................................................................................................28


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis dataset
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC0-312
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 312 h
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BP
Blood pressure
Cmax
Maximum measured concentration of the analyte after oral administration
COVID
Coronavirus disease
CV
Arithmetic coefficient of variation
ECGPCS
ECG plasma concentration set
gCV
geometric coefficient of variation
gMean
Geometric mean
IQRMP
Integrated quality and risk management plan
MedDRA
Medical Dictionary for Regulatory Activities
PKS
Pharmacokinetic parameter set
PR
Pulse rate
RAGe
Report appendix generator
SD
Standard Deviation
SOC
System Organ Class
TS
Treated set
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the 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 revised 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.
The trial is divided into two parts, with the same patients included in both parts. The analyses 
of both parts are described in the TSAP.
Study data will be stored in a trial database within the RAVE EDC 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). 


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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 planned in 
the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary PK endpoints are as defined in Section 2.1.2 of the CTP.
Primary endpoints in Part 1 are AUC0-∞for (C-14) BI 1358894 i.v. and AUC0-∞for 
BI 1358894 p.o.
Primary endpoint of Part 2 is AUC0-312 of BI 1358894.
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 2.1.3 of the CTP.
Secondary endpoint in Part 1 is Cmax of BI 1358894.
Secondary endpoints in Part 2 are Cmax and AUC0-∞of BI 1358894.
Further safety parameters of interest will be as defined in Section 2.2.2.2 of the CTP:

AEs (including clinically relevant findings from the physical examination)


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5.4
OTHER VARIABLES
5.4.1
Demographic and other baseline characteristics
Section 5.2.1 of the CTP: At screening, the medical examination will include demographics, 
height and body weight, smoking and alcohol history (results not mandatory to be entered 
into CRF or to be reported), relevant medical history and concomitant therapy, review of 
inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory 
tests, a physical examination and a neurological examination.


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Body mass index will be calculated as weight (kg) / [height (m)]2.
5.4.2
Treatment compliance and treatment exposure
Treatment compliance will not be analysed as a specific endpoint, cf. Section 4.3 of the CTP.
Treatment exposure is defined as the number of doses and the total dose of BI 1358894 per 
treatment and per subject. 


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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.
The trial is divided into two parts, with the same patients included in both parts.
In Part 1, each subject is planned to be treated with a single oral dose (two non-radiolabelled 
tablets) of BI 1358894 (T1) on Day 1. Five hours after the administration of the tablet, the 
subjects will receive an i.v. microtracer dose of [C-14]-BI 1358894 (R1). 
In Part 2, each subject is planned to be treated with a single oral suspension of BI 1358894 
either under fasted (R2) or fed (T2) conditions on Day 1 in each period separated by a 
washout period of at least 17 days between the two drug administrations. The subjects will be 
randomly allocated to the two treatment sequences T2-R2 or R2-T2.
Single oral drug administrations of each period are separated by a washout period of at least 
17 days.
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs
Analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first administration of 
BI 1358894 in Part 1
On-
treatment
BI Tab
Date/time of first administration 
of BI 1358894 tablet in Part 1
Date/time of start of infusion of 
BI 1358894 (C-14) in Part 1
On-
treatment
BI Tab/C14
Date/time of start of infusion of 
BI 1358894 (C-14) in Part 1
Date/time of end of infusion of 
BI 1358894 (C-14) in Part 1 + REP 
(11*24h)
Follow-up
F/U BI
Date/time of end of infusion of 
BI 1358894 (C-14) in Part 1 
+ REP (11*24h)
Date/time of first administration of 
BI 1358894 in Part 2
On-
treatment
BI fasted
Date/time of administration of 
BI 1358894 under fasted 
conditions in Part 2
Date/time of administration of 
BI 1358894 under fasted conditions in 
Part 2 + REP (11*24h)
Follow-up
F/U BI fasted
Date/time of administration of 
BI 1358894 under fasted 
conditions in Part 2 + REP 
(11*24h)
Date/time of administration of 
BI 1358894 under fed conditions in 
Part 2 or 12:00 a.m. on day after 
subject's trial termination date, 
whichever occurs earlier
On-
treatment
BI fed
Date/time of administration of 
BI 1358894 under fed 
conditions in Part 2
Date/time of administration of 
BI 1358894 under fed conditions in 
Part 2 + REP (11*24h)
Follow-up
F/U BI fed
Date/time of administration of 
BI 1358894 under fed 
conditions in Part 2 + REP 
(11*24h)
Date/time of administration of 
BI 1358894 under fasted conditions in 
Part 2 or 12:00 a.m. on day after 
subject's trial termination date, 
whichever occurs earlier


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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 phases 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
In disposition, demographics and baseline characteristics, all subjects will be analysed 
together (i.e., one “Total” column).
Safety laboratory data, vital signs and ECG will be analysed by treatment (BI, BI fasted, BI 
fed) with clear differentiation between baseline (cf. Section 6.7) and on-treatment 
measurements. Measurements will be considered on-treatment, if they were taken within the 
on-treatment phases as defined in Table 6.1: 1. 
The following labels will be used for the comparison of treatments:
Table 6.1: 2
Overview of treatments for intra-individual comparison
Treatment
Short label
R1
100 µg BI 1358894 (C-14)
BI (C-14) 100 ug iv
T1
100 mg BI 1358894
BI 100 mg tablet
R2
100 mg BI 1358894 under fasted conditions
BI 100 mg fasted
T2
100 mg BI 1358894 under fed conditions
BI 100 mg fed
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, it will be 
decided whether a discrepant data value can be used in the 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 the BI reference document “Identify and Manage Important 
Protocol Deviations (iPD)” (2). Additionally, all iPDs will be documented in the DV sheet.
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the decision log. 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 and the table below will be supplemented accordingly by the time of 
the RPM.


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iPDs will be summarized and listed. Table 6.2: 1 below specifies which kind of iPDs could 
potentially lead to exclusion from which analysis set (cf. Section 6.3). The decision on 
exclusion of subjects from analysis sets will be made at the latest at the RPM, after discussion 
of exceptional cases and implications for analyses.
Non-important COVID-19 related PDs will only be listed.
Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief Description
Excluded from which 
analysis set
A1
Inclusion Criteria Not Met
PKS
A2
Exclusion Criteria Violated
PKS
B1
Informed consent not available/not done
TS, PKS
B2
Informed consent too late
None
C1
Incorrect trial medication intake
PKS
C2
Randomisation not followed
PKS
C3
Non-compliance
PKS
C4
Medication code broken inappropriately
PKS
C5
Incorrect intake of trial medication
PKS
C6
Improper washout between treatments
PKS
D1
Prohibited medication use
PKS
D2
Mandatory medication not taken
PKS
D3
Improper washout of prohibited concomitant 
medication
PKS
E1
Certain violations of procedures used to measure 
primary or secondary data
PKS
F1
Certain violations of time schedule used to measure 
primary or secondary data such as incorrect 
duration of infusion
PKS
G1
Incorrect intake of meal
PKS
6.3
SUBJECT SETS ANALYSED
Subject sets will be used as defined in the Section 7.3 of the CTP:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 


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secondary and was not excluded due to a protocol violation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model based analyses of PK parameters will be based on the PKS.
In addition, the following subject set for a certain analysis of ECG data will be used.
All ECG analyses are performed on the TS, except for the exposure-response analyses, which 
are performed on the ECGPCS defined below.

ECG plasma concentration set (ECGPCS):
This subject set includes all subjects from the TS who provide at least one pair of a 
valid drug plasma concentration and a corresponding (i.e. time-matched) ECG 
endpoint to be used in the exposure-response analyses. The decision whether a time 
deviation between PK blood sampling and ECG recording is acceptable (and thus 
whether the pair of values will be used) is to be made no later than at the RPM before 
data base lock.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
ECGPCS
Disposition
X
IPDs
X
Primary endpoints
X
Secondary endpoints
X
Further PK endpoints
X
Safety parameters 
(except for exposure-response 
analyses of ECG data)
X
Exposure-response analyses of 
ECG data
X
Demographic/baseline 
conditions 
X
Exposure
X
6.5
POOLING OF CENTRES
This section is not applicable because the trial is performed in only one centre.


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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 reported in the CTR.
CTP Section 7.5.1: It is not planned to impute missing values for safety parameters.
One exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
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 (5). 
CTP Section 7.5.2: PK parameters that cannot be reasonably calculated based on the 
available drug concentration-time data will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
A separate baseline is defined for each treatment period: Baseline is the last available off-
treatment value before administration of the respective treatment (BI, BI fasted, BI fed). Off-
treatment in this context means that a value measured within an on-treatment phase, as 
defined in Table 6.1: 1, will not be used as baseline for any study treatment.
There will be a centralised evaluation of 12-lead ECG recordings at the time points specified 
in Table 6.7: 1.
Three triplicate ECGs will be recorded as the baseline before the each oral drug 
administration, but only all 3 single ECGs of the first of the 3 triplicates will be transferred to 
the database. Triple ECGs (3 single ECGs recorded within 180 sec) will be recorded on all 
on-treatment time points with centralised ECG evaluation. 
The baseline value of an ECG variable is defined as the mean of the triple ECG measurements 
prior to first study drug administration. For all on-treatment assessments, only the first of the 
three replicate ECG at a single assessment time will be centrally evaluated.


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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
2/3/4
1
-01:00
Baseline 
01:00
On-treatment
04:00
08:001
12:00
2
24:00
1 in Part 1 only
For the exposure response analyses, pairs of ECG variables and corresponding plasma 
concentrations will be built using the same planned time points, e.g., the HR change from 
baseline and the plasma concentration measured at planned time 01:00 will build one pair. 
Whether a time deviation between PK blood sampling time and corresponding ECG recording 
is too big for a reliable assessment and the pair has to be excluded from the analysis will be 
decided no later than at the RPM.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
clinical trials and project summaries" (6).
The individual values of all subjects will be listed. Listings will be sorted by treatment 
sequence ("Tab/C14-fasted-fed"  and "Tab/C14-fed-fasted"), 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 with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary. Concomitant non-drug therapies will be coded 
according to the most recent version of MedDRA.
A medication will be considered concomitant, if it

is ongoing at the time of first study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a definition 
of treatments and analysis phases).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
Only descriptive statistics are planned for this section of the CTR.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analyzed as a specific endpoint. Any deviations from 
complete intake will be addressed in the Report Planning Meeting (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINTS
The analysis of primary endpoints will be based on the PKS.
7.4.1
Primary analysis of the primary endpoints
Part 1
The statistical model for the primary endpoint AUC0-∞is an analysis of variance (ANOVA) 
model on the logarithmic scale including “formulation” as fixed effect and “subject” as 
random effect (cf. CTP Section 7.3.1). 
Absolute bioavailability will be estimated by the ratios of the geometric means of AUC0-∞for 
BI 1358894 p.o. (T1) versus AUC0-∞for (C-14) BI 1358894 i.v. (R1). The point estimates for 
the ratios of the geometric means and their two-sided 90% CIs will be provided.
Part 2
The statistical model for the primary endpoint AUC0-312 is an ANOVA model on the 
logarithmic scale including “treatment”, “sequence” and “period” as fixed effects and “subject
within sequence” as random effect (cf. CTP Section 7.3.1). 


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Relative bioavailability will be estimated by the ratios of the geometric means of BI fed (T2) 
versus BI fasted (R2) of AUC0-312 of BI 1358894. The point estimates for the ratios of the 
geometric means and their two-sided 90% CIs will be provided.
Part 1 and 2
Section 7.3.1 of the CTP:
For study part 1 and part 2, point estimates for the ratios of the geometric means 
(test/reference) for the primary endpoints […] and their two-sided 90% confidence intervals 
(CIs) will be provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to “ALL CALC”, the 
value will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
“DESC STATS” the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition “TIME VIOLATION” or “TIME 
DEVIATION”, the value can be used for further analyses based on actual times. If ACEXCO 
is set to “HALF LIFE”, the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to “Included”.
Further details are given in “Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies” (4) and “Description of Analytical Transfer Files and PK/PD 
Data Files” (5).


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.
The secondary endpoints will be statistically analysed in the same way as for the primary 
endpoints.
 
See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.


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7.6.2
Safety parameters
Safety endpoints and tolerability will be analysed as described in Section 7.8 of this TSAP.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For 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 screening, on-treatment or follow-up phases 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 AESIs.
CTP Section 5.2.6.1.4: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
○
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-
fold ULN measured in the same blood sample, or 
○
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), in addition to deaths and SAEs, "other significant" AEs need to be 
listed in the clinical trial report. These will be any non-serious adverse event that led to an 
action taken with study drug (e.g. discontinuation or dose reduced or interrupted).
An overall summary of adverse events will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 


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summarised separately. Separate tables will also be provided for subjects with SAEs and
subjects with AESIs. AEs will also be summarized by maximum intensity.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
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.
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).
Analyses will be based on normalised values, which mean 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 absolute values and change from baseline from laboratory parameters
over time (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.
Unscheduled measurements of laboratory 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 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).
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM at the latest. It is the Investigator's responsibility to 
decide whether a lab value is clinically significant abnormal or not. Standard or project-
specific rules for flagging clinically significant values in an automated manner will not be 
applied in this study.


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Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of absolute values and change from baseline from vital signs over time 
(see Section 6.7) will be provided.
Unscheduled measurements of vital signs will be assigned to planned time points as follows:

Unscheduled measurements prior to the first scheduled measurement within a visit 
will be assigned to the planned time point of the first scheduled measurement of that 
visit.

Other unscheduled measurements will be assigned to the planned time point of the 
previous, most recent scheduled measurement.
Unscheduled measurements of vital signs will be used in calculation of descriptive statistics 
by planned time point as follows:

If an unscheduled measurement is the last available off-treatment value before study 
drug administration, this unscheduled measurement will be used in the statistical 
analysis as baseline (as this is in accordance with the definition of baseline, cf. 
Section 6.7).

At post-baseline time points, descriptive statistics by planned time point will be 
calculated based on the last value of the subject within 20 minutes of the scheduled 
measurement of that planned time point. The rationale for this rule is that these 
measurements are interpreted to be repeat measurements of the scheduled 
measurement (e.g. for confirmation of a particular value).
An unscheduled measurement more than 20 minutes after the time of the scheduled 
measurement of that planned time point will be listed, but will not be used in 
calculation of descriptive statistics. These measurements are interpreted as off-
schedule vital signs measurements, taken for other reasons.
If an unscheduled measurement is taken at exactly the same time as the scheduled 
measurement, this unscheduled measurement will be considered to be done after the 
scheduled measurement, and will potentially qualify to be the “last value of the subject 
within 20 minutes of the scheduled measurement of that planned time point”.
If the time of measurement is missing for a scheduled measurement, the scheduled 
measurement will be used in calculation of descriptive statistics (as time difference 
between scheduled and unscheduled cannot be assessed).
If the time of measurement is missing for an unscheduled measurement, this 
measurement will be listed but will be ignored for the calculation of descriptive 
statistics.


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Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study 
treatment) if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.4
ECG
Abnormal findings will be reported as baseline conditions (prior to first study drug 
administration) or as AEs (from first study drug administration onwards) if judged clinically 
relevant by the investigator. 
The ECG exposure response analysis will be based on the ECGPCS. All other descriptive 
analysis of ECG endpoints will be based on the TS. 
Generally, ECG measurements will not be included in the statistical analysis if one of the 
following applies:

No date or time available for ECG measurement

Pre-dose measurement done after first drug administration

On-treatment measurement done before first drug administration

Measurement is a repeated measurement

More than 3 single ECGs (i.e., measurements from 4th single ECG onwards will not 
be included)

Unscheduled measurements
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR, only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
For all subjects with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding time profiles will be shown.
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 renal function group. 
Exposure-response assessment
To assess the relationship between changes from baseline in QTcF and HR and the time-
matched plasma concentrations of each subject group, several plots will be provided. For a list 


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of time points with scheduled ECG assessments and a time-matched plasma concentration, 
refer to Table 6.7: 1.
For the handling of missing values, see Section 6.6.
The remaining section describes the analysis for QTcF only, however the same plots will be 
performed for HR.
To investigate if there is a potential delayed or accelerated (e.g. due to metabolites) effect of 
the drug on QTcF, a general visual impression will be provided by overlaying time profiles of 
plasma concentrations and QTcF changes from baseline. These figures will be generated for 
each subject (presented in the Statistical Appendix of the CTR), as well as for means per 
subject group (presented in the End-of-Text part of the CTR).
For a visual inspection of the relationship between BI 1358894 plasma concentration and 
QTcF changes from baseline, a scatterplot of the individual values of BI 1358894 plasma 
concentration against QTcF changes from baseline will be created with separate symbols for 
each subject group. For QTcF a horizontal reference line at 60 msec will be added. Vertical 
lines at the gMean of Cmax of the respective subject group will also be added.
Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval (values log-transformed using the natural 
logarithm) will be estimated by applying a random coefficient model using all time points. A 
scatterplot of ln(QTcF) vs ln(RR) including the overall regression line will be included in the 
Statistical Appendix of the CTR. The resulting (fixed effect) slope together with two-sided 
95% confidence intervals will be included in the footnote for this plot.
7.8.5
Others
Suicidality assessment
Suicidality monitoring will be performed as described in Section 5.2.5.1 of the CTP, results 
will only be listed. No further analysis will be prepared. Findings will also be reported as 
AEs.
Physical and neurological examinations
Physical and neurological examination findings will be reported as relevant medical 
history/baseline condition (if a condition already exists before first administration of study 
treatment) or as AE (if condition emerges after first administration of study treatment) and 
will be summarized as such. No separate listing or analysis of physical or neurological 
examination findings will be prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: “Statistical Principles for Clinical Trials”, ICH Guideline Topic 
E9; Note For Guidance on 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
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON
6
KM Asset BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials 
and Project Summaries”, current version; KMED
7
KM Asset BI-KMED-BDS-HTG-0066: “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


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9.
ADDITIONAL SECTIONS
9.1
DETAILED DESCRIPTION OF ENDPOINTS FOR ECG
QT, PR, QRS and RR baseline and on-treatment measurements (see Table 6.7: 1) are included 
in the centralised ECG evaluation. 
For each single ECG, measurements of QT, PR, QRS and preceding RR interval of four 
cardiac cycles will be determined and stored in the database as raw data. Their mean values 
will be used as the QT, PR, QRS, and RR interval values, respectively, for this ECG.
QTcF, HR and QTcB will be calculated based on the derivation rules as follows:
From the four cardiac cycles of a single ECG, the HR (measured in beats per minute, 
beats/min) will be calculated as
 [	
/] = 60 000


where RR is the mean of the four RR intervals (measured in msec).
Similarly, the QT interval corrected for HR according to Fridericia’s formula (QTcF) for a 
single ECG will be derived as

 [] = 1000

 
/
∗
[],
where QT
 is the mean of the four QT intervals and  RR
 is the mean of the corresponding 
preceding RR intervals of the four cardiac cycles for this ECG.
Likewise, the HR-corrected QT interval according to Bazett’s formula (QTcB) for a single 
ECG is given by
#
 [] = 1000

 
/$
∗
[].
In case of triplicate ECGs at a time point, the respective ECG variable will be averaged over 
the triplicate ECG measurements at this time point (arithmetic mean). Note that in case of 
missing values the averaging is simply done for the available values.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1
09-FEB-2021
None
This is the final TSAP