Clinical trial NCT03892616
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2019-04-08; Completion date: 2019-07-03
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of this trial is to investigate the relative bioavailability of a single dose of BI 1358894 administered as tablet formulation 2 (TF2a, TF2b) under fasted conditions compared with the tablet formulation 1 (TF1) of BI 1358894 under fed conditions following oral administration and to investigate the effect of food on the exposure with TF2 (TF2a, TF2b).

Detailed description:

Arms: arm 1: 1 tablet of 100 milligram (mg) BI 1358894 was administrated as a single oral dose with 240 milliliter (mL) water 30 minutes (min) after a high-fat, high-calorie breakfast as treatment A (TF1; fed conditions) followed by a washout period of at least 17 days, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2a fed conditions) as treatment B followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 hours (h) (TF2a fasted conditions) as treatment C. arm 2: 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2b; fed conditions) as treatment D followed by at least 17 days of washout, followed by 1 tablet of 100 mg BI 1358894 was administrated as a single oral dose with 240mL water 30 min after a high-fat, high-calorie breakfast (TF1; fed conditions) as treatment A followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2a; fed conditions) as treatment B. arm 3: 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2b; fasted conditions) as treatment E followed by washout period of at least 17 days, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2a; fed conditions) as treatment B followed by at least 17 days of washout, followed by 1 tablet of 100 mg BI 1358894 was administrated as a single oral dose with 240mL water 30 min after a high-fat, high-calorie breakfast (TF1; fed conditions) as treatment A. arm 4: 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2a; fasted conditions) as treatment C followed by washout period of at least 17 days, followed by 1 tablet of 100 mg BI 1358894 was administrated as a single oral dose with 240mL water 30 min after a high-fat, high-calorie breakfast (TF1; fed conditions) as treatment A followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2b; fed conditions) as treatment D. arm 5: 1 tablet of 100 mg BI 1358894 was administrated as a single oral dose with 240mL water 30 min after a high-fat, high-calorie breakfast (TF1; fed conditions) as treatment A followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2b; fasted conditions) as treatment E followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2a; fasted conditions) as treatment C. arm 6: 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2b; fasted conditions) as treatment E followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2b; fed conditions) as treatment D followed by at least 17 days of washout, followed by 1 tablet of 100 mg BI 1358894 was administrated as a single oral dose with 240mL water 30 min after a high-fat, high-calorie breakfast (TF1; fed conditions) as treatment A. arm 7: 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2a; fed conditions) as treatment B followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2a; fasted conditions) as treatment C followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2b; fed conditions) as treatment D. arm 8: 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2a; fasted conditions) as treatment C followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2b; fasted conditions) as treatment E followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2a; fed conditions) as treatment B. arm 9: 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2a; fed conditions) as treatment B followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2b; fed conditions) as treatment D followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2b; fasted conditions) as treatment E. arm 10: 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2b; fed conditions) as treatment D followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2a; fasted conditions) as treatment C followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2b; fasted conditions) as treatment E. arm 11: 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2a; fasted conditions) as treatment C followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2a; fed conditions) as treatment B followed by at least 17 days of washout, followed by 1 tablet of 100 mg BI 1358894 was administrated as a single oral dose with 240mL water 30 min after a high-fat, high-calorie breakfast (TF1; fed conditions) as treatment A. arm 12: 1 tablet of 100 mg BI 1358894 was administrated as a single oral dose with 240mL water 30 min after a high-fat, high-calorie breakfast (TF1; fed conditions) as treatment A followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water after an overnight fast of at least 10 h (TF2b; fasted conditions) as treatment E followed by at least 17 days of washout, followed by 2 tablets of 50mg BI 1358894 (total: 100mg) administrated as a single oral dose with 240 mL water 30 min after a high-fat, high-calorie breakfast (TF2b; fed conditions) as treatment D.
Interventions: intervention 1: BI 1358894 (B) intervention 2: BI 1358894 (C) intervention 3: BI 1358894 (D) intervention 4: BI 1358894 (E) intervention 5: BI 1358894 (A)
Intervention descriptions: intervention 1: Tablet formulation 2 (TF2a), fed intervention 2: Tablet formulation 2 (TF2a), fasted intervention 3: Tablet formulation 2 (TF2b), fed intervention 4: Tablet formulation 2 (TF2b), fasted intervention 5: Tablet formulation 1 (TF1), fed

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:
c26426667-03
EudraCT No.
2018-003603-19
BI Trial No.
1402-0010
BI Investigational
Medicinal Product
BI 1358894
Title
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)
Lay Title
A study in healthy men to test if taking different formulations of 
BI 1358894 with or without food influences the amount of 
BI 1358894 in the blood
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Principal 
Investigator
Phone:
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 02 April 2019
Page 1 of 84
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
22 January 2019
Revision date
02 April 2019
BI trial number
1402-0010
Title of trial
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)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
Results from the first-in-human study with BI 1358894 using TF1 showed a limited 
bioavailability under fasted conditions while the intake of food increased the
exposure and bioavailability of BI 1358894. Two additional formulations were 
subsequently developed, TF2
 
, to 
investigate the adequate formulation with no or negligible food effect and higher 
exposure under fasted conditions for further clinical development.
Trial objectives
To investigate the relative bioavailability of TF2
under fasted conditions vs. TF1 under fed conditions.
To investigate the food effect on the exposure of BI 1358894 with TF2
.
Trial design
Randomised, open-label, single-dose, incomplete blocks crossover design.
Trial endpoints:
Primary endpoints: AUC0-tz and Cmax of BI 1358894
Secondary endpoints: AUC0-72 and AUC0-of BI 1358894
Number of subjects 
total entered
24 (20 evaluable subjects)
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)


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Test product 1
Tablet formulation 2; TF2
of BI 1358894
dose
100 mg
mode of admin.
Oral with 240 mL of water following a high fat, high calorie breakfast when fed 
(treatment B), or after an overnight fast of at least 10 h when fasted (treatment C).
Test product 2
Tablet formulation 2; TF2
of BI 1358894
dose
100 mg
mode of admin.
Oral with 240 mL of water following a high fat, high calorie breakfast when fed
(treatment D), or after an overnight fast of at least 10 h when fasted (treatment E).
Reference product
Tablet formulation 1; TF1 of BI 1358894
dose
100 mg
mode of admin.
Oral with 240 mL of water following a high fat, high calorie breakfast (treatment 
A).
Duration of treatment
One day (single dose) for each treatment.
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary endpoints. Additionally, their two-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to 
the two one-sided t-test procedure, each at a 5% significance level. Since the main 
focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified. The statistical model will be an analysis of 
variance (ANOVA) on the logarithmic scale including effects for ‘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
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 blood
8
Suicidality assessment (C-SSRS)10
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
x
x
x
x
1-3 (three periods separated by a wash-out of at least 17 days)
2
-3 to -1
-72:007
08:00
Ambulatory visit
x
x
2/3/4
1
-1:30
06:30
Admission to trial site
x5
x
-1:00
07:00
Allocation to treatment sequence
(visit 2 only)
x2, 9, 13
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast (for 
treatments A, B and D)12
0:00
08:00
Drug administration
0:10
08:10
x
0:20
08:20
x
0:30
08:30
x
x
x
1:00
09:00
x
x
x
x
1:30
09:30
x
x
2:00
10:00
240 mL fluid intake
x
x
3:00
11:00
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x
x
x
5:00
13:00
x
x
x
6:00
14:00
x
x
x
7:00
15:00
x
8:00
16:00
Snack (voluntary)3
x
x
x
10:00
18:00
Dinner3
x
12:00
20:00
x
x
x
x
2
24:00
08:00
Breakfast3
x
x
x
x
x
34:00
18:00
x
x
x
3
48:00
08:00
Breakfast3
x
x
x
x
4
72:00
08:00
Breakfast (voluntary)3, Discharge 
from trial site11
x
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
x
7
144:00
08:00
Ambulatory visit
x
x
x
x
x
9
192:00
08:00
Ambulatory visit
x
x
x
x
11
240:00
08:00
Ambulatory visit
x
x
x
x
x
14
312:00
08:00
Ambulatory visit
x
x
x
x
x
FU
5
17 to 22
End of trial (EoTrial) examination4
x
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening, 
alcohol breath 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.


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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.
Only urine drug screening and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
safety laboratory can be omitted if the screening examination is performed between Day -3 and Day -1.
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.
One blood sample for pharmacogenomics will be taken on Visit 2. If not feasible at Day 1, the sample may also be 
drawn at any later day.
10. Suicidality assessment will be performed at screening, at discharge from trial site for each period and at end of trial.
11. Confirmation of fitness includes physical examination, vital signs, ECG, suicidality assessment (C-SSRS), and
recordings of AEs and concomitant therapies assessed on Day 4 as well as evaluation of safety laboratory assessed on 
Day 2.
12. High fat, high calorie breakfast will be administered only for treatment A (TF1), treatment B (TF2 
 fed)
and treatment D (TF2 
 fed). Subjects in treatments C (TF2 
 fasted) and E (TF2 
 fasted) will not receive any breakfast. All subjects will be admitted to the trial site after an overnight fast 
of at least 10 h for all treatments.
13. Only for visit 2. For visit 3 and 4, predose values for safety laboratory will be derived from the Day 14 of the preceding 
visit.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................15
1.2.1
BI 1358894 .............................................................................................15
1.2.1.1
Nonclinical pharmacology.......................................................15
1.2.1.2
Safety pharmacology ...............................................................15
1.2.1.3
Toxicology...............................................................................16
Repeat-dose toxicity studies......................................16
1.2.1.3.1
Reproductive and developmental toxicity.................18
1.2.1.3.2
Phototoxicity..............................................................18
1.2.1.3.3
1.2.1.4
Nonclinical pharmacokinetics..................................................19
1.2.1.5
Clinical experience in humans.................................................20
1.2.2
Residual Effect Period..........................................................................27
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................27
1.4
BENEFIT - RISK ASSESSMENT ...................................................................27
1.4.1
Procedure-related risks ........................................................................27
1.4.2
Drug-related risks and safety measures..............................................27
1.4.3
Overall statement..................................................................................29
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 30
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......30
2.1.1
Main objectives......................................................................................30
2.1.2
Primary endpoints ................................................................................30
2.1.3
Secondary endpoints.............................................................................30
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 32
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................33


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3.3.1
Main diagnosis for trial entry..............................................................33
3.3.2
Inclusion criteria...................................................................................33
3.3.3
Exclusion criteria ..................................................................................34
3.3.4
Withdrawal of subjects from treatment or assessments ...................35
3.3.4.1
Discontinuation of trial treatment............................................36
3.3.4.2
Withdrawal of consent to trial participation ............................36
3.3.4.3
Discontinuation of the trial by the sponsor..............................36
3.3.5
Replacement of subjects .......................................................................37
4.
TREATMENTS........................................................................................ 38
4.1
INVESTIGATIONAL TREATMENTS ..........................................................38
4.1.1
Identity of the Investigational Medicinal Products ...........................38
4.1.2
Selection of doses in the trial and dose modifications........................38
4.1.3
Method of assigning subjects to treatment groups ............................38
4.1.4
Drug assignment and administration of doses for each subject .......39
4.1.5
Blinding and procedures for unblinding ............................................40
4.1.6
Packaging, labelling, and re-supply ....................................................40
4.1.7
Storage conditions.................................................................................41
4.1.8
Drug accountability ..............................................................................41
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................41
4.2.1
Other treatments and emergency procedures....................................41
4.2.2
Restrictions............................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment .........................42
4.2.2.2
Restrictions on diet and life style.............................................42
4.3
TREATMENT COMPLIANCE.......................................................................42
5.
ASSESSMENTS....................................................................................... 44
5.1
ASSESSMENT OF EFFICACY.......................................................................44
5.2
ASSESSMENT OF SAFETY............................................................................44
5.2.1
Physical examination ............................................................................44
5.2.2
Vital signs...............................................................................................44
5.2.3
Safety laboratory parameters..............................................................44
5.2.4
Electrocardiogram................................................................................47
5.2.5
Other safety parameters.......................................................................48
5.2.5.1
Suicidality assessment .............................................................48
5.2.5.2
Neurological examinations ......................................................48
5.2.6
Assessment of adverse events...............................................................49
5.2.6.1
Definitions of adverse events...................................................49


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Adverse event ............................................................49
5.2.6.1.1
Serious adverse event ................................................49
5.2.6.1.2
AEs considered ‘Always Serious’.............................49
5.2.6.1.3
Adverse events of special interest .............................50
5.2.6.1.4
Intensity (severity) of AEs.........................................51
5.2.6.1.5
Causal relationship of AEs ........................................51
5.2.6.1.6
Suicidal risk assessed by the C-SSRS    
5.2.6.1.7
(paper version)...........................................................52
5.2.6.2
Adverse event collection and reporting ...................................52
AE collection.............................................................52
5.2.6.2.1
AE reporting to the sponsor and timelines ................53
5.2.6.2.2
Information required..................................................53
5.2.6.2.3
Pregnancy ..................................................................54
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................54
5.3.1
Assessment of pharmacokinetics .........................................................54
5.3.2
Methods of sample collection...............................................................54
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................54
5.3.3
Analytical determinations ....................................................................55
5.3.3.1
Analytical determination of BI 1358894 plasma     
concentration............................................................................55
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................55
5.4
ASSESSMENT OF BIOMARKER..................................................................55
5.5
BIOBANKING ...................................................................................................55
6.
INVESTIGATIONAL PLAN.................................................................. 57
6.1
VISIT SCHEDULE............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................57
6.2.1
Screening period....................................................................................57
6.2.2
Treatment periods.................................................................................57
6.2.3
Follow-up period and trial completion ...............................................58
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 59
7.1
STATISTICAL DESIGN – MODEL ...............................................................59
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................59
7.3
PLANNED ANALYSES....................................................................................59
7.3.1
Primary endpoint analyses...................................................................60
7.3.2
Secondary endpoint analyses ...............................................................62


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7.3.4
Safety analyses.......................................................................................62
7.4
INTERIM ANALYSES .....................................................................................63
7.5
HANDLING OF MISSING DATA ..................................................................63
7.5.1
Safety......................................................................................................63
7.5.2
Pharmacokinetics..................................................................................63
7.6
RANDOMISATION ..........................................................................................63
7.7
DETERMINATION OF SAMPLE SIZE ........................................................63
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 66
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................66
8.2
DATA QUALITY ASSURANCE .....................................................................67
8.3
RECORDS..........................................................................................................67
8.3.1
Source documents .................................................................................67
8.3.2
Direct access to source data and documents.......................................68
8.3.3
Storage period of records.....................................................................68
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................68
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......68
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................69
8.6
TRIAL MILESTONES .....................................................................................69
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................70
9.
REFERENCES......................................................................................... 71
9.1
PUBLISHED REFERENCES...........................................................................71
9.2
UNPUBLISHED REFERENCES.....................................................................72
10. APPENDICES .......................................................................................... 74
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE ................................74
10.2
LIST OF INACTIVE INGREDIENTS IN THE TF2.....................................80
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 81
11.1
GLOBAL AMENDMENT 1 .............................................................................81
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-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 h
AUC0-72
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 72 h
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
Borderline Personality Disorder
CA
Competent authority
CHO
Chinese hamster ovary
CI
Confidence interval
CK
Creatine kinase
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CRO
Contract research organisation 
CRP
C-reactive protein
C-SSRS
Columbia Suicidal Severity Rating scale
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol


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CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
CYP
Cytochrome P450
DILI
Drug induced liver injury
DRF
Dose range finding
ECG
Electrocardiogram
eCRF
Electronic case report form
ECT
Electro-convulsive therapy
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EFD
Embryo-foetal development
EoTrial
End of trial
ESR
Erythrocyte sedimentation rate
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FDA
Food and drug administration
FE
Food effect
FIH
First in Human
FST
Forced swim test
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
GLDH
Glutamate deshydrogenase
GLP
Good Laboratory Practice
gMean
Geometric mean
hERG
Human ether-a-go-go related gene
HR
Heart rate
IB
Investigator’s brochure
IC50
Half maximum inhibitory concentration
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry


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LVSP
Left ventricular systolic pressure
MDA
Methylenedioxyamphetamine
MDD
Major depressive disorder
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRTpo
Mean residence time of the analyte in the body, extravascular
NIMH
National institute of mental health
NOAEL
No observed adverse effect level
NRS
Numeric ranking scale
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
PT
Preferred term
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
RBC
Red blood cell
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOC
System organ class
SOP
Standard operating procedure
SRD
Single-rising dose
SUSAR
Suspected unexpected serious adverse reaction
T
Test product or treatment
TF1/2
Tablet formulation 1/2
TRP
Transient receptor potential
TRPC 4/5
Transient receptor potential cation channel, subfamily C, members 4 and 5
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VAS
Visual analog scale


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administration
WBC
White blood cell
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) as an adjunct to antidepressant therapy and for the 
treatment of borderline personality disorder (BPD).
MDD is a debilitating disease characterised by low mood and often by low self-esteem, low 
energy, and a loss of interest. It can strongly impact a person’s life and health, including 
significantly increased risk of suicidality, and is difficult to treat, even with systematic 
antidepressant strategies. In the National Institute of Mental Health (NIMH) funded STAR*D 
trial of >4000 patients with nonpsychotic depression, about 30% of the patients did not reach 
remission after 4 different medications [P06-11895] and continued to experience residual 
symptoms [R16-5475] that significantly impacted the patients’ quality of life [R06-2872]. 
When monotherapy is insufficient, clinicians employ different augmentation strategies 
including add-on treatment with lithium or atypical antipsychotics. When augmentation 
strategies also fail, convulsive therapies such as electro-convulsive therapy (ECT) may be 
used.
Borderline personality disorder (BPD) is a chronic mental disorder with an estimated 
prevalence of around 2% in the general community [R16-5476] and severely impaired quality 
of life [R16-5474]. The main symptom clusters of BPD include impulsive-behavioural
dyscontrol, cognitive-perceptual symptoms, disturbed interpersonal relations, and affective 
instability. Patients with BPD have high rates of deliberate self-harm and a rate of completed 
suicide that is 50 times higher than in the general population [R16-5477]. Even the presence 
of a single diagnostic feature of BPD is predictive for poor functioning and psychiatric illness 
burden [R16-5483]. Treatment guidelines recommend psychotherapy as the mainstay of 
treatment, but pharmacotherapy is commonly used as an adjunctive, symptom-targeted 
component of treatment. However, no drug is approved for the treatment of BPD.
TRPC4 and TRPC5 form ion channels that are involved in the regulation of neuronal 
excitability. They are most highly expressed in the amygdala, frontal cortex, hippocampus, 
and hypothalamus [R15-3888, R16-5350], which are involved in modulation and processing 
of emotion and affect. Pre-clinically, treatment with BI 1358894 has shown diminished fear 
and anxiety and increased social interaction without impairing other brain functions such as 
learning and memory behaviours.
It is hypothesized that in patients with affective disorders, an overactive amygdala is a major 
contributor to attentional bias to negative stimuli, pessimistic thoughts, and anxiety [R16-
5473] and there is growing evidence supporting the role of amygdala in the emotion 
processing disturbances observed in patients with BPD [R16-5472]. Therefore, treatment 
with BI 1358894 has the potential to improve affective symptoms and emotion control in 
patients with MDD and BPD.


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1.2
DRUG PROFILE
1.2.1
BI 1358894
For a more detailed description of the BI 1358894 profile, please refer to the current 
Investigator’s Brochure (IB) [c10354149].
1.2.1.1
Nonclinical pharmacology
Transient receptor potential canonical (TRPC) channels are Ca2+-permeable nonselective 
cation channels implicated in diverse physiological functions, including smooth muscle 
contractility and synaptic transmission. 
BI 1358894 was profiled using patch clamp electrophysiology and was shown to be a highly 
potent inhibitor of TRPC4 and TRPC5 without species selectivity. In cells expressing human 
TRPC4 and TRPC5 and stimulated with carbachol, the IC50 was 1.2 nM (hTRPC4) and 
0.2 nM (hTRPC5), respectively. 
BI 1358894 was investigated in several standard behavioural tests in rodents, such as Forced 
Swim Test (FST) [n00252903], Marble Burying Test [n00252207] and Elevated Plus Maze 
Test [n00252277]. The in vivo pharmacology studies demonstrated consistent 
pharmacological effects in line with anxiolytic and/or antidepressant efficacy. In the FST, 
half maximal efficacy was demonstrated at a plasma exposure of 77 nM, indicating that at 
this plasma exposure, free brain levels are in the range of the in vitro IC50 [n00253628]. 
BI 1358894 is highly selective against more than 10 ion channels (including other TRPs, 
potassium channels, calcium channels and sodium channels) with more than 1000-fold 
selectivity for TRPC4 and at least 200-fold selectivity for TRPC5 [n00248384]. The effect of 
BI 1358894 on more than 120 targets was evaluated at 1 μM [n00252179]. BI 1358894 was 
shown to be highly selective.
1.2.1.2
Safety pharmacology
General and safety pharmacology studies have been conducted with BI 1358894 to address 
the core battery of the central nervous system (CNS) [n00253725], cardiovascular 
[n00253723, n00253727, n00254034], renal and hepatic [n00253732], respiratory 
[n00253732], and GI function [n00253729]. The results demonstrated an acceptable profile 
for clinical trials in healthy volunteers.
BI 1358894-related effects on the CNS of rats were limited to an early and transient increase 
of motility at dose levels of 10, 30, and 100 mg/kg (nocturnal motility test). This was 
considered to reflect an increased arousal or decreased anxiety in a novel environment 
associated with the intended efficacy (anti-depressive and anxiolytic effect). The absence of 
detectable locomotor effects in the two Modified Irwin studies might be due to differences in 
the study design.
In the cardiovascular (CV) rat study, long-lasting decreases in arterial blood pressure 
(10 mmHg) were present at ≥10 mg/kg. Additionally, BI 1358894 induced dose-dependent 


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and long-lasting increases in heart rate (15 – 20 bpm) in rat and dog at ≥30 mg/kg after single 
oral dose in the general pharmacology studies. However, increase in heart rate was no longer 
detectable after 4-day repeat-dosing in rats at 30 mg/kg. In rat telemetry at 100 mg/kg, 
transient increases in PR duration and body temperature were noted. None of the 
cardiovascular findings could be confirmed in dog safety pharmacology or toxicity studies. 
Other ECG parameters, including QT and QTc intervals, and left ventricular pressure 
parameters (LVSP and dP/dtmax) were not affected by BI 1358894.
Transient effects of BI 1358894 on the respiratory function (increases in respiratory rate and 
minute volume) were seen in male rats treated with 1000 mg/kg.
Altered electrolyte (Cl-, Na+, Ca2+) and urea urinary excretion at ≥10 mg/kg was regarded to 
be indicative of a change in rat renal function. Increases in total and conjugated bilirubin 
levels were not reproduced after repeated dosing for 4 weeks. Rat kidney and liver injury 
biomarkers were not altered. No structural degenerative correlates were present in the 
microscopic examination in toxicity studies.
Dose-dependent decreased gastric emptying was noted at 30 mg/kg (-22%) and 100 mg/kg 
(-29%). No effects on consistency of intestinal contents and intestinal transit were noted at 
any dose level.
The influence of BI 1358894 on human ether-a-go-go related gene (hERG)-mediated 
potassium current in stably transfected CHO cells (Chinese hamster ovary) was determined to 
evaluate the potential proarrhythmic risk [n00253752]. The IC50 for tail current inhibition 
was 1.15 μM, suggesting a selectivity ratio of about 200 against hERG-encoded channel 
[hTRCP 1/5 = 5 nM]. These preclinical data do not suggest a proarrhythmic risk.
1.2.1.3
Toxicology
The nonclinical safety program investigating the in vivo toxicological profile of BI 1358894 
comprised repeat-dose studies up to 4 weeks of once daily oral (gavage) treatment and a 
complete battery of in vitro and in vivo studies assessing the genotoxic potential of the 
compound. Additionally, a 4-week oral repeat-dose (non-GLP) study in mice was performed.
Rats and dogs were employed as the animal species for general toxicology investigations on 
BI 1358894, because in vitro and in vivo profiling supported the suitability of both species 
for nonclinical safety profiling of BI 1358894.
Repeat-dose toxicity studies
1.2.1.3.1
Repeat dose non-GLP toxicity study in mice, rats and dogs revealed toxicologically relevant 
effects on the skin, Harderian glands, and hepatic function in mice, the vascular system in rats, 
the CNS function in dogs, and the digestive tract in all three species. In addition, 
haematology evaluation revealed increases of white blood cell (WBC) counts in all species.
A 4-week toxicity testing in mice identified skin, Harderian glands, and gastrointestinal tract 
as main target organs in this species at doses ≥500 mg/kg QD. Clinical pathology evaluation 
indicated a slight to moderate increase in plasma total bilirubin, but without any microscopic 


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degenerative correlate. Administration of BI 1358894 was clinically well tolerated up to 
1500 mg/kg. Minimal to slight epidermal hyperplasia was observed in the skin. In the 
Harderian glands, crystal deposits (mainly a carboxylic acid metabolite of BI 1358894) 
induced minimal to severe degeneration and necrosis of the glandular tissue. A metabolite of 
BI 1358894 was the major compound-related constituent as shown by mass spectrometry 
analysis. Due to the species-specific metabolism, this mouse finding was considered to be of 
limited toxicological relevance. Multifocal erosion/ulceration, graded minimal to slight in 
severity, affected the mucosa of the stomach and the intestine and minimal to moderate 
epithelial vacuolation of the villi and minimal villous atrophy were present in the duodenum. 
Other BI 1358894-related pathological findings in the hematopoietic and lymphoid organs 
(at ≥7 mg/kg) associated with increased reticulocyte and WBC counts in blood, the liver 
(at ≥30 mg/kg), and the heart (at 1500 mg/kg) were regarded as non-adverse due to their 
adaptive character.
Repeat-dose toxicity testing in rats revealed no serious clinical signs of toxicity, no 
toxicologically relevant effects on body weight and food and water consumption, and no 
ophthalmology findings were noted. The main findings in clinical pathology were indicative 
of a minimal inflammatory response starting at 200 mg/kg, characterised by leukocytosis, 
hyperproteinaemia, and hyperglobulinemia. On Day 5 after the start of treatment, minimal to 
moderate periarterial inflammation was present in the mesentery, pancreas, and/or liver at 
≥30 mg/kg, with dose-related increases in incidence and severity. In a few animals given 
≥200 mg/kg, arterial inflammation and necrosis focally affected the pancreas and the serosa 
of the intestine. In a 4-week DRF 'reversibility' study where animals were sacrificed and 
microscopically examined on Day 5 and at the end of the treatment period (Day 28), 
perivascular/mesenteric inflammation induced by BI 1358894 occurred early after start of 
dosing and resolved over 4 weeks despite continued treatment, indicating the transient 
character of the inflammation. Other BI 1358894-related pathological findings in the kidneys 
(at ≥7.5 mg/kg), the heart and the liver (at ≥30 mg/kg), and the mandibular glands (at 
≥1000 mg/kg) were considered to be non-adverse due to their adaptive character, low 
magnitude, and/or absence of pathological correlates. All changes were fully reversible or 
greatly ameliorated over a 4-week off-treatment recovery period.
In repeat-dose toxicity testing in dogs, no spontaneous deaths occurred up to 1000 mg/kg, the 
highest tested dose, administered for 11 days. Decreased body weight, reduced food 
consumption and faecal alterations occurred at ≥150 mg/kg. Distinct clinical signs of toxicity 
were present at ≥500 mg/kg, starting on the 3rd day of treatment (gait abnormalities, 
decreased motor activity, one episode of convulsions, trembling). In addition, a territorial 
behaviour was shown by dogs administered 150 mg/kg over 4 weeks. Pathology and clinical 
pathology investigations did not reveal any pertinent findings which could have explained the 
clinical signs. Administration of BI 1358894 did not result in any pertinent changes in 
ophthalmology and cardiovascular investigation. Clinical pathology evaluation revealed a 
limited number of changes at ≥500 mg/kg: moderate decreases in reticulocyte counts, 
minimal increases in WBC and neutrophil counts, slight increases in phosphate and minimal 
decreases in calcium levels in the blood, and slightly to moderately reduced urinary sodium 
and chloride excretion. Few relevant BI 1358894-related histopathological findings were 
noted at ≥500 mg/kg, namely (multi)focal minimal to slight erosion/ulceration in the oral 
cavity, esophagus and duodenum. Changes observed in the thymus (decreased weight, 


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reduced size, lymphoid depletion), the spleen (decreased weight), the liver (decreased 
glycogen content), and the salivary glands (secretory depletion) were regarded as unspecific 
response to stress or secondary to reduced food consumption. No BI 1358894-related 
findings were observed during a 4-week recovery period.
An overview of estimated safety margins (exposure multiples) is presented in Table: 1.2.1.3.1: 
1 below. The comparison revealed safety margins of ≥9 for Cmax and for AUC0-24.
Table: 1.2.1.3.1: 1
Overview of estimated safety margins (exposure multiples) for 
BI 1358894 based on the NOAELs of the 4-week oral toxicity studies 
in rats and dogs and the 4-week oral DRF study in mice
Species
NOAEL 
[mg/kg]
Mean Cmax at 
NOAEL [nM] 
in m/f
Mean AUC0-24 
at NOAEL 
[nM.h] in m/f
Human to Animal Safety 
Margin in m/f
Based on 
multiples of 
Cmax
Based on 
multiples of 
AUC0-24
Rat
30
1960 / 3600
26300 / 53900
9 / 17
9 / 19
Dog
30
7190 / 4240
137000 / 57300
34 / 20
49 / 20
Mouse
30
7750 / 6270
89400 / 101000
37 / 30
32 / 36
m: male; f: female; safety margins related to predicted human exposure at estimated therapeutic dose (35 mg QD)
Reproductive and developmental toxicity
1.2.1.3.2
Data from two dose range finding studies for effects of BI 1358894 on embryo-foetal 
development (EFD) have been recently conducted in rats and rabbits. The results in rats 
showed no maternal nor embryofetal toxicity at exposures corresponding to 29- (Cmax) and 
33-fold (AUC0-24) of an estimated human efficacious plasma level of 210 nM and an AUC0-24
of 2800 nM/h. The EFD study in rabbits resulted in maternal toxicity, most strikingly 
evidenced by a decrease of food intake to approximately 10% of control animals. Embryo-
and fetotoxicity, in form of spontaneous abortions and/or uterine deaths, occurred also at all 
dose levels and were considered to be secondary to the overt maternal toxicity. At the lowest 
dose level the corresponding Cmax was 1.24-fold and the AUC0-24 1.53-fold of the estimated 
human efficacious plasma level. Details can be found in the Investigator’s Brochure 
[c10354149].
Based on these data, a benefit-risk assessment of BI 1358894 was conducted with regards to 
healthy male participants and concluded that the poor tolerability of BI 1358894 in rabbits 
does not negatively affect the safety data derived from the repeat-dose toxicity studies in 
mice, rats, and dogs. The safety profile with regard to general toxicity has not changed and 
the new data do not change the risk-benefit profile of BI 1358894 with regard to conduct of 
the present trial.
Phototoxicity
1.2.1.3.3
BI 1358894 is unlikely to cause phototoxicity. For more detailed information, please refer to 
the Investigator’s Brochure [c10354149].


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1.2.1.4
Nonclinical pharmacokinetics
Drug Absorption and Disposition
The disposition of BI 1358894 is characterized in rats by low clearance and moderate volume 
of distribution. High oral bioavailability (81.9 %) in rats suggests an at least moderate 
bioavailability in humans. The plasma protein binding of BI 1358894 was high in all 
investigated species, with unbound fractions of 0.26 % (mouse), 0.42 % (rat), 0.31 % (dog), 
and 0.25 % (human).
In a quantitative whole body autoradiography study, the extent of distribution of 
[14C] BI 1358894 from plasma into tissues was considered to be moderate [n00252628]. 
Highest concentrations of radioactivity were found in the Harderian gland (up to 27 times 
higher than in plasma), the liver (up to 14 times), and the walls of the gastrointestinal tract 
(up to 9.4 times higher than in plasma). Lowest tissue-to-plasma ratios were found in total 
eyeball (1% of plasma level), nasal mucosa (3%), and CNS (11% to 23%). While the total 
eyeball was exposed to drug-related radioactivity throughout the entire timeframe of 
investigation, drug-related radioactivity in the skin was below the limit of quantification. 
Qualitative evaluation of the autoradiograms, however, revealed discernible photo-
luminescence signals in lipid-rich parts of the skin until the last time-point of investigation.
The terminal half-lives for BI 1358894 in rats were 6.21 h (male) and 7.91 h (female) and 
longer for [14C] BI 1358894 – related radioactivity with 14.0 h (male) and 14.2 h (female). 
The fraction of total exposure for BI 1358894 ([14C] BI 1358894 – related radioactivity) was 
31% (males) and 49% (females). Similar proportions of parent compound and drug-related 
radioactivity after oral and intravenous administration indicated a low first pass effect. After 
intravenous (short term infusion) administration, 0.8% of the total administered radioactive 
dose was excreted in the urine within 24 h. In faeces, 55.7% (males) or 45.4% (females) of 
the total dose was recovered within 24 h. Excretion was slow, with a faecal excretion of 
81.4% (mean of males and females) within 168 h. The biliary excretion in anesthetized rats 
was 12.4% (males) or 16.5% (females) of the dose within 6 h.
Potential pharmacokinetic interactions
The inhibition potential of BI 1358894 was investigated for human CYP enzymes 
CYP1A1/2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 [n00253492]. BI 1358894 was a 
competitive in vitro inhibitor of CYP2C9, 2C8, 2D6, 2C19 and 2B6 with Ki values of 
3.71 μM (CYP2C9), 4.82 μM (CYP2C8), 5.51 μM (CYP2D6), 10.1 μM (CYP2C19) and 
13.6 μM (CYP2B6). Due to binding of BI 1358894 to plastic surfaces and microsomal 
protein, the actual concentrations of BI 1358894 in incubations were lower than the nominal 
concentrations. Therefore, it has to be taken into account that the actual Ki data could be
slightly lower than the measured values. Irreversible inhibition by BI 1358894 was not 
observed for any of the CYP enzymes under investigation. Depending on the level of 
exposure during drug therapy, in vivo inhibition of multiple CYP enzymes by BI 1358894 
may be possible.


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The in vitro potential of BI 1358894 and the metabolite BI 1361608 to induce rat CYP 
enzymes (CYP1A1, 2B1, 2C7, 2C11, 2D1, 2E1, 3A1/2, 4A) in rat hepatocytes was 
investigated [n00253490]. An induction potential towards CYP3A1 mRNA was seen with 
BI 1358894 concentration-dependent at high concentrations of ≥5 μM, and to a lesser extent
with BI 1361608 at 20 μM.
The potential for BI 1358894 to induce human CYP enzymes was investigated in vitro at 
BI 1358894 concentrations up to 100 μM using sandwich cultured human hepatocytes 
prepared from three donors. BI 1358894 was not an inducer of CYP1A2 but might be a weak 
inducer for both CYP2B6 and CYP2C8. BI 1358894 was an inducer of CYP3A4 mRNA and
enzyme activity up to 25 μM [n00256526].
1.2.1.5
Clinical experience in humans
A First-in-Human (FIH) trial (Trial 1402-0001 [c13880029]) is currently being conducted to 
explore the safety, tolerability, and pharmacokinetics (PK) of single rising oral doses of 
BI 1358894 in healthy male subjects (single-blind, partially randomised, placebo-controlled
parallel group design) and to evaluate the effect of food on the relative bioavailability of 
BI 1358894 (open-label, randomised, two-way cross-over design). The SRD part of the study
has been completed involving 55 subjects in 7 dose groups with single oral doses of 3 mg, 
6 mg, 10 mg, 25 mg, 50 mg, 100 mg or 200 mg of BI 1358894 administered under fasted 
conditions. In each of the 7 dose groups 6 subjects were assigned to BI 1358894 and 2 
subjects to placebo. At a dose level of 200 mg, the SRD part was stopped because of a less 
than dose proportional increase in exposure (Cmax and AUC0-24), which was considered to be 
possibly related to a reduced solubility of the film-coated tablets under fasting conditions. 
The further dose escalation in the SRD part was not stopped because of safety issues. Up to a 
single dose of 200 mg administered under fasting conditions, BI 1358894 was safe and well 
tolerated in all doses. There were no serious adverse events (SAEs) or dose limiting adverse
events (AEs). In accordance with the trial protocol, the study continued with the FE food 
effect (FE) part at a dose level of 50 mg and 100 mg of BI 1358894 administered under fasted 
and fed conditions, according to an open-label, two-period crossover design. Since in this 
dose group no dose limiting no safety signals precluding a further dose escalation of 
BI 1358894.
With 100 mg of BI 1358894 tested under fed conditions, a geometric mean exposure of
AUC0-24 of 6780 nmol*h/L and Cmax of 517 nmol/L was observed, i.e. close to the exposure 
limit (AUC0-24 = 9500 nmol*h/L, Cmax = 980 nmol/L) specified in the former trial protocol. A 
further dose escalation such as 200 mg of BI 1358894 administered under fed conditions was 
expected to exceed the former exposure limit. The exposure threshold was increased based on 
available clinical data up to 200 mg fasted and 100 mg fed in 1402-0001 to the current 
exposure threshold of 1960 nM for Cmax and 26300 nM/h for AUC0-24.
At the time of CTA submission of the current trial, the multiple rising dose (MRD) study 
(Trial 1402-0002) has been initiated. This double-blind, randomized and placebo-controlled 
within dose groups, parallel-group comparison study will evaluate the safety, tolerability, and 
PK of multiple rising oral doses of BI 1358894. In addition, this study will investigate the 
interaction with midazolam in a nested, open, fixed-sequence, intra-individual comparison


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study. Overall, 50 healthy male subjects are planned to enter the study and the doses of 
BI 1358894 investigated will range from 10 to 200 mg once daily over 14 days. Midazolam 
will be administered as an oral microdose on Day -1 and concomitantly with BI 1358894 on 
Day 1 and Day 14.
Safety evaluations of Trial 1402-0001 included physical examination, vital signs, ECG, 
laboratory tests, and adverse events. Data analysis from this study is currently on-going. In 
the tested dose range, BI 1358894 was well tolerated with a low frequency of AEs in all dose 
groups. There were no AEs considered to be dose limiting and no SAEs; all subjects 
completed the study per protocol.
Adverse Events
There were no AEs considered to be dose limiting and no SAEs. All subjects completed the 
study per protocol. All AEs were of mild to moderate intensity; no AE of severe intensity was 
reported. 
The following results were observed (see also Table 1.2.1.5: 1 and Table 1.2.1.5: 2 for a more 
detailed overview of AEs):

In the SRD part, 22 of 42 subjects on BI 1358894 and 3 of 13 subjects on placebo 
reported at least one AE.

In the FE part, 16 of 20 subjects (all on BI 1358894) reported at least one AE. The 
higher prevalence of AEs in the FE part compared to the SRD part might be related to 
the two treatment periods and the longer period of safety monitoring.

SRD: The frequency of subjects with at least one AE in the highest dose group 
(200 mg fasted) was comparable to the 50 mg and 100 mg fasted dose groups.

Food Effect: The frequency of subjects with at least one AE in the 50 mg dose group 
(fasted and fed period) was higher compared to the SRD part. In contrast, the 
frequency of subjects with at least one AE in the dose group 100 mg (fasted and fed 
period) was similar to the SRD part. The subjects with the highest exposure (100 mg 
fed period) had a slightly lower frequency of adverse events compared to the fasted
period.

At the System Organ Class (SOC) level, the most frequently reported AEs were 
nervous system disorders, reported in 21 subjects in the SRD part (19 of 42 subjects 
on BI 1358894 and 2 of 13 subjects on placebo) and 16 of 20 subjects in the FE part 
(all on active). 

At the Preferred Term (PT) level, the following AEs were observed in more than one 
subject:
Headache in 18 subjects in the SRD part (17 of 42 subjects on active and 1 of 
13 subjects on placebo) and in 15 of 20 subjects in the FE part (all on active),

Dizziness in 3 subjects in the SRD part (2 of 42 subjects on active and 1 of 
13 subjects on placebo) and 7 of 20 subjects in the FE part (all active),

Fatigue in 3 subjects in the FE part (all on active), and

Disturbance in attention in 2 subjects in the FE part (all on active).


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
No dose dependent increase in frequency was observed for any of these AEs.

AEs of moderate intensity were mainly observed in subjects on BI 1358894:

Injury due to a cycling accident in one subject 6 days after dosing (6 mg 
SRD);

Syncope because of a vasovagal reaction during blood drawing in one subject 
on placebo (25 mg dose group, SRD);

Back pain in one subject 2 days after dosing, resolved in 11 hours (50 mg 
SRD);

Nasopharyngitis in one subject 4 days after dosing (100 mg, FE, fasted);

Headache in 10 subjects (2 SRD, 8 FE, all on active) with an onset mostly 
4-7 hours after dosing and resolved mainly within a few hours.
There were no protocol-specified AEs of special interest (AESI) and no other significant AEs 
according to ICH E3. Per protocol AESI was hepatic injury, as defined by AST and/or ALT ≥
3-fold ULN combined with total bilirubin ≥2-fold ULN, and/or aminotransferase elevations ≥
10 fold ULN.
There were isolated events of apathy, auditory disorder and abnormal dreams in 3 subjects 
treated with either 3 mg or 6 mg of BI 1358894. Since no comparable events were reported 
for the remaining dose groups up to a single dose of 200 mg of BI 1358894 and due to the 
lack of a temporal relationship between dosing and event, these events are considered as 
chance findings and not drug related. Further, no changes in the Bowdle-VAS were seen for 
these subjects.
Additional Safety Assessments
There were no clinically relevant changes of laboratory values. In particular there were no 
changes of ESR or CRP suggesting an inflammatory event.
Explorative analysis of the Bowdle-VAS scores showed a comparable pattern between 
subjects across all dose groups. There were in particular no abnormalities for the score 
‘feeling high’ and ‘changes of perception’, which may indicate psychedelic effects. The 
occasional occurrence of ‘drowsy’ was evenly distributed between active and placebo.
The suicidality assessment based on C-SSRS did not reveal an individual subject who 
developed suicidal ideation by end of the study.
ECGs recorded from Day 1 pre-dose until Day 2/34h post-dose were analyzed centrally. 
After each dose group absolute values and changes in ECG parameters were reported by the 
ECG core lab to the sponsor and CRO. No dose dependent trend of a possible QTcF 
prolongation was observed (the maximum individual QTcF interval across all dose groups of 
the SRD part was 432 ms, and for the FE part 450 ms). 
Based on the prespecified criteria in 1402-0001 orthostatic testing did not reveal a subject 
with a positive test after dosing, i.e. no reduction in systolic blood pressure (BP) of 
≥20 mmHg or in diastolic BP of ≥10 mmHg within 3 minutes of standing, no orthostatic 
symptoms and no increase of heart rate > 100/min during orthostatic testing. Monitoring of 
vital signs and adverse events conducted in the further course of the study did also not reveal 


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


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Table 1.2.1.5: 2
Frequency [N (%)] of subjects with adverse events treated with 
BI 1358894 – 1402-0001 FE part
System Organ Class,
Preferred Term
BI 50mg 
(fast)
(N=8)
BI 50mg 
(fed)
(N=8)
BI 100mg 
(fast)
(N=12)
BI 100mg 
(fed)
(N=12)
Total with adverse events
7 (87.5)
7 (87.5)
8 (66.7)
6 (50.0)
Nervous system disorders
7 (87.5)
7 (87.5)
8 (66.7)
5 (41.7)
Headache
7 (87.5)
6 (75.0)
7 (58.3)
4 (33.3)
Dizziness
3 (37.5)
2 (25.0)
3 (25.0)
2 (16.7)
Disturbance in attention
2 (25.0)
0 (0.0)
0 (0.0)
0 (0.0)
Head discomfort
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Paraesthesia
1 (12.5)
0 (0.0)
0 (0.0)
0 (0.0)
Skin and subcutaneous tissue 
disorders 
0 (0.0)
2 (25.0)
0 (0.0)
1 (8.3)
Pruritus generalised
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Rash macular
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Skin reaction
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Acne
0 (0.0)
0 (0.0)
0 (0.0)
1 (8.3)
General disorders and 
administration site conditions
1 (12.5)
0 (0.0)
0 (0.0)
2 (16.7)
Fatigue
1 (12.5)
0 (0.0)
0 (0.0)
2 (16.7)
Musculoskeletal and connective 
tissue disorders
0 (0.0)
1 (12.5)
2 (16.7)
0 (0.0)
Musculoskeletal chest pain
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Arthralgia
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Back pain
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Gastrointestinal disorders
1 (12.5)
1 (12.5)
0 (0.0)
0 (0.0)
Flatulence
0 (0.0)
1 (12.5)
0 (0.0)
0 (0.0)
Nausea
1 (12.5)
0 (0.0)
0 (0.0)
0 (0.0)
Infections and infestations
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Nasopharyngitis
0 (0.0)
0 (0.0)
1 (8.3)
0 (0.0)
Dose Groups 2, 3 and 6 already have sample results available up to 192 h and, therefore, were 
used to calculate PK parameters dependent on the terminal rate constant (lambda z). Half-life 
as calculated from these 3 DGs is around 45 to 52 h (gMean) and appears to be independent 
of dose.


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Table 1.2.1.5: 3
Summary of gMean (gCV %) PK parameters of 3, 6, 10, 25, 50, 100 
and 200 mg BI 1358894 administered under fasted conditions [SRD 
part; clinical trial 1402-0001]
Dose Group:
DG1
DG2
DG3
DG4
DG5
DG6
DG7
Dose [mg], 
formulation
3 mg, 
tablet
6 mg, 
tablet
10 mg, 
tablet
25 mg, 
tablet
50 mg, 
tablet
100 mg, 
tablet
100 mg, 
tablet
200 mg, 
tablet
fasted
fasted
fasted
fasted
fasted
fasted
fasted
fasted
N=6
N=6
N=6
N=6
N=6
N=6
Without 
#
N=5
N=6
AUC0-24
[nmol*h/L]
166 
(15.7)
269 
(28.9)
400 
(13.9)
937 
(43.4)
1670 
(32.8)
919 
(1130)
2210 
(58.4)
4130 
(30.4)
AUC0-24/D 
[nmol*h/L/mg]
55.5 
(15.7)
44.8 
(28.9)
40.0 
(13.9)
37.5 
(43.4)
33.4 
(32.8)
9.19 
(1130)
22.1 
(58.4)
20.7 
(30.4)
AUC0-72 
[nmol*h/L]
261 
(17.9)
445 
(31.6)
651 
(14.5)
1780 
(31.1)
3040 
(27.7)
2000 
(1320)
5010 
(40.4)
8720 
(32.1)
AUC0-72/D 
[nmol*h/L/mg]
87.1 
(17.9)
74.1 
(31.6)
65.1 
(14.5)
71.2 
(31.1)
60.9 
(27.7)
20.0 
(1320)
50.1 
(40.4)
43.6 
(32.1)
AUC0-tz
[nmol*h/L]
288 
(18.5)
569 
(32.7)
861 
(17.7)
2380 
(29.7)
4170 
(26.2)
2520 
(2670)
7120 
(37.9)
12600 
(42.0)
AUC0-∞
[nmol*h/L]
353* 
(25.1)
603 
(33.6)
930 
(20.4)
2580 
(30.2)
4530 
(24.5)
3000 
(1570)
7730 
(39.8)
13900 
(44.8)
AUC0-∞/D 
[nmol*h/L/mg]
118* 
(25.1)
100 
(33.6)
93.0 
(20.4)
103 
(30.2)
90.6
(24.5)
30.0 
(1570)
77.3 
(39.8)
69.7 
(44.8)
Cmax [nmol/L]
27.6 
(30.0)
35.9 
(33.8)
59.7 
(13.4)
84.2 
(44.2)
183 
(56.3)
94.3 
(735)
206 
(72.8)
385 
(26.8)
Cmax/D 
[nmol/L/mg]
9.20 
(30.0)
5.99 
(33.8)
5.97 
(13.4)
3.37 
(44.2)
3.66 
(56.3)
0.943 
(735)
2.06 
(72.8)
1.92 
(26.8)
tmax [h]1
2.0 
(1-4)
2.5 
(1-5)
1
(1-3)
5
(1-6)
1
(0.5-2.5)
2.25 
(1-6)
3
(1-6)
5
(1-8)
1tmax median (range), D Dose-normalized, DG dose group, 
2sensitivity analysis without subject 
 who had substantially lower BI 1358894 plasma concentrations
* values are based on planned sampling time points up to 96 h only


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Table 1.2.1.5: 4
Summary of gMean (gCV %) PK parameters of 50 mg and 100 mg 
BI 1358894 administered under fasted conditions and after a high 
calorie, high fat meal [relative BA food effect part; clinical trial 
1402-0001]
Dose [mg]/
condition
50 mg
Fasted
(N=8)
50 mg
Fed
(N=8)
100 mg
Fasted
(N=12)
100 mg
Fed
(N=12)
AUC0-24 [nmol*h/L]
1570 (36.7)
2980 (25.1)
2350 (40.6)
6780 (12.2)
AUC0-24/D 
[nmol*h/L/mg]
31.4 (36.7)
59.6 (25.1)
23.5 (40.6)
67.8 (12.2)
AUC0-72 [nmol*h/L]
3120 (20.9)
5110 (28.9)
4600 (49.2)
11600 (14.8)
AUC0-72/D 
[nmol*h/L/mg]
62.4 (20.9)
102 (28.9)
46.0 (49.2)
116 (14.8)
AUC0-tz [nmol*h/L]
4440 (23.5)
6940 (36.2)
6320 (53.4)
15500 (19.3)
AUC0-∞[nmol*h/L]
5060 (29.3)
7900 (42.9)
6930 (54.6)*
17200 (21.8)
AUC0-∞/D 
[nmol*h/L/mg]
101 (29.3)
158 (42.9)
69.3 (54.6)*
172 (21.8)
Cmax [nmol/L]
149 (59.4)
237 (24.9)
210 (38.8)
517 (8.61)
Cmax/D [nmol/L/mg]
2.99 (59.4)
4.74 (24.9)
2.10 (38.8)
5.17 (8.61)
tmax [h]1
5 (1-5)
5 (2.98-6)
2.5 (1-6)
6 (0.5-7)
*N=11 due to drop out of subject #
 PK samples of this subject up to 96 hours available only
Table 1.2.1.5: 5
Summary of preliminary statistical evaluation of food effect [FE part] 
– adjusted by-treatment geometric means and relative bioavailability
Dose
PK 
Parameter
Fasted 
adjusted 
gMean
Fed adjusted 
gMean
Ratio 
fed/fasted
90 % Confidence Interval
50 mg 
(n = 8)
Cmax
149 nmol/L
237 nmol/L
1.59 
1.14
2.21
AUC0-24
1570 nmol*h/L
2982 nmol*h/L
1.90
1.46
2.47
AUC0-72
3121 nmol*h/L
5112 nmol*h/L
1.64
1.38
1.94
AUC0-∞
5059 nmol*h/L
7904 nmol*h/L
1.56
1.32
1.85
100 mg 
(n = 12)
Cmax
210 nmol/L
517 nmol/L
2.46
2.03
2.98
AUC0-24
2353 nmol*h/L
6777 nmol*h/L
2.88
2.36
3.51
AUC0-72
4601 nmol*h/L
11598 nmol*h/L
2.52
2.04
3.12
AUC0-∞
6966 nmol*h/L
17232 nmol*h/L
2.47
2.00
3.06


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1.2.2
Residual Effect Period
The Residual Effect Period (REP) of BI 1358894 is approximately 14 days. This is the period 
after the last dose with measurable drug levels and/or pharmacodynamic effects is still likely 
to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Results from the FIH study with BI 1358894 using the reference tablet formulation 1 (TF1)
showed a limited bioavailability under fasted conditions while the intake of food increased 
the exposure and bioavailability of BI 1358894 (see Section 1.2.1). Two additional 
formulations were subsequently developed, 
 to 
investigate the adequate formulation with no or negligible food effect and higher exposure 
under fasted conditions for further clinical development.   
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.
1.4.1
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period and, in rare cases in sensitive subjects, in a syncope. 
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
1.4.2
Drug-related risks and safety measures
Risks derived from observations in non-clinical studies:
Rats and dogs were employed as the animal species for general toxicology investigations on 
BI 1358894, because in vitro and in vivo profiling supported the suitability of both species 
for nonclinical safety profiling of BI 1358894. In addition, recent EFD studies in rats and 
rabbits were also conducted.
As summarised in Section 1.2.1, potential risks observed in non-clinical studies are a long 
lasting decrease in the blood pressure in rats, an increase in heart rate in rats and dogs, and 
signs of a short lasting episode of arterial/ perivascular inflammation in rats. All findings 
were observed within 5 days after the start of treatment. The CV effects observed in rodents 
and non-rodents can be easily monitored in a Phase I study (CV effects). Perivascular/ 
mesenteric inflammation induced by BI 1358894 occurred early after the start of dosing and 
resolved despite continued treatment, indicating its transient character. The non-clinical 


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safety data support clinical Phase I trials in non-childbearing humans with daily oral 
administration for up to 4 weeks. The conclusion drawn from the EFD studies corroborated
the statement from the general toxicity and concluded that the safety profile and subsequent 
benefit-risk profile was not changed. Furthermore available safety data from healthy 
volunteers in the SRD did not raise any significant safety concerns related to BI 1358894.
Risks related to the mode of action and nature of the target:
The TRP family members are ion channels considered to play a crucial role in physiological 
processes such as to act as a cellular sensor or to support signal transmission [R18-0249]. The 
subtypes TRPC4 and TRPC5 form ion channels that are involved in the regulation of 
neuronal excitability. They are highly expressed in the amygdala, in the frontal cortex, 
hippocampus, and hypothalamus [R15-3888, R16-5350], which are involved in modulation 
and processing of emotion and affect. In preclinical studies, inhibition of these receptors by 
BI 1358894 has resulted in diminished fear and anxiety and increased social interaction 
without impairing other brain functions such as learning and memory behaviours. In 
accordance with these findings, TRPC5 deficient mice display an anxiolytic-like phenotype 
[R15-3888]. This supports the assumption that CNS effects in healthy subjects due to an 
inhibition of TRPC 4/5 are limited to a reduced anxiety. However, clinical data with 
compounds inhibiting this target have yet to be published.
The human safety and tolerability profile in healthy male subjects from the FIH SRD study 
was satisfactory for single doses up to 200 mg under fasted conditions (Trial 1402-0001).
Relevance of animal models:
Human TRPC4 and TRPC5 proteins show high homology with the rat, mouse and dog 
proteins, and potency of BI 1358894 to the target is comparable across species. In addition, 
expression at the protein level is similar across different species including human. Rat and 
dog had good oral bioavailability, significant systemic exposure and good tolerability after 
oral dosing of a nanosuspension of BI 1358894. Finally, all known metabolites formed after 
incubation of human hepatocytes with BI 1358894 were covered with the combination of rat 
and dog. Overall, pharmacodynamic activity, pharmacokinetics and metabolism all indicated 
that rat and dog were suitable species for nonclinical safety profiling of BI1358894.
It should be highlighted that toxicity study in rats [n00250347] did not reveal any 
toxicologically relevant effects of BI 1358894 on the immune system up to the highest tested 
dose of 2000 mg/kg (1000 mg/kg twice daily). Furthermore, the pharmacological effects of 
BI 1358894 are dose dependent and no evidence for irreversible effects has been observed. 
Therefore, despite the novelty of the target, BI 1358894 is not considered a high-risk 
compound.
Risk minimization:
The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers:


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-
The dose selected for the current study was already investigated in the FIH SRD 
study. A higher dose was also investigated and was well tolerated.
-
Adequate safety monitoring will be performed (e.g. vital signs (including blood 
pressure and pulse rate), ECGs, safety laboratory tests including CRP, ESR, hormone 
parameters, suicidality assessment and assessment of adverse events)
-
Subjects will be hospitalized from Day 1 up to Day 4 of each treatment period and 
will be discharge only after a formal assessment and confirmation of fitness by an 
investigator or qualified designee. During the in-clinic stay, the subjects will be under 
medical observation and thoroughly monitored for both expected and unexpected 
events.
Drug induced liver injury:
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.6.1.4, adverse events of special interest.
1.4.3
Overall statement
In summary, although not therapeutically tested in humans to date, BI 1358894 has the 
potential to become an oral treatment for major depressive disorder as an adjunct to 
antidepressant therapy and for the treatment of borderline personality disorder. Based upon 
preclinical data for BI 1358894, the clinical data from the on-going FIH study, as well as the 
implemented safety measures described above, healthy subjects will not be exposed to undue 
risks in relation to the important information expected from this trial as a basis for further 
clinical development of this compound. Healthy volunteers are not expected to have any 
direct benefit from participation in the clinical trial with BI 1358894, as is the usual case in 
such Phase I trials. Considering the medical need for the development of a safer and more 
effective treatment for patients with mood and borderline personality disorders, the Sponsor 
considers that the benefit outweighs the potential risks and justifies exposure of healthy 
human volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of a single dose of 
100 mg BI 1358894 administered as the tablet formulation 2 (TF2) conventional and TF2 
non-conventional under fasted conditions compared with the tablet formulation 1 (TF1) of
100 mg of BI 1358894 under fed conditions following oral administration. In addition, this 
trial will investigate the food effect on the exposure of BI 1358894 with TF2 conventional 
and TF2 non-conventional.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 1358894:

Cmax (maximum measured concentration of the analyte in plasma)

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)
2.1.3
Secondary endpoints
The following pharmacokinetic parameters will be determined for BI 1358894:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

AUC0-72 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 72 h)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, single-dose, incomplete blocks
crossover trial in healthy male subjects in order to compare the test treatments TF2 
 in fasted state (C and E) to the reference treatment 
TF1 in fed state (A) to investigate the relative bioavailability of tablet formulation. 
Additionally, it will evaluate the food effect on test treatments. The test treatments will be 
one single dose of 100 mg BI 1358894 of the TF2 
in a fed state (B) and in the 
fasted state (C) and TF2 
in the fed state (D) and in the fasted state (E). The 
reference treatment to compare the bioavailability of tablet formulations will be one single 
dose of 100 mg BI 1358894 of the TF1 (A) administered to subjects in the fed state.
Twenty-four subjects will be randomly allocated to 12 treatment sequences. For details, refer 
to Section 4.1.
The planned 24 subjects to be included in the study will be assigned to three cohorts, each 
consisting of eight subjects. The cohorts will be treated at least one week apart. The second 
and third cohort will be dosed after a careful review by the Investigator of the safety data
from all subjects in the preceding cohort(s).
Table 3.1: 1
Treatment sequences
Blocks/Sequences
1
2
3
4
5
6
7
8
9
10
11
12
Period 1
A
D
E
C
A
E
B
C
B
D
C
A
Period 2
B
A
B
A
E
D
C
E
D
C
B
E
Period 3
C
B
A
D
C
A
D
B
E
E
A
D
There will be a washout period of at least 17 days between the treatments, i.e. the dose in the 
first treatment period and the dose in the second treatment period are separated by at least 
17 days. In each subject, an assessment of safety laboratory, vital signs, ECG and AEs will be 
conducted on the last day of the preceding period prior to next dosing. These data will be 
reviewed by the Investigator to confirm the eligibility of the subject before the following 
dosing.
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 GROUPS
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between formulations is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between formulations [R94-1529]. The incomplete blocks design was chosen for this study 


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instead of a full 5x5 crossover design due to the long apparent terminal half-life of 
BI 1358894 (between 54.8 and 82.5 h) resulting in a long washout period (17 days).
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of BI 1358894, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 24 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 which is a standard population in 
early clinical development.
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 50 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


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5. Male subjects who meet any of the following criteria from at least 30 days before the first 
administration of trial medication until 30 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 (IUD) that started at least 2 months prior to first study drug 
administration, or barrier method (e.g. diaphragm with spermicide)
-
Sexually abstinent
-
A vasectomy performed at least 1 year prior to screening (with medical assessment of 
the surgical success)
-
Surgically sterilised female partner (including hysterectomy, bilateral tubal occlusion 
or bilateral oophorectomy)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. C-Reactive Protein (CRP) > upper limit of normal (ULN), erythrocyte sedimentation rate 
(ESR) ≥15 millimeters/h, liver or kidney parameter above ULN, or any other laboratory 
value outside the reference range that the investigator considers to be of clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) (Lists of excipients are provided in the Investigator’s Brochure Section 4.2
for Tablet Formulation 1 and in Appendix 10.2 for Tablet Formulation 2 conventional and 
Tablet Formulation 2 non-conventional.)
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)


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14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study
In addition, the following trial-specific exclusion criteria apply:
23. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
24. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
For study restrictions, refer to Section 4.2.2.
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.


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3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment or trial participation, 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 shows a raised CRP level of >3.00 mg/dL or an ESR of ≥20 millimetres/hour
6. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP<90/50 mmHg) or hypertension 
(BP>180/100 mmHg) or of clinically relevant changes in ECG requiring intervention as 
well as unexplained liver enzyme elevations at any time during the trial.
7. The subject 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
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:


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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 one 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
5. Occurrence of severe non-serious adverse reactions (i.e., severe non-serious adverse 
events considered as possibly related to the drug administration) in at least two subjects in 
the same cohort.
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 4 subjects stopped the trial/treatment prematurely due to safety reasons 
and/or due to poor tolerability further inclusion of new subjects will only be possible after 
approval of a substantial amendment.
In case subjects do not complete the trial for reasons other than safety and/or poor tolerability
(e.g., personal reasons), the Clinical Trial Leader (CTL) together with the Principal 
Investigator, the Trial Pharmacokineticist and the Trial Statistician are to decide on a case-by-
case basis, 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 sequence as the 
subject 
 replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products have been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test products are given below:
Substance:
BI 1358894
Pharmaceutical formulation: Tablet Formulation 2 
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 are given below:
Substance:
BI 1358894
Pharmaceutical formulation: Tablet Formulation 1
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
single dose
4.1.2
Selection of doses in the trial and dose modifications
The dose selected for this trial, 100 mg of BI 1358894, has been evaluated in the ongoing 
first-in-human SRD trial (see Section 1.2), in which the highest dose tested was 200 mg and 
was well tolerated.
4.1.3
Method of assigning subjects to treatment groups
The randomisation list will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
list will be allocated to the subjects by the method first come first served. Subjects are then 
assigned to a treatment sequence according to the randomisation list.


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Within the treatment sequence, numbers of the randomisation list will be allocated to subjects
in their order of registration for the study (that is, the first subject registered will be the first 
treated and will receive the first number of the respective treatment sequence in 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.
4.1.4
Drug assignment and administration of doses for each subject
This trial is an incomplete blocks crossover study. All subjects will receive three out of the 
five treatments in randomised order. The treatments to be evaluated are outlined in Table 
4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation Unit strength
Dosage
Total  dose
B (Test)
BI 1358894
Tablet
50 mg
2 tablets (50 mg), single dose, fed
100 mg
C (Test)
BI 1358894
Tablet
50 mg
2 tablets (50 mg), single dose, fasted
100 mg
D (Test)
BI 1358894
Tablet
50 mg
2 tablets (50 mg), single dose, fed
100 mg
E (Test)
BI 1358894
Tablet
50 mg
2 tablets (50 mg), single dose, fasted
100 mg
A (Reference)
BI 1358894
Tablet
100 mg
1 tablet (100 mg), single dose, fed
100 mg
Administration of trial medication will be performed after subjects have fasted overnight; 
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.
In three out of the five treatment periods (treatment A, B and D), 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
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat. 
Subjects will be kept under close medical surveillance until 72 h after 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) unless lower or 
supine position is required for trial-related measurements (e.g., recording of 12-lead ECG) or 
medical reasons (e.g., adverse events).
The treatments 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
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. 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
when the 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
In case of adverse events in need of treatment, the investigator can authorise symptomatic 
therapy.
In case of alterations of blood pressure (hypotension) and heart rate (tachycardia), which 
were reported in nonclinical toxicology studies (see Section 1.2.1.3), first physical 


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interventions will be the treatment of symptoms. If unsuccessful, appropriate drug therapy 
will be initiated according to common guidelines and algorithms of emergency trainings. 
Dependent on individual symptoms, for the treatment of tachycardia this may include 
intravenous administration of beta blockers or appropriate antiarrhythmic drugs. For the 
treatment of hypotension, in addition to volume substitution, administration of vasopressors 
may be a further step. The entire staff of the trial site assuming medical responsibility during 
the conduct of the study is routinely trained in emergency procedures.
If required, any subject with an adverse event in need of treatment will be kept under 
supervision at the trial site or transferred to a hospital until all medical evaluation results have 
returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 2), the water administered with the drug, and an additional 
240 mL of water at 2 h and 4 h post-dose (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 the last study period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 4 h before until 4 h after each administration of trial 
medication.
Poppy-seed containing products should not be consumed starting 4 days before first trial drug 
administration until last PK sampling of the trial.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.


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Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
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, and a physical examination. At 
the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, recordings of AEs and concomitant therapies, and a physical examination including 
determination of weight.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap, GE Medical Systems, Freiburg, Germany) at the times indicated in the Flow 
Chart, after subjects have rested for at least 5 min in a supine position. All recordings should 
be made using the same type of blood pressure recording instrument on the same arm, if 
possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
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)
Erythrocyte Sedimentation Rate (ESR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
and absolute
Neutrophils; Eosinophils; Basophils; Monocytes; Lymphocytes 
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal and clinically 
relevant in the opinion 
of the investigator)
Polymorphnuclear neutrolphils (segs); band neutrophils (stabs); 
eosinophils; basophils; monocytes; lymphocytes
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
--
--
--
X
X
X 
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
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


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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
Calcium
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 at Visit 2 on Day -3 to Day -1, unless screening examination is performed 
between Day -3 and Day -1, and at Visits 2/3/4 on Day 1, Day 2, Day 7, Day 11 and Day 14 (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
Infectious serology (blood)
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 breath alcohol test (e.g. 
Alcotest®7410, Dräger AG, Lübeck, Germany) will be performed at screening and prior to 
each treatment period, and may be repeated at any time during the study at the discretion of 
an investigator or designee. The results will not be included in the CTR
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at Medizinisches 
Versorgungszentrum Dr. Klein Dr. Schmitt & Partner, Kaiserslautern, Germany, with the 
exception of drug screening tests. These tests will be performed at the trial site using 
Multidrogen Pipettiertest (Diagnostik Nord GmbH, Schwerin), or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). Precise electrode placement will be marked with an 
indelible mark on the skin to allow reproducible placement throughout the study.
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 


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assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Suicidality assessment
Suicidality assessment to further evaluate the psychological status of the subject will be 
performed at screening using the Columbia Suicidal Severity Rating scale (C-SSRS). The C-
SSRS is a brief measure which is designed to assess severity and change of suicidality by 
integrating both behaviour and ideation. The C-SSRS was designed to address the need for a 
summary measure to track change in the severity of suicidality across both clinical settings 
and treatment trials.
The original C-SSRS is shown in Appendix 10.1.
5.2.5.2
Neurological examinations
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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Suicidal risk assessed by the C-SSRS (paper version)
5.2.6.1.7
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation. 
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report. 
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the screening visit (using the ‘screening / baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and behavior 
will also be recorded.
After the baseline visit the assessment ‘since last visit’ will be performed at each clinic or 
phone visit (‘since last visit’ version). The investigator is to review positive and negative 
reports for plausibility and clinical relevance. Doubtful reports may be repeated or reports 
may be validated by a consulting psychiatrist. If there is a confirmed positive report of 
suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to 
immediately interview the subject during the clinic visit, and/or is to consult a psychiatrist.
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.
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. 


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Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.


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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.
5.3
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, approximately 3 mL of blood will 
be drawn from an antecubital or forearm vein into a K-EDTA (potassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle.
Sample handling will be described in detail in a separate lab manual.
All plasma samples will be stored at approximately -20°C or below until transfer to the 
analytical laboratory and analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, 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 


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completion of the additional investigations but not later than 5 years after the CTR is 
archived.
5.3.3
Analytical determinations
5.3.3.1
Analytical determination of BI 1358894 plasma concentration
BI 1358894 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis.
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
Not applicable.
5.5
BIOBANKING
Not applicable.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests
will be ± 10 min for the first 4 h after trial drug administration and ± 30 min thereafter.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including 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 5.2.1 to 5.2.5.
6.2.2
Treatment periods
Each subject is expected to participate in 3 treatment periods (Day 1 to 14 in each period). At 
least 17 days will separate two consequent drug administration in-between the treatment 
periods.
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 72 h following drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness on Day 4. On all other study days (Day 5, 7, 9, 11 and 14), the study will be 
performed in an ambulatory fashion.


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If the subject reports headaches during the treatment period the following information and
data should be collected daily until the headache is resolved:

Onset after medication intake (hhh:min)

Headache severity on a Numeric Ranking Scale (NRS) ranging from 0 - 10

Quality of headache (New type of headache vs. similar to previous experienced
episodes of known headaches)

Headache characteristics (pressing or tightening vs. burning vs. pulsating vs.
aggravated by routine physical activity (such as walking or climbing stairs)

Location (all of the following that apply: unilateral, bilateral, holocephal, frontal,
temporal, occipital, facial)

Any acompanying symptoms like (all of the following that apply: nausea and/or
vomiting, photophobia, phonophobia, lacrimation, other)

If Headache is resolved: Overall duration of headache episode (start time and end
time)
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
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 5.2.1 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
The main objective of this trial is to investigate the relative bioavailability of a single dose of
100 mg of BI 1358894 administered as the tablet formulation 2 (TF2)
 
 fasted conditions compared with the reference tablet formulation 1 
(TF1) of 100 mg of BI 1358894 under fed conditions following oral administration, on the 
basis of the primary and secondary pharmacokinetic endpoints, as listed in Section 2.1.2 and 
2.1.3. In addition, this trial will investigate the food effect on the exposure of BI 1358894 
with TF2
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. 
A further objective is to evaluate and compare further pharmacokinetic parameters between 
the treatments. These pharmacokinetic parameters will be assessed by descriptive statistics 
and are specified in Section 2.2.2.1.
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
The relative bioavailability of TF2 
under fasted 
conditions compared with TF1 under fed conditions and the relative BA of TF2 under fed 
conditions compared to TF2 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.
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 deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 


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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 deviation 
(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 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A 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
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-


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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, 10,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2, 3
k = the kth treatment effect, k = 1, 2, …, 5
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1.2) 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 and end of 
REP (see Section 1.2.2) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
In case of two or more treatments, the follow-up will be summarized according to the 
previous treatment. 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.


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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.
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.
7.6
RANDOMISATION
Subjects will be randomised to one of the 12 treatment sequences in a 1:1:1:1:1:1:1:1:1:1:1:1
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 24 subjects in the trial to have at least 20 evaluable subjects, 
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.


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As shown in Section 3.1 the trial design is an incomplete crossover with 5 treatments, 
12 sequences and 3 periods. To ensure optimal statistical properties, the trial was initially 
designed in a balanced manner with 10 sequences (see Blocks 1-10 in Section 3.1). The 
required sample size for a balanced incomplete crossover design is given by  =
 ××
×  , 
where M is the sample size for the corresponding complete crossover design with s
sequences, t treatments and p periods and  shows how many times any given pair of 
treatments (e.g. A and B) appears in the sequences. For a 5×10×3-balanced incomplete 
crossover, the required sample size is therefore n=2M. This means that the precision for this 
design with 20 subjects will be equivalent to the precision of a complete crossover design 
with 10 subjects (e.g. 5×10×5). For a given set of parameters, the number of subjects required 
for a complete crossover is the same to a first approximation regardless of its order (higher 
order complete crossovers have slightly higher power due to increased degrees of freedom). 
Therefore, a 20-subject 5×10×3 design is similar to (but slightly more powerful than) a 10-
subject 2×2×2, and this standard, simpler, design will therefore be used to estimate properties 
of the more complex design. The two additional blocks (CBA and AED) presented in Section 
3.1 are considered to provide additional data in favour of planned comparisons.
The total gCVs calculated in trial 1402-0001 and listed in Table 1.2.1.5: 3 are from 17.7% to
42.0% for AUC0-tz and from 13.4% to 72.8% for Cmax. The corresponding intra-individual 
gCV will then be between 8.8% to 20.4% for AUC0-tz with the intra correlation ρ=0.75, and 
between 8.5% to 43.1% with the intra correlation ρ=0.6. Therefore, various assumptions 
around the gCV of 25%, are considered for this trial. Table 7.7: 1 provides 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.
Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs approximated by a 2x2 crossover trial 
(N=12)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
20.0
1.22
50
41.01
60.96
20.0
1.22
100
82.01
121.93
20.0
1.22
150
123.02
182.89
25.0
1.28
50
39.08
63.98
25.0
1.28
100
78.15
127.95
25.0
1.28
150
156.31
255.91
30.0
1.34
50
37.27
67.08
30.0
1.34
100
74.54
134.16
30.0
1.34
150
149.07
268.33
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).


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The expected 90% confidence interval limits in the table were derived by
CI limit#$$%&,'()%& = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.4.2.


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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), the EU 
regulation 536/2014, 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. See Section 4.1.5 for rules 
about emergency code breaks. 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 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 Clinical Trial Manager (CTM), 
Clinical Research Associates, and investigators of participating trial sites
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany.
Safety laboratory tests will be performed by the local laboratory of the trial site 
Analyses of BI 1358894 concentrations in plasma will be performed at 
 
.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done 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.
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
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.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide. Website: 
statsols.com/wp-content/uploads/2013/10/nQ70_version2_manual.pdf 
(access date: 20 March 2015) ; Los Angeles: Statistical Solutions; 2007.
R15-3888
Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao 
GL, Tsvetkov E, Rodig SJ, Veer A van't, Meloni EG, Carlezon WA, 
Bolshakov VY, Clapham DE. Essential role for TRPC5 in amygdala 
function and fear-related behavior. Cell 2009;137(4):761-772.
R16-5350
Fowler MA, Sidiropoulou K, Ozkan ED, Phillips CW, Cooper DC.
Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent
brain. Plos One 2007;2(6):e573.
R16-5472
Koenigsberg HW, Denny BT, Fan J, Liu X, Guerreri S, Mayson SJ, et al. 
The neural correlates of anomalous habituation to negative emotional
pictures in borderline and avoidant personality disorder patients. Am J 
Psychiatry 2014;171(1):82-90.
R16-5473
Mandell D, Siegle G, Shutt L, Feldmiller J, Thase ME. Neural substrates of 
trait ruminations in depression. J Abnorm Psychol 2014;123(1):35-48.
R16-5474
IsHak WW, Elbau I, Ismail A, Delaloye S, Ha K, Bolotaulo NI, et al.
Quality of life in borderline personality disorder. Harvard Rev Psychiatry 
2013;21(3):138-150.


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R16-5475
McClintock SM, Husain MM, Wisniewski SR, Nierenberg AA, Stewart 
JW, Trivedi MH, et al. Residual symptoms in depressed outpatients who
respond by 50 % but do not remit to antidepressant medication. J Clin
Psychopharmacol 2011;31(2):180-186.
R16-5476
Links PS, Heslegrave R, Reekum R van. Prospective follow-up study of
borderline personality disorder: prognosis, prediction of outcome, and axis 
II comorbidity. Can J Psychiatry 1998;43(3):265-270.
R16-5477
Skodol AE, Siever LJ, Livesley WJ, Gunderson JG, Pfohl B, Widiger TA.
The borderline diagnosis II: biology, genetics, and clinical course. Biol 
Psychiatry 2002;51(12):951-963.
R16-5483
Ellison WD, Rosenstein L, Chelminski I, Dalrymple K, Zimmerman M. 
The clinical significance of single features of borderline personality
disorder: anger, affective instability, impulsivity, and chronic emptiness in 
psychiatric outpatients. J Personal Disord 2016;30(2):261-270.
R18-0249
Minke B. The history of the Drosophila TRP channel: the birth of a new 
channel superfamily. J Neurogenet 2010;24(4):216-233.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c10354149
, Investigator's brochure BI 1358894 in Major Depressive 
Disorder and Borderline Personality Disorder, 1402.P1 & 1402.P2, 
23 Nov 2018.
c13880029
, Safety, tolerability and pharmacokinetics 
of single rising oral doses of BI 1358894 in healthy male subjects (single-
blind, partially randomised, placebo-controlled parallel group design) and 
effect of food on the relative bioavailability of BI 1358894 (open-label, 
randomised, two-way cross-over), 1402-0001, 25 Aug 2018.
n00248384
. Selectivity Test of BI 1358894 on TRPV1, TRPV3, TRPM8, 
TRPC6, TRPA1, hERG, Kv1.3, Cav1.2, Nav1.2, Nav1.7 and Nav1.5. 
Report #: 155. 20 January 2016.
n00250347
 
. BI 1358894: 4-week oral (gavage) 
toxicity study in Sprague Dawley rats. 16B024. 04 July 2017.
n00252179
. Selectivity/ Safety Pharmacology of HC-122608. Report #: 154. 
06 September 2012.
n00252207
. Effects of HC-122608 on mouse marble burying. 
Report #: 213. 18 June 2013.
n00252277
. Effect of HC-122608 in the mouse elevated plus maze. 
Report #: 168. 16 January 2013.


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n00252628
. [14C]BI 1358894: Distribution Study in the Male Pigmented Rat. 
HG96MB. 27 September 2016.
n00252903
. Effect of BI 1358894 in the mouse forced swimming test. 
05 October 2016.
n00253490
. Cytochrome P450 Inducibility in SD rat hepatocytes – Effect on 
in vitro clearance. 18 November 2016.
n00253492
. BI 1358894: In vitro inhibition studies on 
cytochrome P450 dependent metabolic reactions. 8 November 2016.
n00253628
. Prediction of BI 1358894 Pharmacokinetics and 
Therapeutic Dose in Human. 06 December 2016.
n00253723
. Influence of BI 1358894 (10, 30 and 100 mg/kg PO) on 
cardiovascular function (systolic and diastolic arterial pressure, heart rate 
and ECG) and body temperature in conscious rats. GP2014/0251/PH5. 
29 November 2016.
n00253725
. Effects of BI 1358894 on behavior assessed by observation of 
nocturnal activity or in a modified IRWIN-test after oral administration of 
10, 30 and 100 mg/kg. GP2014/0271/0272/PH3. 29 November 2016.
n00253727
. Influence of BI 1358894 (10, 30 and 100 mg/kg PO) 
on hemodynamic and electrocardiographic parameters in conscious dogs. 
GP2014/0269/PH5. 29 November 2016.
n00253729
 Effects of BI 1358894 (10, 30 and 100 mg/kg 
p.o.) on gastrointestinal function in the conscious rat. GP2014/0277/PH4. 
12 December 2016.
n00253732
. Effects of BI 1358894 (10, 30 and 100 mg/kg 
p.o.) on urine- and serum-derived parameters in conscious rats. 
GP2014/0274/PH4. 29 November 2016.
n00253752
. Selectivity test of HC-122608 on TRPV1, TRPV3, TRPM8, 
TRPC6, TRPA1, hERG, Kv1.3, Cav1.2, Nav1.2, Nav1.7 and Nav1.5. 
Report #: 155. 11 January 2013.
n00254034
 
 BI 1358894: Telemetric Evaluation of Cardiovascular 
Effects in the Conscious Dog (Single Oral Administration). WX28PL.10 
July 2017.
n00256526
. Evaluation of Induction Potential of Cytochrome P450 Isoforms 
by BI 1358894 in Cultured Human Hepatocytes. 19 May2017.


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10.
APPENDICES
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE


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10.2
LIST OF INACTIVE INGREDIENTS IN THE TF2 


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
01 March 2019
EudraCT number
EU number
2018-003603-19
BI Trial number
1402-0010
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
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)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Flowchart and associated footnotes
2. Section 1.4.1 Procedure-related risks
3. Section 3.1 Overall trial design and plan
4. Section 3.3.3 Exclusion criteria
5. Section 3.3.4.3 Discontinuation of the trial by the 
Sponsor
6. Section 3.3.5 Replacement of subjects
7. Section 5,2,1 Physical examination
8. Section 5.3.2 Methods of sample collection
9. Section 8.7 Administrative structure of the trial
10. Section 10.1 Columbia-suicide severity rating
scale
11. Section 10.2 List of inactive ingredients in the 
TF2
Description of change
1. Flowchart and associated footnotes
Minor changes were corrected in the flowchart.


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2. Section 1.4.1 Procedure-related risks
A procedure-related risk (syncope) due to venous 
catheter or venepuncture was added to the list.
3. Section 3.1 Overall trial design and plan
A description on the planned group sizes and
planned dosing interval was added. The subjects will 
be dosed in three cohorts of eight subjects each, and 
the cohorts will be separated by one week.
Furthermore, confirmation of subject’s eligibility 
with regards to safety prior to further dosing was 
implemented.
4. / 11. Section 3.3.3 Exclusion criteria / Section 
10.2 List of inactive ingredients in the TF2
The list of excipients for the TF2 conventional and 
non-conventional was added as an appendix and was 
referenced in the corresponding exclusion criterion.
5. Section 3.3.4.3 Discontinuation of the trial by the 
Sponsor
A discontinuation criterion was added to describe 
that severe non-serious drug-related AEs in at least 2 
subjects in the same cohort will lead to 
discontinuation of the trial.
6. Section 3.3.5 Replacement of subjects
Replacement of subjects was further described to 
assure that if more than 4 subjects discontinue the 
trial due to safety and/or poor tolerability, the 
inclusion of further subjects would require a 
substantial amendment. Furthermore subjects who
drop out for reasons unrelated to safety and/or poor 
tolerability could be replaced on a case-by-case 
basis.
7. Section 5.2,1 Physical examination
Minor addition in the list of assessments at EOT to 
include the recording of AEs and concomitant 
therapies in alignment with the flowchart. 
8. Section 5.3.2 Methods of sample collection
Information regarding the PK blood sample 
collection (blood volume and collection tube) was 
amended.


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9. Section 8.7 Administrative structure of the trial
Name and address of the PK laboratory was
amended.
10. Section 10.1 Columbia-suicide severity rating 
scale
Discrepancy regarding the suicidality questionnaire 
was amended. The correct C-SSRS to be used is the 
“screening / baseline”.
Rationale for change
The majority of changes were done based on the 
request of regulatory authorities. In the context of 
this amendment, minor changes due to discrepancies
or administrative aspects were corrected throughout 
the document.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
02 April 2019
EudraCT number
EU number
2018-003603-19
BI Trial number
1402-0010
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
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)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Section 3.1 Overall trial design and plan
2. Section 6.2.2 Treatment periods
Description of change
1. Minor inconsistency regarding the timeframe 
between last safety assessment and start of next 
period was corrected. 
2. The measurement of headache intensity was 
added in the list.
Rationale for change
Minor inconsistencies and omission were corrected 
in the document.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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clinical-trial-protocol-revision-02
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 malesubjects (an open-label, single-dose, randomised,
incomplete blocks crossover design study)
Approval-Therapeutic Area 
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Author-Clinical Trial Leader
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Author-Trial Statistician
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Approval-Team Member Medicine
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Pharmacokineticist
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001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c26426667-03
EudraCT No.
2018-003603-19
BI Trial No.
1402-0010
BI Investigational
Medicinal Product
BI 1358894
Title
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)
Lay Title
A study in healthy men to test if taking different formulations of 
BI 1358894 with or without food influences the amount of 
BI 1358894 in the blood
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Principal 
Investigator
Phone:
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 02 April 2019
Page 1 of 84
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
22 January 2019
Revision date
02 April 2019
BI trial number
1402-0010
Title of trial
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)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
Results from the first-in-human study with BI 1358894 using TF1 showed a limited 
bioavailability under fasted conditions while the intake of food increased the
exposure and bioavailability of BI 1358894. Two additional formulations were 
subsequently developed, TF2 conventional and TF2 non-conventional, to 
investigate the adequate formulation with no or negligible food effect and higher 
exposure under fasted conditions for further clinical development.
Trial objectives
To investigate the relative bioavailability of TF2 conventional and TF2 non-
conventional under fasted conditions vs. TF1 under fed conditions.
To investigate the food effect on the exposure of BI 1358894 with TF2
conventional and TF2 non-conventional.
Trial design
Randomised, open-label, single-dose, incomplete blocks crossover design.
Trial endpoints:
Primary endpoints: AUC0-tz and Cmax of BI 1358894
Secondary endpoints: AUC0-72 and AUC0-of BI 1358894
Number of subjects 
total entered
24 (20 evaluable subjects)
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)


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Test product 1
Tablet formulation 2; TF2 conventional of BI 1358894
dose
100 mg
mode of admin.
Oral with 240 mL of water following a high fat, high calorie breakfast when fed 
(treatment B), or after an overnight fast of at least 10 h when fasted (treatment C).
Test product 2
Tablet formulation 2; TF2 non-conventional of BI 1358894
dose
100 mg
mode of admin.
Oral with 240 mL of water following a high fat, high calorie breakfast when fed
(treatment D), or after an overnight fast of at least 10 h when fasted (treatment E).
Reference product
Tablet formulation 1; TF1 of BI 1358894
dose
100 mg
mode of admin.
Oral with 240 mL of water following a high fat, high calorie breakfast (treatment 
A).
Duration of treatment
One day (single dose) for each treatment.
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary endpoints. Additionally, their two-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to 
the two one-sided t-test procedure, each at a 5% significance level. Since the main 
focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified. The statistical model will be an analysis of 
variance (ANOVA) on the logarithmic scale including effects for ‘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
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 blood
8
Suicidality assessment (C-SSRS)10
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
x
x
x
x
1-3 (three periods separated by a wash-out of at least 17 days)
2
-3 to -1
-72:007
08:00
Ambulatory visit
x
x
2/3/4
1
-1:30
06:30
Admission to trial site
x5
x
-1:00
07:00
Allocation to treatment sequence
(visit 2 only)
x2, 9, 13
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast (for 
treatments A, B and D)12
0:00
08:00
Drug administration
0:10
08:10
x
0:20
08:20
x
0:30
08:30
x
x
x
1:00
09:00
x
x
x
x
1:30
09:30
x
x
2:00
10:00
240 mL fluid intake
x
x
3:00
11:00
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x
x
x
5:00
13:00
x
x
x
6:00
14:00
x
x
x
7:00
15:00
x
8:00
16:00
Snack (voluntary)3
x
x
x
10:00
18:00
Dinner3
x
12:00
20:00
x
x
x
x
2
24:00
08:00
Breakfast3
x
x
x
x
x
34:00
18:00
x
x
x
3
48:00
08:00
Breakfast3
x
x
x
x
4
72:00
08:00
Breakfast (voluntary)3, Discharge 
from trial site11
x
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
x
7
144:00
08:00
Ambulatory visit
x
x
x
x
x
9
192:00
08:00
Ambulatory visit
x
x
x
x
11
240:00
08:00
Ambulatory visit
x
x
x
x
x
14
312:00
08:00
Ambulatory visit
x
x
x
x
x
FU
5
17 to 22
End of trial (EoTrial) examination4
x
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening, 
alcohol breath 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.


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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.
Only urine drug screening and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
safety laboratory can be omitted if the screening examination is performed between Day -3 and Day -1.
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. 
10. Suicidality assessment will be performed at screening, at discharge from trial site for each period and at end of trial.
11. Confirmation of fitness includes physical examination, vital signs, ECG, suicidality assessment (C-SSRS), and
recordings of AEs and concomitant therapies assessed on Day 4 as well as evaluation of safety laboratory assessed on 
Day 2.
12. High fat, high calorie breakfast will be administered only for treatment A (TF1), treatment B (TF2 conventional fed)
and treatment D (TF2 non-conventional fed). Subjects in treatments C (TF2 conventional fasted) and E (TF2 non-
conventional fasted) will not receive any breakfast. All subjects will be admitted to the trial site after an overnight fast 
of at least 10 h for all treatments.
13. Only for visit 2. For visit 3 and 4, predose values for safety laboratory will be derived from the Day 14 of the preceding 
visit.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................15
1.2.1
BI 1358894 .............................................................................................15
1.2.2
Residual Effect Period..........................................................................27
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................27
1.4
BENEFIT - RISK ASSESSMENT ...................................................................27
1.4.1
Procedure-related risks ........................................................................27
1.4.2
Drug-related risks and safety measures..............................................27
1.4.3
Overall statement..................................................................................29
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 30
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......30
2.1.1
Main objectives......................................................................................30
2.1.2
Primary endpoints ................................................................................30
2.1.3
Secondary endpoints.............................................................................30
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 32
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................33


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3.3.1
Main diagnosis for trial entry..............................................................33
3.3.2
Inclusion criteria...................................................................................33
3.3.3
Exclusion criteria ..................................................................................34
3.3.4
Withdrawal of subjects from treatment or assessments ...................35
3.3.4.1
Discontinuation of trial treatment............................................36
3.3.4.2
Withdrawal of consent to trial participation ............................36
3.3.4.3
Discontinuation of the trial by the sponsor..............................36
3.3.5
Replacement of subjects .......................................................................37
4.
TREATMENTS........................................................................................ 38
4.1
INVESTIGATIONAL TREATMENTS ..........................................................38
4.1.1
Identity of the Investigational Medicinal Products ...........................38
4.1.2
Selection of doses in the trial and dose modifications........................38
4.1.3
Method of assigning subjects to treatment groups ............................38
4.1.4
Drug assignment and administration of doses for each subject .......39
4.1.5
Blinding and procedures for unblinding ............................................40
4.1.6
Packaging, labelling, and re-supply ....................................................40
4.1.7
Storage conditions.................................................................................41
4.1.8
Drug accountability ..............................................................................41
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................41
4.2.1
Other treatments and emergency procedures....................................41
4.2.2
Restrictions............................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment .........................42
4.2.2.2
Restrictions on diet and life style.............................................42
4.3
TREATMENT COMPLIANCE.......................................................................42
5.
ASSESSMENTS....................................................................................... 44
5.1
ASSESSMENT OF EFFICACY.......................................................................44
5.2
ASSESSMENT OF SAFETY............................................................................44
5.2.1
Physical examination ............................................................................44
5.2.2
Vital signs...............................................................................................44
5.2.3
Safety laboratory parameters..............................................................44
5.2.4
Electrocardiogram................................................................................47
5.2.5
Other safety parameters.......................................................................48
5.2.5.1
Suicidality assessment .............................................................48
5.2.5.2
Neurological examinations ......................................................48
5.2.6
Assessment of adverse events...............................................................49
5.2.6.1
Definitions of adverse events...................................................49


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Adverse event ............................................................49
5.2.6.1.1
Serious adverse event ................................................49
5.2.6.1.2
AEs considered ‘Always Serious’.............................49
5.2.6.1.3
Adverse events of special interest .............................50
5.2.6.1.4
Intensity (severity) of AEs.........................................51
5.2.6.1.5
Causal relationship of AEs ........................................51
5.2.6.1.6
Suicidal risk assessed by the C-SSRS    
5.2.6.1.7
(paper version)...........................................................52
5.2.6.2
Adverse event collection and reporting ...................................52
AE collection.............................................................52
5.2.6.2.1
AE reporting to the sponsor and timelines ................53
5.2.6.2.2
Information required..................................................53
5.2.6.2.3
Pregnancy ..................................................................54
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................54
5.3.1
Assessment of pharmacokinetics .........................................................54
5.3.2
Methods of sample collection...............................................................54
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................54
5.3.3
Analytical determinations ....................................................................55
5.3.3.1
Analytical determination of BI 1358894 plasma     
concentration............................................................................55
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................55
5.4
ASSESSMENT OF BIOMARKER..................................................................55
5.5
BIOBANKING ...................................................................................................55
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................56
6.
INVESTIGATIONAL PLAN.................................................................. 57
6.1
VISIT SCHEDULE............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................57
6.2.1
Screening period....................................................................................57
6.2.2
Treatment periods.................................................................................57
6.2.3
Follow-up period and trial completion ...............................................58
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 59
7.1
STATISTICAL DESIGN – MODEL ...............................................................59
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................59
7.3
PLANNED ANALYSES....................................................................................59
7.3.1
Primary endpoint analyses...................................................................60
7.3.2
Secondary endpoint analyses ...............................................................62


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7.3.4
Safety analyses.......................................................................................62
7.4
INTERIM ANALYSES .....................................................................................63
7.5
HANDLING OF MISSING DATA ..................................................................63
7.5.1
Safety......................................................................................................63
7.5.2
Pharmacokinetics..................................................................................63
7.6
RANDOMISATION ..........................................................................................63
7.7
DETERMINATION OF SAMPLE SIZE ........................................................63
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 66
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................66
8.2
DATA QUALITY ASSURANCE .....................................................................67
8.3
RECORDS..........................................................................................................67
8.3.1
Source documents .................................................................................67
8.3.2
Direct access to source data and documents.......................................68
8.3.3
Storage period of records.....................................................................68
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................68
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......68
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................69
8.6
TRIAL MILESTONES .....................................................................................69
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................70
9.
REFERENCES......................................................................................... 71
9.1
PUBLISHED REFERENCES...........................................................................71
9.2
UNPUBLISHED REFERENCES.....................................................................72
10. APPENDICES .......................................................................................... 74
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE ................................74
10.2
LIST OF INACTIVE INGREDIENTS IN THE TF2.....................................80
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 81
11.1
GLOBAL AMENDMENT 1 .............................................................................81
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-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-72
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 72 h
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
Borderline Personality Disorder
CA
Competent authority
CHO
Chinese hamster ovary
CI
Confidence interval
CK
Creatine kinase
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CRO
Contract research organisation 
CRP
C-reactive protein
C-SSRS
Columbia Suicidal Severity Rating scale
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol


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CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
CYP
Cytochrome P450
DILI
Drug induced liver injury
DRF
Dose range finding
ECG
Electrocardiogram
eCRF
Electronic case report form
ECT
Electro-convulsive therapy
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EFD
Embryo-foetal development
EoTrial
End of trial
ESR
Erythrocyte sedimentation rate
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FDA
Food and drug administration
FE
Food effect
FIH
First in Human
FST
Forced swim test
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
GLDH
Glutamate deshydrogenase
GLP
Good Laboratory Practice
gMean
Geometric mean
hERG
Human ether-a-go-go related gene
HR
Heart rate
IB
Investigator’s brochure
IC50
Half maximum inhibitory concentration
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry


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LVSP
Left ventricular systolic pressure
MDA
Methylenedioxyamphetamine
MDD
Major depressive disorder
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRTpo
Mean residence time of the analyte in the body, extravascular
NIMH
National institute of mental health
NOAEL
No observed adverse effect level
NRS
Numeric ranking scale
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
PT
Preferred term
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
RBC
Red blood cell
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOC
System organ class
SOP
Standard operating procedure
SRD
Single-rising dose
SUSAR
Suspected unexpected serious adverse reaction
T
Test product or treatment
TF1/2
Tablet formulation 1/2
TRP
Transient receptor potential
TRPC 4/5
Transient receptor potential cation channel, subfamily C, members 4 and 5
TS
Treated set
TSAP
Trial statistical analysis plan
tz
Time of last measurable concentration of the analyte in plasma
ULN
Upper limit of normal
VAS
Visual analog scale
Vss
Apparent volume of distribution at steady state after intravascular 


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administration
WBC
White blood cell
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) as an adjunct to antidepressant therapy and for the 
treatment of borderline personality disorder (BPD).
MDD is a debilitating disease characterised by low mood and often by low self-esteem, low 
energy, and a loss of interest. It can strongly impact a person’s life and health, including 
significantly increased risk of suicidality, and is difficult to treat, even with systematic 
antidepressant strategies. In the National Institute of Mental Health (NIMH) funded STAR*D 
trial of >4000 patients with nonpsychotic depression, about 30% of the patients did not reach 
remission after 4 different medications [P06-11895] and continued to experience residual 
symptoms [R16-5475] that significantly impacted the patients’ quality of life [R06-2872]. 
When monotherapy is insufficient, clinicians employ different augmentation strategies 
including add-on treatment with lithium or atypical antipsychotics. When augmentation 
strategies also fail, convulsive therapies such as electro-convulsive therapy (ECT) may be 
used.
Borderline personality disorder (BPD) is a chronic mental disorder with an estimated 
prevalence of around 2% in the general community [R16-5476] and severely impaired quality 
of life [R16-5474]. The main symptom clusters of BPD include impulsive-behavioural
dyscontrol, cognitive-perceptual symptoms, disturbed interpersonal relations, and affective 
instability. Patients with BPD have high rates of deliberate self-harm and a rate of completed 
suicide that is 50 times higher than in the general population [R16-5477]. Even the presence 
of a single diagnostic feature of BPD is predictive for poor functioning and psychiatric illness 
burden [R16-5483]. Treatment guidelines recommend psychotherapy as the mainstay of 
treatment, but pharmacotherapy is commonly used as an adjunctive, symptom-targeted 
component of treatment. However, no drug is approved for the treatment of BPD.
TRPC4 and TRPC5 form ion channels that are involved in the regulation of neuronal 
excitability. They are most highly expressed in the amygdala, frontal cortex, hippocampus, 
and hypothalamus [R15-3888, R16-5350], which are involved in modulation and processing 
of emotion and affect. Pre-clinically, treatment with BI 1358894 has shown diminished fear 
and anxiety and increased social interaction without impairing other brain functions such as 
learning and memory behaviours.
It is hypothesized that in patients with affective disorders, an overactive amygdala is a major 
contributor to attentional bias to negative stimuli, pessimistic thoughts, and anxiety [R16-
5473] and there is growing evidence supporting the role of amygdala in the emotion 
processing disturbances observed in patients with BPD [R16-5472]. Therefore, treatment 
with BI 1358894 has the potential to improve affective symptoms and emotion control in 
patients with MDD and BPD.


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1.2
DRUG PROFILE
1.2.1
BI 1358894
For a more detailed description of the BI 1358894 profile, please refer to the current 
Investigator’s Brochure (IB) [c10354149].


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1.2.2
Residual Effect Period
The Residual Effect Period (REP) of BI 1358894 is approximately 14 days. This is the period 
after the last dose with measurable drug levels and/or pharmacodynamic effects is still likely 
to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Results from the FIH study with BI 1358894 using the reference tablet formulation 1 (TF1)
showed a limited bioavailability under fasted conditions while the intake of food increased 
the exposure and bioavailability of BI 1358894 (see Section 1.2.1). Two additional 
formulations were subsequently developed, TF2 conventional and TF2 non-conventional, to 
investigate the adequate formulation with no or negligible food effect and higher exposure 
under fasted conditions for further clinical development.   
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.
1.4.1
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period and, in rare cases in sensitive subjects, in a syncope. 
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
1.4.2
Drug-related risks and safety measures
Risks derived from observations in non-clinical studies:
Rats and dogs were employed as the animal species for general toxicology investigations on 
BI 1358894, because in vitro and in vivo profiling supported the suitability of both species 
for nonclinical safety profiling of BI 1358894. In addition, recent EFD studies in rats and 
rabbits were also conducted.
As summarised in Section 1.2.1, potential risks observed in non-clinical studies are a long 
lasting decrease in the blood pressure in rats, an increase in heart rate in rats and dogs, and 
signs of a short lasting episode of arterial/ perivascular inflammation in rats. All findings 
were observed within 5 days after the start of treatment. The CV effects observed in rodents 
and non-rodents can be easily monitored in a Phase I study (CV effects). Perivascular/ 
mesenteric inflammation induced by BI 1358894 occurred early after the start of dosing and 
resolved despite continued treatment, indicating its transient character. The non-clinical 


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safety data support clinical Phase I trials in non-childbearing humans with daily oral 
administration for up to 4 weeks. The conclusion drawn from the EFD studies corroborated
the statement from the general toxicity and concluded that the safety profile and subsequent 
benefit-risk profile was not changed. Furthermore available safety data from healthy 
volunteers in the SRD did not raise any significant safety concerns related to BI 1358894.
Risks related to the mode of action and nature of the target:
The TRP family members are ion channels considered to play a crucial role in physiological 
processes such as to act as a cellular sensor or to support signal transmission [R18-0249]. The 
subtypes TRPC4 and TRPC5 form ion channels that are involved in the regulation of 
neuronal excitability. They are highly expressed in the amygdala, in the frontal cortex, 
hippocampus, and hypothalamus [R15-3888, R16-5350], which are involved in modulation 
and processing of emotion and affect. In preclinical studies, inhibition of these receptors by 
BI 1358894 has resulted in diminished fear and anxiety and increased social interaction 
without impairing other brain functions such as learning and memory behaviours. In 
accordance with these findings, TRPC5 deficient mice display an anxiolytic-like phenotype 
[R15-3888]. This supports the assumption that CNS effects in healthy subjects due to an 
inhibition of TRPC 4/5 are limited to a reduced anxiety. However, clinical data with 
compounds inhibiting this target have yet to be published.
The human safety and tolerability profile in healthy male subjects from the FIH SRD study 
was satisfactory for single doses up to 200 mg under fasted conditions (Trial 1402-0001).
Relevance of animal models:
Human TRPC4 and TRPC5 proteins show high homology with the rat, mouse and dog 
proteins, and potency of BI 1358894 to the target is comparable across species. In addition, 
expression at the protein level is similar across different species including human. Rat and 
dog had good oral bioavailability, significant systemic exposure and good tolerability after 
oral dosing of a nanosuspension of BI 1358894. Finally, all known metabolites formed after 
incubation of human hepatocytes with BI 1358894 were covered with the combination of rat 
and dog. Overall, pharmacodynamic activity, pharmacokinetics and metabolism all indicated 
that rat and dog were suitable species for nonclinical safety profiling of BI1358894.
Risk minimization:
The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers:


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-
The dose selected for the current study was already investigated in the FIH SRD 
study. A higher dose was also investigated and was well tolerated.
-
Adequate safety monitoring will be performed (e.g. vital signs (including blood 
pressure and pulse rate), ECGs, safety laboratory tests including CRP, ESR, hormone 
parameters, suicidality assessment and assessment of adverse events)
-
Subjects will be hospitalized from Day 1 up to Day 4 of each treatment period and 
will be discharge only after a formal assessment and confirmation of fitness by an 
investigator or qualified designee. During the in-clinic stay, the subjects will be under 
medical observation and thoroughly monitored for both expected and unexpected 
events.
Drug induced liver injury:
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.6.1.4, adverse events of special interest.
1.4.3
Overall statement
In summary, although not therapeutically tested in humans to date, BI 1358894 has the 
potential to become an oral treatment for major depressive disorder as an adjunct to 
antidepressant therapy and for the treatment of borderline personality disorder. Based upon 
preclinical data for BI 1358894, the clinical data from the on-going FIH study, as well as the 
implemented safety measures described above, healthy subjects will not be exposed to undue 
risks in relation to the important information expected from this trial as a basis for further 
clinical development of this compound. Healthy volunteers are not expected to have any 
direct benefit from participation in the clinical trial with BI 1358894, as is the usual case in 
such Phase I trials. Considering the medical need for the development of a safer and more 
effective treatment for patients with mood and borderline personality disorders, the Sponsor 
considers that the benefit outweighs the potential risks and justifies exposure of healthy 
human volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of a single dose of 
100 mg BI 1358894 administered as the tablet formulation 2 (TF2) conventional and TF2 
non-conventional under fasted conditions compared with the tablet formulation 1 (TF1) of
100 mg of BI 1358894 under fed conditions following oral administration. In addition, this 
trial will investigate the food effect on the exposure of BI 1358894 with TF2 conventional 
and TF2 non-conventional.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 1358894:

Cmax (maximum measured concentration of the analyte in plasma)

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)
2.1.3
Secondary endpoints
The following pharmacokinetic parameters will be determined for BI 1358894:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

AUC0-72 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 72 h)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, single-dose, incomplete blocks
crossover trial in healthy male subjects in order to compare the test treatments TF2 
conventional and TF2 non-conventional in fasted state (C and E) to the reference treatment 
TF1 in fed state (A) to investigate the relative bioavailability of tablet formulation. 
Additionally, it will evaluate the food effect on test treatments. The test treatments will be 
one single dose of 100 mg BI 1358894 of the TF2 conventional in a fed state (B) and in the 
fasted state (C) and TF2 non-conventional in the fed state (D) and in the fasted state (E). The 
reference treatment to compare the bioavailability of tablet formulations will be one single 
dose of 100 mg BI 1358894 of the TF1 (A) administered to subjects in the fed state.
Twenty-four subjects will be randomly allocated to 12 treatment sequences. For details, refer 
to Section 4.1.
The planned 24 subjects to be included in the study will be assigned to three cohorts, each 
consisting of eight subjects. The cohorts will be treated at least one week apart. The second 
and third cohort will be dosed after a careful review by the Investigator of the safety data
from all subjects in the preceding cohort(s).
Table 3.1: 1
Treatment sequences
Blocks/Sequences
1
2
3
4
5
6
7
8
9
10
11
12
Period 1
A
D
E
C
A
E
B
C
B
D
C
A
Period 2
B
A
B
A
E
D
C
E
D
C
B
E
Period 3
C
B
A
D
C
A
D
B
E
E
A
D
There will be a washout period of at least 17 days between the treatments, i.e. the dose in the 
first treatment period and the dose in the second treatment period are separated by at least 
17 days. In each subject, an assessment of safety laboratory, vital signs, ECG and AEs will be 
conducted on the last day of the preceding period prior to next dosing. These data will be 
reviewed by the Investigator to confirm the eligibility of the subject before the following 
dosing.
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 GROUPS
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between formulations is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between formulations [R94-1529]. The incomplete blocks design was chosen for this study 


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instead of a full 5x5 crossover design
 
resulting in a long washout period (17 days).
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of BI 1358894, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 24 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 which is a standard population in 
early clinical development.
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 50 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


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5. Male subjects who meet any of the following criteria from at least 30 days before the first 
administration of trial medication until 30 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 (IUD) that started at least 2 months prior to first study drug 
administration, or barrier method (e.g. diaphragm with spermicide)
-
Sexually abstinent
-
A vasectomy performed at least 1 year prior to screening (with medical assessment of 
the surgical success)
-
Surgically sterilised female partner (including hysterectomy, bilateral tubal occlusion 
or bilateral oophorectomy)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. C-Reactive Protein (CRP) > upper limit of normal (ULN), erythrocyte sedimentation rate 
(ESR) ≥15 millimeters/h, liver or kidney parameter above ULN, or any other laboratory 
value outside the reference range that the investigator considers to be of clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) (Lists of excipients are provided in the Investigator’s Brochure Section 4.2
for Tablet Formulation 1 and in Appendix 10.2 for Tablet Formulation 2 conventional and 
Tablet Formulation 2 non-conventional.)
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)


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14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study
In addition, the following trial-specific exclusion criteria apply:
23. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
24. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
For study restrictions, refer to Section 4.2.2.
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.


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3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment or trial participation, 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 shows a raised CRP level of >3.00 mg/dL or an ESR of ≥20 millimetres/hour
6. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP<90/50 mmHg) or hypertension 
(BP>180/100 mmHg) or of clinically relevant changes in ECG requiring intervention as 
well as unexplained liver enzyme elevations at any time during the trial.
7. The subject 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
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:


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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 one 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
5. Occurrence of severe non-serious adverse reactions (i.e., severe non-serious adverse 
events considered as possibly related to the drug administration) in at least two subjects in 
the same cohort.
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 4 subjects stopped the trial/treatment prematurely due to safety reasons 
and/or due to poor tolerability further inclusion of new subjects will only be possible after 
approval of a substantial amendment.
In case subjects do not complete the trial for reasons other than safety and/or poor tolerability
(e.g., personal reasons), the Clinical Trial Leader (CTL) together with the Principal 
Investigator, the Trial Pharmacokineticist and the Trial Statistician are to decide on a case-by-
case basis, 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 sequence as the 
subject 
 replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products have been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test products are given below:
Substance:
BI 1358894
Pharmaceutical formulation: Tablet Formulation 2 conventional / Tablet Formulation 2 non-
conventional
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 are given below:
Substance:
BI 1358894
Pharmaceutical formulation: Tablet Formulation 1
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
single dose
4.1.2
Selection of doses in the trial and dose modifications
The dose selected for this trial, 100 mg of BI 1358894, has been evaluated in the ongoing 
first-in-human SRD trial (see Section 1.2), in which the highest dose tested was 200 mg and 
was well tolerated.
4.1.3
Method of assigning subjects to treatment groups
The randomisation list will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
list will be allocated to the subjects by the method first come first served. Subjects are then 
assigned to a treatment sequence according to the randomisation list.


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Within the treatment sequence, numbers of the randomisation list will be allocated to subjects
in their order of registration for the study (that is, the first subject registered will be the first 
treated and will receive the first number of the respective treatment sequence in 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.
4.1.4
Drug assignment and administration of doses for each subject
This trial is an incomplete blocks crossover study. All subjects will receive three out of the 
five treatments in randomised order. The treatments to be evaluated are outlined in Table 
4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation Unit strength
Dosage
Total  dose
B (Test)
BI 1358894
Tablet
50 mg
2 tablets (50 mg), single dose, fed
100 mg
C (Test)
BI 1358894
Tablet
50 mg
2 tablets (50 mg), single dose, fasted
100 mg
D (Test)
BI 1358894
Tablet
50 mg
2 tablets (50 mg), single dose, fed
100 mg
E (Test)
BI 1358894
Tablet
50 mg
2 tablets (50 mg), single dose, fasted
100 mg
A (Reference)
BI 1358894
Tablet
100 mg
1 tablet (100 mg), single dose, fed
100 mg
Administration of trial medication will be performed after subjects have fasted overnight; 
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.
In three out of the five treatment periods (treatment A, B and D), 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
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat. 
Subjects will be kept under close medical surveillance until 72 h after 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) unless lower or 
supine position is required for trial-related measurements (e.g., recording of 12-lead ECG) or 
medical reasons (e.g., adverse events).
The treatments 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
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. 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
when the 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
In case of adverse events in need of treatment, the investigator can authorise symptomatic 
therapy.
In case of alterations of blood pressure (hypotension) and heart rate (tachycardia), which 
were reported in nonclinical toxicology studies (see Section 1.2.1.3), first physical 


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interventions will be the treatment of symptoms. If unsuccessful, appropriate drug therapy 
will be initiated according to common guidelines and algorithms of emergency trainings. 
Dependent on individual symptoms, for the treatment of tachycardia this may include 
intravenous administration of beta blockers or appropriate antiarrhythmic drugs. For the 
treatment of hypotension, in addition to volume substitution, administration of vasopressors 
may be a further step. The entire staff of the trial site assuming medical responsibility during 
the conduct of the study is routinely trained in emergency procedures.
If required, any subject with an adverse event in need of treatment will be kept under 
supervision at the trial site or transferred to a hospital until all medical evaluation results have 
returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 2), the water administered with the drug, and an additional 
240 mL of water at 2 h and 4 h post-dose (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 the last study period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 4 h before until 4 h after each administration of trial 
medication.
Poppy-seed containing products should not be consumed starting 4 days before first trial drug 
administration until last PK sampling of the trial.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.


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Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
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, and a physical examination. At 
the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, recordings of AEs and concomitant therapies, and a physical examination including 
determination of weight.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap, GE Medical Systems, Freiburg, Germany) at the times indicated in the Flow 
Chart, after subjects have rested for at least 5 min in a supine position. All recordings should 
be made using the same type of blood pressure recording instrument on the same arm, if 
possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
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)
Erythrocyte Sedimentation Rate (ESR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
and absolute
Neutrophils; Eosinophils; Basophils; Monocytes; Lymphocytes 
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal and clinically 
relevant in the opinion 
of the investigator)
Polymorphnuclear neutrolphils (segs); band neutrophils (stabs); 
eosinophils; basophils; monocytes; lymphocytes
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
--
--
--
X
X
X 
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
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


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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
Calcium
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 at Visit 2 on Day -3 to Day -1, unless screening examination is performed 
between Day -3 and Day -1, and at Visits 2/3/4 on Day 1, Day 2, Day 7, Day 11 and Day 14 (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
Infectious serology (blood)
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 breath alcohol test (e.g. 
Alcotest®7410, Dräger AG, Lübeck, Germany) will be performed at screening and prior to 
each treatment period, and may be repeated at any time during the study at the discretion of 
an investigator or designee. The results will not be included in the CTR
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
with the 
exception of drug screening tests. These tests will be performed at the trial site using 
Multidrogen Pipettiertest (Diagnostik Nord GmbH, Schwerin), or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). Precise electrode placement will be marked with an 
indelible mark on the skin to allow reproducible placement throughout the study.
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 


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assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Suicidality assessment
Suicidality assessment to further evaluate the psychological status of the subject will be 
performed at screening using the Columbia Suicidal Severity Rating scale (C-SSRS). The C-
SSRS is a brief measure which is designed to assess severity and change of suicidality by 
integrating both behaviour and ideation. The C-SSRS was designed to address the need for a 
summary measure to track change in the severity of suicidality across both clinical settings 
and treatment trials.
The original C-SSRS is shown in Appendix 10.1.
5.2.5.2
Neurological examinations
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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Suicidal risk assessed by the C-SSRS (paper version)
5.2.6.1.7
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation. 
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report. 
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the screening visit (using the ‘screening / baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and behavior 
will also be recorded.
After the baseline visit the assessment ‘since last visit’ will be performed at each clinic or 
phone visit (‘since last visit’ version). The investigator is to review positive and negative 
reports for plausibility and clinical relevance. Doubtful reports may be repeated or reports 
may be validated by a consulting psychiatrist. If there is a confirmed positive report of 
suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to 
immediately interview the subject during the clinic visit, and/or is to consult a psychiatrist.
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.
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. 


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Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.


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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.
5.3
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, approximately 3 mL of blood will 
be drawn from an antecubital or forearm vein into a K-EDTA (potassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle.
Sample handling will be described in detail in a separate lab manual.
All plasma samples will be stored at approximately -20°C or below until transfer to the 
analytical laboratory and analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, 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 


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completion of the additional investigations but not later than 5 years after the CTR is 
archived.
5.3.3
Analytical determinations
5.3.3.1
Analytical determination of BI 1358894 plasma concentration
BI 1358894 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis.
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
Not applicable.
5.5
BIOBANKING
Not applicable.


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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests
will be ± 10 min for the first 4 h after trial drug administration and ± 30 min thereafter.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including 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 5.2.1 to 5.2.5.
6.2.2
Treatment periods
Each subject is expected to participate in 3 treatment periods (Day 1 to 14 in each period). At 
least 17 days will separate two consequent drug administration in-between the treatment 
periods.
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 72 h following drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness on Day 4. On all other study days (Day 5, 7, 9, 11 and 14), the study will be 
performed in an ambulatory fashion.


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If the subject reports headaches during the treatment period the following information and
data should be collected daily until the headache is resolved:

Onset after medication intake (hhh:min)

Headache severity on a Numeric Ranking Scale (NRS) ranging from 0 - 10

Quality of headache (New type of headache vs. similar to previous experienced
episodes of known headaches)

Headache characteristics (pressing or tightening vs. burning vs. pulsating vs.
aggravated by routine physical activity (such as walking or climbing stairs)

Location (all of the following that apply: unilateral, bilateral, holocephal, frontal,
temporal, occipital, facial)

Any acompanying symptoms like (all of the following that apply: nausea and/or
vomiting, photophobia, phonophobia, lacrimation, other)

If Headache is resolved: Overall duration of headache episode (start time and end
time)
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
Genotyping will be performed at visit 2 in those volunteers whose genotypes have not been 
previously determined (for details, see Section 5.6).
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 5.2.1 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
The main objective of this trial is to investigate the relative bioavailability of a single dose of
100 mg of BI 1358894 administered as the tablet formulation 2 (TF2) conventional and TF2 
non-conventional under fasted conditions compared with the reference tablet formulation 1 
(TF1) of 100 mg of BI 1358894 under fed conditions following oral administration, on the 
basis of the primary and secondary pharmacokinetic endpoints, as listed in Section 2.1.2 and 
2.1.3. In addition, this trial will investigate the food effect on the exposure of BI 1358894 
with TF2 conventional and TF2 non-conventional.
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. 
A further objective is to evaluate and compare further pharmacokinetic parameters between 
the treatments. These pharmacokinetic parameters will be assessed by descriptive statistics 
and are specified in Section 2.2.2.1.
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
The relative bioavailability of TF2 (conventional and non-conventional) under fasted 
conditions compared with TF1 under fed conditions and the relative BA of TF2 under fed 
conditions compared to TF2 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.
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 deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 


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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 deviation 
(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 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A 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
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-


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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, 10,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2, 3
k = the kth treatment effect, k = 1, 2, …, 5
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1.2) 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 and end of 
REP (see Section 1.2.2) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
In case of two or more treatments, the follow-up will be summarized according to the 
previous treatment. 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.


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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.
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.
7.6
RANDOMISATION
Subjects will be randomised to one of the 12 treatment sequences in a 1:1:1:1:1:1:1:1:1:1:1:1
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 24 subjects in the trial to have at least 20 evaluable subjects, 
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.


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As shown in Section 3.1 the trial design is an incomplete crossover with 5 treatments, 
12 sequences and 3 periods. To ensure optimal statistical properties, the trial was initially 
designed in a balanced manner with 10 sequences (see Blocks 1-10 in Section 3.1). The 
required sample size for a balanced incomplete crossover design is given by  =
 ××
×  , 
where M is the sample size for the corresponding complete crossover design with s
sequences, t treatments and p periods and  shows how many times any given pair of 
treatments (e.g. A and B) appears in the sequences. For a 5×10×3-balanced incomplete 
crossover, the required sample size is therefore n=2M. This means that the precision for this 
design with 20 subjects will be equivalent to the precision of a complete crossover design 
with 10 subjects (e.g. 5×10×5). For a given set of parameters, the number of subjects required 
for a complete crossover is the same to a first approximation regardless of its order (higher 
order complete crossovers have slightly higher power due to increased degrees of freedom). 
Therefore, a 20-subject 5×10×3 design is similar to (but slightly more powerful than) a 10-
subject 2×2×2, and this standard, simpler, design will therefore be used to estimate properties 
of the more complex design. The two additional blocks (CBA and AED) presented in Section 
3.1 are considered to provide additional data in favour of planned comparisons.


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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), the EU 
regulation 536/2014, 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. See Section 4.1.5 for rules 
about emergency code breaks. 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 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 Clinical Trial Manager (CTM), 
Clinical Research Associates, and investigators of participating trial sites
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany.
Safety laboratory tests will be performed by the local laboratory of the trial site 
Analyses of BI 1358894 concentrations in plasma will be performed at 
 
.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done 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.
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
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.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide. Website: 
statsols.com/wp-content/uploads/2013/10/nQ70_version2_manual.pdf 
(access date: 20 March 2015) ; Los Angeles: Statistical Solutions; 2007.
R15-3888
Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao 
GL, Tsvetkov E, Rodig SJ, Veer A van't, Meloni EG, Carlezon WA, 
Bolshakov VY, Clapham DE. Essential role for TRPC5 in amygdala 
function and fear-related behavior. Cell 2009;137(4):761-772.
R16-5350
Fowler MA, Sidiropoulou K, Ozkan ED, Phillips CW, Cooper DC.
Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent
brain. Plos One 2007;2(6):e573.
R16-5472
Koenigsberg HW, Denny BT, Fan J, Liu X, Guerreri S, Mayson SJ, et al. 
The neural correlates of anomalous habituation to negative emotional
pictures in borderline and avoidant personality disorder patients. Am J 
Psychiatry 2014;171(1):82-90.
R16-5473
Mandell D, Siegle G, Shutt L, Feldmiller J, Thase ME. Neural substrates of 
trait ruminations in depression. J Abnorm Psychol 2014;123(1):35-48.
R16-5474
IsHak WW, Elbau I, Ismail A, Delaloye S, Ha K, Bolotaulo NI, et al.
Quality of life in borderline personality disorder. Harvard Rev Psychiatry 
2013;21(3):138-150.


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R16-5475
McClintock SM, Husain MM, Wisniewski SR, Nierenberg AA, Stewart 
JW, Trivedi MH, et al. Residual symptoms in depressed outpatients who
respond by 50 % but do not remit to antidepressant medication. J Clin
Psychopharmacol 2011;31(2):180-186.
R16-5476
Links PS, Heslegrave R, Reekum R van. Prospective follow-up study of
borderline personality disorder: prognosis, prediction of outcome, and axis 
II comorbidity. Can J Psychiatry 1998;43(3):265-270.
R16-5477
Skodol AE, Siever LJ, Livesley WJ, Gunderson JG, Pfohl B, Widiger TA.
The borderline diagnosis II: biology, genetics, and clinical course. Biol 
Psychiatry 2002;51(12):951-963.
R16-5483
Ellison WD, Rosenstein L, Chelminski I, Dalrymple K, Zimmerman M. 
The clinical significance of single features of borderline personality
disorder: anger, affective instability, impulsivity, and chronic emptiness in 
psychiatric outpatients. J Personal Disord 2016;30(2):261-270.
R18-0249
Minke B. The history of the Drosophila TRP channel: the birth of a new 
channel superfamily. J Neurogenet 2010;24(4):216-233.
9.2
UNPUBLISHED REFERENCES


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10.
APPENDICES
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
01 March 2019
EudraCT number
EU number
2018-003603-19
BI Trial number
1402-0010
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
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)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Flowchart and associated footnotes
2. Section 1.4.1 Procedure-related risks
3. Section 3.1 Overall trial design and plan
4. Section 3.3.3 Exclusion criteria
5. Section 3.3.4.3 Discontinuation of the trial by the 
Sponsor
6. Section 3.3.5 Replacement of subjects
7. Section 5,2,1 Physical examination
8. Section 5.3.2 Methods of sample collection
9. Section 8.7 Administrative structure of the trial
10. Section 10.1 Columbia-suicide severity rating
scale
 
Description of change
1. Flowchart and associated footnotes
Minor changes were corrected in the flowchart.


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2. Section 1.4.1 Procedure-related risks
A procedure-related risk (syncope) due to venous 
catheter or venepuncture was added to the list.
3. Section 3.1 Overall trial design and plan
A description on the planned group sizes and
planned dosing interval was added. The subjects will 
be dosed in three cohorts of eight subjects each, and 
the cohorts will be separated by one week.
Furthermore, confirmation of subject’s eligibility 
with regards to safety prior to further dosing was 
implemented.
4. / 11. Section 3.3.3 Exclusion criteria / 
 
 
 
5. Section 3.3.4.3 Discontinuation of the trial by the 
Sponsor
A discontinuation criterion was added to describe 
that severe non-serious drug-related AEs in at least 2 
subjects in the same cohort will lead to 
discontinuation of the trial.
6. Section 3.3.5 Replacement of subjects
Replacement of subjects was further described to 
assure that if more than 4 subjects discontinue the 
trial due to safety and/or poor tolerability, the 
inclusion of further subjects would require a 
substantial amendment. Furthermore subjects who
drop out for reasons unrelated to safety and/or poor 
tolerability could be replaced on a case-by-case 
basis.
7. Section 5.2,1 Physical examination
Minor addition in the list of assessments at EOT to 
include the recording of AEs and concomitant 
therapies in alignment with the flowchart. 
8. Section 5.3.2 Methods of sample collection
Information regarding the PK blood sample 
collection (blood volume and collection tube) was 
amended.


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9. Section 8.7 Administrative structure of the trial
Name and address of the PK laboratory was
amended.
10. Section 10.1 Columbia-suicide severity rating 
scale
Discrepancy regarding the suicidality questionnaire 
was amended. The correct C-SSRS to be used is the 
“screening / baseline”.
Rationale for change
The majority of changes were done based on the 
request of regulatory authorities. In the context of 
this amendment, minor changes due to discrepancies
or administrative aspects were corrected throughout 
the document.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
02 April 2019
EudraCT number
EU number
2018-003603-19
BI Trial number
1402-0010
BI Investigational Medicinal 
Product(s)
BI 1358894
Title of protocol
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)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Section 3.1 Overall trial design and plan
2. Section 6.2.2 Treatment periods
Description of change
1. Minor inconsistency regarding the timeframe 
between last safety assessment and start of next 
period was corrected. 
2. The measurement of headache intensity was 
added in the list.
Rationale for change
Minor inconsistencies and omission were corrected 
in the document.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26426667
3.0
clinical-trial-protocol-revision-02
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 malesubjects (an open-label, single-dose, randomised,
incomplete blocks crossover design study)
Approval-Therapeutic Area 
02 Apr 2019 15:06 CEST
Author-Clinical Trial Leader
02 Apr 2019 15:41 CEST
Author-Trial Statistician
02 Apr 2019 16:44 CEST
Approval-Team Member Medicine
02 Apr 2019 18:34 CEST
Author-Trial Clinical
Pharmacokineticist
03 Apr 2019 14:47 CEST
Verification-Paper Signature
Completion
05 Apr 2019 08:57 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26426667
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c28702727-01
BI Trial No.:
1402-0010
Title:
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)
Including Protocol Amendment 2 [c26426667-03]
Investigational
Product:
BI 1358894
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
06 AUG 2019 SIGNED
Version:
Final
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................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...............................................................................................19
7.5
SECONDARY ENDPOINTS.............................................................................19
7.5.1
Key secondary endpoints....................................................................................19
7.5.2
Secondary endpoints...........................................................................................19


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7.7
EXTENT OF EXPOSURE.................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................20
7.8.1
Adverse Events ....................................................................................................20
7.8.2
Laboratory data ..................................................................................................22
7.8.3
Vital signs.............................................................................................................22
7.8.4
ECG......................................................................................................................22
7.8.5
Others...................................................................................................................22
8.
REFERENCES....................................................................................................24
10.
HISTORY TABLE..............................................................................................26


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LIST OF TABLES
Table 6.1: 1 
Dosage and treatment schedule of BI 1358894................................................11
Table 6.1: 2
Analysis phases for statistical analysis of AEs, safety laboratory and vital 
signs..................................................................................................................12
Table 6.2: 1
Handling of IPDs..............................................................................................14
Table 6.3: 1
Subject sets analyzed........................................................................................15
Table 10: 1
History table .....................................................................................................26


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADME
Absorption, Distribution, Metabolism and Excretion 
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC0-72
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to 72 h
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity
BI 
Boehringer Ingelheim
BP
Blood pressure
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
C-SSRS
Columbia Suicidal Severity Rating scale
ECG
Electrocardiogram
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPD
Important protocol deviations
IQRMP
Integrated quality and risk management plan
MedDRA
Medical Dictionary For Regulatory Activities
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter set
PR
Pulse rate
RAGe
Report appendix generator


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Term
Definition / description
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class
TS
Treated set
TSAP
Trial Statistical Analysis Plan
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 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.
Study data will be stored in a trial database within Medidata Rave system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
Certara USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The CTP states in Section 7.3.4 that AEs occurring after the residual effect period but prior to 
next intake or end of trial termination date will be assigned to “follow-up”. As a more 
conservative approach, all AEs occurring after intake of trial medication and prior to next 
intake or end of trial termination date will be assigned to the on-treatment period of the 
respective trial medication. I.e., no follow-up phases will be defined in this trial, cf. 
Table 6.1: 2.
All other analyses described in this TSAP are in accordance with the statistical methods 
described in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints are PK endpoints of BI 1358894, as defined in Section 2.1.2 of the CTP:

Cmax (maximum measured concentration of the analyte in plasma)

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints are PK endpoints of BI 1358894, as defined in Section 2.1.3 of the CTP:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity)

AUC0-72 (area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to 72 h)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment 
groups, and selection of doses, cf. Section 4 of the CTP.
Each subject is planned to be treated in three subsequent treatment periods, with one single 
dose in each treatment period. Subjects will receive three out of the five BI 1358894 
treatments described in Table 6.1: 1.
Table 6.1: 1 
Dosage and treatment schedule of BI 1358894
Product
Treatment
Formulation
Unit 
strength
Dosage
Total dose
TF2 
B
Tablet
50 mg
2 tablets (50 mg), single dose, fed
100 mg
C
Tablet
50 mg
2 tablets (50 mg), single dose, 
fasted
100 mg
TF2
D
Tablet
50 mg
2 tablets (50 mg), single dose, fed
100 mg
E
Tablet
50 mg
2 tablets (50 mg), single dose, 
fasted
100 mg
TF1
A
Tablet
100 mg
1 tablet (100 mg), single dose, fed
100 mg
Each subject is planned to be randomly allocated to one of twelve treatment sequences.
Table 6.1: 2 shows definitions of analysis phases within each subject for statistical analyses 
of AEs, safety laboratory and vital signs.


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Table 6.1: 2
Analysis phases for statistical analysis of AEs, safety laboratory and vital 
signs
Study analysis 
phase
Label
Start
End
Screening
Screening
Date of informed consent
Date/time of first administration 
of BI 1358894
On treatment
TF2
 fed,
TF2 
 fas,
TF2 
 
fed,
TF2 
 
fas or
TF1 fed
respectively
Date/time of administration of 
the respective formulation of 
BI 1358894
Date/time of administration of 
study drug in the next treatment 
period
or
0:00 AM on day after subject's 
end of study participation date, 
whatever comes first
AE displays in CTR Section 15.3, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 will 
present results for the on-treatment phase only.
In AE tables in CTR Section 15.3 (but not in Appendix 16.1.13.1.8.2 and Appendix 
16.1.13.1.8.3 AE tables), the following total will be provided in addition: 

"Total on-trt", defined as the total over all on-treatment phases
CTR Appendix 16.1.13.1.8.1 displays will present results for the screening and on-treatment
phases.
Additionally to the total defined above, the following total will be provided in AE tables in 
CTR Section 16.1.13.1.8.1:

"Total", defined as the total over all study phases (screening + on-treatment)
Statistical analyses of safety laboratory tests and vital signs will be conducted by treatment 
period 
, with 
clear differentiation between baseline (cf. Section 6.7) and on-treatment measurements (as 
defined in Table 6.1: 2).
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.


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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. At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an 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).
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 will be supplemented accordingly by the time of the Report 
Planning Meeting.
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. The decision on exclusion of subjects 
from analysis sets will be made at the latest at the Report Planning Meeting, after discussion 
of exceptional cases and implications for analyses. If the data show other IPDs, this table will 
be supplemented accordingly by the time of the Report Planning Meeting.


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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 taken
PKS
C2
Randomization not followed
PKS
C3
Non-compliance
PKS
C4
Incorrect intake of trial medication
PKS
C5
Improper washout between treatments
PKS
D1
Prohibited medication use
PKS
D2
Mandatory medication not taken
PKS
D3
Improper washout of 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
PKS
G1
Incorrect intake of meal
PKS
G2
C-SSRS not conducted at discharge and 
EOT
None
6.3
SUBJECT SETS ANALYSED
Subject sets will be used as defined in the CTP, Section 7.3.


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Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
PKS
Primary PK endpoints 
X
Secondary PK endpoints 
X
Safety parameters & 
treatment exposure
X
Demographic/baseline 
endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.
Data of subjects who failed to complete all periods of the study (dropouts or withdrawals) 
will be reported in the CTR as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal reported in the CTR.
CTP: 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).
Missing data and outliers of PK data are handled according to BI standards (4). 
CTP: 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 study treatment: 


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
Baseline for the treatment in the first treatment period is defined as the last available 
off-treatment value before administration of the respective formulation of BI 
1358894.

Baseline for the treatment in the second and third treatment periods is defined as the 
last available pre-dose value measured on or after Day 14 of the preceding visit.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the Report Planning Meeting.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (5).
The individual values of all subjects will be listed. Listings will be sorted by treatment 
sequence, 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.
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
7.4.1
Primary analysis of the primary endpoints
Primary analysis of the primary endpoints will be performed as defined in Sections 7.3.1 of 
the CTP.
The statistical model for the primary analysis defined in the CTP is an analysis of variance 
(ANOVA) model on the logarithmic scale including "treatment", "period" and "sequence" as 
fixed effects and "subjects within sequences" as random effect. Relative bioavailability of the 
study treatments will be estimated by the ratios of the geometric means

C/A, i.e. TF2 
 fas/ TF1 fed

E/A, i.e.TF2 
 fas/ TF1 fed, i.e. 

B/C, i.e. TF2
 fed/ TF2 
 fas

D/E, i.e. TF2 
 fed/ TF2 
 fas
of the primary endpoints.
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 


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and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the 
value will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (6).
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoints
The same statistical model as used for the primary analysis (Sections 7.3.1 of the CTP) will 
be repeated for the primary endpoints but with all sources of variation ("sequence", "subjects 
within sequences", "period", "treatment") considered as fixed effects.
Primary PK endpoints will be assessed descriptively. The analysis of standard PK parameters 
is performed according to BI standards (4).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
The secondary endpoints will be statistically analysed in the same way as for the primary 
endpoints. The endpoints will also be assessed descriptively. The analysis of standard PK 
parameters is performed according to BI standards (4).
See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report, by treatment and overall.
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 analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to screening or on-treatment phases as defined in Section 6.1. 
AEs will be analysed based on actual treatments, as defined in Table 6.1: 2.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (8) and for the class of 
AESIs.


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CTP: 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) AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately. Separate tables will also be provided for subjects with SAEs, subjects 
with AESIs and subjects with other significant AEs (according to ICH E3 (8)). The frequency 
of subjects with AEs and the frequency of subjects with AEs considered by the investigator to 
be drug related will also be summarised by maximum intensity, primary SOC and preferred 
term.
The 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.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards "Display and Analysis of Laboratory Data" (9).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the Report Planning Meeting 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.
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 vital signs over time (baseline and on-treatment measurements, cf. 
Table 6.1: 2, only) and for the difference from baseline (see Section 6.7) will be provided.
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
Relevant ECG 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 ECG findings will be prepared.
7.8.5
Others
Physical 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 examination findings will be prepared.


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Reports of C-SSRS will be reported as AEs as described in CTP Section 5.2.6.1.7 and will be 
summarized as such. Results of the C-SSRS will only be listed. No further analysis will be 
prepared.
Clinically relevant findings of the neurological examination 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 neurological examinations
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 Trialss, current version
2
001-MCS-40-413_1.0: "Identify and Manage Important Protocol Deviations 
(iPD)", current version; IDEA for CON
3
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE 
dates", current version; KMED
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON
5
KM Asset BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project 
Summaries", current version; KMED
6
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD 
Data Files", current version; IDEA for CON
7
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse 
Event Data from Clinical Trials", current version; KMED
8
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
9
KM Asset BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", 
current version; KMED


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
06-AUG-2019
None
This is the final TSAP