Clinical trial NCT04789304
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2021-04-01; Completion date: 2022-01-14
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this trial are to investigate safety and tolerability of BI 1595043 in healthy male subjects following administration of multiple rising doses over 14 days.

Secondary objectives are the exploration of pharmacokinetics (PK) of BI 1595043 after single and multiple dosing.

Detailed description:

Arms: arm 1: Placebo matching BI 1595043. Patients included in the placebo arm corresponding to dose group 3, also received Midazolam. arm 2: 15 milligram (mg) BI 1595043. Dose group 1. arm 3: 30 mg BI 1595043. Dose group 2. arm 4: 60 mg BI 1595043 + Midazolam. Dose group 3.
Interventions: intervention 1: BI 1595043 intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: BI 1595043 intervention 2: Placebo intervention 3: Midazolam

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c33929558-03
EudraCT No.
2020-004923-18
BI Trial No.
1445-0002
BI Investigational 
Medicinal Product
BI 1595043
Title
Safety, tolerability and pharmacokinetics of multiple rising oral
doses of BI 1595043 (double-blind, randomised, placebo-
controlled, parallel group design) in healthy male subjects
Lay Title
A study to test how healthy men tolerate different doses of 
BI 1595043
Clinical Phase
I
Clinical Trial Lead
Phone: +
Fax: +
Principal 
Investigator
Phone: +
Fax: +
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 23 July 2021
Page 1 of 109
Proprietary confidential information
© 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
10 February 2021
Revision date
23 July 2021
BI trial number
1445-0002
Title of trial
Safety, tolerability and pharmacokinetics of multiple rising oral doses of 
BI 1595043 (double-blind, randomised, placebo-controlled, parallel group design)
in healthy male subjects
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
In this trial, safety, tolerability and pharmacokinetics of BI 1595043 will be 
assessed in healthy male volunteers using multiple rising oral doses in order to 
provide the basis for the clinical development in the indication of Crohn’s disease.
Trial objectives
To investigate safety, tolerability and pharmacokinetics following multiple rising 
doses of BI 1595043
Trial endpoints
Primary endpoint:
the percentage of subjects with drug-related adverse events (AEs)
Secondary endpoints:
AUC0-τ,ss and Cmax,ss, Cmin,ss, RA,AUC, and RA,Cmax of BI 1595043 after the last dose
Trial design
Double-blind, randomised within dose groups, placebo-controlled, parallel-group 
design
Number of subjects 
total entered
50*
each treatment
10 per dose group (8 on BI 1595043 and 2 on placebo)
*Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 50, but is not to exceed 70.
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) 
of 18.5 to 29.9 kg/m2 (inclusive)


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BI Trial No.: 1445-0002
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Test product
BI 1595043 tablets (5 mg and 25 mg)
dose
15 mg q.d., 30 mg q.d., 60 mg q.d., 120 mg q.d. and 60 mg b.i.d.
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h*
* In DG 5 (60 mg b.i.d.), the morning dose to be administered orally with 240 mL of water 
after an overnight fast of at least 8 h, and the evening dose – orally with 240 mL of water 
after fasting at least 3 h
Comparator product
Matching placebo as tablets
dose
Not applicable
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h*
* In DG 5 (60 mg b.i.d.), the morning dose to be administered orally with 240 mL of water 
after an overnight fast of at least 8 h, and the evening dose – orally with 240 mL of water 
after fasting at least 3 h
Probe drug
Midazolam for injection used as oral solution (DG 3-4, 60 mg q.d. and 120 mg q.d.)
dose
75 μg q.d.
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment
BI 1595043 or placebo:
DG 1-4 (15 mg q.d., 30 mg q.d., 60 mg q.d. and 120 mg q.d.): 18 days, including a 
single dose segment on Day 1 with a washout over 4 days, and a multiple dose 
segment over 14 days (Days 5-18)
DG 5 (60 mg b.i.d.): multiple dose segment over 14 days, including a twice daily 
regimen on Days 1-13 and morning dose only on Day 14
Midazolam:
DG 3-4 (60 mg q.d. and 120 mg q.d.): Day -1, Day 1 and Day 18 (a single dose, 
each)
Statistical methods
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
FLOW CHART A (DOSE GROUPS 1-2)
15 mg q.d. and 30 mg q.d. of BI 1595043 or placebo
Visit
Day
Planned time (relative to 
first drug administration) 
[h:min]
Approximate clock time   
of actual day [h:min]
Event and comment
Safety laboratory 15
PK blood BI 1595043 10, 18
PK urine BI 1595043 10, 11, 18
PD blood 10, 19
PD urine 8, 10, 19
12-lead ECG 16
Vital signs (BP, PR) 17
Questioning for AEs and 
concomitant therapy 6
1
-21 to -1
Screening (SCR)1
A
x
x13
2
-3 to -17
-72:00
08:00
Ambulatory visit14
B
x13
x
-1
-14:00
18:00
Admission to trial site
x5
x13
1
-1:00
07:00
Allocation to treatment2
x2
x2
x2
x2
x2,12
x2,13
x2
0:00
08:00
First drug (BI 1595043 or 
placebo) administration
▲
│
0:15
08:15
x
│
0:30
08:30
x
│
0:45
08:45
x
│
1:00
09:00
x
│
x
x9
x
x
1:15
09:15
x
│
1:30
09:30
x
│
2:00
10:00
240 mL fluid intake3
x
│
x9
x
x
2:30
10:30
x
│
3:00
11:00
x
│
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
┼
│
x
x
x
6:00
14:00
x
│
8:00
16:00
Snack (voluntary)3
x
┼
x
x
x
10:00
18:00
Dinner3
│
12:00
20:00
x
┼
x9
x
x 
2
24:00
08:00
Breakfast3
x
┼
x
x9
x13
x
3
48:00
08:00
Breakfast3
x
▼
x13
x
4
72:00
08:00
Breakfast3
x
x13
x
5
95:45
07:45
B
x
x
x
x9
x13
x
96:00
08:00
Drug administration
97:00
09:00
x9
x13
x
6
119:45
07:45
x
x9
x13
x
120:00
08:00
Drug administration
121:00
09:00
x9
x
x
7
143:45
07:45
x
x
x
x9
x13
x
144:00
08:00
Drug administration
145:00
09:00
x9
x
x
8
167:45
07:45
B
x
x13
x
168:00
08:00
Drug administration
169:00
09:00
x
x
9
191:45
07:45
x
x
x9
x13
x


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Visit
Day
Planned time (relative to 
first drug administration) 
[h:min]
Approximate clock time   
of actual day [h:min]
Event and comment
Safety laboratory 15
PK blood BI 1595043 10, 18
PK urine BI 1595043 10, 11, 18
PD blood 10, 19
PD urine 8, 10, 19
12-lead ECG 16
Vital signs (BP, PR) 17
Questioning for AEs and 
concomitant therapy 6
192:00
08:00
Drug administration
193:00
09:00
x9
x
x
10
215:45
07:45
x
x13
x
216:00
08:00
Drug administration
217:00
09:00
x
x
11
239:45
07:45
x9
x13
x
240:00
08:00
Drug administration
241:00
09:00
x9
x
x
12
263:45
07:45
x
x
x
x13
x
264:00
08:00
Drug administration
265:00
09:00
x
x
13
287:45
07:45
B
x9
x13
x
288:00
08:00
Drug administration
289:00
09:00
x9
x
x
14
311:45
07:45
x13
x
312:00
08:00
Drug administration
313:00
09:00
x
x
15
335:45
07:45
x
x
x
x9
x13
x
336:00
08:00
Drug administration
337:00
09:00
x9
x
x
16
359:45
07:45
x13
x
360:00
08:00
Drug administration
361:00
09:00
x
x
17
383:45
07:45
x9
x13
x
384:00
08:00
Drug administration
385:00
09:00
x9
x
x
18
407:45
07:45
B
x20
x2
x
x
x9
x13
x
408:00
08:00
Last drug administration
▲
408:15
08:15
x20
│
408:30
08:30
x20
│
408:45
08:45
x20
│
409:00
09:00
x20
│
x
x9
x
x
409:15
09:15
x20
│
409:30
09:30
x20
│
410:00
10:00
240 mL fluid intake
x20
│
x9
x
x
410:30
10:30
x20
│
411:00
11:00
x20
│
412:00
12:00
240 mL fluid intake, thereafter 
lunch3
x20
┼
│
x
x9
x
x
414:00
14:00
x20
│
416:00
16:00
Snack (voluntary)3
x20
┼
x
x9
x
x
418:00
18:00
Dinner3
│
420:00
20:00
x20
┼
x9
x
x 
19
432:00
08:00
Breakfast3
x20
┼
x
x9
x13
x
442:00
18:00
x20
│
x


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Visit
Day
Planned time (relative to 
first drug administration) 
[h:min]
Approximate clock time   
of actual day [h:min]
Event and comment
Safety laboratory 15
PK blood BI 1595043 10, 18
PK urine BI 1595043 10, 11, 18
PD blood 10, 19
PD urine 8, 10, 19
12-lead ECG 16
Vital signs (BP, PR) 17
Questioning for AEs and 
concomitant therapy 6
20
455:45
07:45
B
│
x9
x13
x
456:00
08:00
Breakfast, confirmation of 
fitness, discharge from trial site
x20
▼
x
21
480:00
08:00
Ambulatory visit
x20
x
22
504:00
08:00
Ambulatory visit
x20
x
23
528:00
08:00
Ambulatory visit
x20
24
552:00
08:00
Ambulatory visit
x20
3
25 to 30
End of trial (EOT) examination4 
C
x
x13
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, ophthalmological examination (exclusion of ocular disorders), check of vital 
signs, assessment of body temperature, ECG, safety laboratory (including drug 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.
2.
The time is approximate; procedures are to be performed and completed within the 3 h prior to drug administration. 
Allocation to treatment may be performed at any time following enrolment but must be completed prior to first drug 
administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, ophthalmological examination 
(exclusion of ocular disorders), body weight, vital signs, assessment of body temperature, ECG, safety laboratory, 
recording of AEs, and concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
ambulatory visit can be omitted if the screening examination is performed on Days -3, -2 or -1. 
8.
First morning urine to be collected for PD evaluation including an aliquot for creatinine analysis (for normalization of 
PD evaluation) (refer to Section 5.2.4 and 5.4).
9.
The ECG recording has to be performed in triplicate at this time. ECG recording will always precede all other study 
procedures scheduled for the same time point (e.g. blood sampling, measurement of vital signs) to avoid compromising 
ECG quality.
10. Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK 
data) including addition of samples and visits as long as the total blood volume removed does not exceed 500 mL per 
subject.
11. A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24 and 24-48.
12. At baseline (i.e. Day 1, prior to drug administration), 3 triplicate ECGs are recorded within approximately one hour. 
The recordings should be separated by at least 15 minutes. 
13. Including assessment of body temperature.
14. PCR test for SARS-COV-2/ COVID-19 will be performed shortly (within 72 hours) before admission to trial site.
15. For details of safety laboratory testing at Visit 1 (A), Visit 2 (B) and Visit 3 (C) refer to Section 5.2.4 and 
Table 5.2.4: 1.
16. For details of 12-lead ECG, refer to Section 5.2.5.
17. For details of vital signs evaluation, refer to Section 5.2.2.
18. For details of PK blood/urine sampling for BI 1595043, refer to Section 5.3.2.
19. For details of PD blood/urine sampling, refer to Section 5.4.1.
20. At this time, an additional blood sample for metabolite identification (MIST) will be taken only in DG 2 (30 mg q.d. of 
BI 1595043) (refer to Section 5.3.2.2).


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FLOW CHART B (DOSE GROUPS 3-4)
60 mg q.d. and 120 mg q.d. of BI 1595043 or placebo with midazolam microdoses
Visit
Day
Planned time (relative to 
first drug administration) 
[h:min]
Approximate clock time   
of actual day [h:min]
Event and comment
Safety laboratory 15
PK blood BI 1595043 10, 18
PK blood Midazolam 10, 18
PK urine BI 1595043 10, 11, 18
PD blood 10, 19
PD urine 8, 10, 19
12-lead ECG 16
Vital signs (BP, PR) 17
Questioning for AEs and 
concomitant therapy 6
1
-21 to -2
Screening (SCR)1,14
A
x
x13
2
-4 to -27
-96:00
08:00
Ambulatory visit14
B
x13
x
-2
-38:00
18:00
Admission to trial site
x5
x13
-1
-25:00
07:00
x2
x2
x2,13
x2
-24:00
08:00
Midazolam administration
-23:45
08:15
x
-23:30
08:30
x
-23:15
08:45
x
-23:00
09:00
x
-22:45
09:15
x
-22:30
09:30
x
-22:00
10:00
240 mL fluid intake3
x
-21:30
10:30
x
-21:00
11:00
x
-20:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
-18:00
14:00
x
-16:00
16:00
Snack (voluntary)3
x
-14:00
18:00
Dinner3
1
-1:00
07:00
Allocation to treatment2
x2
x2
x2
x2
x2
x2,12
x2,13
x2
0:00
08:00
First drug (BI 1595043 or 
placebo) administration & 
Midazolam administration
▲
│
│
0:15
08:15
x
x
│
0:30
08:30
x
x
│
0:45
08:45
x
x
│
1:00
09:00
x
x
│
x
x9
x
x
1:15
09:15
x
x
│
1:30
09:30
x
x
│
2:00
10:00
240 mL fluid intake3
x
x
│
x9
x
x
2:30
10:30
x
x
│
3:00
11:00
x
x
│
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x
┼
│
x
x
x
6:00
14:00
x
x
│
8:00
16:00
Snack (voluntary)3
x
x
┼
x
x
x
10:00
18:00
Dinner3
│
12:00
20:00
x
┼
x9
x
x 
2
24:00
08:00
Breakfast3
x
┼
x
x9
x13
x
3
48:00
08:00
Breakfast3
x
▼
x13
x
4
72:00
08:00
Breakfast3
x
x13
x


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Visit
Day
Planned time (relative to 
first drug administration) 
[h:min]
Approximate clock time   
of actual day [h:min]
Event and comment
Safety laboratory 15
PK blood BI 1595043 10, 18
PK blood Midazolam 10, 18
PK urine BI 1595043 10, 11, 18
PD blood 10, 19
PD urine 8, 10, 19
12-lead ECG 16
Vital signs (BP, PR) 17
Questioning for AEs and 
concomitant therapy 6
5
95:45
07:45
B
x
x
x
x9
x13
x
96:00
08:00
Drug administration
97:00
09:00
x9
x13
x
6
119:45
07:45
x
x9
x13
x
120:00
08:00
Drug administration
121:00
09:00
x9
x
x
7
143:45
07:45
x
x
x
x9
x13
x
144:00
08:00
Drug administration
145:00
09:00
x9
x
x
8
167:45
07:45
B
x
x13
x
168:00
08:00
Drug administration
169:00
09:00
x
x
9
191:45
07:45
x
x
x9
x13
x
192:00
08:00
Drug administration
193:00
09:00
x9
x
x
10
215:45
07:45
x
x13
x
216:00
08:00
Drug administration
217:00
09:00
x
x
11
239:45
07:45
x9
x13
x
240:00
08:00
Drug administration
241:00
09:00
x9
x
x
12
263:45
07:45
x
x
x
x13
x
264:00
08:00
Drug administration
265:00
09:00
x
x
13
287:45
07:45
B
x9
x13
x
288:00
08:00
Drug administration
289:00
09:00
x9
x
x
14
311:45
07:45
x13
x
312:00
08:00
Drug administration
313:00
09:00
x
x
15
335:45
07:45
x
x
x
x9
x13
x
336:00
08:00
Drug administration
337:00
09:00
x9
x
x
16
359:45
07:45
x13
x
360:00
08:00
Drug administration
361:00
09:00
x
x
17
383:45
07:45
x9
x13
x
384:00
08:00
Drug administration
385:00
09:00
x9
x
x
18
407:45
07:45
B
x
x
x2
x
x
x9
x13
x
408:00
08:00
Last drug administration 
& Midazolam 
administration
▲
│
│
408:15
08:15
x
x
│
408:30
08:30
x
x
│


Boehringer Ingelheim
23 Jul 2021
BI Trial No.: 1445-0002
c33929558-03
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Visit
Day
Planned time (relative to 
first drug administration) 
[h:min]
Approximate clock time   
of actual day [h:min]
Event and comment
Safety laboratory 15
PK blood BI 1595043 10, 18
PK blood Midazolam 10, 18
PK urine BI 1595043 10, 11, 18
PD blood 10, 19
PD urine 8, 10, 19
12-lead ECG 16
Vital signs (BP, PR) 17
Questioning for AEs and 
concomitant therapy 6
408:45
08:45
x
x
│
409:00
09:00
x
x
│
x
x9
x
x
409:15
09:15
x
x
│
409:30
09:30
x
x
│
410:00
10:00
240 mL fluid intake
x
x
│
x9
x
x
410:30
10:30
x
x
│
411:00
11:00
x
x
│
412:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x
┼
│
x
x9
x
x
414:00
14:00
x
x
│
416:00
16:00
Snack (voluntary)3
x
x
┼
x
x9
x
x
418:00
18:00
Dinner3
│
420:00
20:00
x
┼
x9
x
x 
19
432:00
08:00
Breakfast3
x
┼
x
x9
x13
x
442:00
18:00
x
│
x
20
455:45
7:45
B
│
x9
x13
x
456:00
08:00
Breakfast, confirmation of
fitness, discharge from trial 
site
x
▼
x
21
480:00
08:00
Ambulatory visit
x
x
22
504:00
08:00
Ambulatory visit
x
x
23
528:00
08:00
Ambulatory visit
x
24
552:00
08:00
Ambulatory visit
x
3
25 to 30
End of trial (EOT) 
examination4 
C
x
x13
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, ophthalmological examination (exclusion of ocular disorders), check of vital 
signs, assessment of body temperature, ECG, safety laboratory (including drug 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.
2.
The time is approximate; procedures are to be performed and completed within the 3 h prior to drug administration. 
Allocation to treatment may be performed at any time following enrolment but must be completed prior to first drug 
administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, ophthalmological examination 
(exclusion of ocular disorders), body weight, vital signs, assessment of body temperature, ECG, safety laboratory, 
recording of AEs, and concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
ambulatory visit can be omitted if the screening examination is performed on Days -4, -3, or -2.
8.
First morning urine to be collected for PD evaluation including an aliquot for creatinine analysis (for normalization of 
PD evaluation) (refer to Section 5.2.4 and 5.4).
9.
The ECG recording has to be performed in triplicate at this time. ECG recording will always precede all other study 
procedures scheduled for the same time point (e.g. blood sampling, measurement of vital signs) to avoid compromising 
ECG quality.


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10. Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK 
data) including addition of samples and visits as long as the total blood volume removed does not exceed 500 mL per 
subject.
11. A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24 and 24-48.
12. At baseline (i.e. Day 1, prior to drug administration), 3 triplicate ECGs are recorded within approximately one hour. 
The recordings should be separated by at least 15 minutes. 
13. Including assessment of body temperature.
14. PCR test for SARS-COV-2/ COVID-19 will be performed shortly (within 72 hours) before admission to trial site.
15. For details of safety laboratory testing at Visit 1 (A), Visit 2 (B) and Visit 3 (C) refer to Section 5.2.4 and 
Table 5.2.4: 1.
16. For details of 12-lead ECG, refer to Section 5.2.5.
17. For details of vital signs evaluation, refer to Section 5.2.2.
18. For details of PK blood/urine sampling for BI 1595043 and PK blood sampling for midazolam, refer to Section 5.3.2.
19. For details of PD blood/urine sampling, refer to Section 5.4.1.


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FLOW CHART C (DOSE GROUP 5)
60 mg b.i.d. of BI 1595043 or placebo
Visit
Day
Planned time (relative to 
first drug administration)
[h:min]
Approximate clock time   
of actual day [h:min]
Event and comment
Safety laboratory 15
PK blood BI 1595043 10, 18
PK urine BI 1595043 10, 11, 18
PD blood 10, 19
PD urine 8, 10, 19
12-lead ECG 16
Vital signs (BP, PR) 17
Questioning for AEs and 
concomitant therapy 6
1
-21 to -1
Screening (SCR)1,14
A
x
x13
2
-3 to -17
-72:00
08:00
Ambulatory visit14
B
x13
x
-1
-14:00
18:00
Admission to trial site
x5
x13
1
-1:00
07:00
Allocation to treatment2
x2
x2
x2
x2
x2,12
x2,13
x2
0:00
08:00
First drug (BI 1595043 or 
placebo) administration
▲
│
0:15
08:15
x
│
0:30
08:30
x
│
0:45
08:45
x
│
1:00
09:00
x
│
x
x9
x
x
1:15
09:15
x
│
1:30
09:30
x
│
2:00
10:00
240 mL fluid intake3
x
│
x9
x
x
2:30
10:30
x
│
3:00
11:00
x
│
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
┼
│
x
x
x
6:00
14:00
x
│
8:00
16:00
Snack (voluntary)3
x
┼
x
x
x
12:00
20:00
Drug administration
x
▼
13:00
21:00
x9
x
x
14:00
22:00
Dinner (voluntary)3
2
23:45
07:45
B
x
x
x9
x13
x
24:00
08:00
Drug administration
25:00
09:00
x9
x
x
36:00
20:00
Drug administration
37:00
21:00
x9
x
x
3
47:45
07:45
x
x
x
x9
x13
x
48:00
08:00
Drug administration
49:00
09:00
x9
x
x
60:00
20:00
Drug administration
61:00
21:00
x9
x
x
4
71:45
07:45
B
x
x13
x
72:00
08:00
Drug administration
73:00
09:00
x
x
84:00
20:00
Drug administration
85:00
21:00
5
95:45
07:45
x
x9
x13
x
96:00
08:00
Drug administration
97:00
09:00
x9
x
x
108:00
20:00
Drug administration


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Visit
Day
Planned time (relative to 
first drug administration)
[h:min]
Approximate clock time   
of actual day [h:min]
Event and comment
Safety laboratory 15
PK blood BI 1595043 10, 18
PK urine BI 1595043 10, 11, 18
PD blood 10, 19
PD urine 8, 10, 19
12-lead ECG 16
Vital signs (BP, PR) 17
Questioning for AEs and 
concomitant therapy 6
109:00
21:00
x9
x
x
6
119:45
07:45
x
x
x13
x
120:00
08:00
Drug administration
121:00
09:00
x
x
132:00
20:00
Drug administration
133:00
21:00
7
143:45
07:45
x9
x13
x
144:00
08:00
Drug administration
145:00
09:00
x9
x
x
156:00
20:00
Drug administration
157:00
21:00
x9
x
x
8
167:45
07:45
x
x
x
x13
x
168:00
08:00
Drug administration
169:00
09:00
x
x
180:00
20:00
Drug administration
181:00
21:00
9
191:45
07:45
B
x9
x13
x
192:00
08:00
Drug administration
193:00
09:00
x9
x
x
204:00
20:00
Drug administration
205:00
21:00
x9
x
x
10
215:45
07:45
x13
x
216:00
08:00
Drug administration
217:00
09:00
x
x
228:00
20:00
Drug administration
229:00
21:00
11
239:45
07:45
x
x
x
x9
x13
x
240:00
08:00
Drug administration
241:00
09:00
x9
x
x
252:00
20:00
Drug administration
253:00
21:00
x9
x
x
12
263:45
07:45
x13
x
264:00
08:00
Drug administration
265:00
09:00
x
x
276:00
20:00
Drug administration
277:00
21:00
13
287:45
07:45
x9
x13
x
288:00
08:00
Drug administration
289:00
09:00
x9
x
x
300:00
20:00
Drug administration
301:00
21:00
x9
x
x
14
311:45
07:45
B
x
x2
x
x
x9
x13
x
312:00
08:00
Last drug administration
▲
312:15
08:15
x
│
312:30
08:30
x
│


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Visit
Day
Planned time (relative to 
first drug administration)
[h:min]
Approximate clock time   
of actual day [h:min]
Event and comment
Safety laboratory 15
PK blood BI 1595043 10, 18
PK urine BI 1595043 10, 11, 18
PD blood 10, 19
PD urine 8, 10, 19
12-lead ECG 16
Vital signs (BP, PR) 17
Questioning for AEs and 
concomitant therapy 6
312:45
08:45
x
│
313:00
09:00
x
│
x
x9
x
x
313:15
09:15
x
│
313:30
09:30
x
│
314:00
10:00
240 mL fluid intake
x
│
x9
x
x
314:30
10:30
x
│
315:00
11:00
x
│
316:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
┼
│
x
x9
x
x
318:00
14:00
x
│
320:00
16:00
Snack (voluntary)3
x
┼
x
x9
x
x
322:00
18:00
Dinner3
│
324:00
20:00
x
┼
x9
x
x 
15
336:00
08:00
Breakfast3
x
┼
x
x9
x13
x
346:00
18:00
x
│
x
16
359:45
07:45
B
x
│
x9
x13
x
360:00
08:00
Breakfast, confirmation of 
fitness, discharge from trial site
x
▼
x
17
384:00
08:00
Ambulatory visit
x
x
18
408:00
08:00
Ambulatory visit
x
x
19
432:00
08:00
Ambulatory visit
x
20
456:00
08:00
Ambulatory visit
x
3
21 to 26
End of trial (EOT) examination4
C
x
x13
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, ophthalmological examination (exclusion of ocular disorders), check of vital 
signs, assessment of body temperature, ECG, safety laboratory (including drug 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.
2.
The time is approximate; procedures are to be performed and completed within the 3 h prior to drug administration. 
Allocation to treatment may be performed at any time following enrolment but must be completed prior to first drug 
administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, ophthalmological examination 
(exclusion of ocular disorders), body weight, vital signs, assessment of body temperature, ECG, safety laboratory, 
recording of AEs, and concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
ambulatory visit can be omitted if the screening examination is performed on Days -3, -2 or -1. 
8.
First morning urine to be collected for PD evaluation including an aliquot for creatinine analysis (for normalization of 
PD evaluation) (refer to Section 5.2.4 and 5.4).
9.
The ECG recording has to be performed in triplicate at this time. ECG recording will always precede all other study 
procedures scheduled for the same time point (e.g. blood sampling, measurement of vital signs) to avoid compromising 
ECG quality.


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10. Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK 
data) including addition of samples and visits as long as the total blood volume removed does not exceed 500 mL per 
subject.
11. A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12 on Day 1 and 0-4, 4-8, 8-12, 12-24 and 
24-48 on Days 14-16.
12. At baseline (i.e. Day 1, prior to drug administration), 3 triplicate ECGs are recorded within approximately one hour. 
The recordings should be separated by at least 15 minutes. 
13. Assessment of body temperature.
14. PCR test for SARS-COV-2/ COVID-19 will be performed shortly (within 72 hours) before admission to trial site.
15. For details of safety laboratory testing at Visit 1 (A), Visit 2 (B) and Visit 3 (C) refer to Section 5.2.4 and 
Table 5.2.4: 1.
16. For details of 12-lead ECG, refer to Section 5.2.5.
17. For details of vital signs evaluation, refer to Section 5.2.2.
18. For details of PK blood/urine sampling for BI 1595043, refer to Section 5.3.2.
19. For details of PD blood/urine sampling, refer to Section 5.4.1.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
FLOW CHART A (DOSE GROUPS 1-2) ....................................................................4
FLOW CHART B (DOSE GROUPS 3-4).....................................................................7
FLOW CHART C (DOSE GROUP 5)........................................................................11
TABLE OF CONTENTS ................................................................................ 15
ABBREVIATIONS.......................................................................................... 20
1.
INTRODUCTION.................................................................................... 23
1.1
MEDICAL BACKGROUND............................................................................23
1.2
DRUG PROFILE...............................................................................................23
BI 1595043 .............................................................................................23
Nonclinical pharmacology.......................................................24
Toxicology...............................................................................26
Nonclinical pharmacokinetics..................................................30
Residual Effect Period .............................................................36
Drug product ............................................................................36
Midazolam .............................................................................................36
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................36
Starting Dose .........................................................................................37
Maximum dose ......................................................................................38
Maximum exposure ..............................................................................38
Escalation scheme .................................................................................39
1.4
BENEFIT - RISK ASSESSMENT ...................................................................39
Expected benefit for the target indication ..........................................40
Procedure-related risks ........................................................................40
Drug-related risks and safety measures..............................................40
Mode of action and nature of the target...................................40
Relevance of animal models....................................................41
Findings in non-clinical safety studies.....................................41
Clinical experience with BI 1595043 ......................................42
Midazolam ...............................................................................43
Drug induced liver injury.........................................................43
Safety measures .......................................................................43
Overall assessment................................................................................44
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 45


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2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......45
Main objectives......................................................................................45
Primary endpoint..................................................................................45
Secondary endpoints.............................................................................45
Safety and tolerability..............................................................46
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 49
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................49
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................51
3.3
SELECTION OF TRIAL POPULATION ......................................................52
Main diagnosis for trial entry..............................................................52
Inclusion criteria...................................................................................52
Exclusion criteria ..................................................................................53
Withdrawal of subjects from treatment or assessments ...................54
Discontinuation of trial treatment............................................54
Withdrawal of consent to trial participation ............................55
Discontinuation of the trial by the sponsor..............................55
Replacement of subjects .......................................................................56
4.
TREATMENTS........................................................................................ 57
4.1
INVESTIGATIONAL TREATMENTS ..........................................................57
Identity of the Investigational Medicinal Products ...........................57
Selection of doses in the trial................................................................58
Method of assigning subjects to treatment groups ............................59
Drug assignment and administration of doses for each subject .......59
Blinding and procedures for unblinding ............................................61
Blinding61
Unblinding and breaking the code...........................................62
Packaging, labelling, and re-supply ....................................................63
Storage conditions.................................................................................63
Drug accountability ..............................................................................63
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................64
Other treatments and emergency procedures....................................64
Restrictions............................................................................................64
Restrictions regarding concomitant treatment .........................64
Restrictions on diet and life style.............................................64
4.3
TREATMENT COMPLIANCE.......................................................................65


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5.
ASSESSMENTS....................................................................................... 67
5.1
ASSESSMENT OF EFFICACY.......................................................................67
5.2
ASSESSMENT OF SAFETY............................................................................67
Physical examination ............................................................................67
Vital signs...............................................................................................67
Ophthalmological examination............................................................67
Safety laboratory parameters..............................................................67
Electrocardiogram................................................................................70
12-lead resting ECG.................................................................70
Other safety parameters.......................................................................72
Assessment of adverse events...............................................................72
Definitions of adverse events...................................................72
Adverse event ............................................................72
Serious adverse event ................................................73
AEs considered ‘Always Serious’.............................73
Adverse events of special interest .............................74
Intensity (severity) of AEs.........................................74
Causal relationship of AEs ........................................74
Adverse event collection and reporting ...................................75
AE collection.............................................................75
AE reporting to the sponsor and timelines ................76
Information required..................................................76
Pregnancy ..................................................................76
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................77
Assessment of pharmacokinetics .........................................................77
Methods of sample collection...............................................................77
Blood sampling for pharmacokinetic analysis.........................77
Blood sampling for metabolism analysis.................................78
Urine sampling for pharmacokinetic analysis..........................79
Pharmacokinetic - pharmacodynamic relationship...........................81
5.4
ASSESSMENT OF BIOMARKERS................................................................81
Methods of sample collection...............................................................81
5.5
BIOBANKING ...................................................................................................82
5.6
OTHER ASSESSMENTS .................................................................................82
Pharmacogenomic evaluation..............................................................82
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................83
6.
INVESTIGATIONAL PLAN.................................................................. 84
6.1
VISIT SCHEDULE............................................................................................84


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................84
Screening period....................................................................................84
Treatment period ..................................................................................84
Follow-up period and trial completion ...............................................85
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 86
7.1
STATISTICAL DESIGN – MODEL ...............................................................86
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................86
7.3
PLANNED ANALYSES....................................................................................86
Primary endpoint analyses...................................................................88
Secondary endpoint analyses ...............................................................88
Safety analyses.......................................................................................91
Pharmacokinetic - pharmacodynamic analysis..................................92
7.4
INTERIM ANALYSES .....................................................................................92
7.5
HANDLING OF MISSING DATA ..................................................................93
Safety......................................................................................................93
Pharmacokinetics..................................................................................93
7.6
RANDOMISATION ..........................................................................................93
7.7
DETERMINATION OF SAMPLE SIZE ........................................................93
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 95
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................95
8.2
DATA QUALITY ASSURANCE .....................................................................96
8.3
RECORDS..........................................................................................................96
Source documents .................................................................................96
Direct access to source data and documents.......................................97
Storage period of records.....................................................................97
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................97
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......97
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................98
8.6
TRIAL MILESTONES .....................................................................................98
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................99
9.
REFERENCES....................................................................................... 100
9.1
PUBLISHED REFERENCES.........................................................................100


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9.2
UNPUBLISHED REFERENCES...................................................................101
10. APPENDICES ........................................................................................ 104
10.1
DRUG SUPPLIES USED FOR DILUTION AND DOSING.......................104
Drug supplies overview.......................................................................104
Required equipment and dosing aids – overview.............................104
Dilution procedure..............................................................................105
In-use stability.....................................................................................105
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 106
11.1
GLOBAL AMENDMENT 1 ...........................................................................106
11.2
GLOBAL AMENDMENT 2 ...........................................................................108


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2
Amount of analyte eliminated in urine over the time interval t1 to t2
ALT
Alanine amino transferase
ANOVA
Analysis of variance
AST
Aspartate amino transferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 extrapolated to infinity
AUC0-24
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 extrapolated 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
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
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
BA
Bioavailability
BI
Boehringer Ingelheim
b.i.d.
Bis in die (twice daily)
BCS
Biopharmaceuticals Classification System
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
Cavg
Average concentration of the analyte in plasma at steady state over a 
uniform dosing interval τ
CD
Crohn’s disease
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
Cmin
Minimum measured concentration of the analyte in plasma
CNS
Central nervous system
Cpre,N
Predose concentration of the analyte in plasma immediately before 
administration of the Nth dose after N-1 doses were administered
CRF
Case Report Form, paper or electronic (sometimes referred to as 
‘eCRF’)
CTM
Clinical Trial Manager


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CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DDI
Drug Drug Interaction
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
fet1-t2
Fraction of administered drug excreted unchanged in urine over the time 
interval from t1 to t2
FIH
First In Human
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
IV
Intravenous
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
LOAEL
Lowest Observed Adverse Effect Level
MCT
Melanin-containing tissues
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MIST
Metabolites in Safety Testing
MRD
Multiple-rising dose
MRT,ex
Mean residence time of the analyte in the body, extravascular
MRT,ex,ss
Mean residence time of the analyte in the body, extravascular at steady 
state
NOAEL
No Observed Adverse Effect Level
NOD
Nucleotide Oligomerization Domain
PCR
Polymerase Chain Reaction


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PD
Pharmacodynamic(s)
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PO
Per oral
PP
Polypropylene
PR
Pulse rate
PTF
Peak-trough fluctuation
PTS
Peak-trough swing
q.d.
Quaque die (once daily)
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
RA,AUC
Accumulation ratio based on AUC0-τ
RA,Cmax
Accumulation ratio based on Cmax,ss
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SNP
Single nucleotide polymorphism
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
T
Test product or treatment
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
TMF
Trial master file
TNF
Tumor necrosis factor
TS
Treated set
TSAP
Trial statistical analysis plan
tz
Time of last measurable concentration of the analyte in plasma
ULN
Upper limit of normal
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
XTC
Ecstasy


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Crohn’s disease (CD) is characterized by transmural inflammation with ulcerative lesions
affecting any site within the gastrointestinal tract, with most frequent involvement of terminal
ileum, often combined with inflammation in colon. CD incidence and prevalence have been
rising in all ethnic groups; the recent incidence and prevalence have been reported to range
from 7.9 to 20.2 and from 161 to 319 per 100,000, respectively (R13-2231). CD typically
follows a relapsing and remitting course, and causes substantial acute and long-term
morbidity and increased mortality. Patients often develop local complications (e.g. fistulas,
abscesses, strictures, or perforation), systemic complications (e.g. uveitis, arthritis), or side
effects of treatment, and may require major surgery. Roughly a third of patients fall into each 
of the categories of mild, moderate, and severe disease.
Unmet need in CD is highest in patients with moderate to severe disease. Patients not
responding to conventional therapy of orally administered aminosalicylates (e.g. 5-ASA),
glucocorticoids and immunomodulator agents (azathioprine or 6-MP), are treated with
biologic TNFα inhibitors (TNFi). Induction therapy with a TNFi results in clinical remission
in fewer than 50% of patients, and only about 25% of patients achieve mucosal healing.
Another 30-40% of patients receiving TNFi have only a limited response, or lose their
response over time (maintenance therapy). Additionally, there remain concerns over infection
and lymphoma risks with these agents. Additional biologic options (vedolizumab,
ustekinumab) offer alternative additional treatments options for patients who fail TNFi, but
response rates to these agents do not exceed those associated with TNFi treatment. Medical
treatment options for fistulizing and fibrotic disease remain limited. Thus, a substantial unmet
need remains for agents with greater efficacy than current therapies, either as a standalone
therapy or in combination with existing therapies.
In CD, vanin enzymes are dysregulated and are linked to development of epithelial barrier
injury through their product cysteamine (R18-3167, R17-3322, R17-3323). As described in
Section 5.2, by reducing cysteamine levels, a vanin inhibitor is expected to provide the
epithelial barrier with a broad protective effect against diverse disease-driving stimuli,
leading to direct epithelial barrier repair resulting in mucosal healing. In addition, a vanin
inhibitor is expected to attenuate chronic inflammation underlying the disease. Oral
medicines with a novel mode of action that includes repair of epithelial barrier (leading to
mucosal healing) would be particularly attractive for the current unmet need in CD and will
provide an additional benefit of convenience of oral vs. parenteral treatments. Therefore,
Boehringer Ingelheim is starting a clinical development program for a vanin inhibitor
candidate, BI 1595043.
1.2
DRUG PROFILE
BI 1595043
Vanin-1 and -2 (Vascular Non-Inflammatory molecules 1 and 2) are extracellular enzymes
expressed on epithelial cells, macrophages, monocytes, T-cells and neutrophils, shed in


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significant amounts into the extracellular milieu, and found in most extracellular
compartments across tissues.
Inflammatory mediators and bacterial endotoxins drive expression of vanin-1 and 2 enzymes,
whose common function is to convert pantetheine into pantothenic acid and cysteamine. It is
through production of cysteamine that vanin enzymes directly impact extracellular metabolic
homeostasis of tissues by depleting cystine in tissues through reducing it to cysteine. Cystine
depletion is understood to alter the intracellular redox balance of tissues, resulting in
increased oxidative stress, endoplasmic reticular stress, and disruption and eventual
destruction of tissue. In addition, cystine depletion is postulated to result in increased
extracellular cysteine levels, enhancing adaptive immune response, increasing CD4+ T-cell
production of pro-inflammatory cytokines IFNγ, IL-4, IL-5 and IL-13.
Therefore, it is expected that inhibition of vanin enzyme function will directly restore tissue 
metabolite homeostasis and redox balance leading to tissue repair, while curbing chronic 
inflammation, which could prove beneficial in diseases characterized by tissue lesions and 
ulceration as well as the presence of chronic inflammation.
For consistency of nomenclature, vanin-1 and vanin-2 isoforms, unless referenced otherwise, 
will be referred to as vanin.
Nonclinical pharmacology
Primary pharmacodynamics
In vitro primary pharmacodynamics
In a human recombinant vanin-1 enzyme activity assay (n00273892), measuring pantothenic 
acid product formation, formed in a 1:1 ratio with cysteamine through cleavage of pantethine, 
BI 1595043 inhibited vanin-1 with an IC50 of 0.17 nM. In human whole blood, containing 
both vanin-1 and vanin-2 (n00273893), BI 1595043 inhibited vanin activity with a mean IC50
value of 1.9 nM. In a human ex vivo colon tissue assay, using non-inflammatory bowel 
disease human colon explants (n00273895), BI 1595043 inhibited vanin activity and lowered 
release of cytokeratin-18 (CK-18). CK-18 is a marker of epithelial injury, elevation of which 
is a hallmark of diseases of the epithelial barrier (R18-2868). Reduction of CK-18 was
interpreted as a signal of epithelial healing. The effect of BI 1595043 on T-lymphocyte 
activity, measured by cytokine production (IFN gamma, IL-4, IL-13, IL-5), was tested in 
human CD3/CD28 stimulated T-cells (n00273897). Cytokine production was significantly 
reduced in a majority of donors, which was interpreted as a sign of decreased inflammation.
In vivo primary pharmacodynamics
In a model of dextran sodium sulfate (DSS) mediated intestinal injury in C57Bl/6 mice 
(n00273898), BI 1595043 demonstrated target engagement, as measured by decreased levels 
of the vanin product, pantothenic acid, in both central plasma compartments and target colon 
tissue, as well as increased levels of the vanin substrate, pantetheine, in the plasma. Mice 
treated with BI 1595043 showed reduced epithelial damage assessed by histology score, but 
formation of inflammatory infiltrate was not significantly altered with BI 1595043. 
BI 1595043 did not reduce intestinal permeability (assessed by detection of sucralose uptake 


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through the colon). While other vanin inhibitors similar to BI 1595043, tested in separate 
studies (n00259753), showed reduction of inflammation and improved barrier integrity, in 
BI 1595043’s case a trend was observed that fell short of statistical significance.
Safety pharmacology
General and safety pharmacology studies have been conducted with BI 1595043 to assess 
possible effects on cardiovascular, CNS, respiratory, renal and hepatic function.
Cardiovascular system
BI 1595043 was tested for blocking hERG-mediated potassium current in HEK293 cells 
(n00270147). BI 1595043 inhibited the current with the IC50 of 157.88 μM or 233-times the 
estimated human therapeutic Cmax. Effect of BI 1595043 on cardiovascular function was 
assessed in conscious male telemetry-instrumented Beagle dogs at oral doses of 3, 10 or 
200 mg/kg (n00271655). At doses of 3 and 10 mg/kg, no BI 1595043-related abnormalities 
were observed. At 200 mg/kg of BI 1595043, decrease in blood pressure with accompanying
increase in heart rate were observed.
Respiratory system
BI 1595043 effects on the respiratory function was assessed at single oral doses of 10, 50 or 
300 mg/kg in rat (n00270318). At doses of 10 and 50 mg/kg, BI 1595043 had no effect on 
the respiratory system. Rats administered 300 mg/kg had mildly lower tidal volume from 
1 through 3 h post-dose and slightly lower minute volume from 1 through 2 h post-dose.
Central nervous system
BI 1595043 effects on neurological function were assessed in rat at single oral doses of 10, 
50 or 300 mg/kg (n00270317). With the exception of transiently lower body temperature at 
300 mg/kg, no effects of BI 1595043 were observed up to 24 hours post-dose.
Renal and hepatic system
The effect of BI 1595043 on urine- and serum-derived parameters was evaluated in rat after a 
single oral dose of 1, 3 or 10 mg/kg (n00275784). BI 1595043 had no relevant effect on 
urinary excretion or serum-based parameters following the oral doses of 1 and 3 mg/kg for 
most parameters assessed. Following the 10 mg/kg dose, BI 1595043 caused only slight 
effects on renal function or renal injury markers during 4 h post-dose.
Further considerations on safety pharmacology
In a vanin-1 knock-out/NOD diabetic mouse model, vanin deficiency aggravated islet cell 
death and diabetes, whereas treatment with super-physiological levels of cysteamine reduced 
pancreatic islet cell death and thus might play a role in islet cell protection (R17-3327). Other 
findings suggest that elevated expression of vanin-1 in pancreatic ductal adenocarcinoma 
cells aggravated loss of pancreatic islet function and was associated with the onset of 
pancreatic cancer-associated new-onset diabetes (R18-2866). However, further studies, 


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assessing the metabolic impact of vanin-1 deficiency, absence of vanin-1 either in knock-out 
mice or by pharmacological inhibition, did not impact glycemic control (R18-2867). 
Pharmacological inhibition of vanin-1 in diabetic rats for 8 days using RR6, a small molecule 
vanin-1 inhibitor, was well tolerated and showed no significant effects on hepatic steatosis in 
diabetic rats (R18-2867). These diverse data suggest that BI 1595043 might impact islet cell 
survival and glycemic control although the findings of different studies are contradictory. 
Thus far conducted safety pharmacology, genetic toxicology and general toxicology studies 
did not indicate any toxicity of BI 1595043 related to glycemic control.
A human missense single nucleotide polymorphism (SNP) (rs2272996) in the gene encoding 
vanin-1 is associated with decreased blood pressure, with the SNP causing faster degradation 
of vanin-1 and significant reduction of vanin-1 plasma levels (R18-2692).
Pharmacodynamic interactions
No pharmacodynamics interaction studies have been carried out to date.
Conflicting literature exists regarding effect of vanin inhibition on acetaminophen 
(paracetamol) toxicity. An earlier study (R18-2954) suggested that vanin-1 deficiency (in 
knock-out mice) might protect mice against acetaminophen-induced liver toxicity. In another 
(R17-3326), acetaminophen-induced liver toxicity was exacerbated in vanin-1 knock-out 
mice compared to wild type littermates.
For a more detailed description of the BI 1595043 profile, please refer to the current 
Investigator’s Brochure (IB) (c31270124).
Toxicology
The nonclinical safety program investigating the in vivo toxicological profile of BI 1595043 
comprised repeat-dose studies up to 13 weeks of once daily oral treatment in rats and dogs 
and a complete battery of in vitro and in vivo studies assessing the genotoxic and phototoxic 
potential of the compound. Rats and Beagle dogs were employed as suitable animal species 
for general toxicology investigations (see Section 1.4.3.2).
A comprehensive detailed description of the BI 1595043 profile is provided in the current IB 
(c31270124). Main findings are summarized in the following sections.
Single dose toxicity
Single-dose toxicity studies were not conducted but acute toxicity information was obtained 
from short-duration toxicity studies, in which high doses of BI 1595043 were administered. 
BI 1595043-related effects were observed in rats at ≥300 mg/kg and in dogs at 200 mg/kg 
after single dose administration. 
In an in vivo genotoxicity assay in rats (n00271724), clinical signs of piloerection, crusty eye 
and hunched posture were observed after administration of 500 mg/kg/day (250 mg/kg BID, 
2 h apart). Decreased motor activity, slight labored breathing, piloerection, and hunched 
posture were noted after administration of 1000 mg/kg/day (500 mg/kg BID, 2 h apart) for 
one day. At 2000 mg/kg/day (1000 mg/kg BID, 2 h apart) in addition to the clinical signs 


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observed at the lower doses, squinty eyes were noted. BI 1595043 induced a reduction in 
body weight gain at 1000 mg/kg/day. Three of six animals administered 2000 mg/kg/day 
were found dead on day 2 (n00271724).
Details of BI 1595043-related effects observed following single doses in a rat CNS study 
(transiently lower body temperature at 300 mg/kg) (n00270317), a rat respiratory study 
(transiently lower tidal and minute volumes at 300 mg/kg) (n00270318) and a dog 
cardiovascular function study (decrease in blood pressure with increase in heart rate) 
(n00271655) are detailed in Section 1.2.1.1. In the dog cardiovascular function study 
(n00271655), at 200 mg/kg, post-dose vomitus was observed in 5 out of 10 animals.
Repeated dose toxicity
In a 13-week GLP study in Wistar Han rats, BI 1595043 was administered for 13 weeks at 
oral doses of 10, 50 and 300 mg/kg/day, followed by a 10-week recovery period (n00268703). 
No mortality was observed. No BI 1595043-related effects on clinical signs or urinalysis 
were observed at any dose level.
At doses of ≥10 mg/kg/day, non-adverse body weight gain increase was observed in males 
and females.
At doses of ≥50 mg/kg/day, non-adverse effects were observed: increased thyroid gland 
weight in male and female without microscopic correlate; decreased AST in male and female.
At doses of 300 mg/kg/day, non-adverse effects were observed: body weight gain reduced in 
males and females; increased kidney weight in males and females without microscopic 
correlate; increased liver weight in males and females correlating to hepatocellular 
hypertrophy (diminished but not absent at the end of recovery); increased mean white blood 
cell counts and absolute lymphocytes counts in males and females (of lower magnitude at the 
end of recovery, suggesting reversibility of the effect); increased total T cell, T helper cell, 
T cytotoxic cell and B cell numbers in males (generally within range of control males at the 
end of recovery, suggesting reversibility of the effect); increased ALT in males and females, 
likely correlated with the incidence of hepatocellular hypertrophy and increase in 
hepatocellular microsomal enzyme activity.
Also, at doses of 300 mg/kg/day, adverse testicular changes (abnormal spermatogenesis, 
minimal spermatid retention) and adverse minimal-to-mild debris within duct lumen of the 
epididymides were observed in males, not present at the end of the recovery phase. The 
findings were considered adverse because they may indicate disruption of the normal 
spermatogenic cycle that could result in effects on fertility (R18-2864).
Ophthalmology findings:
During pretest-evaluation, no abnormalities were identified by indirect ophthalmoscopy. At the 
end of BI 1595043 dosing, unilateral or bilateral visualization of cataract was noted, a descriptive 
term used synonymous with a change in lens opacity, in rats in the 50 mg/kg/day group (1/20 rats
with unilateral cataract) and 300 mg/kg/day group (8/20 male [7 bilateral and 1 unilateral] and 
7/20 female rats [all bilateral]). No abnormalities were observed in control animals. At the end of 
recovery, this finding was observed in a total of 0/10 male and 4/10 female rats from the control 
group and 9/10 males (all bilateral) and 8/10 females (all bilateral) from 300 mg/kg/day group.
Thus, the finding was not reversible at the end of recovery. However, upon thorough histologic 


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examination, there was no microscopic evidence of cataract formation correlating to any of these 
ophthalmoscopic observations in any rats. Due to a lack of histologic correlate, this finding is 
considered non-adverse.
Under the conditions of this study the NOAEL at steady state was considered to be 
50 mg/kg/day, which corresponded to a Cmax of 39,900 nM and AUC0-24 of 188,000 nM•h in 
males and Cmax of 50,500 nM and AUC0-24 of 240,000 nM•h in females. As compared to the 
estimated human exposure at the predicted therapeutic dose, exposures at the NOAEL are 
about 58- and 75- fold higher for Cmax in male and female respectively; and 54- and 69-fold 
higher for AUC in male and female respectively.
In a 13-week GLP study in Beagle dogs with a 10-week recovery period (n00270419), 
BI 1595043 was administered for at least 13 weeks in low- and mid-dose groups at oral doses 
of 3 and 10 mg/kg/day. High dose group dogs were given 200 mg/kg/day on days 1 and 2, 
which was reduced to 100 mg/kg/day on day 3 due to adverse vomitus/emesis. The female 
high dose dogs received 100 mg/kg/day from day 3 to the end of the dosing phase. Due to 
poor tolerability, male dogs in the high dose group receiving 100 mg/kg/day were not dosed 
between days 21 and 34; dosing resumed on day 35 at 30 mg/kg/day for the remainder of the 
dosing phase.
BI 1595043-related moribundity occurred in one male dog at the 100 mg/kg/day dose level
and resulted in humane euthanasia on day 16. Decrease in body weight corresponded to 
decreased food consumption, instances of liquid feces, vomitus, salivation, shivering or 
trembling and dehydration were observed. On day 16, results of blood tests showed increased 
absolute lymphocytes, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, and 
gamma-glutamyl transferase. At necropsy, the macroscopic observation of depressed foci in 
the liver corresponded microscopically to moderate panlobular hepatocellular degeneration 
with slight bile duct hyperplasia and moderate mononuclear parenchymal infiltrate. The 
macroscopic observation of abnormal coloration of the lung correlated microscopically to 
severe acute alveolar inflammation; and laryngeal ulcer. Decreased cellularity in the axillary 
lymph node and moderate decreased cellularity in the thymus.
There were no BI 1595043-related effects on ophthalmology, physical examinations,
urinalysis or immunophenotyping observed at any dose level.
At doses of 3 mg/kg/day and 10 mg/kg/day, no abnormalities were observed.
At doses of 30 mg/kg/day, reversible adverse effects on the liver was seen in males consisted 
of hepatocellular degeneration and loss of parenchyma (not evident in recovery animals).
At doses of ≥100 mg/kg/day, reversible non-adverse effects were observed: increases in mean 
heart rate in females; changes in hematology parameters (increased in red blood cell 
parameters (mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution 
width), increased absolute neutrophils, decreased mean platelet volume) in females; increases 
in partial thromboplastin time and activated partial thromboplastin time in a single male dog; 
increase in mean triglycerides in males and females; increased creatinine in females.
Also, at doses of ≥100 mg/kg/day, administration of BI 1595043 resulted in adverse 
reactions: vomitus/emesis at 200 mg/kg/day which required dose reduction (to 
100 mg/kg/day in females and 30 mg/kg/day in males); shivering or trembling in males 
at 200 mg/kg/day (decreased in frequency with a reduction in dose to 100 mg/kg/day); 


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decreases in body weight and food consumption in males and females (comparable to control 
at the end of recovery); reversible increases in ALT, AST and alkaline phosphatase in males 
and females; increases in total bilirubin, direct bilirubin and gamma-glutamyl transferase in a 
single male correlated microscopically to slight periportal hepatocellular degeneration.
Under the conditions of this study the NOAEL at steady state was considered to be 
10 mg/kg/day, which corresponded to a Cmax of 8,550 nM and AUC0-24 of 81,700 nM•h in 
males and Cmax of 10,700 nM and AUC0-24 of 81,400 nM•h in females. As compared to the
estimated human exposure at the predicted therapeutic dose, exposures at the NOAEL are 
about 13- and 16- fold higher for Cmax in male and female respectively, and about 23- fold 
higher for AUC in both sexes.
Genotoxicity
BI 1595043 was not mutagenic in the bacterial reverse gene mutation (Ames) test 
(n00271737) up to the dose limit of 5000 μg/ plate, and in the in vitro micronucleus assay 
(n00271739) up to the dose limit of 1 mM. In the in vivo rat bone marrow micronucleus 
assay (n00271724), BI 1595043 was concluded to be negative up to dose levels of 
1000 mg/kg/day. Evaluation at the highest dose level of 2000 mg/kg/day was not 
conducted due to the overt clinical signs and mortality (see Section 1.2.1.2).
Carcinogenicity
Carcinogenicity studies have not yet been conducted.
Reproductive and developmental toxicity
Definitive embryo-fetal development toxicity studies have been completed in rat and rabbit 
(n00278622, n00278281). Maternal and embryo-fetal toxicity were not observed in these 
studies (rat NOAEL AUC 125,000 nM•h and Cmax 25,500 nM, rabbit NOAEL AUC 323,000 
nM•h and Cmax 97,400 nM). Teratogenicity (digit malformations) was observed in rat 
(LOAEL AUC 6,900  nM•h and Cmax 2,270 nM) (n00278622). Teratogenicity was not 
observed in rabbit (NOAEL AUC 323,000 nM•h and Cmax 97,400 nM) (n00278281).
In the 13-week rat study (n00268703), there were adverse microscopic effects on the testis 
and epididymis at 300 mg/kg/day of BI 1595043 in males (see Section 1.2.1.2). No adverse 
effects on the reproductive tract were seen at 50 mg/kg/day in males, and at doses up to 
300 mg/kg/day in female rats. No effects on the reproductive tract were seen in the 13-week 
dog study (n00270419).
Local tolerance
No local tolerance studies have been conducted.
Other toxicity studies
BI 1595043 exhibits an absorption band in the spectral region of 290-700 nm with 
absorbance peaks at 290 and 310 nm (molar extinction coefficient of 12505 L mol-1 cm-1 in 
PBS) (n00267953). In an in vitro assay using BALB/c 3T3 mouse fibroblasts (n00272671), 


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BI 1595043 did not demonstrate phototoxic potential up to concentrations of 100 μg/mL. 
Overall, it is considered that BI 1595043 is unlikely to cause phototoxicity at clinically 
relevant doses.
For a more detailed description of the BI 1595043 profile, please refer to the current IB 
(c31270124).
Nonclinical pharmacokinetics
Methods of analysis
To support GLP toxicity studies, GLP LC/MS/MS assay methods were validated for 
quantification of BI 1595043 in rat plasma (lower limit of quantitation (LLOQ): 5.00 nM) 
(n00270399), dog plasma (LLOQ: 15.0 nM) (n00270319), and rabbit plasma (LLOQ: 
5.00 nM) (n00275663).
Absorption
The pharmacokinetics (PK) of BI 1595043 following single intravenous (IV) or oral (PO)
doses were investigated in male Wistar Han rats, male beagle dogs, and female minipigs
(n00274794).
The PK parameters in animals (n00274794) are summarized in Table 1.2.1.3: 1. The 
disposition of BI 1595043 is characterized in rats, dogs and minipigs by low-to-moderate 
clearance (CL) and a moderate volume of distribution (Vss). The half-life (t1/2) was short in 
rats, short-to moderate in dogs, and moderate-to-long in minipigs. The bioavailability (BA) 
in rats and dogs was high, while the BA in minipigs was moderate.
Table 1.2.1.3: 1
Mean PK parameters in rats, dogs and minipigs for BI 1595043
PK Parameter
Male Han Wistar Rat
(n=3 mean ± SD)
Male Beagle Dog
(n=3, mean ±SD)
Female Minipig
(n=3, mean ± SD)
Route of 
Administration
IV
PO
IV
PO
IV
PO
Dose (mg/kg)
11
12
0.4
4
0.4
4
CL 
(mL/min/kg)
18.6 ± 4.6
--
6.6 ± 0.4
--
10.8 ± 4.2
--
Vss (L/kg)
2.32 ± 0.49
--
1.70 ± 0.14
--
2.43 ± 0.12
--
t1/2 (h)
3.0 ± 0.66
3.11 ± 0.75
4.30 ± 0.72
8.68  ± 1.60
12.1 ± 0.83
8.63 ± 1.30
tmax (h)
median (range)
--
2
(2-2)
--
0.83
(0.5-1)
--
3
(2-4)
Cmax (nM)
--
7,850 ± 2,920
--
5,097 ± 365
--
293 ± 119
AUC0-inf
(nM•h)
2,370 ±670
22,100 ± 7,290
2,550 ± 140
27,570 ± 4,110
1,750 ± 770 4,740 ± 1,380
Ae renal
(% dose)
±
17.7 ± 5.2
19.6 ± 4.1
11.8 ± 1.0
6.7 ± 2.1
1.0 ± 0.49
Renal CL 
(mL/min/kg)
±
3.5
1.3 ± 0.27
0.73 ± 0.15
0.77 ± 0.45
0.35 ± 0.06
BA (%) 2
--
72.5 3
--
119
--
21.9


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1.
Three IV dose levels (0.01, 0.1, 1 mg/kg) were tested in the rat. The results of the highest dose tested are represented in 
this table.
2.
BA values are model based and incorporate non-linear binding to target.
3.
Rat BA was calculated based on modeling of all available rat PK data.
Distribution
Plasma protein binding
The binding of [14C]-BI 1595043 to plasma proteins was assessed in rat, dog and human 
plasma in vitro by equilibrium dialysis (n00275691). Binding in rat and human plasma is 
concentration-dependent due to saturable binding to target in plasma, ranging from 60.5-45.8% 
bound in rat plasma at concentrations from 0.001 to 100 μM, and 78.5% - 49.5% bound in 
human plasma at concentrations from 0.001 to 1 μM. Concentration-dependent binding was 
not observed in dog plasma (46.2% - 43.4% bound at all concentrations tested).
Distribution in pigmented rat
Quantitative tissue distribution of total drug-related radioactivity was investigated in male
pigmented (Long-Evans) rats administered a single 10 mg/kg oral dose of [14C]-BI 1595043
(n00273365).
As measured by autoradiography, tissue:plasma ratios were variable, ranging from 0.045 to 
15 at 1 h post dose. At 24 h post dose, tissue:plasma ratios ranged from not detectable to 650, 
with the highest levels of radioactivity found in the liver, renal cortex, skin, cutis, eyeball, 
and melanin-containing tissues (MCT) of the ocular bulb. At 168 h post dose radioactivity 
was not measurable in any tissue. Radioactivity was detectable in the CNS only at 1 h post 
dose at levels of up to 8.1% in relation to the levels in whole blood. These results suggest low 
penetration of [14C]-BI 1595043 into the CNS.
The approximate half-lives (β-phase) of radioactivity in total eyeball and MCT of the ocular
bulb, based on limited data (2 data points) from 24 to 168 h, were 42 and 45 h, respectively.
The approximate half-life of radioactivity in plasma was determined to be 3.3 h. These data 
indicate high affinity and long-term (yet reversible) exposure of radioactivity to ocular tissues. 
In the skin and cutis, approximate half-lives calculated from 1 to 24 h were 12 and 15 h, 
respectively. These data indicate moderate affinity and medium-term exposure of 
radioactivity to the integumentary system.
Metabolism
Data from hepatocyte incubations, conducted in both human and preclinical species (rat, dog,
minipig), in addition to in vivo data from preclinical species, were used to predict human
hepatic clearance. From this in vitro - in vivo correlation, hepatic clearance in human was
estimated to be 1.7 mL/min/kg. Based on this estimate, hepatic clearance is considered to be
the major route of elimination in humans. Additionally, renal clearance was estimated to be
0.4 mL/min/kg based on data scaled from non-rodent species (n00274794).


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Excretion
In Wistar Han rats, excretion of radioactivity was assessed after a PO dose (10 mg/kg) or an
IV dose (2 mg/kg) of [14C]-BI 1595043 (n00275520). Little to no difference in excretion
patterns were noted between PO and IV dosing, indicating good absorption.
Following the PO dose and collection of urine up to 96 h, 30.8% and 51.1% of the 
administered radioactivity was recovered from male and female rats, respectively, while the 
recovery of total radioactivity in feces was 62.8% and 43.7% in male and female rats, 
respectively. These data indicate slight differences in excretion patterns between male and 
female rats, with female rats showing slightly more urinary excretion than male rats, and 
male rats showing slightly more fecal excretion than female rats.
The excretion of radioactivity after IV and PO dosing was rapid, with >90% of dosed 
radioactivity recovered within 24 h for both male and female rats.
In bile duct cannulated rats administered an IV dose of [14C]-BI 1595043 the biliary excretion 
within 6 h was 28.0%. This time course in bile suggests that biliary excretion is not 
completed within this time interval.
Pharmacokinetic drug interactions
No pharmacokinetic drug interaction studies have been conducted.
Toxicokinetics
PK parameters were assessed in GLP-toxicological studies (n00268703, n00270419) and are 
displayed in Table 1.2.1.3: 2:
Table 1.2.1.3: 2
PK parameters in GLP toxicological studies following oral 
administration of BI 1595043
Study Type
(Study or
Report No.)
Dose
(mg/kg
/day)
Cmax (nM)1
AUC0-241
(nM•hr)
Cmax Multiple2
AUC 
Multiple2
M
F
M
F
M
F
M
F
10
7,050
11,700
15,600
28,500
10
17
4
8
13 Week Rat
50
39,900
50,500
188,000
240,000
59
74
54
69
(n00268703)
300
167,000
188,000
1,910,000 2,080,000
246
277
547
595
3
2,570
2,190
25,600
18,800
4
3
7
5
13 Week Dog
10
8,550
10,700
81,700
81,400
13
16
23
23
(n00270419)
30
35,700
NA
352,000
NA
53
NA
101
NA
100
NA
127,000
NA
1,580,000
NA
187
NA
452
Human
30 mg/day
678
3,494
1.
Data shown are end of study exposures
2.
Multiples calculated based on estimated human therapeutic exposure
Exposures corresponding to NOAEL dose are listed in bold.
For a more detailed description of the BI 1595043 profile, please refer to the current IB 
(c31270124).


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Residual Effect Period
The residual effect period (REP) for BI 1595043 is 6 days and is projected based on 5 times 
terminal t1/2 preliminary PK data of Trial 1445-0001 (up to 29.3 h in DG 5, see Table 1.2.1.5: 
2). This is the period after the last dose with measurable drug levels and/or pharmacodynamic 
effects still likely to be present. Conservatively, all AEs reported until the end of trial 
examination will be considered on treatment.
Drug product
Please refer to Section 4.1.
For a more detailed description of the BI 1595043 profile, please refer to the current IB 
(c31270124).
Midazolam
Midazolam is a sensitive substrate of CYP3A, used both in vitro and in vivo as a probe drug 
for CYP3A drug interactions. Absorption is rapid, with maximum concentrations reached 
around 15 to 30 min. Clearance is also rapid, with an elimination half-life of 1.5 to 2.5 h. The 
PK of midazolam has been found to be dose proportional over a range of at least 0.001 µg to 
3 mg (R17-3022). For further information, refer to the summary of product characteristics 
(R20-0572).
1.3
RATIONALE FOR PERFORMING THE TRIAL
This is the second trial with BI 1595043 and the first with multiple dose administration. The 
objective of this trial is to investigate the safety, tolerability, and pharmacokinetics of 
BI 1595043 in healthy male subjects. The chosen population of healthy volunteers using 
multiple rising oral doses is adequate to provide the basis for the phase 2 clinical 


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development program of BI 1595043 in the indication of CD. This trial will also provide in 
the selected population of healthy male subjects pharmacokinetic information at steady state 
exposure.
A phase 1 SRD trial (1445-0001) explored safety, tolerability and pharmacokinetics in 
healthy male subjects after single doses administered as oral solution. At the time of 1445-
0002 (MRD) clinical trial protocol preparation, a snapshot analysis was performed covering 
the safety results of dose groups 1 to 7, i.e. up to 90 mg BI 1595043 (c34604736). At the time 
of the MRD CTP amendment, the safety results of dose group 8, i.e. 160 mg BI 1595043, 
become available. Up to this dose level there were no dose-limiting AEs and no SAEs.
In the planned multiple dose trial, no dose level will be tested which was not already tested in 
the SRD study and was shown to be safe and well tolerated. Within each dose group, all 
actively treated individuals will receive the same BI 1595043 dose. The next higher dose will 
only be administered to the next group, if the treatment in the preceding dose group was safe 
and showed acceptable tolerability.
In in vitro DDI screening studies, BI 1595043 showed time-dependent inhibition as well as 
induction of CYP3A (n00280589, n00281141). To assess the potential impact of BI 1595043 
on CYP3A clinically, the effect of BI 1595043 on the midazolam pharmacokinetics will be 
evaluated in dose groups 3-4 (60 mg q.d. and 120 mg q.d.). The subjects of these dose groups 
will receive a microdose of midazolam before start (i.e. without treatment with BI 1595043) 
and immediately after the first and the last treatment with BI 1595043 (i.e. on Days -1, 1 and 
18). A microdose results in a low concentration of midazolam that is not pharmacologically 
active, and thus will not interfere with the evaluation of BI 1595043.
The safety and pharmacokinetics data obtained in this MRD study will serve to define 
appropriate doses for further clinical studies with BI 1595043.
Starting Dose
The starting dose corresponds to 15 mg of BI 1595043 as tablets. This dose level is 10.7-fold 
lower (about 9.4%) the maximum tested dose to date (160 mg single dose as oral solution) in
the SRD study. Up to 160 mg single dose, BI 1595043 was shown to be safe and well 
tolerated.
BI 1595043 is a BCS class I compound with high permeability and high solubility. Fast 
disintegration was also observed with the tablet formulation (within 1-3 min). Thus, no 
substantial difference in bioavailability is expected between oral solution and tablet 
formulation. In Trial 1445-0001, BI 1595043 was administered as oral solution and was 
rapidly absorbed with tmax of 0.5 to 1.5 hour, which is in line with BCS class I properties. 
Additionally, the starting dose of 15 mg BI 1595043 is 10.7-fold lower than the maximum 
dose tested to date, the exposure at the starting dose of 15 mg of BI 1595043 q.d. as tablets 
will unlikely exceed the maximum exposure been tested to date (i.e. 160 mg single dose as 
oral solution). Further dose escalation will be guided by preliminary PK analysis (see 
Sections 1.4.3.7 and 7.4).


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Maximum dose
The maximum doses of this trial are 120 mg q.d. and 60 mg b.i.d. over 2 weeks, and these
doses will not be exceeded in this trial. Additional doses could be explored on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Furthermore, dose escalation will be guided 
by preliminary PK analysis (see Sections 1.4.3.7 and 7.4). Should at the planned highest dose
the therapeutic window not be sufficiently characterized, a study protocol amendment will 
describe further escalation steps.
The current therapeutic dose is estimated to be 30 mg q.d. (see Section 1.2.1.4). Additional 
higher exposures (doses) are planned for several reasons.
First, subsequent clinical studies in patients may show that the required therapeutic doses and 
exposures are significantly higher than predicted. Also, higher doses / exposures might be 
required for more severe disease states, i.e. while higher doses and exposures may still be 
well tolerated, they provide a larger magnitude of therapeutic effects.
Second, testing of doses higher than the predicted therapeutic dose is justified to account for 
uncertainties in translation from preclinical data to human.
Third, even if eventually the therapeutic dose turns out to be as low as 30 mg, higher than 
therapeutic doses and exposures are typically explored in the well-controlled clinical 
environment of phase I trial if supported by the currently available safety data, in order to 
provide a sufficient safety margin for potential subsequent trials, e.g.

To cover higher exposures, in case exposures in CD patients are higher than estimated 
based on healthy volunteer data

To cover exposures that may be possibly seen in trials in patients with impaired 
excretion function, such as renal / hepatic impairment, where substantial increases in 
exposure may be observed

To cover exposures that may be possibly achieved in subsequent drug-drug 
interaction trials
In dose group 5 (60 mg b.i.d.), BI 1595043 will be evaluated in a twice-daily regimen. The
projected AUC0-24,ss of BI 1595043 at 60 mg dose b.i.d. are comparable to the AUC0-24,ss of 
BI 1595043  in dose group 4 (120 mg q.d.), but have a lower peak to trough ratio (see Table 
1.2.1.5: 3). This dose group is added to gain additional insights on the impact of dosing
frequency on PD and safety, which may be important for designing subsequent clinical trials. 
Both of these dose groups are predicted to achieve lower exposure than the maximum 
exposure of the SRD study (i.e. after a single dose of 160 mg as oral solution).
Maximum exposure
For this trial, the maximum doses of 120 mg q.d. and 60 mg b.i.d. administered over 2 weeks 
have been selected. 120 mg q.d. dose is predicted to result in a Cmax,ss of 2692 nmol/L and 
AUCτ,ss of 13450 nmol·h/L, 60 mg b.i.d. dose is predicted to result in a Cmax,ss of 1441


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nmol/L and AUCτ,ss of 13450 nmol·h/L, based on the data from 1445-0001 (SRD) study (see 
Section 1.2.1.5).
The maximum doses of 120 mg q.d. and 60 mg b.i.d. over 2 weeks will only be administered 
if predicted geometric mean values of Cmax,ss or AUCτ,ss do not exceed the maximum 
geometric mean exposure of the SRD study (i.e. Cmax of 4620 nM and AUC0-24 of 17900
nmol·h/L after a 160 mg single dose (based on preliminary PK data)). Otherwise, dose
escalation will be stopped at lower doses (see Section 1.4.3.7).
Referring to NOAEL established in the 13-week toxicology studies (see Section 1.2.1.2), the 
multiple doses of 120 mg q.d. are predicted to result in about 15 / 19-fold (Cmax,ss) and 14 / 
18-fold (AUC24,ss) lower exposures compared to male / female rats and about 3 / 4-fold 
(Cmax,ss) and 6 / 6-fold (AUC24,ss) lower exposures compared to male / female dogs. The 
multiple doses of 60 mg b.i.d. are predicted to result in about 28 / 35-fold (Cmax,ss) and 3 / 4-
fold (AUC24,ss) lower exposures compared to male / female rats and about 6 / 7-fold (Cmax,ss) 
and 6 / 6-fold lower exposures compared to male / female dogs.
Escalation scheme
The following dose levels of BI 1595043 are intended to be investigated: 15 mg q.d, 30 mg 
q.d, 60 mg q.d, 120 mg q.d. and 60 mg b.i.d. administered as tablets over 2 weeks.
In dose groups 1-4 (15 mg q.d. – 120 mg q.d.), dose escalation will be 2-fold compared to the 
preceding dose level.
In dose group 5, 60 mg dose will be evaluated in a twice-daily regimen. In this dose group, 
the projected exposures of BI 1595043 are comparable to 60 mg q.d. for Cmax,ss and 120 mg 
q.d. for AUC0-24,ss (i.e. dose groups 3-4); thus, no escalation step is applicable.
Upon repeated dosing, the clearance of BI 1595043 is assumed not to change over time, and
multiple dose PK was projected based on single dose results. The estimated steady state
exposures after once daily and twice daily administration of BI 1595043 at the proposed 
doses are shown in Table 1.2.1.5: 3.
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 to for the development of BI 1595043, 
which represents a novel approach for the treatment of patients with CD. Subjects are 
exposed to risks of study procedures and risks related to the exposure to the trial medication.


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Expected benefit for the target indication
BI 1595043, a first-in-class vanin inhibitor, will be developed in CD. There is a substantial 
unmet medical need for agents with greater efficacy than current therapies, like 
aminosalicylates (e.g. 5-ASA), glucocorticoids, immunomodulator agents (azathioprine or 
6-MP), biologic TNFα inhibitors (TNFi), or other biologic options (vedolizumab, 
ustekinumab). Concerns over infection- and lymphoma risks attached to some of these 
treatments remain. Treatment options for fistulizing and fibrotic disease are limited.
In CD, direct barrier injury is believed to be (at least partially) channeled through vanin 
enzymes and their product, cysteamine. By reducing cysteamine levels, a vanin inhibitor is 
expected to lead to direct epithelial barrier repair, resulting in mucosal healing, and to 
attenuate the chronic inflammation that is underlying the disease. Oral medicines with a novel 
mode of action that includes repair of epithelial barrier would address the unmet medical 
need in CD.
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
Factors of risk may derive from particular knowledge or the lack thereof, regarding (1) the
mode of action, (2) the nature of the target, (3) the relevance of animal models and/or (4) 
findings in non-clinical safety studies.
Mode of action and nature of the target
Vanin-1 and -2 are extracellular enzymes expressed in humans on epithelial (lung, kidney, 
and intestinal tract), liver-, and immunological cells. It is shed in significant amounts into the 
extracellular milieu, and is found in most tissues. It’s function is to convert pantetheine into 
pantothenic acid and cysteamine. Through the production of cysteamine, vanin is directly 
impacting extracellular metabolic homeostasis of different tissues by chemically reducing and 
depleting cysteine, resulting in increased oxidative stress, endoplasmic reticular stress, and 
disruption and eventual destruction of tissue. Therefore, it is expected that vanin inhibition 
will directly restore tissue metabolite homeostasis and redox balance leading to tissue repair 
in CD-patients.
As described in Section 1.2.1, the human missense SNP (rs2272996) in the gene, encoding 
vanin-1, is associated with decreased blood pressure (R18-2692). Considering this data as 
well as the findings from the dog telemetry study, blood pressure and heart rate will be 
closely monitored after BI 1595043 administration.


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In toxicology studies with BI 1595043, there were no adverse histological pancreas findings 
or a lack of glycemic control. However, considering the conflicting literature, described in 
Section 1.2.1.1 about pancreatic islet cell survival, fasting blood glucose levels will be 
closely monitored as a precautious measure.
Since there might be a relationship between vanin inhibition and acetaminophen 
(paracetamol) induced liver toxicity, in this study, acetaminophen will be strictly prohibited 
as concomitant medication.
Relevance of animal models
Vanin-1 is expressed in preclinical species including mouse, rat, and dog. Rat and Beagle dog 
were chosen as the rodent and non-rodent toxicology species due to the conserved amino acid 
sequence for vanin-1 (>78% compared to human) and previously demonstrated 
pharmacological activity of vanin inhibitors in these species (n00261263, n00261387). 
However, as rodents lack vanin-2, there is a considerable discrepancy between species. In 
dogs, vanin-1 mRNA levels are high in the lung, liver, spleen and kidney. Comparative 
expression in tissues is generally lower in the rat, although tissue distribution is comparable.
While dogs possess a vanin-2 gene, its expression in dog tissues is not characterized. Target 
risk assessments generated for vanin-1 and vanin-2 did not reveal any unique on target 
concerns for vanin-2 when compared to vanin-1. However, any unique effects mediated by 
vanin-2 may not be evaluated in rodent studies, but dog toxicity studies would inform on 
potential vanin-2 effects. Potency of BI 1595043 in dog whole blood was comparable to 
human; while in mouse whole blood, BI 1595043 displayed twenty-five-fold lower potency.
In conclusion, rat and dog were considered suitable species for nonclinical safety profiling of 
BI 1595043, with dog as the most sensitive species. Confidence in the suitability of rat and 
dog as toxicology species was increased by favorable oral pharmacokinetics characteristics 
(see Section 1.2.1.3), demonstration of pharmacological activity of BI 1595043 in the rat and 
dog dose range finding studies (n00266340, n00266444), and similar metabolite profiles in 
human and rat/dog.
Findings in non-clinical safety studies
Toxicology data of BI 1595043 support clinical studies in men with daily oral administration 
for up to 91 days. 
In the rat 13-week study (n00268703), signs of reproductive toxicity were seen in male rats at 
300 mg/kg/day (adverse microscopic effects on the testis and epididymis), not considered 
relevant in humans at planned clinical doses due to large safety margins. Under the 
conditions of this study the NOAEL at steady state was considered to be 50 mg/kg/day, 
which corresponded to a Cmax of 39,900 nM and AUC0-24 of 188,000 nM•h in males and Cmax
of 50,500 nM and AUC0-24 of 240,000 nM•h in females. With regard to the non-adverse 
ophthalmology findings (visualization of cataract, descriptively synonymous with a change in 
lens opacity), no microscopic evidence of correlating cataract formation was observed upon 
thorough histologic examination in any rat. Likewise, no ophthalmology findings were 
observed in 1-week repeat-dose toxicity study in rats (n00266340) and in the 2-week and 
13-week studies in dogs (most sensitive toxicological species) (n00266444, n00270419),


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which suggests an unlikely clinical relevance for human subjects receiving single and 
multiple doses in the planned dose range.
In the dog 13-week study (n00270419), once daily oral administration of BI 1595043 resulted 
in moribundity at 100 mg/kg/day in one male dog. Based on reversible adverse effects on the 
liver in male dogs at 30 mg/kg/day, liver enzymes parameters will be closely monitored after 
BI 1595043 administration. Under the conditions of this study the NOAEL at steady state 
was considered to be 10 mg/kg/day, which corresponded to a Cmax of 8,550 nM and AUC0-24 
of 81,700 nM•h in males and Cmax of 10,700 nM and AUC0-24 of 81,400 nM•h in females.
BI 1595043 has a low risk for QT prolongation based on results of the dog telemetry study 
(n00271655). The observed decreases in blood pressure with accompanying increases in heart 
rate in dogs may be related to the pharmacological inhibition of vanin (R18-2692). Based on 
these findings, blood pressure and heart rate will be closely monitored after BI 1595043 
administration.
Embryo-fetal development toxicity studies have been completed in rat and rabbit (n00278622, 
n00278281). Maternal and embryo-fetal toxicity were not observed in these studies (rat 
NOAEL AUC 125,000 nM•h and Cmax 25,500 nM, rabbit NOAEL AUC 323,000 nM•h and 
Cmax 97,400 nM). Teratogenicity (digit malformations) was observed in rat (LOAEL AUC 
6,900 nM•h and Cmax 2,270 nM) (n00278622). There is a very low risk of relevant systemic 
exposure through exposure to seminal fluid in women of child-bearing potential (WOCBP)
partners of male subjects dosed with BI 1595043. Given the results of the embryo-fetal 
development study in rats, BI 1595043 currently falls into a category of possible human 
teratogenicity (R20-3402) for which additional birth barrier contraception (condom) is not 
strictly required. However, considering the limited clinical data available for BI 1595043, 
study subjects will be conservatively required to follow the birth control measures as 
specified in inclusion criterion No. 5. In addition, unprotected sexual intercourse with a 
pregnant female partner and sperm donation is not allowed throughout the study and until 30 
days after trial completion.
The risk of genotoxicity and phototoxicity is low. Carcinogenicity and local tolerance has not 
yet been examined. Reproductive studies have not yet been completed.
Overall, it should be highlighted that all toxicological findings occurred at exposures far 
beyond the current estimated therapeutic exposure (Cmax,ss of 678 nM and AUC24,ss of 
3494 nM•h with 30 mg q.d. of BI 1595043) supporting consideration of large safety margin 
across the planned dose range in the study.
Clinical experience with BI 1595043
As summarized in Section 1.2.1.5, eight dose groups in the first in human 1445-0001 SRD
study were completed. In the tested dose range, BI 1595043 was well tolerated with a low 
frequency of AEs. There were no AEs considered to be dose limiting and no SAEs.
This MRD study includes dose levels that have been tested in the SRD study.
At the starting dose of 15 mg q.d., the steady state AUC0-24,ss and Cmax,ss of BI 1595043 are 
projected to be approximately 9.8-fold and 13.5-fold lower, respectively, than the exposure 
after a single dose of 160 mg as oral solution, the highest dose level tested to date. 


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At the highest proposed doses of 120 mg q.d. and 60 mg b.i.d., the steady state AUC0-24,ss and 
Cmax,ss of BI 1595043 are projected to be approximately 1.3-fold and 1.7-fold (120 mg q.d.) 
and 1.3-fold and 3.2-fold (60 mg b.i.d.) lower, respectively, than the maximum exposure (i.e. 
after a single dose of 160 mg as oral solution) of the SRD study.
Midazolam
Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant and
frequently used for preoperative sedation, anxiolysis and amnesia. There is a long-lasting
safety experience with midazolam at doses of 1mg and beyond. The administered oral
microdose of 75 μg of midazolam is far below the dose range used in the clinical setting.
Based on numerous published studies (R17-3022, R17-3023), treatment risks with a
microdose of midazolam (i.e. 1/100 of a pharmacologically active dose) are considered
unlikely. For further information, refer to the summary of product characteristics (R20-0572).
Drug induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.7.1.4, adverse events of special interest.
Safety measures
The following safety measures will be applied in order to minimize the risk for healthy
volunteers:

Careful dose selection, no dose will be included which has not been previously 
studied in the FIH SRD study.

The dose escalation factor is limited to 2 (applicable to dose groups 1-4). No 
escalation factor is applicable from dose group 4 to 5 (see Section 1.3.4).

For safety reasons, each dose group of 10 subjects (8 on active drug, 2 on placebo) 
will be divided into 2 cohorts of 5 subjects each (4 on active drug, 1 on placebo). Both 
cohorts will be dosed in a randomized fashion and each drug administration will be 
separated by at least 10 min.

For each dose group, the 2 cohorts will be separated by at least 70 h (between 
treatment of the first subject of each cohort) to account for any intolerability resulting 
from 3 repeated doses of BI 1595043. A continuous safety evaluation, including 
results of safety laboratories, ECG readings, recordings of vital signs and adverse 
events will be performed before the individual subject and the subsequent cohort is 
dosed.

Interim measurements of BI 1595043 plasma concentrations will be performed. Based 
on the preliminary data from the FIH SRD study it is considered unlikely that multiple 
doses of BI 1595043 up to 120 mg q.d. and 60 mg b.i.d. will exceed the maximum 
acceptable exposure limit (exposure at the maximum dose of 160 mg in the preceding 


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FIH SRD study, i.e. Cmax of 4620 nM and AUC0-24 of 17900 nM•h). However, in the 
unlikely event that at least 1 subject of one dose group exceeds or if the estimated 
systemic exposure (group gMean values) of the next dose level is expected to exceed 
the maximum acceptable exposure limit, dose escalation will be stopped (see Section 
7.4).

Repeated standard safety laboratory measurements will be performed before and 
during the treatment period (refer to Flow Chart and Section 5.2.4) with special focus 
on plasma glucose levels and liver enzymes.

Safety monitoring (including e.g. vital signs, repeated triplet 12-lead ECGs and 
adverse events) with a special focus on blood pressure and heart rate measurements.

Ophthalmological examination at Screening and EoTrial Visit (see Section 5.2.3).

Prior to each dose escalation, a documented Safety Review will be performed by the
Principal Investigator (or an authorized deputy) and the Clinical Trial Leader (or an
authorized deputy). For details, refer to Section 3.1.

Subjects will be hospitalized from Day -1 to Day 20 in dose groups 1-2, from Day -2 
to Day 20 in dose groups 3-4, and from Day -1 to Day 16 in dose group 5; and will be 
discharged only after a formal assessment and confirmation of fitness by an 
investigator or qualified designee. Throughout the study, subjects will be under close 
medical observation and thoroughly monitored for both, expected and unexpected 
adverse events.

Exclusion of acetaminophen (paracetamol) as concomitant medication.

Due to observed teratogenicity in rat, women will not be enrolled in this study.
Overall assessment
BI 1595043, a first-in-class vanin inhibitor, has been thus far administered to 48 healthy 
subjects in the preceding FIH SRD study. This is the second trial with BI 1595043 and the 
first with multiple dose administration. Despite the novelty of the target, non-clinical safety 
data in relevant animal species, preliminary clinical data obtained in 1445-0001 SRD study, 
the inhibitory mode of action as well as the comprehensive risk assessment suggest that 
BI 1595043 is not a high-risk compound and support the application of multiple doses of 
BI 1595043 in this MRD trial.
Based on the risk mitigation strategy, comprising of safety precautions and stopping rules, 
healthy subjects should not be exposed to undue risks by the intake of BI 1595043. Healthy 
volunteers are not expected to have any direct benefit from participation in this trial, as is 
usually the case in Phase I studies. Considering the high medical need for novel, effective and 
safe treatment for CD, it is believed that the benefit of this trial outweighs the potential risks 
and justifies exposure of healthy volunteers to BI 1595043.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
The primary objectives of this trial are to investigate safety and tolerability of BI 1595043 in 
healthy male subjects following oral administration of multiple rising doses over 14 days.
Secondary objectives are the exploration of pharmacokinetics (PK) of BI 1595043 after 
single and multiple oral dosing.
Primary endpoint
The primary endpoint for assessment of safety and tolerability of BI 1595043 is the 
percentage of subjects with drug-related adverse events.
Secondary endpoints
BI 1595043:
After the last dose:

AUC0-τ,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)

Cmin,ss (minimum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)

RA, Cmax (accumulation ratio based on Cmax,ss)

RA, AUC (accumulation ratio based on AUC0-τ,ss)


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Safety and tolerability
Safety and tolerability of BI 1595043 will be assessed based on:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate, body temperature)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This multiple-rising dose trial is designed as double-blind (see Section 4.1.5.1), randomised 
(within dose groups) and placebo-controlled within parallel dose groups.
It is planned to include a total of 50 healthy male subjects in the trial. The subjects will be
assigned to 5 groups consisting of 10 subjects per group; the groups will be dosed
sequentially (see Table 3.1: 1). The investigator (after consultation with the sponsor) is
allowed to alter the scheduled dose groups (e.g., add low and/or intermediate dose groups) on
the basis of experience gained during the study (for instance, based on preliminary PK data),
provided the planned and approved highest dose is not exceeded. Thus, the actual number of
subjects entered may be more than 50, but is not to exceed 70. Such changes, which are based
on preliminary PK data, may be implemented via non-substantial CTP amendments. Changes 
based on safety findings will be implemented only via substantial CTP amendments. Should 
at the planned highest dose the therapeutic window not be sufficiently characterized, a 
substantial CTP amendment will describe further escalation steps.
In dose groups 1-4 (15 mg q.d. – 120 mg q.d.), the trial consists of two segments and each 
subject included in the trial is expected to participate in the two segments. The single dose 
segment starts on Day 1 with a consecutive washout-period up to Day 5, followed by the 
multiple dose segment with a 2 week treatment period from Day 5 to Day 18 and discharge 
from the trial site on Day 20. The split of the trial in two segments with exposure data after 
single and multiple doses in the same subject will significantly contribute to the interpretation 
of steady state PK data obtained in the multiple dose segment.
In dose group 5 (60 mg b.i.d.), no single dose segment is planned because the exposure data 
at 60 mg after single dose administration will be investigated in dose group 3 (60 mg q.d.). 
Thereby, multiple dose administration starts b.i.d. on Day 1 through Day 13, followed by 
only morning dose administration on Day 14 in order to investigate PK profile of BI 1595043 
at steady state beyond 12 h after last treatment. In this dose group, discharge is planned on 
Day 16, i.e. at least 48 h after last study drug administration.
In addition, the study will evaluate the effect of BI 1595043 on the pharmacokinetic profile of 
midazolam in dose groups 3-4 (60 mg q.d. and 120 mg q.d.). This segment follows an open, 
fixed sequence, intra-individual comparison design that is nested in the overall design of the 
trial.
Within each dose group, 8 subjects will receive BI 1595043 and 2 will receive placebo. Only
one dose is tested within one dose group. For safety reasons, the dose groups will consist of
two cohorts of 5 subjects each with 4 subjects on active treatment and 1 subject on placebo.
For each dose group, the 2 cohorts will be separated by at least 70 h (between treatment of
the first subject of each cohort).
For the evaluation of the effect of BI 1595043 on the PK of midazolam, participating subjects 
of dose groups 3-4 (60 mg q.d. and 120 mg q.d.) will receive a midazolam microdose on Day 
-1 without treatment of BI 1595043, and concomitantly to BI 1595043 on Day 1 and Day 18.


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The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
4
5
Daily dose (mg)
15 mg 
q.d.
30 mg 
q.d.
60 mg 
q.d.
120 mg 
q.d.
60 mg 
b.i.d.
Number of subjects
10
10
10
10
10
Subjects receiving placebo
2
2
2
2
2
Subjects receiving BI 1595043
8
8
8
8
8
The groups will be dosed consecutively in ascending order, and a time interval of at least 
7 days will be maintained between the last drug administration to subjects in the previous 
dose group and the first drug administration to subjects in the next higher dose group. 
The decision to treat the next dose group will be based upon safety, tolerability and 
pharmacokinetic data of all the preceding dose groups.
The next dose group will only be treated if, in the opinion of the investigator, no safety 
concerns have arisen in the preceding dose groups (i.e. no dose-limiting events occurred),
within this MRD study and if none of the pre-specified trial-specific stopping criteria have 
been met (refer to Section 3.3.4.2). Both SRD and MRD trials are performed at the same 
clinical site to allow for ease in cross trial alignment. 
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled Safety Review meeting can be requested anytime by the Principal Investigator 
(or an authorised deputy) or the sponsor of the study (for instance, due to the occurrence of 
any unforeseen adverse events).
Although no formal Safety Review meeting will take place within a given dose group, safety 
will be continuously monitored during this trial, and an individual will only be dosed in the 
absence of any safety concern (i.e. no dose-limiting events occurred) and if none of the pre-
specified trial-specific stopping criteria have been met (refer to Section 3.3.4.2).
At minimum, data from at least 7 subjects need to be available for escalation to the next 
higher dose. For the minimum dataset with regards to preliminary PK data, see Section 7.4. 
The minimum data set for review consists of the following:

AEs in the current and preceding dose groups up to at least 48 h after final dosing of 
the current dose group, including clinically relevant findings from ancillary safety 
testing listed below (Note: AEs may be ongoing at the time of Safety Reviews and AE 
information may be subject to change prior to Database Lock)

Results from 12-lead ECG in the current and preceding dose groups up to at least 48 h 
after final dosing of the current dose group 

Vital signs in the current and preceding dose groups up to at least 48 h after final 
dosing of the current dose group


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
Clinical laboratory tests in the current and preceding dose groups up to at least 48 h 
after final dosing of the current dose group

Preliminary PK data for the selected time as per Section 7.4

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the Clinical Trial Leader (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs, and out-of-range 
laboratory results (if considered clinically significant). In addition, and depending on the 
results and findings, suitable experts from the sponsor or external institutions may be 
consulted on an as needed basis. In these cases, expert recommendations will be documented 
in the minutes of the Safety Review and considered for the decision making. Dose escalation 
will only be permitted if no safety concerns exist neither in the opinion of the Principal 
Investigator (or an authorised deputy) nor the Clinical Trial Leader (or an authorised deputy).
Safety Reviews can be conducted face-to-face or by video/telephone conference. The Clinical 
Trial Leader is responsible for the organisation and minutes of the reviews. Minutes will be 
signed off by the Principal Investigator (or an authorised deputy) and Clinical Trial Leader 
(or an authorised deputy), and will be filed in the ISF and TMF.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For multiple-rising dose trials, the sequential rising dose design described in Section 3.1 is 
viewed favourably under the provision not to expose the study subjects to undue risks.
Double-blind conditions regarding the subject’s treatment (active or placebo) are maintained 
within each dose group. However, subjects and investigators will be aware of the dose of 
drug administered. The disadvantage of the trial design is a possible observer bias with regard 
to the dose-dependent effects; in addition, the sequential dosing of groups could potentially 
result in time-related effects. However, as such effects are expected to be small relative to the 
differences between the doses in the broad range investigated, unbiased comparisons between 
treatments can still be expected.
It is standard in multiple rising dose trials involving healthy volunteers to include a placebo 
group to control for safety and tolerability of the trial medication. Each dose group consists of 
10 subjects, with 8 on active treatment, and 2 on placebo. For data analysis purposes, the
placebo control group will include the subjects of all dose groups treated with placebo. Eight 
subjects per active treatment group are generally considered to be sufficient for the 
exploratory evaluation of safety and pharmacokinetics.
In dose groups 1-4 (15 mg q.d. – 120 mg q.d.), after the first dose (single dose segment), a 
sufficient wash-out period will be included before the second dose (first dose of the multiple 
dose segment) is administered. This will allow for appropriate calculation of pharmacokinetic 
parameters after a single dose administration and for comparison with pharmacokinetic 
parameters at steady state.


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In dose group 5 (60 mg b.i.d.), BI 1595043 will be evaluated in order to study the impact of 
dosing frequency on PD and safety.
To evaluate a possible clinically relevant DDI due to induction of CYP3A4 by BI 1595043, 
an assessment of the effect of BI 1595043 on the midazolam metabolism will be conducted in 
dose groups 3-4 (60 mg q.d. and 120 mg q.d.) The evaluation of a potential CYP3A4 
interaction with BI 1595043 using a microdose of midazolam is considered to be acceptable. 
A microdose of midazolam is not expected to have any pharmacological effects and subjects
will not be exposed to undue risks. In additions, the evaluation of the investigational drug 
will not be influenced. This DDI assessment will be critical for defining concomitant 
medication restrictions in further clinical studies with BI 1595043.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 50 healthy male subjects will enter the study. The actual number of subjects 
entered may exceed the total of 50 if additional intermediate doses are tested (see Section 
3.1). Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included (refer to Section 1.4.3.3).
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.
Main diagnosis for trial entry 
The study will be performed in healthy subjects.
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, body 
temperature), 12-lead ECG, and clinical laboratory tests
2. Age of 18 to 50 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5. Male subjects who meet any of the following criteria from at least 30 days before the first 
administration of trial medication until 30 days after trial completion:
-
Use of adequate contraception, i.e. use of condom (male subjects) plus any of the
following methods (female partners): intrauterine device, hormonal contraception 
(e.g. implants, injectables, combined oral or vaginal contraceptives) that started at 
least 2 months prior to first drug administration to the male subject, or barrier 
method (e.g. diaphragm with spermicide), or surgically sterilised (including bilateral 
tubal occlusion, hysterectomy or bilateral oophorectomy), or postmenopausal, 
defined as at least 1 year of spontaneous amenorrhea


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-
Sexually abstinent
-
Vasectomised (vasectomy at least 1 year prior to enrolment) in combination with a 
barrier method (i.e. condom)
Unprotected sexual intercourse (i.e. without use of condom) with a pregnant female 
partner and sperm donation is not allowed throughout the study and until 30 days after 
trial completion.
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 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval 
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial


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19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study
In addition, the following trial-specific exclusion criteria apply:
23. History of acute pancreatitis
24. History of relevant ophthalmological disorders (with exception of myopia and hyperopia) 
or detection of ocular disorders in slit lamp examination at screening.
For study restrictions, refer to Section 4.2.2.
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 1.2.1.6), 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.
Due to teratogenicity observed in embryo-fetal development study in rat and the theoretically 
possible risk that relevant systemic concentrations being achieved in women of child-bearing 
potential (WOCBP) from exposure to seminal fluid of subject receiving BI 1595043, 
adequate contraception as outlined in Section 3.3.2 is a prerequisite for participation in the 
study.
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


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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. An AE or clinically significant laboratory change or abnormality occurs that the 
investigator assesses as warranting discontinuation of treatment. This may include cases 
of sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg), clinically relevant changes in ECG requiring intervention, or unexplained 
hepatic enzyme elevations at any time during the trial
6. 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
7. The subject has a serious adverse event or a severe non-serious adverse reaction 
considered at least possibly related to the IMP administration.
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
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.
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
3. Dose escalation will be terminated if more than 50% of the subjects at one dose level 
show drug-related and clinically relevant adverse events of moderate or severe intensity, 
or if at least one drug-related serious adverse event is reported
4. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate conduct 
of the trial


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5. The sponsor decides to discontinue the further development of the investigational product
6. Dose escalation will be stopped if at least 2 subjects on active treatment at one dose level 
have relevant individual QT prolongations, i.e. a QTc increase of greater than 60 ms from 
baseline in connection with absolute QT or QTc greater than 500 ms, as confirmed by a 
repeat ECG recording
7. Dose escalation will be stopped, if the Cmax,ss or AUCτ,ss of at least 1 subject of one dose 
group increases above the following exposure thresholds or if the estimated gMean 
exposure is expected to exceed Cmax of 4620 nM and an AUC0-24 of 17900 nM•h at the 
maximum dose of 160 mg in the FIH SRD study
8. Occurrence of severe non-serious adverse events considered as dug-related by the 
investigator in 2 subjects of the same dose group (10 subjects).
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 4 applies).
Replacement of subjects
If some subjects do not complete the trial, the Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. A replacement subject will be assigned a unique trial subject number, and will be 
assigned to the same treatment as the subject he replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product (BI 1595043 and matching placebo) has been manufactured by 
BI Pharma GmbH & Co. KG, Germany.
Midazolam has been manufactured by 
and has a market 
authorization.
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 1595043
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology:
3-0-0 (DG 1), 1-0-0 (DG 2), 2-0-0 (DG 3), 4-0-0 (DG 4), 
2-0-2 (DG 5)
Route of administration:
oral
Duration of use:
DG 1-4: 1 day single dose and, after a washout period of at least 
4 days, 14 days q.d. dosing
DG 5: 13 days b.i.d. followed by 1 day morning dosing
Substance:
BI 1595043
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg
Posology:
0-0-0 (DG 1), 1-0-0 (DG 2), 2-0-0 (DG 3), 4-0-0 (DG 4), 
2-0-2 (DG 5)
Route of administration:
oral
Duration of use:
DG 1-4: 1 day single dose and, after a washout period of at least 
4 days, 14 days q.d. dosing
DG 5: 13 days b.i.d. followed by 1 day morning dosing
The characteristics of the reference product (placebo) are given below:
Substance:
Matching placebo to 5 mg BI 1595043
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany


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Unit strength:
Not applicable
Posology:
3-0-0 (DG 1), 1-0-0 (DG 2), 2-0-0 (DG 3), 4-0-0 (DG 4), 
2-0-2 (DG 5)
Route of administration:
oral
Duration of use:
DG 1-4: 1 day single dose and, after a washout period of at least 
4 days, 14 days q.d. dosing
DG 5: 13 days b.i.d. followed by 1 day morning dosing
Substance:
Matching placebo to 25 mg BI 1595043
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Not applicable
Posology:
0-0-0 (DG 1), 1-0-0 (DG 2), 2-0-0 (DG 3), 4-0-0 (DG 4), 
2-0-2 (DG 5)
Route of administration:
oral
Duration of use:
DG 1-4: 1 day single dose and, after a washout period of at least 
4 days, 14 days q.d. dosing
DG 5: 13 days b.i.d. followed by 1 day morning dosing
The characteristics of the probe drug are given below (only in DG 3-4):
Substance:
Midazolam 1 mg/mL
Pharmaceutical formulation: Solution for injection (to be used as oral solution)
Source:
Unit strength:
5 mg/ 5 mL diluted to 50 μg/mL•1.5 mL (75 μg)
Posology:
1-0-0 (DG 3), 1-0-0 (DG 4)
Route of administration:
oral
Duration of use:
DG 3-4: single doses on Day -1, Day 1 and Day 18
Selection of doses in the trial
The doses of BI 1595043 selected for this trial cover the subtherapeutic as well as the 
estimated therapeutic range and include a safety margin (see Section 1.2).
The dose of midazolam used for the DDI evaluation was chosen to be 75 μg, within the
definition of a microdose, i.e. a 1/100th of the therapeutic dose (in case of midazolam 7.5 mg)
or 100 μg whichever is smaller. Since midazolam PK is dose proportional ranging from the
microdose to the therapeutic dose, the microdose should still accurately predict CYP3A4 DDI
liability, while remaining below a pharmacologically active concentration. 


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A solution for injection was chosen for administration as an oral solution, as a solution for 
injection is meant to be diluted and, thus, there is data available regarding the stability and 
compatibility of a diluted solution. Furthermore, the solution for injection contains 
midazolam in isotonic saline solution, while the oral solution has added excipients, making it 
less than ideal for such a dilution. Finally, the IV solution has been successfully diluted and 
administered orally as a microdose in previous clinical studies without any reports of AEs 
(R17-3022, R17-3023).
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects are allocated to 1 of the 
10 dose cohorts (2 cohorts per dose group), the following subjects will be allocated to one of 
the other dose cohorts. Therefore, the allocation of subjects to dose cohorts is not influenced 
by trial personnel, but only by the subjects’ temporal availability. Because the study includes 
healthy subjects from a homogenous population, relevant imbalances between the dose 
groups are not expected.
Subjects will be assigned to treatments (active treatment or placebo) prior to the first 
administration of trial medication. For this purpose, the randomisation scheme will be 
provided to the trial site in advance. Numbers of the randomisation scheme will be allocated 
to subjects by the method ‘first come - first served’ at the time of registration. Subjects are 
then assigned to treatment according to the randomisation scheme. Once a subject number 
has been assigned, it cannot be reassigned to any other subject. Additional information 
regarding treatment assignment of replacements can be found in Section 3.3.5.
The randomisation procedure is described in Section 7.6.
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of units for 
placebo corresponds to the number of units of the corresponding dose level.


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Table 4.1.4: 1
BI 1595043 and placebo treatments, oral administration
Dose
group
Substance
Pharmaceutical 
form
Unit strength(s)
Number of units per 
administration
Total daily
dose
1
BI 1595043
Tablet
5 mg
3 tablet q.d. for 15 days**
15 mg
2
BI 1595043
Tablet
5 mg and 25 mg
1 tablet 25 mg and 1 tablet 
5 mg q.d. for 15 days**
30 mg
3
BI 1595043
Tablet
5 mg and 25 mg
2 tablets 25 mg and 2 tablets
5 mg q.d. for 15 days**
60 mg
4
BI 1595043
Tablet
5 mg and 25 mg
4 tablets 25 mg and 4 tablets 
5 mg q.d. for 15 days**
120 mg
5
BI 1595043
Tablet
5 mg and 25 mg
2 tablets 25 mg and 2 tablets 
5 mg b.i.d. for 13 day, 
and 2 tablets 25 mg and 2 
tablets 5 mg q.d. for 1 day
120 mg***
1-5
Placebo*
Tablet
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
** One single dose during single dose segment (Day 1), and after washout q.d. treatment for additional 14 days 
(Day 5 to Day 18) in the multiple dose segment
*** On Day 14 (last treatment), the total daily dose is 60 mg because only the morning dose to be administered
Table 4.1.4: 2
Midazolam treatments, oral administration (only dose groups 3-4)
Dose
group
Substance
Pharmaceutical 
form
Unit strength(s)
Number of units per 
administration
Total daily 
dose
3
Midazolam
Solution for 
injection (used 
as oral solution)
5 mg/5 mL (diluted
to 50 μg/mL)
1.5 mL on Day -1, 1.5 mL on 
Day 1 and 1.5 mL on Day 18
75 μg
4
Midazolam
Solution for 
injection (used 
as oral solution)
5 mg/5 mL (diluted
to 50 μg/mL)
1.5 mL on Day -1, 1.5 mL on 
Day 1 and 1.5 mL on Day 18
75 μg
In dose groups 1-4, the trial will be divided into two segments (single dose and multiple 
dose). During the single dose segment (Days 1 to 4), subjects will receive one single dose of 
BI 1595043 (or placebo) on Day 1. The multiple dose segment starts on Day 5 and subjects 
will receive multiple doses of BI 1595043 (or placebo) once daily for 14 days (Days 5 to 18).
In dose group 5, multiple doses of BI 1595043 administered for 14 days: b.i.d. from Day 1 to 
13 and q.d. on Day 14 (morning administration).
In dose groups 3-4, midazolam microdose will be administered on Day -1 (i.e. without 
BI 1595043), Day 1 and Day 18 (immediately after BI 1595043 administration).
The tablets for dosing (BI 1595043 and placebo) will be dispensed by pharmacists or
qualified pharmacy staff members or qualified medical study personnel at the trial site under
the responsibility of the investigator.


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In dose groups 3-4, the oral solutions for dosing midazolam will be prepared according to the 
instruction given in Appendix 10.1 by pharmacists or qualified pharmacy staff members or 
qualified medical study personnel at the trial site under the responsibility of the investigator.
In dose groups 1-4, administration of trial medication will be performed after subjects have 
fasted overnight; fasting is to start no later than 10 h before the scheduled dosing.
In dose group 5, administration of trial medication in the morning will be performed after 
subjects have fasted overnight; fasting is to start no later than 8 h before the scheduled dosing
(on Days 1-14). On Days 1-13, administration of trial medication will be performed in the 
evening as well, approximately 12 h after the morning dose, after subjects have fasted at least 
for 3 h before the scheduled dosing.
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a sitting or standing position. For 
drug administration, the so-called four-eye principle (two-person rule) should be applied. For 
this, 1 authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (dispensing of BI 1595043 or placebo), if 
correct dosage cannot be ensured otherwise. To ensure a dosing interval of 24 h, the 
administration of trial medication should take place at the same time every day.
Subjects will be kept under close medical surveillance from the evening of Day -1 until the 
morning of Day 20 (DG 1-2), Day -2 to 20 (DG 3-4) and Day -1 to 16 (DG5). During the first 
2 h after drug administration, subjects are not allowed to lie down (i.e. no declination of the 
upper body of more than 45 degrees from upright posture except for medical examination) or
to sleep.
Blinding and procedures for unblinding
Blinding
The list below summarizes the masking/blinding level of individual functions involved in the 
trial.
Role/function
Timing of Unblinding / receiving access to the 
treatment information (including rationale)
Subject
Blinded (not to dose level) until data ready for final 
analysis.
Investigator / Site Staff
Blinded (not to dose level) until data ready for final 
analysis.
Unblinded Pharmacist / 
Unblinded Pharmacy Staff
Prior to first subject entered.
Clinical Trial Team and 
Database
After treatment allocation within dose group has 
completed.
Bioanalytical Staff
As requested for analysis of bioanalytical samples (to 
allow exclusion of PK samples taken from placebo-treated 
subjects from the bioanalytical analyses). Also, 


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Role/function
Timing of Unblinding / receiving access to the 
treatment information (including rationale)
bioanalytical data for the interim / preliminary PK analysis 
will be transferred to BI via a data file which itself will be 
unblinding.
Pharmacokineticist
As requested for the interim / preliminary PK analysis.
Drug metabolism scientist
As requested for conduct of the metabolites in safety 
testing (MIST) analysis.
ECG laboratory
Within the central ECG lab, the staff involved with 
interval measurements will be blinded with respect to 
subject, treatment, recording date and time as well as 
planned time points of the ECGs. The staff involved with 
the morphological analyses will be blinded with respect to 
treatment. For the quality control of the measurements, 
certain members of the ECG evaluation team will review 
the entire portfolio of ECG measurements for each subject 
blinded to treatment, recording date and time, and the time 
point relative to drug administration.
If a preliminary analysis of ECG data is required during 
the trial, a part of the staff of the central ECG lab 
(different from the ECG evaluation team) may be 
unblinded. This part of the staff will receive the necessary 
information, which will be stored with no access to the 
ECG evaluation team.
During the time a role/function is blinded, the randomisation schemes are kept restricted by 
the global Randomization Team (gRT) per Sponsor SOP. Access to the randomisation 
schemes will be controlled and documented.
The evaluation of the effect of BI 1595043 on the pharmacokinetic profile of midazolam 
(only dose groups 3-4) 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.
Unblinding and breaking the code
The investigator or designee will be supplied with a set of sealed envelopes containing the 
medication codes for each subject according to the randomisation scheme. The envelopes will 
be kept unopened at the trial site until the end of data collection. An envelope may only be 
opened in emergency situations when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or otherwise assure safety of 
trial participants. If the envelope for a subject is opened, the sponsor must be informed 


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immediately. The reason for breaking the code must be documented on the envelope and/or 
appropriate CRF page along with the date and the initials of the person who broke the code.
Regarding the evaluation of the effect of BI 1595043 on the pharmacokinetic profile of 
midazolam (only dose groups 3-4), the midazolam treatment information will be known as 
the midazolam administration be conducted in an open fashion. Therefore, no emergency 
envelopes will be provided.
Packaging, labelling, and re-supply
BI 1595043 and matching placebo:
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice.
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
Midazolam:
Midazolam for injection used as oral solution will be obtained by the clinical trial site from a
public pharmacy.
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.
Drug accountability
The investigator or designee will receive the investigational drugs from the sponsor when the 
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority,  e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol


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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 trial 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  PROCEDURES, 
RESTRICTIONS
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.
Restrictions
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.
Acetaminophen (paracetamol) is prohibited as concomitant mediation in this study. If 
necessary, short-term use of ibuprofen or acetylsalicylic acid is acceptable.
Drugs with a known hepatotoxicity profile should be avoided during the entire study.
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.
In dose groups 1-4, no food is allowed for at least 10 h before and 4 h after the first and last 
BI 1595043 or placebo intake (Days 1 and 18) as well as on Day -1 for midazolam 
administration (DG 3-4). From 1 h before until 4 h after drug administration, fluid intake is 


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restricted to the water administered with the drug, and an additional 240 mL of water 2 h and 
4 h post-dose (mandatory for all subjects). On the remaining dosing days (Days 5 to 17), food 
is not allowed for at least 10 h before and 2 h after drug intake. Standard meals (light 
breakfast, lunch, snack, dinner, snack) will be served approximately 2, 4, 8, 10 and 12 h after 
drug administration. From 1 h before until 2 h after drug administration, fluid intake is 
restricted to the water administered with the drug, and an additional 240 mL of water served 
at 2 h post-dose.
In dose group 5, same food and fluid restriction as described above are applicable to the 
morning dose administration from Day 1 through 14. No food is allowed for at least 8 h 
before and 4 h after the first and last BI 1595043 or placebo intake (Days 1 and 14). From 1 h 
before until 4 h after drug administration, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water 2 h and 4 h post-dose (mandatory for all 
subjects). On the remaining dosing days (Days 2 to 13), food is not allowed for at least 8 h 
before and 2 h after drug intake. Standard meals (breakfast, lunch, snack) will be served 
approximately 2, 4 and 8 h after the morning dose. For the evening dose administration from 
Day 1 through 13, which has to be approximately 12 h apart from the morning dose, no food 
is allowed for approximately 4 h before and 2 h after drug administration. Dinner will be 
served approximately 2 h after the evening dose. From 1 h before until 2 h after drug 
administration, fluid intake is restricted to the water administered with the drug, and an 
additional 240 mL of water served at 2 h post-dose.
During the days of urine collection, total fluid intake should be at least 1.5 litres and should 
not exceed 3.5 litres.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each study period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or
chocolate) are not allowed from 10 h before the first administration of trial medication until 
last PK sampling of the trial.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Subjects with pregnant or non-pregnant WOCBP partners should use male contraception (i.e. 
condom) to avoid exposure of an existing embryo/fetus. Additional contraception 
requirements detailed in Inclusion Criterion No. 5 must be considered.
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.


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


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported),
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a physical examination. At 
the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, and a physical examination including determination of weight.
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, 
) 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.
Body temperature will be measured orally or under the armpit (axillary method) or in the ear 
(tympanic method) at each ambulatory visit, at admission to the trial site, and each day in the 
morning during in-house stay (refer to Flow Chart).
Ophthalmological examination
A slit lamp examination (e.g. 
 Jena RSL 110) will be conducted by an 
ophthalmologist at Screening and EoTrial examination to exclude findings suspicious for 
signs of cataract and/or other ocular disorders.
Data from ophthalmological examination will not be transferred to the CRF/database, only 
abnormal findings will be recorded as AEs if judged clinically relevant by the Investigator.
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 10 h
in dose groups 1-4, and at least 8 h in dose group 5. 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 5.2.4: 1 and 5.2.4: 2. Reference ranges will be provided in the 
ISF, Section 10.


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Manual differential white blood cell count will be performed if there is an abnormality 
detected with the automatic blood cell count. Urine microscopic examinations will be 
performed in addition to urinalysis (Stix) in order to correctly evaluate possible abnormalities 
detected at the urinalysis (Stix).
Table 5.2.4: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count (Erythrocytes), absol. 
Reticulocytes, absol.
White Blood Cells (Leucocytes), absol. 
Platelet Count (Thrombocytes), absol.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/ Leukocytes; Eosinophils/ Leukocytes; 
Basophils/ Leukocytes; Monocytes/ Leukocytes; 
Lymphocytes/ Leukocytes
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/ Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; Lymphocytes/ 
Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase
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
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 5.2.4: 1
Routine laboratory tests (cont).
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Electrolytes
Sodium
Potassium
Calcium
X
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
Urine creatinine 
for normalization of 
PD measurement 
(pantetheine) D
Urine creatinine D
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):
DG 1-2: on Days -3 to -1, 5, 8, 13, 18 and 20; 
DG 3-4: on Days -4 to -2, 5, 8, 13, 18 and 20;
DG 5: on Days -3 to -1, 2, 4, 9, 14 and 16
C: parameters to be determined at Visit 3 (end of trial examination)
D: urine creatinine is not a safety parameter but listed here for technical reasons. The samples are aliquoted from
the urine samples collected for pantetheine analysis at Visit 2 (for time points refer to Flow Chart):
DG 1-4: on Days 1, 5, 7, 12, 15 and 18:
DG5: on Days 1, 3, 8, 11 and 14.
The tests listed in Table 5.2.4: 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. Drug screening will be performed at screening and after admission to the trial site. 
Infectious serology will be performed at screening only.


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Table 5.2.4: 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)
COVID-191
SARS CoV-2 PCR test
1 evaluation will be performed shortly (within 72 hours) before admission to trial site as per Flow Chart
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest® 
6510 and Alcotest® 5510, 
) will be performed at admission to the trial site, 
and may be repeated at any time during the study at the discretion of an investigator or 
designee. The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.4: 1 and 5.2.4: 2 will be performed at 
 
, with the exception of 
drug screening. These tests will be performed at the trial site using e.g.Triage® TOX Drug 
Screen, 
, or Combur9 Test®, or comparable test systems. SARS-CoV-2 virus PCR test 
will be performed either by
 or the trial site.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
Electrocardiogram
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (e.g. Mortara device, 
.) at the time 
points given in the Flow Chart. Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). Precise electrode placement will be marked with an 
indelible mark on the skin to allow reproducible placement throughout the study.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.


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All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database.
Storing
All ECGs will be stored electronically at the site.
Data transfer
For time points of triplicate ECGs specified in the Flow Chart, ECGs will be transferred 
electronically to the central ECG lab
for evaluation.
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a) Central ECG lab (only triplicate ECGs)
Central ECG lab evaluation will be performed post-study for the first of three 
replicate ECGs per time point in the Flowchart.
For baseline, where 3 triplicate ECGs are recorded, only the first triplicate ECG (i.e. 
3 single ECGs) will be evaluated. The remaining second and third replicate ECgs will 
be stored for additional analyses if required.
This will include the determination of cardiac QRS-axis as assessed by the ECG 
machine’s algorithm as well as the intervals RR, PR, QRS and QT measured semi-
automatically.
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will 
be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 


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used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR.
For automatic interval measurements no lead will be provided. After quality control, 
the fiducial point markings will be reviewed by the cardiologist assigned to the study.
For blinding arrangements see Section 4.1.5. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader. For quality assurance and control of the measurements, all ECGs of a 
subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and, to detect 
accidental switching of leads and/or false subject assignments of the ECGs. After 
quality control, the fiducial point markings will be reviewed by the cardiologist 
assigned to the study.
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements (R07-4722, R16-0366) as well as the FDA requirements for annotated 
digital ECGs (R09-4830).
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the 
computerised ECG system or their manual corrections by the investigators will be 
used.
In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data transfer) for
cardiologic assessment by the central lab. In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the subject will be 
removed from the trial and will receive the appropriate medical treatment.
Other safety parameters
Not applicable.
Assessment of adverse events
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.


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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
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’
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 5.2.7.2, 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.


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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
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 5.2.7.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.


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Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
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.


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A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial:
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) 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
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
Pregnancy
Once 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.


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The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
Plasma samples will be collected for the purpose of pharmacokinetic analysis: BI 1595043 in 
all dose groups and midazolam in dose groups 3-4 (60 mg q.d. and 120 mg q.d.). Only in 
dose group 2 (30 mg of BI 1595043 q.d.), additional blood samples will be collected for 
metabolism analysis of BI 1595043. Furthermore, urine samples are to be collected for 
pharmacokinetic analysis of BI 1595043. The time points of the samples collection are 
indicated in the Flow Chart.
Date and clock times of drug administration and pharmacokinetic sampling will be recorded
in the CRFs. The actual sampling times will be used for determination of pharmacokinetic 
parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. as a result of preliminary PK data), including addition of 
samples and visits, as long as the total blood volume taken per subject does not exceed 
500 mL. Such changes would be implemented via non-substantial CTP Amendments.
Methods of sample collection
Blood sampling for pharmacokinetic analysis
BI 1595043:
For quantification of BI 1595043 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma, the 
second aliquot will contain the remaining plasma. The process from blood collection until 
transfer of plasma aliquots into the freezer should be completed in less than 90 min, with 


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interim storage of blood samples and aliquots at room temperature. The time each aliquot was 
placed in the freezer will be documented. Until transfer on dry ice to the analytical 
laboratory, the aliquots will be stored upright at approximately -20°C or below at the trial 
site. The second aliquot will be transferred to the analytical laboratory after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory, the plasma 
samples will be stored at approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, day, and 
planned sampling time. Further information such as matrix and analyte may also be provided.
Plasma samples will be transferred to 
.
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g., 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 CTR is archived.
Midazolam:
For quantification of midazolam plasma concentrations, 4 mL of blood will be taken from an
antecubital or forearm vein into a K2-EDTA-anticoagulant blood drawing tube at the times
indicated in the Flow Chart. Blood will be withdrawn by means of either an indwelling
venous catheter or by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in
polypropylene tubes. The first aliquot should contain at least 1.0 mL plasma the second
aliquot should contain the remaining plasma. The process from blood collection until transfer
of plasma aliquots into the freezer should be completed within 90 min, with interim storage 
of blood samples and aliquots at room temperature. For each aliquot the time when the 
sample was placed in the freezer will be documented. Until transfer on dry ice to the 
analytical laboratory, the aliquots will be stored upright at about -20°C or below at the trial 
site. The second aliquot will be transferred to the analytical laboratory after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory, plasma samples 
will be stored at about -20°C or below until analysis.
At a minimum, sample tube labels should list the following information: BI trial number,
subject number, visit, and planned sampling time. Further information, such as matrix and
analyte, may also be provided.
Plasma samples will be transferred to 
Blood sampling for metabolism analysis
Additional K2-EDTA plasma samples for the identification of drug metabolites will be 
investigated in dose group 2 (30 mg of BI 1595043 q.d.). Based on the knowledge gained 
during the trial conduct, e.g. from preliminary PK results, the dose group may be modified to 
a different one. The change will be implemented via a non-substantial CTP amendment.


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The blood samples will be drawn after the last dose at the same time points as PK samples on 
Day 18 to 23 (see Flow Chart). At each of these times, 2.7 mL blood will be needed for 
metabolite analysis. Apart from the storage temperature (see below), the blood samples will 
be processed in the same way as the PK samples (see Section 5.3.2.1).
Two plasma aliquots will be obtained and stored in polypropylene (PP) tubes. The first 
aliquot (labelled as MIST-1 samples), should contain at least 0.5 mL plasma. The remaining 
plasma will be the second aliquot (labelled as MIST-2 samples). The process from blood 
collection to the transfer of plasma aliquots into the freezer should be completed within 
90 min, with interim storage of blood samples on crushed ice between blood collection and 
centrifugation. Until transfer on dry ice to the metabolism laboratory, the aliquots will be 
stored at the trial site. Samples will be positioned upright and will be frozen at approximately 
-70°C or below. The second aliquot (MIST-2) will be shipped to the metabolism laboratory 
after the metabolism scientist has acknowledged safe arrival of the first aliquot. At the 
metabolism laboratory, the plasma samples will be stored at approximately -70°C or below 
until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, planned sampling time and ‘MIST-1’ or ‘MIST-2’. Further information 
such a matrix and analyte may also be provided.
Plasma samples dedicated to metabolism investigation are transferred to:
Phone:
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
drug metabolism will be reported separately and will not be included in the CTR. The study 
samples will be discarded after completion of the experiments but not later than 5 years after 
the CTR has been archived. 
Urine sampling for pharmacokinetic analysis
A blank urine sample will be collected before administration of trial medication (within 3 h 
before drug dosing) and two 0.5 mL aliquots will be retained to check for analytical 
interference by concomitant or rescue medication. 
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
2 L polyethylene (PE) containers and stored at room temperature. Subjects are told to empty 
their bladders at the end of each sampling interval.
The urine weight/volume for each collection interval will be documented (however, no
correction for the specific gravity of urine is done, i.e. 1 L is defined to be equal to 1 kg).
Two 0.5 mL aliquots will be stored in polypropylene (PP) tubes for bioanalytical 
measurements. If more than one collection container is used in a sampling interval, the 


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contents of all containers have to be mixed before aliquots are prepared. Mixing should be 
done by transferring the entire content of all collection containers into a single PE/PP or glass 
container, and stirring the mixed fractions for about 1 min (manually or using a stir bar or 
other stirring device made of PE, PP, Teflon or glass).
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned collection time. Further information, such as matrix and analyte may also be 
provided.
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
approximately -70°C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory, the 
urine samples will be stored at approximately -20°C or below until analysis.
After completion of the trial, the urine samples may be used for further methodological 
investigations (e.g., for stability testing or 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 CTR has been archived.


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Pharmacokinetic - pharmacodynamic relationship
An analysis of the relationship between pharmacokinetic and pharmacodynamic parameters 
may be investigated in an exploratory manner, see Section 7.3.5.
5.4
ASSESSMENT OF BIOMARKERS
Pantothenic acid:
Pan-vanin activity will be analyzed with an assay detecting pantothenic acid generation in 
human whole blood from subjects pre- and post-treatment with BI 1595043. Whole blood is 
ex vivo supplemented with an appropriate amount of exogenous pantethine substrate. The 
generated pantothenic acid product will be analyzed using a fit-for-purpose LC-MS/MS 
assay.
Pantetheine:
Vanin hydrolyzes pantetheine to provide cysteamine to tissues. An increase in the levels of 
plasma pantetheine will suggest pharmacological inhibition of vanin post-treatment with BI 
1595043. Plasma and urine levels of pantetheine will be determined at various time-points 
using fit-for-purpose LC-MS/MS assay. Urine pantetheine levels will be normalized to the 
urinary creatinine concentration.
The analysis of Pantetheine in plasma and urine will be performed in a staged approach. The 
initial analysis will focus on selected time points and depending on these results a decision 
will be made about further analysis of all samples. This is due to the exploratory nature of the 
mechanism being tested and the timing of effect on candidate biomarkers in the study.
Methods of sample collection
Pantothenic acid (blood):
For quantification of pantothenic acid generation in whole blood, about 1.2 mL of blood will 
be drawn 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. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle. The EDTA-anticoagulated blood sample could be 
stored in ice water or on ice up to 6 hours before conduct of the further processing. A total of 
500 µL of whole blood will processed according to a laboratory manual at the study site. The 
laboratory manual will be filed in the ISF and TMF.
A total of 80 µL plasma aliquot will be obtained and stored in polypropylene tube. The time, 
each sample was placed in the freezer, will be documented. Until transfer on dry ice to the 
analytical laboratory, the aliquots will be stored upright at approximately -20°C or below at 
the trial site.
Pantetheine (blood):
For quantification of pantetheine in plasma samples, whole blood (about 1.2 mL) will be 
drawn from an antecubital or forearm vein using 1.2 mL EDTA tubes. Blood samples will be 
processed to plasma by centrifugation at approximately 2000 g to 4000 g at 4 to 8°C for 


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15 min. The plasma is then aliquoted into two tubes and moved into storage in an upright 
position at approximately -70°C until analysis.
Pantetheine (urine):
First morning urine samples will be collected at various time points as shown in the Flow 
Chart and will be aliquoted into three tubes: two tubes with at least 5.0 mL each for 
pantetheine analysis and one tube with at least 5.0 mL for creatinine analysis (for 
normalization of PD measurement). The two tubes with urine samples for pantetheine 
analysis will be moved into storage in an upright position at approximately -70°C until 
analysis. The tube with urine sample for creatinine analysis will be transferred to the local 
laboratory of the trial site for analysis on the day of collection. Until transfer, this sample to 
be stored at 2-8°C.
At a minimum, the sample tube labels should list BI trial number, subject number, day, and 
planned sampling time. Further information such as matrix and analyte may also be provided.
PD sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. as a result of preliminary PK/PD data), including addition 
of samples and visits, as long as the total blood volume taken from each subject does not 
exceed 500 mL. Such changes would be implemented via non-substantial CTP Amendments.
After completion of the study, the samples may be used for further biomarker investigations. 
The study samples will be discarded after completion of any additional investigations but not 
later than 5 years after the CTR has been archived.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Pharmacogenomic evaluation
Pharmacogenomic evaluations are not considered necessary for assessment of response to 
BI 1595043 and will not be conducted.


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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure. The biomarkers and pharmacodynamic 
parameters and measurements outlined in Section 5.4 are of exploratory nature.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
For the first 4h after trial drug administration, the acceptable deviation from the scheduled 
time for vital signs and ECG will be ± 15 min, and ± 30 min for laboratory tests. Thereafter, 
the acceptable deviation will be ± 30 min.
The tolerance for drug administration will be ± 1 min on Days 1 and 18, and ± 10 min on all 
other treatment days.
If several activities are scheduled at the same time point in the Flow Chart, ECG should be 
the first and meal the last activity. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological 
parameters.
For planned individual plasma concentration sampling times and urine collection intervals, as 
well as PD sampling times, refer to the Flow Chart. While these nominal times should be 
adhered to as closely as possible, the actual sampling times will be recorded and used for the 
determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
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 5.2.2 to 5.2.5.
Treatment period
In dose groups 1-4, treatment period consists of a single dose segment on Day 1 and, after a 
washout period of 4 days, a multiple dose segment over 14 days. Each subject will receive a 
single dose of BI 1595043 or placebo on Day 1 and then daily multiple daily doses of 
BI 1595043 or placebo q.d. for 14 days from Day 5 to Day 18.


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In dose group 3-4, a single midazolam microdose will be administered on Day -1, Day 1 and 
Day 18.
In dose group 5, treatment period consists of a multiple dose segment over 14 days: daily 
multiple daily doses of BI 1595043 or placebo b.i.d. for 13 days from Day 1 to Day 13 and a 
single dose of BI 1595043 or placebo on Day 14.
Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
In dose groups 1-2 and 5, study participants will be admitted to the trial site in the morning of 
Day 1 (or in the evening of Day -1); and in the morning of Day -1 (or in the evening of Day -
2) in dose groups 3-4. The subjects will be kept under close medical surveillance for at least 
48 h following the last drug administration, i.e. will stay hospitalised up to Day 20 in dose 
groups 1-4 or up to Day 16 in dose group 5. The subjects will then be allowed to leave the 
trial site after formal assessment and confirmation of their fitness by the investigator or 
 
designee. On all other study days, subjects will conduct visits to the trial site in an ambulatory 
fashion.
For details on time points and procedures for collection of plasma and urine samples for PK / 
PD analysis, refer to Flow Chart and Section 5.3.2 and 5.4.1.
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.
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, ophthalmological 
investigation and physical examination during the follow-up period, see Sections 5.2.2 to 
5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved.
(S)AEs persisting after a subject’s EoTrial Visit must be followed until they have resolved, 
have been sufficiently characterised, or no further information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objectives of this trial will be assessed by calculating descriptive statistics for 
safety as well as for PK and PD parameters, which will be compared between the treatment 
groups.
 
 
The relative bioavailability of midazolam administered alone (Reference, R) compared with 
co-administration with BI 1595043 (single dose) (Test 1, T1) and compared with co-
administration with BI 1595043 (steady state) (Test 2, T2) will evaluated separately for dose 
groups 3 (60 mg q.d.) and 4 (120 mg q.d.).
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in this study.
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the study; i.e., confidence intervals are considered as interval estimates for 
effects.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treatment assignment will be 
determined based on the first treatment the subjects received. The treated set will be 
used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was not excluded due to a 
protocol violation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.
Descriptions of possible additional analysis sets will be provided in the TSAP, to be finalised 
prior to database lock.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(iPD) categories will be specified in the iPD specification file prior to trial initiation, iPDs 


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will be identified no later than in the Report Planning Meeting, and the iPD categories will be 
updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1.3 and 2.2.2.2 for BI 1595043 will be 
calculated according to the relevant SOP of the Sponsor 
Plasma and urine concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol violation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol 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 and urine concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
Plasma/urine concentration data and parameters of a subject which are flagged for exclusion 
will be reported with its individual values but will not be included in the statistical analyses.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report).
Biomarkers
Exploratory biomarker endpoints (see Section 2.2.2) of a subject will be included in the
statistical biomarker analyses if they are not flagged for exclusion due to a protocol deviation
relevant to the evaluation of biomarkers (to be decided no later than in the Report Planning
Meeting). Exclusion of a subject’s data will be documented in the Clinical Trial Report.
Relevant protocol deviation affecting biomarker analyses may be, for example:

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


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Primary endpoint analyses
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards.
The analysis will be based on the treated set (TS) and will be descriptive in nature.
Secondary endpoint analyses
Primary analyses
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively. Analyses will 
be performed for the parent drug and for metabolites.


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Safety analyses
Safety will be assessed as defined by the endpoints listed in Section 2.1.2 and 2.2.2 based on 
the treated set (TS). Safety analyses will be descriptive in nature and will be based on BI 
standards. 
For all analyses the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. The placebo group in the safety evaluation 
will consist of all subjects treated with placebo, regardless of the dose group in which they 
were treated. The test treatment groups will be compared to the placebo group in a descriptive 
way. Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Measurements (such as ECGs, 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 the first trial medication intake and end of 
REP (see Section 1.2.1.6) will be assigned to the treatment period. Events occurring after the 
REP but prior to trial termination date will be assigned to ’follow-up’. These assignments 


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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 database lock will be 
reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (called analysing treatments) may be defined in the 
TSAP in order to provide summary statistics for other than above periods, such as combined 
treatments, on-treatment totals, or periods without treatment effects (such as screening and 
post-study 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 5.2.7.1) 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 possibly clinically significant values 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. 
The ECG variables QT, PR, QRS, and RR obtained from the centralised evaluation of 
12-lead ECG recordings will be the basis for the derivation of quantitative and categorical
ECG endpoints with regard to QT/QTc interval, HR, PR interval, and QRS duration. These 
endpoints and their analyses will be described in the TSAP.
Pharmacokinetic - pharmacodynamic analysis
An association of BI 1595043 plasma concentrations and the exploratory biomarker (see 
Section 2.2.2.3) may be investigated in an exploratory manner.
The relationship between plasma concentrations and ECG endpoints will be investigated in 
an exploratory manner. Further details will be specified in the TSAP.
7.4
INTERIM ANALYSES
No formal interim analysis is planned.
However, a preliminary analysis of available safety data and preliminary PK parameters after 
the last dose (Cmax,ss and AUC0-24,ss) of BI 1595043 will be performed for each dose group 
before proceeding to the next higher level. This ensures that treatment in the current dose 
group was safe and well tolerated and allows further dose escalation.
In contrast to the final PK calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows. Therefore, minor deviations may occur between preliminary and final results. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification information. The 
preliminary results will be distributed to the investigator and the trial team.


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Depending on the results of available preliminary PK analysis and the tolerability and safety 
of the compound, changes to the dosing schedule (e.g., additional intermediate doses),) and 
additional PK preliminary analysis may be performed if requested by the Clinical Trial Lead, 
the investigator, or Trial Clinical Pharmacokineticist. Preliminary PK results will not be 
reported in the CTR.
Preliminary exploratory analysis of available PD/ biomarker parameters may be performed 
for each DG after all subjects of respective DG have been randomized. The details of 
exploratory PD/ biomarker analysis will be specified in the TSAP. No formal PD/ biomarker 
report will be written.
No inferential statistical interim analysis is planned. However, after completion of each dose 
group the investigator (or his or her deputy) is allowed to postpone further dose progression 
until a preliminary analysis of the data has been performed.
7.5
HANDLING OF MISSING DATA
Safety
It is not planned to impute missing values for safety parameters.
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Subjects will be randomised within each dose group in a 4:1 ratio (test treatment to placebo).
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 50 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 10 subjects per dose group (8 on active treatment, and 2
on placebo) is commonly used in multiple-rising dose studies of the present type and is in 
general considered as sufficient for the exploratory evaluation of multiple dose safety and 
pharmacokinetics.


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Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 50, but will not exceed 70 subjects entered.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the  subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the responsible Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) and competent authority (CA) according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number,
and social security number) have properly been removed or redacted to ensure subject
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication


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
Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
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.
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.
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

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
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.


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The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
, under the supervision of the Principal Investigator.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of clinical trial managers (CTM), Clinical 
Research Associates, and investigators of participating trial sites
The trial medication (BI 1595043 and matching placebo) will be provided by the 
 
Midazolam will be provided by the 
 
Safety laboratory tests will be performed by the local laboratory of the trial site 
Analyses of BI 1595043 concentrations in plasma and urine and midazolam in plasma will be 
performed at 
 
Analyses of BI 1595043 metabolites concentrations in plasma will be performed at the 
 
 
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation 
) for evaluation.
Biomarker analysis 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 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
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center
for Biologics Evaluation and Research (CBER) (2005).
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R13-2231
Baumgart DC, Sandborn WJ. Crohn's disease. Lancet 2012;380:1590-1605.
R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015).
R17-3022
Halama B, Hohmann N, Burhenne J, Weiss J, Mikus G, Haefeli WE, et al. 
A nanogram dose of the CYP3A probe substrate midazolam to evaluate 
drug interactions. Clin Pharmacol Ther 2013;93(6):564-571.
R17-3023
Hohmann N, Kocheise F, Carls A, Burhenne J, Haefeli WE, Mikus G. 
Midazolam microdose to determine systemic and pre-systemic metabolic 
CYP3A activity in humans. Br J Clin Pharmacol 2014;79(2):278-285.
R17-3322
Berruyer C, Pouyet L, Millet V, Martin FM, LeGoffic A, Canonici A, et al. 
Vanin-1 licenses inflammatory mediator production by gut epithelial cells 
and controls colitis by antagonizing peroxisome proliferator-activated 
receptor gamma activity. J Exp Med 2006;203(13):2817-2827.
R17-3323
Martin F, Penet MF, Malergue F, Lepidi H, Dessein A, Galland F, et al. 
Vanin-1-/- mice show decreased NSAID- and Schistosoma-induced 
intestinal inflammation associated with higher glutathione stores. J Clin 
Invest 2004;113(4):591-597.
R17-3326
Ferreira DW, Goedken MJ, Rommelaere S, Chasson L, Galland F, Naquet 
P, et al. Enhanced hepatotoxicity by acetaminophen in vanin-1 knockout 
mice is associated with deficient proliferative and immune responses. 
Biochim Biophys Acta Mol Basis Dis 2016;1862(4):662-669.
R17-3327
Roisin-Bouffay C, Castellano R, Valero R, Chasson L, Galland F, Naquet 
P. Mouse vanin-1 is cytoprotective for islet beta cells and regulates the 
development of type 1 diabetes. Diabetologia 2008;51(7):1192-1201.


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R18-2692
Wang YJ, Tayo BO, Bandyopadhyay A, Wang H, Feng T, Franceschini N, 
et al. The association of the vanin-1 N131S variant with blood pressure is 
mediated by endoplasmic reticulum-associated degradation and loss of 
function. Plos Genet 2014;10(9):e1004641.
R18-2864
Creasy DM. Evaluation of testicular toxicity in safety evaluation studies: 
the appropriate use of spermatogenic staging. Toxicol Pathol 
1997;25(2):119-131.
R18-2866
Kang M, Qin W, Buya M, Dong X, Zheng W, Lu W, et al. VNN1, a 
potential biomarker for pancreatic cancer-associated new-onset diabetes, 
aggravates paraneoplastic islet dysfunction by increasing oxidative stress. 
Cancer Lett 2016;373:241-250.
R18-2867
Diepen JA van, Jansen PA, Ballak DB, Hijmans A, Rutjes FPJT, Tack CJ, 
et al. Genetic and pharmacological inhibvition of vanin-1 activity in animal 
models of type 2 diabetes. Sci Rep 2016;6:21906.
R18-2868
Aida Y, Abe H, Tomita Y, Nagano T, Seki N, Sugita T, et al. Serum 
cytokeratin 18 fragment level as a noninvasive biomarker for non-alcoholic 
fatty liver disease. Int J Clin Exp Med 2014;7(11):4191-4198.
R18-2954
Matthews HC, Concas D, Kudo H, Anstee Q, Thomas H, Cox R, et al. Cell 
surface pantetheinase, vanin-1, increases oxidative damage in 
acetaminophen induced liver injury via a reduction in glutathione. Int Liver 
Cong 2010, 45th Ann Mtg of the European Association for the Study of the 
Liver (EASL), Vienna, 14 - 18 Apr 2010. J Hepatol 2010;52(Suppl 
1):S311-S312.
R18-3167
Gensollen T, Bourges C, Rihet P, Rostan A, Millet V, Noguchi T, et al. 
Functional polymorphisms in the regulatory regions of the VNN1 gene are 
associated with susceptibility to inflammatory bowel diseases. Inflamm 
Bowel Dis 2013;19(11):2315-2325.
R20-0572
Midazolam 1 mg/ml solution for injection or infusion (Accord Healthcare) 
(summary of product characteristics updated 02-Jul-2018). Website: 
medicines.org.uk/emc/product/6045/smpc/print (access date: 21 February 
2020); 2018.
R20-3402
Recommendations related to contraception and pregnancy testing in clinical 
trials (version 1.1, CTFG 21/09/2020). Website: hma.eu/fi 
leadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups 
/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Version_1.1.pdf 
(access date: 16 October 2020) ; Clinical Trial Facilitation Group (CTFG), 
Head of Medicine Agencies (HMA); 2020.
9.2
UNPUBLISHED REFERENCES
c31270124
Investigator's Brochure BI 1595043 Crohn's Disease. Current version.
c34604736
Preliminary snapshot analysis, 1445-0001. 17Dec2020.


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c34816263
Preliminary data analysis ECG, 1445-0001. 14Dec2020.
n00259753
Pharmacodynamics of BI764122 in the dextran sulfate sodium model of 
colon injury in mice. 19Oct2018.
n00261263
BI 764122: Four-week oral (gavage) toxicity and toxicokinetics study in the 
dog followed by a four-week recovery period. 20May2019.
n00261387
BI 764122: Four-week oral (gavage) toxicity and toxicokinetics study in the 
rat followed by a four-week recovery period. 05Apr2019.
n00266340
BI 1595043: One week oral (gavage) exploratory study in the rat. 
19Sep2019.
n00266444
BI 1595043: An oral (gavage) dose escalation study in the dog. 
02Aug2019.
n00267953
Determination of the molar extinction coefficient of BI 1595043 XX. 
02Apr2019.
n00268703
BI 1595043: Thirteen-week oral (gavage) toxicity and toxicokinetics study 
in the rat followed by a ten-week recovery period. Report in progress.
n00270147
BI 1595043: Effect on hERG inactivating tail currents recorded from stably 
transfected HEK 293 cells. 29Jan2020.
n00270317
BI 1595043: Central nervous system safety pharmacology evaluation 
following oral gavage administration to male and female rats. 03Mar2020.
n00270318
BI 1595043: Respiratory safety pharmacology evaluation using head-out 
plethysmography following oral gavage administration to male rats. 
03Mar2020.
n00270319
Validation of an LC/MS/MS method for the quantitation of BI 1595043 in 
EDTA dog plasma. 20Dec2019.
n00270399
Validation of an LC/MS/MS Method for the quantitation of BI 1595043 in 
EDTA rat plasma. 06Feb2020.
n00270419
BI 1595043: Thirteen-week oral (gavage) toxicity and toxicokinetics study 
in the dog followed by a ten-week recovery period. Report in progress.
n00271655
BI 1595043: Cardiovascular safety pharmacology evaluation by oral gavage 
to male telemetry-instrumented conscious dogs. 13Mar2020.
n00271724
BI 1595043: In vivo mammalian erythrocyte micronucleus assay in rats. 
05Mar2020.
n00271737
BI 1595043: Bacterial reverse mutation with an independent repeat assay. 
Report in progress.
n00271739
BI 1595043: In vitro mammalian cell micronucleus assay in human 
peripheral blood lymphocytes (HPBL) cells. 09Mar2020.
n00272671
BI 1595043: neutral red uptake phototoxicity assay in BALB/c 3T3 mouse 
fibroblasts. 24Feb2020.


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n00273365
Quantitative whole-body autoradiography in male pigmented rats after 
single oral administration of [14C]BI 1595043. 05Nov2019.
n00273892
Inhibition of recombinant human vanin-1 enzymatic activity. 25Feb2020.
n00273893
Vanin inhibition in human whole blood. 03Mar2020.
n00273895
Human colon explant assay-release of CK-18 and cysteamine production. 
06Jan2020.
n00273897
Impact of Vanins’ Inhibition on Human CD4+ T Cells Effector Functions. 
Report in progress.
n00273898
Pharmacodynamics of BI 1595043 in the dextran sulfate sodium model of 
colon injury in mice. 07Apr2020.
n00274794
BI 1595043 Nonclinical expert statement. Report in progress.
n00275520
Excretion of radioactivity in urine, feces and bile after oral and intravenous 
administration of [14C]BI 1595043 to rats. 07Feb2020.
n00275663
Validation of an LC/MS/MS Method for the quantiation of BI 1595043 in 
EDTA rabbit plasma. Report in progress.
n00275691
Species comparison of in vitro binding of [14C]BI 1595043 to rat, dog and 
human plasma proteins. Report in progress.
n00275784
Effects of BI 1595043 (1, 3 and 10 mg/kg p.o.) on urine- and serum-derived 
parameters in conscious rats. 19Feb2020.
n00278281
A GLP Embryo-fetal Development Study of BI 1595043 by Oral Gavage in 
Rabbits. 
 20R006. 9001543. 02Dec2020.
n00278622
A GLP Embryo-fetal Development Study of BI 1595043 by Oral Gavage in 
Rats. 
 20R005. 9001542. Report in progress.
n00280589
BI 1595043: In vitro Evaluation as Direct and Timedependent Inhibitor of 
Cytochrome P450 Isoenzymes in Human Liver Microsomes. 
 
G-A-VIT-20-012. A510/20LU. 21Sep2020.
n00281141
BI 1595043: In vitro cytochrome P450 enzyme induction in primary human 
hepatocytes and assessment of CYP induction potential using the basic 
models R3 and F2 according to FDA and EMA guidance. 
 
A008/20STC. B7088. 16Oct2020.


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10.
APPENDICES
10.1
DRUG SUPPLIES USED FOR DILUTION AND DOSING
Drug supplies overview
a) Midazolam
 1 mg/mL solution for injection or infusion 5 mg/5 mL, 
5 mL ampoules
b) Isotonic Sodium Chloride Solution 0.9%, 100 ml bottles 
c) Empty, appropriately labelled glass container, preferably with lid 
Required equipment and dosing aids – overview
Dosing and diluting syringes:

2-part disposable 
 NORM-JECT® Syringes 2 mL

2-part disposable 
 NORM-JECT® Syringes 20 mL

Blunt, non-bevelled needle tip

 Combi-Stopper®
Only CE certified syringes WITHOUT rubber stoppers are to be used!
      


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Dilution procedure
Solution preparation for oral use 
Step 1: 
Open the commercial isotonic saline solution (0.9% NaCl).
Step 2: 
Attach a needle tip to the 2 mL syringe and withdraw a bit more than 1 mL of 
the midazolam solution [concentration: 1 mg/mL] from the originator 
ampoule using a 2 mL syringe.
Step 3:
Remove any air bubbles in syringe (turn upside down and gently push out air 
by depressing the plunger); ensure that exactly 1 mL midazolam solution 
remains in the 2 mL syringe.
Step 4:
Remove and dispose of needle tip; transfer the full 1 mL of midazolam 
solution into an appropriate glass container (with cap) by completely
depressing the plunger on the 2 mL syringe.
Step 5: 
Attach a needle tip to the 20 mL syringe and withdraw a bit more than 19 mL 
isotonic saline solution into the 20 mL syringe; remove air bubbles (see 
Step 3) and ensure exactly 19 mL isotonic saline solution remains in the 20 ml 
syringe.
Step 6:
Remove and dispose of needle tip; transfer the full 19 mL of isotonic saline 
solution into the same glass container with the midazolam solution by 
completely depressing the plunger on the 20 mL syringe.
Step 7:
Following addition of the midazolam and saline solutions into the glass 
container, ensure the glass container is closed using the corresponding cap. 
The content of the glass container should be mixed thoroughly by swirling 
gently for approximately 1 minute.
Step 8:
Extract a little more than 1.5 mL of the dilution solution using a needle tip 
and a new 2mL syringe; remove bubbles (see Step 3) and ensure that exactly 
1.5 mL of the diluted midazolam solution (final concentration: 50 µg/mL) 
remains in the 2 mL syringe. Remove and dispose of the needle tip and close 
the syringe with a cap; the solution is now ready for oral administration. 
The final midazolam microdose Oral Solution concentration is 50 µg/mL, for 
administration of 1.5 mL (75 µg), which will be administered per os directly from the 
syringe.
In-use stability
The chemical in-use stability of the dilution solution is 24 h after its preparation, incl. storage 
at room temperature (15-25°C) in 
2-part disposable 
 NORM-JECT®
syringes until administration.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1 
Date of amendment
08 March 2021
EudraCT number
EU number
2020-004923-18
BI Trial number
1445-0002
BI Investigational Medicinal 
Product(s)
BI 1595043
Title of protocol
Safety, tolerability and pharmacokinetics of multiple 
rising oral doses of BI 1595043 (double-blind, 
randomised, placebo-controlled, parallel group 
design) in healthy male subjects
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Flow Chart B (pages 7-9) 
2. Flow Chart C (page 13)
3. Section 1.4.3.3.
4. Section 3.3.2.
5. Section 4.2.2.2
Description of change
1. On Days 1 and 18, PK time points at 10 h post-
dose (i.e. planned time 10:00 and 418:00) removed.
2. On Day 14, PK time point at 10 h post-dose (i.e.
planned time 322:00) removed.
3. Clarification to assessment of clinical relevance of 
the ophthalmology findings in non-clinical studies 
added.
4. Use of male contraception (i.e. condom) defined 
in study inclusion criterion No. 5.
5. Use of male contraception (i.e. condom) defined 
in the study restrictions for subjects with pregnant or 
non-pregnant WOCBP partners.
Rationale for change
Changes are based on the regulatory feedback
of FAMHP after review of the study protocol as part 


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of the approval procedure.
With this amendment small inconsistencies in the 
study protocol have been corrected.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
23 July 2021
EudraCT number
EU number
2020-004923-18
BI Trial number
1445-0002
BI Investigational Medicinal 
Product(s)
BI 1595043
Title of protocol
Safety, tolerability and pharmacokinetics of multiple 
rising oral doses of BI 1595043 (double-blind, 
randomised, placebo-controlled, parallel group 
design) in healthy male subjects
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Title Page
2. Clinical Trial Protocol Synopsis
3. Flow Chart B (pages 7) 
4. Flow Chart C (page 11)
5. Section 1.2.1.5.
6. Section 1.3.
7. Section 1.4.
8. Section 3.3.4.3.
9. Section 4.1.4.
10. Section 4.2.2.2.
11. Section 5.2.4.
12. Section 5.4.1.
Description of change
1. The Principal Investigator’s address changed.
2. The Trial Site’s address changed. Fasting 
requirements in DG 5 changed.
3. On Day -2, temperature measurement at 
admission to trial site added.
4. On Day -1, temperature measurement at 
admission to trial site added.
5-8. The preliminary PK and safety data of 160 mg 
single dose of the FIH SRD study added. The actual 
exposure of 160 mg single dose replaced the 
projected exposure, thus, the maximum allowable 


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Trial Protocol
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001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
systemic exposure in the MRD study updated. The 
safety margins re-calculated.
9-11. Fasting requirements in DG 5 changed.
12. Reference to a laboratory manual (pantetheine, 
urine) removed.
Rationale for change
Changes are based on:
1) availability of preliminary PK and safety data of 
160 mg single dose of the FIH SRD study, and
2) upcoming move of the 
(Trial Site).
With this amendment minor inconsistencies in the 
study protocol have been corrected.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c33929558
3.0
clinical-trial-protocol-version-03
Safety, tolerability and pharmacokinetics of multiple rising oral doses of BI 1595043
(double-blind, randomised, placebo-controlled, parallel group design) in healthy male
subjects
Author-Trial Statistician
26 Jul 2021 09:01 CEST
Approval-Clinical Program Leaders
26 Jul 2021 13:09 CEST
Author-Clinical Trial Leader
26 Jul 2021 15:23 CEST
Verification-Paper Signature
Completion
26 Jul 2021 16:52 CEST


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3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c38236282-01
BI Trial No.:
1445-0002
Title:
Safety, tolerability and pharmacokinetics of multiple rising oral 
doses of BI 1595043 (double-blind, randomised, placebo-
controlled, parallel group design) in healthy male subjects
Including Protocol Amendment 2 [c33929558-03]
Investigational
Product:
BI 1595043
Responsible trial 
statistician:
Phone: +
Fax: +
Date of statistical 
analysis plan:
10-Mar-2022 SIGNED
Version:
Final
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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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................20
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........21
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................21
7.3
TREATMENT COMPLIANCE........................................................................21
7.4
PRIMARY ENDPOINTS...................................................................................21
7.4.1
Primary analysis of the primary endpoints......................................................21
7.5
SECONDARY ENDPOINTS.............................................................................21
7.5.1
Key secondary endpoints....................................................................................21
7.5.2
Secondary endpoints...........................................................................................22
7.5.2.1
Secondary endpoint analysis.................................................................................22


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7.7
EXTENT OF EXPOSURE.................................................................................26
7.8
SAFETY ANALYSIS..........................................................................................26
7.8.1
Adverse Events ....................................................................................................26
7.8.2
Laboratory data ..................................................................................................27
7.8.3
Vital signs.............................................................................................................28
7.8.4
ECG......................................................................................................................29
7.8.5
Others...................................................................................................................31
7.8.5.1
Physical examination ............................................................................................31
7.8.5.2
Body weight ..........................................................................................................31
7.8.5.3
Ophthalmological examination.............................................................................32
8. 
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............33
9.
REFERENCES....................................................................................................34
11.
HISTORY TABLE..............................................................................................42


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data, vital signs and ECG .............................................13
Table 6.3: 1
Subject sets analyzed........................................................................................15
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation for 
dose groups 1-4 ................................................................................................17
Table 6.7: 2
Time schedule of 12-lead ECG recordings with centralised evaluation for 
dose group 5 .....................................................................................................18
Table 11: 1
History table .....................................................................................................42


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity
AUC0-τ,ss 
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
Cmin,ss
Minimum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
RA, Cmax
Accumulation ratio based on Cmax,ss
RA, AUC
Accumulation ratio based on AUC0-τ,ss
BI 
Boehringer Ingelheim
Cmax
Maximum measured concentration of the analyte in plasma
COVID
Coronavirus disease
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
ECGPCS
ECG plasma concentration set
gCV
geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
ICH
International Conference On Harmonisation
IPD
Important protocol deviations
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary For Regulatory Activities
PD
Pharmacodynamics


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Term
Definition / description
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
PR
Pulse rate
QRS 
complex
Combination of the Q, R, and S waves
QT interval
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTcB
QT interval, heart rate corrected according to Bazetts formula
QTcF
QT interval, heart rate corrected according to Fridericias formula
RAGe
Report appendix generator
RPM
Report Planning Meeting
RR interval
ECG interval from the peak of the R wave to the peak of the subsequent R 
wave
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1) the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to 
include detailed procedures for executing the statistical analysis of the primary variables and 
other data.
This TSAP assumes familiarity with the CTP and its amendments. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 "Statistical Methods 
and Determination of Sample Size". Therefore, TSAP readers may consult the revised CTP 
for more background information on the study, e.g., on study objectives, study design and 
population, treatments, definition of measurements and variables, planning of sample size, 
randomisation.
Study data will be stored in a trial database within Medidata Rave system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), 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 revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint for assessment of safety and tolerability of BI 1595043 is the 
percentage of subjects with drug-related adverse events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints are PK endpoints of BI 1595043, as defined in Section 2.1.3 of the 
CTP:
After the last dose:

AUC0-τ,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)

Cmin,ss (minimum measured concentration of the analyte in plasma at steady state over
a uniform dosing interval τ)

RA, Cmax (accumulation ratio based on Cmax,ss)

RA, AUC (accumulation ratio based on AUC0-τ,ss)


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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.
Subjects will receive tablets containing

either 15 mg q.d, 30 mg q.d., 60 mg q.d., 120 mg q.d. or 60 mg b.i.d. of BI 1595043
(test treatments)
or

a matching placebo (reference treatment)
Patients of dose group 1-4 (15 mg q.d, 30 mg q.d., 60 mg q.d., 120 mg q.d.) receive treatment 
for 18 days, including a single dose segment on Day 1 with a washout over 4 days, and a 
multiple dose segment over 14 days (Days 5-18).
Patients of dose group 5 (60 mg b.i.d.) receive treatment as a multiple dose segment over 14 
days, including a twice daily regimen on Days 1-13 and morning dose only on Day 14.
Additionally all patients of dose group 3-4 (60 mg q.d. and 120 mg q.d.) will receive 75 µg
q.d. Midazolam for injection used as oral solution at Day -1, Day 1 and Day 18.
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made for placebo subjects).


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For statistical analysis of AEs, the following analysis phases are defined for each subject. 
Table 6.1: 1
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data, vital signs and ECG 
Study analysis 
phase
Label
Start
End
Screening1
Screening
Date of informed consent
Date/time of first administration 
of study drug
On treatment
Placebo,
15 mg BI q.d.,
30 mg BI q.d.,
60 mg BI
q.d.+Mid,
120 mg BI
q.d.+Mid or
60 mg BI b.i.d.
respectively
Date/time of first administration 
of study drug
12:00 a.m. on day after last 
contact date 
1 See Section 6.7 for definition of baseline, which will be used in the statistical analyses of safety laboratory data, ECG and 
vital signs.
AE summary tables will present results for the on-treatment phase only. All AEs will be 
listed.
In AE tables in CTR Section 15.3 (but not in Appendix 16.1.13.1.8.1 and Appendix 
16.1.13.1.8.2 AE tables), the following total will be provided in addition: 

"Total BI", defined as the total over all on-treatment phases involving BI

"Total on-trt", defined as the total over all on-treatment phases, including placebo
Safety laboratory data, ECG, vital signs and PK parameters will be analysed based on 
treatment groups (Placebo, 15 mg BI q.d., 30 mg BI q.d., 60 mg BI q.d., 120 mg BI q.d. or 60 
mg BI b.i.d.) with clear differentiation between baseline (cf. Section 6.7) and on-treatment 
measurements. Measurements will be considered on-treatment, if they were taken within the 
on-treatment phases as defined in Table 6.1: 1.
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting. At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 


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whether it is an important PD (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) and the DV domain template.
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 template. If the data show other IPDs, the definition in the DV domain template
will be supplemented accordingly by the time of the Report Planning Meeting.
IPDs will be summarized and listed. Which kind of IPDs could potentially lead to exclusion 
from which analysis set is specified in the DV domain template. The decision on exclusion of 
subjects from analysis sets will be made at the latest at the Report Planning Meeting, after 
discussion of exceptional cases and implications for analyses.
Non-important COVID-19 related PDs will only be listed.
6.3
SUBJECT SETS ANALYSED
The treated set (TS) and pharmacokinetic parameter analysis set (PKS) will be used as 
defined in the CTP, Section 7.3.
In addition, the following subject sets will be used:
All ECG analyses are performed on the TS, except for the exposure-response analyses, which 
are performed on the ECGPCS defined below.

ECG plasma concentration set (ECGPCS):
This subject set includes all subjects from the TS who provide at least one pair of a 
valid drug plasma concentration and a corresponding (i.e. time-matched) ECG 
endpoint to be used in the exposure-response analyses. For placebo subjects, the 
plasma concentration is set to zero and hence always considered as valid. The 
decision whether a time deviation between PK blood sampling and ECG recording is 
acceptable (and thus whether the pair of values will be used) is to be made no later 
than at the RPM before data base lock. For subjects treated with active drug, the 
decision about concentration value validity needs to be made within the Clinical 
Pharmacology Group.
For biomarker analyses the pharmacodynamic parameter set (PDS) will be used, which is 
defined as following:

This set includes all subjects in the treated set (TS) who provide at least one 
biomarker endpoint that was not excluded due to a protocol violation relevant to the 
evaluation of biomarker or due to biomarker non-evaluability. Thus, a subject will be 
included in the PDS, even if he/she contributes only one biomarker parameter value to 
the statistical assessment.


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Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
PKS  
PDS
ECGPCS
Disposition
X
IPDs
X
Primary endpoint 
X
Secondary PK endpoints 
X
Further PK endpoints 
X
Further exploratory 
biomarker endpoints
X
Safety parameters 
(except for exposure-
response analyses of ECG 
data)
X
Exposure-response 
analyses of ECG data
X
Demographic/baseline 
characteristics
X
Treatment exposure
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
CTP: “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 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.”
CTP: “It is not planned to impute missing values for safety parameters.”
One exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).


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If single cardiac cycles of an ECG are missing, the arithmetic mean for this single ECG will 
be computed with the reduced (1, 2 or 3) number of cardiac cycles. If replicate ECG 
recordings are missing, the arithmetic means per time point will be computed with the 
reduced number (1 or 2) of recordings.
For the classification of the on-treatment QTc/QT intervals into ‘no new onset’ / ‘new onset’ 
categories, the handling of missing value is described in Section 10.3.
For the exposure-response analyses, missing plasma concentration values with ‘BLQ’ in the 
comment field will be replaced by ½ LLOQ for subjects on active drug. For placebo subjects, 
the missing plasma concentration values will be replaced by 0 for the exposure-response 
analyses.
Missing data and outliers of PK and PD data are handled according to BI standards (4) and 
(5).
CTP: “Pharmacokinetic 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
In all analyses (except for analyses of ECG variables), baseline is defined as the last available
value prior to first administration of study drug.
A centralised evaluation of 12-lead ECG recordings is performed at the time points specified 
in Table 6.7: 1 and Table 6.7: 2.


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Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation for dose 
groups 1-4 
Visit
Day
Planned time [hh:mm] - relative to first study drug admin.
Study phase
2
1
-1:00
Baseline
01:00
On-treatment
02:00
12:00
2
24:00
5
95:45
97:001
6
119:45
121:001
7
143:45
7
145:001
9
191:45
193:001
11
239:451
241:001
13
287:451
289:001
15
335:45
337:001
17
383:451
385:001
18
407:45
409:00
410:00
412:00
416:00
420:00
19
432:00
20
455:451
1 According to CTP flow chart, there is no time-matched PK sample for several ECG measurements, i.e. measurements at 
planned time 97:00, 121:00, 145:00, 193:00, 239:45, 241:00, 287:45, 289:00, 337:00, 383:45, 385:00 and 455:45. This ECG 
measurement will not be used in the exposure-response model, which will be applied to time matched pairs of ECG 
measurements and PK samples.


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Table 6.7: 2
Time schedule of 12-lead ECG recordings with centralised evaluation for dose 
group 5 
Visit
Day
Planned time [hh:mm] - relative to first study drug admin.
Study phase
2
1
-1:00
Baseline
01:00
On-treatment
02:00
13:001
2
23:45
25:001
37:001
3
47:45
49:001
61:001
5
95:45
97:001
109:001
7
143:451
145:001
157:001
9
191:451
193:001
205:001
11
239:45
241:001
253:001
13
287:451
289:001
301:001
14
311:45
313:00
314:00
316:00
320:00
324:00
15
336:00
16
359:45
1 According to CTP flow chart, there is no time-matched PK sample for several ECG measurements, i.e. measurements at 
planned time 13:00, 25:00, 37:00, 49:00, 61:00, 97:00, 109:00, 143:45, 145:00, 157:00, 191:45, 193:00, 205:00, 241:00, 
253:00, 287:45, 289:00 and 301:00. This ECG measurement will not be used in the exposure-response model, which will be 
applied to time matched pairs of ECG measurements and PK samples.


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Three triplicate ECGs will be recorded as the baseline before drug administration, but only 
the first ECG of each of the 3 baseline triplicate will be transferred to the database. At all 
other time points, 1 triplicate ECG will be recorded, but only the first single ECG of the 
triplicate will be transferred to the database. The baseline value of an ECG variable is defined 
as the mean of the ECG variable values prior to drug administration. 
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database. Unscheduled ECGs (for 
safety reasons) will be transferred to the central ECG lab but will not be included into the 
statistical analysis of interval lengths.
For the exposure response analyses, pairs of ECG variables and corresponding plasma 
concentrations will be built using the same planned time points, e.g., the HR change from 
baseline and the plasma concentration measured at planned time 0:30 will build one pair. 
Whether a time deviation between PK blood sampling time and corresponding ECG 
recording is too big for a reliable assessment and the pair has to be excluded from the 
analysis will be decided no later than at the RPM.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the Report Planning Meeting.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (6).
The individual values of all subjects will be listed. Listings will be sorted by treatment or 
sequence group, subject number and visit (if visit is applicable in the respective listing). AE 
listings will be sorted by assigned treatment (see Section 7.8.1 below for details). The listings 
will be contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical 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. These will be based on the 
TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary. Concomitant non-drug therapies will be coded 
according to the most recent version of MedDRA.
Only descriptive statistics are planned for this section of the CTR.
CTP: Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
A medication will be considered concomitant to a dose group, if it

is ongoing at the time of 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.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analyzed as a specific endpoint. Any deviations from 
complete intake will be addressed in the Report Planning Meeting (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoints
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis 
of the percentage of subjects with drug related AEs, which is the primary endpoint of this 
trial.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.


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7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.
7.5.2.1
Secondary endpoint analysis
The PK endpoints will be assessed descriptively.. The analysis of standard PK parameters is 
performed according to BI standards (4).
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
CTP: Plasma/urine concentration data and parameters of a subject which is flagged for 
exclusion will be reported with its individual values but will not be included in the statistical 
analyses.
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the 
value will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (5).


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


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
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 Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted).
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately. Separate tables will also be provided for subjects with SAEs and
subjects with AESIs. AEs will also be summarized by maximum intensity.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards “Display and Analysis of Laboratory Data” (9).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
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).


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Clinically significant abnormal laboratory values are only those identified either in the 
Investigator's comments or at the Report Planning Meeting at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as possibly clinically significant values will be highlighted in the listings.
Possibly clinically significant laboratory values will be listed in Section 15.4.1.
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.
Urinary creatinine (from spot samples) was measured as part of routine safety lab, but will 
not be analysed or listed. This is a technical parameter and is not useful for safety evaluation.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate, oral body temperature) 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).

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.


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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.
If a scheduled measurement is “not done”, and the unscheduled measurement is 
within 20 minutes of the “not done” assessment, the unscheduled will be used in 
calculation of descriptive statistics at the respective time point.
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study
treatment) if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.4
ECG
Abnormal findings will be reported as baseline conditions (prior to first administration of 
study treatment) or as AEs (after first administration of study treatment) if judged clinically 
relevant by the investigator. 
Descriptive analysis of ECG endpoints will be based on the TS. The evaluation of the 
relationship between plasma concentration and change in ECG endpoints (exposure-response 
analysis) will be based on the ECGPCS.
ECG measurements will not be included in the statistical analysis if one of the following 
applies:

No date or time available for ECG measurement

Pre-dose measurement done after first drug administration

On-treatment measurement done before first drug administration

Measurement is a repeated measurement

More than 3 single ECGs (i.e., measurements from 4th single ECG onwards will not 
be included)

Unscheduled measurements


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Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR, only listings will be provided. Occurrences of notable findings will be 
flagged.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
For all subjects with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding time profiles will be presented in figures.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the absolute 
values and changes from baseline over time of QTcF, HR, QT, PR and QRS. The time 
profiles of mean and SD for the changes from baseline on treatment will be displayed 
graphically by treatment.
Exposure-response analysis
For QTcF and HR changes from baseline, the relationship to the corresponding plasma 
concentrations will be evaluated using a random coefficient model. For subjects in the 
ECGPCS, all time points with available ECG endpoints and valid time-matched drug plasma 
concentrations will be included. For the handling of missing values, see Section 6.6.
The response variable will be the change from baseline in QTcF (ΔQTcF). The placebo 
subjects will be included in the analysis, setting their plasma concentrations to zero.
As a first step, it is investigated if there is a potential delayed or accelerated (e.g. due to 
metabolites) effect of the drug on QTcF. A general visual impression will be provided by 
overlaying time profiles of plasma concentrations and QTcF changes from baseline (ΔQTcF). 
These figures will be generated for each subject (presented in the Statistical Appendix of the 
CTR), as well as for means per dose group (presented in the End-of-Text part of the CTR).
The relationship between BI 1595043 plasma concentrations and QTcF changes from 
baseline will be investigated in an exploratory manner using a random coefficient model to 
estimate the difference in mean QTcF change from baseline between BI 1595043 and placebo 
and its 90% confidence interval at the geometric mean of Cmax (after single dose) and of
Cmax,ss for each dose group. Additionally, the estimated overall slope with its 90% confidence
interval will be provided. The used random coefficient model is based on a white paper from 
Garnett et. al. [R18-0143] (10) with ΔQTcF as response variable, centered baseline QTcF and 
plasma concentration as continuous covariates, treatment, time and day as fixed categorical 
effects, and a random intercept and slope for each subject.


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Restricted maximum likelihood estimation will be performed, and the Kenward-Roger 
method will be applied to adjust standard errors and estimate denominator degrees of 
freedom. For more details refer to Section 10.4.
For visualization, a scatterplot of the BI 1595043 plasma concentration against the following 
individual QTcF values will be provided: For each subject on active treatment and each time 
point, subtract the mean value of all individual observed ΔQTcF values from the placebo 
group for this time point from the individual observed ΔQTcF value for this subject and time 
point. This results in estimates for “individual ΔΔQTcF” values, which should only be used 
for plotting purposes. The corresponding regression line and its pointwise confidence bands 
as well as the geometric mean of Cmax for each dose will additionally be displayed in the plot.
The goodness of fit of the above model will be checked. The visual checks will include the 
inspection of concentration-QTcF quantile plots (see [R18-0143] (10)) and residual plots.
To check model assumptions, the conditional residuals will be plotted and presented in the 
Statistical Appendix of the CTR. In case of non-linearity or if there is evidence for a delayed 
effect, further models will be explored in order to better characterise the PK-ECG 
relationship (e.g. effect compartment models, non-linear models, etc.).
All of the above described graphical and statistical analyses for the exposure-reponse analysis 
will be also performed for HR in place of QTcF.
Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval will be estimated separately for off-drug 
values and active treatment, by applying the random coefficient model described in 
Section 10.2 using the QTcF and RR variable values per time point. A scatterplot of QTcF vs 
RR including the overall regression lines will be included in the Statistical Appendix of the 
CTR. The resulting (fixed effect) slope together with two-sided 95% confidence intervals will 
be included in the footnote for this plot.
7.8.5
Others
7.8.5.1
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized as 
such. No separate listing or analysis of physical examination findings will be prepared.
7.8.5.2
Body weight
Body weight will only be listed.


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7.8.5.3
Ophthalmological examination
A slit lamp examination will be conducted by an ophthalmologist at Screening and EoT. 
Abnormal findings will be recorded as AEs if judged clinically relevant by the Investigator. 
No separate listing or analysis of ophthalmological examination will be prepared. 


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8. 
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION 
The treatment information in each dose group will be released based on a treatment-
information-request when all subjects of the respective dose group have been randomized.


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9.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of 
Clinical Trials, current version
2
BI-VQD-12045_40-413: "Identify and Manage Important Protocol Deviations 
(iPD)", current version; KMED
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-TCMP-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-0066: "Analysis and Presentation of Adverse 
Event Data from Clinical Trials", current version; KMED
8
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
9
KM Asset BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of 
Laboratory Data", current version; KMED
10
Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white 
paper on concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018. 
45(3): 383-397. [R18-0143]
11
BI Statistical Position Paper: "Statistical Methods for PK", current version; KMED


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
10-MAR-2022
None
This is the final TSAP