Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 74
Healthy volunteers: yes

Brief summary:
The main objective of the single-rising dose (SRD) part and the multiple rising dose (MD) part is to investigate safety, tolerability, pharmacokinetics and pharmacodynamics (for MD part only) following single rising doses and multiple oral doses of BI 1323495 in healthy male Japanese subjects genotyped as poor metabolizers (PM) and extensive metabolizers (EM) of UGT2B17.

The main objective of the drug-drug interaction (DDI) part is to investigate the relative bioavailability of a single oral dose of BI 1323495 when given alone (treatment R) or in combination with itraconazole (treatment T) in healthy male subjects genotyped as PM of UGT2B17.

Detailed description:

Arms:
arm 1: Participants were administered on Day 1 a single oral dose of 10 milligram (mg) of BI 1323495 film-coated tablet together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication. arm 2: Participants were administered on Day 1 a single oral dose of 30 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration.

One authorized employee of the trial site was witness of the administration of the trial medication. arm 3: Participants were administered on Day 1 a single oral dose of 100 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication. arm 4: Participants were administered on Day 1 a single oral dose of 30 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication. arm 5: Participants were administered on Day 1 a single oral dose of 70 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication. arm 6: Participants were administered on Day 1 a single oral dose of 150 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication. arm 7: This arm comprises all placebo treated participants in trial part SRD, regardless of the dose group in which they were treated. Participants were randomized within each dose group in a 3:1 ratio (test treatment to placebo).

Participants were administered on Day 1 a single oral dose of placebo film-coated tablet(s) together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication. arm 8: Participants were administered from Day 1 to Day 10 two times per day (bid) an oral dose of 30 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water, At Day 11 participants were administered only a single dose in the morning. Participants took a normal caloric meal 30 minutes (min) before drug administration. Subjects fasted for 4 hours (h) after intake of morning dose. Morning and evening dose were taken with a 12 h time interval approximately at the same time each day during the treatment phase. One authorized employee of the trial site was witness of the administration of the trial medication. arm 9: Participants were administered from Day 1 to Day 11 one time per day (qd) an oral dose of 60 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. Participants took a normal caloric meal 30 minutes (min) before drug administration. Subjects fasted for 4 hours (h) after intake of morning dose. One authorized employee of the trial site was witness of the administration of the trial medication. arm 10: This arm comprises all placebo treated participants in trial part MD, regardless of the dose group in which they were treated. Participants were randomized within each dose group in a 3:1 ratio (test treatment to placebo). Participants were administered from Day 1 to Day 11 one time per day (qd) an oral dose of placebo film-coated tablets or two times per day (bid) an oral dose of placebo together with about 240 milliliter (mL) of water. Participants took a normal caloric meal 30 minutes (min) before drug administration. Subjects fasted for 4 hours (h) after intake of morning dose. One authorized employee of the trial site was witness of the administration of the trial medication. arm 11: * Period 1: Participants were administered the reference treatment (R) which consisted of a single oral dose of 10 milligram (mg) film-coated tablet of BI 1323495 together with about 240 milliliter (mL) of water on Day 1 of Period 1. One authorized employee of the trial site was witness of the administration of the trial medication.
* Period 2: Participants were administered the test treatment (T) which consisted of a single oral dose of 10 milligram (mg) film-coated tablet of BI 1323495 with about 240 milliliter (mL) of water on Day 1 of Period 2, together with multiple oral doses of 200 mg itraconazole from Day -3 to Day 7, in total 10 doses, as oral solution formulation. One authorized employee of the trial site was witness of the administration of the trial medication.

Administration of BI 1323495 in treatment R and T were separated by at least 11 days.

Interventions: intervention 1: BI 1323495 intervention 2: Placebo intervention 3: Itraconazole
Intervention descriptions: intervention 1: BI 1323495 intervention 2: Placebo intervention 3: Itraconazole

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c31942019-03
BI Trial No.
1405-0003
BI Investigational
Medicinal Product
BI 1323495 
Title
Safety, tolerability and pharmacokinetics of single rising oral 
doses and multiple oral doses of BI 1323495 versus placebo in 
healthy male Japanese subjects genotyped as poor and extensive 
metabolizers of UGT2B17 (single-blind, randomised, placebo-
controlled [within dose groups] trial), including an investigation 
of drug-drug interaction with itraconazole in healthy male 
subjects genotyped as poor metabolizers of UGT2B17 (an open-
label, two-period, fixed sequence trial)
Lay Title
A study in healthy Japanese men to test how different doses of BI 
1323495 are tolerated and how itraconazole influences the 
amount of BI 1323495 in the blood
Clinical Phase
I
Clinical Trial Leader
Telephone: 
, Fax:
Principal 
Investigator
Phone:
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 25 FEB 2021
Page 1 of 107
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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
12 Aug 2020
Revision date
25 Feb 2021
BI trial number
1405-0003
Title of trial
Safety, tolerability and pharmacokinetics, of single rising oral doses and multiple 
oral doses of BI 1323495 versus placebo in healthy male Japanese subjects 
genotyped as poor and extensive metabolizers of UGT2B17 (single-blind, 
randomised, placebo-controlled [within dose groups] trial), including an 
investigation of drug-drug interaction with itraconazole in healthy male subjects 
genotyped as poor metabolizers of UGT2B17 (an open-label, two-period, fixed 
sequence trial)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
SRD and MD part: The objective of this trial is to investigate the safety, tolerability,
pharmacokinetics, and pharmacodynamics (for MD part only) of BI 1323495 in 
healthy male Japanese subjects genotyped as poor (PM) and extensive metabolizers
(EM) of UGT2B17. The chosen population of healthy male subjects receiving 
single rising oral doses and multiple oral doses are considered adequate to provide 
the basis for the clinical development program of BI 1323495 in Japan.
DDI part: Based on in vitro data, CYP3A4 and P-gp are involved in metabolism and 
transport of BI 1323495, respectively. It is therefore necessary to explore in 
UGT2B17 PM the relative bioavailability of BI 1323495 in plasma when given 
alone versus when given together with a strong CYP3A4 and P-gp inhibitor.
Trial objectives
SRD and MD part: To investigate safety, tolerability, pharmacokinetics, and
pharmacodynamics (for MD part only) following single rising doses and multiple 
oral doses of BI 1323495 in PM and EM of UGT2B17.
DDI part: To investigate the relative bioavailability of a single oral dose of BI 
1323495 when given alone (treatment R) or in combination with itraconazole 
(treatment T) in PM of UGT2B17.


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Trial endpoints
SRD part:
Primary endpoint to assess safety and tolerability of BI 1323495 is the percentage 
(%) of subjects with drug-related adverse events
Secondary endpoints:
Cmax, and AUC0-∞of BI 1323495
MD part:
Primary endpoint to assess safety and tolerability of BI 1323495 is the percentage 
(%) of subjects with drug-related adverse events
Secondary endpoints:
After the first dose: AUC0-12 and Cmax of BI 1323495
After the last dose: AUCτ,ss and Cmax,ss of BI 1323495
DDI part:
Primary endpoints:
Cmax and AUC0-∞of BI 1323495
Secondary endpoints:
AUC0-tz of BI 1323495
Trial design
SRD and MD part: Single-blind, randomised within dose groups, placebo-
controlled parallel-group design
DDI part: Open-label, two-treatment, two-period, fixed sequence design
Number of subjects 
total entered
74 (SRD 36, MD 24 and DDI 14)*
each treatment
SRD part for PM : 8 per dose group (6 on BI 1323495 and 2 on placebo) 
SRD part for EM: 4 per dose group (3 on BI 1323495 and 1 on placebo)
MD part for PM: 12 per dose group (9 on BI 1323495 and 3 on placebo)
DDI part for PM: 14
* Additional subjects may be entered to allow additional testing 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 and none of the stopping 
criteria apply. Thus, the actual number of subjects entered may exceed 74, but will 
not exceed 90 subjects.
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 20 to 45 years (inclusive), body mass index (BMI) of 
18.5 to 25 kg/m2 (inclusive)
Test product 1
BI 1323495, film-coated tablets (dose strength 10 mg, 50 mg)


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dose
SRD part for PM : 10 mg, 30 mg and 100 mg qd
SRD part for EM: 30 mg, 70 mg and 150 mg qd
MD part for PM 30 mg bid and 60 mg qd
DDI part for PM: 10 mg
mode of admin.
SRD and MD part: Oral with 240 mL of water after a standardized meal
DDI part: Oral with 240 mL of water after an overnight fast of at least 10 h
Test product 2
(Only for DDI part)
Itraconazole oral solution (ITRIZOLE® Oral Solution 1% 
])
dose
200 mg q.d.
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 9 h
Comparator products:
(Only for SRD part)
Matching placebo tablets
dose:
Not applicable
mode of admin.:
Oral with 240 mL of water after a standardized breakfast
Duration of treatment
SRD part; 
Single dose 1 day
MD part:
30 mg bid; 11 days, 10 days twice daily (bid) dosing and single dose on day 11
60 mg qd; Once daily, multiple doses over 11 days
DDI part;
Treatment R (BI 1323495 alone):
Single dose of 10 mg BI 1323495 (Day 1)
Treatment T (itraconazole + BI 1323495):
10 days of itraconazole treatment (200 mg itraconazole once daily from Day -3 to 
Day 7) combined with a single dose of 10 mg BI 1323495 on the fourth day of the 
itraconazole treatment (Day 1, 1 h after the itraconazole administration)
Wash-out period:
Administrations of BI 1323495 will be separated by a wash-out phase of at least 11
days


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Statistical methods
SRD and MD part: Descriptive statistics will be calculated for all endpoints. 
DDI part: Relative bioavailability will be estimated by the ratios of the geometric 
means (Treatment T/Treatment R) for the primary and secondary endpoints. 
Additionally, their two-sided 90% confidence intervals (CIs) will be provided. This 
method corresponds to the two one-sided t-test procedure, each at a 5% significance 
level. Since the main focus is on estimation and not testing, a formal hypothesis test 
and associated acceptance range are not specified. The statistical model will be an 
analysis of variance (ANOVA) on the logarithmic scale including effects for 
‘subject’ and ‘treatment’. CIs will be calculated based on the residual error from the 
ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
SRD part
Visit
Day
Planned time (relative to 
BI 1323495 or placebo 
administration [h:min])
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory6,9
PK blood 8
PK urine10
Medical Examination
Vital signs (BP, PR)9
12-lead ECG,9
Questioning for AEs and 
concomitant therapy12
SCR
1
-28 to 
-8
Screening (SCR)1
including 
pharmacogenomics test 
UGT2B17
xA,7
x
x
x
Treatment period
2
-1
-18:00
15:00
Ambulatory visit2
xB,7
x
-12:00
21:00
Admission to trial site
114
-2:00
07:00
Allocation to treatment
x
x
x
x
x11
x
-0:30
08:30
Standardized breakfast
0:00
09:00
BI 1323495 or placebo 
administration3
▲
│
0:20
09:20
x
│
x
x
x
0:40
09:40
x
│
x
x
x
1:00
10:00
x
│
x
x
x
1:30
10:30
x
│
x
x
x
2:00
11:00
240 mL fluid intake
x
│
x
x
x
3:00
12:00
x
│
x
x
x
4:00
13:00
240 mL fluid intake, 
thereafter lunch4
xB
x
┼
│
x
x
x
5:00
14:00
x
│
x
6:00
15:00
x
│
x
x
x
7:00
16:00
x
│
x
8:00
17:00
Snack(voluntary)4
x
┼
x
x
x
9:00
18:00
x
│
x
10:00
19:00
Dinner4
x
│
x
x
x
12:00
21:00
x
┼
x
x
x 
2
24:00
09:00
Breakfast4
xB
x
┼
x
x
x
28:00
13:00
Lunch4
│
32:00
17:00
Snack(voluntary)
│
34:00
19:00
Dinner4
x
┼
x
x
3
48:00
09:00
Discharge from trial site
x
▼
x
x
4
72:00
09:00
Ambulatory visit
x
x
x
5
96:00
09:00
Ambulatory visit
x
x
x
6
120:00
09:00
Ambulatory visit
x13
x
7
144:00
09:00
Ambulatory visit
x13
x
8
168:00
09:00
Ambulatory visit
xB
x13
x
x
x
x
EOT
3
9 to 
15 
End of trial (EOT) 
examination5
xA
x
x
x
x
PK: pharmacokinetics, ECG: electrocardiogram, BP: blood pressure, PR: pulse rate, AE: adverse event
Clock time should be adjusted based on actual administration time


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1.
Subject must be informed and written informed consent obtained prior to starting any screening 
procedures. Screening procedures include medical examination, check of vital signs, ECG (12-lead ECG), 
chest x-ray, safety laboratory (including drug screening), pharmacogenetic analysis for UGT2B17 
genotype, demographics (including determination of body height and weight, smoking and alcohol 
history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. 
2.
Safety laboratory to be taken and to be medically evaluated on Day -1 prior to administration of BI 
1323495. Axillary temperature measurement will be conducted during Day -1.
3. Oral with 240 mL of water after a standardized breakfast.
4. If several actions are indicated at the same time point, the intake of meals will be the last action.
5. EOT includes medical examination, vital signs, ECG, safety laboratory, recording of AEs and concomitant 
therapies.
6. Letters A and B describe different sets of safety laboratory examinations (see Section 5.2.3).
7.
Urine drug screening and alcohol breath test will be performed at screening and prior to dosing at Day -1 
of Visit 2. A breath alcohol test may be repeated at any time during the trial at the discretion of an 
investigator or designee. 
8.
PK samples for determination of plasma level of BI 1323495 as detailed in Section 5.3.2. Sampling times 
and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 
approximately 400 mL per subject.
9. For allowed deviation from the scheduled time please refer to Section 6.1.
10. PK urine samples for determination of BI 1323495 amount eliminated in urine are to be taken at following 
time intervals: a blank urine sample is to be obtained within 3 h 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, 24-34, and 
34-48 h (see Section 5.3.2.3).
11. Triplicate ECG. Three triplicate ECGs are recorded within approximately 1 h. The recordings of each 
triplicates should be separated by at least 15 min (refer to the Section 5.2.4) This measurement should be 
conducted within -12 h from administration.
12. AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at 
the time points indicated in the Flow Chart.
13. PK plasma samples are to be taken in UGT2B17 PM group only.
14. PGx samples will be collected during Day 1.


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DDI part
Period
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory5,10
PK blood, BI 1323495
PK blood, Itraconazole
Medical Examination
Vital signs (BP, PR)10
12-lead ECG10
Questioning for AEs and 
concomitant therapy 7
SCR
1 -28 to 
-8
Screening (SCR)1
including 
pharmacogenomics test 
UGT2B17
xA,3
x
x
x
Period 1/ Treatment R (BI 1323495 alone)8
2
-1
-18:00
15:00
Ambulatory visit
xB,3
x
-12:00
21:00
Admission to trial site
1
-2:00
07:00
Allocation to treatment2
x2
x2
x2
x2
x2
x2
0:00
09:00
BI 1323495 
administration
0:20
09:20
x
0:40
09:40
x
1:00
10:00
x
1:30
10:30
x
2:00
11:00
240 mL fluid intake
x
3:00
12:00
x
4:00
13:00
240 mL fluid intake, 
thereafter lunch4
x
x
x
x
5:00
14:00
x
6:00
15:00
x
7:00
16:00
Snack (voluntary)4
x
8:00
17:00
x
9:00
18:00
x
10:00
19:00
Dinner4
x
12:00
21:00
x
x 
2
24:00
09:00
Breakfast (voluntary)4
xB
x
x
x
x
34:00
19:00
Discharge from trial site
x
x
3
47:00
08:00
Ambulatory visit
x
x
4
71:00
08:00
Ambulatory visit
xB
x
x
5
95:00
08:00
Ambulatory visit
x
x
6
119:00
08:00
Ambulatory visit
x
x
7
143:00
08:00
Ambulatory visit
x
x
8
167:00
08:00
Ambulatory visit
x
x
x


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DDI part (cont’d)
Period
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory5, 10
PK blood, BI 1323495
PK blood, Itraconazole
Medical Examination
Vital signs (BP, PR)10
12-lead ECG10
Questioning for AEs and 
concomitant therapy 7
Period 2/ Treatment T (BI 1323495 + itraconazole) 8
3
-3
-72:00
09:00
Ambulatory visit, itraconazole 
administration
xB,2,3
x
x2
-2
-48:00
09:00
Ambulatory visit, itraconazole 
administration
x2
-1
-24:00
09:00
Ambulatory visit, itraconazole 
administration11
xC,2,3
x9
x2
-12:00
21:00
Admission to trial site2
112
-2:00
07:00
x2
x2
x2
x2
x2
-1:00
08:00
Itraconazole administration
x9
0:00
09:00
BI 1323495 administration
0:20
09:20
x
0:40
09:40
x
1:00
10:00
x
1:30
10:30
x
2:00
11:00
240 mL fluid intake
x
3:00
12:00
x
4:00
13:00
240 mL fluid intake, thereafter lunch4
x
x
x
x
5:00
14:00
x
6:00
15:00
x
7:00
16:00
Snack (voluntary)4
x
8:00
17:00
x
9:00
18:00
x
10:00
19:00
Dinner4
x
12:00
21:00
x
x 
2
23:00
08:00
Itraconazole administration
xB,2
x
24:00
09:00
Breakfast (voluntary)4
x
x
x
x
28:00
13:00
Lunch (voluntary)
31:00
16:00
Snack (voluntary)
34:00
19:00
Discharge from trial site
x
x
3
47:00
08:00
Ambulatory visit, itraconazole 
administration
x9
x9
x
4
71:00
08:00
Ambulatory visit, itraconazole 
administration
xC,2
x9
x
5
95:00
08:00
Ambulatory visit, itraconazole 
administration
x9
x
6
119:00
08:00
Ambulatory visit, itraconazole 
administration
xC,2
x9
x
7
143:00
08:00
Ambulatory visit, itraconazole 
administration
x9
x9
x
8
167:00
08:00
Ambulatory visit
xB
x
x
x
EOT 4
16 to 
23
End of trial (EOT) examination6
xA
x
x
x
x
Clock time should be adjusted based on actual administration time
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include medical examination, check of vital signs, ECG(12-lead ECG), chest x-ray, safety laboratory 
(including drug screening), pharmacogenetic analysis for UGT2B17 genotype, demographics (including determination 


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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; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
Urine drug screening and alcohol breath test
4.
If several actions are indicated at the same time, the intake of meals will be the last action.
5.
Letters A, B and C define different sets of safety laboratory examinations (for details refer to Section 5.2.3)
6.
At the end of trial visit the EOT examination includes medical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. 
7.
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.
8.
Administration of BI 1323495 in treatment R and T will be separated by at least 11 days.
9.
Blood collection takes place at the indicated times. Itraconazole will be administered immediately thereafter.
10. For allowed deviation from the scheduled time please refer to Section 6.1.
11. Axillary temperature measurement will be conducted during Day -1.
12.  PGx samples will be collected during Day 1.


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MD part (30 mg bid)
Visit
Day
Planned time (relative to first 
drug administration [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory2
PK blood, 4
PK urine5
PD blood (NE activity)
12-lead ECG7
Medical examination 
Vital signs8
Questioning for AEs and 
concomitant therapy 9
1
-28 
to -8
Screening (SCR)1
including pharmacogenomics test 
UGT2B17
xA
x
x
x
2
-1
-16:00 17:00 Admission to trial site
x B, 6, 10,
11
x
120
-01:00 08:00 Allocation to treatment12
xC,12
x12
x12
x12
x12,13
x12
x12
x12
-00:30 08:30 breakfast
00:00
09:00 First drug administration15
▲
00:20
09:20
x
│
00:40
09:40
x
│
01:00
10:00
x
│
x
x
01:30
10:30
x
│
02:00
11:00 240 mL fluid intake
xD
x
│
x
x
x
x
03:00
12:00
x
│
04:00
13:00 240 mL fluid intake, thereafter 
lunch3
x
┼
x
x
x
05:00
14:00
x
│
06:00
15:00
x
│
x
x
x
07:00
16:00
x
│
08:00
17:00 Snack 3
x
┼
x
x
x
09:00
18:00
x
│
10:00
19:00
x
│
11:30
20:30 Dinner
│
12:00
21:00 Drug administration
xD
x14
▼
x14
x
x
x
2
23:30
08:30 Breakfast
xB, 12
x12
x12
x12
24:00
09:00 Drug administration
x14
28:00
13:00 Lunch3
x
32:00
17:00 Snack
35:30
20:30 Dinner
36:00
21:00 Drug administration
x14
x


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MD part (30 mg bid) (cont’d)
Visit
Day
Planned time (relative to first drug 
administration [h:min]
Approximate clock time of actual 
day [h:min]
Event and comment
Safety laboratory2
PK blood, 4
PK urine5
PD blood (NE activity)
12-lead ECG7
Medical examination 
Vital signs8
Questioning for AEs and 
concomitant therapy 9
3
47:30
08:30 Breakfast
x12
x12
48:00
09:00 Drug administration
x14
52:00
13:00 Lunch3
x
56:00
17:00 Snack 
59:30
20:30 Dinner3
x
60:00
21:00 Drug administration
x14
4
71:30
08:30 Breakfast
x12
x12
72:00
09:00 Drug administration
x14
76:00
13:00 Lunch3
x
80:00
17:00 Snack 
83:30
20:30 Dinner3
x
84:00
21:00 Drug administration
5
95:30
08:30 Breakfast
xB, 12
x12
x12
x12
x12
96:00
09:00 Drug administration16
x14
100:00 13:00 Lunch3
x
104:00 17:00 Snack 
107:30 20:30 Dinner3
x
108:00 21:00 Drug administration
6
119:15 08:15
x12
x12
119:30 08:30 Breakfast
120:00 09:00 Drug administration16
x14
124:00 13:00 Lunch3
x
128:00 17:00 Snack 
131:30 20:30 Dinner3
x
132:00 21:00 Drug administration


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MD part (30 mg bid) (cont’d)
Visit
Day
Planned time (relative to first drug 
administration [h:min]
Approximate clock time of actual 
day [h:min]
Event and comment
Safety laboratory2
PK blood, 4
PK urine5
PD blood (NE activity)
12-lead ECG7
Medical examination 
Vital signs8
Questioning for AEs and 
concomitant therapy 9
7
143:15 08:15
x12
x12
143:30 08:30 Breakfast
144:00 09:00 Drug administration16
x14
148:00 13:00 Lunch3
x
152:00 17:00 Snack 
155:30 20:30 Dinner3
x
156:00 21:00 Drug administration
8
167:15 08:15
xB, 12
x12
x12
x12
x12
167:30 08:30 Breakfast
168:00 09:00 Drug administration16
x14
172:00 13:00 Lunch3
x
176:00 17:00 Snack 
179:30 20:30 Dinner3
x
180:00 21:00 Drug administration
9
191:15 08:15
x12
x12
191:30 08:30 Breakfast
192:00 09:00 Drug administration16
x14
196:00 13:00 Lunch3
x
200:00 17:00 Snack 
203:30 20:30 Dinner3
x
204:00 21:00 Drug administration
10
215:15 08:15
x12
x12
215:30 08:30 Breakfast
216:00 09:00 Drug administration16
x14
220:00 13:00 Lunch3
x
224:00 17:00 Snack 
227:30 20:30 Dinner3
x
228:00 21:00 Drug administration


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MD part (30 mg bid) (cont’d)
Clock time should be adjusted based on actual administration time
1
Subject must be informed and written informed consent obtained prior to starting any screening procedures. 
Screening procedures include medical examination, check of vital signs, ECG (12-lead ECG), chest x-ray, safety 
Visit
Day
Planned time (relative to first drug 
administration [h:min]
Approximate clock time of actual 
day [h:min]
Event and comment
Safety laboratory2
PK blood, 4
PK urine5
PD blood (NE activity)
12-lead ECG7
Medical examination 
Vital signs8
Questioning for AEs and 
concomitant therapy 9
11
239:00 08:00
x12,13
x12
x12
x12
239:30 08:30 Breakfast
240:00 09:00 Last drug administration15
xB, 14
x14
▲
x14
240:20 09:20
x
│
240:40 09:40
x
│
241:00 10:00
x
│
x
x
241:30 10:30
x
│
242:00 11:00 240 mL fluid intake
xD
x
│
x
x
x
x
243:00 12:00
x
│
244:00 13:00 240 mL fluid intake, thereafter 
lunch3
x
┼
x
x
x
245:00 14:00
x
│
246:00 15:00
x
│
x
x
247:00 16:00
x
│
248:00 17:00 Snack3
x
┼
x
x
x
249:00 18:00
x
│
250:00 19:00
x
│
251:30 20:30 Dinner
│
252:00 21:00
xD
x
┼
x
x
x
x
12
264:00 09:00
xD
x
┼
x
x
x
x
13
288:00 09:00
xB
x
▼
x
14
312:00 09:00
xD
x
x
x
x
15
336:00 09:00
x
x
16
360:00 09:00
xD
x
x
x
x
17
384:00 09:00
x
18
408:00 09:00 discharge from trial site17
xD
x
x
x
x
3
19 to 
21
End of trial (EOT) examination18
xA
x
x19
x
x


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c31942019-03
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laboratory (including drug screening), pharmacogenetic analysis for UGT2B17 genotype, 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
Letters A, B, C and D describe different sets of safety laboratory examinations (see Section 5.2.3)
3
If several actions are indicated at the same time, the intake of meals will be the last action. 
4
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 taken does not 
exceed 400 ml per subject.
5
During the days of urine collection, total fluid intake should be at least 1.5 litres and should not exceed 3.0 litres 
per day. 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, and 8-12 h at baseline, 240-244, 
244-248, 248-252, 252-264, 264-288 h at Day 11.
6
Infection Test on SARS-CoV-2 will be performed at Visit 2 Day -1.
7
At Screening visit (SCR) and EoT: ECGs recordings are performed as single ECGs. All other scheduled ECG 
recordings are performed as triplicate ECGs. Recording time points may be adapted based on information 
obtained during the trial. ECG recording will always precede all other study procedures scheduled for the same 
time (see Section 5.2.4).
8
Vital signs assessments will include pulse rate, systolic and diastolic blood pressure, height and weight. Height to 
be measured only at SCR, weight at SCR and at Day 1 and Day 11 prior to morning dose. Axillary body
temperature to be measured at Day-1.
9
AEs and concomitant therapies will be recorded throughout the trial whenever reported, but will be specifically 
asked for at the times indicated in the Flow Chart above.
10 Urine drug screening and alcohol breath test will be performed at screening and prior to dosing at Day 1 of Visit 
2. A breath alcohol test may be repeated at any time during the trial at the discretion of an investigator or 
designee.
11 Safety laboratory to be taken and to be medically evaluated on Day -1 prior to administration of BI 1323495.
12 The time is approximate; the procedures are to be performed and completed within 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. 
Only on Day 1: PD blood (NE activity): at pre-dose time point, two samples (2x5 ml) will be collected.
13 3 triplicate ECGs are recorded within approximately one hour. The recordings should be separated by at least 15 
minutes. The 15 minutes refer to the start of the first recording within a triplicate ECG.
14 Samples to be taken within 15 min prior to drug administration
15 At Day 1 and Day 11 subjects should have a normal caloric breakfast 30 minutes before drug administration in the 
morning. The breakfast should be consumed within 30 minutes prior to trial drug intake in the morning. Subjects 
will then fast for 4 hours after intake of morning dose. At Day 11, subjects will take only a single dose of study 
drug in the morning.
16 Morning and evening dose should be taken with a 12 h time interval (e.g. 9:00 h and 21:00 h) approximately at the 
same time each day during the treatment phase, within a time window of +/- 1 hour.
On days 1 to 10: subjects stay at the site and take morning and evening dose under surveillance of site staff.
Drug administration should take place with food. Breakfast will be provided 30 minutes prior to the morning dose, 
and dinner will be provided 30 minutes prior to the evening dose.
17 Subjects are only allowed to leave the trial site after formal assessment and confirmation of their fitness by the 
investigator or designee.
18 At EOT, the examination includes physical examination, vital signs, ECG, safety laboratory, recording of AEs, 
and concomitant therapies. 
19 At EOT only if clinical relevant finding at EOT.
20 PGx samples will be collected during Day 1.


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MD part (60 mg qd)
Visit
Day
Planned time (relative to first 
drug administration [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory2
PK blood, 4
PK urine5
PD blood (NE activity)
12-lead ECG7
Medical examination 
Vital signs8
Questioning for AEs and 
concomitant therapy 9
1
-28 
to -8
Screening (SCR)1
including pharmacogenomics test 
UGT2B17
xA
x
x
x
2
-1
-16:00 17:00 Admission to trial site
x B, 6, 10, 
11
x
120
-01:00 08:00 Allocation to treatment12
xC,12
x12
x12
x12
x12,13
x12
x12
x12
-00:30 08:30 breakfast
00:00
09:00 First drug administration15
▲
00:20
09:20
x
│
00:40
09:40
x
│
01:00
10:00
x
│
x
x
01:30
10:30
x
│
02:00
11:00 240 mL fluid intake
xD
x
│
x
x
x
x
03:00
12:00
x
│
04:00
13:00 240 mL fluid intake, thereafter 
lunch3
x
┼
x
x
x
05:00
14:00
x
│
06:00
15:00
x
│
x
x
x
07:00
16:00
x
│
08:00
17:00 Snack 3
x
┼
x
x
x
09:00
18:00
x
│
10:00
19:00
x
│
11:30
20:30 Dinner
│
12:00
21:00
xD
x14
│
x14
x
x
x
2
23:30
08:30 Breakfast
xB, 12
│
x12
x12
x12
24:00
09:00 Drug administration
x14
▼
28:00
13:00 Lunch3
x
32:00
17:00 Snack
35:30
20:30 Dinner
36:00
21:00
x


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25 FEB 2021
BI Trial No.: 1405-0003
c31942019-03
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MD part (60 mg qd) (cont’d)
Visit
Day
Planned time (relative to first 
drug administration [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory2
PK blood, 4
PK urine5
PD blood (NE activity)
12-lead ECG7
Medical examination 
Vital signs8
Questioning for AEs and 
concomitant therapy 9
3
47:30
08:30 Breakfast
x12
x12
48:00
09:00 Drug administration
x14
52:00
13:00 Lunch3
x
56:00
17:00 Snack 
59:30
20:30 Dinner3
x
60:00
21:00
4
71:30
08:30 Breakfast
x12
x12
72:00
09:00 Drug administration
x14
76:00
13:00 Lunch3
x
80:00
17:00 Snack 
83:30
20:30 Dinner3
x
84:00
21:00
5
95:30
08:30 Breakfast
xB, 12
x12
x12
x12
x12
96:00
09:00 Drug administration16
x14
100:00 13:00 Lunch3
x
104:00 17:00 Snack 
107:30 20:30 Dinner3
x
6
119:15 08:15
x12
x12
119:30 08:30 Breakfast
120:00 09:00 Drug administration16
x14
124:00 13:00 Lunch3
x
128:00 17:00 Snack 
131:30 20:30 Dinner3
x
7
143:15 08:15
x12
x12
143:30 08:30 Breakfast
144:00 09:00 Drug administration16
x14
148:00 13:00 Lunch3
x
152:00 17:00 Snack 
155:30 20:30 Dinner3
x


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25 FEB 2021
BI Trial No.: 1405-0003
c31942019-03
Trial Protocol
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MD part (60 mg qd) (cont’d)
Visit
Day
Planned time (relative to first drug 
administration [h:min]
Approximate clock time of actual 
day [h:min]
Event and comment
Safety laboratory2
PK blood, 4
PK urine5
PD blood (NE activity)
12-lead ECG7
Medical examination 
Vital signs8
Questioning for AEs and 
concomitant therapy 9
8
167:15 08:15
xB, 12
x12
x12
x12
x12
167:30 08:30 Breakfast
168:00 09:00 Drug administration16
x14
172:00 13:00 Lunch3
x
176:00 17:00 Snack 
179:30 20:30 Dinner3
x
9
191:15 08:15
x12
x12
191:30 08:30 Breakfast
192:00 09:00 Drug administration16
x14
196:00 13:00 Lunch3
x
200:00 17:00 Snack 
203:30 20:30 Dinner3
x
10
215:15 08:15
x12
x12
215:30 08:30 Breakfast
216:00 09:00 Drug administration16
x14
220:00 13:00 Lunch3
x
224:00 17:00 Snack 
227:30 20:30 Dinner3
x
11
239:00 08:00
x12,13
x12
x12
x12
239:30 08:30 Breakfast
240:00 09:00 Last drug administration15
xB, 14
x14
▲
x14
240:20 09:20
x
│
240:40 09:40
x
│
241:00 10:00
x
│
x
x
241:30 10:30
x
│
242:00 11:00 240 mL fluid intake
xD
x
│
x
x
x
x
243:00 12:00
x
│
244:00 13:00 240 mL fluid intake, thereafter 
lunch3
x
┼
x
x
x
245:00 14:00
x
│
246:00 15:00
x
│
x
x


Boehringer Ingelheim
25 FEB 2021
BI Trial No.: 1405-0003
c31942019-03
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MD part (60 mg qd) (cont’d)
Visit
Day
Planned time (relative to first drug 
administration [h:min]
Approximate clock time of actual 
day [h:min]
Event and comment
Safety laboratory2
PK blood, 4
PK urine5
PD blood (NE activity)
12-lead ECG7
Medical examination 
Vital signs8
Questioning for AEs and 
concomitant therapy 9
247:00 16:00
x
│
248:00 17:00 Snack3
x
┼
x
x
x
249:00 18:00
x
│
250:00 19:00
x
│
251:30 20:30 Dinner
│
252:00 21:00
xD
x
┼
x
x
x
x
12
264:00 09:00
xD
x
┼
x
x
x
x
13
288:00 09:00
xB
x
▼
x
14
312:00 09:00
xD
x
x
x
x
15
336:00 09:00
x
x
16
360:00 09:00
xD
x
x
x
x
17
384:00 09:00
x
18
408:00 09:00 discharge from trial site17
xD
x
x
x
x
3
19 to 
21
End of trial (EOT) examination18
xA
x
x19
x
x
Clock time should be adjusted based on actual administration time
1
Subject must be informed and written informed consent obtained prior to starting any screening procedures. 
Screening procedures include medical examination, check of vital signs, ECG (12-lead ECG), chest x-ray, safety 
laboratory (including drug screening), pharmacogenetic analysis for UGT2B17 genotype, 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
Letters A, B, C and D describe different sets of safety laboratory examinations (see Section 5.2.3)
3
If several actions are indicated at the same time, the intake of meals will be the last action. 
4
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 taken does not 
exceed 400 ml per subject.
5
During the days of urine collection, total fluid intake should be at least 1.5 litres and should not exceed 3.0 litres 
per day. 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 h at baseline, 240-
244, 244-248, 248-252, 252-264, 264-288 h at Day 11.
6
Infection Test on SARS-CoV-2 will be performed at Visit 2 Day -1.
7
At Screening visit (SCR) and EoT: ECGs recordings are performed as single ECGs. All other scheduled ECG 
recordings are performed as triplicate ECGs. Recording time points may be adapted based on information 
obtained during the trial. ECG recording will always precede all other study procedures scheduled for the same 
time (see Section 5.2.4).
8
Vital signs assessments will include pulse rate, systolic and diastolic blood pressure, height and weight. Height to 
be measured only at SCR, weight at SCR and at Day 1 and Day 11 prior to morning dose. Axillary body 


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c31942019-03
Trial Protocol
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temperature to be measured at Day-1.
9
AEs and concomitant therapies will be recorded throughout the trial whenever reported, but will be specifically 
asked for at the times indicated in the Flow Chart above.
10 Urine drug screening and alcohol breath test will be performed at screening and prior to dosing at Day 1 of Visit 
2. A breath alcohol test may be repeated at any time during the trial at the discretion of an investigator or 
designee.
11 Safety laboratory to be taken and to be medically evaluated on Day -1 prior to administration of BI 1323495.
12 The time is approximate; the procedures are to be performed and completed within 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. Only on Day 1: PD blood (NE activity): at pre-dose time point, two samples 
(2x5 ml) will be collected.
13 3 triplicate ECGs are recorded within approximately one hour. The recordings should be separated by at least 15 
minutes. The 15 minutes refer to the start of the first recording within a triplicate ECG.
14 Samples to be taken within 15 min prior to drug administration
15 At Day 1 and Day 11 subjects should have a normal caloric breakfast 30 minutes before drug administration in the 
morning. The breakfast should be consumed within 30 minutes prior to trial drug intake in the morning. Subjects 
will then fast for 4 hours after intake of morning dose. 
16 Subjects stay at the site and take morning dose under surveillance of site staff.
Drug administration should take place with food. Breakfast will be provided 30 minutes prior to the morning dose.
17 Subjects are only allowed to leave the trial site after formal assessment and confirmation of their fitness by the 
investigator or designee.
18 At EOT, the examination includes physical examination, vital signs, ECG, safety laboratory, recording of AEs, 
and concomitant therapies.
19 At EOT only if clinical relevant finding at EOT.
20 PGx samples will be collected during Day 1.


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BI Trial No.: 1405-0003
c31942019-03
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TABLE OF CONTENTS
TITLE PAGE...................................................................................................... 1
CLINICAL TRIAL PROTOCOL SYNOPSIS................................................ 2
FLOW CHART .................................................................................................. 6
TABLE OF CONTENTS................................................................................. 21
ABBREVIATIONS .......................................................................................... 25
1.
INTRODUCTION.................................................................................... 29
1.1.
MEDICAL BACKGROUND............................................................................29
1.2.
DRUG PROFILE...............................................................................................29
BI 1323495 .............................................................................................29
Itraconazole ...........................................................................................35
Residual Effect Period..........................................................................35
1.3.
RATIONALE FOR PERFORMING THE TRIAL........................................36
1.4.
BENEFIT - RISK ASSESSMENT ...................................................................37
Procedure-related risks ........................................................................37
Drug-related risks and safety measures..............................................38
Potential interaction between itraconazole and BI 1323495.............41
Benefit –Risk Assessment Summary...................................................41
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 43
2.1.
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......43
Main objectives......................................................................................43
Primary endpoint..................................................................................43
Secondary endpoint ..............................................................................43
Safety and tolerability..............................................................44
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 47
3.1.
OVERALL TRIAL DESIGN AND PLAN ......................................................47
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..............................................................53
Inclusion criteria...................................................................................53
Exclusion criteria ..................................................................................53
Withdrawal of subjects from treatment or assessments ...................55


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Discontinuation of trial treatment............................................56
Withdrawal of consent to trial participation ............................56
Discontinuation of the trial by the sponsor..............................56
Replacement of subjects .......................................................................57
4.
TREATMENTS........................................................................................ 58
4.1.
INVESTIGATIONAL TREATMENTS ..........................................................58
Identity of the Investigational Medicinal Products ...........................58
Selection of doses in the trial and dose modification .........................59
Method of assigning subjects to treatment groups ............................61
Drug assignment and administration of doses for each subject .......62
Blinding and procedures for unblinding ............................................65
Blinding ...................................................................................65
Unblinding and breaking the code...........................................66
Packaging, labelling, and re-supply ....................................................66
Storage conditions.................................................................................66
Drug accountability ..............................................................................67
4.2.
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................67
Other treatments and emergency procedures....................................67
Restrictions............................................................................................67
Restrictions regarding concomitant treatment .........................67
Restrictions on diet and lifestyle..............................................68
4.3.
TREATMENT COMPLIANCE.......................................................................69
5.
ASSESSMENTS ....................................................................................... 70
5.1.
ASSESSMENT OF EFFICACY.......................................................................70
5.2.
ASSESSMENT OF SAFETY............................................................................70
Medical examination.............................................................................70
Vital signs...............................................................................................70
Safety laboratory parameters..............................................................70
Electrocardiogram................................................................................73
Other safety parameters.......................................................................74
Assessment of adverse events...............................................................74
Definitions of adverse event ....................................................74
Adverse event ............................................................74
Serious adverse event ................................................74
AEs considered ‘Always Serious’.............................75
Adverse events of special interest .............................75
Intensity (severity) of AEs.........................................75
Causal relationship of AEs ........................................76
Adverse event collection and reporting ...................................77


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AE collection.............................................................77
AE reporting to the sponsor and timelines ................78
Information required..................................................78
Pregnancy ..................................................................78
5.3.
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................78
Assessment of pharmacokinetics .........................................................78
Methods of sample collection...............................................................79
Blood sampling for pharmacokinetic analysis of BI 1323495.79
Blood sampling for pharmacokinetic analysis of itraconazole 79
Urine sampling for pharmacokinetic analysis..........................80
5.4.
ASSESSMENT OF BIOMARKER(S) .............................................................81
Biochemical and cellular biomarkers..................................................81
Methods of sample collection..................................................81
5.5.
BIOBANKING ...................................................................................................82
5.6.
OTHER ASSESSMENTS .................................................................................82
UGT2B17 genotyping ...........................................................................82
Pharmacogenomic evaluation..............................................................82
5.7.
APPROPRIATENESS OF MEASUREMENTS.............................................83
6.
INVESTIGATIONAL PLAN.................................................................. 84
6.1.
VISIT SCHEDULE............................................................................................84
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 ......................................................................................... 87
7.1.
STATISTICAL DESIGN – MODEL ...............................................................87
7.2.
NULL AND ALTERNATIVE HYPOTHESES ..............................................87
7.3.
PLANNED ANALYSES....................................................................................87
Primary endpoint analyses...................................................................89
Secondary endpoint analyses ...............................................................90
Safety analyses.......................................................................................92
Pharmacokinetic - pharmacodynamic analysis (Only MD 
part)
..................................................................................................93
7.4.
INTERIM ANALYSES .....................................................................................93


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7.5.
HANDLING OF MISSING DATA ..................................................................93
Safety
..................................................................................................93
Pharmacokinetics..................................................................................93
7.6.
RANDOMISATION ..........................................................................................93
7.7.
DETERMINATION OF SAMPLE SIZE ........................................................94
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE ...................................................... 96
8.1.
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................96
8.2.
DATA QUALITY ASSURANCE .....................................................................97
8.3.
RECORDS..........................................................................................................97
Source documents .................................................................................97
Direct access to source data and documents.......................................98
Storage period of records.....................................................................98
8.4.
EXPEDITED REPORTING OF ADVERSE EVENTS .................................99
8.5.
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......99
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................99
8.6.
TRIAL MILESTONES .....................................................................................99
8.7.
ADMINISTRATIVE STRUCTURE OF THE TRIAL ................................100
9.
REFERENCES ....................................................................................... 101
9.1.
PUBLISHED REFERENCES.........................................................................101
9.2.
UNPUBLISHED REFERENCES...................................................................103
10. APPENDICES......................................................................................... 104
11. DESCRIPTION OF GLOBAL AMENDMENT(S) ............................ 105
11.1. GLOBAL AMENDMENT 1 ...........................................................................105
11.2. GLOBAL AMENDMENT 2 ...........................................................................106


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
AEt1-t2
Amount of analyte that is eliminated in urine from the time interval t1 to t2
ALCOA
attributable, legible, contemporaneous, original, accurate (dimension of 
integrity)
ALT
Alanine transaminase
ANOVA
Analysis of variance
aPTT
activated partial thromboplastin time 
AUC0-12
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to 12 hour after administration
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours after drug administration
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUCss 
Area under the concentration-time curve of the analyte in plasma at steady 
state
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUCτ 
Area under the concentration-time curve of the analyte in plasma during a 
dosage interval
%AUCtz-∞
Percentage of AUCtz-∞obtained by extrapolation
BA
Bioavailability
BI
Boehringer Ingelheim
bid
bis in die
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CatC
Cathepsin C 
CF
Cystic Fibrosis 
CFTR
Cystic Fibrosis Transmembrane conductance Regulator 
CI
Confidence interval
CK
Creatine Kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration


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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
COPD
Chronic obstructive pulmonary disease
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P450
DDI
Drug-drug interaction
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EM
Extensive metabolizer
EMA
European Medicines Agency
EOT
End of trial
FDA
Food and Drug Administration
fet1-t2
fraction of administered drug excreted unchanged in urine from time point 
t1 to t2
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GFR
Glomerular filtration rate
GGT
Gamma-Glutamyl Transferase
GLDH
Glutamate dehydrogenase
GLP
Good Laboratory Practice
gMean
Geometric mean
GOT
Glutamic Oxaloacetic Transaminase
GPT
Glutamic Pyruvic Transaminase
hERG 
human Ether-à-go-go-Related Gene
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
IC50 
Half maximal inhibitory concentration
ICF
Informed consent form


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IEC
Independent Ethics Committee
IGRA
Interferon gamma release assay
INR
International Normalization Ratio
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
K2-EDTA 
dipotassium ethylenediaminetetraacetic acid
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MB
Myocardial band
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multi rising dose
MRT,ex
Mean residence time of the analyte in the body, extravascular
NE
Neutrophil elastase
NSP
Neutrophil serine protease
P-gp
P-glycoprotein
PD
Pharmacodynamic(s)
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PLS
Papillon-Lefèvre syndrome 
PM
Poor metabolizer
PMDA
Pharmaceuticals and Medical Devices Agency
PP
Polypropylene
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
corrected QT
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
T
Test product or treatment
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma


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t1/2
Terminal half-life of the analyte in plasma
TMF
Trial Master File
TMM
Team Member Medicine
TS
Treated set
TSAP
Trial Statistical Analysis Plan
tz
Time of last measurable concentration of the analyte in plasma
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WOCBP
Woman of childbearing potential 
XTC
Ecstasy
λz 
Terminal rate constant in plasma


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1.
INTRODUCTION
BI 1323495 is an oral, reversible inhibitor of neutrophil elastase (NE). It is under 
development for the treatment of emphysema in patients with chronic obstructive 
pulmonary disease (COPD) and for the treatment of Cystic Fibrosis (CF). 
1.1.
MEDICAL BACKGROUND
COPD is a chronic and irreversibly progressive disease of the lung that is characterized by 
persistent respiratory symptoms and airflow limitation. The chronic airflow limitation is 
caused by a mixture of small airways disease and parenchymal destruction (emphysema). In 
emphysema, chronic inflammation causes destruction of the lung parenchyma. COPD is a 
leading cause of morbidity and mortality worldwide that induces a substantial and 
increasing economic and social burden [P17-01597].
The irreversible, progressive loss of lung function in COPD patients is partially attributed to 
an abundance of pulmonary proteinases that are not adequately inhibited by endogenous 
anti-proteases leading to excessive proteolysis of the lung connective tissue [R16-2239]. 
The increased proteolysis is the direct result of the activation of neutrophils and 
macrophages by extrinsic (e.g. cigarette smoke, infections) and intrinsic (e.g. inflammatory 
cytokines) stimuli associated with COPD. 
Neutrophil elastase is one of the pulmonary proteases produced and stored in neutrophils 
and released in large quantities after activation. High levels of NE have been detected in 
sputum and bronchoalveolar lavage fluids of patients with various chronic respiratory 
diseases, including COPD [R16-2237], CF, bronchiectasis, and alpha1-antitrypsin 
deficiency, and there is a positive correlation between the level of NE activity and the 
clinical symptoms [R18-0132]. Besides the deleterious effect on lung connective tissue, 
neutrophil elastase increases mucus production in lung epithelial cells [R17-2928] and can 
delay the resolution phase of chronic lung inflammation [R17-2929].
Inhibition of NE by an orally available inhibitor is expected to result in reduced distal 
airway destruction related to damage to pulmonary elastin and connective tissue with 
possible secondary anti-inflammatory [R17-2929] and anti-mucus hypersecretory effects 
[P02-06423, R17-2928].
1.2.
DRUG PROFILE
BI 1323495
BI 1323495 is a potent, highly selective, reversible inhibitor of the enzymatic activity of 
neutrophil elastase. It inhibits the isolated enzyme with an IC50 of 0.4 nM BI 1323495 
exhibits > 4,000x selectivity versus the related neutrophil serine proteases Cathepsin G and 
proteinase 3 and has no activity against 44 tested unrelated receptors, transporters, and 
enzymes up to a concentration of 10 µM.
The toxicology program of BI 1323495 to date includes repeat-dose toxicity trials up to 13 
weeks in Wistar rats and cynomolgus monkeys, the complete standard battery of 


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genotoxicity trials, and the in vitro phototoxicity assay. Pivotal trials were performed in 
compliance with GLP (Good Laboratory Practice). 
General and safety pharmacology trials included in vitro hERG (human Ether-à-go-go-
Related Gene) potassium channel trials, cardiovascular assessments in conscious 
cynomolgus monkeys, effects on the central nervous system and respiratory system in rats.
The 4- and 13week trials resulted in no observed adverse effect levels in rat or cynomolgus 
monkey of 300 and 200 (males)/600 (females) mg/kg/day or 250 and 300 mg/kg/day, 
respectively. The associated mean exposures combined for males and females from the 4-
week trials were 33,000 and 54,700 nM (Cmax) and 179,000 and 471,000 nM·h (AUC0-24), 
respectively.
For a detailed description of the BI 1323495 profile, please refer to the current 
Investigator’s Brochure (IB) [c21238478-05].
Clinical experience
At the time of preparing this trial protocol, three Phase I trials with administration of single 
doses of BI 1323495 to healthy male volunteers have been completed, trials 1405-0001 was 
first-in-man trial, 1405-0007 investigated relative BA (Bioavailability) and food effect, and 
1405-0009 investigated drug interaction with itraconazole. In addition to this, 1405-0002, 
multiple rising dose (MRD) trial in healthy subjects is currently ongoing, and analysis of the 
DDI trial (1405-0015) with Rosuvastatin (BRCP and OATP1B1 substrate) and Dabigatran 
(P-gp substrate) is ongoing.
In the single rising dose (SRD) trial 1405-0001, single-dose treatment with up to 600 mg BI 
1323495 or placebo was safe and well tolerated. There was no relationship between the 
occurrence of AEs and dose. Three AEs in subjects receiving BI 1323495 were judged as 
moderate in intensity, all other AEs were classified as mild. No severe or serious AEs were 
reported. The most frequently reported treatment-emergent AE was headache, reported for 6
out of 48 subjects (12.5%) receiving BI 1323495 and 2 out of 15 subjects (13.3%) receiving 
placebo. The next-most frequently reported treatment-emergent AEs were fatigue and 
diarrhea, each reported for 2 out of 48 subjects (4.2%) receiving BI 1323495. In one subject 
receiving 300 mg BI 1323495, a mild (<2-fold upper limit of normal [ULN]) and transient 
elevation of alanine transaminase (ALT) and glutamate dehydrogenase (GLDH) was 
reported.
The level of exposure to BI 1323495 was dependent on the expression pattern of the enzyme
UGT2B17 in the intestine. While homozygous and heterozygous carriers of the wild type 
allele (UGT2B17 *1/*1 and *1/*2) could not be distinguished based on their exposures, 
AUCs and Cmax were increased in subjects with homozygous deletion of UGT2B17 (*2/*2),
compared with the other genotypes (Table 1.2.1: 1) [c26492551]. 
After the first-pass metabolism, the same pharmacokinetic properties apply to all genotypes. 
gMean (geometric mean) plasma exposure increased in a less than dose-proportional 
manner. Multiple plasma concentration peaks were observed in the profiles of nearly all 
subjects treated. Subjects with genotype *2/*2 did not show as many peaks as the other 
genotypes in the concentration-time profiles. The terminal half-life was similar over all dose 
groups, except for being longer in the 600 mg dose group.


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Table 1.2.1: 1
AUC0-∞and Cmax for genotypes *1/*1 and *1/*2 compared with 
genotype *2/*2 after single oral administration of BI 1323495 in 
trial 1405-0001
BI 1323495
dose
Genotype
N
AUC0-∞[nmol∙h/L]
Cmax [nmol/L]
gMean
gCV (%)
gMean
gCV (%)
10 mg
*1/*1, *1/*2
6
143
102
10.5
66.3
30 mg
*1/*1, *1/*2
3
438
95.3
24.8
89.6
*2/*2
3
1780
21.2
142
11.2
60 mg
*1/*1, *1/*2
6
824
77.7
47.1
77.6
100 mg
*1/*1, *1/*2
5
2100
74.1
125
68.6
*2/*2
1 a
4240
-
308
-
200 mg
*1/*1, *1/*2
4
2670
49.8
138
86.5
*2/*2
2
7170
4.44
632
18.0
300 mg
*1/*1, *1/*2
5
2400
115
136
123
*2/*2
1 a
11 500
-
712
-
450 mg
*1/*1, *1/*2
6
1780
102
136
74.2
600 mg
*1/*1, *1/*2
6
3820
71.9
195
90.8
a
In dose groups with only 1 subject with genotype *2/*2, the individual values for the subject are displayed, rather 
than gMean and gCV.
Direct target engagement of BI 1323495 in blood was evaluated using an ex vivo NE 
activity assay. Median maximum placebo-corrected % NE inhibition ranged from 77.37% to
101.55%, and was >100% for BI 1323495 doses of 100 mg and higher. The 
pharmacokinetic (PK)/ Pharmacodynamics (PD) evaluation showed a clear BI 1323495 
plasma concentration-NE inhibition relationship with an IC95 of around 70 nmol/L. 
For further details on safety and tolerability as well as on pharmacokinetics and biomarker 
data of the SRD trial refer to the IB (c21238478-05).
In the food effect trial 1405-0007, a randomised 2-way crossover trial to compare the 
relative bioavailability of a single dose of 100 mg BI 1323495 (50 mg tablet) administered 
in the fasted state versus fed state (high-fat), maximum plasma concentrations were higher 
and were reached earlier in the fed state compared with in the fasted state. Median tmax was 
2.00 h in the fed state and 3.52 h in the fasted state.
In the fed state, AUC0-tz increased by 66.02% (gMean ratio: 166.02%, 90% CI: 143.17% to
192.53%); Cmax by 135.50% (gMean ratio: 235.50%, 90% CI: 179.82% to 308.42%), and
AUC0-∞by 59.39% (gMean ratio: 159.39%, 90% CI: 140.11% to 181.34%) compared with 
in the fasted state.
Higher exposure to BI 1323495 when subjects were in the fed state held true over all 
genotypes. Subjects with the *2/*2 genotype had considerably higher exposures when 
compared with subjects with genotypes *1/*1 and *1/*2. The percentage increases in AUC0-
tz, Cmax, and AUC0-∞under fed conditions when compared with fasted conditions were 
similar for genotypes *1/*1 or *1/*2, and genotype *2/*2. Therefore, the results indicate 
that the food effect on AUC0-tz, Cmax, and AUC0-∞ was likely independent of genotype.


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Treatment-emergent AEs were reported for 5 out of the 12 treated subjects (41.7%). 
Adverse events were reported for 3 out of 12 subjects (25.0%) in the BI 1323495 fasted
treatment period and for 2 out of 11 subjects (18.2%) in the BI 1323495 fed treatment 
period. No subjects were reported with AEs in both treatment periods.
Infections and infestations occurred in 2 of the 12 subjects (16.7%): influenza in 1 subject in 
the BI 1323495 fasted treatment period, and otitis externa in 1 subject in the BI 1323495 fed
treatment period. Headache was reported in 2 of the 12 subjects (16.7%), one in each 
treatment period. Mouth injury was reported in 1 of the 12 subjects (8.3%) in the 
BI 1323495 fasted treatment period. The only investigator-defined drug-related AE was 
mild headache reported for 1 subject [c27223001].
Trial 1405-0009, a two-period fixed sequence trial in healthy male subjects with UGT2B17 
extensive metabolizer status, investigated the effects of multiple doses of itraconazole – a 
strong CYP3A4 and P-gp inhibitor - on the relative bioavailability of a single dose of 10 mg 
BI 1323495. 
Preliminary results for BI 1323495 PK showed a modest increase in exposure to BI 1323495 
in gMean AUC0-∞and Cmax of 1.69-fold (1.46 to 1.95) and 1.37-fold (1.21 to 1.56),
respectively, when administered together with itraconazole.
Treatment-emergent AEs were reported for 6 out of the 14 treated subjects (42.9%).
Investigator defined drug-related AEs were reported for 3 subjects (21.4%), all of them with 
mild or moderate diarrhea under treatment with itraconazole alone or itraconazole + BI 
1323495. No relevant changes in vital signs, ECG, or laboratory parameters were reported
[c29983104]. 
In summary, single doses of BI 1323495 investigated so far in clinical trials with healthy 
subjects were safe and well tolerated. 
MRD trial 1405-0002, this trial is currently ongoing and investigates the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of multiple twice daily oral doses of BI 1323495 
in healthy subjects that are UGT2B17 EMs or PMs. The following represents an interim 
summary of the clinical safety data recorded until completion of 5 dose groups in EMs and 2
dose groups in PMs. In the five completed EM dose groups, 27 male healthy subjects and 15
female healthy subjects (not of child-bearing potential or using adequate contraception
methods) received multiple twice daily doses of BI 1323495 of 10 mg, 30 mg, 70 mg, 120 
mg, or 150 mg over 10.5 days. In the two completed PM dose groups, 6 male healthy 
subjects and 5 female healthy subjects (not of child-bearing potential or using adequate 
contraception methods) received multiple twice daily doses of BI 1323495 of 10 mg or 30 
mg. 19 (14 male, 5 female) healthy EM or PM subjects received placebo.
Two subjects in the 120 mg dose group and one subject in the 150 mg dose group had AUC 
exposures exceeding the pre-defined exposure cap of AUC0-24 (11500 nM*h); no subject 
exceeded the predefined exposure cap for Cmax (1900 nM). One subject in the 70 mg dose 
group had increased blood pressure, and one subject in the 150 mg dose group had a 
prolongation of the QTcB interval, both considered drug related. In the other subjects, 
multiple bid doses of BI 1323495 were associated with no clinically relevant changes in 


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safety lab, ECG, and vital signs observed. No deaths or serious AEs were reported in this 
trial. Any AEs were reported in 36 (64.3%) of the 56 subjects treated with BI 1323495, and 
9 (47.4%) of the 19 subjects treated with placebo.
Investigator-defined drug-related AEs were reported for 11 (19.6%) of 56 subjects treated 
with BI 1323495 and 1 (5.3%) of 19 subjects receiving placebo. Headache of mild intensity 
was the most frequently reported drug related AE. No other drug related AEs were reported 
in more than one subject treated with BI 1323495. One subject in the placebo group had an
AE of severe intensity (abdominal discomfort) that was considered related. One EM subject 
in the 30 mg dose group had an AE of severe intensity (headache; not considered related to 
study medication). All other reported AEs were of mild or moderate intensity. Overall, three 
AEs led to treatment discontinuation: One each in the EM dose groups 30 mg 
(nausea/vomiting, moderate, not considered related), 70 mg (blood pressure increased, 
moderate, considered related), and 150 mg (electrocardiogram QT prolonged, mild, 
considered related). There was no apparent relationship of the occurrence of AEs with dose.
For the detail, please refer below Table 1.2. 1: 2.In summary, multiple doses of BI 1323495 
investigated so far in clinical trials with healthy subjects were safe and well tolerated.
Table 1.2. 1: 2
Summary of AEs in study 1405-0002
BI 1323495 (bid dosing)
System Organ Class
Extensive 
metabolizers
Poor 
metabolizers
Total on BI 
1323495
Total
Preferred Term
Placebo
10 
mg
30 
mg
70 
mg
120 
mg
150 
mg
10 
mg
30 
mg
Number of subjects, N (%)
19 (100)
9 
(100)
9 
(100)
9 
(100)
9 
(100)
9 
(100)
5 
(100)
6 
(100)
56 (100)
75 (100)
Total with any drug related 
AEs
1 (5.3)
2 
(22.2)
3 
(33.3)
1 
(11.1)
0
(0)
4 
(44.4)
0 (0)
1 
(16.7)
11 (19.6)
12 (16)
Gastrointestinal disorders/
1 (5.3)
1 
(11.1)
2 
(22.2)
1 
(16.7)
4 (7.1)
5 (6.7)
Abdominal discomfort
1 (5.3)
1 (1.3)
Abdominal pain
1 (5.3)
1 
(11.1)
1 (1.8)
2 (2.7)
Abdominal pain (middle)
1 
(16.7)
1 (1.8)
1 (1.3)
Abdominal pain (upper)
1 
(11.1)
1 (1.8)
1 (1.3)
Diarrhea
1 
(11.1)
1 
(11.1)
2 (3.6)
2 (2.7)
Flatulence
1 
(11.1)
1 
(11.1)
2 (3.6)
2 (2.7)
Investigations/
1 
(11.1)
1 
(11.1)
2 (3.6)
2 (2.7)
Blood pressure increased
1 
(11.1)
1 (1.8)
1 (1.3)
Electrocardiogram QT 
prolonged
1 
(11.1)
1 (1.8)
1 (1.3)
Nervous system disorders/
2 
(22.2)
3 
(33.3)
1 
(11.1)
1 
(11.1)
7 (12.5)
7 (9.3)
Headache
1 
(11.1)
3 
(33.3)
1 
(11.1)
1 
(11.1)
6 (10.7)
6 (8)
Restless legs syndrome
1 
(11.1)
1 
(11.1)
2 (3.6)
2 (2.7)
Synkope
1 
(11.1)
1 (1.8)
1 (1.3)


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The following preliminary pharmacokinetic parameters of BI 1323495 were obtained in 
plasma in trial 1405-0002 (Table 1.2.1: 2).
Table 1.2. 1: 3
gMean (gCV) PK parameters after multiple bid doses of BI 1323495 
in plasma of UGT2B17 EM or PM subjects
Day 1 Cmax
[nmol/L]
Day 1 AUC0-12
[nmol*h/L]
Day 11 Cmax,ss
[nmol/L]
Day 11 AUCτ,ss
[nmol*h/L]
RACmaxss&
RAAUCt,ss&
Extensive Metabolizers (*1/*1, *1/*2)
10 mg 
bid [N=9]
23.5 (31.4)
118 (56.7)
37.5 (49.6)
237 (60.9)
1.59
(0.914-2.45)
2.00
(1.47-2.84)
30 mg 
bid [N=9]
62.0 (57.1)
264 (60.4)
64.4 (78.7)
474 (86.0)
1.06
(0.648-1.99)
1.96
(1.14-2.47)
70 mg 
bid
[N=9]
123 (50.0)
738 (47.9)
281 (48.0)*
2500 (59.4)*
2.31
(1.44-6.06)
3.56
(2.18-6.37)
120 mg 
bid
[N=9]
152 (67.5)
957 (65.9)
362 (77.7)
2850 (69.3)
2.38 
(1.62-2.92)
2.98
(2.21-3.71)
150 mg 
bid
[N=9]
117 (76.4)
704 (87)
265 (46.0)*
2080 (41.6)*
2.55* 
(1.71-7.57)
3.45*
(1.96-7.70)
Poor Metabolizers (*2/*2)
10 mg 
bid [N=5]
85.3 (30.1)
432 (27.2)
109 (25.4)
740 (19.4)
1.27
(1.05-1.75)
1.71
(1.28-2.26)
30 mg 
bid [N=6]
216 (39.7)
1310 (29.1)
300 (32.6)
2380 (28.1)
1.39
(0.629-1.97)
1.81
(1.47-2.26)
*N=8, & gMean (min-max)
Pharmacokinetic in UGT2B17 extensive metabolizer
The pharmacokinetic data showed considerable inter-individual variability . There was a 
less than proportional increase in exposure parameters Cmax,ss and AUCτ,ss from 10 to 30 mg 
bid, but a more than dose proportional increase from 30 to 70 mg dose group. The 120 mg 
bid dose group showed less than dose proportional increase compared to the 70 mg bid DG. 
Following 150 mg bid dosing, the exposure was only comparable to 70 mg bid DG, that was  
interpreted to be caused by usage of a higher tablet strength (150 mg) with dissolution 
problems.  Unexpected high accumulation ratios were observed for both Cmax and AUCτ for 
the three highest DGs (see Table 1.2.1:3) with also a high inter-individual variability. 
Pharmacokinetic in UGT2B17 poor metabolizer
The inter-individual variability was considerably lower in PMs as compared to EMs. 
Exposure to BI 1323495 at steady state was approximately ~3 to 5-fold higher based on 
Cmax,ss and AUCτ,ss in PMs as compared to EMs. The accumulation ratios at 10 mg bid and 
30 mg bid were comparable between both PMs and EMs at the same dose level. However, 
the exposure in the 30 mg bid DG in PMs was at single dose twice as high as for the 70 mg 


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bid DG in EM, but still did not lead to such high accumulations as observed in the higher 
dose groups in the EMs suggesting that the UGT2B17 metabolism plays a role in the 
unexpected high accumulation behavior in EMs. The exposure of the 30 mg bid DG in PMs 
was comparable to the 70 mg bid DG in EMs.
In the seven completed dose groups, three subjects ( 1 subject of the 70 mg bid DG and 2 
subjects of the 120 mg bid DG) exceeded the pre-defined exposure caps of AUC0-24 (11500 
nM*h). The exposure of subject 
 following 150mg dosing was not observed but 
a predicted AUC0-24 at steady state, as this 
 subject discontinued from the study on 
Day 6 following PI decision linked to an AE .
Preliminary PK results do not indicate an obvious effect of gender on the pharmacokinetics 
of BI 1323495. 
No obvious effects of genotype (*1/*1 versus *1/*2 EMs) on the pharmacokinetics of BI 
1323495 was observed in the completed dose groups.
For further details refer to the IB (c21238478-05).
Itraconazole
Absorption of itraconazole solution is fast with maximum plasma concentration being 
reached within approximately 2.0 h after oral administration in fasting condition. 
Bioavailability of itraconazole liquid increases by 10-70% when given under fasting 
condition compared to administration together with food. Mean peak plasma concentrations 
were 738 ng/mL after a single dose of 200 mg itraconazole solution (fasting) and 2500 
ng/mL after 15 days of daily treatment with 200 mg itraconazole solution (fasting). 
Pharmacokinetics of itraconazole is non-linear. The half-life of itraconazole after multiple 
doses of 200 mg once daily with solution formulation was approximately 40 h.
In the liver, itraconazole is metabolized extensively to more than 30 metabolites (R17-
3743). Its main metabolite, OH-itraconazole, accounts for about twice the concentration of
plasma itraconazole at trough. It has been shown in vitro that CYP3A4 is mainly responsible 
for the formation of this metabolite (R18-2644). FDA, EMA, and PMDA classify 
itraconazole as strong index inhibitor of CYP3A (R18-0241, P15-06991, and P15-06298). 
However, not only itraconazole contributes to the in vivo inhibition of CYP3A observed 
after itraconazole administration but also three of its metabolites (OH-itraconazole, keto-
itraconazole, and N desalkyl-itraconazole) (R10-1102).
For further details, please refer to the package insert for ITRIZOLE® Oral Solution 1% 
(R20-1269).
Residual Effect Period
The Residual Effect Period (REP, i.e., the period after the last dose with measurable drug 
levels and/or pharmacodynamic effects still likely to be present) of BI 1323495 is 
approximately 7 days.
When given together with itraconazole (Treatment T), it is expected that plasma exposure of 
BI 1323495 could be increased (albeit within the exposures explored in the clinical trial 


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1405-0001), and the time of relevant plasma exposure could be prolonged. This might result 
in a prolonged period in which adverse effects could potentially occur. 
For the use of itraconazole in Treatment T, the REP is defined as 9 days after last 
administration of itraconazole on Day 7 in Period 2.
1.3.
RATIONALE FOR PERFORMING THE TRIAL
The UGT2B17 polymorphism is geographically unequally distributed, with differences 
likely driven by ethnicity. Within Asian populations, the *2/*2 genotype is predominant, 
with UGT2B17 extensive metabolizers (EMs; genotypes *1/*1 or *1/*2) comprising only 
approximately 15% of the general population (R19-1805). The three parts of this trial take 
into consideration the distribution of this pharmacogenetic polymorphism in the Asian 
population.
SRD part and MD part
The objective of this trial is to investigate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of BI 1323495 in healthy male Japanese subjects. The chosen 
population of healthy male subjects receiving single rising oral doses and multiple oral 
doses are considered adequate to provide the basis for the clinical development program of 
BI 1323495 in Japan. Additionally, investigation of difference between PM and EM of 
UGT2B17 genotype will provide more insight to development of BI 1323495.
In 1405-0002, PK after multiple administrations were investigated in Caucasian UGT 2B17 
EM and PM populations. This result indicated that PK characteristics after multiple drug 
administration were slightly different between UGT2B17 phenotype groups (e.g., the 
exposure in the 30 mg bid DG in PMs was at single dose twice as high as for the 70 mg bid 
DG in EM, but still did not lead to high accumulations as observed in the higher dose groups 
in the EMs, etc…), which might be caused by UGT2B17 metabolic capability (please see in 
detail in section 1.2.1). Since the UGT2B17 polymorphism is geographically unequally 
distributed (e.g., UGT2B17 PM is predominant in Asian population), the investigation of 
PK after multiple drug administrations in Japanese could provide comprehensive PK taking 
account into the racial PK difference, which is beneficial for clinical development program 
of BI 1323495 in Asian region.
In the airways affected by neutrophilic inflammation, NE is considered a major component 
of the pathophysiology of emphysema development in COPD and of tissue destruction and 
exacerbations in CF. In MD parts, the NE activity after zymosan stimulation of peripheral 
blood will be assessed as a pharmacodynamic outcome for the effects of BI 1323495 after 
multiple drug administrations in UGT 2B17 PM population, which provides comprehensive 
PK-PD relationship covering both UGT 2B17 genotype groups.
The dose range selected for this trial is expected to cover the potential therapeutic dose 
range(s) in the further clinical development program of BI 1323495 for both UGT2B17 PMs 
and EMs.


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Drug-drug interaction (DDI) part
Based on in vitro data in human hepatocytes, BI 1323495 is metabolized via glucuronidation 
by UGT2B7 and UGT2B17 and via various phase I biotransformations by CYP 3A4. The in 
vitro ratio of metabolism via glucuronidation to oxidation was in the range of 7:1 to 2:1. 
Additionally, BI 1323495 is an in vitro substrate of P-glycoprotein (P-gp) (c21238478-05). 
Therefore, in this trial, the focus is on the DDI victim potential of BI 1323495 with regard to 
CYP3A4 and P-gp inhibition as this may lead to clinically relevant increases in exposures 
with potential impact on patient safety. The victim potential of BI 1323495 upon inhibition 
of CYP 3A4 / P-pg in UGT2B17 EM has already been assessed (trial 1405-0009), 
suggesting that a modest increase in exposure to BI 1323495 in gMean AUC0-∞and Cmax of 
1.69- fold  and 1.37-fold, respectively, occurs when administered together with itraconazole. 
In addition, dedicated DDI assessment in a UGT2B17 PM population is required to evaluate 
the comprehensive victim potential of BI 1323495 by strong CYP3A4/P-gp inhibitor 
considering UGT2B17 genotypes, since UGT2B17 PM, when treated with a strong inhibitor 
of CYP 3A4 and P-gp, lack two main metabolic pathways and may experience a more 
pronounced effect of CYP 3A / P-gp inhibition on exposures to BI 1323495. This DDI 
assessment in UGT2B17 poor metabolizers is performed in a Japanese population as the 
high prevalence of UGT2B17 PM subjects in this population greatly facilitates the conduct 
of this assessment.
Itraconazole is chosen for this trial as perpetrator drug, as this drug is recommended as 
strong inhibitor of CYP3A by EMA (P15-06991), as strong index inhibitor of CYP3A by 
FDA (R18-0241), and as strong inhibitor of CYP3A by PMDA (P15-06298) and it is an 
inhibitor of P-gp (R18-0241). Moreover, safety and tolerability of itraconazole were 
acceptable in previous drug-drug interaction trials (c02336088, c03355329, c08928447).
1.4.
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation in the trial, however, is of major importance for the development of a 
new orally available drug, which is expected to improve the prognosis of patients with 
COPD and emphysema by slowing the natural course of the disease, especially the 
progressive decline in lung function and lung density associated with the progression of 
tissue destruction. Furthermore, it is expected that patients with CF will benefit by 
experiencing less frequent pulmonary exacerbations and slowing of the natural course of the 
disease.
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, as well as in feeling of light-headedness or in syncope.
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (400 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.


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Drug-related risks and safety measures
Drug-induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors. Therefore, this trial requires timely detection, evaluation, and follow-up of 
laboratory alterations in selected liver laboratory parameters to ensure subjects´ safety; see 
also Section 5.2.6.1.4, adverse events of special interest.
BI 1323495
BI 1323495 is a potent and highly selective inhibitor of NE. Taking into account the mode 
of action, the nature of the target, non-clinical findings, and the relevance of animal species 
and models, BI 1323495 is not considered a high-risk compound. Two compounds with the 
same mode of action as BI 1323495 have already been tested in phase I and II clinical trials 
with no relevant safety issues detected (c21238478-05).
The formation of active NE, together with two other neutrophil serine proteases (NSPs: 
Cathepsin G, Proteinase 3), is catalysed by Cathepsin C (CatC) in maturing neutrophil 
precursor cells in the bone marrow. A human genetic disease exists, Papillon-Lefèvre 
syndrome (PLS), in which patients completely lack functional NSPs (including NE) due to 
complete deficiency for CatC. The neutrophils of PLS patients upon activation are unable to 
release active NSPs, including NE. The phenotype of these patients can be looked at as a 
human model of a pharmacologically induced complete suppression of NE (and other 
NSPs). Despite this complete lack of functional neutrophil serine proteases, which may be 
expected to weaken the microbicidal capacity of neutrophils, the associated 
immunodeficiency in Papillon-Lefèvre syndrome patients is generally mild.
The target organs in the preclinical assessment of toxicity with BI 1323495 were the liver 
and kidney, and coagulation pathway in rodents, and as responsive organ, the immune 
system and coagulation pathway in the cynomolgus monkey.
Effects on the liver were indicated by increases in liver enzymes (Aspartate transaminase
[AST], ALT, or GLDH), decreases in cholesterol and triglycerides, and an increase in total 
bilirubin in rats at 600 or 900 mg/kg/day. Biliary hyperplasia was observed in female rats 
given 900 mg/kg/day for 4-weeks. The liver findings were still present at the end of the 4-
wk recovery period, but they were not seen in the 13-week toxicity trials although male rats 
achieved high exposures. The drug exposure was much higher in these animals than those 
expected in man and observed in the SRD trial 1405-0001.
Risk mitigation and monitoring: Although alterations are not specifically expected, liver 
function tests including total and direct bilirubin will be monitored as part of the standard 
safety laboratory assessments (see Section 5.2.3). Subjects with impaired liver function will 
be excluded from participation in this trial.
Effects on the kidneys at exposures with BI 1323495 high above those expected in man 
were accompanied by increases in creatinine levels and changes in blood urea values in the 
2-week mice and rat trials. In the 4-week trial in rats, tubular basophilia was observed in the 


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kidneys of males and female rats at the highest dose tested. These effects were still present 
at the end of the 4-week recovery period. In the 13-week trial, tubular degeneration was 
seen in male rats at the highest dose tested but recovered fully within the 8-week recovery 
period.
Risk mitigation and monitoring: Serum creatinine, urea, and electrolyte levels will be 
assessed, and glomerular filtration rate will be estimated as part of the standard safety 
laboratory assessments (see Section 5.2.3). Subjects with impaired renal function will be 
excluded from participation in this trial.
The coagulation pathway was affected in rats, showing a dose-independent increase in 
fibrinogen. An increase is regarded toxicologically not relevant. A reduction in platelet 
counts was associated with BI 1323495 exposure in both rodent and non-rodent species. 
This was accompanied at very high exposures by minor increases in prothrombin time in 
male rats. No bleeding events occurred.
Risk mitigation and monitoring: Platelet count, prothrombin time and activated partial 
thromboplastin time (aPTT) will be measured as part of the standard safety laboratory 
assessments (see Section 5.2.3). Monitoring will be done for any signs of bleeding or 
bleeding-related adverse events. Use of concomitant drugs that inhibit platelet aggregation 
or coagulation (e.g. acetylsalicylic acid) will be prohibited (ref. Section 4.2.2).
The immune system showed an increase in the number of primarily B-lymphocytes in the 
cynomolgus monkey. In the spleen, increased cellularity in the lymphocyte-rich region was 
observed, and the lymph nodes showed an increase in germinal center development in the 
13-week monkey trial at high exposures. These effects were considered to be toxicologically 
not relevant.
In the SRD and food effect trial, single dose administration of BI 1323495 up to 600 mg 
under fasted conditions and 100 mg under fasted and fed conditions was well tolerated, with 
no clinically relevant changes in safety lab, ECG, and vital signs observed (ref. Section 
1.2.1).
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken 
into consideration when BI 1323495 is administered.
COVID-19
A thorough assessment has been conducted to evaluate whether the mechanism of action of 
BI 1323495 to inhibit NE may suggest an increased probability of contracting COVID-19 or 
of experiencing severe disease in case of such an infection. The key aspects of the 
assessment are summarised below. The full written documentation of this assessment (BI 
1323495: Benefit-Risk assessment in context of COVID-19 infection) is filed in the trial 
master file (TMF).
NE is an important component of the innate immune system, targeting proteins and 
virulence factors of various bacteria and thereby helping to fend off bacterial infections. 


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However, it is only one among a large number of antimicrobial mechanisms of which 
neutrophils make use to kill bacterial pathogens.
The phenotype of patients with PLS is well described. No increased risk of viral infections 
has been observed in PLS patients. Likewise, no such risk has been reported in previous 
clinical trials (including those in populations of patients with respiratory diseases) upon 
treatment with inhibitors of NE or inhibitors of the mechanistically related CatC (referenced 
in the IB (c21238478-05)). Therefore, short-lived suppression of NE activity upon 
administration of single doses of BI 1323495 is not expected to be associated with an 
increased risk of acquiring an infection with a viral pathogen targeting the airways, e.g. 
SARS-CoV-2, nor of a particularly severe clinical presentation in case of such an infection.
Currently available evidence does also not suggest an increased risk of bacterial 
superinfection in case of COVID-19 upon treatment with BI 1323495. Suppression of NE 
will only be transient in this trial assessing administration of single doses and multiple doses 
for 11 days, and represents a limited intervention into the overall armamentarium available 
to neutrophils to control bacterial infection. Furthermore, high levels of active NE have even 
been reported to impair antibacterial defence by cleavage of CXCR1, CD14, or CD16 on 
neutrophils, and by cleavage of opsonins from target bacteria, thereby impairing 
phagocytosis. Consistent with these considerations, studies investigating the effects of CatC 
or NE inhibitors in healthy subjects or patients with respiratory diseases have not revealed 
an increased risk of bacterial infections, nor of aggravated clinical courses of influenza 
infections.
The healthy subject population of this study, as defined by the in- and exclusion criteria, is 
not affected by any clinically relevant concomitant diseases that might put them at an 
increased risk of experiencing a severe clinical course of COVID-19 in case of SARS-CoV-
2 infection.
Based on these considerations, the benefit/risk assessment for the administration of BI 
1323495 to healthy subjects remains unaltered also in face of the COVID-19 pandemic.
Risk mitigation:
Ensure that the general measures implemented by the government to control the spread of 
COVID-19 in the Japanese population are adhered to. COVID-19 infection testing such as 
PCR test will be conducted before hospitalization.
Itraconazole
In this trial itraconazole will be used in a standard clinical dose of 200 mg once daily for 10
days. Multiple dosing of 200 mg itraconazole up to 15 days was of acceptable tolerability in 
healthy subjects (c02336088, c03355329, c08928447, R17-3742). Addition to this, BI 
1323495 will not have potential to be CYP3A4 inhibitor.
For a detailed description of the potential risks of itraconazole treatment, please refer to the 
package insert for ITRIZOLE® Oral Solution 1% (R20-1269).


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In order to address the risk of hepatotoxicity, only subjects with normal liver enzyme values 
will be included into the trial. Safety laboratory parameters will be monitored closely. 
An individual subject will discontinue the treatment if the subject shows an elevation of 
AST and/or ALT ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN 
(measured in the same blood sample, see Section 3.3.4.1). 
Further, most of the reported cases of serious hepatotoxicity during itraconazole treatment 
occurred in patients that suffered from concomitant liver diseases, had other significant 
diseases, or took concomitant hepatotoxic drugs. Subjects with liver diseases or a medical 
history of drug-induced liver failure are excluded from trial participation.
Itraconazole has shown a dose-related increase in maternal toxicity, embryotoxicity and 
teratogenicity in nonclinical trials at high doses, and therefore itraconazole must not be used 
during pregnancy. Woman of childbearing potential (WOCBP) have to use a highly 
effective method of contraception until the menstrual period after the last itraconazole dose 
(R18-2644, R18-2643). For risk mitigation, only male subjects will be included into this 
clinical trial.
Considering these safety measures and taking into account the reported acceptable 
tolerability of itraconazole, the planned administration of itraconazole does not represent an 
undue risk to healthy male volunteers.
Potential interaction between itraconazole and BI 1323495
It is likely that concomitant administration of BI 1323495 with itraconazole may cause an 
increase of plasma concentrations and t1/2 of BI 1323495. The effect of itraconazole in 
increasing Cmax and AUC of other drugs can be as high as 3.4-fold and 11-fold, respectively, 
as seen with oral midazolam, a sensitive CYP3A4 substrate, when co-administered with oral 
itraconazole 200 mg/d (R01-0516, R18-2644). Inhibition of P-gp may increase exposure of 
sensitive P-gp substrates like fexofenadine by factor 3-4 (R08-1652, P07-13746) and 
increase digoxin exposure by ~1.7-fold (R15-3252). Therefore, a low dose of 10 mg BI 
1323495 has been selected for this trial (see Section 4.1.2). Based on the only modest effect 
of co-administration with oral itraconazole in UGT2B17 EMs in the DDI trial 1405-0009, 
the expected effect of co-administration with oral itraconazole on BI 1323495 exposures in 
the PM population of this trial is not expected to come close to the maximum effects 
observed with other drugs.
Benefit –Risk Assessment Summary
In summary, BI 1323495 has the potential to become an oral treatment for patients with 
COPD. Based upon preclinical and clinical data with BI 1323495 and clinical information 
from competitor compounds as well as the implemented safety measures described above, 
healthy subjects will not be exposed to undue risks in relation to the important information 
expected from this trial as a basis for further clinical development of this compound. 
Healthy volunteers are not expected to have any direct benefit from participation in this 
trial.
Considering the medical need of the development of an effective treatment to slow the 
progression of COPD for patients with this disease and potentially other Respiratory 


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diseases in the future, the Sponsor considers that the benefit outweighs the potential risks 
and justifies exposure of healthy male volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1.
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
SRD part and MD part; To investigate safety, tolerability, pharmacokinetics, and
pharmacodynamics (for MD part only) following single rising doses and multiple oral doses 
of BI 1323495 in healthy male Japanese subjects genotyped as PM and EM of UGT2B17.
DDI part; To investigate the relative bioavailability of a single oral dose of BI 1323495 
when given alone (treatment R) or in combination with itraconazole (treatment T) in healthy 
male subjects genotyped as PM of UGT2B17.
Primary endpoint
SRD and MD part; The primary endpoint for assessment of safety and tolerability of BI 
1323495 is the percentage of subjects with drug-related adverse events.
DDI part; The following pharmacokinetic parameters will be determined for BI 1323495:
•
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
•
Cmax (maximum measured concentration of the analyte in plasma)
Secondary endpoint
SRD part; The following pharmacokinetic parameters will be determined if feasible:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
DDI part; The following pharmacokinetic parameters will be determined for BI 1323495 if 
feasible:

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)
MD part; The following pharmacokinetic parameters will be determined if feasible:
After the first dose of BI 1323495:

AUC0-12 (area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval of 12 h after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma after the first dose)
After the last dose of BI 1323495:


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
AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ)
Safety and tolerability
Safety and tolerability of BI 1323495 will be assessed based on:
•
Adverse events (including clinically relevant findings from the medical examination)
•
Safety laboratory tests
•
12-lead ECG
•
Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1.
OVERALL TRIAL DESIGN AND PLAN
SRD part for PM
This single rising dose part is designed as single-blind, randomised, and placebo-controlled 
within dose groups.
It is planned to include a total of 24 healthy male subjects in the trial part. 
The subjects will be assigned to 3 groups consisting of 8 subjects per group; the groups will 
be dosed sequentially (see Table 3.1: 1). Within each dose group, 6 subjects will receive BI 
1323495 and 2 will receive placebo. Only one dose is tested within each dose group.
The trial schedule and design are depicted in Figure 3.1: 1.
Figure 3.1: 1
Trial design “SRD part for PM”
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups for UGT2B17 PM
Dose Group
1
2
3
Dose (mg)
10
30
100
Number of subjects
8
8
8
Subjects receiving placebo
2
2
2
Subjects receiving active drug
6
6
6


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SRD part for EM
This single rising dose part is designed as single-blind, randomised, and placebo-controlled 
within dose groups.
It is planned to include a total of 12 healthy male subjects in the trial part. 
The subjects will be assigned to 3 groups consisting of 4 subjects per group; the groups will 
be dosed sequentially (see Table 3.1: 2). Within each dose group, 3 subjects will receive BI 
1323495 and 1 will receive placebo. Only one dose is tested within each dose group.
The trial schedule and design is depicted in Figure 3.1: 2.
Figure 3.1: 2 
Trial design “SRD part for EM”
The dose groups to be evaluated are outlined in Table 3.1: 2 below.
Table 3.1: 2
Dose groups for UGT2B17 EM
Dose Group
1
2
3
Dose (mg)
30
70
150
Number of subjects
4
4
4
Subjects receiving placebo
1
1
1
Subjects receiving active drug
3
3
3
DDI part for PM
This part will be performed as an open-label, two-treatment, two-period, fixed sequence trial 
in healthy male subjects in order to compare the test treatment (T) to the reference treatment 
(R). The treatments will be one oral single dose of 10 mg BI 1323495 administered as tablet 
formulation together with multiple oral doses of 200 mg itraconazole as oral solution 
formulation (concentration: 10 mg/mL) (T) and one single dose of 10 mg BI 1323495 as 
tablet formulation given alone (R). DDI part will be initiated after 10 mg safety was 
confirmed in SRD part for PM subjects.
In the first treatment period (Period 1, Visit 2), all subjects are planned to undergo treatment 
R, and in the second treatment period (Period 2, Visit 3), all subjects are planned to undergo 
treatment T. For details, refer to Section 4.1.


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The trial schedule and design is depicted in Figure 3.1: 3.
There will be a washout period of at least 11 days between the administrations of BI 
1323495.
Figure 3.1: 3
Trial design “DDI part for PM”
An overview of all relevant trial activities is provided in the flowchart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
MD part for PM
This multiple dose part is designed as single-blind, randomised, and placebo-controlled 
within dose groups.
It is planned to include a total of 24 healthy male subjects in the trial part.
The dose groups to be evaluated are 30 mg bid and 60 mg qd.
The following figures show an overview over the visit structure. Detailed schedules of all 
relevant trial activities are provided in the Flow Charts.
Table 3.1: 4 Overview for MD part, for details see Flow Charts
Dose escalation and safety review
The groups will be dosed consecutively in ascending order of the doses, and a time interval 
of at least 7 d will be maintained between the last drug administration to subjects in the 
previous dose group (dose group N) and the first drug administration to subjects in the 
subsequent dose group (dose group N+1). The decision to treat the next dose group will be 
based upon safety and tolerability of all the preceding dose groups. The next dose group will 
only be treated if, in the opinion of the Principal Investigator (or authorised deputy, sub 
investigator), clinical trial leader (CTL) and Team Member Medicine (TMM), no safety 
concerns have arisen in the preceding dose groups, i.e. no dose-limiting events occurred, 
Visit No.
1
3
Day
  -28 to -8
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19 to 21
Drug admin
x
x
x
x
x
x
x
x
x
x
x
Type of Visit
Ambulatory
Admission to site
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Stationary
Discharge
Amburatory
2


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and if none of the pre-specified trial-specific stopping criteria have been met (refer to 
Section 3.3.4.1).
A documented safety review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime for any reasonable cause by 
the Principal Investigator, or an authorised deputy, Sub Investigator, or the sponsor of the 
trial, e.g. in case of any unforeseen adverse events. Dose escalation will only be permitted if 
no safety concerns exist in the opinion of the Principal Investigator (or an authorised deputy, 
Sub Investigator), the CTL and TMM.
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, and if none of the pre-specified trial-specific stopping 
criteria have been met (refer to Section 3.3.4.1).
At minimum, data from 2/3 of subjects on active drug need to be available for escalation to 
a higher dose. The minimum data set for review consists of the following:

AEs in the current and preceding dose groups up to at least 7 d post dosing 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 3 d 
post dosing

Vital signs in the current and preceding dose groups up to at least 3 d post dosing.

Clinical laboratory tests in the current and preceding dose groups up to at least 7 d 
post dosing

Review 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, Sub Investigator, CTL and TMM after in-depth analysis of all available 
safety data, especially serious adverse event (SAE)s, AEs, and out-of-range laboratory
results that are considered clinically significant by the investigator. Dose escalation will 
only be permitted if no safety concerns exist neither in the opinion of the Principal 
Investigator (or an authorised deputy, Sub Investigator), CTL and TMM. 
Safety Reviews can be conducted face-to-face or by video/telephone conference. The CTL
is responsible for the organisation and minutes of the reviews. Minutes will be signed off by 
the Principal Investigator (or an authorised deputy, Sub Investigator), CTL and TMM, and 
will be filed in the investigator site file (ISF) and TMF. 
Additional subjects may be entered to allow additional testing 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 and none of the stopping criteria apply. Thus, 
the actual number of subjects entered may exceed 50, but will not exceed 62 subjects. CTP 
will be amended if additional subject entry has decided.


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3.2.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
SRD part
For single -rising dose trials, the sequential rising dose design described in Section 3.1 is 
viewed favourably under the provision not to expose the subjects to undue risks, since the 
main trial objective is to investigate safety and tolerability of BI 1323495.
Single-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 the 
drug administered. The disadvantage of this 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 single rising dose trials involving healthy subjects to include a placebo 
group to control for safety and tolerability of the trial medication. 
SRD part for PM
Each dose group consists of 8 subjects, with 6 on active treatment, and 2 on placebo. For 
data analysis purposes, the placebo control group will include all subjects that were treated 
with placebo, regardless of the groups they were treated. Six subjects per active treatment 
group are generally considered to be sufficient for the exploratory evaluation of 
pharmacokinetics.
SRD part for EM
Each dose group consists of 4 subjects, with 3 on active treatment, and 1 on placebo. For 
data analysis purposes, the placebo control group will include all subjects that were treated 
with placebo, regardless of the groups they were treated. Three subjects per active treatment 
group are considered to be reasonable taking into account the low proportion of UGT2B17 
EM in Japanese, and be sufficient for the exploratory evaluation of pharmacokinetics.
DDI part for PM
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between treatments is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments (R94-1529). Because of the long half-life (about 40 h) of itraconazole 
and its metabolites, a fixed sequence design was selected, with administration of 
itraconazole in the second trial period only. This design is not expected to lead to systematic 
errors in the estimation of the treatment effects since nonspecific time-effects are unlikely 
due to the short trial duration. For itraconazole trials, this design is recommended by the 
Innovation and Quality in Pharmaceutical Development’s 
 
(R17-3744).
For this PK drug-drug interaction part of this trial, open-label treatment is acceptable, 
because the primary endpoints of this trial are PK endpoints derived from measurement of 


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plasma concentrations of BI 1323495. These endpoints are not expected to be affected by 
knowledge of treatment.
MD part for PM
Single-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 the 
drug administered. The disadvantage of this 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 dosing trials involving healthy volunteers to include a placebo 
group to control for safety and tolerability of the trial medication. In the MD part, each dose 
group consists of 12 subjects, with 9 on active treatment, and 3 on placebo. 9 subjects per 
active treatment group in the MRD part, is considered to be sufficient for the exploratory 
evaluation of safety, pharmacokinetics, and pharmacodynamics.
The treatment period of 11 days is considered adequate for collection of safety, 
pharmacokinetic, and pharmacodynamic data after multiple dosing at steady state to inform 
subsequent studies along the clinical development path. The treatment period is adequately 
covered by non-clinical toxicology data from animal studies.
3.3.
SELECTION OF TRIAL POPULATION
It is planned that 74 healthy male genotyped UGT2B17 (62 poor metabolizers and 12 
extensive metabolizers) will enter the trial. These subjects will be recruited from the 
volunteers' pool of the trial site. 
Based on UGT2B17 genotyping, the predicted phenotypes are defined as having the 
following alleles: extensive metabolizers (*1/*1 or *1/*2), poor metabolizers (*2/*2).
In the SRD part, both PM and EM subjects will participate, as assessments for both 
UGT2B17 metabolizer groups are needed to fully characterize the pharmacokinetic 
properties of BI 1323495 in a Japanese population. In the DDI part, only PM subjects will 
participate, as the DDI effect of itraconazole in an UGT2B17 EM population has already 
been assessed (trial 1405-0009) and the extent of DDI is expected to be affected by the 
UGT2B17 metabolizer status, but not by ethnicity. In the MD part, 30 mg bid and 60 mg qd 
groups in UGT2B17 PM group will be investigated, which would be reasonable to ensure 
the safety profiles after multiple administrations of BI 1323495 in Japanese population 
taking account the following points; 1) majority of Japanese population is considered to be 
PM subjects, 2) the exposure of BI 1323495 was higher in UGT2B17 PM than in UGT2B17 
EM.
Subjects who participated to one of these parts can not participate to other part.
Only male subjects will be included in the trial because no data on reproductive toxicology 
are available at this time.


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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 trial will be performed in healthy male 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 medical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory tests
2. Japanese ethnicity, according to the following criteria:
-
born in Japan, have lived outside of Japan <10 years, and have parents and 
grandparents who are Japanese
3. Age of 20 to 45 years (inclusive) at screening
4. BMI of 18.5 to 25.0 kg/m2 (inclusive) at screening
5. Signed and dated written informed consent prior to admission to the trial, in 
accordance with Good Clinical Practice (GCP) and local legislation
6. Subjects who agree to minimize the risk of making their partner pregnant by fulfilling 
any of the following criteria starting from the first administration of trial medication 
until 90 days after last administration of trial medication
- Use of adequate contraception, any of the following methods plus condom: 
intrauterine device, combined oral contraceptives that started at least 2 months prior 
to the first drug administration.
- Vasectomized (vasectomy at least 1 year prior to enrolment)
- Surgical sterilization (including bilateral tubal occlusion, hysterectomy or bilateral 
oophorectomy) of the subject’s female partner
7. Subjects genotyped as UGT2B17 poor metabolizers, i.e. carrying allele of UGT2B17 
gene (*2/*2) (DDI and MD part only)
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 40 to 90 mmHg, or pulse rate 
outside the range of 40 to 99 bpm
3. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance


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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 (Subjects who were positives to Hepatitis B 
surface antigen, Hepatitis B surface antibody, Hepatitis B core antibody, Hepatitis C 
antibodies, HIV-1 and HIV-2 antigen and/or antibody, T-SPOT and Syphilis test)
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 3 months (4 months
for new active ingredients) 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 than 30 g per day for males)
16.Drug abuse or positive drug screening
17.Blood donation of more than 400 mL within 12 weeks or 200 mL within 30 days or 
plasma donation within 2 weeks prior to administration or intended blood donation 
during the trial
18.Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19.Inability to comply with the dietary regimen of the trial site
20.A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms 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 trial
requirements, or has a condition that would not allow safe participation in the trial


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23.History of disease that affects the present situation
In addition, the following trial-specific exclusion criteria apply:
24.Current or history of relevant kidney, urinary tract diseases or abnormalities (e.g. 
nephrolithiasis, hydronephrosis, acute or chronic nephritis, renal injury, renal failure)
25.Estimated glomerular filtration rate according to Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI*) formula < 80 mL/min at screening
26.Within 10 days prior to administration of trial medication, use of any drug that could 
reasonably inhibit platelet aggregation or coagulation (e.g. acetylsalicylic acid)
27.History of drug induced liver injury
28.Liver enzymes (ALT, AST, Gamma-Glutamyl Transferase [GGT]) above upper limit 
of normal at the screening examination
29. Known relevant immunodeficiency, as judged by the investigator
30.History and/or presence of tuberculosis; positive result for interferon gamma release 
assay (IGRA) (i.e. T-SPOT), or history of pneumococcal infection
31.Axillary temperature of more than 37.7°C on Day -1
32.Subjects who have received live or live-attenuated vaccine in the 4 weeks prior to 
dosing
33.C-reactive protein above upper limit of laboratory reference range at screening
* Estimated glomerular filtration rate by Japanese CKD-EPI formula
For trial 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 1.2.3), the discontinued subject should if possible be 
questioned for AEs and concomitant therapies at or after the end of the REP in order to 
ensure collection of AEs and concomitant therapies throughout the REP, if not contrary to 
any consent withdrawal of the subject.


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Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment or trial participation, without the need 
to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial 
procedures and, in the opinion of both, the investigator and sponsor representative, is 
not willing or able to adhere to the trial requirements in the future 
3. The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
4. The subject is no longer able to participate in the trial for other medical reasons, such 
as surgery, adverse events (AE)s, or diseases
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of 
total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be 
followed up according to the DILI checklist provided in the ISF
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 
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. 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.


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3. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate 
conduct of the trial.
4. The sponsor decides to discontinue the further development of the investigational 
product.
5. Dose escalation will be stopped if at least 1/3 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.
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
Replacement of subjects
In SRD and MD part, if some subjects do not complete the trial, or there is not a sufficient 
number of subjects on active within one dose group the Trial Clinical Leader together with 
the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many 
subjects will be replaced. In DDI part, if more than 2 subjects do not complete the trial, the 
CTL 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 1323495 as tablet formulation has been manufactured by BI 
Pharma GmbH & Co. KG. Itraconazole oral solution will be prepared by a site pharmacy
department.
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Test product 1
Substance:
BI 1323495
Pharmaceutical formulation: Tablet, film-coated
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg and 50 mg
Posology:
1-0-0 and 1-0-1 (30 mg bid only)
Route of administration:
Oral
Duration of use:
SRD part: Single dose
MD part: 11 days
DDI part: Single dose for each treatment R and T
Test product 2
Name:
ITRIZOLE® Oral Solution 1% [
]
Substance:
Itraconazole
Pharmaceutical formulation: Oral solution
Source:
Site pharmacy department
Holder of marketing
authorisation:
Unit strength:
10 mg/mL
Posology:
20 mL-0-0
Route of administration:
Oral
Duration of use:
10 days in treatment T
The characteristics of the reference product (placebo) are given below:
Substance:
Placebo


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Pharmaceutical formulation: Tablet, film-coated
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Not applicable
Posology:
1-0-0 and 1-0-1 (30 mg bid only)
Route of administration:
Oral
Duration of use:
SRD part: Single dose
MD part: 11 days
DDI part: Sing dose for each treatment R and T
Selection of doses in the trial and dose modification
SRD part
The doses selected for this trial are assumed to cover the therapeutic dose. 
Maximum dose for each UGT2B17 genotype group
The maximum doses are 100 mg and 150 mg under fed condition for UGT2B17 PM and 
EM, respectively. The human exposure caps are a Cmax gMean value of 1900 nM and AUC0-
24 gMean value of 11500 nM·h [c21238478-05]. For the current trial, Cmax gMean and AUC 
gMean are predicted to be below the exposure cap and not to exceed exposures that were 
already achieved (maximum values of Cmax and AUC0-24 were 717 nM and 6790 nM·h, 
respectively) and considered safe in individual PM subjects participating in the first-in-
human trial 1405-0001. The expected margins versus human exposure caps (Table 4.1.2: 1) 
are considered reasonable; therefore, single administration of the maximum dose in each 
UGT2B17 genotype group are considered safe.
Table 4.1.2: 1
Predicted PK parameters for the maximum dose group in each UGT 
2B17 genotype group after single dose administration of BI 1323495
in the fed state
AUC0-24
AUC0-∞
Cmax
Model Prediction
(gMean)
Exposure 
multiple
Model Prediction
(gMean)
Exposure 
multiple
Model Prediction
(gMean)
Exposure 
multiple
UGT 2B17 PM
100 mg
4380
2.6
7210
1.6
374
5.1
UGT 2B17 EM
150 mg
1620
7.1
2610
4.4
142
13 
Model prediction: Single dose, tablet formulation, fed condition, Male, Mean body weight 65 kg, UGT 2B17 genotype 
(PM or EM)
Exposure multiple: calculated as ratio of predicted exposure to exposure cap (AUC0-24,ss: 11500 nM·h, Cmax,ss: 1900 nM)


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MD part
In this part, 30 mg bid and 60 mg qd under fed condition is selected as the dose to be tested 
for UGT2B17 PM. The human exposure caps are a Cmax gMean value of 1900 nM and 
AUC0-24 gMean value of 11500 nM·h [c21238478-05]. For the current trial, Cmax gMean 
and AUC gMean are predicted to be below the exposure cap. In addition, multiple doses of 
BI 1323495 investigated, including UGT2B17 PM 10 mg bid and 30 mg bid group, so far in 
clinical trials with healthy subjects were safe and well tolerated (please see Section 1.2.1 in 
detail); therefore, multiple administrations of 30 mg bid and 60 mg qd in UGT2B17 PM
group are considered safe.
Table 4.1.2: 2
Predicted PK parameters for 30 mg bid and 60 mg qd in UGT 2B17 
PM genotype group after multiple dose administrations of BI 
1323495 in the fed state 
AUC0-24,ss
Cmax,ss
Model Prediction
(gMean)
Exposure 
multiple
Model Prediction
(gMean)
Exposure multiple
UGT 2B17 PM
30 mg bid
6160
1.9
350
5.4
60 mg qd
6010
1.9
496
3.8
Model prediction: bid: twice daily, qd: once daily, assuming tablet formulation, fed condition, Male, Mean body weight 65 
kg, UGT 2B17 genotype (PM)
Exposure multiple: calculated as ratio of predicted exposure to exposure cap (AUC0-24,ss: 11500 nM·h, Cmax,ss: 1900 nM)
DDI part
Perpetrator (itraconazole)
The dose of itraconazole selected for this trial reflects standard clinical doses, is considered 
sufficient to yield significant CYP3A and P-gp inhibition, and has been used successfully 
and safely in previous drug-drug-interaction trials (c02336088, c03355329, c08928447,
c27223001).
Victim (BI 1323495)
For the current trial, a dose of 10 mg BI 1323495 under fasted condition is selected, which 
is same to that tested in trial 1405-0009. The predicted exposure of a dose 10 mg BI 
1323495 alone under fasted condition in UGT2B17 PM is displayed in Table 4.1.2: 2. The 
exposure multiples of Cmax and AUC were 32 and 12-19, respectively.
In trial 1405-0001, in the 200 mg dose group - the dose group with highest mean exposures -
gMean values for Cmax and AUC0-24 were 229 nM and 2390 nM·h, respectively. 
(c26492551). The ratios of these gMean plasma exposure parameters at the 200 mg dose 
group to the predicted exposure for the current trial (Cmax: 59.9 nM, AUC0-24: 609 nM·h) are 
approximately 4.
The victim potential of BI 1323495 upon inhibition of CYP 3A4 / P-pg in UGT2B17 EM 
has already been assessed in trial 1405-0009, suggesting that a modest increase in exposure 
to BI 1323495 in gMean AUC0-∞and Cmax of 1.69- fold and 1.37-fold, respectively, occurs 


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when BI 1323495 10 mg single administered together with itraconazole. UGT2B17 PM, 
when treated with a strong inhibitor of CYP 3A4 and P-gp such as itraconazole, lack two 
main metabolic pathways and may experience a more pronounced effect of CYP 3A / P-gp 
inhibition of exposures to BI 1323495. The predicted exposure after single dose 
administration of 10 mg BI 1323495 alone and with 200 mg itraconazole in UGT2B17 PM 
by PopPK model based on the clinical trials (1405-0001 and 1405-0007) are shown in Table 
4.1.2: 2. In this simulation, the inhibition effect by itraconazole on PK of BI 1323495 
mainly affects the bioavailability but not the elimination which was observed in UGT2B17 
EM in trial 1405-0009. From this simulation, the exposure multiple of the predicted 
exposure with itraconazole in UGT2B17 PM are more than 5 and the predicted exposure are 
still lower than that experienced in trial 1405-0001. Considering these findings, it is 
considered to be safe for increases of BI 1323495 plasma exposures in UGT 2B17 PM when 
10 mg BI 1323495 administered given together with itraconazole.
Table 4.1.2: 3
Predicted PK parameters after 10 mg BI 1323495 single 
administration under fasted condition (BI 1323495 alone and with 
itraconazole)
AUC0-24
AUC0-∞
Cmax
Model Prediction
(gMean)
Exposure 
multiple
Model 
Prediction
(gMean)
Exposure 
multiple
Model Prediction
(gMean)
Exposure 
multiple
UGT 2B17 PM
10 mg
609
19
963
12
59.9
32
10 mg + 200
mg 
itraconazole
1260
9.1
2000
5.8
121
16
Model prediction: Single dose, tablet formulation, fasted condition, Male, Mean body weight 65 kg, UGT 2B17 PM
Exposure multiple: calculated as ratio of predicted exposure to exposure cap (AUC0-24,ss: 11500 nM·h, Cmax,ss: 1900 nM)
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. During the screening, UGT2B17 genotype will be determined and 
subject will be categorized into 2 groups: PM (genotype *2/*2) or EM (genotype *1/*1 and
*1/*2). Allocation of PM subjects to SRD part, MD part or DDI part will be decided by 
subject availability with ‘first come first served’ principle. Therefore, the allocation of PM 
subject is not influenced by trial personnel, but only by the subjects’ temporal availability.
SRD part (For PM and EM)
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 3 dose cohorts, 
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 trial includes healthy subjects from a 
homogenous population, relevant imbalances between the dose groups are not expected.


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Subjects will be assigned to treatments (active treatment or placebo) prior to the first 
administration of trial medication. For this purpose, the randomisation list will be provided 
to the trial site in advance. Numbers of the randomisation list will be allocated to subjects by 
the method ‘first come first served’. Subjects are then assigned to treatment according to the 
randomisation list. Once a subject number has been assigned, it cannot be reassigned to any 
other subject.
The randomisation procedure is described in Section 7.6.
DDI part (For PM)
There is only one treatment sequence investigated in this part, and each subject will be
allocated to the same treatment sequence (R-T). Subjects will be allocated by the method 
‘first come first served’. Once a subject number has been assigned, it cannot be reassigned 
to any other subject.
All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same
calendar day. In case this is not feasible (e.g. due to logistical or recruitment reasons), the
group may be split into several cohorts as required. Treatment of all subjects on the same
calendar day is acceptable (for safety margin to exposure reached in previous SRD trial 
1405-0001 refer to Section 1.2.1; for discussion of trial-associated risks and safety measures 
see Section 1.4.1 and 1.4.2).
MD part (For PM)
The subjects willing to participate will be recruited to dose group according to their 
temporal availability. As soon as enough subjects are allocated to 1 of the 2 dose cohorts, 
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 trial 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 list will be provided 
to the trial site in advance. Numbers of the randomisation list will be allocated to subjects by 
the method ‘first come first served’. Subjects are then assigned to treatment according to the 
randomisation list. Once a subject number has been assigned, it cannot be reassigned to any 
other subject.
The randomisation procedure is described in Section 7.6.
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Tables 4.1.4: 1, 4.1.4: 2 and 4.1.4: 3. The 
number of tablets for placebo corresponds to the number of tablets in the corresponding 
dose level.


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Table 4.1.4: 1
BI 1323495 and placebo* treatments, tablets of SRD part for PM
Dose
group
Substance
Pharmaceutical 
form
BI 1323495
10 mg
BI 1323495  
50 mg
Total dose of 
BI 1323495
1
BI 
1323495
Tablet, 
film-coated
1
0
10 mg
2
BI 
1323495
Tablet, 
film-coated
3
0
30 mg
3
BI 
1323495
Tablet, 
film-coated
0
2
100 mg
1-3
Placebo*
Tablet, 
film-coated
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups
Table 4.1.4: 2
BI 1323495 and placebo* treatments, tablets of SRD part for EM 
Dose
group
Substance
Pharmaceutical 
form
BI 1323495
10 mg
BI 1323495  
50 mg
Total dose of 
BI 1323495
1
BI 
1323495
Tablet, 
film-coated
3
0
30 mg
2
BI 
1323495
Tablet, 
film-coated
2
1
70 mg
3
BI 
1323495
Tablet, 
film-coated
0
3
150 mg
1-3
Placebo*
Tablet, 
film-coated
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups
Table 4.1.4: 3
Dosage and treatment schedule in the DDI part
Treatment 
period
Treatment
Substance
Formulation
Unit 
strength
Dosage
Total 
dose
1
R (Reference)
BI 1323495
Tablet, 
film-coated
10 mg
1 tablet as single dose
(Day 1)
10 mg
2
T (Test)
BI 1323495
Itraconazole
Tablet, 
film-coated
Oral solution
10 mg
10 mg/mL
1 tablet as single dose
(Day 1)
20 mL (200 mg) qd 
for 10 days (Days -3 to 7)
10 mg
2000 mg


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Table 4.1.4: 4
BI 1323495 and placebo treatments, tablets of MD part for PM 
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Number of units  
per administration
Total daily 
dose of BI 
1323495
1
BI 
1323495
Tablet, 
film-coated
10 mg
3 tablets bid*
60 mg
1
Placebo
Tablet, 
film-coated
--
3 tablets bid*
--
2
BI 
1323495
Tablet, 
film-coated
10 mg
50 mg
1 tablet each qd
60 mg
2
Placebo
Tablet, 
film-coated
--
1 tablet each qd
60 mg
*On Day 11, Subjects will receive a single dose in the morning only. On all other trial days, 
BI 1323495 will be administered bid.
SRD part
For BI 1323495 treatment, a standardized meal (400-500 kcal with fat contributing to ca. 
150 kcal) content [P12-10638]) will be served 30 min before drug administration. The 
subjects must completely consume the meal prior to drug intake.
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 standing /sitting position. For 
drug administration, the so-called four-eye principle (two-person rule) should be applied. 
For this, one authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (e.g. reconstitution), if correct dosage 
cannot be ensured otherwise.
During the first 4 h after drug administration, the 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.
Subjects will be kept under close medical surveillance until 48 h after administration of BI 
1323495.
DDI part
Administration of trial medication will be performed after subjects have fasted overnight; 
No food is allowed within 10 h before and for at least 4 h after intake of BI 1323495. 
Subjects will be advised to not consume any food within 9 h before and 1 h after 
itraconazole administrations. 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 
standing / sitting position. For drug administration, the so-called four-eye principle (two-
person rule) should be applied. For this, one authorised employee of the trial site should 


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witness the administration of trial medication, and – if applicable – its preparation (e.g. 
reconstitution), if correct dosage cannot be ensured otherwise.
During the first 4 h after drug administration, the 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.
Subjects will be kept under close medical surveillance until 34 h after administration of BI
1323495.
MD part
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 standing /sitting position. For 
drug administration, the so-called four-eye principle (two-person rule) should be applied. 
For this, one authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (e.g. reconstitution), if correct dosage 
cannot be ensured otherwise.
On first day of treatment (Day 1) and last day of treatment (Day 11), where PK profile 
sampling takes place, administration of BI 1323495 (Day 1, Day 11) in the morning will be 
performed following a standardized normal caloric meals, which is to start and be completed 
within 30 minutes before the scheduled dosing. 
On all other treatment days and in the evening of Day 1, subjects should take the study 
medication with food, preferably within 30 min after a meal. On treatment days, breakfast 
will be provided 30 minutes prior to the morning dose administration and dinner will be 
provided 30 minutes prior to the evening dose administration.
Subjects should take their morning doses on all treatment days at the same time as on the 
first day, +/- 1 hour. The evening dose should be taken 12 hours +/-1 hour after the 
scheduled time of the morning dose.
Following the first administration of trial medication, subjects will stay in inhouse 
confinement until Day 18. During the first 4 h after drug administration, they 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 (Only for Day 1 and Day 11 
morning). 
For restrictions with regard to diet see Section 4.2.2.2.
Blinding and procedures for unblinding
Blinding
SRD and MD part
SRD and MD part is designed single-blind. The treatments administered (active or placebo) 
will be blinded to subjects, but will be known to the investigators (outcome assessors). Only 
the current dose level will be known to the subjects due to the rising dose design.


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A single–blind design is considered acceptable because the potential bias in this type of trial
seems to be low and according to trial procedures it is assured that the investigator's 
knowledge of the next treatment does not influence the decision to enter a subject.
All trial data will be handled open label. This means that trial functions of the sponsor are 
unblinded (including clinical trial manager (CTM), data manager, statistician, bioanalyst, 
pharmacokineticist, pharmacometrician, drug metabolism scientist as well as dedicated 
personnel of the trial site). 
Access to the randomisation schedule will be controlled and documented by a signed 
confidentiality statement, which will be stored in the TMF. 
DDI part
DDI part 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
As this trial will be conducted single blind or open-label, subjects’ treatment assignments 
will be known to investigators. Therefore, no emergency envelopes will be provided.
Packaging, labelling, and re-supply
BI 1323495 tablets
BI 1323495 tablets 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. Examples of the labels will be 
available in the ISF.
Itraconazole oral solution
Itraconazole oral solution will be obtained by the clinical trial site from a public pharmacy. 
The drug will be dispensed out of the original, unmodified packages.
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.


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Drug accountability
The investigator, or a designee, will receive the investigational drugs from the sponsor when 
the following requirements are fulfilled:

Approval of the clinical trial protocol (CTP) by the Institutional Review Board (IRB)

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification from the regulatory authority, e.g. competent authority (CA)

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated CTP  
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 adequately documenting
that the subjects were provided the doses specified by the CTP and will 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 investigational 
medicinal product remains in the investigator’s possession. 
All unused trial medication will be disposed locally by the trial site upon written 
authorisation of the CTM. 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 authorize
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 trial days) on the appropriate pages of the CRF.


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Known inhibitors/inducers of CYP3A and P-gp activity, drugs with a known hepatotoxicity 
profile, drugs which are contraindicated to be co-administered with itraconazole (ref. R18-
2644), as well as acetylsalicylic acid or other drugs that may inhibit platelet aggregation or 
coagulation should be avoided during the entire trial; if necessary, short term use of 
ibuprofen is acceptable.
Restrictions on diet and lifestyle
Poppy-seeds containing foods should not be consumed starting 3 days before the first drug 
administration in each treatment period, in order to avoid false-positive results in the drug-
screen.
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. Standardized meals will be served at the times
indicated in the Flow Chart. 
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 collected. 
Alcoholic beverages are not permitted from 7 days before the first administration of trial 
medication until after the last PK sample collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before until 24 h after administration of BI 1323495.
Smoking is not allowed during in-house confinement. 
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.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire trial.
SRD part
From 1 h before trial medication intake until lunch, fluid intake is restricted to the water
provided with standard meal, water administered with the drug, and an additional 240 mL of 
water served at 2 h and 4 h post-dose (mandatory for all subjects). From lunch until 24 h 
post-dose, total fluid intake is restricted to 3 L.
During the days of urine collection, total fluid intake should be at least 1.5 litres and should 
not exceed 3.5 litres.
DDI part
No food is allowed within 10 h before and for at least 4 h after intake of BI 1323495. 
Subjects will be advised not to consume any food within 9 h before and 1 h after 
itraconazole administrations.
On Day 1, from 1 h before intake of BI 1323495 (Period 1) or itraconazole (Period 2), 
respectively, fluid intake is restricted to the water administered with the drug, water
provided with standard meal, and an additional 240 mL of water at 2 h and 4 h post-dose 


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(mandatory for all subjects). From lunch until 23 h post-dose, total fluid intake is restricted 
to 3 L.
MD part
While admitted to the trial site, the subjects are restricted from consuming any other foods 
or beverages than those provided by the site staff. Standardised meals will be served at the 
time points described in Flow Chart. A standardized normal caloric breakfast (e.g., a roll 
with cheese or sausage, including some dietary fat) should be served and finished within 30 
minutes prior to dose administration. 
In the evening of Day 1 and on Days 2 to 10, drug intake should occur with food. 
Breakfast will be provided 30 minutes prior to the morning dose administration and dinner 
will be provided 30 minutes prior to the evening dose administration.
On Days 1 and 11, from 1 h before drug intake until lunch, fluid intake is restricted to the 
water administered with the drug, fluid provided with food and an additional 240 mL of 
water served at 2 h and 4 h post-dose (mandatory for all subjects). From lunch until 24 h 
post-dose, total fluid intake is restricted to 3.0 litres.
During the days of urine collection, total fluid intake should be at least 1.5 litres and should 
not exceed 3.5 litres.
4.3.
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial site under 
supervision of the investigating physician or a designee. The measured plasma 
concentrations and/or urinary excretion of trial medication will provide additional 
confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
ASSESSMENTS
5.1.
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2.
ASSESSMENT OF SAFETY
Medical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history, relevant medical history and concomitant therapy, review of 
inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory 
tests, and a physical examination. After screening, at the time pionts indicated in the Flow 
chart, it will include review of vital signs, 12-lead ECG, laboratory tests, and a physical
examination.
Vital signs
Systolic and diastolic blood pressures (BP), as well as pulse rate (PR), will be measured by a 
blood pressure monitor, at the times indicated in the Flow Chart, after subjects have rested 
for at least 5 min in a supine position. All recordings should be made using the same type of 
blood pressure recording instrument and on the same arm, if possible.
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by 
the trial site at the time points indicated in the Flow Chart after the subjects have fasted for 
at least 10 h, except 4 h post dosing on Day 1 of SRD part and screening. For retests, at the 
discretion of the investigator or designee, overnight fasting is not required. The parameters 
that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will be 
provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
D1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X
X
Automatic WBC relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; 
Basophils/ Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
--
X
Automatic WBC 
differential
Neutrophil, absol.; Eosinophils, absol.; Basophils, 
absol.; Monocytes, absol.; Lymphocytes, absol.
X
X
--
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal and clinically 
relevant in the opinion of 
the investigator)
Neut. Poly (segs; Neutrophils Bands;  
Eosinophils/Leukocytes; Basophils/ Leukocytes; 
Monocytes/ Leukocytes; Lymphocytes/Leukocytes; 
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
--
--
--
X
--
--
--
--
--
--
--
--
Enzymes
AST [Aspartate transaminase] /GOT 
ALT [Alanine transaminase] /GPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is 
elevated and clinically relevant in the opinion of the 
investigator] 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
Hormones
Thyroid Stimulating Hormone
X
--
--
--
Substrates
Glucose (Plasma)
Creatinine
GFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
Electrolytes
Sodium
Potassium
X
X
X
X
--
--
--
--
1
A: parameters to be determined at Visit 1 and EOT 
B: parameters to be determined at Visit 2 and 3 (for trial days and time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (for trial days and time points refer to Flow Chart)
D: parameters to be determined at Visit 2 (only for MD part)
2
Microscopic examination if erythrocytes, leukocytes, nitrite or protein in urinalysis are abnormal in urine


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
D1
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
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
Urine sediment2
Only positive findings will be reported (for instance, 
the presence of sediment bacteria, casts in sediment, 
squamous epithelial cells, erythrocytes, leukocytes)
1
A: parameters to be determined at Visit 1 and EOT 
B: parameters to be determined at Visit 2 and 3 (for trial days and time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (for trial days and time points refer to Flow Chart)
D: parameters to be determined at Visit 2 (only for MD part)
2
Microscopic examination if erythrocytes, leukocytes, nitrite or protein in urinalysis are abnormal in urine
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Infectious serology is planned to be performed at screening only. Drug screening will 
be performed at screening and prior to first dose in each treatment period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B surface antibody (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
T-SPOT
Syphilis test (RPR, TP antibody method)
Imaging test
Chest x-ray (For checking onset or history of tuberculosis)
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
prior to each treatment period, and may be repeated at any time during the trial at the 
discretion of an investigator or designee. The results will not be included in the CTR.


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The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at the local 
laboratory of the trial site or/and at a CRO designated by the sponsor. Laboratory data will 
be transmitted electronically from the site to BI.
Electrocardiogram
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph at the time points given in the Flow Chart. Precise 
electrode placement will be marked with an indelible mark on the skin to allow reproducible 
placement throughout the trial.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min 
in a supine position. ECG recording will always precede all other trial 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 as print out.
Evaluation
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 trial, the QT and QTcF values generated by the computerised ECG 
system or their manual corrections by the investigators will be used. 
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the subject will be 
removed from the trial and will receive the appropriate medical treatment.


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Other safety parameters
Not applicable.
Assessment of adverse events
Definitions of adverse event
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a medicinal product and which does not 
necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable 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, medical 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 jeopardize 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 hospitalization or development of dependency or 
abuse


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The following events will be handled as ‘deemed serious for any other reason’. An AE that 
possibly leads to disability will be ‘deemed serious for any other reason’ and reported as an 
SAE.
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 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor 
and timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the electronic data capture (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 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) 
≥3 folds ULN combined with an elevation of total bilirubin ≥2 folds ULN measured in 
the same blood draw sample, or

Aminotransferase (ALT, and/or AST) elevations ≥10 folds 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 these parameters 
are analyzed, 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:


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


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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.
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 is AEs (serious and non-serious) and AESIs in 
Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial:
o
The investigator does not need to actively monitor the subject for new AEs 
but should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF


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AE reporting to 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 h) 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 a male subject has been enrolled in the clinical trial and has taken trial medication, and 
if a partner of the male subject becomes pregnant, the investigator must report any drug 
exposure during pregnancy in this partner within 24 h by means of Part A of the Pregnancy 
Monitoring Form to the sponsor’s unique entry point, after a written consent of the pregnant 
partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition
5.3.
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
Date and clock times of drug administration and pharmacokinetic sampling will be recorded
in the CRFs.
Exact times of plasma sampling will be documented in the CRFs by the medical personnel. 
The actual sampling times will be used for determination of pharmacokinetic parameters.


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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 
approximately 400 mL. Such changes would be implemented via non-substantial CTP 
Amendments.
After successful analysis, the samples may be used for further methodological investigations 
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte 
and/or its metabolite(s) including anti-drug antibodies (if applicable) will be generated by 
these additional investigations. The trial samples will be discarded after completion of the 
additional investigations, but not later than 5 years after the CTR is archived.
Methods of sample collection
Blood sampling for pharmacokinetic analysis of BI 1323495
For quantification of BI 1323495 concentrations in plasma, 3 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 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 process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 90 min, with interim storage of blood samples 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. Details on sample handling, processing and shipments are described in the lab 
manual.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. Further information such as matrix and analyte may also be
provided.
Blood sampling for pharmacokinetic analysis of itraconazole
For quantification of itraconazole concentrations in plasma, 3 mL of blood will be drawn 
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 venepuncture with a metal needle.


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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 process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 90 min, with interim storage of blood samples 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. Details on sample handling, processing and shipments are described in the lab 
manual.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, 
planned sampling time, and the analyte ‘Itra’.
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 urine containers and stored. Patients 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 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 on a sampling interval, the 
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 of using a stir bar 
or other stirring device made of PE/PP, teflon or glas). Generally, the collection container 
should be shaken upon addition of every urine fraction to ensure proper distribution of 
urine.
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
about -20 °C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory the 
urine samples will be stored at about -20 °C or below until analysis. Details on sample 
handling, processing and shipments are described in the lab manual.
At a minimum, the sample tube labels should list BI trial number, patient number, visit, and 
planned collection time. Further information, such as matrix and analyte may also be 
provided.


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5.4.
ASSESSMENT OF BIOMARKER(S) 
Biochemical and cellular biomarkers
Biomarkers will be assessed to monitor pharmacodynamic drug effects over the course of 
the observation time. Assessment of biomarkers in blood will be done in MD part. 
Direct target engagement of BI 1323495 in blood will be evaluated in MD part of the trial 
using an ex vivo NE activity assay. For timepoints where time-matched safety lab is 
available, neutrophil count will be used for normalisation of NE activity. Otherwise, the last 
timepoint with neutrophil count closest to sampling for NE activity assessment will be used 
for normalisation.
Methods of sample collection 
Blood samples will be taken at time points indicated in the Flow Chart.
A maximum of approximately 20 ml blood will be collected per biomarker sampling time-
point per subject for the pre-specified biomarker analyses. This sums up to a total blood 
volume of approximately 60 mL collected for biomarker analyses over the 3 weeks 
observational period. 
Detailed instructions for biomarker blood sampling, processing, storage and shipment of the 
different biofluids will be provided in the lab manual/site’s ISF.
Target engagement assay
For the assessment of direct target engagement of BI 1323495, at least 5 mL of blood will 
be collected at the mandated time points as stated in the Flow Chart (PD blood (NE 
activity)). At the pre-dose time point 2 x 5 mL of blood will be collected. 
PD sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK/PD data), including addition of samples 
and visits, as long as the total blood volume taken from each subject does not exceed 400 
ml. Such changes would be implemented via non-substantial CTP amendment.


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Analyses of the biomarkers will be conducted at Boehringer Ingelheim or contractors of 
Boehringer Ingelheim.
After completion of the study the samples may be used for further biomarker investigations. 
Because this analysis is explorative, result will not be share to subjects. The study samples 
will be discarded after completion of any additional investigations but not later than 5 years 
after the CTR has been signed.
5.5.
BIOBANKING
Not applicable.
5.6.
OTHER ASSESSMENTS
UGT2B17 genotyping
In this trial, all subjects will be prospectively genotyped for UGT2B17 in order to determine 
their UGT2B17 allele/copy number count and their metabolizer status (poor versus 
extensive metabolizer). Extensive metabolizers are defined by carrying at least one 
functional allele/copy (*1 allele) of the UGT2B17 gene (*1/*1 homozygous and *1/*2 
heterozygous individuals) whereas poor metabolizers are homozygous for the *2 allele, a 
non-functional deletion of the complete UGT2B17 encoding sequence, and thus lack 
expression of UGT2B17.
For this purpose, a sample of at most 9 mL of blood per subject will be taken at the 
screening examination. Genomic DNA will be extracted from blood samples according to 
standard molecular genetics methods and analyzed by TaqMan® or other standard 
genotyping technologies. Analysis will be conducted at Boehringer Ingelheim or contractors 
of Boehringer Ingelheim. The results will be available before inclusion of subjects into the 
trial and included in the final report. The result can be utilized for re-screening over 
screening period, if needed.
Collected sample and data will be managed with unique code number, therefore subject 
anonymity will be secured. As a matter of subject enrollment convenience, result will be 
informed to subject. If consent is withdrawn, all samples and the data that had already been 
collected up to the time of withdrawal of consent will still be used. The samples will not be 
stored upon completion of the genotype analysis and will be destroyed before the end of the 
clinical trial.
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
obtained at the Day 1 from each subject whose genotype has not been previously 
determined. 
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of 
drugs. 


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The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified 
by the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the 
pharmacogenomic data in the CTR. However, the data may be part of the CTR, if necessary.
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 and 
pharmacodynamic 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 and pharmacodynamic
parameters and measurements outlined in Section 5.3 are generally used assessments of 
drug exposure. 


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6.
INVESTIGATIONAL PLAN
6.1.
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Trial measurements and assessments scheduled to occur ‘before’ trial medication 
administration at Day 1 are to be performed and completed within a 3 h-period prior to the 
trial medication administration (including blank values for PK and biomarker). A blank 
urine sample for PK will be collected within 3 h before drug administration.
The acceptable deviation from the scheduled time for vital signs and ECG will be ± 10 min 
for the first 4 h after trial medication administration and ± 30 min thereafter (± 60 min for 
MD part). For laboratory test, the acceptable deviation is ± 30 min.
If several activities are scheduled at the same time point in the Flow chart, ECG should be 
the first and meal the last activity. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned individual plasma concentration sampling times and urine collection intervals, 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for 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 trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital
signs, and medical examination, refer to Sections 5.2.1 to 5.2.4. All inclusion and exclusion 
criteria will be reviewed before treatment period.
Genotyping will be performed for all subjects who will participate to treatment period (for 
details, see Section 5.6). 
Treatment period
SRD part


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Each subject will receive one dose of trial medication (BI 1323495 or placebo) at Visit 2.
Trial participants will be admitted to the trial site in the evening of Day -1 and kept under 
close medical surveillance for at least 48 h following the first drug administration. 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 trial days, subjects will be 
treated in an ambulatory fashion.
DDI part
Each subject is expected to participate in 2 treatment periods (Days -1 to 1, 2, 3, 4, 5, 6, 7 
and 8 in Period 1 and Days -3, -2, -1, 1, 2, 3, 4, 5, 6, 7 , and 8 in Period 2). At least 11 days 
will separate BI 1323495 drug administrations in the first and second treatment period.
On Day 1 of each treatment period, trial participants will be admitted to the trial site. They 
will be kept under close medical surveillance for at least 34 h following administration of 
BI 1323495, respectively. The subjects will then be allowed to leave the trial site after 
formal assessment and confirmation of their fitness. On all other trial days, subjects will be 
treated in an ambulatory fashion.
MD part
Trial participants will be admitted to the trial site in the evening of Day -1 and kept under 
close medical surveillance for at least 48 h following the first drug administration. A subject 
who is eligible for the study will be randomised on Day 1 and receive the first dose of 
BI 1323495 or placebo. For 30 mg bid group, up to Day 10, each subject will receive 
multiple bid doses of BI 1323495 or placebo, and a last single dose on Day 11. For 60 mg 
qd group, up to Day 11, each subject will receive multiple doses of BI 1323495 or placebo.
Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
 designee. 
Study participants will stay at the site under medical surveillance until Day 18. The subjects 
will then be allowed to leave the trial site after formal assessment and confirmation of their 
fitness by the investigator or 
 designee.
For details on time points and procedures for collection of plasma and urine samples for PK 
analysis, refer to Flow Chart and Section 5.3.2. 
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG, vital signs and medical examination 
during the follow-up period, see Sections 5.2.1 to 5.2.6.


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Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the End of Trial 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 End of Trial Visit 
must be followed until they have resolved, have been sufficiently characterized, or no 
further information can be obtained. 
If a subject discontinues from the trial, the subject will be followed until the investigator, or 
sub-investigator, is convinced of the subject’s safety. If follow-up is not possible or comes 
to an end, follow-up should be formally completed after discussion with the sponsor. If a 
subjectstops attending trial assessments, the investigator should assess the subject’s status as 
comprehensively as possible and the well-being of the subject should be monitored. 
However, if the subject withdraws from the trial, it is the subject’s choice whether or not to 
participate in further assessments; he cannot be compelled.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1.
STATISTICAL DESIGN – MODEL
SRD and MD part : The main objectives of SRD and MD part will be assessed by using
descriptive statistics for safety and tolerability of BI 1323495 as well as for PK parameters
and PD parameters (MD part only), which will be compared between the treatment groups.
Further analyses of these endpoints comprise the power model for assessment of dose 
proportionality. 
DDI part: The main objective of this part is to investigate the relative bioavailability of BI 
1323495 in plasma when given as oral single dose of 10 mg together with multiple doses of 
itraconazole (Test, T) as compared to when given alone as oral single dose (Reference, R) 
on the basis of the primary and secondary pharmacokinetic endpoints, as listed in Sections 
2.1.2 and 2.1.3. This part will be evaluated statistically by use of a linear model for
logarithmically transformed PK endpoints. A further objective is to evaluate and compare 
further pharmacokinetic parameters between the treatments. These pharmacokinetic 
parameters will be assessed by descriptive statistics. The assessment of safety and 
tolerability is a further objective of this part, and will be evaluated by descriptive statistics. 
7.2.
NULL AND ALTERNATIVE HYPOTHESES
SRD and MD part: Safety and tolerability of different dose groups of BI 1323495 are to be 
determined on the basis of the investigated parameters in comparison to placebo. It is not 
planned to test any statistical hypotheses with regard to these variables in a confirmatory 
sense. Instead, they will be described in their entirety and evaluated by descriptive statistical 
methods. Confidence intervals will be computed and will have to be interpreted in the 
perspective of the exploratory character of the study, i.e. confidence intervals are considered 
as interval estimates for effects.
DDI part: The relative bioavailability of BI 1323495 in plasma when given with multiple 
oral doses of itraconazole (T) versus single oral dose of BI 1323495 alone (R) will be 
estimated by the ratios of the geometric means (T/R), and their corresponding 2-sided 90% 
confidence intervals (CIs) will be provided. This method corresponds to the two one-sided t-
test procedure, each at the 5% significance level. Since the main focus is on estimation and 
not testing, a formal hypothesis test and associated acceptance range is not specified.
7.3.
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:


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
Treated set (TS): The treated set includes all subjects who were randomised (SRD
and MD part) / allocated (DDI part) and treated with at least one dose of trial 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 primary or secondary PK endpoint that was 
not excluded due to a protocol deviation relevant to the evaluation of PK or due to 
PK non-evaluability (as specified in the following subsection ‘Pharmacokinetics’).
Thus, a subject will be included in the PKS, even if he contributes only one primary 
or secondary PK parameter value for one period to the statistical assessment.
Descriptive and model-based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IQRM plan. IPDs will be identified no later than in 
the Report Planning Meeting, and the IPD categories will be updated as needed. Further 
analysis sets will be defined in TSAP, if required.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2 for BI 1323495 will be 
calculated according to BI internal SOP. Noncompartmental pharmacokinetic parameters
will be calculated based on actual sampling times using a validated pharmacokinetic 
software (e.g. Phoenix® WinNonlin®).
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 deviation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma 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

A predose concentration of BI 1323495 is >5% Cmax value of that subject in the 
respective treatment period (only DDI part).


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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.
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling 
times will be used for the calculation of pharmacokinetic parameters. Concentrations used in 
the pharmacokinetic calculations will be in the same format as in the bioanalytical report
(that is to the same number of decimal places provided in the bioanalytical report).
Primary endpoint analyses
SRD and MD part:
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.
DDI part:
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: subject and treatment. The effect 
'subject' will be considered as random, whereas the effect ‘treatment’ will be considered as 
fixed. The model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response measured on subject m receiving treatment k,
= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n,
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received treatment k,
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables. The indices ‘B’ and ‘W’ correspond to ‘between’ and ‘within’ variability, 
respectively.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1.2) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally, their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t distribution. These quantities will 


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then be backtransformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Sensitivity analysis
The same statistical model as stated above will be repeated for the primary endpoints but 
with ‘subject’ considered as fixed effects.
Further exploratory analyses
In addition to the model-based approach, all parameters will be calculated and analysed 
descriptively. Furthermore, mean plasma concentration time curves as well as individual 
profiles will be provided.
Secondary endpoint analyses
Primary analyses
The secondary endpoints (refer to Section 2.1.3) in SRD, MD and DDI parts will be 
calculated according to the BI internal SOP. They will be assessed descriptively. The 
secondary endpoint in DDI part will be assessed statistically using the same methods as 
described for the primary PK endpoints.
Further exploratory analyses
SRD part:
Dose proportionality will be explored via graphical checks and if applicable via the power 
model stated below. The analysis will be performed for the pharmacokinetic endpoints 
AUC0-∞and Cmax specified in Section 2.1.3.
The power model describes the functional relationship between the dose level and PK 
endpoint on the log scale via
 =  log (xkm) = μ +   b ∙ log (Dk) +  ekm ,
where 
ykm
logarithm of response (PK parameter) measured on subject m receiving dose 
k,
μ
the overall mean,
β
slope parameter of linear regression line,
D
level of dose k, k=1,…, 3,
ekm
the random error associated with the mth subject who was administered dose
level k where (e~!(0, ") iid).
The slope parameter β together with its two-sided 90% confidence interval will be 
estimated. Additionally, the r-fold change #$%& together with its 90% CI will be derived.
DDI part:


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The secondary endpoints AUC0-tz (refer to Section 2.1.3) will be assessed statistically using 
the same methods as described for the primary PK endpoints in Section 7.3.1.


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Safety analyses
Safety will be assessed as defined by the endpoints listed in Section 2.1.2 and 2.2.2.1 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. In SRD part, 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. In DDI part, the test treatment groups (BI 
1323495+itraconazole) will be compared to the reference group (BI 1323495 alone) 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 intake of trial medication will be 
assigned to the screening period, those between the first trial medication intake and end of 
REP (see Section 1.2.3) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
These assignments including the corresponding time intervals will be defined in detail in the 
TSAP. Note that AEs occurring after the last per protocol contact but entered before 
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-trial intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.6.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.


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Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined 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. 
Relevant ECG findings will be reported as AEs.
Pharmacokinetic - pharmacodynamic analysis (Only MD part)
The relationship of BI 1323495 plasma concentrations and biomarker results will be
investigated in an exploratory manner for the NE activity. Other correlations will be
explored as applicable.
7.4.
INTERIM ANALYSES
No interim analysis is planned.
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 BI internal SOP.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6.
RANDOMISATION
In SRD and MD part, subjects will be randomised within each dose group in a 3:1 ratio (test 
treatment to placebo). In DDI part, randomisation is not applicable, because all subjects will 
receive the same treatment in the same order.
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).


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7.7.
DETERMINATION OF SAMPLE SIZE
SRD: It is planned to include a total of 36 subjects in this trial. The planned sample size is 
not based on a power calculation. The size of 8 subjects per dose group for PM subjects (6 
on active treatment, and 2 on placebo) is commonly used in single-rising dose trials of the 
present type and is in general considered as sufficient for the exploratory evaluation of 
single dose safety and pharmacokinetics. The size of 4 subjects per dose group for EM 
subjects (3 on active treatment, and 1 on placebo) is considered sufficient for an exploratory 
analysis.
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 36, but will not exceed 48 subjects entered.
MD: It is planned to include a total of 24 subjects in this part. The planned sample size is 
not based on a power calculation. The size of 12 subjects each in theses dose groups for PM 
subjects (9 on active treatment, and 3 on placebo) is commonly used in multiple dose trials 
of the present type and is in general considered as sufficient for the exploratory evaluation 
of multiple dose safety and pharmacokinetics.
DDI: It is planned to enter 14 subjects in the DDI part, accounting for up to 2 dropouts or 
non PK evaluable subjects. The planned sample size is not based on a power calculation but 
is considered sufficient to achieve the aims of this exploratory trial.
With this sample size, the following precision in estimating the ratio of geometric means
(T/R) can be expected with 95% tolerance probability. Precision is defined as the ratio of
upper CI limit to the relative BA estimate. Note that the precision is independent of the 
actual ratio of geometric means. The observed coefficient of variation (gCV%) after a single 
oral dose of BI 1323495 (10 mg) in trial 1405-0001 was roughly 66.3% for Cmax and 104% 
for AUC. The reported variability originated from a parallel group estimates total 
variability. However, for this trial as a crossover trial intra-individual gCV is needed. 
Assuming the correlation between two responses of the same subjects ρ=0.5 for Cmax and 
ρ=0.75 for AUC, we can estimate the intraindividual variability out of the total variability. 
The calculated values would be roughly 44.7% for Cmax and 44.9% for AUC.
In the group of subjects treated with 10 mg BI 1323495 in trial 1405-0001, all individuals
were UGT2B17 extensive metabolizer, thus the calculated intra-individual variability is
representative for the subjects of this study.
The observed intra-individual coefficient of variation (gCV%) after a single oral dose of BI 
1323495 (10 mg) after fed and fasted conditions in trial 1405-0007 was roughly 35% for 
Cmax and 19% for AUC0-tz. 
For various assumptions for the gCV, Table 7.7: 1 provides an overview of the achievable
precision for estimating the ratio of geometric means (test/reference). For illustrative


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purposes, the expected 90% confidence intervals are displayed for different values of the
ratios T/R of geometric means.
Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a two-period, fixed sequence trial 
(N=12)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
30.0
1.334
100
74.99
133.36
30.0
1.334
150
112.48
200.03
30.0
1.334
200
149.98
266.71
40.0
1.459
100
68.54
145.90
40.0
1.459
150
102.81
218.85
40.0
1.459
200
137.08
291.80
50.0
1.589
100
62.93
158.91
50.0
1.589
150
94.39
238.37
50.0
1.589
200
125.85
317.83
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit upper, lower = exp (ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either
confidence interval limit on the log-scale, which was obtained from the achievable precision
on the original scale.
The calculation was performed as described by Julious (R11-5230) using R Version 3.4.2.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) 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 investigator or delegate must give a full explanation to trial subjects based on the 
subject information form. A language understandable to the subject should be chosen and 
technical terms and expressions avoided, if possible.


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The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent 
form. If a trial collaborator has given a supplementary explanation, the trial collaborator also 
signs (or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available 
and should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2.
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well 
as identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3.
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
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.


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If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date 
subject was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

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 (CRA), 
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).


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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. 
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, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in 
the ICF.
8.6.
TRIAL MILESTONES
The start of the trial is defined as the date 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.


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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.
When the trial is completed, the investigator should inform the head of the trial site in 
writing of the completion of the trial, and the head of the trial site should promptly inform 
the IRB and sponsor in writing of the completion.
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 CTL, 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 CTM, CRA and investigators of 
participating trial sites
The trial medication will be provided by the 
 
.
Safety laboratory tests will be performed by the local laboratory of the trial site.
Analyses of BI 1323495 and itraconazole concentrations and biomarker in plasma will be 
performed at the 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI. 
Data management and statistical evaluation will be done by BI or contract research 
organization 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
P02-06423
Kohri K, Ueki IF, Nadel JA. Neutrophil elastase induces mucin 
production by ligand-dependent epidermal growth factor receptor 
activation. Am J Physiol 2002; 283(3, Part 1):L531-L540.
P07-13746
Heeswijk RPG van, Bourbeau M, Campbell P, Seguin I, Chauhan BM, 
Foster BC, Cameron DW. Time-dependent interaction between 
lopinavir/ritonavir and fexofenadine. J Clin Pharmacol 46, 758-767 
(2006).
P12-10638
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions: 
final (21 June 2012, CPMP/EWP/560/95/Rev. 1). 
http://.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline
/2012/0 7/WC500129606.pdf (access date: 14 September 2012); 2012.
P15-06298
Ministry of Health, Labour and Welfare. Drug interaction guideline for 
drug development and labeling recommendations (draft). 
http://www.solvobiotech.com/documents/Japanese_DDI_guideline_(draf
t)_2014Jan.pdf (access date: 22 June 2015); Ministry of Health, Labour 
and Welfare; 2014.
P15-06991
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions (21 
June 2012, CPMP/EWP/560/95/rev. 1 corr. 2). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_gui
deline/2012/0 7/WC500129606.pdf (access date: 8 July 2015); London: 
European Medicines Agency (EMA); 2012.
P17-01597
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global 
strategy for the diagnosis, management, and prevention of chronic 
obstructive lung disease (2017 report). http://goldcopd.org/gold-2017-
global-strategy-diagnosis-management-prevention-co pd/ (accessd date: 
9 February 2017); Global Initiative for Chronic Obstructive Lung 
Disease (GOLD); 2017.
R01-0516
Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided 
in patients receiving the systemic antimycotics ketoconazole or 
itraconazole. Clin Pharmacol Ther 1994. 55(5):481-485. 
R08-1652
Kharasch ED, Bedynek PS, Walker A, Whittington D, Hoffer C. 
Mechanism of ritonavir changes in methadone pharmacokinetics and 
pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein 
activities. Clinical Pharmacology and Therapeutics, advance online 
publication 9 July 2008, doi:10.1038/clpt.2008.102 Clin Pharmacol Ther 
2008.


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R10-1102
Templeton IE, Thummel KE, Kharasch ED, Kunze KL, Hoffer C, 
Nelson WL, Isoherranen N. Contribution of itraconazole metabolites to 
inhibition of CYP3A4 in vivo. Clin Pharmacol Ther 2008; 83(1):77-85. 
Clin Pharmacol Ther 1994. 55(5):481-485.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & 
Francis Group; 2010.
R15-3252
Jalava KM, Partanen J, Neuvonen PJ. Itraconazole decreases renal 
clearance of digoxin. Ther Drug Monit 1997. 19(6):609-613.
R16-2237
Piccioni PD, Kramps JA, Rudolphus A, Bulgheroni A, Luisetti M. 
Proteinase/proteinase inhibitor imbalance in sputum sol phases from 
patients with chronic obstructive pulmonary disease: suggestions for a 
key role played by antileukoprotease. Chest 1992; 102(5):1470-1476.
R16-2239
Owen CA. Roles for proteinases in the pathogenesis of chronic 
obstructive pulmonary disease. Int J Chronic Obstruct Pulm Dis 2008; 
3(2):253-268.
R17-2928
Park JA, He F, Martin LD, Li Y, Chorley BN, Adler KB. Human 
neutrophil elastase induces hypersecretion of mucin from well-
differentiated human bronchial epithelial cells in vitro via a protein 
kinase Cdelta-mediated mechanism. Am J Pathol 2005; 167(3):651-661.
R17-2929
Vago JP, Tavares LP, Sugimoto MA, Lima GLN, Galvao I, Caiux TR 
de, et al. Proresolving actions of synthetic and natural protease inhibitors 
are mediated by annexin A1. J Immunol 2016; 196(4):1922-1932.
R17-3742
Barone JA, Moskovitz BL, Guarnieri J, Hassell AE, Colaizzi JL, 
Bierman RH, et al. Food interaction and steady-state pharmacokinetics of 
itraconazole oral solution in healthy volunteers. Pharmacotherapy 1998; 
18(2):295-301.
R17-3743
Willems L, Geest R van der, Beule K de. Itraconazole oral solution and 
intravenous formulations: a review of pharmacokinetics and 
pharmacodynamics. J Clin Pharm Ther 2001; 26:159-169.
R17-3744
Liu L, Bello A, Dresser MJ, Heald D, Komjathy SF, O'Mara E, et al. 
Best practices for the use of itraconazole as a replacement for 
ketoconazole in drug-drug interaction studies. J Clin Pharmacol 2016. 
56(2):143-151.
R18-0132
Ilumets H, Rytila PH, Sovijarvi AR, Tervahartiala T, Myllarniemi M, 
Sorsa TA, et al. Transient elevation of neutrophil proteinases in induced 
sputum during COPD exacerbation. Scand J Clin Lab Invest 2008; 
68(7):618-623.
R18-0241
Guidance for industry: clinical drug interaction studies - study design, 
data analysis, and clinical implications (draft guidance, this guidance 
document is being distributed for comment purposes only) (October 
2017, clinical 
pharmacology).https://www.fda.gov/downloads/drugs/guidances/ucm292


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362.pdf (access date: 19 January 2018); Silver Spring: U.S. Department 
of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER) 2017.
R18-2643
Sporanox 10 mg/ml oral solution (Janssen-Cilag) (summary of product 
characteristics, updated 01-Mar-2018). https://www.medicines.org.uk/
emc/product/1522/smpc/print (access date: 14 August 2018); 2018.
R18-2644
Sempera Liquid 10 mg/ml, Loesung zum Einnehmen (Janssen-Cilag) 
(Fachinformation, Stand der Information: Dezember 2017). 2017.
R19-1805
Xue et al., Adaptive Evolution of UGT2B17 Copy-Number Variation. 
Am. J. Hum. Genet. 2008; 83: 337–346
R20-1269
Itrizole oral solution 1 % (Janssen) (prescribing information, revised: 
February 2018). 2018.
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2.
UNPUBLISHED REFERENCES
c02336088
Relative bioavailability of a single oral dose of BI 691751 when 
administered alone or in combination with multiple oral doses of 
itraconazole in healthy male subjects (an open-label, randomised, 
twoperiod, two-sequence crossover study). 1334.10. 09 Jan 2015.
c03355329
, Relative bioavailability of a single oral 
dose of BI 425809 when administered alone or in combination with 
multiple oral doses of itraconazole in healthy male subjects (an open-
label, two-period, fixed-sequence trial). 1346.10. 03 Dec 2015.
c08928447
, Effect of multiple doses of itraconazole 
on the pharmacokinetics of a single oral dose of BI 1026706 in healthy 
male subjects (an open-label, randomised, two-period, two-sequence 
crossover study). 1320.20. 29 Sep 2016.
c21238478-05
Investigator’s Brochure BI 1323495. COPD. 24 Aug 2020.
c26492551
 Safety, tolerability, 
pharmacokinetics, and pharmacodynamics of single rising oral doses of 
BI 1323495 in healthy male subjects (single-blind, partially randomised, 
placebo-controlled parallel group design). Report 1405-0001. 04 
November 2019.
c27223001
Relative bioavailability of BI 1323495 following oral administration 
under fed and fasted conditions in healthy male subjects (an open-label,
randomised, single-dose, two-period, two-sequence crossover study). 
1405.0007. 21 November 2019
c29983104
Relative bioavailability of a single oral dose of BI 1323495 when
administered alone or in combination with multiple oral doses of
itraconazole in healthy male subjects (an open-label, one-way crossover 
study) 1405.0009


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10.
APPENDICES
Not applicable.  


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1.
GLOBAL AMENDMENT 1 
Date of amendment
23 SEP 2020
BI Trial number
1405-0003
BI Investigational Medicinal 
Product(s)
BI 1323495
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1323495 versus placebo in 
healthy male Japanese subjects genotyped as poor 
and extensive metabolizers of UGT2B17 (single-
blind, randomised, placebo-controlled [within dose 
groups] trial), including an investigation of drug-
drug interaction with itraconazole in healthy male 
subjects genotyped as poor metabolizers of 
UGT2B17 (an open-label, two-period, fixed 
sequence trial)
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
Section 1.4.2
Description of change
Amended description of risk mitigation action for 
COVID-19.
Rationale for change
Updated to accept other than PCR testing.
Section to be changed
Section 4.1.2
Description of change
Adding more explanation about rationale of 
selecting 10 mg for DDI part.
Rationale for change
Based on comment from authority.
Section to be changed
Section 5.6.1


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Description of change
Adding more explanation about handling of 
genotyping samples and result.
Rationale for change
Based on comment from authority.
11.2.
GLOBAL AMENDMENT 2 
Date of amendment
25 FEB 2020
BI Trial number
1405-0003
BI Investigational Medicinal 
Product(s)
BI 1323495
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses and multiple oral doses of BI 
1323495 versus placebo in healthy male Japanese 
subjects genotyped as poor and extensive 
metabolizers of UGT2B17 (single-blind,
randomised, placebo-controlled [within dose groups] 
trial), including an investigation of drug-drug 
interaction with itraconazole in healthy male 
subjects genotyped as poor metabolizers of 
UGT2B17 (an open-label, two-period, fixed 
sequence trial)
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
Flowchart 
Description of change
Minor correction due to typo to SRD part and DDI 
part.
New Flowchart for additional MD part added.
Rationale for change
Same as above
Section to be changed
Section 1.2.1
Description of change
Updated safety and PK information from ongoing 
studies (1405-0002).
Rationale for change
Updated to latest information.


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Section to be changed
Section 1.3
Description of change
Added rationale for additional MD part
Rationale for change
Same ad above
Section to be changed
Section 2
Description of change
Added endpoints for MD part including PD.
Primary end points is same with SRD part.
Secondary endpoints newly added for MD part.
PK related further objectives added for MD part.
PD endpoints in MD part added.
Rationale for change
Same as above
Section to be changed
Section 3.1, 3.2 and 3.3
Description of change
Added explanation of additional MD part study 
design.
Rationale for change
Same as above
Section to be changed
Section 4.1
Description of change
Added dose selection rationale and drug assignment 
for additional MD part
Rationale for change
Same as above
Section to be changed
Section 4.2
Description of change
Added explanation about restriction for additional 
MD part.
Rationale for change
Same as above
Section to be changed
Section 5.4.1
Description of change
Added explanation about detailed process of 
additional PD analysis for additional MD part.
Rationale for change
Same as above
Section to be changed
Section 6.2.2
Description of change
Added explanation about visit schedule of treatment 
period in additional MD part.
Rationale for change
Same as above
Section to be changed
Section 7
Description of change
Added explanation planned analysis and 
determination of sample size for additional MD part.


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Rationale for change
Same as above


 
 
 
 
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c31942019
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clinical-trial-protocol-version-03
Safety, tolerability and pharmacokinetics of single rising oral doses and multiple oral
doses of BI 1323495 versus placebo in healthy male Japanese subjects genotyped as
poor and extensive metabolizers of UGT2B17 (single-blind, randomised,
placebo-controlled [within dose groups] trial), including an investigation of
drug-drug interaction with itraconazole in healthy male subjects genotyped as ...
Author-Trial Clinical
Pharmacokineticist
11 Mar 2021 12:38 CET
Approval-Clinical Trial Leader
11 Mar 2021 12:39 CET
Approval-Therapeutic Area 
11 Mar 2021 14:05 CET
Author-Trial Statistician
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12 Mar 2021 09:32 CET
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c36762184-01
BI Trial No.:
1405-0003
Title:
Safety, tolerability and pharmacokinetics of single rising oral 
doses and multiple oral doses of BI 1323495 versus placebo in 
healthy male Japanese subjects genotyped as poor and extensive 
metabolizers of UGT2B17 (single-blind, randomised, placebo-
controlled [within dose groups] trial), including an investigation 
of drug-drug interaction with itraconazole in healthy male 
subjects genotyped as poor metabolizers of UGT2B17 (an open-
label, two-period, fixed sequence trial)
Investigational
Product:
BI 1323495
Responsible trial 
statistician:
Phone: 
Date of statistical 
analysis plan:
27 Aug 2021 SIGNED
Version:
1
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................15
6.3
SUBJECT SETS ANALYSED...........................................................................16
6.5
POOLING OF CENTRES .................................................................................17
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................18
7.
PLANNED ANALYSIS......................................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........20
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................21
7.4
PRIMARY ENDPOINTS...................................................................................21
7.4.1
Primary analysis of the primary endpoints......................................................21
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoints...............................................................................................22
7.5
SECONDARY ENDPOINTS.............................................................................23
7.5.1
Key secondary endpoints....................................................................................23
7.5.2
Secondary endpoints...........................................................................................23


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7.7
EXTENT OF EXPOSURE.................................................................................25
7.8
SAFETY ANALYSIS..........................................................................................26
7.8.1
Adverse Events ....................................................................................................26
7.8.2
Laboratory data ..................................................................................................27
7.8.3
Vital signs.............................................................................................................27
7.8.4
ECG......................................................................................................................28
7.8.5
Others...................................................................................................................28
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............29
9.
REFERENCES....................................................................................................30
11.
HISTORY TABLE..............................................................................................32


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LIST OF TABLES
Table 6.1: 1
Analysis phases and labels for statistical analyses in the SRD and MD parts.13
Table 6.1: 2
Analysis phases and labels for statistical analyses in DDI part .......................14
Table 6.3: 1
Subject sets analysed........................................................................................17
Table 11: 1
History table .....................................................................................................32


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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
AUC0-12
Area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval of 12 h after administration of the first dose
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady
state over a uniform dosing interval τ
BI 
Boehringer Ingelheim
BP
Blood pressure
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
COVID
Coronavirus disease
CRF
Case Report Form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DDI
Drug-drug interaction
ECG
Electrocardiogram
EM
Extensive metabolizer
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IPD
Important protocol deviations
IQRMP
Integrated quality and risk management plan


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Term
Definition / description
MD
Multiple doses
MedDRA
Medical Dictionary For Regulatory Activities
NE
Neutrophil Elastase
PD
pharmacodynamic
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
PM
Poor metabolizer
PR
Pulse rate
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
SRD
Single rising dose
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 protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
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 (Version 9.4 or higher, 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
or higher, 
).


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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 ENDPOINTS
Section 2.1.2 of the CTP:
SRD and MD part; The primary endpoint for assessment of safety and tolerability of BI 
1323495 is the percentage of subjects with drug-related adverse events.
DDI part; The following pharmacokinetic parameters will be determined for BI 1323495:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP:
SRD part; The following pharmacokinetic parameters will be determined if feasible:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
DDI part; The following pharmacokinetic parameters will be determined for BI 1323495 if 
feasible:

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)
MD part; The following pharmacokinetic parameters will be determined if feasible:
After the first dose of BI 1323495:

AUC0-12 (area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval of 12 h after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma after the first dose)
After the last dose of BI 1323495:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)


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


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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.
SRD part, PM: 24 subjects were planned to be treated with 

doses of 10 mg (1 x 10 mg tablet), 30 mg (3 x 10 mg tablets), or 100 mg (2 x 50 mg 
tablets) of BI 1323495 on Day 1 (test treatment)

or matching placebo (reference treatment).
SRD part, EM: 12 subjects were planned to be treated with 

doses of 30 mg (3 x 10 mg tablets), 70 mg (2 x 10 mg tablets and 1 x 50 mg tablet) or 
150 mg (3 x 50 mg tablets) of BI 1323495 on Day 1 (test treatments)

or matching placebo (reference treatment).
MD part, PM: 24 subjects were planned to be treated with 

doses of 30 mg (3 x 10 mg tablets twice daily for 10 days and single dose on Day 11) 
or 60 mg (1 x 10 mg tablet and 1 x 50 mg tablet once daily for 11 days) of BI 
1323495 (test treatment)

or matching placebo (reference treatment).
DDI part, PM: Subjects were planned to be treated with

a dose of 10 mg (1 tablet as single dose on Day 1 of period 1) of BI 1323495
(reference treatment) 

and – after a washout period of at least 11 days – doses of 10 mg (1 tablet as single 
dose on Day 1) of BI 1323495 and 200 mg of itraconazole once daily on Days -3 to 7 
(test treatment).
In the SRD and MD parts, subjects are planned to be randomised within each dose group in a 
3:1 ratio (test treatment to placebo). In the DDI part, randomisation is not applicable, because 
all subjects are planned to receive the same treatment in the same order.
The following study phases will be defined for the analysis of AEs:


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Table 6.1: 1
Analysis phases and labels for statistical analyses in the SRD and MD parts
Study 
analysis 
phase
Label
Start
End
Screening1
Screening
Date of informed consent
Date/time of first 
administration of BI 1323495
or placebo
On treatment
Placebo
SRD PM 10 mg,
SRD PM 30 mg,
SRD PM 100 mg,
SRD EM 30 mg,
SRD EM 70 mg,
SRD EM 150 mg,
MD PM 30 mg BID,
MD PM 60 mg QD,
respectively
Date/time of first 
administration of BI 1323495
or placebo
Date/time of last 
administration of BI 1323495 
or placebo + REP (7 days, i.e., 
7 * 24 h)
or
12:00 a.m. on day after last 
contact date
(whichever occurs first)
Follow-up
Placebo
F/U SRD PM 10 mg,
F/U SRD PM 30 mg,
F/U SRD PM 100 mg,
F/U SRD EM 30 mg,
F/U SRD EM 70 mg,
F/U SRD EM 150 mg,
F/U MD PM 30 mg BID,
F/U MD PM 60 mg QD,
respectively
Date/time of last 
administration of BI 1323495
or placebo + REP (7 days, i.e., 
7 * 24 h)
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.
For the DDI part of this trial, the following separate phases will be defined for the analyses of 
AEs:


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Table 6.1: 2
Analysis phases and labels for statistical analyses in DDI part
Study 
analysis 
phase
Label
Start
End
Screening1
Screening
Date of informed consent
Date/time of first 
administration of study drug
On 
treatment:
BI 
Treatment
DDI BI
Date/time of first 
administration of BI 1323495
or placebo 
Date/time of first
administration of BI 1323495 
+ REP (7 days, i.e., 7 * 24 h)
On 
treatment:
Itraconazole 
(ITZ)
DDI ITZ
Date/time of first 
administration of itraconazole
Date/time of BI 1323495 
administration in treatment 
period 2
or 
alternatively, 0:00h on the day 
after trial termination date in 
case of no further treatment
On 
treatment-
BI+ ITZ
DDI BI+ITZ
Date/time of BI 1323495 
administration in treatment 
period 2
Date/time of last 
administration of itraconazole 
+ REP (9 days, i.e., 9 * 24 h)
or
12:00 a.m. on day after last 
contact date
(whichever occurs first)
Follow-up
BI
F/U DDI BI
End of DDI BI treatment 
phase (i.e. Date/time of first 
administration of BI 1323495 
+ REP (7 days, i.e., 7 * 24 h))
First drug administration of 
itraconazole 
or 
alternatively, 0:00h on the day 
after trial termination date in 
case of no further treatment
Follow-up
BI
F/U DDI BI+ITZ
End of DDI BI+ITZ treatment 
phase (i.e. Date/time of last 
administration of itraconazole
+ REP (9 days, i.e., 9 * 24 h))
until 0:00h on the day after 
trial termination 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.
Two types of AE displays will be provided in the report:
A. Section 15.3 and Appendix 16.1.13.1.8 (only for ClinicalTrials.gov and EudraCT) of the 
CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the
study treatment (short label)). Screening and follow-up periods will not be included in
this analysis. The following totals will be provided in addition (Section 15.3 only):

a total over all on treatment phases involving BI (“Total BI”)


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
a total over all on treatment phases included in this analysis (“Total on-trt”)
B. Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of
the CTR displays:

Screening

On treatment (labelled with the name of the study treatment (short label))

Follow-up (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all on treatment phases involving BI (“Total BI”)

a total over all study phases (“Total”)
Tables of vital signs and laboratory values will present results by dose group and study 
period.
For detailed information on the handling of the treatments refer to Technical TSAP ADS plan
and Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
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).
If any IPDs are identified, they are to be summarised into categories and will be captured in 
the decision log. Categories which are considered to be IPDs in this trial are defined in the 
integrated quality and risk management plan (IQRMP). If the data show other IPDs, the 
definition in the IQRMP will be supplemented accordingly by the time of the RPM.
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 RPM, after discussion of 
exceptional cases and implications for analyses. If the data show other IPDs, this table will be 
supplemented accordingly by the time of the RPM.
Non-important COVID-19 related PDs will only be listed.


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6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:
[…]
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomised (SRD and 
MD part) / allocated (DDI part) and treated with at least one dose of trial 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 primary or secondary PK endpoint that was 
not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK 
non-evaluability (as specified in the following subsection ‘Pharmacokinetics’). Thus, 
a subject will be included in the PKS, even if he contributes only one primary or 
secondary PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.
[…]
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 deviation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma 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

A predose concentration of BI 1323495 is >5% Cmax value of that subject in the
respective treatment period (only DDI part).


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The descriptive analysis of PK concentrations and endpoints will be based on the ADS ADPC 
and ADPP, respectively, as described at the beginning of Section 7.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of PK endpoints
X
Analyses of PD endpoint
X
Safety parameters 
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
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
Section 3.3.4 of the 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 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.
Section 7.5.1 of the 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).
Missing data and outliers of PK data are handled according to BI standards (see (4) and (5)).


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Section 7.5.2 of the CTP: 
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before administration of BI 1323495 in
each treatment period. 
Section 6.1. of the CTP:
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
CTP Flow Chart.
Trial measurements and assessments scheduled to occur ‘before’ trial medication 
administration at Day 1 are to be performed and completed within a 3 h-period prior to the 
trial medication administration (including blank values for PK and biomarker). A blank urine 
sample for PK will be collected within 3 h before drug administration. 
The acceptable deviation from the scheduled time for vital signs and ECG will be ± 10 min 
for the first 4 h after trial medication administration and ± 30 min thereafter (± 60 min for 
MD part). For laboratory test, the acceptable deviation is ± 30 min.
Adherence to time windows will be checked via the consistency check listings at the RPM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (6) with the exception of those generated for PK concentrations and 
parameters following BI standards for PK/PD analysis (10).
PK evaluation will be performed by 
 and monitored by the department 
 at 
. Descriptive statistics of 
PK endpoints and plasma concentrations will be presented in Section 15.6 of the CTR.
The individual values of all subjects will be listed. Listings will be sorted by treatment group, 
subject number and visit (if visit is applicable in the respective listing). AE listings will be 
sorted by 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
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 are actual missing values. Percentages will be 


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based on all subjects in the respective subject set whether they have non-missing values or 
not.
Exclusion of PK parameters
The ADS “ADPP” (PK parameters) 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 will include parameters if they are not flagged for 
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS “ADPC” (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and 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 (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in (5) and (11).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the CTR.
Concomitant diseases will be coded according to the most recent version of Medical 
Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded using the 
World Health Organization Drug Dictionary (WHO-DD). The coding version number will be 
displayed as a footnote in the respective output. Concomitant non-drug therapies will be 
coded according to the most recent version of MedDRA.
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.


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7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP:
Compliance will be assured by administration of all trial medication in the trial site under 
supervision of the investigating physician or a designee. The measured plasma 
concentrations and/or urinary excretion of trial medication will provide additional 
confirmation of compliance. 
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see CTP Section 3.3.4.1).
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the RPM (cf. Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoints
For the SRD and MD parts of this trial, the primary endpoint for assessment of safety and 
tolerability of BI 1323495 is the percentage of subjects with drug-related AEs. The analysis 
will be based on the treated set (TS) and will be descriptive in nature. 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 treatment-emergent drug-related AEs.
For the DDI part of this trial, relative bioavailability of BI 1323495 in plasma is to be 
determined based on the primary PK endpoints AUC0-∞and Cmax on the PKS (cf. Section 
5.1).
Section 7.3.1 of the CTP:
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: subject and treatment. The effect 
'subject' will be considered as random, whereas the effect ‘treatment’ will be considered as 
fixed. The model is described by the following equation:
ykm = + sm + k + ekm, where 
ykm = logarithm of response measured on subject m receiving treatment k,
= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n,
k = the kth treatment effect, k = 1, 2,


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ekm = the random error associated with the mth subject who received treatment k,
where  ~ (0, 
) i.i.d.,  ~ (0, 
 ) i.i.d. and sm, ekm are independent random 
variables. The indices ‘B’ and ‘W’ correspond to ‘between’ and ‘within’ variability, 
respectively.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see CTP Section 2.1.2) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally, their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t distribution. These quantities will 
then be back transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
The implementation for this analysis will be accomplished by using the CSD macros based 
on PKS. The following SAS code can be used:
PROC MIXED DATA=indata;
CLASS subject treatment;
MODEL logpk = treatment / DDFM=KR;
RANDOM subject;
LSMEANS treatment / PDIFF CL ALPHA=0.1;
ESTIMATE 'T-R' treatment -1 1;
RUN;
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoints
Section 7.3.1 of the CTP: 
The same statistical model as stated above will be repeated for the primary endpoints but 
with ‘subjects’ considered as fixed effect.
The following SAS code can be used to fit the model:
PROC GLM DATA=indata;
CLASS subject treatment;
MODEL logpk = treatment subject;
LSMEANS treatment / PDIFF CL ALPHA=0.1;
ESTIMATE 'T-R' treatment -1 1;
RUN;
Section 7.3.1 of the CTP:


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In addition to the model-based approach, all parameters will be calculated and analysed 
descriptively. Furthermore, mean plasma concentration time curves as well as individual 
profiles will be provided.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
Secondary PK endpoints in all trial parts will be assessed descriptively. The secondary 
endpoint in the DDI part will be assessed statistically using the same methods as described 
for the primary PK endpoints (cf. Section 7.4.1)
Section 7.3.2. of the CTP:
SRD part (both EM and PM):
Dose proportionality will be explored via graphical checks and if applicable via the power 
model stated below. The analysis will be performed for the pharmacokinetic endpoints AUC0-
∞and Cmax specified in CTP Section 2.1.3.
The power model describes the functional relationship between the dose level and PK 
endpoint on the log scale via
 =  () =  +  ∙ () +  ,
where 
ykm
logarithm of response (PK parameter) measured on subject m receiving dose 
k,

the overall mean,
β
slope parameter of linear regression line,

level of dose k, k=1,…, 3,
ekm
the random error associated with the mth subject who was administered dose 
level k where (~(0, ) iid).
The slope parameter β together with its two-sided 90% confidence interval will be estimated. 
Additionally, the r-fold change  !" together with its 90% CI will be derived.
DDI part (only PM):
The secondary endpoints AUC0-tz (refer to CTP Section 2.1.3) will be assessed statistically 
using the same methods as described for the primary PK endpoints in Section CTP 7.3.1.
In SRD part, the dose proportionality will be assessed and reported for EM and PM subjects 
separately.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3).
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to screening, on-treatment or follow-up phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1 and 
Table 6.1:2.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of adverse events of special interest (AESIs).
Section 5.2.6.1.4 of the CTP:
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) 
≥3 folds ULN combined with an elevation of total bilirubin ≥2 folds ULN measured in the 
same blood draw sample, or

Aminotransferase (ALT, and/or AST) elevations ≥10 folds ULN.
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 System Organ 
Class (SOC) and preferred term. AEs which were considered by the investigator to be drug 
related will be summarised. Separate tables will also be provided for subjects with SAEs and
subjects with AESIs. AEs will also be summarised 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 


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by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised 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).
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the Report Planning Meeting at the latest. It is the 
Investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values in an 
automated manner will not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study
treatment) if judged clinically relevant by the investigator, and will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Unscheduled measurements of vital signs will be assigned to planned time points in the same 
way as described above for laboratory data. However, for vital signs, descriptive statistics 


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will be calculated by planned time point based on the last value of the subject at that planned 
time point (or assigned to that planned time point).
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 analysed as such.
7.8.4
ECG
Abnormal findings will be reported as baseline conditions (prior to first study drug 
administration) or as AEs (from first study drug administration onwards) if judged clinically 
relevant by the investigator. 
7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized as 
such. No separate listing or analysis of physical examination findings will be prepared.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database after completion of
enrolment, i.e. the randomization has been completed.


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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
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD)", 
current version; IDEA for CON
3
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE 
dates", current version; KMED
4
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed 
within Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
5
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMED.
6
KM Asset BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project 
Summaries", current version; KMED
7
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse 
Event Data from Clinical Trials", current version; KMED
8
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
9
KM Asset BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", 
current version; KMED
10
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics 
and Pharmacodynamic Noncompartmental Analyses”, current version, KMED.
11
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and 
PK/PD Data Files”, 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
1
27-AUG-2021
None
This is the final TSAP.