Clinical trial NCT04567316
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2020-10-19; Completion date: 2021-01-10
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main objective of this trial is to investigate the basic pharmacokinetics of BI 1358894 and its metabolites, total radioactivity, including mass balance, excretion pathways and metabolism following a single oral dose of \[14C\] BI 1358894 in Part 1 and to investigate the pharmacokinetics of BI 1358894 and its metabolite(s) following multiple-dose treatment over 21 days with non- radiolabelled compound of BI 1358894 in Part 2.

Detailed description:

Arms: arm 1: \[14C\]-radiolabelled BI 1358894 (part 1) arm 2: BI 1358894 (part 2)
Interventions: intervention 1: [14C]-radiolabelled BI 1358894 intervention 2: BI 1358894
Intervention descriptions: intervention 1: Part 1 intervention 2: Part 2

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c31118084-01
EudraCT No.
2020-002054-25
BI Trial No.
1402-0015
BI Investigational
Medicinal Product
BI 1358894
Title
A phase I, open-label trial to investigate metabolism and 
pharmacokinetics of a single dose of [14C] BI 1358894 
administered as oral solution (Part 1) and multiple doses of 
BI 1358894 administered as film-coated tablets (Part 2) in 
healthy male volunteers
Lay Title
A study in healthy men to test how BI 1358894 is taken up and 
handled by the body
Clinical Phase
I
Trial Clinical 
Monitor
Phone:
Fax:
Principal 
Investigator
Phone:
Fax:
Status
Final Protocol
Version and Date
Version: 1.0
Date: 21 August 2020
Page 1 of 81
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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BI Trial No.: 1402-0015
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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
21 August 2020
Revision date
Not applicable
BI trial number
1402-0015
Title of trial
A phase I, open-label trial to investigate metabolism and 
pharmacokinetics of a single dose of [14C] BI 1358894 administered as
oral solution (Part 1) and multiple doses of BI 1358894 administered as 
film-coated tablets (Part 2) in healthy male volunteers
Principal Investigator:
Trial site
 
Clinical phase
I
Trial rationale
The trial is intended to investigate the basic pharmacokinetics, excretion 
pathways and metabolism of BI 1358894 and its metabolites.
Trial objective
To investigate the basic pharmacokinetics after a single dose of 
BI 1358894 and its metabolites, total radioactivity including mass 
balance, excretion pathways and metabolism following a single oral dose 
of 100 mg [14C] BI 1358894 given to healthy male subjects.
To investigate the pharmacokinetics of BI 1358894 and its metabolite(s) 
following treatment with 100 mg BI 1358894, once daily over 21 days.
Trial design
Open-label, single period and single arm design with 2 treatment parts 
(Part 1 single dose with radiolabelled compound and Part 2 multiple doses
with non-radiolabelled compound).


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Trial endpoints:

Part 1:
Primary endpoints: 
-
Mass balance recoveries of total radioactivity in urine and faeces
-
Amount of radioactivity excreted as a percentage of the 
administered dose (fe0-t2) for urine and faeces
Secondary endpoints:
Assessment of the oral pharmacokinetics of [14C] BI 1358894 by 
calculating the following parameters:
-
for total radioactivity and for BI 1358894: Cmax and AUC0-tz

Part 2:
Secondary endpoints: 
-
Pharmacokinetics of BI 1358894

AUC0-24 (area under the concentration-time curve of the analyte in 
plasma over the time interval from 0 to 24h)

Cmax (maximum measured concentration of the analyte in plasma)

AUCτ,ss (area under the concentration-time curve of the analyte in 
plasma at steady state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in 
plasma at steady state over a uniform dosing interval τ)
Number of subjects 
total entered
16 
each treatment
8 (per Part)
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 65 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Test product 1
Carbon 14 labelled BI 1358894 ([14C] BI 1358894) as oral solution
dose
100 mg on Day 1 (Part 1)
- in 10 mL oral solution (10 mg/mL)
containing a radioactive dose of 3.7 MBq (100 µCi)
mode of admin.
Oral


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BI Trial No.: 1402-0015
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Trial Protocol
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Test product 2
BI 1358894 film-coated tablet formulation
dose
100 mg (2x50 mg) QD (Part 2)
mode of admin.
Oral with 240 mL of water 
Duration of treatment
Treatment Part 1:
On Day 1, a single dose of radiolabelled oral solution (Test product 1)
Treatment Part 2:
Non-radiolabelled film-coated tablets (Test product 2) from Day 1 to 
Day 21. 
Statistical methods
Descriptive statistics and graphical displays.


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FLOW CHART
Flow Chart: Part 1 (Single dose)
Visit
Day
Planned time (relative to first 
drug administration 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood/plasma 
2, 9
PK urine 
5
PK faeces
4
12-lead ECG 
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy
1
-21 to -2
Screening (SCR)1
A
x
x
2
-1
-21:00
11:00
Admission to trial site
B13,17
x
1
-2:00
06:00
x3,8,16
x3
x3
x14
x3
x3
0:00
08:00
Drug administration (labelled 
compound)
▲
│
▲
│
0:20
08:20
x
│
│
0:40
08:40
x
│
│
1:00
09:00
x16
x
│
│
x
x
2:00
10:00
240 mL water intake
x
│
│
3:00
11:00
x
│
│
4:00
12:00
Lunch, 240 mL water intake6
x16
x
┼
│
x
x
6:00
14:00
x
│
│
8:00
16:00
x16
x
┼
│
10:00
18:00
Dinner6
x
│
│
12:00
20:00
Snack6
x
┼
│
x
x
2
24:00
08:00
x16,17
x
┼
┼
x
x
36:00
20:00
x
│
│
3
48:00
08:00
x
┼
┼
4
72:00
08:00
x
┼
┼
5
96:00
08:00
x
┼
┼
6
120:00
08:00
x
┼
┼
7
144:00
08:00
x
┼
┼
8
168:00
08:00
B8
┼
┼
x
x
9
192:00
08:00
x
┼
┼
10
216:00
08:00
┼
┼
11
240:00
08:00
x
┼
┼
12
264:00
08:00
┼
┼
13
288:00
08:00
x
┼
┼
14
312:00
08:00
┼
┼
15
336:00
08:00
Discharge from trial site15
B8
x
▼
▼
x
x


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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/plasma 
2, 9
PK urine
5
PK faeces
4
Vital signs (BP, PR), 
ECG
Questioning for AEs & 
concomitant medication
2
20
461:00
13:00
Start home collection10, 11
▲
┼
▼
21
485:00
13:00
Admission to trial site10
x16, 17
x
▲
▼
22
509:00
13:00
Discharge from trial site10
x
27
629:00
13:00
Start home collection10, 11
▲
┼
▼
28
653:00
13:00
Admission to trial site10
x16, 17
x
▲
▼
29
677:00
13:00
Discharge from trial site10
x
34
797:00
13:00
Start home collection10, 11
▲
┼
▼
35
821:00
13:00
Admission to trial site10
x16, 17
x
▲
▼
36
845:00
13:00
Discharge from trial site10
x
41
965:00
13:00
Start home collection10,11
▲
┼
▼
42
989:00
13:00
Admission to trial site10
x16, 17
x
▲
▼
43
1013:00
13:00
Discharge from trial site10
x
48
1133:00
13:00
Start home collection10. 11
▲
┼
▼
49
1157:00
13:00
Admission to trial site10
x16, 17
x
▲
▼
50
1181:00
13:00
Discharge from trial site10
x
3
16-50
End of trial (EOT) 
examination7,12,15
C17
x
x
A, B & C: safety laboratory sets (see Table 5.2.3: 1)
1.
Screening includes subject information, informed consent, physical examination, check of vital signs, ECG, safety 
laboratory (including drug and virus screening), 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.
Pharmacokinetics (PK): BI 1358894 and metabolites in plasma; [14C]-radioactivity in whole blood and plasma. At all 
time points, samples for [14C]-radioactivity in whole blood and plasma will be taken. Samples for PK assessment of cold 
BI 1358894 will be collected for al PK samples taken and for its metabolites in plasma which will be collected at the 
metabolite PK time points in the Flow Chart, after intake of radiolabelled drug on Day 1. PK sampling for the 
metabolites will continue as long as radioactivity in plasma is above LLOQ (< 30 dpm/mL)
3.
The time is approximate; the procedure is to be performed within a time window of 3 h prior to drug administration.
4.
All stools (for [14C]-radioactivity assessment 
 will be collected quantitatively from Day 1 in 
sampling intervals as defined in the Flow Chart after intake of [ C]  BI 1358894. Thereafter, if warranted, 24 h 
collections are to be performed on days 21-22, 28-29, 35-36, 42-43, and 49-50. A blank sample will be collected before 
drug administration on Day 1. Collection of the predose faeces sample will start from approximately -48 h before drug 
administration. Faeces sampling for [14C]-radioactivity assessment will be stopped when the release criteria for 
radioactivity recovery (Section 3.1) have been met (earliest stopping on day 15). “┼” means end of last collection 
interval, start of following collection interval. All samples: planned for determination of [14C]-radioactivity. 
5.
Urine collection intervals (for PK/[14C]-radioactivity assessment 
 (planned time): on Day -1 or 
Day 1 predose (blank) sample, on Day 1 prior to start of urine collection voiding of the bladder, and at the intervals
defined in the Flow Chart up to 336 h after drug administration. Thereafter, if warranted, 24 h collections are to be 
performed on days 21-22, 28-29, 35-36, 42-43, and 49-50. Urine sampling for PK will be stopped when release criteria 
for radioactivity recovery (Section 3.1) have been met (earliest stopping on day 15). “┼” means end of last collection 
interval, start of following collection interval. All samples: planned for determination of [14C]-radioactivity, BI 1358894 
and its metabolites. 
6.
If several actions are indicated at the same time point, the intake of meals will be the last action.


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7.
End-of-trial (EOT) examination to be performed within 1 to 7 days after last discharge from the study centre, or, if all 
once-weekly 24 h sampling periods are needed, prior to discharge on Day 50. EOT examination includes physical 
examination, vital signs, ECG, safety laboratory, recording of AEs and concomitant therapies, neurological examination 
and suicidality assessment (C-SSRS). 
8.
Subjects are to be fasted for at least 10 h before sample is taken.
9.
Blood sampling for an individual subject can be stopped if [14C]-radioactivity in plasma is below limit of detection 
(<LLOQ 30 dpm/mL) at two consecutive sampling time points for this subject.
10. The planned times for admission, discharge, start and end of the urine and faeces collection intervals are approximate. 
The procedures are to be performed within a time window of ± 4 h to the planned time. 
11. Subjects are to collect faeces at home within 24 h intervals before admission to once-weekly in-house collection 
intervals. Home collection intervals: Day 20-21, 27-28, 34-35, 41-42, and 48-49. If faeces are collected in the 
subsequent in-house collection interval, faeces collected at home will be discarded. If no faeces is collected in the 
subsequent in-house collection interval (no defecation), faeces collected at home will be used instead for analysis.
12. For definition of the individual subject’s end of trial see Section 6.2.3
13. Urine drug and alcohol screening will be done at this time point.
14. Subjects will collect a pre-dose faeces sample at home in specific containers provided by 
15. Confirmation of fitness includes physical and neurological examination, vital signs, ECG, suicidality assessment (C-
SSRS) only at Day 15 and EOT, recordings of AEs and concomitant therapies as well as evaluation of safety laboratory 
assessed on Day 8.
16. At this time point, only a sample for haematocrit measurement is taken.
17. PCR testing for SARS-CoV-2 will be performed at admission on Day – 1, on Day 2, at each admission to the trial site
for the 24-h visits and at EOT.


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Flow Chart: Part 2 (Multiple dose)
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment 
Safety laboratory
PKplasma 
2, 9
PK urine
5
12-lead ECG 
Vital signs (BP, PR)
Questioning for AEs & 
concomitant medication 
1
-21 to -2
Screening (SCR)1
A
x
x
x
2
-1
-21:00
11:00
Admission to trial site
B10, 11
x
1
-2:00
06:00
x3
x3
x3
x3
-0:30
07:30
Standard continental breakfast
0:00
08:00
Drug administration
0:30
08:30
x
1:00
09:00
x
2:00
10:00
x
4:00
12:00
Lunch6
x
5:00
13:00
x
6:00
14:00
x
7:00
15:00
x
8:00
16:00
x
10:00
18:00
Dinner6
x
12:00
20:00
Snack6
x
14:00
22:00
x
2
24:00
08:00
Drug administration12
x11
x3
x3
3
48:00
08:00
Drug administration12
4
72:00
08:00
Drug administration12
5
96:00
08:00
Drug administration12
6
120:00
08:00
Drug administration12
7
144:00
08:00
Drug administration12
B8
x3
x3
x3
x3
144:30
08:30
x
145:00
09:00
x
146:00
10:00
x
148:00
12:00
Lunch6
x
149:00
13:00
x
150:00
14:00
x
151:00
15:00
x
152:00
16:00
x
154:00
18:00
Dinner6
x
156:00
20:00
Snack6
x
158:00
22:00
x
8
168:00
08:00
Drug administration12
x3
9
192:00
08:00
Drug administration12
x3
x3
10
216:00
08:00
Drug administration12
11
240:00
08:00
Drug administration12
x3
x3
12
264:00
08:00
Drug administration12
13
288:00
08:00
Drug administration12
14
312:00
08:00
Drug administration12
B8
x3
x3
x3
x3
312:30
08:30
x
313:00
09:00
x
314:00
10:00
x
316:00
12:00
Lunch6
x
317:00
13:00
x


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Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment 
Safety laboratory
PKplasma 
2, 9
PK urine
5
12-lead ECG 
Vital signs (BP, PR)
Questioning for AEs & 
concomitant medication 
318:00
14:00
x
319:00
15:00
x
320:00
16:00
x
322:00
18:00
Dinner6
x
324:00
20:00
Snack6
x
326:00
22:00
x
15
336:00
08:00
Drug administration12
x3
x3
16
360:00
08:00
Drug administration12
17
384:00
08:00
Drug administration12
x3
x3
18
408:00
08:00
Drug administration12
19
432:00
08:00
Drug administration12
x3
x3
20
456:00
08:00
Drug administration12
21
480:00
08:00
Drug administration12
B8
x3
x3
x3
x3
480:30
08:30
x
481:00
09:00
x
482:00
10:00
x
484:00
12:00
Lunch6
x
485:00
13:00
x
486:00
14:00
x
487:00
15:00
x
488:00
16:00
x
490:00
18:00
Dinner6
x
492:00
20:00
Snack6
x
494:00
22:00
x
22
504:00
08:00
x
23
528:00
08:00
x
25
576:00
08:00
x
27
624:00
08:00
Breakfast6 (voluntary), 
Discharge from trial site after 
confirmation of fitness4
B8
x
x
x
30
696:00
08:00
Ambulatory visit
x
x
34
792:00
08:00
Ambulatory visit
x
x
37
864:00
08:00
Ambulatory visit
x
x
41
960:00
08:00
Ambulatory visit
x
x
44
1032:00
08:00
Ambulatory visit
x
x
48
1128:00
08:00
Ambulatory visit
x
x
51
1200:00
08:00
Ambulatory visit
x
x
55
1296:00
08:00
Ambulatory visit
x
x
58
1368:00
08:00
Ambulatory visit
x
x
3
62
End of trial (EOT) examination7,9
C11
x
x
x
x
A, B & C: safety laboratory sets (see Table 5.2.3: 1)
1.
Screening includes subject information, informed consent, physical examination, check of vital signs, ECG, safety 
laboratory (including drug and virus screening), demographics (including determination of body height and weight, 
smoking status and alcohol history), relevant medical history, concomitant therapy, review of inclusion/exclusion 
criteria, neurological examination and suicidality assessment (C-SSRS).
2.
Pharmacokinetics (PK): BI 1358894 and metabolite(s) in plasma.


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3.
The time is approximate; the procedure is to be performed within a time window of 3 h prior to drug administration.
4.
Confirmation of fitness includes physical and neurological examination, vital signs, ECG, suicidality assessment (C-
SSRS), recordings of AEs and concomitant therapies as well as evaluation of safety laboratory assessed on Day 21.
5.
Urine collection (for PK assessment 
planned time): A predose urine sample collected and stored 
on Day -1 or Day 1 predose will serve as blank sample. Urine collection is to be performed as described in the Flow 
Chart. 
6.
If several actions are indicated at the same time point, the intake of meals will be the last action.
7.
End-of-trial (EOT) examination includes physical examination, vital signs, ECG, safety laboratory, recording of AEs and 
concomitant therapies, neurological examination and suicidality assessment (C-SSRS). The EOT assessments will be 
performed after the last PK sample on Day 62 has been taken.
8.
Subjects are to be fasted for at least 10 h before sample is taken.
9.
For definition of the individual subject’s end of trial see Section 6.2.3
10. Urine drug and alcohol screening will be done at this time point.
11. PCR testing for SARS-CoV-2 will be performed at admission on Day – 1, on Day 2 and at EOT.
12. A standard continental breakfast will be provided approx. 30 min prior to each daily drug administration from Day 1 to 
Day 21.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ................................................................................ 11
ABBREVIATIONS.......................................................................................... 15
1.
INTRODUCTION.................................................................................... 18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE...............................................................................................19
1.2.1
BI 1358894 .............................................................................................19
1.2.2
Residual Effect Period..........................................................................22
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
1.4
BENEFIT - RISK ASSESSMENT ...................................................................22
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 24
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......24
2.1.1
Main objectives......................................................................................24
2.1.2
Primary endpoints ................................................................................24
2.1.3
Secondary endpoints.............................................................................24
2.2.2.4
Safety and tolerability..............................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................30
3.3.1
Main diagnosis for trial entry ..............................................................30
3.3.2
Inclusion criteria...................................................................................30
3.3.3
Exclusion criteria ..................................................................................31
3.3.4
Withdrawal of subjects from treatment or assessments ...................33
3.3.4.1
Discontinuation of trial treatment ............................................33
3.3.4.2
Withdrawal of consent to trial participation ............................34
3.3.4.3
Discontinuation of the trial by the sponsor..............................34
3.3.5
Replacement of subjects .......................................................................34


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4.
TREATMENTS........................................................................................ 35
4.1
INVESTIGATIONAL TREATMENTS ..........................................................35
4.1.1
Identity of the Investigational Medicinal Products ...........................35
4.1.2
Selection of doses in the trial................................................................36
4.1.3
Method of assigning subjects to treatment groups ............................36
4.1.4
Drug assignment and administration of doses for each subject .......36
4.1.5
Blinding and procedures for unblinding ............................................37
4.1.6
Packaging, labelling, and re-supply ....................................................37
4.1.7
Storage conditions.................................................................................37
4.1.8
Drug accountability ..............................................................................38
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................38
4.2.1
Other treatments and emergency procedures....................................38
4.2.2
Restrictions............................................................................................38
4.2.2.1
Restrictions regarding concomitant treatment .........................38
4.2.2.2
Restrictions on diet and life style.............................................39
4.3
TREATMENT COMPLIANCE.......................................................................39
5.
ASSESSMENTS....................................................................................... 40
5.1
ASSESSMENT OF EFFICACY.......................................................................40
5.2
ASSESSMENT OF SAFETY............................................................................40
5.2.1
Physical examination ............................................................................40
5.2.2
Vital signs...............................................................................................40
5.2.3
Safety laboratory parameters ..............................................................40
5.2.4
Electrocardiogram................................................................................43
5.2.5
Other safety parameters.......................................................................44
5.2.5.1
Suicidality assessment .............................................................44
5.2.5.2
Neurological examination........................................................45
5.2.6
Assessment of adverse events...............................................................45
5.2.6.1
Definitions of adverse events...................................................45
Adverse event ............................................................45
5.2.6.1.1
Serious adverse event ................................................46
5.2.6.1.2
AEs considered ‘Always Serious’.............................46
5.2.6.1.3
Adverse events of special interest .............................46
5.2.6.1.4
Intensity (severity) of AEs.........................................47
5.2.6.1.5
Causal relationship of AEs ........................................47
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................48
AE collection.............................................................48
5.2.6.2.1
AE reporting to the sponsor and timelines ................49
5.2.6.2.2
Information required..................................................49
5.2.6.2.3
Pregnancy ..................................................................49
5.2.6.2.4
5.2.6.3
Collection and reporting of the adverse event headache .........49
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................50


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5.3.1
Assessment of pharmacokinetics .........................................................50
5.3.2
Methods of sample collection for Part 1 .............................................50
5.3.2.1
Sampling of whole blood and plasma......................................50
5.3.2.4
Sampling of urine.....................................................................51
5.3.2.5
Sampling of faeces...................................................................52
5.3.2.6
Collection of vomit ..................................................................52
5.3.3
Methods of sample collection for Part 2 .............................................52
5.3.3.1
Sampling of plasma..................................................................52
5.3.3.2
Sampling of urine.....................................................................53
5.3.5
Pharmacokinetic - pharmacodynamic relationship...........................54
5.4
ASSESSMENT OF BIOMARKER..................................................................54
5.5
BIOBANKING ...................................................................................................54
5.6
OTHER ASSESSMENTS .................................................................................54
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................54
6.
INVESTIGATIONAL PLAN.................................................................. 55
6.1
VISIT SCHEDULE............................................................................................55
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................55
6.2.1
Screening period....................................................................................55
6.2.2
Treatment periods.................................................................................56
6.2.3
Follow-up period and trial completion ...............................................56
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 57
7.1
STATISTICAL DESIGN – MODEL ...............................................................57
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................57
7.3
PLANNED ANALYSES....................................................................................57
7.3.1
Primary endpoint analyses...................................................................58
7.3.2
Secondary endpoint analyses ...............................................................58
7.3.4
Safety analyses.......................................................................................58


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7.4
INTERIM ANALYSES .....................................................................................59
7.5
HANDLING OF MISSING DATA ..................................................................60
7.5.1
Safety......................................................................................................60
7.5.2
Pharmacokinetics..................................................................................60
7.6
RANDOMISATION ..........................................................................................60
7.7
DETERMINATION OF SAMPLE SIZE ........................................................60
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 61
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................61
8.2
DATA QUALITY ASSURANCE .....................................................................62
8.3
RECORDS..........................................................................................................62
8.3.1
Source documents .................................................................................62
8.3.2
Direct access to source data and documents.......................................63
8.3.3
Storage period of records.....................................................................63
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................63
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......63
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................64
8.6
TRIAL MILESTONES .....................................................................................64
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................65
9.
REFERENCES......................................................................................... 66
9.1
PUBLISHED REFERENCES...........................................................................66
9.2
UNPUBLISHED REFERENCES.....................................................................67
10. APPENDICES .......................................................................................... 68
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)...............68
10.1.1 Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening ................................................................................68
10.1.2 Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last 
Visit
..................................................................................................71
10.2
RADIATION BURDEN CALCULATION .....................................................74
10.3
COVID-19 SITE SPECIFIC MEASURES......................................................77
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 81
11.1
GLOBAL AMENDMENT 1 .............................................................................81


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
Aefaeces, t1-t2
Amount of analyte eliminated in faeces over the time interval t1 to t2
Aefaeces, 0-t2
Amount of analyte eliminated in faeces from time 0 to the last quantifiable 
timepoint
Aeurine, t1-t2
Amount of analyte eliminated in urine over the time interval t1 to t2
Aeurine, 0-t2
Amount of analyte eliminated in urine from time 0 to the last quantifiable 
timepoint
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ
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
BCRP
Breast cancer resistance protein
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BPD
Borderline Personality Disorder
CA
Competent authority
CI
Confidence interval
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
CLR, t1-t2
Renal clearance of the analyte in plasma from the time point t1 to t2
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady-state
over a uniform dosing interval τ
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTM
Clinical Trial Manager
CTP
Clinical trial protocol


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CTR
Clinical trial report
Cum Ae
Cumulative recovery of [14C]-radioactivity
Cum %Ae
Cumulative recovery of [14C]-radioactivity expressed as a percentage of 
the dose
CYP3A4
Cytochrome P450 3A4
DG
Dose Group
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
fefaeces, t1-t2
Fraction of administered drug excreted unchanged in urine over the time 
interval from t1 to t2
feurine, t1-t2
Fraction of administered drug excreted unchanged in the faeces over the 
time interval from t1 to t2
FIM
First-in-Man
FU
Follow-up
GCP
Good Clinical Practice
GI
Gastro-intestinal
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
iPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
MDA
Methylenedioxyamphetamine
MDD
Major Deperessive Disorder
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
MRT,ex
Mean residence time of the analyte in the body, extravascular
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)


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PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QD
Once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected unexpected serious adverse reaction
T
Test product or treatment
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
XTC
Ecstasy 


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1.
INTRODUCTION
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) and borderline personality disorder (BPD). BI 1358894 has 
been characterised to be an inhibitor of P-glycoprotein (P-gp), Breast cancer resistance 
protein (BCRP) and of the Organic anion transporting polypeptides (OATP) 1B1 and 1B3 
in-vitro. This trial should investigate the basic pharmacokinetics, excretion pathways and 
metabolism of BI 1358894 and its metabolites.
1.1
MEDICAL BACKGROUND
Major depressive disorder is a debilitating disease characterised by low mood and often by 
low self-esteem, low energy, and a loss of interest. It can strongly impact a person’s life and 
health, including significantly increased risk of suicidality, and is difficult to treat, even with 
systematic antidepressant strategies. In the National Institute of Mental Health funded 
STAR*D trial of >4000 patients with nonpsychotic depression, about 30% of the patients did 
not reach remission after 4 different medications [P06-11895] and continued to experience 
residual symptoms [R16-5475] that significantly impacted the patients’ quality of life 
[R06-2872]. When monotherapy is insufficient, clinicians employ different augmentation 
strategies including add-on treatment with lithium or atypical antipsychotics. When 
augmentation strategies also fail, convulsive therapies such as electro-convulsive therapy 
may be used.
Borderline personality disorder (BPD) is a chronic mental disorder with an estimated 
prevalence of around 2% in the general community [R16-5476] and severely impaired quality 
of life [R16-5474]. The main symptom clusters of BPD include impulsive-behavioural 
dyscontrol, cognitive-perceptual symptoms, disturbed interpersonal relations, and affective 
instability. Patients with BPD have high rates of deliberate self-harm and a rate of completed 
suicide that is 50 times higher than in the general population [R16-5477]. Even the presence 
of a single diagnostic feature of BPD is predictive for poor functioning and psychiatric illness 
burden [R16-5483]. Treatment guidelines recommend psychotherapy as the mainstay of 
treatment, but pharmacotherapy is commonly used as an adjunctive, symptom-targeted 
component of treatment. However, no drug is approved for the treatment of BPD.
TRPC4 and TRPC5 form ion channels that are involved in the regulation of neuronal 
excitability. They are most highly expressed in the amygdala, frontal cortex, hippocampus, 
and hypothalamus [R15-3888, R16-5350], which are involved in modulation and processing 
of emotion and affect. Pre-clinically, treatment with BI 1358894 has shown diminished fear 
and anxiety and increased social interaction without impairing other brain functions such as 
learning and memory behaviours.
It is hypothesized that in patients with affective disorders, an overactive amygdala is a major 
contributor to attentional bias to negative stimuli, pessimistic thoughts, and anxiety 
[R16-5473] and there is growing evidence supporting the role of amygdala in the emotion 
processing disturbances observed in patients with BPD [R16-5472]. Therefore, treatment 
with BI 1358894 has the potential to improve affective symptoms and emotion control in 
patients with MDD and BPD.


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1.2
DRUG PROFILE
1.2.1
BI 1358894
For a detailed description of the BI 1358894 profile, please refer to the current Investigator’s 
Brochure (IB) [c10354149].
Pharmacokinetics in Humans
Human PK data are currently available from the FIM study 1402-0001, which consisted of an 
SRD part (tested doses: 3 mg – 200 mg BI 1358894) and of a food effect part (tested doses: 
50 mg and 100 mg BI 1358894 under fasted and fed conditions) [c24903142].
Following oral administration of film-coated tablets in fasted state BI 1358894 reached 
maximum plasma concentrations after 1 to 5 hours. Thereafter BI 1358894 plasma 
concentrations declined in a multiphasic fashion implying multi-compartmental distribution 
and exhibited a long terminal phase, which seems to be dose-independent.
Cmax, AUC0-72 and AUC0-∞of BI 1358894 increased in a dose dependent way. Preliminary 
statistical evaluation showed that the increase in Cmax and AUC0-72 was less than dose 
proportional. AUC0-∞increased slightly less than dose proportional when given without food.
Also the food effect was dependent on the administered dose. While the exposure of 
BI 1358894 increased by factor 1.6 for the 50 mg dose, a food effect of factor 2.5 was 
observed for the 100 mg dose.
After completion of the food effect assessment, a dose of 200 mg BI 1358894 has been given 
after a high-calorie, high-fat meal in the SRD part of 1402-0001 [c24903142]. Compared to 
the cohort receiving 200 mg under fasted conditions, food increased exposure by about 
2.4-fold (exposure of 200 mg BI 1358894, fed conditions: Cmax = 857 nM, AUC0-24 = 
11640 nM*h).
Based on PK data of previous dose groups (DGs) in the 200 mg fed DG PK blood sampling 
was extended to 672 h. Sampling from 240 h to 672 h revealed another phase with low 
plasma concentrations and long terminal half-life of about 200 h. The proportion of AUC 
beyond 192 h is less than 20% of total AUC. Hence, it is not expected that this phase 
markedly contributes to accumulation or steady state attainment.
Preliminary PK data from the MRD study 1402-0002 [c28667517] support this observation. 
In the first dose groups (10 mg and 25 mg), an accumulation ratio (based on AUC0-24) of 2.5 
was observed. Steady state seems to be achieved after about 2 weeks. Both accumulation 
ratio and approximation of steady state attainment are in line with an effective half-life of 
~ 50 to 70 h.
Safety and tolerability in healthy subjects
At the time of preparing this trial protocol, seven Phase I trials with administration of 
BI 1358894 to approximately 217 healthy subjects and 73 MDD patients have been 
conducted. Preliminary data on safety and tolerability observed in these trials are given 
below:


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1402-0001, SRD-part: In the SRD-part of the 1402-0001 study [c24903142], safety, 
tolerability, PK and PD of rising single doses of BI 1358894 has been investigated in 8 DGs 
(3 mg – 6 mg – 10 mg – 25 mg – 50 mg – 100 mg – 200 mg fasted – 200 mg fed) with 
planned 8 subjects (6 on active, 2 on placebo). The most frequent drug related AE was 
headache, which has been reported by 18 of 48 subjects on active treatment. While headache 
occurred in 50% of subjects on active treatment in DG 2 and in DG 5-8, it was reported by 
only 1 subject in DG 1 and by 2 subjects in DG 4. The intensity of headache was mild (16 x) 
to moderate (2 x). The two cases of moderate headache have been observed in DG 5 and 7.
Beyond headache the following drug-related AEs have been observed (each in 1 subject 
only): delayed auditive perception, dizziness, head pressure, back pain, lightheadedness, 
tiredness and loss of concentration. These AEs were of mild to moderate intensity.
1402-0001, food effect part: This part of the 1402-0001 study [c24903142] investigated the 
effect of food on the kinetics of 50 mg (N=8) and 100 mg (N=12) BI 1358894, given as a 
single dose in two trial periods. The most frequent drug related AE was headache, which has 
been reported by 15 of 20 subjects (in nine subjects drug related headache occurred in both 
trial periods).
Beyond headache the following drug-related AEs have been observed: dizziness (5 subjects), 
tiredness (3 subjects), lightheadedness (2 subjects), loss of concentration (2 subjects), and 
meteorism, back pain, intermittent hip pain, head pressure, exacerbation of face acne and skin 
irritation with itching at the whole body (1 subject each). All drug related AEs were of mild 
or moderate intensity.
1402-0002, MRD-study: Trial 1402-0002 [c28667517] investigated safety, tolerability, PK 
and PD of rising multiple doses BI 1358894 (administered over 14 days) in a double-blinded 
fashion in a total of five DGs (10 mg, 25 mg, 50 mg, 100 mg and 200 mg) with a total of 
50 subjects (40 on active, 10 on placebo) has been already finished.
Overall, the most frequent drug related AE is headache which has been reported by 17 of 
40 subjects. Frequency of drug related headache was not dose-dependent and was even less 
frequent in higher DGs (50 mg, 100 mg). Drug-related headache was mainly of mild 
intensity. Moderate intensity has been reported only for three subjects in DG 2 (2 x) and 
DG 4 (1 x).
In the 25 mg DG seven from ten subjects reported drug related headache. In four cases the 
affected subjects suffered from intermittent headache that lasted over 9-12 days. In one 
subject this was accompanied by drug related nausea on Day 6 and 9. Due to this continuous 
impairment the subject withdrew informed consent prior to dosing on Day 10.
Beyond headache the following drug-related AEs have been observed: orthostatic 
dysregulation (6 subjects), dizziness (5 subjects), tiredness (3 subjects), heartburn (2 subjects) 
and stomach cramps, blurred vision, acneiform skin (face), nausea, loose stool, flatulence, 
decreased concentration, head pressure, fasciculation (finger), and pressure on both eyes 
(1 subject each). These AEs were of mild intensity and did not follow a specific pattern of 
distribution.
1402-0003: Trial 1402-0003 [c28123801] investigated the effect of a single dose of 
BI 1358894 compared to placebo on BOLD responses in modulation brain processing of 
emotional and cognitive stimuli on the amygdala and related brain structure using fMRI in 


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unmedicated patients with depression in a randomized, placebo-controlled, parallel-group 
study. Overall, 73 patients with MDD (males and females) were treated either with 
BI 1358894 (25 patients), with citalopram (24 patients) used as a positive control, or placebo 
(24 patients).
The overall summary showed that there were no deaths and SAEs. There were also no reports
of AESIs, severe AEs, AEs leading to discontinuation of trial drug, or other significant AEs.
The frequency of patients with any AEs was higher in the BI 1358894 treatment group 
(23 patients) than in the citalopram (15 patients) and placebo (14 patients) groups. The most
common AE was headache. In the BI 1358894 treatment group, headache was reported by 
17 patients compared with 13 patients in the citalopram and 10 patients in the placebo groups.
Overall safety results from trial 1402-0003 [c28123801] are in line with the safety results of 
Phase I trials.
1402-0005: Trial 1402-0005 [c28698771] investigated the pharmacodynamic effects of a 
single dose of BI 1358894 on CCK-4 induced anxiogenic/panic-like symptoms using the 
Panic Symptom Scale (PSS) in preselected CCK-4 sensitive healthy volunteers in a double-
blind, randomized, placebo-controlled, crossover study. In this trial, 20 patients were treated 
with a single dose of 100 mg BI 1358894 and placebo (10 patients in the sequence 
BI 1358894, placebo; 10 patients in the sequence placebo, BI 1358894).
The overall summary showed that there were no deaths and SAEs. There were also no reports
of AESIs, AEs leading to discontinuation of trial drug, or other significant AEs. The most
common AE was headache and was most frequently reported in the BI 1358894 treatment
group (10 subjects) than in the placebo group (1 subject). 
Overall, the results of Trial 1402-0005 [c28698771] are in line with the pooled safety 
analysis of Phase I trials.
1402-0007: Trial 1402-0007 [c28714279] investigated the effect of the CYP3A4 inhibitor 
itraconazole on the kinetics of the CYP3A4 substrate BI 1358894 in 16 healthy subjects. A 
single dose of 10 mg BI 1358894 has been given alone and together with multiple doses of 
itraconazole. The most frequent drug related AE was headache reported by five subjects. In 
one case headache was of severe intensity. All subjects completed the trial.
1402-0009: Trial 1402-0009 investigated the relative bioavailability of rosuvastatin (Part 1) 
and dabigatran (Part 2) given alone and together with BI 1358894 in 28 healthy male subjects 
(14 in each part). Final results are not yet available at the time of CTA, however no safety 
findings in conflict with previous observations were reported.
1402-0010: Trial 1402-0010 [c28907328] investigated the relative bioavailability of different 
trial formulations of BI 1358894. The 24 participating subjects had to undergo three 
treatment periods. In each trial period a single dose of 100 mg BI 1358894 has been 
administered. The most frequent drug related adverse event was headache, that has been 
reported by about 50% of subjects. Drug related dizziness and tiredness was reported by two 
subjects each. All drug related adverse events were of mild or moderate intensity.
For a more detailed description of BI 1358894, please refer to the current Investigator’s 
Brochure (IB) [c10354149].


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1.2.2
Residual Effect Period
Based on an effective half-life of 50 to 70 h the Residual Effect Period (REP) of BI 1358894 
has been determined to be 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
This trial is intended to examine the metabolism in humans, the mass-balance of excretion, 
plasma and urinary concentrations of BI 1358894 and its metabolites, total radioactivity in 
blood, plasma, urine and faeces and the resulting PK parameters after single dosing. Major 
tasks involve the structure elucidation of metabolites as well as the [14C]-radioactivity in 
blood cells, plasma, urine and faeces. This study will also help to determine the metabolic 
pathways following oral administration of [14C] BI 1358894 and BI 1358894. The second 
part of the study is intended to investigate the pharmacokinetics of BI 1358895 and its 
metabolite(s) following multiple oral administration of 100 mg BI 1358894 in healthy 
volunteers.
The data are necessary for in-depth understanding of the pharmacokinetics of BI 1358894 
including quantitative determination of elimination pathways and drug metabolites and are 
required for submission to regulatory authorities.
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 of the compound. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
The single dose administration of up to 200 mg BI 1358894 under fasted and fed conditions 
has been well tolerated by healthy subjects in the single rising dose trial 1402-0010 
[c28907328] as well as the single dose administration of 100 mg under fasted and fed 
administration in the relative bioavailability trial 1402-0010 [c28907328]. In addition, the 
multiple dose administration of up to 200 mg BI 1358894, once daily for 14 days was also 
well tolerated [c28667517]). There were no deaths or other serious adverse events. Adverse 
events, mostly reported as mild, had no apparent dose or exposure relationship. In view of the 
non-proportional increase of exposure there is an acceptable safety margin between the 


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highest exposure observed in preceding phase I studies and the exposure at 100 mg of 
BI 1358894 q.d. in the planned study. Therefore no undue risk is expected from the single 
dose and multiple dose administration of 100 mg BI 1358894 to healthy subjects planned for 
this trial. A more detailed description of BI 1358894 tolerability in healthy subjects can be 
found in Section 1.2.1.
Drug-induced liver injury (DILI)
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.6.1.4, adverse events of special interest.
Administration of 14C-marked BI 1358894 in Part 1
[14C] BI 1358894 is labelled with the isotope [14C] which is necessary for the purposes of this
mass balance trial. Therefore, subjects will be exposed to ionizing radiation. The effective
dose that each subject receives from one administration of 3.7 MBq is approximately 
0.51 mSv (see Appendix 10.2). For biomedical investigations in small groups of healthy 
volunteers, an effective dose ≤ 1.0 mSv is considered acceptable.
Summary of benefit-risk assessment
In a previous trial in healthy volunteers, single oral doses up to 200 mg BI 1358894 and 
multiple oral doses up to 200 mg BI 1358894 administered once daily over 14 days were safe 
and well-tolerated. In the current trial, either a single oral dose or multiple oral doses of 
100 mg BI 1358894, once daily over 21 days, will be administered to healthy male subjects 
which will provide an appropriate safety margin to the highest dose safely tested in the 
MRD [c28667517]. In addition, the subjects will stay at the trial site under close medical 
surveillance until Day 15 in the single dose part and until Day 27 in the multiple dose part.
In Part 1, each participant will receive a single dose of [14C]-radiolabelled BI 1358894.The 
risk associated with the expected maximal radiation burden falls in ICRP category 2a with
minor level risk. This is considered to be acceptable.
The trial design is optimized to collect as much relevant information as possible on the
pharmacokinetics of BI 1358894 without exposing participating volunteers to undue risk.
However, there is always the potential of serious adverse events (SAEs) occurring with intake
of trial medication. Risks to subjects will be minimized and addressed by eligibility criteria,
safety laboratory examinations, ECG and vital sign measurements, in-house observation
periods and verbal communication concerning AEs.
If the investigator should have any clinical concern, the safety of the subjects will be of
paramount importance. The investigator has the discretion to remove subjects from the study
should there be any safety concerns or if the subject’s wellbeing is at jeopardy.
The risk to participating subjects is minimized and justified when compared to the potential
benefit that a successful clinical development of BI 1358894 could provide to the treatment
of major depressive disorder and borderline personality disorder.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the basic pharmacokinetics of BI 1358894
and its metabolites, total radioactivity, including mass balance, excretion pathways and 
metabolism following a single oral dose of 100 mg [14C] BI 1358894 in Part 1 and to 
investigate the pharmacokinetics of BI 1358894 and its metabolite(s) following multiple-dose 
treatment over 21 days with non- radiolabelled compound at a dose of 100 mg of BI 1358894 
QD in Part 2.
2.1.2
Primary endpoints
Part 1:
The following pharmacokinetic parameters will be determined for BI 1358894:

Mass balance recoveries of [14C] BI 1358894 total radioactivity in urine and faeces 
after single oral dose

Amount of radioactivity excreted as a percentage of the administered dose (fe0-t2) for 
urine and faeces
2.1.3
Secondary endpoints
Part 1:
The following pharmacokinetic parameters will be determined for total [14C] BI 1358894 and 
BI 1358894 after single dose administration:

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)

Cmax (maximum measured concentration of the analyte in plasma)
Part 2:
The following pharmacokinetic parameters will be determined for BI 1358894:

AUC0-24 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24)

Cmax (maximum measured concentration of the analyte in plasma)

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)


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
Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)


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2.2.2.4
Safety and tolerability
Safety and tolerability of BI 1358894 will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Suicidality assessment (C-SSRS)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as an open-label, single arm and single- or multiple dose trial in 
healthy male subjects in order to investigate the basic pharmacokinetics of BI 1358894, [14C]-
radioactivity, including mass balance, excretion pathways and metabolism following a single 
oral dose of [14C] BI 1358894 in Part 1 and to investigate the pharmacokinetics of BI 
1358894 and its metabolite(s) following multiple oral doses of 100 mg BI 1358894 
administered as film-coated tablets in Part 2.
Part 1:
The planned radioactive dose per subject is 3.7 MBq (100 µCi).The [14C] labelled drug will 
be administered on Day 1. Subjects will remain at the study site from admission on Day – 1 
up to discharge on Day 15 following the fulfilment of release criteria. Subjects will then be 
readmitted to the study centre for 24 h collection intervals of urine and faeces on Days 21, 28, 
35, 42 and 49, if release criteria have not been met. Within 24 h before each of these once 
weekly in-house collection intervals, subjects are to collect faeces at home. This 24-h interval 
home collection faeces will be used for analysis in case no defecation occurs in the 
subsequent 24 h in-house collection interval.
For determination of whether release criteria have been reached for individual subjects, [14C]-
radioactivity will be measured in excreta (urine and faeces). The actual recovery results will 
be reported as a percentage of the administered dose.
If one of the following release criteria is true (i.e., release criteria have been met), 24 h 
collection intervals after Day 15 will not be performed any longer/will be stopped:
-
Greater than or equal to 90% of the administered dose has been recovered in urine and 
faeces combined over the investigational period, or
-
If <1% of the dose administered has been collected in urine and faeces within 2 
separate, consecutive 24 h intervals, and
-
Concentration of total radioactivity in plasma <5% of Cmax of total radioactivity in 
plasma
If the mass balance recovery is less than 90% on Day 15, subjects will still be asked to return 
to the clinic for 24 h collection of urine and faeces on Days 21, 28, 35, 42 and 49 or until the 
recovery is deemed to be sufficient for mass balance purposes. If a subject is unable to attend 
one of these visits, they may be allowed to reschedule the visit if needed.
Irrespective of whether release criteria have been met or not after collection interval Day 49-
50, no further collections are planned.
Part 2:
Non-radiolabelled compound will be administered at the site from Day 1 to Day 21. Subjects 
will remain at the study site from admission on Day – 1 up to discharge on Day 27.
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.


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This is a standard design for a [14C]-human study for investigation of absorption, distribution,
metabolism, and excretion including determination of mass balance. Inclusion of a control
groups is not required for this investigation.
The elimination of BI 1358894 is multiphasic, therefore it cannot be excluded that prolonged 
sampling is necessary in humans. Hence, following in-house excreta collection after 
radioactive dosing on Day 1, subjects will return on a weekly basis for in-house 24 h 
collection intervals for up to 7 weeks after last dosing as long as release criteria are not met 
(Section 3.1).
Part 2 is a standard design for a multiple dose study in order to characterise the 
pharmacokinetics of BI 1358894 and its metabolite(s) with validated LC-MS methods over a 
longer time period and under well controlled conditions in healthy volunteers.
Blinding is not necessary, because all subjects receive the same dose per study part.
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma and urine concentrations of the analyte, which are provided by 
a bioanalytical laboratory.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy male subjects (8 in each Part) will enter the study. They will be 
recruited from the volunteers' pool of the trial site or, if necessary, via external databases and 
advertisements.
Only healthy male subjects will be included in this trial because they are an ideal population 
for the objectives of this trial, since they provide relatively stable physiological, biochemical 
and hormonal conditions, i.e. the absence of disease-related variations and relevant 
concomitant medications.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1.
Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests
2.
Age of 18 to 65 years (inclusive)


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3.
BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4.
Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5.
Male subjects who meet any of the following criteria from screening until 90 days after 
trial completion:
-
Use of adequate contraception of the female partner, e.g. any of the following
methods plus condom: implants, injectables, combined oral or vaginal 
contraceptives, intrauterine device that started at least two months prior to first 
study drug administration or barrier method (e.g. diaphragm with spermicide) or,
-
Sexually abstinent or,
-
A vasectomy performed at least 1 year prior to screening (with medical 
assessment of the surgical success) or,
-
Surgically sterilised female partner (including hysterectomy, bilateral tubal 
occlusion, or bilateral oophorectomy) or,
-
Postmenopausal female partner, defined as at least 1 year of spontaneous 
amenorrhea (in questionable cases a blood sample with levels of FSH above 
40 U/L and estradiol below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1.
Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2.
Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 40 to 100 bpm
3.
Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4.
C-reactive protein (CRP) > upper limit of normal (ULN), liver or kidney parameter 
above ULN
5.
Any evidence of a concomitant disease assessed as clinically relevant by the investigator
6.
Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or
hormonal disorders
7.
Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy or simple hernia 
repair)
8.
Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
9.
History of relevant orthostatic hypotension, fainting spells, or blackouts
10. Chronic or relevant acute infections
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication
or its excipients)


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12. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
13. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
15. Inability to refrain from smoking on specified trial days
16. Alcohol abuse (average consumption of more than 21 units per week)
17. Drug abuse or positive drug screening
18. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
19. Intention to perform excessive physical activities within 4 days prior to the 
administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
22. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
24. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
25. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
For Part 1 only:
26. Participation in another ADME study with a radiation burden of >0.1 mSv in the period 
of 1 year prior to screening
27. Exposure to radiation for diagnostic reasons (except dental X-rays and plain X-rays of 
thorax and bony skeleton (excluding spinal column)) in the period of 1 year prior to 
screening
28. Irregular defecation pattern (less than a mean of one bowel movement every 1 or 2 days)
In addition, the following SARS-CoV-2 specific exclusion criterion apply:
29. A positive test indicating an ongoing infection with SARS-CoV-2 and clinical symptoms 
suggestive of the disease.
For study restrictions, refer to Section 4.2.2.


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3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1.
The subject wants to discontinue trial treatment, without the need to justify the decision
2.
The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3.
The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4.
The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5.
The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
6.
The subject shows a raised CRP level of >30.0 mg/L
7.
An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP<90/50 mmHg) or hypertension 
(BP>180/100 mmHg) or of clinically relevant changes in ECG requiring intervention as 
well as unexplained liver enzyme elevations at any time during the trial.
8.
The subject experiences a serious adverse reaction which is considered at least possibly 
related to the IMP administration
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.


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


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Radiolabelled BI 1358894 (test product 1) is administered as oral solution. The oral solution 
contains a mixture of [14C]-radiolabelled BI 1358894 and non-radiolabelled BI 1358894 and 
is manufactured by BI Pharma GmbH & Co. KG. The solution from this mixture is made by 
Non-radiolabelled film coated tablets of BI 1358894 (test product 2) 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:
Test product 1
Name:
[14C] BI 1358894 oral solution
Substance:
BI 1358894 mixed with [14C] BI 1358894
Pharmaceutical formulation: Oral solution
Source:
Unit strength:
100 mg
- Containing [14C]-radiolabelled BI 1358894 corresponding to a 
radioactive dose of 3.7 MBq (100 µCi)
- In a solution of 10 mL volume (concentration of BI 1358894 
10 mg/mL)
Posology:
1-0-0
Route of administration:
oral
Duration of use:
Single dose
Test product 2
Substance:
BI 1358894
Pharmaceutical formulation: Film-coated tablet (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:
21 days


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4.1.2
Selection of doses in the trial
The dose selected for this trial is one of the standard clinical doses (see Section 1.2).
The dose of 100 mg BI 1358894 is below the already tested highest dose of 200 mg of 
BI 1358894 for 2 weeks in healthy subjects. In healthy volunteers, this dose was safe and 
well-tolerated (Section 1.2). A dose of 100 mg, administered as multiple dose, is considered 
adequate for the objectives of the current trial.
The dose on Day 1, Part 1 administered as oral solution will include 3.7 MBq (100 μCi) of 
[14C]-radiolabelled BI 1358894. The radiolabelled dose of 3.7 MBq is required to provide 
sufficient analytical sensitivity to enable metabolite quantification in a sufficiently low range. 
The total effective dose (radiation burden) amounts to 0.51 mSv. This is below the limit of 
1.0 mSv and considered acceptable. Radiation burden calculations are presented in
Appendix 10.2. For the benefit-risk assessment, see Section 1.4.
4.1.3
Method of assigning subjects to treatment groups
This is an open-label, phase I, single- or multiple-dose study. All subjects in each Part receive 
the same dose. Each subject will be assigned a subject number prior to dosing on Day 1 of 
Visit 2.
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 open-label, single period and single arm with 2 treatment parts. 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
per day
T1 (Test 
product 1)
BI 1358894
Oral solution
10 mg/mL
10 mL (100 mg) on Day 1
100 mg
T2 (Test 
product 2)
BI 1358894
Film-coated 
tablet
50 mg
2 tablets x 50 mg, q.d. (Day 1 to 
Day 21)
100 mg
In Part 1, in the morning of Day 1, following an overnight fast of at least 10 h, all subjects 
will receive one single oral dose of the radiolabelled trial drug ([14C] BI 1358894 oral 
solution 10 mg/mL (10 mL; 3.7 MBq)) followed by the administration of about 200 mL of 
water.
 will determine both the weight of drug product and the total dose of 
[ C]-radioactivity administered for each volunteer.
In Part 2, subjects will receive a multiple-dose treatment of non-radiolabelled 100 mg 
BI 1358894 as film-coated tablets once daily from Day 1 to Day 21 following a standard 


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continental breakfast administered approximately 30 minutes prior to each dosing. The 
investigator (or authorised designee) will administer the trial medications as an oral dose 
together with about 240 mL of water to subjects who are in a sitting position.
Part 1 and Part 2:
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.
Subjects will be kept under close medical surveillance until Day 15 for Part 1 and until 
Day 27 for Part 2. During the first 4 h after drug administration, subjects are not allowed to 
lie down (i.e. no declination of the upper body of more than 45 degrees from upright posture)
except for medical examination or if necessary for any medical reasons (e.g. AEs).
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
Non-radiolabelled drug supply will be provided by BI. Radiolabelled drug supplies 
manufacturing will be provided by 
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.
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.


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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority,  e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. 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 PRODECURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.


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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 on Day 1, 
Part 1.
On Day 1 of Part 1, fluid intake is restricted from 1 h before drug intake until lunch to the 
200 mL of water following the drug administration and to the 240 mL at 2 h and 4 h post-
dose (mandatory for all subjects). From lunch until 24 h post-dose, total fluid intake is 
restricted to 3000 mL.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 48 h before the first administration of trial medication until after the last PK 
sample is collected.
Poppy-seed containing products should not be consumed starting 3 days prior to first trial
drug administration until after the last PK sample of the trial.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before until 24 h after each administration of trial 
medication.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 96 h (4 days)
before the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion of trial medication will provide additional confirmation of 
compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported), 
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG, laboratory tests, a physical examination and a 
neurological examination. At the end of trial examination, it will include review of vital 
signs, 12-lead ECG, laboratory tests, a physical examination including determination of 
weight and a neurological examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor 
at the times indicated in the Flow Chart, after 
subjects have rested for at least 5 min in a supine position. All recordings should be made 
using the same type of blood pressure recording instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 4 h 
at screening and EOT visits and at least 10 h for all other time points. For retests, at the 
discretion of the investigator or designee, overnight fasting is not required.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10.
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.
For each Part, SARS-CoV-2 specific test will be conducted at admission on Day – 1, on Day 
2, at each admission to the trial site for the 24-h visits (Part 1 only) and at EOT.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes count
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neutrophils Bands;  
Eosinophils/Leukocytes; Basophils/ Leukocytes; Monocytes/ 
Leukocytes; Lymphocytes/Leukocytes;.
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
PCR
SARS-CoV-2
--
X
X
Hormones
Thyroid Stimulating Hormone 
Free T3 - Triiodothyronine  
Free T4 – Thyroxine 
X
X
X
--
--
--
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
Albumin (Protein Electrophoresis)
Alpha-1-Globulin (Protein Electrophoresis)
Alpha-2-Globulin (Protein Electrophoresis)
Beta-Globulin (Protein Electrophoresis) 
Gamma-Globulin (Protein Electrophoresis) 
C-Reactive Protein (Quant)  
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine Hemoglobin (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 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (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. It is planned to perform these tests during screening only. Drug screening will be 
performed at screening and at admission on Day – 1.


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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 and drug restrictions, a urine alcohol and drug test 
(e.g. ADVIA Chemistry XPT system) will be performed at admission on Day – 1, 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
.
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 
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. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven.
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.


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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
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 the time points 
indicated in the Flow Chart. 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.
The original English version can be found in Appendix 10.1.


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5.2.5.2
Neurological examination
As a general additional safety measure, a physical neurological examination will be
performed at the time points specified in the respective Flow Chart.
The neurological examination will include the following assessments:
- General level of arousal
- Orientation
- Eye movement
- Pupil size and pupil reactivity
- Reflexes
- Assessment of muscle strength
- Gait
- Romberg test
- Tremor
- Point-to-point movements
- Sensitivity
Documentation, Assessment, and Reporting:
Results will be documented in source data at the clinical trial site and assessed for clinical
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant
findings of the neurological examination will be reported as Adverse Events (during the trial)
or as baseline conditions (at screening).
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.


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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 
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.


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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.
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)


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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
5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(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.


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
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.
Pregnancy
5.2.6.2.4
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.2.6.3
Collection and reporting of the adverse event headache
If the subject reports headaches during the treatment period the following information and
data should be collected daily until the headache is resolved:


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
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 accompanying symptoms like (all of the following that apply: nausea and/or 
vomiting, photophobia, phonophobia, lacrimation, other)

If Headache is resolved: Overall duration of headache episode (start time and end
time)
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood and urine samples will be collected at the time 
points/time intervals indicated in the Flow Chart. The actual sampling times will be recorded 
and used for determination of pharmacokinetic parameters.
5.3.2
Methods of sample collection for Part 1
5.3.2.1
Sampling of whole blood and plasma
Whole blood and plasma will be collected at time points shown in the Flow Chart:
-
To determine [14C]-radioactivity concentrations in whole blood and plasma
-
To determine concentrations of BI 1358894 in plasma
-
To identify metabolites of BI 1358894 in plasma
Blood for pharmacokinetics of BI 1358894 and for quantification of its metabolites will be 
taken from an antecubital or forearm vein into a K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)- anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Withdrawal of blood will be done via an indwelling cannula or by direct 
venepuncture.
For a detailed description of blood sampling, sample volume, sample handling, sample
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory
manual.
Premature stopping of blood sampling
In case [14C]-radioactivity in plasma samples is not detectable (<LLOQ 30 dpm/mL) at two 
consecutive time points for a subject, blood sampling can be stopped for this subject.


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However, all samples until 24 h after the last drug administration have to be taken.
For a detailed description of blood sampling, sample volume, sample handling, sample 
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory 
manual.
5.3.2.4
Sampling of urine
During the trial urine will be collected at time points or in intervals as indicated in the Flow 
Chart:
-
to determine [14C]-radioactivity concentrations in urine
-
to determine concentrations of BI 1358894 in urine
A blank sample will be taken prior to drug administration. For urine collection, the weight of 
the containers has to be determined prior to and at the end of the collection interval. The urine 
volume (weight will be set equal to volume, i.e. 1 kg = 1 L, without correction for specific 
gravity of urine) for each collection interval will be documented. The exact start and end 
times of the urine collection intervals will be recorded in the CRF.
All samples after intake of [14C] BI 1358894 are planned to be used for determination of
[14C]-radioactivity.


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On Day 1 of Part 1, samples until and including the collection interval 12-24 h are planned to 
be used for analysis of BI 1358894.
 
For a detailed description of urine sampling, preparation of collection containers, sample
storage, sample handling, labelling, and sample shipment refer to the laboratory manual.
5.3.2.5
Sampling of faeces
Faeces will be collected for the analysis of [14C]-radioactivity 
 in
intervals as indicated in the Flow Chart. A blank sample will be taken prior to drug
administration.
All faeces samples after intake of [14C] BI 358894 are planned to be used for determination of 
[14C]-radioactivity.
For a detailed description of faeces sampling, sample preparation, sample storage, labelling,
and sample shipment refer to the laboratory manual.
5.3.2.6
Collection of vomit
If after trial drug administration vomiting occurs in a volunteer within 12 h after radioactive
drug administration, the vomit will be collected for determination of weight and [14C]-
radioactivity.
5.3.3
Methods of sample collection for Part 2
5.3.3.1
Sampling of plasma 
Plasma will be collected at time points shown in the Flow Chart:
-
To determine concentrations of BI 1358894 in plasma
Blood for pharmacokinetics of BI 1358894
will be 
taken from an antecubital or forearm vein into a K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)- anticoagulant blood drawing tube at the times indicated in 
the Flow Chart.


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For a detailed description of blood sampling, sample volume, sample handling, sample
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory
manual.
5.3.3.2
Sampling of urine 
During Part 2 of the trial urine will be collected at time points as indicated in the Flow Chart:
-
To determine concentrations of BI 1358894 in urine
A blank sample will be taken prior to first drug administration. For urine collection, the 
weight of the containers has to be determined prior to and at the end of the collection. The 
urine volume (weight will be set equal to volume, i.e. 1 kg = 1 L, without correction for 
specific gravity of urine) for each collection will be documented.
For a detailed description of urine sampling, preparation of collection containers, sample
storage, sample handling, labelling, and sample shipment refer to the laboratory manual.
5.3.3.3
After completion of the trial, the plasma and urine samples may be used for further 
methodological investigations, e.g., for stability testing, assessment of metabolites. However, 
only data related to the analyte and/ or its metabolite(s) will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations, but not later than 5 years after the final study report has been signed.


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5.3.5
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.
5.6
OTHER ASSESSMENTS
Not applicable.
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 in human mass-balance trials.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 of each Part are to be performed and completed within a 3 h-period 
prior to the trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests
will be ± 30 min on Day 1 of Part 1 and ± 90 min for the other days in Visit 2.
In Part 1, the planned times for admission, discharge, start and end of the urine and faeces 
collection intervals are approximate. The procedures are to be performed within a time 
window of ± 4 h to the planned time.
In Part 2, the acceptable deviation from the planned times for blood sampling during the 
ambulatory visits (from Day 30 to Day 62) will be ± 180 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, 12-
lead ECG recordings and urine/faeces collection 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 and urine/faeces collection intervals, refer to the Flow 
Chart. While these nominal times should be adhered to as closely as possible, the actual 
sampling times will be recorded and used for the determination of pharmacokinetic 
parameters. If beginning or end of a urine/faeces collection interval and a blood sample are 
scheduled for the same time point, urine/faeces collection should be done first, with 
withdrawal of the blood sample as closely to the planned time point as possible.
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 5.2.4.


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6.2.2
Treatment periods
On Day – 1, all study participants will be admitted to the trial site and kept under close 
medical surveillance as indicated in the Flow Chart.
In Part 1, subjects will receive a single dose of [14C] BI 1358894 in the morning of Day 1.
Subjects will be readmitted to the trial site for 24 hours collection intervals of urine and
faeces on Days 21, 28, 35, 42 and 49, if release criteria have not been met on Day 15. Within 
24 h before each of these once-weekly in-house collection intervals, subjects are to collect 
faeces at home. This 24-h interval home collections will be used for analysis in case no 
defecation occurs in the subsequent 24-h in-house collection interval. Otherwise it will be 
discarded.
Once release criteria are reached, home collections will be stopped.
If a subject is unable to attend one of these visits, they may be allowed to reschedule the visit,
if needed.
Irrespective of whether release criteria have been met or not after the last collection interval
on Day 50, no further collections are planned.
In Part 2, subjects will receive a single daily dose of BI 1358894 from Day 1 up to Day 21.
For Part 1 and Part 2:
For details on time points and procedures for collection of plasma, urine and faeces samples 
for PK analysis, refer to Flow Chart and Sections 5.3.2 and 5.3.3.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.1 to 5.2.6.
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 basic pharmacokinetics of BI 1358894
and its metabolites, total radioactivity, including mass balance, excretion pathways and 
metabolism following a single oral dose of 100 mg [14C] BI 1358894 in Part 1 and to 
investigate the pharmacokinetics of BI 1358894 and its metabolite(s) following multiple-dose
treatment over 21 days with non-radiolabelled compound at a dose of 100 mg of BI 1358894 
QD in Part 2.
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
No confirmatory analysis will be conducted for this study. Data will be reported with
descriptive statistics only.
7.3
PLANNED ANALYSES
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement,
compliance with intake of trial medication, treatment dispensing errors, prohibited
concomitant medication, completeness and consistency of data) will be assessed by the trial 
team. Important protocol deviation (iPD) categories will be specified in the iQRMP prior to 
trial initiation, iPDs will be identified no later than in the Report Planning Meeting, and the 
iPD categories will be updated as needed.
Plasma/urine/faeces 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:

A pre-dose concentration is >5% of the Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve.


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The following analysis sets will be defined for this trial:

Treated set (TS)
This subject set includes all subjects who entered the study who were documented to 
have received at least one dose of study drug

Pharmacokinetic set (PKS)
This subject set includes all subjects in the TS who provide at least one primary or
secondary PK parameter that was not excluded according to the description above.
Thus, a subject will be included in the PKS, even if he/she contributes only one PK
parameter value to the statistical assessment.
7.3.1
Primary endpoint analyses
The primary endpoints (refer to Section 2.1.2) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472). All parameters will be calculated and analysed 
descriptively.
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).


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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.
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 formal interim analysis is planned.
Exploratory data analysis will be performed during the conduct of the trial, using the subject 
data as it is being collected. This analysis will involve descriptive and graphical presentation 
of primary, secondary and further endpoints. It will be performed to evaluate the mass 
balance and metabolism of BI 1358894, as well as enable the review of safety data. The 
information collected during the ongoing review of subject data will also enable further 
project planning. This analysis is not foreseen to lead to changes to the planned study.


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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
Randomization is not applicable in this open-label and single group clinical study. Per part, 
all subjects will receive the same treatment. Consecutive subject numbers will be assigned via
the EDC system.
7.7
DETERMINATION OF SAMPLE SIZE
For this exploratory trial, no prospective calculations of statistical precision or power have
been made. The planned sample size of 8 evaluable subjects per study part, 16 subjects in 
total, has been selected for practical reasons and is judged as being adequate to get reliable 
results regarding the trial objectives.


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


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


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
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, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking 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 
biobanking 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.


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A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
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 Trial Clinical Monitor, 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 managers (CTM), Clinical 
Research Associates, and investigators of participating trial sites
The non-radiolabelled trial medication will be provided by the 
The radiolabelled trial medication will be provided by
Safety laboratory tests will be performed by the local laboratory of the trial site 
Analyses of non-radiolabelled BI 1358894 concentrations in plasma will be performed at the 
Department of
Analyses of [14C] radioactivity concentrations in plasma, urine and faeces will be performed 
at the
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P06-11895
Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longer-term 
outcomes in depressed outpatients requiring one or several treatment steps: 
a STAR*D report. Am J Psychiatry 2006; 163(11):1905-1917.
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.
R15-3888
Riccio A, Li Y, Moon J et al. Essential Role for TRPC5 in Amygdala 
Function and Fear-Related Behavior. Cell 2009; 137, 761-772.
R16-5350
Fowler M.A., Sidiropoulou K., Ozkan E.D., Phillips C.W., Cooper D.C. 
Corticolimic expression of TRPC4 and TRPC5 channels in the rodent brain. 
PloSONE 2007; e573.
R16-5472
Koenigsberg HW, Denny BT, Fan J 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 et al. Quality of life in borderline personality 
disorder. Harvard Rev Psychiatry 2013; 21(3): 138-150.
R16-5475
McClintock SM, Husain MM, Wisniewski SR 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.


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c10354149
 Investigator's Brochure BI 1358894 in Major Depressive 
Disorder and Borderline Personality Disorder. 31 Jan 2020.
c24903142
 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  
17 Oct 2019.
c28123801
 A single dose, randomized, 
placebo controlled Phase I study on the effects of BI 1358894 on functional 
MRI measurements in an emotional processing paradigm in patients with 
Major Depressive Disorder  1402-0003  24 Jul 2020.
c28667517
  Safety, tolerability, and 
pharmacokinetics of multiple rising oral doses of BI 1358894 (double-
blind, randomised, placebocontrolled, parallel-group design) and evaluation 
of midazolam interaction (nested, open, fixed-sequence, intra-individual 
comparison) in healthy male subjects  1402-0002  16 Jan 2020.
c28698771
. A double-blind, randomised, 
two-way cross-over, single-dose, placebo-controlled trial to investigate the 
effects of BI 1358894 on cholecystokinin tetrapeptide (CCK-4) induced 
panic symptoms in healthy male subjects  1402-0005  13 Feb 2020.
c28714279
 Relative 
bioavailability of a single oral dose of BI 1358894 when administered alone 
or in combination with multiple oral doses of itraconazole in healthy male 
subjects (an open-label, fixed sequence study)  1402-0007  29 Jan 2020.
c28907328
 Relative bioavailability and food
effect of a single dose of different solid formulations of BI 1358894 
compared to a single dose of the reference tablet formulation of BI 1358894 
following oral administration under fed and fasted conditions in healthy 
male subjects (an open-label, single-dose, randomised, incomplete blocks 
crossover design study)  1402-0010  27 Apr 2020.


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


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


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10.2
RADIATION BURDEN CALCULATION


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10.3
COVID-19 SITE SPECIFIC MEASURES
This section contains a risk assessment for study 1402-0015 with BI 1358894 due to the 
circumstances created by the coronavirus disease-19 (COVID-19) pandemic. In addition, 
the document summarizes the mitigation approaches to be followed to minimize the risk 
of spreading severe acute respiratory syndrome coronavirus 2 (SARS CoV-2).
Risk Assessment
BI 1358894 is a TRPC4/5 inhibitor in development for treatment of Major Depressive 
Disorder and for the treatment of Borderline Personality Disorder (BoPD). It is expected 
that treatment with BI 1358894 has the potential to improve affective symptoms and 
emotion control, especially in patients with MDD who inadequately respond to the current 
standard of care (SSRI; SNRI) and in patients with BoPD, where no approved drug 
treatment is currently available
Relevant information on the product
BI 1358894 is a highly potent and selective TRPC4/5 Inhibitor (transient receptor 
potential cation channel, subfamily C, members 4 and 5). It has the potential to address 
core symptoms of MDD and BoPD as it targets TRPC4/5 ion channels. TRPC4 and 
TRPC5 are highly expressed in pyramidal neurons of the amygdala in the frontal cortex, 
hippocampus, and hypothalamus, brain areas that are involved in circuits contributing to 
emotional control. BI 1358894 is thought to decrease neuronal excitability leading to 
normalization of the activation state of limbic circuits, which are known to be important 
for emotional control.
BI 1358894 is characterised by high bioavailability after oral intake, moderate volume of 
distribution, low clearance and long terminal half-life. Excretion occurs almost exclusively 
via faeces. After administration of BI 1358894 tablets, maximum plasma concentrations of 
BI 1358894 occurred around 1 to 5 hours after dosing. The terminal half-life was 41 to 52 
hours for blood. Steady state was reached after 11 to 14 days of BI 1358894 dosing.
Currently, repeat dose toxicity studies up to 13 weeks revealed toxicologically relevant 
effects on the skin (mice), Harderian glands (mice), hepatic function (mice), the vascular 
system (rats), male genital tract (rats), the Central Nervous System (CNS) function 
(dogs), and the digestive tract, renal function, and white blood cell parameters (mice, rats 
and dogs).
Minimal to moderate subacute perivascular inflammation was observed in animals dosed at
≥30 mg/kg/day. The inflammation was centred around arterioles and small- to medium-sized 
muscular arteries of the mesentery and sometimes extended into the serosa of the digestive 
tract. In few animals dosed at 200 or 1000 mg/kg/day, diffuse slight inflammation and 
minimal to moderate focal necrotizing vasculitis were also noted. Vascular findings were no 
longer present after continued dosing at the same dose level for 4 or 13 weeks.


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Minimally to moderately increased extramedullary hematopoiesis (EMH) in the spleen 
correlated with increased spleen weights at all dose levels. At ≥30 mg/kg/day, minimally to 
slightly increased myelopoiesis was present in the bone marrow (sternum) and minimal 
toslight extramedullary myelopoiesis was also observed in the axillary, mandibular, and 
mesenteric lymph nodes. These findings correlated also with increases in reticulocytes and 
WBC noted in hematology at all dose levels. These findings were considered to be a 
physiologic adaptive response of hematopoietic and lymphoid organs to increased demand in 
context with perivascular inflammation.
In summary, toxicological investigations for BI 1358894 did not show any relevant effect 
on the function of the cardio-vascular system, the respiratory system or immune system so 
far. At this time point (16 Apr 2020) the toxicological investigation did not show any 
evidence that BI 1358894 may alter the susceptibility for a SARS-CoV2 infection or may 
facilitate the development of severe COVID-19.
Clinical safety was analysed for 7 completed Phase I clinical trials with 217 healthy 
volunteers and 73 patients with MDD so far (DLP 01 April 2020). There were no deaths 
or SAEs in any of these trials. Overall, BI 1358894 was well tolerated in healthy male 
subjects and in male and female patients with MDD.
In general, there were no clinically relevant findings in the clinical laboratory evaluation, 
including no treatment-emergent signs of inflammation based on erythrocyte 
sedimentation rate (ESR), C-reactive proteins (CRP), and faecal laboratory tests (faecal 
occult blood and faecal calprotectin). No evidence of significant changes in blood pressure, 
heart rate and ECG were observed so far.
Considerations around drug-drug-interactions are not included in this benefit-risk assessment
– for those it should be referred to the protocol, Investigator’s Brochure and the most recent 
label of the respective medication(s) used for treatment of COVID-19.
Benefit and risk conclusions and recommendations
BI 1358894 is a highly specific inhibitor of the TRPC 4/5 channels. TRPC 4/5 channels 
are predominantly located in the CNS. All investigation into distribution and function of 
TRPC 4/5 (preclinical and clinical) so far have not identified any interference with the 
immune system, the respiratory system or the cardio-vascular system. A modulatory 
impact on the patient’s immune system for TRPC 4/5 inhibitor is so far not expected so 
that susceptibility to vis-à-vis infections should not be affected. Therefore, subjects 
participating in Phase I trials are at this time point not considered to be at a higher risk 
for a SARS-CoV2 infection due to BI 1358894 intake than currently posed by the 
ordinary environment.
For the upcoming Phase I trial, the benefit-risk for the trial participants treated with 
BI 1358894 remain unchanged in relation to the COVID-19 pandemic since:
-
The mode of action does not appear to have a substantial effect on clinically 
relevant organs (e.g. respiratory or cardiovascular system) critically affected by
COVID-19.
-
There is currently no evidence that intake of BI 1358894 leads to


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immunosuppression.
-
The healthy volunteers are in general without common co-morbidities associated 
with severe course of COVID-19.
Since every subject will be assessed thoroughly and individual benefit-risk assessments 
are made prior to study entrance by the investigator also in respect of potential COVID-
19, the risk for subjects participating in these studies will not differ from the current 
general risk of COVID-19 with all its consequences.
The investigators will take the totality of information related to each single subject and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide 
upon each subject’s (continued) participation in the planned trials. BI as the sponsor, 
where required, will support the investigator in their decision finding. It is acknowledged 
that the investigator may decide to implement protocol deviations where this protects the 
safety, well- being and/or is in the best interest of the patient.
Study design key points
The study population for this study consists of healthy subjects with minimized COVID 
19 infection risk (free of COVID-19 symptoms, negative PCR test(s) before 
investigational medicinal product [IMP] administration) and with minimized impact of 
COVID-19, if contracted during the study (eg, during the COVID-19 pandemic the 
upper age is 70 years (inclusive), upper body mass index [BMI] ≤29.9 kg/m2).
Subjects will stay in-house from Day – 1 until Day 15 for Part 1 (following a single dose 
administration on Day 1). Subjects will then come back for 24-h in-house stay at several 
time points if they did not reach the release criteria (see Flow Chart). For subjects 
enrolled in Part 2, they will stay in-house from Day – 1 until Day 27 (following multiple 
doses administration of 100 mg BI 1358894, once daily over 21 days) and will return for 
ambulatory visits from Day 30 to Day 62 (see Flow Chart).
At the time of the follow-up examination (Day 16 – Day 50 for Part 1 and Day 62 for 
Part 2) BI 1358894 is expected to be eliminated.
SARS-CoV-2 containment measures to the CTP
The following SARS-CoV-2 containment measures will be taken during the study:
-
The study will be conducted in accordance with guidance from the Central 
Committee on Research Involving Human Subjects (CCMO [Centrale Commissie 
Mensgebonden Onderzoek]) on conducting Phase 1 trials in Clinical Research 
Units in The Netherlands during the COVID 19 pandemic.
-
During the entire study, the clinical research unit will implement all 
recommendations issued by the Dutch Government, including specific guidelines 
related to clinical research executed in clinical research units with respect to 
minimizing the risk of disease spreading, e.g., social distancing, disinfection, 
hygiene, and wearing of personal protection equipment by study staff. Details on 
specific procedures are described in the Site Specific Manual.


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-
Polymerase chain reaction (PCR) testing for SARS-CoV-2 will be performed 
at the following time points:
o
1 nasopharyngeal PCR test directly before admission to the unit on Day –
1 and 1 additional nasopharyngeal PCRs on Day 2 for confirmatory 
purpose.
o
Repeated nasopharyngeal PCR test at follow-up visit.
-
Physical exams will be limited to the necessary visits (screening, discharge 
and follow-up).
-
In cases where subjects are not able to attend study visits due to the presence of a 
SARS-CoV 2 infection, the Investigator will discuss with the Sponsor potential 
mitigation approaches (including, but not limited to, extending the visit window, 
conducting evaluations via video link or phone call, allowing for safety 
procedures to be conducted at a local facility). The rationale (e.g., the specific 
limitation imposed by the SARS-CoV-2 infection that led to the inability to 
perform the protocol-specified assessment) and outcome of the discussion will be 
documented in the electronic case report form (eCRF).
-
A subject should not be admitted if there was any contact with a COVID-19 
patient within the last 2 weeks prior to admission to the clinical research unit.
-
If a subject is tested to be SARS-CoV-2 positive on Day – 1, the subject will be 
excluded from participation with reference to exclusion criterion #29, and 
referred for treatment.
-
If a subject becomes ill and/or is tested to be SARS-CoV-2 positive after the first 
administration of study treatment, dosing will be stopped. The subject will be 
isolated from other study participants and referred for treatment. The subject will 
be followed up in quarantine in the clinical research unit until complete 
elimination of the study compound or will be asked to quarantine at home 
according to guidelines of the Dutch government.
Conclusion of COVID-19 risk containment
Given the profile of the compound and given the study design, the COVID-19 risk 
minimization strategy as summarized above is considered adequate. The BI trial team 
and the 
 Principal Investigator and supporting staff recommend study continuation 
as per latest version of the protocol and with implementation of the measures detailed in 
this appendix to the protocol.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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clinical-trial-protocol-version-01
A phase I, open-label trial to investigate metabolism and pharmacokinetics of a single
dose of [14C] BI 1358894 administered as oral solution (Part 1) and multiple doses
of BI 1358894 administered as film-coated tablets (Part 2) in healthy male volunteers
Author-Trial Clinical
Pharmacokineticist
21 Aug 2020 12:06 CEST
Author-Clinical Trial Leader
21 Aug 2020 14:04 CEST
Verification-Paper Signature
Completion
21 Aug 2020 14:59 CEST
Approval-
 Medicine
21 Aug 2020 16:07 CEST
Approval-Team Member Medicine
21 Aug 2020 21:14 CEST
Author-Trial Statistician
24 Aug 2020 09:16 CEST


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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c34271221-01
BI Trial No.:
1402-0015
Title:
A phase I, open-label trial to investigate metabolism and 
pharmacokinetics of a single dose of [14C] BI 1358894 
administered as oral solution (Part 1) and multiple doses of 
BI 358894 administered as film-coated tablets (Part 2) in healthy 
male volunteers
Final protocol [c31118084-01]
Investigational
Product(s):
BI 1358894
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
11 MAR 2021 SIGNED
Version:
1
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINTS.....................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoint .......................................................................................8
5.2.2
Secondary endpoints.............................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................10
6.1
TREATMENTS...................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................11
6.3
SUBJECT SETS ANALYSED...........................................................................11
6.5
POOLING OF CENTRES .................................................................................12
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................12
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................12
7.
PLANNED ANALYSIS......................................................................................13
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........14
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................14
7.3
TREATMENT COMPLIANCE........................................................................14
7.4
PRIMARY ENDPOINTS...................................................................................14
7.4.1
Primary analysis of the primary endpoint........................................................14
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoints...............................................................................................15
7.5
SECONDARY ENDPOINTS.............................................................................15
7.5.1
Key secondary endpoints....................................................................................15
7.5.2
Secondary endpoints...........................................................................................15
7.7
EXTENT OF EXPOSURE.................................................................................16
7.8
SAFETY ANALYSIS..........................................................................................16


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7.8.1
Adverse Events ....................................................................................................16
7.8.2
Laboratory data ..................................................................................................17
7.8.3
Vital signs.............................................................................................................18
7.8.4
ECG......................................................................................................................19
7.8.5
Others...................................................................................................................19
8.
REFERENCES....................................................................................................20
10.
HISTORY TABLE..............................................................................................22


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LIST OF TABLES
Table 6.1: 1
Part 1 - Analysis phases for statistical analysis of AEs, safety laboratory 
data and vital signs ...........................................................................................10
Table 6.1: 2
Part 2 - Analysis phases for statistical analysis of AEs, safety laboratory 
data and vital signs ...........................................................................................10
Table 6.3: 1
Subject sets analysed ........................................................................................12
Table 10: 1
History table .....................................................................................................22


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ
BI 
Boehringer Ingelheim
BP
Blood pressure
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
Arithmetic coefficient of variation
fe0-t2
Fraction of administered drug excreted unchanged over the time interval 
from 0 to t2
gCV
geometric coefficient of variation
gMean
Geometric mean
PKS
Pharmacokinetic parameter set
PR
Pulse rate
RAGe
Report appendix generator
REP
Residual Effect Period
RPM
Report Planning Meeting
SD
Standard deviation
TS
Treated set
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1) the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the 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. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 "Statistical Methods and Determination of 
Sample Size". Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
The trial consists of two parts. The analyses of both parts (Part 1 and Part 2) are described in 
the TSAP. 
Study data as collected in the eCRF will be stored in a trial database within the RAVE EDC 
system. All study data also including external data will then be uploaded to the CDR data 
warehouse.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, 
), 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, 
).


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


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints for Part 1 are the PK endpoints of BI 1358894 as defined in CTP 
Section 2.1.2:

Mass balance recoveries of [14C] BI 1358894 total radioactivity in urine and faeces 
after single oral dose

Amount of radioactivity excreted as a percentage of the administered dose (fe0-t2) for 
urine and faeces
No primary endpoint is defined for Part 2.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
For Part 1, the secondary PK endpoints will be determined for total [14C] BI 1358894 and 
BI 1358894 after single dose administration, as defined in Section 2.1.3 of the CTP:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
For Part 2, the secondary PK endpoints will be determined for BI 1358894, as defined in 
Section 2.1.3 of the CTP:

AUC0-24 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24)

Cmax (maximum measured concentration of the analyte in plasma)

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups, 
and selection of doses, cf. Section 4 of the CTP.
The trial consists of Part 1 and Part 2 and the two parts will be analysed separately. 
In Part 1, subjects are planned to be treated with a single dose of BI 1358894 mixed with 
[14C] BI 1358894.
For statistical analyses of AEs, safety laboratory data, and vital signs the following separate 
analysis phases will be defined for each subject:
Table 6.1: 1
Part 1 - Analysis phases for statistical analysis of AEs, safety laboratory data 
and vital signs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of administration 
of study drug
On-treatment
BI 1358894 SD
Date/time of administration 
of study drug
Date/time of administration 
of study drug + REP 
(14 days * 24 h)
Follow-up
F/U BI 1358894 SD
Date/time of administration 
of study drug + REP 
(14 days * 24 h)
12:00 a.m. on day after  trial 
completion date
SD = Single Dose
In Part 2, subjects are planned to be treated with multiple dose of 100 mg BI 1358894 as 2 
film-coated tablets once daily (2 tablets x 50 mg, q.d.) from Day 1 to Day 21.
Table 6.1: 2
Part 2 - Analysis phases for statistical analysis of AEs, safety laboratory data 
and vital signs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
BI 1358894 MD
Date/time of first 
administration of study drug
Date/time of last 
administration of study drug 
+ REP (14 days * 24 h)
Follow-up
F/U BI 1358894 MD
Date/time of last 
administration of study drug 
+ REP (14 days * 24 h)
12:00 a.m. on day after trial 
completion date
MD = Multiple Doses
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. 


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More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the RPM. At this meeting, it will be decided whether a 
discrepant data value can be used in the analyses or whether it must be corrected in the 
clinical database. Each protocol deviation must be assessed to determine whether it is an 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 DV 
domain. If the data show other iPDs, the definition in the DV domain will be supplemented 
accordingly by the time of the RPM.
iPDs will be summarized and listed. In the DV domain it is also specified 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 RPM at the latest after discussing exceptional 
cases and implications for the analyses.
Non important Covid-19 related protocol deviations will be listed.
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects entered the study who were documented to have 
received at least one dose of study drug.

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one primary or 
secondary PK parameter that was not excluded because of iPDs relevant to the 
statistical evaluation of PK endpoints as defined in Section 7.3 of the CTP.
The two trial parts (Part 1 and Part 2) will be analysed separately. Therefore, the two analysis 
sets will be split into TS/PKS of Part 1 and TS/PKS of Part 2.

The discussion of all exceptional cases and problems and the decisions on the 
allocation of subjects to analysis sets will be made at latest at the RPM.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
IPDs
X
Demographic/baseline endpoints
X
Primary and secondary PK 
endpoints
X
Further PK endpoints
X
Safety parameters and 
treatment exposure
X
6.5
POOLING OF CENTRES
This section is not applicable, because the trial is 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 Section 7.5.1: It is not planned to impute missing values for safety parameters.
One exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
Missing data and outliers of PK data are handled according to BI standards (4) and (5) 
CTP Section 7.5.2: PK parameters that cannot be reasonably calculated based on the 
available drug concentration-time data will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The last non-missing value determined prior to first BI 1358894 administration will be 
defined as baseline (in both parts). 
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (6)
The individual values of all subjects will be listed. Listings will be sorted by treatment group, 
subject number and visit (if visit is applicable in the respective listing). AE listings will be 
sorted by treatment group, subject number and AE onset date (see Section 7.8.1 below for 
details). The listings will be contained in Appendix 16.2 (SDL) of the CTR.
If not stated otherwise, the data of Part 1 and Part 2 will be analysed separately.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary. Concomitant non-drug therapies will be coded 
according to the most recent version of MedDRA.
A medication will be considered concomitant, if it

is ongoing at the time of first study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a definition 
of treatments and analysis phases).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
CTP Section 7.3.4: Previous and concomitant therapies will be presented per treatment 
group without consideration of time intervals and treatment periods.
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 (cf. Section 5.4.2). Any 
deviations from complete intake will be addressed in the RPM (cf. Section 6.2) and described 
in the CTR.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoint
The primary endpoints of Part 1 will be analysed descriptively (cf. Section 7.3.1 of the CTP). 
The analysis is performed according to BI standards (4) and will be based on the PKS.
Exclusion of PK parameters (applies to Part 1 and Part 2)
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/urine concentrations (applies to Part 1 and Part 2)
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). 


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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" (5).
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoints
Not applicable.
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 CTP.
7.5.2
Secondary endpoints
Secondary PK endpoints of both parts will be assessed descriptively. This will be based on the 
PKS. The analysis of PK parameters is performed according to BI standards (4).
See Section 7.4.1 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.


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7.7
EXTENT OF EXPOSURE
For Part 1 treatment exposure will only be listed by means of the date and time of drug 
administration 
For Part 2 descriptive statistics are planned for this section of the report.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to screening, on-treatment or follow-up phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1 and 
Table 6.1: 2.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of AESIs.


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CTP Section 5.2.6.1.3: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
○
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-
fold ULN measured in the same blood sample, or 
○
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8) in addition to deaths and SAEs, "other significant" AEs need to be 
listed in the CTR. These will be any non-serious adverse event that led to an action taken with 
study drug (e.g. discontinuation or dose reduced or interrupted).
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. AEs will also be summarized by maximum intensity. Separate tables 
will be provided for subjects with SAEs and subjects with AESIs.
The SOCs will be sorted by total frequency; preferred terms will be sorted by total frequency 
(within SOC).
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
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. These 
data will be summarized with descriptive statistics. Headache episodes with onset during 
screening and Follow-up phase will be listed only. 
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.


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Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided for the on-treatment phase. Frequency tables of changes 
between baseline and last value on treatment with respect to the reference range will be 
presented. Qualitative urinalysis results will be listed only.
CTP Section 7.3.4: Values outside the reference range as well as values defined as possibly 
clinically significant will be highlighted in the listings. 
Unscheduled measurements of laboratory data will be assumed to be repeat measurements of 
the most recent scheduled measurement (e.g. for follow-up or confirmation of a particular 
value). Therefore, unscheduled measurements will be assigned to the planned time point of 
the previous scheduled measurement. Descriptive statistics will be calculated by planned time 
point based on the worst value of the subject at that planned time point (or assigned to that 
planned time point).
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM at the latest. It is the Investigator's responsibility to 
decide whether a lab value is clinically significant abnormal or not. Standard or project-
specific rules for flagging clinically significant values in an automated manner will not be 
applied in this study.
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 and for the difference from baseline (see 
Section 6.7) will be provided. 
Unscheduled measurements of vital signs will be assigned to planned time points as follows:

Unscheduled measurements prior to the first scheduled measurement within a visit 
will be assigned to the planned time point of the first scheduled measurement of that 
visit.

Other unscheduled measurements will be assigned to the planned time point of the 
previous, most recent scheduled measurement.
Unscheduled measurements of vital signs will be used in calculation of descriptive statistics 
by planned time point as follows:

If an unscheduled measurement is the last available off-treatment value before study 
drug administration, this unscheduled measurement will be used in the statistical 
analysis as baseline (as this is in accordance with the definition of baseline, cf. 
Section 6.7).


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
At post-baseline time points, descriptive statistics by planned time point will be 
calculated based on the last value of the subject within 20 minutes of the scheduled 
measurement of that planned time point. The rationale for this rule is that these 
measurements are interpreted to be repeat measurements of the scheduled 
measurement (e.g. for confirmation of a particular value).
An unscheduled measurement more than 20 minutes after the time of the scheduled 
measurement of that planned time point will be listed, but will not be used in 
calculation of descriptive statistics. These measurements are interpreted as off-
schedule vital signs measurements, taken for other reasons.
If an unscheduled measurement is taken at exactly the same time as the scheduled 
measurement, this unscheduled measurement will be considered to be done after the 
scheduled measurement, and will potentially qualify to be the “last value of the subject 
within 20 minutes of the scheduled measurement of that planned time point”.
If the time of measurement is missing for a scheduled measurement, the scheduled 
measurement will be used in calculation of descriptive statistics (as time difference 
between scheduled and unscheduled cannot be assessed).
If the time of measurement is missing for an unscheduled measurement, this 
measurement will be listed but will be ignored for the calculation of descriptive 
statistics.
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. 
7.8.5
Others
Suicidality assessment
Suicidality monitoring will be performed as described in Section 5.2.5.1 of the CTP, results 
will only be listed. No further analysis will be prepared. Findings will also be reported as 
AEs.
Physical and neurological examinations
Physical examination findings including neurological examination finding 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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TSAP for BI Trial No: 1402-0015
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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version
2.
001-MCS-40-413_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.
KM Asset BI-KMED-TMCP-MAN-0014: "Noncompartmental PK/PD Analyses of 
Clinical Studies", current version; KMED
5.
KM Asset BI-KMED-TMCP-MAN-0010: "Description of Analytical Transfer Files,
PK/PD Data files and ADA files", current version; KMED
6.
KM Asset BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and 
Project Summaries", current version; KMED
7.
KM Asset BI-KMED-BDS-HTG-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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Boehringer Ingelheim
TSAP for BI Trial No: 1402-0015
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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1
11-MAR-21
None
This is the final TSAP