Clinical trial NCT03971539
Conditions: Asthma
Sponsor: Boehringer Ingelheim
Start date: 2019-07-15; Completion date: 2020-10-26
Enrollment: 68 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In both parts, the primary comparisons of interest are between the percentage of patients with drug-related adverse events at each dose and placebo during single and multiple dosing regimens. Based on these, the primary trial objective is to assess safety and tolerability of BI 894416 at each dose.

Secondary measures of interest are the geometric means of BI 894416 plasma AUC0-∞ and Cmax after single dose in SRD part and AUC0-8 and Cmax after single dose as well as AUCτ,ss and Cmax,ss after 7 days multiple dosing in MRD part. The objective is to assess the pharmacokinetics of BI 894416 following single and multiple administration.

Detailed description:

Arms: arm 1: Single rising dose (SRD) part: Placebo film-coated tablet matching BI 894416 taken once orally with 240 milliliter of water after an overnight fast of at least 10 hours. arm 2: Single rising dose (SRD) part: 75 milligram (mg) BI 894416 film-coated tablet taken once orally with 240 milliliter of water after an overnight fast of at least 10 hours. arm 3: Single rising dose (SRD) part: 125 milligram (mg) BI 894416 film-coated tablet taken once orally with 240 milliliter of water after an overnight fast of at least 10 hours. arm 4: Single rising dose (SRD) part: 170 milligram (mg) BI 894416 film-coated tablet taken once orally with 240 milliliter of water after an overnight fast of at least 10 hours. arm 5: Multiple rising dose (MRD) part: Placebo film-coated tablet matching BI 894416 taken for 9 days orally with 240 milliliter of water. Administration of Placebo at Day 1 and Day 9 once daily in the morning (q.d.) and at Day 2 to Day 8 three times daily at an interval of 8 hours (t.i.d.). Morning dose to be taken after an overnight fast of at least 10 hours, afternoon dose to be taken after fasting for 2 hours. arm 6: Multiple rising dose (MRD) part: 10 milligram (mg) BI 894416 film-coated tablet taken for 9 days orally with 240 milliliter of water. Administration of BI 894416 at Day 1 and Day 9 once daily in the morning (q.d.) and at Day 2 to Day 8 three times daily at an interval of 8 hours (t.i.d.). Morning dose to be taken after an overnight fast of at least 10 hours, afternoon dose to be taken after fasting for 2 hours. arm 7: Multiple rising dose (MRD) part: 25 milligram (mg) BI 894416 film-coated tablet taken for 9 days orally with 240 milliliter of water. Administration of BI 894416 at Day 1 and Day 9 once daily in the morning (q.d.) and at Day 2 to Day 8 three times daily at an interval of 8 hours (t.i.d.). Morning dose to be taken after an overnight fast of at least 10 hours, afternoon dose to be taken after fasting for 2 hours. arm 8: Multiple rising dose (MRD) part: 50 milligram (mg) BI 894416 film-coated tablet taken for 9 days orally with 240 milliliter of water. Administration of BI 894416 at Day 1 and Day 9 once daily in the morning (q.d.) and at Day 2 to Day 8 three times daily at an interval of 8 hours (t.i.d.). Morning dose to be taken after an overnight fast of at least 10 hours, afternoon dose to be taken after fasting for 2 hours. arm 9: Multiple rising dose (MRD) part: 60 milligram (mg) BI 894416 film-coated tablet taken for 9 days orally with 240 milliliter of water. Administration of BI 894416 at Day 1 and Day 9 once daily in the morning (q.d.) and at Day 2 to Day 8 three times daily at an interval of 8 hours (t.i.d.). Morning dose to be taken after an overnight fast of at least 10 hours, afternoon dose to be taken after fasting for 2 hours.
Interventions: intervention 1: BI 894416 intervention 2: Placebo
Intervention descriptions: intervention 1: BI 894416 film-coated tablet. intervention 2: Placebo film-coated tablet matching BI 894416.

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c21616656-06
EudraCT No.
2019-000805-60
BI Trial No.
1371-0008
BI Investigational 
Medicinal Product(s)
BI 894416
Title
Safety, tolerability, pharmacokinetics 
 of 
single rising oral doses and multiple rising oral doses of 
BI 894416 versus placebo in male patients with asthma (single-
blind, randomised, placebo-controlled, parallel group design).
Lay Title
Evaluation of safety and tolerability of BI 894416 in patients with 
mild asthma.
Clinical Phase
Phase Ib
Clinical Trial Leader
Phone: 
Fax: 
Principal 
Investigator
Phone 
Status
Final Protocol (Revised Protocol (based on global amendment 5))
Version and Date
Version: 6.0
Date: 14 Oct 2020
Page 1 of 120
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
05 April 2019
Revision date
14 October 2020
BI trial number
1371-0008
Title of trial
Safety, tolerability, pharmacokinetics 
 of single rising oral 
doses and multiple rising oral doses of BI 894416 versus placebo in male patients 
with asthma (single-blind, randomised, placebo-controlled, parallel group design).
Principal Investigator
Phone 
Trial site
Clinical phase
Phase Ib
Trial rationale
In this trial, safety and tolerability of BI 894416 will be assessed in patients with 
mild asthma using single rising oral doses and multiple rising oral doses
 
 
Trial objectives
To investigate safety, tolerability, pharmacokinetics 
 
following single and multiple rising doses of BI 894416
Trial endpoints
Primary endpoint to assess safety and tolerability of BI 894416 is the percentage of 
patients with drug-related adverse events
Secondary endpoints:
Efficacy Endpoints (for lung function and small airway assessment) from MRD 
part: Airway Resistance (Raw) after 7 days of treatment
Single-rising dose (SRD) part: AUC0-∞and Cmax of BI 894416
Multiple-rising dose (MRD) part:

After the first dose: AUC0-8 and Cmax of BI 894416

After the last dose: AUCτ,ss and Cmax,ss of BI 894416
Trial design
Single-blind, randomised within dose groups, placebo-controlled parallel-group 
design


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Number of patients
total entered
80*
each treatment
10 per dose group (8 on BI 894416 and 2 on placebo) for SRD and MRD part
* Additional patients may be entered to extend the number of patients within a dose 
group or 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 and exposure in the respective trial part will not be 
exceeded. Thus, the actual number of patients entered may exceed 80 (may exceed 
40 per trial part) but is not to exceed 100 (is not to exceed 50 per trial part).
Diagnosis
Patients with mild asthma
Main criteria
for inclusion
Male patients with mild asthma, age of 18 to 55 years (inclusive), body mass index 
(BMI) of 18.5 to 32 kg/m2 (inclusive)
Test product
BI 894416 as tablet formulation
dose
SRD part: 75 mg, 125 mg, 170 mg (interim dose, added based on preliminary PK 
data), 175 mg, 225 mg
MRD part: 10 mg t.i.d., 25 mg t.i.d., 50 mg t.i.d., 60 mg (interim dose, added based 
on preliminary PK data), 70 mg t.i.d.
mode of admin.
Oral with 240 mL of water
Comparator product(s)
Matching placebo(s)
dose
Not applicable
mode of admin.
Oral with 240 mL of water
Duration of treatment
BI 894416 and placebo:
Single rising dose (SRD) Part 1 day
Multiple rising dose (MRD) and 9 days
Statistical methods
Descriptive statistics will be calculated for all endpoints.


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FLOW CHARTS
SINGLE-RISING DOSE (SRD) PART – OVERVIEW
Trial Period
Screening
Treatment
Follow Up
Visit
1
2
3
4
5
6
7
8
Day 
-28 to -3
-3 to -1
1
2
3
4
5
8
15 to 17
Visit type
O
O
I
O
O
O
O
O
Informed consent1
X
Demographics2,3
X
Review of in/exclusion 
criteria
X
X
Medical History3
X
Baseline Medications
X
Reversibility Testing
X
Physical Examination
X20
X
X
X
 
Bodyplethysmography
X
X
Vital Signs5
X
X
X
X
X
X
X
Safety Laboratory test6
A
B16, 21
C,B
C
B
C
C
Drug Screening7
X
X
Cotinine Test
X
X
Stationary Admission
X
Treatment Allocation8
X
12-lead ECG9
X15
X17
X18
X18
X
X
X
Continuous ECG 
monitoring10
X
Pharmacogenomic 
sampling11
X
BI 894416 or placebo
administration8
X19
PK blood9,12
X
X
X
X
X
PD
 
PK urine13
◄-
-
-►
Adverse Events14
X
X
X
X
X
X
X
X
Concomitant Therapy14
X
X
X
X
X
X
X
X
O = Outpatient, I = Inhouse
1.
Patient must be informed and written informed consent obtained prior to starting any screening procedures.
2.
Including determination of body height and weight, smoking history and alcohol history.
3.
Data are not needed to be entered in the electronic case report form (eCRF) again if already collected and entered in 
eCRF for a previous screening for this study within 30 days before current screening.
4.
 
5.
Vital signs must be completed prior to bodyplethysmography.
6.
Letters A, B, and C describe different sets of safety laboratory examinations (see Section 5.2.4)
7.
Drug screening will be performed at screening and prior to dosing on Day 1 of visit 3. A breath alcohol test will be 
performed prior to BI 894416 or placebo administration in Visit 3, and may be repeated at any time during the study at 
the discretion of an investigator or designee.
8.
At Day 1 the following procedures must be completed prior to BI 894416 or placebo administration: Safety laboratory, 
neurological examination, Vital signs, ECG, 
 and PK samplings. The respective procedures are to be performed and 
completed within 3 h prior to BI 894416 or placebo administration. Allocation to treatment at Visit 3 could be performed 
at any time following enrolment but had to be completed prior to BI 894416 or placebo administration.
9.
PK samplings and ECGs should be done in direct sequence for matching reasons. Please refer to Flow Chart “SRD part –
Time schedule”;


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10. Continuous ECG monitoring to be done starting at least 15 minutes pre-dose of BI 894416 or placebo administration and 
for at least 4 hours following BI 894416 or placebo administration (3-lead ECG recording).
11. This sample is optional. In case a patient takes part in both a SRD and a MRD dose group only one pharmacogenomic 
sample is to be taken. The pharmacogenomics sample requires a separate consent.
12. PK samples for plasma level determination of BI 894416 
 assay are to be taken at the time 
points as outlined in Flow Chart “SRD part – Time schedule” and in Section 5.3.2.2 Sampling times and periods may be 
adapted based on information obtained during the trial (e.g. preliminary PK 
) including addition of samples 
and visits as long as the total blood volume taken does not exceed 500 mL per patient.
13. PK urine samplings for determination of BI 894416 amount eliminated in urine are to be taken at following time 
intervals: A blank urine sample is to be obtained within 3 hours prior to administration of trial medication. Other urine 
samples are to be collected over the stated post-dose intervals 0-4, 4-8, 8-12, 12-24 and 24-48 h (see Flow Chart “SRD 
part – Time schedule”; Section 5.3.2.3).
14. AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked at time points 
indicated in the Flow Chart “SRD part – Time schedule” below.
15. 12-lead ECG and rhythm strip over at least 15 min.
16. Safety laboratory to be taken and to be medically evaluated within 3 days (within 76 hours) prior to administration of BI 
894416; this ambulatory visit including safety laboratory, neurological exam, ECG and adverse event questioning can be 
omitted if the screening examination is performed on Day -3, Tables 5.2.4: 1 and 5.2.4: 2.
17. Three triplicate ECGs are recorded within approximately one hour. The recordings should be separated by at least 15 
minutes (refer to Flow Chart “SRD part – Time schedule” and Section 5.2.5.1).
18. All ECGs at this day will be done as triplicate ECG (for details refer to SRD part – Time schedule and Section 5.2.5.1).
19. Oral with 240 mL of water after an overnight fast of at least 10 h. (please also refer to Section 4.2.2.2)
20. Physical examination includes an echocardiography (stress) test in the screening period in patients aged 45 and older.
21. SARS-CoV-2 PCR Test will be done at Visit 2 only. Result must be available prior to randomization. If Visit 2 is 
omitted (see footnote 16), the test must be performed on day -3 to -1.


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SRD PART – TIME SCHEDULE
Visit
Day
Planned time (relative to BI 
894416 or placebo
administration [h:min])
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory6
PK blood 
8,9,10
PD blood assay 8,9
Physical Examination9
Neurological examination9
Vital signs (BP, PR)9,12
12-lead ECG9,10
Continuous ECG monitoring
Questioning for AEs and 
concomitant therapy16
1
-28 to -3
Screening (SCR)1
A7
X17
X
X
X
2
-3 to -1
-72:00
08:00
Ambulatory visit2
B2
X
X13
X
3
1
-3:00
06:00
Admission, 
treatment 
allocation
C7
X
X
X
X
X
X14
X15
X
0:00
08:00
BI 894416 or 
placebo 
administration3
▲
│
│
0:15
08:15
X
│
0:30
08:30
X
X
X14
│
X
0:45
08:45
X
X
│
X
1:00
09:00
X
X
X14
│
X
1:30
09:30
X
X
X14
│
2:00
10:00
240 mL fluid 
intake
X
X
X
X14
│
│
X
2:30
10:30
X
X
X14
│
3:00
11:00
X
X
X14
│
X
4:00
12:00
240 mL fluid 
intake, thereafter 
lunch4
B
X
X
X
X
X14
▼
X
6:00
14:00
X
X
X14
X
8:00
16:00
Snack (voluntary)4
X
X
X
X14
X
10:00
18:00
X
11:00
19:00
Dinner
12:00
20:00
X
X
X14
X
2
24:00
08:00
Breakfast4
C
X
X
X
X
X14
X
3
28:00
12:00
Lunch4
X
3
32:00
16:00
Snack (voluntary)
3
34:00
18:00
Discharge from 
trial site
X
X
X
X
4
3
48:00
08:00
Ambulatory visit
B
X
X
X
X
X
5
4
72:00
08:00
Ambulatory visit
X
X
X
X
6
5
96:00
08:00
Ambulatory visit
X
X
7
8
168:00
08:00
Ambulatory visit
C
X
X
8
15 to 17
Final Follow Up 
Visit5
C
X
X
X
X
X
1.
Patient must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, reversibility testing (Appendix 10.3), neurological examination, 
bodyplethysmography, 
, check of vital signs, ECG (12-lead ECG and rhythm strip over at least 15 
min), safety laboratory (including drug screening), demographics (including determination of body height and weight, 
smoking and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. 
Demographic and medical history data are not needed to be entered in the electronic case report form (eCRF) again if 


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already collected and entered in eCRF for a previous screening for this study within 30 days before current screening. 
2.
Safety laboratory to be taken and to be medically evaluated within 3 days (within 76 hours) prior to administration of BI 
894416; this ambulatory visit including safety laboratory, neurological exam, ECG and adverse event questioning can be 
omitted if the screening examination is performed on Day -3.
3.
Oral with 240 mL of water after an overnight fast of at least 10 h; (please also refer to Section 4.2.2.2)
4.
If several actions are indicated at the same time point, the intake of meals will be the last action.
5.
Final Follow up Visit includes physical examination, neurological examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies.
6.
Letters A, B and C describe different sets of safety laboratory examinations (see Section 5.2.4).
7.
Drug screening will be performed at screening and prior to dosing on Day 1 of visit 3. A breath alcohol test will be 
performed prior to BI 894416 or placebo administration at Visit 3, and may be repeated at any time during the study at 
the discretion of an investigator or designee. Pharmacogenomic samples will be collected if needed (This sample is 
optional. In case a patient takes part in both a SRD and a MRD dose group only one pharmacogenomic sample is to be 
taken.).
8.
PK samples for plasma level determination of BI 894416 
 are to be 
taken at the time points as outlined in Flow Chart “SRD part – Time schedule” and in Section 5.3.2.2 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 500 mL per patient.
9.
For allowed deviation from the scheduled time please refer to Section 6.1.
10. PK samplings and ECGs should be done in direct sequence for matching reasons.
11. PK urine samplings for determination of BI 894416 amount eliminated in urine are to be taken at following time 
intervals: A blank urine sample is to be obtained within 3 hours prior to administration of trial medication. Other urine 
samples are to be collected over the stated post-dose intervals 0-4, 4-8, 8-12, 12-24 and 24-48 h (see Flow Chart “SRD 
part – Time schedule”; Section 5.3.2.3).
12. Vital signs must be completed prior to bodyplethysmography.
13. Three triplicate ECG are recorded within approximately one hour. The recordings should be separated by at least 15 
minutes (refer to Flow Chart “SRD part – Time schedule” and to Section 5.2.5.1);
14. Triplicate ECG (refer to Flow Chart “SRD part – Time schedule” and to Section 5.2.5.1);
15. Continuous ECG monitoring to be done starting at least 15 minutes pre-dose of BI 894416 or placebo administration and 
for at least 4 hours following BI 894416 or placebo administration (3-lead ECG recording).
16. 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 “SRD part -Time schedule”.
17. Physical examination includes an echocardiography (stress) test in the screening period in patients aged 45 and older.


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MULIPLE-RISING DOSE (MRD) PART – OVERVIEW
Trial Period
Screening
Treatment
Follow Up
Visit
1
2
3
4
5
6
7
8
Day 
-28 to -3
-3 to -1
-1
1
2
3
4
5
6
7
8
9 / 
EOT
10
11
12
13
16
23 to 30
Visit type
O
O
I
O
O
O
O
O
Informed consent1
X
Demographics2,3
X
Review of in/exclusion 
criteria
X
X
Medical History3
X
Baseline Medication
X
Physical Examination
X22
X
X
X
X
X
X
Reversibility Testing4
X
Neurological examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Laboratory test6
A
B17,23
C
B
C
B
C
C
C
C
C
Drug Screening7
X
X
Cotinine Test
X
X
X
Stationary Admission
X
Discharge from site
X
Body plethysmography
X
X
X
X
12-lead ECG9
X
X18
X19
X19
X
X
X
X
X
X
X19
X19
X
X
X
X
X
Pharmacogenomic sampling10
X
Treatment Allocation11
X
BI 894416 or placebo
administration11,12
X20
X21
X21
X21
X21
X21
X21
X21
X20
PK blood9,13,14
X
X
X
X
X
X
X
X
X
X
 
PK urine15
◄-
-►
◄-
-►
Adverse Events16
X17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Therapy16
X17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
O = Outpatient, I = Inhouse, EOT = End of Treatment


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1.
Patients must be informed and written informed consent obtained prior to starting any screening procedures.
2.
Including determination of body height and weight, smoking and alcohol history.
3.
Data are not needed to be entered in the electronic case report form (eCRF) again if already collected and entered in eCRF for a previous screening for this study within 30
days before current screening.
4.
Reversibility testing (Appendix 10.3) can be omitted if patient took part in one of the SRD groups before.
5.
Vital signs must be completed prior to bodyplethysmography.
6.
Letters A, B and C describe different sets of safety laboratory examinations (see Section 5.2.4).
7.
Urine drug screening will be performed at screening and prior to dosing on Day 1 of visit 3. A breath alcohol test will be performed prior to BI 894416 or placebo
administration in Visit 3, and may be repeated at any time during the study at the discretion of an investigator or designee.
8.
 
9.
PK samplings and ECGs should be done in in direct sequence for matching reasons. Please refer to Flow Chart “MRD part – Time schedule”;
10. This sample is optional. A separate consent is required. In case a patient takes part in both a SRD and a MRD dose group only one pharmacogenomic sample is to be taken.
11. At Day 1 the following procedures must be completed prior to BI 894416 or placebo administration: Safety laboratory, neurological examination, Vital signs, ECG, PD and PK 
samplings. The respective procedures are to be performed and completed within 3 h prior to BI 894416 or placebo administration. Allocation to treatment at Visit 3 could be 
performed at any time following enrolment but had to be completed prior to BI 894416 or placebo administration.
12. BI 894416 or placebo administration at Day 1 and Day 9 once daily in the morning (qd) and at Day 2 to Day 8 three times daily at an interval of 8 hours (tid). 
13. PK samples for plasma level determination of BI 894416 
 are to be taken at the time points as outlined in Flow Chart “MRD part – Time 
schedule”; Section 5.3.2.2 and in Appendix 10.2. 
, Section 
5.3.2.2 and in Appendix 10.2. 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 500 mL per patient.
14.
15. PK urine samplings for determination of BI 894416 amount eliminated in urine are to be taken at following time intervals: A blank urine sample is to be obtained within 3 
hours 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 and 12-24h after BI 894416 or placebo administration on Day 1 and Day 9 only.
16. AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked at time points indicated in the Flow Chart “MRD part – Time schedule”.
17. Safety laboratory to be taken and to be medically evaluated within 3 days (within 76 hours) prior to administration of BI 894416; this ambulatory visit for safety laboratory and 
questioning for AEs and concomitant therapies can be omitted if the screening examination is performed on Day -3 or if lab sample can be taken on Day -1 and the lab results 
can be medically evaluated before BI 894416 or placebo administration at Day 1, Tables 5.2.4: 1 and 5.2.4: 2.
18. Three triplicate ECGs are recorded within approximately one hour. The recordings should be separated by at least 15 minutes (refer to Flow Chart “MRD part – Time schedule” 
and to Section 5.2.5.1);
19. Triplicate ECG (refer to Flow Chart “MRD part – Time schedule” and to Section 5.2.5.1);
20. Oral with 240 mL of water after an overnight fast of at least 10 h; (please also refer to Section 4.2.2.2)
21. Oral with 240 mL of water


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22. Physical examination includes an echocardiography (stress) test in the screening period in patients aged 45 and older. Assessment can be omitted if patient took part in one of 
the SRD groups before.
23. SARS-Cov-2 PCR Test will be done at Visit 2 only. Result must be available prior to randomization. Result must be available prior to randomization. If Visit 2 is omitted (see 
footnote 17), the test must be performed on day -3 to -1.


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MRD PART / TIME SCHEDULE 
Visit
Day
Planned time (relative to BI 
894416 or placebo 
administration [h:min])
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory7
PK blood
10, 11 12,13
PK urine
11 14
Physical Examination11
Neurological examination11
Bodyplethysmography and 
Vital signs (BP, PR)11
12-lead ECG 11,13
Questioning for AEs and 
concomitant therapy11,20
1
-28 to -3
Screening (SCR)1
A8
X21
X
X
X
X
2
-3 to -1
B9
X
X9
3
-1
-17:00
15:00
Admission
X
X16
X
X
X18
X
3
1
-1:00
07:00
X
X
X17
X19
X
3
1
-0:05
07:55
C8
X
3
1
0:00
08:00
BI 894416 or placebo 
administration2
▲
│
3
1
0:15
08:15
X
│
3
1
0:30
08:30
X
│
X
X19
3
1
0:45
08:45
X
│
3
1
1:00
09:00
240 mL fluid intake
X
│
X
X19
3
1
1:30
09:30
X
│
X19
3
1
2:00
10:00
X
│
│
X
X19
X
3
1
2:30
10:30
X
│
X19
3
1
3:00
11:00
240 mL fluid intake
X
│
X
X19
3
1
4:00
12:00
X
┼
X
X
X19
X
3
1
5:00
13:00
Lunch
│
3
1
6:00
14:00
X
│
X
X19
3
1
8:00
16:00
X
┼
X
X19
X
3
1
9:00
17:00
│
3
1
10:00
18:00
X
│
3
1
11:00
19:00
Dinner
│
3
1
12:00
20:00
X
┼
X
X19
X
3
2
22:30
06:30
│
X
X
X
3
2
23:00
07:00
│
3
2
23:55
07:55
B
X
│
3
2
24:00
8:00
BI 894416 or placebo
administration2
▼
X19
3
2
25:00
09:00
Breakfast
X
3
2
28:00
12:00
X
X
3
2
29:00
13:00
Lunch
3
2
32:00
16:00
BI 894416 or placebo
administration3,4
X
X
3
2
33:00
17:00
3
2
34:00
18:00
X
X
X
3
2
35:00
19:00
Dinner
3
2
40:00
24:00
BI 894416 or placebo
administration3
X
3
3
47:00
07:00
X
X
X
X
3
3
47:55
07:55
C
3
3
48:00
8:00
BI 894416 or placebo
administration2
3
3
49:00
09:00
Breakfast
X
3
3
52:00
12:00
X
X
3
3
53:00
13:00
Lunch
3
3
56:00
16:00
BI 894416 or placebo
administration3,4
X
X
X
3
3
57:00
17:00


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Visit
Day
Planned time (relative to BI 
894416 or placebo 
administration [h:min])
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory7
PK blood
10, 11 12,13
PD blood assay 10, 11
PK urine
11 14
Physical Examination11
Neurological examination11
Bodyplethysmography and 
FeNO11,15
Vital signs (BP, PR)11
Nasal Brushing11
12-lead ECG 11,13
Questioning for AEs and 
concomitant therapy11,20
3
3
58:00
18:00
X
X
X
3
3
59:00
19:00
Dinner
3
3
64:00
24:00
BI 894416 or placebo
administration3
X
3
4
70:30
06:30
X
X
X
X
3
4
71:00
07:00
X
3
4
72:00
8:00
BI 894416 or placebo 
administration2
3
4
73:00
09:00
Breakfast
X
3
4
76:00
12:00
X
X
3
4
77:00
13:00
Lunch
3
4
80:00
16:00
BI 894416 or placebo
administration3,4
X
X
X
3
4
81:00
17:00
3
4
82:00
18:00
X
3
4
83:00
19:00
Dinner
3
4
88:00
24:00
BI 894416 or placebo
administration3
X
3
5
95:00
07:00
X
X
3
5
95:55
07:55
B
X
X
3
5
96:00
8:00
BI 894416 or placebo
administration2
3
5
97:00
09:00
Breakfast
3
5
98:00
12:00
X
X
3
5
101:00
13:00
Lunch
3
5
104:00
16:00
BI 894416 or placebo
administration3,4
X
X
X
3
5
105:00
17:00
3
5
106:00
18:00
X
3
5
107:00
19:00
Dinner
3
5
112:00
24:00
BI 894416 or placebo
administration3
3
6
119:00
07:00
X
X
3
6
119:55
07:55
3
6
120:00
8:00
BI 894416 or placebo
administration2
3
6
121:00
09:00
Breakfast
3
6
124:00
12:00
X
3
6
125:00
13:00
Lunch
3
6
128:00
16:00
BI 894416 or placebo
administration3,4
X
X
X
3
6
131:00
19:00
Dinner
3
6
136:00
24:00
BI 894416 or placebo
administration3
3
7
143:00
07:00
X
X
3
7
143:55
07:55
X
X
3
7
144:00
8:00
BI 894416 or placebo
administration2
3
7
145:00
09:00
Breakfast
3
7
148:00
12:00
X
3
7
149:00
13:00
Lunch
3
7
151:55
15:55
3
7
152:00
16:00
BI 894416 or placebo
administration3,4
X
X
X


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Visit
Day
Planned time (relative to BI 
894416 or placebo 
administration [h:min])
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory7
PK blood
10, 11 12,13
PD blood assay 10, 11
PK urine
11 14
Physical Examination11
Neurological examination11
Bodyplethysmography and 
FeNO11,15
Vital signs (BP, PR)11
Nasal Brushing11
12-lead ECG 11,13
Questioning for AEs and 
concomitant therapy11,20
3
7
155:00
19:00
Dinner
3
7
159:55
23:55
3
7
160:00
24:00
BI 894416 or placebo
administration3
3
8
167:00
07:00
X
X
3
8
167:55
07:55
C
X
X
3
8
168:00
8:00
BI 894416 or placebo
administration2
3
8
169:00
09:00
Breakfast
3
8
172:00
12:00
X
3
8
173:00
13:00
Lunch
3
8
175:55
15:55
X
X
3
8
176:00
16:00
BI 894416 or placebo
administration3,4
X
X
X
3
8
179:00
19:00
Dinner
3
8
183:55
23:55
X
3
8
184:00
24:00
BI 894416 or placebo
administration3
3
9
190:30
06:30
X
X
X17
X
3
9
191:00
07:00
X16
3
9
191:55
07:55
X
X
X19
3
9
192:00
08:00
BI 894416 or placebo
administration2,5
▲
3
9
192:15
08:15
X
│
3
9
192:30
08:30
X
│
X
X19
3
9
192:45
08:45
X
│
3
9
193:00
09:00
240 mL fluid intake
X
│
X
X19
3
9
193:30
09:30
X
│
X19
3
9
194:00
10:00
X
X
│
X
X19
3
9
194:30
10:30
X
│
X19
3
9
195:00
11:00
240 mL fluid intake
X
│
X
X19
3
9
196:00
12:00
X
X
┼
X
X
X19
X
3
9
197:00
13:00
Lunch
│
3
9
198:00
14:00
X
│
X
X19
3
9
200:00
16:00
X
X
┼
X
X
X19
3
9
202:00
18:00
X
│
3
9
204:00
20:00
X
┼
X
X19
X
3
10
216:00
08:00
Discharge from site
X
X
▼
X
X
X19
X
4
11
240:00
08:00
Ambulatory Visit
C
X
X
X
X
X
5
12
264:00
08:00
Ambulatory Visit
X
X
X
X
X
6
13
288:00
08:00
Ambulatory Visit
C
X
X
X
X
7
16
Ambulatory Visit
C
X
X
X
X
X
8
23-30
Final 
Follow Up Visit6
C
X
X
X16
X17
X
X
1.
Patient must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, reversibility testing (Appendix 10.3; Reversibility testing can be omitted if 
patient took part in one of the SRD groups before), neurological examination, check of vital signs, ECG (12-lead ECG 
and rhythm strip over at least 15 min), safety laboratory (including drug screening), bodyplethysmography,
 
demographics (including determination of body height and weight, smoking and alcohol history), relevant medical 
history, concomitant therapy and review of inclusion/exclusion criteria. Demographic and medical history data are not 
needed to be entered in the electronic case report form (eCRF) again if already collected and entered in eCRF for a 
previous screening for this study within 30 days before current screening.


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2.
Oral with 240 mL of water after an overnight fast of at least 10 h; (please also refer to Section 4.2.2.2)
3.
Oral with 240 mL of water;
4.
Patient must be fasted for 2 h prior to trial medication administration. Afterwards snack (voluntary) 1 h after BI 894416 
or placebo administration (see Section 4.2.2.2); 
5.
To be done between 7-10 am
6.
Final FU Visit includes physical examination as well.
7.
Letters A, B and C describe different sets of safety laboratory examinations (see Section 5.2.4).
8.
Urine drug screening will be performed at screening and prior to dosing on Day 1 of Visit 3. A breath alcohol test will be 
performed prior to BI 894416 or placebo administration in Visit 3, and may be repeated at any time during the study at 
the discretion of an investigator or designee. Pharmacogenomic samples will be collected if needed. (This sample is 
optional. In case a patient takes part in both a SRD and a MRD dose group only one Pharmacogenomics sample is to be 
taken.).
9.
Safety laboratory to be taken and to be medically evaluated within 3 days (within 76 hours) prior to administration of BI 
894416; this ambulatory visit for safety laboratory and questioning for Aes and concomitant therapies can be omitted if 
the screening examination is performed on Day -3 or if lab sample can be taken on Day -1 and the lab results can be 
medically evaluated before BI 894416 or placebo administration at Day 1.
10. PK samples for plasma level determination of BI 894416 and 
 are to be 
taken at the time points as outlined in Flow Chart “MRD part – Time schedule”; Section 5.3.2.2 and in Appendix 10.2. 
 
Section 5.3.2.2 and in Appendix 10.2. Sampling times and periods may be adapted based on information obtained during 
the trial (e.g. preliminary PK or PD data) including addition of samples and visits as long as the total blood volume taken 
does not exceed 500 mL per patient
11. For allowed deviation from the scheduled time please refer to Section 6.1.
12.
 
13. PK samplings and ECGs should be done in direct sequence for matching reasons.
14. 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 within 3 hours 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 and 12-24 h after BI 894416 or placebo administration on Day 1 and Day 9 only.
15.
 
16. To be done between 7-10 am and at Day 9 and Visit 8 +/- 30 min of the time conducted at D-1;
17. Vital signs must be completed prior to bodyplethysmography.
18. Three triplicate ECGs are recorded within approximately one hour. The recordings should be separated by at least 15 
minutes (refer to Flow Chart “MRD part – Time schedule” and to Section 5.2.5.1); 
19. Triplicate ECG (refer to Flow Chart “MRD part – Time schedule” and to Section 5.2.5.1);
20. Aes and concomitant therapies will be recorded throughout the trial, but will be specifically asked at time points 
indicated in the “MRD part – Time schedule”
21. Physical examination includes an echocardiography (stress) test in the screening period in patients aged 45 and older.
Assessment can be omitted if patient took part in one of the SRD groups before.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHARTS.................................................................................................4
SINGLE-RISING DOSE (SRD) PART – OVERVIEW..............................................4
SRD PART – TIME SCHEDULE.................................................................................6
MULIPLE-RISING DOSE (MRD) PART – OVERVIEW.........................................8
MRD PART / TIME SCHEDULE ..............................................................................11
TABLE OF CONTENTS ................................................................................ 15
ABBREVIATIONS.......................................................................................... 20
1.
INTRODUCTION.................................................................................... 25
1.1
MEDICAL BACKGROUND............................................................................25
1.2
DRUG PROFILE...............................................................................................25
BI 894416 ...............................................................................................25
1.2.1
Residual Effect Period..........................................................................26
1.2.2
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................26
1.4
BENEFIT - RISK ASSESSMENT ...................................................................27
Expected benefit for the target indication ..........................................28
1.4.1
Procedure-related risks ........................................................................28
1.4.2
Drug-related risks and safety measures..............................................29
1.4.3
Risks related to BI 894416.......................................................29
1.4.3.1
Drug-induced liver injury ........................................................33
1.4.3.2
Summary of safety measures ...................................................33
1.4.3.3
SARS-CoV-2 and COVID-19 related risks and safety measures.....35
1.4.4
Backgound on SYK and viral infection...................................35
1.4.4.1
Risk related to compound ........................................................35
1.4.4.2
Risk related to patients with underlying conditions contracting 
1.4.4.3
COVID-19................................................................................35
Procedure-related risks.............................................................36
1.4.4.4
Overall assessment................................................................................36
1.4.5
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 38
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......38
Main objectives......................................................................................38
2.1.1
Primary endpoint..................................................................................38
2.1.2
Secondary endpoints.............................................................................38
2.1.3
Safety and tolerability..............................................................39
2.2.2.1


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 42
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................42
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................48
3.3
SELECTION OF TRIAL POPULATION ......................................................48
Main diagnosis for trial entry..............................................................49
3.3.1
Inclusion criteria...................................................................................49
3.3.2
Exclusion criteria ..................................................................................49
3.3.3
Withdrawal of patients from treatment or assessments....................51
3.3.4
Discontinuation of trial treatment............................................51
3.3.4.1
Withdrawal of consent to trial participation ............................52
3.3.4.2
Discontinuation of the trial by the sponsor..............................52
3.3.4.3
Discontinuation of the trial –Stopping rules............................52
3.3.4.4
Discontinuation of a study part (SRD, MRD) .........................53
3.3.4.5
Replacement of patients .......................................................................53
3.3.5
4.
TREATMENTS........................................................................................ 54
4.1
INVESTIGATIONAL TREATMENTS ..........................................................54
Identity of the Investigational Medicinal Products ...........................54
4.1.1
Selection of doses in the trial and dose modification .........................54
4.1.2
Method of assigning patients to treatment groups ............................57
4.1.3
Drug assignment and administration of doses for each patient .......58
4.1.4
Blinding and procedures for unblinding ............................................59
4.1.5
Blinding59
4.1.5.1
Unblinding and breaking the code...........................................60
4.1.5.2
Packaging, labelling, and re-supply ....................................................60
4.1.6
Storage conditions.................................................................................60
4.1.7
Drug accountability ..............................................................................61
4.1.8
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................61
Other treatments and emergency procedures....................................61
4.2.1
Restrictions............................................................................................62
4.2.2
Restrictions regarding concomitant treatment .........................62
4.2.2.1
Restrictions on diet and life style.............................................62
4.2.2.2
4.3
TREATMENT COMPLIANCE.......................................................................63
5.
ASSESSMENTS....................................................................................... 64
5.1
ASSESSMENT OF EFFICACY.......................................................................64
Bodyplethysmography 
64
5.1.1
5.2
ASSESSMENT OF SAFETY............................................................................64


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Medical examinations...........................................................................64
5.2.1
Neurological examination.....................................................................65
5.2.2
Vital signs...............................................................................................65
5.2.3
Safety laboratory parameters..............................................................65
5.2.4
 
12-lead resting ECG.................................................................68
5.2.5.1
Continuous ECG monitoring ...................................................70
5.2.5.2
Assessment of adverse events...............................................................71
5.2.6
Definitions of adverse events...................................................71
5.2.6.1
Adverse event ............................................................71
5.2.6.1.1
Serious adverse event ................................................71
5.2.6.1.2
AEs considered ‘Always Serious’.............................72
5.2.6.1.3
Adverse events of special interest .............................72
5.2.6.1.4
Intensity (severity) of AEs.........................................73
5.2.6.1.5
Causal relationship of AEs ........................................73
5.2.6.1.6
Adverse event collection and reporting ...................................74
5.2.6.2
AE collection.............................................................74
5.2.6.2.1
AE reporting to the sponsor and timelines ................74
5.2.6.2.2
Information required..................................................75
5.2.6.2.3
Pregnancy ..................................................................75
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................75
Assessment of pharmacokinetics .........................................................75
5.3.1
Methods of sample collection...............................................................76
5.3.2
Blood sampling for pharmacokinetic analysis.........................76
5.3.2.1
Urine sampling for pharmacokinetic analysis..........................78
5.3.2.3
5.5
BIOBANKING ...................................................................................................81
5.6
OTHER ASSESSMENTS .................................................................................81
Pharmacogenomic evaluation..............................................................81
5.6.1
Methods and timing of sample collection................................81
5.6.1.1
Analytical determinations........................................................81
5.6.1.2
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................82
6.
INVESTIGATIONAL PLAN.................................................................. 83
6.1
VISIT SCHEDULE............................................................................................83


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................84
Screening period....................................................................................84
6.2.1
Treatment period ..................................................................................85
6.2.2
Follow-up period and trial completion ...............................................85
6.2.3
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
7.3.1
Secondary endpoint analyses ...............................................................89
7.3.2
Safety analyses.......................................................................................91
7.3.4
7.4
INTERIM ANALYSES .....................................................................................92
7.5
HANDLING OF MISSING DATA ..................................................................93
Safety......................................................................................................93
7.5.1
Pharmacokinetics..................................................................................93
7.5.2
7.6
RANDOMISATION ..........................................................................................93
7.7
DETERMINATION OF SAMPLE SIZE ........................................................94
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 95
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ..........................................................................................................95
8.2
DATA QUALITY ASSURANCE .....................................................................96
8.3
RECORDS..........................................................................................................96
Source documents .................................................................................96
8.3.1
Direct access to source data and documents.......................................97
8.3.2
Storage period of records.....................................................................97
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................98
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY.......98
Collection, storage and future use of biological samples and 
8.5.1
corresponding data ...............................................................................98
8.6
TRIAL MILESTONES .....................................................................................98
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................99
9.
REFERENCES....................................................................................... 101
9.1
PUBLISHED REFERENCES.........................................................................101


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9.2
UNPUBLISHED REFERENCES...................................................................103
10. APPENDICES ........................................................................................ 104
10.1
RECRUITMENT, COHORT AND TIME-INTERVAL SCHEME ...........104
10.2
TIME SCHEDULES FOR PHARMACOKINETIK (PK) 
 
...........................................................................105
10.3
REVERSIBILITY TESTING [P05-12782]....................................................106
10.4
BODY PLETHYSMOGRAPHY MEASUREMENT TECHNIQUE AND 
SPIROMETRY ................................................................................................107
10.5
STANDARD CONVERSION TABLE FOR DIFFERENT ALCOHOL 
TYPES...............................................................................................................108
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 109
11.1
GLOBAL AMENDMENT 1 ...........................................................................109
11.2
GLOBAL AMENDMENT 2 ...........................................................................112
11.3
GLOBAL AMENDMENT 3 ...........................................................................114
11.4
GLOBAL AMENDMENT 4 ...........................................................................116
11.5
GLOBAL AMENDMENT 5 ...........................................................................120


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
 
ALCOA
attributable, legible, contemporaneous, original, accurate (dimension of 
integrity)
AMP
Auxiliary Medicinal Product
ANOVA
Analysis of variance
AUC
Area under the Curve
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
 
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at 
steady state over a uniform dosing interval τ
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUMCt1-t2
Area under the first moment curve of the analyte in plasma over the time 
interval t1 to t2
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BA
Bioavailability
b.i.d.
bis in die (twice daily dosing)
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BMS
Biomarker set
BP
Blood pressure
CA
Competent authority
CCDS
Company Core Data Sheet
 
CDISC
Clinical Data Interchange Standards Consortium 


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CI
Confidence interval
 
 
 
 
 
 
 
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state
 
 
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Clinical Trial Lead
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DDI
Drug Drug Interaction
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
electronic Case Report Form
eDC
electronic Data Capture 
EDTA
Ethylenediaminetetraacetic acid
EoT
End of Treatment
EoTrial
End of Trial
ePRO
electronic Patient Reported Outcome
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor


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FAS
Full Analysis Set
FC
Flow Chart
 
 
FEV1
Forced Expiratory Volume (Pressure) in 1 second
FOB
Faecal occult blood
FVC
Forced (expiratory) Vital Capacity
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
GINA
Global Initiative for Asthma
gMean
Geometric mean
HPC
Human Pharmacology Centre
HPLC-MS/MS
High performance liquid chromatography with tandem mass spectrometry
HR
Heart rate
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
iPD
Important protocol deviation
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
LoEE
List of Essential Element 
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose


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MST
Medical Sub Team
NOTEL
No toxic effect level
OPU
Operative Unit
PE
Polyethylene
PEF
Peak Expiratory Flow
PfOS
Powder for reconstitution of an oral solution
PFT
Pulmonary Function Test
PIB
Powder in the bottle
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
p.o.
per os (oral)
PP
Polypropylene
ppb
Parts per billion
PR
Pulse rate
PTF
Peak-Trough Fluctuation
PTS
Peak-trough swing
q.d.
quaque die (once a day)
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
Raw
Airway Resistance
REP
Residual Effect Period
RR
Respiratory rate
RV
Residual Volume
SAE
Serious Adverse Event
s.c.
subcutaneous
SCR
Screening
SMC
Safety Monitoring Committee


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SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected unexpected serious adverse reaction
SYK
Spleen Tyrosine Kinase
T
Test product or treatment
 
 
 
 
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
US PI
US Package Insert
 
 
 
 
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
BI 894416 is an oral, selective non-receptor protein tyrosine kinase SYK (spleen tyrosine 
kinase) inhibitor under clinical development for the indication of uncontrolled severe 
persistent asthma.
This trial will be performed to investigate the safety, tolerability, pharmacokinetics a
 
 of single rising oral doses and multiple rising oral doses of BI 894416 
versus placebo in male patients with mild asthma.
1.1
MEDICAL BACKGROUND
Asthma is a heterogeneous disease characterized by a chronic inflammatory process of the 
airways and driven by both the innate and adaptive immune pathways [R14-4230, 
P08-01263]. In severe asthma, the T type 2 inflammation (T2) -high and T2-low, and the 
non-T2 pathways are involved associated with a mixed pattern of inflammation involving 
eosinophil, basophil, mast, neutrophil, innate lymphoid and dendritic cells [R15-5888, R16-
0945].
SYK is a non-receptor cytoplasmic tyrosine kinase that is predominantly expressed in cells of 
hematopoietic lineage, including B cells, T cells, monocytes, NK cells, mast cells, basophils, 
and neutrophils [R15-5470]. SYK is a key component of the signal transduction associated 
with the T2-high and T2-low, and non-T2 asthma pathways that is activated through 
interaction with allergens and a number of innate and adaptive immune receptors including 
Fc receptors on basophils, mast, B- and T cells. SYK is essential for the FcεR1-mediated 
activation and degranulation of mast cells and basophils. SYK is also important in the signal 
propagation of the dectin family of innate receptors, present on macrophages, dendritic cells 
and neutrophils. Furthermore, SYK has important roles in B-cell and T-cell development, 
with partially redundant functions with Zeta-chain-associated protein kinase of 70 kDa 
(ZAP70) [R15-5470, R16-5298].
For more details on medical background see the current version of the Investigator’s 
Brochure (IB) [c03536505].
1.2
DRUG PROFILE
BI 894416
1.2.1
BI 894416 is a potent and selective inhibitor of SYK. Based on pre-clinical in vitro and in 
vivo data, SYK inhibition is expected to have effect on the non-T2 and T2 inflammatory 
pathway components of severe asthma.
So far, BI 894416 was investigated in one clinical phase I first-in-man trial (BI study number 
1371-0001) and one clinical phase I drug-drug interaction trial (BI study number 1371-0004) 
in both healthy male volunteers. In addition, the effect of a high-fat, high-calorie breakfast on 


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BI 894416 absorption is investigated in phase I trial 1371-0021 (study is ongoing at time of 
preparation of this protocol).
Trial 1371-0001 consisted of two trial parts, a single-rising dose (SRD) part and a relative 
bioavailability (rel BA) part. Single-dose treatment with up to 70 mg BI 894416 or placebo as 
oral solution in the SRD part of trial 1371-0001 as well as administration of three single 
doses (10, 10, and 40 mg BI 894416) as tablet or oral solution in the rel BA part was safe and 
well tolerated. For details on safety and tolerability as well as on pharmacokinetics and 
biomarker data of trial 1371-0001 refer to the IB [c03536505].
Trial 1371-0004 investigated the effect of strong inhibition of CYP3A and inhibition of 
P-glycoprotein on an oral single dose of BI 894416. In that trial 3 mg BI 894416 was given 
without (period 1) or together with 200 mg itraconazole q.d. (period 2; 3 days pre-treatment, 
a fourth dose of itraconazole 1 h before BI 894416, and a fifth dose of itraconazole 23 h 
following BI 894416 dosing). Preliminary PK data (based on planned time points) indicate 
that the ratios of Cmax, AUC0-tz and AUC0-∞of BI 894416 in plasma when given together with 
itraconazole and when given alone resulted in a 1.13, 1.42 and 1.43 fold increase in gMean 
exposure, respectively. BI 894416, alone or together with itraconazole, was assessed as safe 
and well-tolerated in trial 1371-0004. For more details refer to the IB [c03536505].
For a more detailed description of the BI 894416 profile, please refer to the current 
Investigator’s Brochure (IB) [c03536505].
Residual Effect Period
1.2.2
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 894416 has not been 
defined yet. However, the elimination half-life of BI 894416 is short (gMean terminal half-
life between 2.96 and 5.31 h in the SRD part of trial 1371-0001) and the mode of action is 
reversible. This suggests that the occurrence of any potential adverse effects would likely be 
limited to a short time period (i.e. few days).
Conservatively, a minimum observation period of 2 weeks after last administration with 
BI 894416 or placebo has been selected, i.e. the individual patient’s end of trial is 14 days 
following last dosing with BI 894416 or placebo at the earliest. 
All AEs reported between administration of BI 894416 and the individual patient’s end of 
trial will be counted as on-treatment AEs.
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 894416 is an oral SYK (spleen tyrosine kinase) inhibitor that is being developed for 
patients with severe asthma.
The first single rising dose study was conducted in healthy volunteers (1371-0001). In trial 
1371-0001 doses of BI 894416 up to 70 mg were given and assessed as safe and well-
tolerated. In this trial, safety and tolerability of BI 894416 will be assessed in patients with 


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asthma using single rising oral doses and multiple rising oral doses.
 
 
 
 
 
 
 
 
 
In this trial, up to 225 mg single dose and 70 mg three times a day (tid) are planned to be 
administered on the basis of calculations using the predicted systemic exposure and 
consideration of the human cap for exposure. The mean human cap for exposure (AUC0-24) 
has been set 3-fold below exposure at the dog NOAEL and 7-fold below the lowest exposure 
in dogs where neurologic effects were observed. For details on exposures, please refer to 
Section 4.1.2.
Based on its half-life, its reversible mode of action, and results from preclinical studies, BI 
894416 is not expected to have long-term effects following single dose and no expected 
carry-over effect for the minimum 21 day interval between single and multiple rising dosing. 
Therefore, for patients willing to participate in one of the MRD dose groups a previous 
participation in one dose group of the SRD part is allowed if BI 894416 has been 
administered in the SRD part more than 21 days prior to planned first administration of BI 
894416 in the MRD part.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this study is without any therapeutic benefit for patients in the single rising 
dose (SRD) portion of the study. Patients enrolled in the study will receive some benefit from 
thorough investigation of their health status including pulmonary testing, review by 
physicians experienced in respiratory medicine, a review of current medications and the 
requirement for inhaled corticosteroid use. Patients may also have some short term clinical 
benefit in the multiple rising dose (MRD) portion of the study should there be an effect on 
lung function or airway resistance. For patients beyond 44 years of age at screening, there 
will also be an assessment of stress cardiac ultrasound, which could be beneficial for 
screened (and not enrolled) patients with relevant finding, for further general medical follow-
up.
 
 


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The patients are exposed to the risks of the study procedures and the risks related to the 
exposure to the trial medication as noted below.
Expected benefit for the target indication
1.4.1
Asthma is a heterogeneous disease that is driven by the innate and adaptive immune pathway. 
In severe asthma, both the T2-high and T2-low, and the non T2 inflammation pathways are 
involved, and associated with a mixed pattern of inflammation involving eosinophil, 
basophil, mast, neutrophil, innate lymphoid and dendritic cells. Up to 50% of severe asthma 
is driven by the non T2 and/or T2-low alone or in combination with the T2-high pathway. 
This non T2 / T2-low component represents an area of unmet medical need that does not 
respond as well to high dose inhaled corticosteroids or other current controller therapy, or 
current T2-high monoclonal antibodies targeted therapies. One subgroup of steroid-resistant 
asthma includes those patients with late-onset (post-puberty), obese patients with difficult to 
treat asthma symptoms. As such, inclusion criteria have been set to allow the potential for 
patients to be included up to 55 years of age and up to BMI of 32.
Spleen tyrosine kinase (SYK) is a key component of signal transduction associated with the 
T2-high and T2-low, and non-T2 asthma pathways that is activated through interaction with 
allergens and a number of innate and adaptive immune receptors including Fc receptors on 
basophils, mast, B and T cells. SYK is also important in the signal propagation of the dectin 
family of innate receptors, present on macrophages, dendritic cells and neutrophils.
Such a therapy would meet a substantial unmet need for patients with asthma, for those with 
a non T2 and/or T2-low component, whether early/late-onset or steroid resistant, and could 
become a safe and effective alternate or add on also in T2 asthma to high dose inhaled 
corticosteroids, oral systemic corticosteroids or T2-high biological monoclonal antibodies.
Procedure-related risks
1.4.2
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
ECG electrodes may cause local and typically transient skin reactions.
The total volume of blood (including volume needed for the Platelet Function Assay) 
withdrawn during the entire study per patient will not exceed the volume of a normal blood 
donation (500 mL). No health-related risk to patients is expected from this blood withdrawal.
Patients will be followed up until 14 days after the last treatment. 
 
 
ther study 


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procedures such as spirometry, bodyplethysmography, 
 and blood pressure 
measurement are not expected to cause any adverse events.
An echocardiography (stress) test will only be performed in patients over 45 years of age.
Complications may include arrhythmias, hypotension, acute coronary syndrome, heart 
failure, light-headedness, exercise-related injury, body aches and fatigue. Acute coronary 
syndrome is rare. Complications are rare, especially with patients having no pre-existent 
reason for testing or cardiac history, both of which would have been excluded in any case.
Drug-related risks and safety measures
1.4.3
Risks related to BI 894416
1.4.3.1
No specific risk is expected in patients volunteering in this study from a point of view of age 
(specifically 45 to 55 years of age) or BMI above 29 (specifically 30 to 32) based on the 
mechanism of this drug.
Potential effects on immune cells
SYK is involved in the function of basophil, mast, neutrophil and dendritic cells. Moreover, 
SYK is implicated in the development and function of both T cells and B cells. For details 
refer to the IB [c03536505].
The risk due to effects of BI 894416 on immune cells to patients participating in this trial is 
expected to be low, for the following reasons:

Inhibition of SYK is not expected to have a negative effect with regards to the 
immune response of innate immune cells to viral or bacterial infections due to
redundancy in the infection immune response. The key neutrophil and dendritic cell 
functions most likely will be triggered by alternative pathways.

Any potential changes in T cell populations in humans related to SYK inhibition are 
expected to be reversible and are likely of a lower magnitude than what was observed 
in the rat, as the maintenance of peripheral T cells in humans is controlled primarily 
through homeostatic mechanisms that control peripheral proliferation [R17-1830]. 

Human ex vivo lymphocyte pharmacology BI 894416 data showed an offset (i.e. 
required higher exposure) for inhibition of B cell (B-cell receptor) compared to 
basophil (CD63) activation. In vitro studies showed that BI 894416 had no effect on 
B-cell proliferation or IgM expression at concentrations up to 10 µM. At higher 
concentrations, IgE production was decreased, and IgG production was increased.
Risk mitigation and monitoring: Patients with a history or diagnosis of relevant 
immunological disease will be excluded from trial participation (see Section 3.3.3). Adverse 
events will be monitored for an increase in infectious adverse events. Safety laboratory 
testing contains WBC, differential blood count, CRP, serum immunoglobulins and 
differentiation of lymphocytes (including T-cell subsets and B-cell numbers).


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Tumour biology and carcinogenicity
The SYK pathway has been hypothesized to act as both a tumour suppressor and a tumour 
promoter in different types of human cancers [R16-4459]. An increased risk of 
carcinogenic/metastatic potential in epithelial cancers has been reported in the literature 
related to SYK knock-out, but not related to SYK inhibition. Allelic deletion of SYK has 
been associated with breast adenocarcinoma [R15-4770]. However, there is no evidence that 
pharmacologic inhibition of SYK will increase carcinogenicity or metastatic risk. Preclinical 
data with a potent and selective tool SYK inhibitor, BI 1002494, are in line with an absence 
of a carcinogenic effect due to inhibition of SYK enzymatic function [n00243171]. 
Risk mitigation and monitoring: Only male patients are included in this trial. In view of the 
extended time necessary to induce a carcinogenic effect, administration of BI 894416 for up 
to 9 days is not considered a relevant carcinogenic risk to patients participating in this study. 
Accordingly, no further risk mitigation is required in this study.
Platelet aggregation and bleeding risk
A role of SYK in platelet function has been demonstrated in literature [R15-5470]. Several 
platelet functions rely on SYK signalling (e.g. collagen receptor GPVI) but others are 
independent of SYK [R16-5240]. In vitro studies using human platelets demonstrated that at 
concentrations up to 100 μM, BI 894416 had no effect on extrinsic or intrinsic coagulation 
pathways. Also, BI 894416 did not inhibit ADP-induced platelet aggregation up to 100 μM. 
However, BI 894416 inhibited collagen- and arachidonic acid-induced platelet aggregation at 
3 μM and 5 μM. However, platelet function as measured by bleeding time is not affected by a 
drug unless all the platelet pathways are inhibited due to redundancy within the system. 
Therefore, no risk for bleeding exists with regard to platelet inhibition unless a patient is also 
on another antiplatelet drug that blocks these other pathways.
Risk mitigation and monitoring: Use of any other concomitant drug that could reasonably 
inhibit platelet aggregation or coagulation (e.g. acetylsalicylic acid) will be prohibited (see 
Sections 3.3.3 and 4.2.2.1). Adverse events will be monitored for any signs of bleeding or 
bleeding-related adverse events.
Bone density
SYK is reported to be involved in osteoclast differentiation, development and function. For 
details see the IB [c03536505]. In this trial, patients are exposed to BI 894416 for only 9 
days. Due to the extremely slow turnover of bone tissue, no relevant effect on bone is 
expected with this short-term administration, and no specific monitoring of bone density is 
necessary in this trial.
Mortality / morbidity in preclinical studies
Mortality / sacrifice due to morbidity occurred in CByB6F1 non-transgenic mice and in 
Wistar Han rats. Clinical signs preceding morbidity were similar in both rodent species and 
included respiratory changes (rapid, shallow, and/or labored breathing), decreased motor 
activity, ruffled fur, hunched or prostrate posture, eye changes (squinting, discharge) and/or 


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hypothermia. One humane sacrifice due to overt neurotoxicity was done in one dog in a 3-day 
escalation study as described in the next section. Details are listed in the IB [c03536505].
Risk mitigation and monitoring: Patients will be in-house at the trial site under close medical 
observation for 34 h after administration of BI 894416 or placebo in the SRD part and during 
the administration period until 24 h after the last administration of BI 894416 or placebo in 
the MRD part. Safety laboratory will be done at pre-defined time points during the trial. Vital 
signs and ECGs will be measured frequently during the trial, and patients will be instructed to 
report AEs spontaneously and will be asked at pre-defined time points for AEs. In case of 
AEs in need of treatment, the investigator can authorise symptomatic therapy. In those cases, 
patients will be treated as necessary and, if required, kept under supervision at the trial site or 
transferred to a hospital until all medical evaluation results have returned to an acceptable 
level.
Neurotoxicity
In dog toxicology studies, acute adverse neurological effects with tremor and movement 
disorder assessed as dyskinesia (paresis / rigidity) were observed at high exposures (IB 
[c03536505]). One dog was euthanized due to overt neurotoxicity in 3-day escalation study at 
90 mg/kg/day. In dose escalation study in dogs with assessment of neurotoxicity 
[n00245394], all clinical signs of neurotoxicity were reversible with cessation of dosing. No 
structural changes were observed on histopathology. Peripheral nerve conduction velocity 
and EEG were unchanged. No specific mechanism causing the neurological effects in dogs 
has been elucidated. Therefore, it has not been determined whether the neurological changes
are species specific; however, external expert review considered this is most likely a 
channelopathy specific to dog and not likely to occur in man (see IB).
Risk mitigation and monitoring: Patients with relevant neurological disorder in the medical 
history are excluded from trial participation (see Section 3.3.3). Neurological examinations
will be performed at screening, and patients with clinically relevant findings in the 
neurological examination will be excluded from study participation (see Section 3.3.3). At 
pre-defined time points during the trial, neurological examinations will be performed. If 
necessary (investigator decision), unscheduled neurological examinations may be added at 
any time during the trial. Relevant findings in the neurological examination during the trial 
will be reported as AEs. If necessary, patients may be sent for further, more specific 
evaluation and treatment to a neurologist.
Genotoxicity, reproductive and developmental toxicity
Genetic toxicology results by weight of evidence indicate that BI 894416 is not mutagenic or 
clastogenic. In the 2-week repeat dose range finding study in male rats [n00240179], 
degeneration of spermatids of the testes was observed at ≥400 mg/kg/day, which is 
considered a secondary effect, related to overt toxicity and morbidity.
Risk mitigation: Men able to father a child must ensure that two medically approved and 
highly effective methods of birth control throughout the trial, and for a period of at least 28 
days after last trial drug intake is used. They must use one barrier method, i.e. condom or 
occlusive cap with spermicide, or vasectomized partner, and one highly effective non-barrier 


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method including oral, injected or implanted hormonal contraceptives, intrauterine device or 
system.
Female partner: WOCBP must use a highly effective method of birth control per ICH M3 
(R2) that results in a low failure rate of less than 1% per year when used consistently and 
correctly during the study, and for a period of at least 28 days after the last dose of study 
drug.
Acceptable methods of birth control for this trial are:

Combined (estrogen and progestogen containing) hormonal birth control that prevents
ovulation (oral, intravaginal, transdermal).

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable,
implantable).

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion

Vasectomised sexual partner with documented absence of sperm.
Or

Patients must abstain from male-female sex. This is defined as being in line with the
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation,
symptothermal, post-ovulation methods; declaration of abstinence for the duration of
exposure to study drug; and withdrawal are not acceptable.
Phototoxicity
Patients will be advised to avoid direct exposure to sun and UV light during the entire study 
(see Section 4.2.2.2). Further protective measures would not be necessary given the low 
phototoxic potential of BI 894416.
Potential effects on QT interval
Preclinical studies suggested no proarrhythmic potential or cardiovascular liability with 
BI 894416. However, statistical results of first-in-man trial 1371-0001 showed a slight and 
possibly dose- and concentration-dependent increase of QTcF interval. At gMean Cmax of the 
70 mg dose group, placebo- and baseline-corrected predicted mean QTcF increase was 5.9 
ms (upper limit of the 90% CI was 10.5 ms).
Risk mitigation: Patients with cardiovascular disorders, patients who used drugs that cause 
QT/QTc prolongation, patients that show a marked baseline prolongation of QT/QTc interval 
or any other relevant ECG finding at screening, and patients with a history of additional risk 
factors for Torsade de Pointes arrhythmia are excluded from trial participation (see Section 
3.3.3). Moreover, patients are in-house under close observation for 34 h following drug 
administration in the SRD part and following 24 h following last administration of BI 894416 
or placebo in the MRD part, and ECGs are done pre- and post-dose at the time points given in 
the Flow Charts.


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Drug-induced liver injury
1.4.3.2
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´
safety, see also Section 5.2.6.1.4.
Summary of safety measures
1.4.3.3
The following precautionary measures will be taken in this study in order to minimise the risk 
for patients:

Dose selection is based on safety, PK and 
results of previous first-in-man trial 
1371-0001, the mode of action, the expected pharmacologically active exposure, 
expected systemic exposures after single- and multiple-dose administration, and 
toxicity findings in preclinical studies. Escalation factor between dose steps decrease 
with increasing doses. For details see Sections 4.1.2.

A maximum acceptable human exposure has been defined for single and multiple-
dose based on toxicity findings (see Section 4.1.2). Dose escalation is guided by 
preliminary analysis of BI 894416 PK (Cmax and AUC0-24 for single dose; Cmax,ss
AUC0-24,ss for multiple dose). The exposure in the next higher single-dose group will 
be predicted based on preliminary data of the current and preceding single dose 
groups and the exposure in the next higher multiple-dose group will be predicted 
based on preliminary data of the current and preceding single-dose and multiple dose 
groups. The next higher dose level will only be administered if 
1. predicted gMean value for AUC0-24 of the next dose group does not exceed the maximum 
acceptable human exposure of 36,150 nM*h (see Section 4.1.2), 
2. the upper limit of the 95% prediction interval for AUC0-24 of individual patients in the 
next dose group does not exceed 63,000 nM*h and 3) predicted gMean value for Cmax of 
the next dose group does not exceed 5,233 nM.

SRD part only: For safety reasons, each dose group of 10 patients (8 on active and 2 
on placebo) will be divided into two cohorts of 2 patients each (1st and 2nd cohort) and 
one cohort of 6 patients (3rd cohort). The first 2 cohorts will be dosed in a single 
blinded, fixed-sequence fashion (1st cohort: ‘active – placebo’; 2nd cohort: ‘active-
active’). The 3rd cohort will consist of 5 patients on active and 1 patient on placebo 
(1st active, remaining 4 active plus 1 placebo randomised) in a single blind fashion. 
The first trial medication administration of cohort 1 and the first trial medication
administration of cohort 2 will be separated by at least 22 hours. This time interval is 
expected to be sufficient to detect relevant first acute effects of BI 894416 prior to 
dosing the second patient with BI 894416 at one dose level. The first trial medication
administration of cohort 2 and the first trial medication administration of cohort 3 will 
be separated by at least 46 hours (Section 3.1 and Appendix 10.1).

MRD part only: For safety reasons, each dose group of 10 patients (8 on active and 2 
on placebo) will be divided into two cohorts of 2 patients each (1st and 2nd cohort) and 
one cohort of 6 patients (3rd cohort). The first 2 cohorts will be dosed in a single 
blinded, fixed-sequence fashion (1st cohort: ‘active – placebo’; 2nd cohort: ‘active-
active’). The 3rd cohort will consist of 5 patients on active and 1 patient on placebo 


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(1st active, remaining 4 active plus 1 placebo randomised) in a single blind fashion. 
The first trial medication administration of cohort 1 and the first trial medication
administration of cohort 2 will be separated by at least 70 hours. The first trial 
medication administration of cohort 2 and the first trial medication administration of 
cohort 3 will be separated by at least 70 hours (Section 3.1 and Appendix 10.1).

A documented Safety Review takes place prior to next dose level, both for the MRD 
and for the SRD part. The next dose level in either part is only permitted if there are 
no safety concerns precluding the next dose level in the SRD and MRD part and if 
none of the pre-specified stopping criteria are met. The minimum time interval 
between dosing of the first patient of an SRD dose group (dose group N) and dosing 
of the first patient of the subsequent SRD dose group (dose group N+1) is at least 12 
days. The minimum time interval between first dosing of the first patient of an MRD 
dose group (dose group N) and first dosing of the first patient of the subsequent MRD 
dose group (dose group N+1) is at least 21 days. For details see Section 3.1 and 
Appendix 10.1.

Patients with relevant neurological disorder in the medical history are excluded from 
trial participation (see Section 3.3.3). Neurological examinations will be performed at 
screening, baseline and pre-defined time points during treatment (see Flow Charts and 
Section 5.2.2). Additional neurological examinations may be performed as necessary 
upon investigator judgment. If necessary, patients may be sent for further evaluation 
and treatment to a local neurologist.

Patients 45 years of age and older will be screened for potential cardiovascular issues 
at screening by an echocardiography and echocardiography stress test. These patients 
would be excluded from the trial. The procedure is implemented because of the early 
nature of this program and not because of any specific cardiac risk of this compound.

Safety laboratory examinations will be performed at pre-defined time points before 
and for at least two weeks after the last trial medication administration. These 
examinations include extensive standard safety laboratory examinations. In addition, 
immune monitoring (including white blood cell count, differential blood count, 
lymphocyte differentiation and immunoglobulins) will be included as detailed in Flow 
Charts (time points) and Section 5.2.4 (test details).

A thorough ECG and heart rate monitoring including continuous ECG monitoring for 
4 h post dose (SRD part only) and in addition frequent 12-lead ECG and vital signs 
measurements at time points as described in the Flow Chart are planned.

In the SRD part, patients will be confined for at least 34 h after study trial medication
administration to the trial site. In the MRD part, patients will be confined to the trial 
site during the administrations of BI 894416 or placebo until 24 h after the last 
administration. During in-house confinement the patients are under medical 
observation and are monitored for both expected and unexpected adverse events.

Patients with female partners of child-bearing potential must be ready and able to use 
highly effective methods of birth control per ICH M3 (R2) that result in a low failure 
rate of less than 1% per year when used consistently and correctly. A list of 
contraception methods meeting these criteria is provided in the patient information

A documented Safety Review takes place prior to start of each dose group (see 
Section 3.1).


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SARS-CoV-2 and COVID-19 related risks and safety measures
1.4.4
Backgound on SYK and viral infection
1.4.4.1

SYK-coupled immune receptors are largely restricted to the CLEC family of innate 
receptors and the Fc family of immunoglobulin-signaling receptors. There is no 
evidence in the literature suggesting that coronavirus mediated innate signaling is 
associated with SYK-coupled receptors [R20-1374].
Although some target cells (e.g. neutrophil and dendritic cells) also play a role in 
response to viral or bacterial infections, inhibition of the SYK is not expected to have 
a negative effect with regards to the immune response of innate immune cells to viral 
or bacterial infections, due to a high level of redundancy in the immune response.

Pre-clinical studies conducted in B-cells and T-cells, BI 894416 had no effect on T-
cell proliferation or activation, and only IL-2 secretion was significantly inhibited at 
concentrations relevant to estimated human efficacious exposures. BI 894416 had no 
effect on B-cell proliferation or IgM expression, but a mild effect on switching from 
IgE to IgG was observed. Preclinical safety data from a similar SYK inhibitor 
TAVALISSE (fostamatinib) did not show any effect of SYK inhibition on viral 
(influenza) clearance from the lungs of rats [R13-1374].

Safety data from a similar SYK inhibitor TAVALISSE (fostamatinib) did not show an 
overall increase in infections in Ph III 52 week studies in patients with rheumatoid 
arthritis who have not improved with disease-modifying anti-rheumatic drugs 
(DMARDs). In a study of 923 patients, serious adverse events of infections or 
infestations occurred at frequency of < 1% in any active dose arm. Other non-serious 
adverse events did not show an increased rate of infections when compared to 
placebo.
Risk related to compound
1.4.4.2
To date, 186 number of patients have been treated with BI 894416 in single or multiple dose 
studies. In the SRD healthy volunteer trial 1371-0001, one subject was reported with a severe 
AE of respiratory tract infection, which was not considered drug-related. In this SRD/MRD 
study in asthma patients, one event of upper respiratory, two events of lower respiratory tract 
infection and one event of otitis externa in 3 patients was reported. None of these events were 
serious or related to drug administration.
Based on the mode of action and available clinical data, it is not expected, that use of BI 
894416 would place healthy volunteers or asthma patients at increased risk of contracting or 
altering the response to any Coronavirus infection in general. The benefit risk of BI 894416
therefore remains unchanged in regards to the safety of the clinical trial participants.
Risk related to patients with underlying conditions contracting COVID-19
1.4.4.3
Patients with moderate to severe asthma maybe at higher risk of developing severe symptoms 
from infection with COVID-19, which can affect patients’ respiratory tract, cause an asthma 


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exacerbation, and possibly lead to pneumonia and acute respiratory disease 
(https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/asthma.html).
Treatment with BI 894416 is not known to increase this risk. Based on the mode of action 
and available clinical data, it is not expected that use of BI 894416 would place asthma 
patients at increased risk of contracting SARS-CoV-2 or would lead to a more severe disease. 
The benefit risk of BI 894416 therefore remains unchanged in regards to the safety of the 
clinical trial participants.
Procedure-related risks
1.4.4.4
For a defined period of the study, patients will be in-house at the trial site. During this phase, 
there is a potential risk for spreading the infection within a cohort or to the site staff, if an 
infected subject was enrolled into the trial. Also, there are trial procedures, e.g. collecting
blood samples, recording of ECG, or assessing vital signs, that are impossible to perform 
from a distance of 1.5 to 2 meters, which is the generally recommended distance to keep 
between humans, in order to prevent the transmission of SARS-CoV-2.
Risk mitigation: A risk management plan has been set up at the site detailing specific 
cautionary measures, e.g. hygiene rules, wearing of face masks and physical distance which 
is filed in the ISF. In addition, a screening on SARS-CoV-2 has been implemented, to be 
performed as part of the safety assessments on Day -3 to -1. Patients positive for SARS-CoV-
2 must not be randomized in accordance with exclusion criteria 4, 5, and 10. In case a 
COVID-19 infection is suspected in a patient during trial participation, SARS-CoV-2 testing 
is to be initiated without delay to enable patient exclusion or discontinuation (see withdrawal 
criteria).
Overall assessment
1.4.5
BI 894416 is a highly specific SYK inhibitor that has been adequately characterised in pre-
clinical studies. The non-clinical safety package supports administration of BI 894416 for up 
to 4 weeks duration to men. At higher exposures, dose-limiting toxicities were identified in 
the mouse, rat, and dog. These toxicities are either monitorable, reversible, or safety margins 
have been defined (see Section 4.1.2) to the maximum acceptable exposure in this study.
Data from oral administration of three SYK inhibitors other than BI 894416 are available and 
provide additional information on safety and tolerability of this class of drug in man.
Published data indicate acceptable safety and tolerability of these three other SYK inhibitors 
in healthy volunteers.
In previous first-in-man trial 1371-0001, single doses of up to 70 mg BI 894416 were given 
and were assessed as safe and well-tolerated.
Inhibition of SYK has the potential to address a substantial unmet need for patients with 
severe asthma, especially those with a non T2 and/or T2-low component, whether early/late-
onset or steroid resistant, and could become a safe and effective alternate also in T2 asthma to 
high dose inhaled corticosteroids, oral systemic corticosteroids or T2-high biological 
monoclonal antibodies.


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Transition from single dose regimen to multiple dose studies requires assessment of safety, 
tolerability and pharmacokinetics of BI 894416 in patients. 
 
 
Potential risks for the patients in relation to the COVID-19 pandemic situation have been 
evaluated together with the principle investigator. With regard to study treatment, no relevant 
impact is expected on the subject’s health condition (like e.g. increased susceptibility to 
infections, immune suppression, or impaired lung function). In the unlikely case that despite 
all implemented measures a COVID-19 case occurs in a trial participant while in the study, 
the withdrawal criterion for patients experiencing an infection has been added to also cover 
study discontinuation in case of confirmed COVID-19 disease.
To minimize the risk that infected patients spread the infection to others during the trial, 
patients are only to be admitted to the site at Visit 3, if they fulfill the strict criteria as laid out 
by the Robert Koch Institute (RKI) for allowing medical staff to return to their workplace 
(Category III persons) after having been tested SARS-CoV-2 positive, see: 
https://www.rki.de, particularly 
https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Entlassmanagement.html. 
This includes a symptom-free interval of 48 hours and a negative PCR test (see Section 
5.2.4). As RKI recommendations may be subject to change, current recommendations will be 
re-assessed on a periodic basis and trial procedures adapted accordingly, if applicable.
Considering the medical need for an effective and safe treatment of severe asthma, the benefit 
of this trial is assessed to outweigh the potential risks.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
The trial will be performed to compare several doses of BI 894416 with placebo in patients 
with mild asthma. In the first part, doses will be compared in an SRD format. In the second 
part, doses will be compared in an MRD format over 7 days.
In both parts, the primary comparisons of interest are between the percentage of patients with 
drug-related adverse events at each dose and placebo during single and multiple dosing 
regimens. Based on these, the primary trial objective is to assess safety and tolerability of BI 
894416 at each dose.
Secondary measures of interest are the geometric means of BI 894416 plasma AUC0-∞and 
Cmax after single dose in SRD part and AUC0-8 and Cmax after single dose as well as AUCτ,ss
and Cmax,ss after 7 days multiple dosing in MRD part. The objective is to assess the 
pharmacokinetics of BI 894416 following single and multiple administration.
Additional secondary measures of interest in the MRD portion of this trial are the mean 
Airway Resistance (Raw post dose) after 7 days of tid treatment at each dose and placebo of 
MRD part. The objective is to support identification of an efficacious dose in patients using 
“Raw”, a measure for airway resistance, as an outcome.
 
 
All primary and secondary comparisons will be descriptive and made on an on-treatment 
basis.
Primary endpoint
2.1.2
Primary endpoint to assess safety and tolerability of BI 894416 is the percentage of patients 
with drug-related adverse events.
Secondary endpoints
2.1.3
Efficacy Endpoints: (for lung function and small airway assessment) from MRD part:

Raw after 7 days of treatment
Pharmacokinetic Endpoints for BI 894416:
SRD part:


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
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)
MRD part:
After the first dose:

AUC0-8 (area under the concentration-time curve of the analyte in plasma over the 
time interval 0 to 8h)

Cmax (maximum measured concentration of the analyte in plasma)
After the last dose:

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)
Safety and tolerability
2.2.2.1
Safety and tolerability of BI 894416 will be assessed based on:

AEs (including clinically relevant findings from the physical examination and the 
neurological examination)

Safety laboratory tests

12-lead ECG

For the SRD part: Continuous ECG monitoring


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The 1371-0008 study is a randomised, placebo-controlled, single-blind, parallel group study 
assessing safety and tolerability as well as PK
 of single and multiple rising doses of 
BI 894416 versus placebo in patients with mild asthma. The study will be conducted at a 
single Phase I center in Germany.
A total of 32 patients will be treated with a single dose of BI 894416 in the SRD portion (Part 
1) of the trial and a total of 32 patients will be treated up to 7 days with tid dosing and 2 days 
with qd dosing of BI 894416 in the MRD portion (Part 2) of the trial. Both part 1 and part 2 
consist of 4 dose groups comprising 10 patients per group. However, the number of patients 
within a dose group may be extended or additional patients may be entered to part 1 and/or
part 2 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 patients entered may exceed 80 (may exceed 40 per 
trial part) but is not to exceed 100 (is not to exceed 50 per trial part). Such changes may be 
implemented via non-substantial CTP Amendments under the presumption that exposures 
above the previously defined limits are not exceeded (as expected for a dose escalation 
criteria).
PK 
 measures will be used to characterize the dose-exposure-response relationship 
with regards to BI 894416 plasma concentrations a
 
 Preliminary PK measure will be assessed prior to each dose escalation during 
the study to ensure that predicted gMean of Cmax of patients does not exceed 5,233 nM, 
predicted gMean values for AUC0-24 do not exceed the maximum acceptable human exposure 
of 36,150 nM*h and that the upper limit of the 95% prediction interval for AUC0-24 of 
individual patients in the next dose group does not exceed 63,000 nM*h.
 airway resistance measures will also be taken to assess early efficacy 
signals in patients at therapeutically relevant doses.
Safety Monitoring Committee (SMC) members are selected from within the trial team to 
review individual and aggregated PK and safety data at the conclusion of dosing for each 
dose group, to determine the acceptability of safety and tolerability, and recommend next 
dose level/dose escalation. Details of the SMC responsibilities and procedures are described 
in the SMC Charter.
Part 1 (SRD Portion):
Part 1 is designed as single-blind, randomised, and placebo-controlled within parallel dose 
groups.
A total of 40 male patients is planned to participate in the SRD part, according to 4 sequential 
groups comprising 10 patients per group. However, additional patients may be entered to 
allow testing of additional doses or to extend the number of patients within a dose group on 


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the basis of experience gained during the trial conduct (e.g. preliminary PK data), provided 
the planned and approved highest dose is not exceeded. Thus, the actual number of patients 
entered in the SRD part may exceed 40, but will not exceed 50 patients entered. In addition 
the dosage of the highest SRD dose group may be reduced, e.g. to ensure that predicted 
exposure is below the exposure limit (Section 4.1.2). Such changes may be implemented via 
non-substantial CTP Amendments.
In the event that a dose level needs to be given in this trial that is expected to exceed the 
exposure limits (Section 4.1.2), a thorough review of safety information obtained during the 
trial will be conducted and a substantial amendment will be submitted to CA and IEC for 
approval prior to dosing that dose level.
Within each dose group, 8 patients are planned to receive BI 894416 and 2 are planned to 
receive placebo. Only one dose is tested within each dose group. Each dose group will consist 
of 3 cohorts which will be treated subsequently for safety reasons (please also refer to Section 
4.1.4 and Appendix 10.1).
The dose groups to be evaluated are outlined in Table 3.1: 1 below. Selection of doses, the 
maximal acceptable human systemic exposure limit and the exposure multiples are described 
in Section 4.1.2.
Table 3.1: 1
SRD Dose groups
Dose Group
1
2
5
3
4
Dose [mg]
75 125
170**
175
225*
Number of patients
10 10
10
10
10
Patients receiving placebo
2
2
2
2
2
Patients receiving active drug
8
8
8
8
8
*
The dosage may be reduced to a dose >175 mg and <225 mg in case that preliminary PK analysis predict that a dose 
lower than 225 mg is needed to not exceed the limits of exposure (Section 4.1.2).
** With CTP version 3.0, an interim dose group (dose group 5) of 170 mg is inserted between dose group 2 and 3. 10 
patients will be enrolled, 2 patients receiving placebo and 8 patients receiving active drug. Enrollment follows the cohort 
scheme as described below (see also Section 4.2.1).
On the first study day of each dose level, the 1st cohort (active-placebo) will be treated in the 
following order: First patient (active – sentinel patient) followed later by the second patient 
(placebo).
The 2nd cohort (active-active) will be treated not earlier than 22 hours later (minimum time 
interval between 1st patient of 1st cohort and 1st patient of 2nd cohort).
The 3rd cohort (1st active, remaining 4 active plus 1 placebo randomised) will be treated not 
earlier than 46 hours later (minimum time interval between 1st patient of 2nd cohort and 1st
patient of 3rd cohort) to avoid an overlap.


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The dose groups will normally be investigated consecutively in ascending order of doses, 
maintaining a time interval of at least 12 days between the first trial medication 
administration in the previous dose group (dose group N) and the first trial medication 
administration of the subsequent dose group (dose group N+1). The decision to proceed to 
the next dose group will be based upon the safety, tolerability, and pharmacokinetic data of 
the preceding dose groups and will only take place once sufficient information is available 
(see below). In case a lower dose level is chosen, a non-substantial amendment may be used 
in case the previously defined exposure limits are not expected to be exceeded.
Part 2 (MRD Portion):
Part 2 is designed as single-blind, randomised, and placebo-controlled within parallel dose 
groups.
A total of 40 male patients is planned to participate in the MRD part, according to 4 
sequential groups comprising 10 patients per group. However, additional patients may be 
entered to allow testing of additional doses or to extend the number of patients within a dose 
group on the basis of experience gained during the trial conduct (e.g. preliminary PK data), 
provided the planned and approved highest dose is not exceeded. Thus, the actual number of 
patients entered in the MRD part may exceed 40, but will not exceed 50 patients entered. 
Such changes may be implemented via non-substantial CTP Amendments. In addition the 
dosage of the highest MRD dose group may be reduced, e.g. to ensure that predicted 
exposure is below the exposure limit (Section 4.1.2). The highest MRD dose might also be 
reduced to ensure that exposure covered during preceding SRD part (obtained exposure) will 
not be exceeded by predicted gMean exposure values Cmax,ss and AUC0-24,ss (Section 4.1.2).
In the event that the sponsor and SMC agree to investigate a dose level that is expected to 
exceed the exposure limits (Section 4.1.2), a thorough review of safety information will be 
conducted and a substantial amendment will be submitted to CA and IEC for approval prior 
to dosing that dose level.
Within each dose group, 8 patients are planned to receive BI 894416 and 2 are planned to 
receive placebo. Only one dose is tested within each dose group. Each dose group will consist 
of 3 cohorts which will be treated subsequently for safety reasons (please also refer to Section 
4.1.4 and Appendix 10.1).
The dose groups to be evaluated are outlined in Table 3.1: 2 below. Selection of doses, the 
maximal acceptable human systemic exposure limit and the exposure multiples are described 
in Section 4.1.2.


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Table 3.1: 2
MRD Dose groups
Dose Group
1
2
3
5
4
Dose [mg] tid
10 25
50
60**
70*
Number of patients
10 10
10
10
10
Patients receiving placebo
2
2
2
2
2
Patients receiving active drug
8
8
8
8
8
* The dosage may be reduced to a dose >50 and <70 mg tid in case that preliminary PK analysis predict that a dose lower 
than 70 mg tid is needed to not exceed the limits of exposure (Section 4.1.2) or to not exceed the exposure covered by the 
SRD part of the trial with predicted gMean Cmax,ss and AUC0-24,ss values.
** With CTP version 5.0, an interim dose group (dose group 5) of 60 mg tid is inserted between dose group 3 and 4. 10 
patients will be enrolled, 2 patients receiving placebo and 8 patients receiving active drug. Enrollment follows the cohort 
scheme as described below (see also Section 4.2.1).
On the first study day of each dose level, the 1st cohort will be treated in the following order: 
First patient (active – sentinel patient) followed by the second patient (placebo).
The 2nd cohort (active-active) will be treated not earlier than 70 hours later (minimum time 
interval between 1st patient of 1st cohort and 1st patient of 2nd cohort).
The 3rd cohort (1st active, remaining 4 active plus 1 placebo randomised) will be treated not 
earlier than 70 hours later (minimum time interval between 1st patient of 2nd cohort and 1st
patient of 3rd cohort).
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 21 days between the first trial medication administration in the 
previous dose group (dose group N) and the first trial medication administration of the 
subsequent dose group (dose group N+1). The decision to proceed to the next dose group will 
be based upon the safety, tolerability, and pharmacokinetic data of the preceding MRD dose 
group and on the data from previous SRD group and will only take place once sufficient 
information is available (see below).
Safety Monitoring Committee (SMC) before dose escalation in SRD and MRD part
Progression from one SRD dose group to the next higher SRD group and from one MRD 
group to the next higher MRD group would only be allowed after a PK and safety analysis of 
the observed results from the preceding SRD and MRD dose groups, respectively. For this a 
documented Safety Review, performed by a Safety Monitoring Committee (SMC), must take 
place prior to each dose escalation. The dose escalation decision tree (Figure 3.1:1 and 
Appendix 10.1) shows when the SRD and MRD groups can be started dependent on the 
review of previous SRD and MRD data. The next dose level will only be given if, in the 
opinion of the Principal Investigator (or an authorised deputy) and SMC, no safety concerns 
arose in the preceding dose group(s) (i.e., no dose-limiting events occurred) and if none of the 
pre-specified trial-specific stopping criteria were met (refer to Section 3.3.4.3)
(Discontinuation of the trial by the sponsor). Furthermore, an unscheduled safety review 
meeting can be requested anytime for any reasonable cause by the Principal Investigator (or 


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an authorised deputy) or the Sponsor of the study, e.g. because of any unforeseen adverse 
events, etc.
Although no formal Safety Review will be done within a dose group (e.g., between cohorts of 
the same dose level), safety will be monitored closely and continuously by the investigator 
during this trial, and an individual will only be dosed in the absence of any safety concern.
At minimum, data from six patients on active drug (BI 894416) from every required dose 
group (see Figure 3.1:1 and Appendix 10.1) need to be available for escalation to a higher 
dose / start of the next higher MRD dose group. For minimum dataset with regards to 
preliminary PK data see Section 7.4 (Preliminary PK analyses). For each safety review 
meeting, all relevant available safety data of both SRD and MRD parts should be included in 
the review. The minimum data set for dose escalation in SRD or MRD part is described 
below.
For escalation to the next higher dose in the SRD part, the minimum data set for review 
consists of the following data:

AEs in the preceding dose groups from SRD part up to at least 7 days post 
BI 894416, 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 patient to change prior to Database Lock.

Results from 12-lead ECG and continuous ECG monitoring from SRD part in the 
preceding dose groups up to at least 3 days post BI 894416 administration.

Vital signs in the preceding dose groups from SRD part up to at least 3 days post BI 
894416 administration.

Clinical laboratory tests in the preceding dose groups from SRD part up to at least 7 
days after dosing with BI 894416.

Preliminary PK data as per Section 7.4 (Preliminary PK analyses).

Check of criteria for stopping patient treatment as per Section 3.3.4.3
(Discontinuation of the trial by the sponsor)
For escalation to the next higher dose in the MRD part, the minimum data set for review 
consists of the following data:

AEs in the preceding dose groups from SRD and MRD part up to at least 7 days post 
last BI 894416 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 patient to change prior to Database Lock.

Results from 12-lead ECG (from SRD and MRD part) and continuous ECG 
monitoring (from SRD part, only) in the preceding dose groups up to at least 4 days 
(MRD part) or up to at least 3 days (SRD part) post last BI 894416 administration.

Vital signs in the preceding dose groups from SRD and MRD parts up to at least 4 
days (MRD part) or up to at least 3 days (SRD part) post last BI 894416 
administration.

Clinical laboratory tests in the preceding dose groups from SRD and MRD parts up to 
at least 7 days after last dosing with BI 894416.


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
Preliminary PK data from previous SRD and MRD parts as per Section 7.4
(Preliminary PK analyses).

Check of criteria for stopping patient treatment as per Section 3.3.4.3
(Discontinuation of the trial by the sponsor)
An overview of all relevant trial activities is provided in the Flow Charts. For visit schedules 
and details of trial procedures at selected visits, refer to Section 6 and to Flow Charts, 
respectively.
A dose-escalation decision tree for the trial is shown below in Figure 3.1:1 and Appendix 
10.1.
Figure 3.1:1
Dose group escalation overview
The figure shows the timepoints at which the SMC will assess available data from previous dose groups in order to conduct 
safety review meetings for escalation to a higher dose group in the SRD or MRD part. For more details see text in Section 
3.1 and Appendix 10.1. For each safety review meeting, all relevant available safety data of both SRD and MRD parts 
should be included in the review.
MRD 5
SRD 1 = 75 mg qd
SRD 2 = 125 mg qd
SRD 5 = 170 mg qd***
SRD 3 = 175 mg qd
SRD 4 = 225 mg qd*
MRD 1 = 10 mg tid
MRD 2 = 25 mg tid
MRD 3 = 50 mg tid
MRD 5 = 60 mg tid***
MRD 4 = 70 mg tid**


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*
SRD, 225 mg dose: The highest dose might be reduced, in case preliminary PK analysis predict that expected exposure 
would exceed exposure limit (see Section 4.1.2).
** MRD 70 mg tid: The highest MRD dose might be reduced, in case preliminary PK analysis predict that expected 
exposure would exceed exposure limit (see Section 4.1.2) or to ensure that exposure covered during preceding SRD part 
will not be exceeded by the predicted gMean Cmax and AUC0-24 values.
***interim dose group added based on preliminary PK data (see also Section 4.2.1).
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
For single- and multiple-rising dose trials, the sequential rising dose design described in 
Section 3.1 is viewed favourably under the provision not to expose the patients involved to 
undue risks.
Single-blind conditions regarding the patient’s treatment (active or placebo) are maintained 
within each dose group. However, patients and investigators will be aware of the dose of BI 
894416 administered. The disadvantage of the trial design is a possible observer bias with 
regard to the dose-dependent effects; in addition, the sequential dosing of groups could 
potentially result in time-related effects. However, as such effects are expected to be small 
relative to the differences between the doses in the broad range investigated, unbiased 
comparisons between treatments can still be expected.
It is standard in single and multiple rising dose trials to include a placebo group to control for 
safety, tolerability,
of the trial medication. Each dose group 
consists of 10 patients, with 8 on active treatment, and 2 on placebo. For data analysis 
purposes, the placebo control group will include all patients of all dose groups treated with 
placebo. Eight patients per active treatment group are generally considered to be sufficient for 
the exploratory evaluation of pharmacokinetics.
3.3
SELECTION OF TRIAL POPULATION
Only male patients will be included in the trial because no data on reproductive toxicology 
are available at this time and because, until availability of the results of the 26-week 
Tg.rasH2 carcinogenicity study, study populations are restricted to male patients (see IB 
c03536505). It is planned that approximately 80 male patients in total will enter the study.
The actual number of patients entered may exceed the total of 80 if additional intermediate or 
lower doses are tested or if number of patients of a dose group is extended (see Section 3.1).
 
 In addition, the target 
patient population may allow for an early clinical read-out of efficacy from the MRD 
portion e.g. changes in airway resistance (Raw), 
 
 Assessment of safety in a patient population is 
considered more relevant for subsequent studies in the development program.
A log of all patients 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.


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Main diagnosis for trial entry
3.3.1
Outpatients with a history of asthma are eligible for inclusion if they meet all the inclusion 
criteria (Section 3.3.2) and none of the exclusion criteria (Section 3.3.3). Please refer to 
Section 8.3.1 (Source Documents) for the documentation requirements pertaining to the in-
and exclusion criteria.
Patients may participate once in the SRD and once in the MRD portions of the study (for 
details see exclusion criterion #13).
Inclusion criteria
3.3.2
Patients will only be included into the trial, if they meet the following criteria:
1. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial. Medication washout and medication restrictions 
according to protocol are allowed only after informed consent is obtained.
2. Male patients aged at least 18 years but not more than 55 years at the time of informed 
consent. 
3. Men able to father a child must be ready and able to use highly effective methods of birth 
control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when 
used consistently and correctly. A list of contraception methods meeting these criteria is 
provided in the patient information.
4. Pre-bronchodilator clinic measured FEV1 of ≥ 70% of predicted normal at the screening 
visit (Visit 1). Calculations will be based on Global Lung Function Initiative (GLI) 
formula (R15-0845).
5. A diagnosis of asthma, diagnosed by a physician.
6. Patients should be non-smokers or ex-smokers who stopped smoking at least 12 weeks 
prior to screening and are expected to be able to not smoke for the duration of the study. 
7. Patients must be able to perform all trial related procedures including pulmonary function 
tests, nasal brushings.
8. BMI of 18.5 to 32 kg/m2 (incl.)
9. For MRD part: Patients are allowed to be on stable inhaled low dose corticosteroid 
(please refer to GINA guidelines) for at least 4 weeks prior to screening.
Exclusion criteria
3.3.3
Patients will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR, echocardiography and 
echocardiography stress test or ECG and including the neurological examination) is 
deviating from normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. 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 judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular (stress), metabolic, 
immunological or hormonal disorders
6. Relevant abnormality on stress echocardiography for those 45 of age and older at 
screening.
7. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
8. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
9. History of relevant orthostatic hypotension, fainting spells, or blackouts
10. Chronic or relevant acute infections
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients)
12. Use of drugs within 30 days prior to administration of trial medication that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
13. Participation in another trial where an investigational drug other than BI 894416 has been 
administered within 60 days or 5 half-lives (whichever is greater) prior to planned 
administration of trial medication, or current participation in another trial involving 
administration of investigational drug. In case of planned participation in the MRD part in 
this trial the previous participation in one dose group of the SRD part is allowed if BI 
894416 has been administered more than 21 days prior to planned administration of BI 
894416 in the MRD part. (Participation in an SRD dose group after the patient has 
participated in the MRD part is not allowed.)
14. Alcohol abuse (consumption of more than 24 g per day) (please refer to Appendix 10.5)
15. Drug abuse or positive drug screening
16. Blood donation of more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
17. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
18. Inability to comply with dietary regimen of trial site
19. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
20. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome) 
21. Patient unable or unwilling to comply with study requirements, or has a condition that 
would not allow safe participation in the study 
22. History of relevant neurological disorder affecting the peripheral or central nervous 
system (this includes, but is not limited to: stroke, epilepsy, inflammatory or atrophic 
diseases affecting the nervous system, cluster headache or any cancer of the nervous 
system)*
23. History of immunological disease except allergy not relevant to the trial (such as mild 
hayfever or dust mite allergy) and except asthma in childhood or adolescence


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24. History of cancer (other than successfully treated basal cell carcinoma)
25. Use of any drug that could reasonably inhibit platelet aggregation or coagulation (e.g. 
acetylsalicylic acid) within 10 days prior to administration of trial medication, or planned 
use during the trial or within 7 days after last dose of trial medication.
* Febrile seizures in childhood or adolescence, recovered carpal tunnel syndrome, recovered uncomplicated meningitis, 
recovered herpes zoster, tension headache, occasional benign tics (e.g. due to stress) or minor par- or dysesthesia (e.g. as a 
side effect of prior blood withdrawal) do not constitute a history of relevant neurological disorder.
For study restrictions, refer to Section 4.2.2.
Withdrawal of patients from treatment or assessments
3.3.4
Patients 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 patient is removed from or withdraws from the trial prior to the first administration of 
trial medication, at least the basic information of this patient will be entered in the case report 
form (eCRF). The minimum requirements to enter in eCRF will be listed in an ´eCRF 
instruction guide´.
At the time of discontinuation, a complete end of trial examination will be performed, if 
possible, and the information will be recorded in the eCRF.
Discontinuation of trial treatment
3.3.4.1
An individual patient must discontinue trial treatment if:
1. The patient withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication
3. The patient is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)
4. One adverse event of severe intensity or one SAE occurs. 
5. The patient 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) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
6. The patient experiences an infection with SARS-CoV-2 (as confirmed by PCR testing, 
see Section 5.2.4).
In addition to these criteria, the physician may discontinue patients at any time based on his 
or her clinical judgment.
A patient can also be removed from the trial if eligibility criteria are being violated or if the 
patient fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).


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If a patient is removed from or withdraws from the trial prior to administration of trial 
medication, basic data of this patient will be entered in the case report form (eCRF) or trial 
database and will not be reported in the clinical trial report (CTR).
If a patient is removed from or withdraws from the trial after first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the eCRF. In this case, the data will be included in the eCRF/trial database 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 eCRFs. These 
discontinuations will be discussed in the CTR.
Even if the trial treatment is discontinued, the patient remains in the trial and, given his 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Charts and Section 6.2.3.
Withdrawal of consent to trial participation
3.3.4.2
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a patient wants to withdraw consent, the investigator should be 
involved in the discussion with the patient 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
3.3.4.3
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk assessment. More specifically, the trial will be terminated if more than 50% 
of the actively dosed patients 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.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP or the CTP by a trial site or investigator, disturbing the appropriate 
conduct of the trial
The sponsor decides to discontinue the further development of the investigational product.
Discontinuation of the trial –Stopping rules
3.3.4.4
1. Dose escalation will be stopped as soon as at least 2 patients at one dose level on active 
drug showed relevant individual QT prolongation, i.e. absolute QT or QTc greater than 
500 ms or a QTc increase of greater 60 ms from baseline, which has been confirmed by a 
repeat ECG recording.
2. Dose escalation in the respective trial part will be stopped if the estimated systemic 
exposure of the next dose level is expected to exceed Cmax of 5233 nM (group gMean 
values), AUC0-24 of 36,150 nM·h, (group gMean values) or 63,000 nM*h (for the 95th


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percentile of any given patient in the next dose group). In this case, an interim dose level 
lower than the planned next dose level may be given, or the highest dose group of the 
SRD and/or MRD part may be reduced, or additional patients may be entered in the 
current dose group, as long as the expected systemic exposure is not expected to exceed 
the above mentioned levels. Alternatively, the next dose level may be given if the 
previous dose levels are deemed safe after thorough review and after a substantial 
amendment has been approved by both competent authority and IEC.
3. Dose escalation to the highest dose group (70 mg tid) in the MRD part will not be done if 
the estimated systemic exposure (gMean Cmax,ss or AUC0-24,ss) is expected to exceed the 
plasma exposure levels observed in the SRD part of the trial. In this case, the dose of the 
highest MRD dose group may be reduced to a dose >50 mg and <70 mg tid as long as the 
expected systemic exposure (gMean Cmax,ss and AUC0-24,ss) is covered by the 
(preliminary) values measured in the SRD part (Section 4.1.2).
Discontinuation of a study part (SRD, MRD)
3.3.4.5
Dose escalation from an interim dose to the next planned dose level might be stopped, if the 
next dose level is not considered to contribute significantly to the PK analysis and the safety 
data set (e.g. if the dose difference is small).
If the SRD is stopped temporarily because criteria are met, the MRD will continue in the 
meantime.
Replacement of patients
3.3.5
In case that one dose group in this trial is completed by less than 6 patients on active 
treatment (due to e.g. drop-outs or recruitment reasons), the clinical trial leader together with 
the trial pharmacokineticist and the trial statistician are to decide if and how many patients 
will be replaced. A maximum of 3 patients can be replaced in each dose group (SRD and 
MRD). Only those patients will be replaced, which have not withdrawn due to adverse drug 
reactions or adverse events based on study procedures. A replacement patient will be 
assigned a unique patient number, and will be assigned to the same treatment as the patient he 
replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 894416 and placebo tablets.
Identity of the Investigational Medicinal Products
4.1.1
The characteristics of the test products are given below:
Table 4.1.1: 1
Test products
Substance:
BI 894416 
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength:
10 mg, 25 mg or 100 mg
Posology:
SRD part – single dose
MRD part – tid dosing
Method and route of administration:
p.o.
The characteristics of the reference product (placebo) are given below:
Substance:
Placebo matching BI 894416 to match 10mg, 25mg 
and 100mg BI 894416 tablets
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength:
0 mg 
Posology:
SRD part- single dose
MRD part – tid dosing
Method and route of administration:
p.o.
Selection of doses in the trial and dose modification
4.1.2
Maximum exposure (exposure cap)
The human exposure cap, which will be used to limit dosing, corresponds to a Cmax gMean 
value of 5,233 nM and AUC0-24 gMean value of 36,150 nM·h, the latter corresponding to 
3-fold below exposure at the dog NOAEL and 7-fold below the lowest exposure in dogs 
where neurologic effects were observed. In addition, predicted exposures above 63,000 nM∙h
will not be permitted for the 95th percentile of any given patient of the next dose group in this 
study. A neurological clinical examination assessment will be done in this trial at pre-defined 
time points (see Flow Charts). For more details on toxicology data supporting the selected 
human exposure cap, please see the current version of the Investigator’s Brochure (IB) 
[c03536505].


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Maximum dose
Maximum dose is described below, and this dose will not be exceeded in this trial. The doses 
selected for this trial cover the estimated therapeutic range and are expected to be necessary 
for successful development of BI 894416.
For the highest single dose in the SRD part, the Cmax gMean value is predicted to slightly 
exceed the upper limit of exposure (see Table 4.1.2: 1 below). This dose will only be given if 
exposure (Cmax) at high doses is lower than currently predicted, i.e. the dose escalation 
stopping criterion referring to plasma exposure prediction is not reached (see Section 3.3.4.4) 
after single dose administration of up to 175 mg. Note: Before this trial, highest dose given to 
humans was 70 mg, i.e. predictions for doses higher than 70 mg are based on extrapolation 
and actual exposures may differ from predictions.
In case that preliminary PK analysis during the trial predict that exposure limit (see above) is 
exceeded with the highest SRD dose, the dose may be reduced to a dose > 175 and <225 mg, 
as long as the predicted exposure at this reduced dose does not exceed the exposure limit.
In case the sponsor and SMC agree to test a dose level that is expected to exceed the maximal 
acceptable exposure defined above, this would only be done after approval of a substantial 
amendment by competent authority and IEC (according to Section 7.5 of EMA guideline on 
strategies to identify and mitigate risks for first-in-human and early clinical trials with IMPs 
[R18-1299]).
Preliminary PK analysis
Dose escalation will be guided by preliminary PK analysis to ensure that the expected AUC 
and Cmax gMean values and the expected individual values (95th Percentile for AUC0-24) for 
exposure at the next planned dose level do not exceed the maximum acceptable exposure.
Interim Dose Levels
With CTP version 3.0, an interim single dose group of 170 mg (SRD group 5) is added 
following dose group 2 (125 mg). Dose escalation to the next MRD dose group (dose group 
3) may occur, as long as the expected systemic exposure (gMean Cmax,ss and AUC0-24,ss) is 
covered by the (preliminary) values measured in the interim SRD 5 dose group. See also 
Section 3.1.
With CTP version 5.0, an interim multiple dose group of 60 mg tid (MRD group 5) is added 
following dose group 3 (50 mg tid). Dose escalation to the next MRD dose group (dose group 
4) may occur, as long as the expected systemic exposure (gMean Cmax,ss and AUC0-24,ss) is 
covered by the (preliminary) values measured in the highest SRD dose group. See also 
Section 3.1.
SRD part
Table 4.1.2: 1 shows predicted PK parameters for single dose administration. Exposure 
multiples are calculated as a ratio of the maximal acceptable human exposure divided by 
predicted systemic exposure after single dosing.


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Table 4.1.2: 1 Predicted SRD PK parameters
Dosing 
Regimen 
[mg]
AUC0-24
[nM*h] 
(gMean)
Exposure 
multiple1
AUC0-24
[nM*h] (95th 
percentile)
Exposure 
multiple2
Cmax
[nM]
(gMean)
Exposure 
multiple3
75 mg q.d.
12730
2.840
23262
2.708
1861
2.812
125 mg q.d.
21557
1.677
40152
1.569
3132
1.671
170 mg q.d.
29043
1.245
55171
1.142
4255
1.230
175 mg q.d.
29897
1.209
56794
1.109
4380
1.195
225 mg q.d.
38849
0.931
72987
0.863
5658
0.925
1 in relation to AUC gMean exposure limit (36150 nM*h)
2 in relation to 95th percentile exposure limit (63000 nM*h)
3 in relation to Cmax gMean exposure limit (5233 nM)
The new interim dose 170 mg was inserted based on modelling from previous SRD part PK 
data.
Predicted PK parameters have been adapted for doses ≥ 175 mg based on preliminary PK 
analysis including data from 75 mg and 125 mg dose groups.
Table 4.1.2: 2 SRD PK parameters obtained for doses up to 170 mg q.d.*
Dosing 
Regimen 
[mg]
gMean AUC0-24
[nM*h] (gCV 
[%])
gMean Cmax [nM]
(gCV [%])
75 mg q.d.
15200 (38.2)
2340 (29.7)
125 mg q.d.
25700 (29.9)
4128 (26.1)
170 mg q.d.
31700 (20.6)
5280 (24.3)
* Results from preliminary pharmacokinetic non-compartmental analysis
MRD part
Table 4.1.2: 2 shows predicted PK parameters for multiple dose administration. Exposure 
multiples are calculated as a ratio of the maximal acceptable human exposure divided by 
predicted systemic exposure after multiple dosing.


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Table 4.1.2: 3 Predicted MRD PK parameters
Dosing 
Regimen 
[mg]
AUC0-
24,ss 
[nM*h] 
(gMean)
Exposure 
multiple1
AUC0-24,ss
[nM*h] 
(95th 
percentile)
Exposure 
multiple2
Cmax,ss [nM]
(gMean)
Exposure 
multiple3
10 mg t.i.d.
3691
9.794
6931
9.090
261
20.021
25 mg t.i.d.
13695
2.640
27453
2.295
960
5.450
50 mg t.i.d.
27577
1.311
52616
1.197
1929
2.712
60 mg t.i.d.
31727
1.139
61596
1.023
2241
2.335
70 mg t.i.d.
37732
0.958
72492
0.869
2648
1.977
1 in relation to AUC gMean exposure limit (36150 nM*h)
2 in relation to 95th percentile exposure limit (63000 nM*h)
3 in relation to Cmax gMean exposure limit (5233 nM)
The new interim dose 60 mg tid was inserted based on modelling from previous MRD part 
PK data. Predicted PK parameters have been adapted for doses ≥ 60 mg tid based on 
preliminary PK analysis including data from 10 mg tid, 25 mg tid and 50 mg tid dose groups.
The predicted exposure for 60 mg tid (AUC0-24,ss) is 31727nM*h. The predicted exposure is 
covered by the exposure (AUC0-24) obtained after administration of 170 mg q.d. (31700 
nM*h). The difference of 27 nM*h is considered neglectable, taking the PK variability into 
consideration. In addition, the predicted exposure does not exceed the 95th percentile
exposure limit for AUC0-24,ss for 60 mg tid (61596 nM*h vs.63000 nM*h).
Table 4.1.2: 4 MRD PK parameters obtained for doses up to 50 mg t.i.d.*
Dosing 
Regimen 
[mg]
gMean AUC0-24
[nM*h] 
(gCV [%])
gMean Cmax
[nM]
(gCV [%])
10 mg t.i.d.
4410 (48.6)
299 (42.7)
25 mg t.i.d.
14400 (19.8)
985 (19.4)
50 mg t.i.d.
16200 (33.5)
1290 (52.1)
* Results from preliminary pharmacokinetic non-compartmental analysis
Method of assigning patients to treatment groups
4.1.3
Prior to the screening visit, patients will be contacted in writing and informed about the 
planned visit dates. The patients willing to participate will be recruited to the dose groups (3 
cohorts per dose group) according to their temporal availability. As soon as enough patients 
are allocated to 1 of the 24 dose cohorts, the following patients will be allocated to one of the 
other dose cohorts. Therefore, the allocation of patients to dose cohorts is not influenced by 
trial personnel, but only by the patients’ temporal availability. Because the study includes 


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patients from a homogenous population, relevant imbalances between the dose groups are not 
expected.
Patients 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. Patients are then assigned to treatment according to the predefined
randomisation list.
The randomisation procedure is described in Section 7.6.
Drug assignment and administration of doses for each patient
4.1.4
The treatments to be evaluated are outlined in Table 4.1.4: 1 (SRD part) and 4.1.4: 2 (MRD 
part). The number of units for placebo corresponds to the number of units of the 
corresponding dose level.
Table 4.1.4: 1
BI 894416 and placebo* treatments, tablets to be administered in 
SRD part
Dose
group
Substance
BI 894416
10 mg
BI 894416  
25 mg
BI 894416
100 mg
Total dose of
BI 894416
Total daily dose 
of BI 894416
SRD 1
BI 894416
0
3
0
75 mg
75 mg
SRD 2
BI 894416
0
1
1
125 mg
125 mg
SRD 5
BI 894416
2
2
1
170 mg
170 mg
SRD 3
BI 894416
0
3
1
175 mg
175 mg
SRD 4
BI 894416
0
1
2
225 mg
225 mg
* Placebo is given to the 2nd patient of first cohort and to one patient of last cohort (randomised)
Table 4.1.4: 2
BI 894416 and placebo* treatments, tablets to be administered in 
MRD
Dose
group
Substance
BI 894416  
10 mg
BI 894416  
25 mg
BI 894416  
100 mg
Total daily dose of 
BI 894416 
MRD 1
BI 894416
1 t.i.d.
0
0
30 mg
MRD 2
BI 894416
0
1 t.i.d.
0
75 mg
MRD 3
BI 894416
0
2 t.i.d.
0
150 mg
MRD 5
BI 894416
1 t.i.d.
2 t.i.d.
0
180 mg
MRD 4
BI 894416
2 t.i.d.
2 t.i.d.
0
210 mg
* Placebo is given to the 2nd patient of first cohort and to one patient of last cohort (randomised)
The trial medication will be administered to the patients, while in a sitting or standing 
position, as an oral dose together with about 240 mL of water under supervision of the 
investigating physician or an authorised designee (please refer to Flow Charts). The so-called 
four-eye principle (two person rule) should be applied for administration of trial medication.


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For this, 1 authorised employee of the trial site should witness the administration of trial 
medication, and its preparation, if correct dosage cannot be ensured otherwise.
SRD: Administration of BI 894416 or placebo will be performed after patients have fasted 
overnight; fasting is to start no later than 10 h before the scheduled dosing.
SRD: During the first 4 h after drug administration, the patients 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.
Patients will be kept under close medical surveillance until 34 h after dosing in SRD part.
MRD: Administration of BI 894416 or placebo on Days 1 (single dose) and 9 (single dose)
will be performed after patients have fasted overnight; fasting is to start no later than 10 h 
before the scheduled dosing. On the other study days, no food is allowed for at least 2 h 
before and 1 h after each intake of BI 894416 or placebo.
MRD: In MRD dose group patients will be hospitalized from Day -1 until Day 10. At Day 1 
and Day 9 a single dose will be administered to patients whereas from Day 2 until Day 8
BI 894416 will be administered tid.
Patients will be kept under close medical surveillance until Day 10 in MRD part (please refer 
to MRD Flow Chart).
MRD: During the first 4 h after BI 894416 administration on Day 1 and Day 9, the patients 
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.
For restrictions with regard to diet, see Section 4.2.2.2.
Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
A single–blind design is considered acceptable because the potential bias in this type of study 
is expected to be low and according to study procedures it is assured that the investigator's 
knowledge of the next treatment does not influence the decision to enter a patient.
At the trial site, administration and preparation of trial medication will be performed as 
described in Section 4.1.4 to ensure blinding of patients.
All trial data will be handled open label. This means that trial functions of the sponsor are 
unblinded (including clinical trial leader, trial data manager, trial statistician, bioanalyst, trial 
pharmacokineticist, trial pharmacometrician,
 
 safety monitoring committee member, as well as dedicated personnel of the trial 
site).


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In addition, the trial pharmacokineticist, trial bioanalyst and trial pharmacometrician may 
receive the randomisation codes to perform the interim / preliminary PK analysis.
Within the central ECG lab, the staff involved with interval measurements will be blinded 
with respect to the treatment and also with regard to the recording date and time as well as 
planned time points of the ECGs. The interval measurements for a given patient will be 
performed in a random and blinded sequence by a single technician.
If an interim safety analysis of ECG data is required, a part of the staff of the central ECG lab 
may be unblinded. This part of the staff will be strictly separated from the blinded staff 
members who are involved with ECG interval measurements and assessments of ECGs.
Access to the randomisation schedule will be controlled and documented.
Unblinding and breaking the code
4.1.5.2
As this trial will be conducted single-blind, patients’ treatment assignments will be known to 
investigators. Therefore, no emergency envelopes will be provided. There will be a 24h/7d 
contact number of the site be provided on the patients’ trial identification card in case 
emergency healthcare professionals need to unblind a patient. 
Packaging, labelling, and re-supply
4.1.6
BI 894416 tablets
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice.
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the patient information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the patient information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
Storage conditions
4.1.7
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
4.1.8
The investigator or designee will receive the investigational drugs from the sponsor when the 
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial patients. 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 patient, 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 patients. The 
investigator or designee will maintain records that document adequately that the patients were 
provided the doses specified by the CTP and reconcile all investigational medicinal products 
received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused trial medication will be disposed of locally by the trial site upon written 
authorisation of the clinical trial leader. Receipt, usage, and disposal of trial medication must 
be documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
Other treatments and emergency procedures
4.2.1
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, patients 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.


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Restrictions
4.2.2
Restrictions regarding concomitant treatment
4.2.2.1
Besides allowed low dose inhaled corticosteroids (please refer to GINA guidelines), no 
concomitant therapy is allowed. All concomitant or rescue therapies will be recorded 
(including time of intake on study days) on the appropriate pages of the eCRF if adverse 
events require treatment, the investigator can authorise symptomatic therapy.
In the event of rescue medication use, patients should be washed out of any inhaled short-
acting β2-adrenergic agonist for at least 6 hours prior to reversibility and lung function tests.
Acetylsalicylic acid or other drugs that may inhibit platelet aggregation or coagulation should 
be avoided during the entire study. If necessary, paracetamol may be given occasional if 
adverse event require treatment.
Drugs that may increase exposure of BI 894416 should be avoided during the entire study. 
Based on in vitro data, CYP3A is involved in metabolism of BI 894416. In addition, 
BI 894416 is an in vitro substrate of P-glycoprotein. Data of drug-drug interaction trial 1371-
0004 (see Section 1.2.1) indicate that inhibition of CYP3A and P-glycoprotein may cause 
mild increases of BI 894416 plasma concentrations. Therefore administration of CYP3A and 
P-glycoprotein inhibitors should be avoided during the entire study in emergency cases.
BI 894416 is also a substrate of organic cation transporter 2 (OCT2). It is not excluded that 
inhibition of OCT2 could increase BI 894416 plasma exposure. Therefore administration of 
inhibitors of OCT2 should be avoided during the entire study.
Restrictions on diet and life style
4.2.2.2
Poppy-seeds containing foods should not be consumed starting 3 days before (first) trial drug 
administration until the last PK sampling of the trial to avoid positive drug screening tests.
While admitted to the trial site the patients are restricted from consuming any foods or drinks 
other than those provided. Standardised meals will be served at the time points described in 
the Flow Charts.
After availability of preliminary PK data of separate clinical trial 1371-0021 (clinical phase I 
trial in healthy volunteers investigating the effect of a high-fat, high-calorie breakfast on BI 
894416 bioavailability) the time of food in relation to drug intake (e.g. earlier breakfast) may
be adapted by clarification letter or by non-substantial amendment to the CTP.
For SRD: No food is allowed for at least 10 h before and 4 h after trial medication intake.
For SRD: From 1 h before drug intake until 4 h after trial medication intake, fluid intake is 
restricted to the water administered with the trial medication, and an additional 240 mL of 
water served at 2 h and 4 h post-dose (mandatory for all patients). From 4 h after drug intake 
on Day 1 until 24 h post-dose, fluid intake is restricted to 3,000 mL.


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For MRD: On Days 1 and 9, no food is allowed for at least 10 h before and 4 h after 
BI 894416 or placebo intake. On all other study days, no food is allowed for at least 2 h 
before and 1 h after drug intake.
For MRD:

On Days 1 and 9, from 1 h before BI 894416 or placebo intake until 4 h after BI 894416 
or placebo intake, fluid intake is restricted to the water administered with BI 894416 or 
placebo, and an additional 240 mL of water served at 1 h and 3 h after BI 894416 or 
placebo dosing (mandatory for all patients). From 4 h after drug intake on Days 1 and 9 
until 24 h post-dose, fluid intake is restricted to 3,000 mL.

On all other study days, fluid intake from 30 min before drug administration until 30 min
after drug administration is restricted to the water administered with the drug.
 
 
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before the (first) administration of trial medication until after the 
last PK sample is collected.
Alcoholic beverages are not allowed starting 48 h before the (first) trial drug administration 
until after the last PK sample is collected.
Smoking is not allowed during the trial.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during the in-house confinement at the trial site.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the administration of trial medication until the end of trial examination. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion of trial medication will provide additional confirmation of 
compliance.
Patients 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 eCRF 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
Bodyplethysmography 
5.1.1
ATS/ERS criteria [P05-12782] are to be fulfilled (including calibration). Spirometry will be 
conducted with the patient in a seated position and it is preferable that the same trained 
individual performs the tests for a given patient. Maneuvers will be conducted in triplicate. 
The highest FEV1 and FVC from an acceptable maneuver will be selected regardless of 
whether they come from different maneuvers or from the same maneuver (with a maximum 
of five attempts).
Calculations will be based on Global Lung Function Initiative (GLI) formula [R15-0845].
Reversibility testing [P05-12782] for the qualifying PFT at the Screening Visit (Visit 1): the 
procedure is described in Appendix 10.3.
Constant-volume variable-pressure body plethysmography will be used in the trial, following 
the methodology and calibration procedures described by Coates et al. 1997 [R98-1487].
Body plethysmography will be performed during the Screening visit (Visit 1) and for patients 
in MRD at Day -1, at Day 9 and at Visit 8.
MRD part: 
 
(secondary endpoint) (Section 
2.2.2, Appendix 10.3).
 
 
 
5.2
ASSESSMENT OF SAFETY
Medical examinations
5.2.1
At screening, the medical examination will include demographics including 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, a physical examination (including a echocardiography followed by a 
echocardiography stress test in patients aged 45 and older), and a neurological examination. 
At the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, a physical examination, and a neurological examination.


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Neurological examination
5.2.2
At the time points specified in the Flow Charts, a physical neurological examination will be 
performed.
The neurological examination will include the following assessments:

General level of arousal

Orientation

Eye movement

Pupil size and pupil reactivity

Reflexes

Assessment of muscle strength

Gait

Romberg test

Tremor

Point-to-point movements

Sensitivity
Documentation, Assessment and Reporting
Results will be documented in source data at the clinical trial site and assessed for clinical 
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant 
findings of the neurological examination will be reported as Adverse Events (during the trial) 
or as baseline conditions (at screening). Case narratives may be written if necessary.
Vital signs
5.2.3
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 Charts, after patients have rested for 
at least 5 min in a supine position. All recordings should be made using the same type of 
blood pressure recording instrument on the same arm if possible.
Safety laboratory parameters
5.2.4
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 Charts after the patients have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee 
for retests or drug screening.
The parameters that will be determined are listed in Tables 5.2.4: 1 and 5.2.4: 2. Reference 
ranges will be provided in the ISF, Section 10.
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 5.2.4: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count (RBC) 
Reticulocytes (relative and absolute)
White Blood Cells (WBC) 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC differential, 
relative and absolute
Neutrophil; eosinophils; basophils; monocytes; 
lymphocytes
X
X
X
Manual differential WBC (if 
automatic
differential WBC is abnormal)
Polymorphnuclear neutrophils (segs), band neutrophils 
(stabs), eosinophils, basophils, monocytes, 
lymphocytes
Immunoglobulins in serum
IgA
IgD
IgE, total and specific
IgG
IgM
X
X
X
X
X
--
--
--
--
--
X
X
X
X
X
Lymphocyte
differentiation (relative
and absolute; except
for ratio)
T cells (CD3+), T helper cells (CD3+CD4+), cytotoxic 
T cells (CD3+CD8+), B cells (CD19+), natural killer 
cells (CD16+CD56+CD3-), CD4:CD8 ratio
X
--
X
Coagulation
Activated partial thromboplastin time (aPTT) 
Prothrombin time (Quick’s test and INR)
X
X
X
X
X
X
Platelet Function (via Platelet Function Assay)
See below
Enzymes
AST [Aspartate transaminase]/GOT, SGOT 
ALT [Alanine transaminase]/GPT, SGPT
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT) 
Creatine kinase [CK]; CK-MB only if CK is elevated] 
Lactate dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone (TSH)
X
--
--
Molecular Diagnostics
PCR test for the detection of SARS-CoV-2
X
Substrates
Plasma glucose
Creatinine
Total bilirubin
Direct bilirubin
Total protein
C-Reactive Protein (CRP)
Uric acid
Total cholesterol
Triglycerides
X
X
X
X
X
X
X
X
X
X
X
X
X
--
X
--
--
--
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Calcium
Inorganic phosphate
X
X
X
X
X
X
X
--
X
X
X
X
1 A, B and C are different sets of laboratory values. The Flow Charts defines at what time point which set is to be 
investigated


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Table 5.2.4: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
Infectious serology 
(blood)
QuantiFERON-TB Gold
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
Urinalysis (Stix)
Urine nitrite 
Urine protein 
Urine glucose 
Urine ketone 
Urobilinogen 
Urine bilirubin 
Urine erythrocytes
Urine leucocytes
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment1
(microscopic examination 
if erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
1 A, B and C are different sets of laboratory values. The Flow Charts defines at what time point which set is to be 
investigated
The tests listed in Table 5.2.4: 2 are screening laboratory tests to check eligibility, which may 
be repeated as required. The results will not be entered in the eCRF/database and will not be 
reported in the CTR.
Table 5.2.4: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
To encourage compliance with alcohol restrictions, a breath alcohol test will be performed 
during Screening Visit and before (first) drug administration (SRD and MRD part) and may 
be repeated at any time during the study at the discretion of an investigator or designee. The 
results will not be included in the CTR.
The laboratory tests listed in Table 5.2.4: 1 and 5.2.4: 2 will be performed at 
 
or at 


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 & 
. The 
drug screening tests will be performed at the trial site.
 
 
 
 
 
 
Cotinine Test
A qualitative urine cotinine test will be performed on all patients at Visit 1, and Visit 3.1, and 
Visit 3.9 prior to the (first) morning dose. If the qualitative test is positive at Visit 1, the site 
should discuss the result regarding potential exposure to nicotine and remind the patient to 
refrain from smoking according to inclusion criterion #6.
If the qualitative test at Visit 3.1. is positive, the site should consider to not randomize the 
patient.
All randomized patients with a positive qualitative cotinine test should be referred to a 
quantitative cotinine test. Results of the quantitative test are not decisive for patient eligibility 
but should support the interpretation of PK parameter analysis.
The tests will be performed at the facilities of the 
 
 and at the 
 & 
.
Molecular test for SARS-CoV-2
The test will be performed on all eligible patients at Visit 2. The result must be available prior 
to randomization. If positive, the patient must not be randomized.
The test will be conducted according to the recommendations of Robert-Koch-Institute in 
Germany 
(https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Entlassmanagement.html)
i.e. performed on two swabs obtained at the same time from oro- and nasopharynx (single 
PCR test sufficient after transfer of two swabs from oro- and nasopharynx to the same 
transport media, or use of the same swab in both oro- and nasopharynx).
 
5.2.5
12-lead resting ECG 
5.2.5.1
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 Charts. Precise
electrode placement will be performed according to the method of Wilson, Goldberger and 


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Einthoven modified by Mason and Likar (hips and shoulders instead of ankles and wrists). In 
the SRD and MRD part, precise electrode placement will be marked with an indelible mark 
on the skin to allow reproducible placement throughout the study.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all patients are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after patients have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart of the SRD and/or MRD part.
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 collected by the investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point in the Sponsor’s database.
Storage
All ECGs will be stored electronically in the System provided by 
.
Data transfer
All triplicate ECGs will be transferred electronically to the central ECG laboratory (
 
) for evaluation.
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in a document that is filed 
in the TMF.
Evaluation
a) Central ECG lab
Central ECG lab evaluation will be performed (during the study and/or after the study) for 
the first of three replicate ECGs per time point. For baseline, all three ECGs of the 
triplicate ECG on Day 1 pre-dose will be evaluated. For the three triplicate ECGs on Day
-3 to -1 all ECGs will be evaluated. This will include the determination of cardiac QRS-
axis as assessed by the ECG machine’s algorithm as well as the intervals RR, PR, QRS 


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and QT measured semi-automatically. Heart rate (HR) and the QT interval corrected for 
HR (QTc e.g. QTcF and QTcB) will be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one patient will be performed on the same 
lead. The intervals will be measured from four cardiac cycles (beats) in lead II. If lead II 
shows a flat T wave or is not measurable for any reason, lead V5 will be used, or if that 
lead is not measurable, then lead I will be used. The lead actually used will be reported in 
the CTR. For automatic interval measurements no lead will be provided
For blinding arrangements see Section 4.1.5.1. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular patient should be evaluated by a 
single reader. For quality assurance and control of the measurements, all ECGs of a 
patient will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and, to detect accidental 
switching of leads and/or false patient assignments of the ECGs. After quality control, the 
fiducial point markings will be reviewed by the cardiologist assigned to the study.
Evaluation of ECGs will comply with the ICH E14 guidance document and supplements 
[R07-4722, R16-0366] as well as the FDA requirements for annotated digital ECGs [R09-
4830].
b) Trial site (SRD and MRD part)
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a patient and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the computerised 
ECG system or their manual corrections by the investigators will be used. In doubtful 
cases, ECGs may be sent upfront (i.e. prior to the regular data transfer) for cardiologic 
assessment by the central lab. In this case, these centrally measured results would 
overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the patient will be 
removed from the trial and will receive the appropriate medical treatment.
Continuous ECG monitoring
5.2.5.2
In the SRD part, cardiac rhythm (including heart rate) will be monitored by means of 
continuous 3-lead ECG recording for at least 15 min before drug administration (for baseline 
assessment) and for 4 h following drug administration). This continuous ECG monitoring 
supports the early detection of adverse events such as clinically relevant bradycardia, 
tachycardia, or arrhythmia at the trial site. Beyond this clinical evaluation at the trial site, no 
further data collection or analyses are performed based on continuous ECG monitoring.


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


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AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in Section 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor 
and timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o An elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) 
≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN measured 
in the same blood sample, or
o Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF or 
in eDC, as applicable. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, etc.) 
without lab results (ALT, AST, total bilirubin) available, the Investigator should make sure 
that these parameters are analysed, if necessary in an unscheduled blood test. Should the 
results meet the criteria of hepatic injury alert, the procedures described in the DILI checklist 
should be followed.


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


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Adverse event collection and reporting
5.2.6.2
AE collection
5.2.6.2.1
Upon enrolment into a trial, the patient’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently.
Patients 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 patient will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, patients will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Charts. 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 eCRF(s) by the 
investigator:

From signing the informed consent onwards until an individual patient’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs

After the individual patient’s end of trial:
o
The investigator does not need to actively monitor the patient 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 eCRF
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific reporting process 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 send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.


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Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual patient’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
5.2.6.2.4
Once the male patient has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant within 28 days after last drug 
intake, the investigator must report any drug exposure during pregnancy in a partner of the 
male trial participant immediately (within 24 hours) by means of Part A of the Pregnancy 
Monitoring Form to the sponsor’s unique entry point, after a written consent of the pregnant 
partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
5.3.1
Date and clock times of drug administration and pharmacokinetic sampling will be recorded 
in Source data and in the eCRFs.
Exact times of plasma sampling will be documented in the eCRFs by the medical personnel 
or sent as electronic files to the trial data manager. The actual sampling times will be used for 
determination of pharmacokinetic parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. as a result of preliminary PK data), including addition of 
samples and visits, as long as the total blood volume taken per patient does not exceed 
500 mL. Such changes would be implemented via non-substantial CTP Amendments.


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Methods of sample collection
5.3.2
Blood sampling for pharmacokinetic analysis
5.3.2.1
BI 894416
For quantification of BI 894416 concentrations in plasma, 2.7 mL of blood will be drawn
from an antecubital or forearm vein into an K2-EDTA (tripotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Charts and Appendix 10.2. Blood will be withdrawn by means of either an 
indwelling venous catheter or by venepuncture with a metal needle.
Minor changes to the sampling methodology, which do not affect the results, may be made 
and communicated to the investigator without need for a protocol amendment.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
second aliquot should contain remaining plasma. The process from blood collection until 
transfer of plasma aliquots into the freezer should be completed within 60 min, with interim 
storage of blood samples in ice water or on ice. The time each aliquot was placed in the 
freezer will be documented. Until transfer on dry ice to the analytical laboratory, the aliquots 
will be stored upright at approximately -20°C or below at the trial site. The second aliquot 
will be transferred to the analytical laboratory after the bioanalyst has acknowledged safe 
arrival of the first aliquot. At the analytical laboratory, the plasma samples will be stored at 
approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, patient number, visit, and 
planned sampling time. Further information such as matrix and analyte may also be provided. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g., for stability testing
 
 
. The study samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the CTR is 
archived.
 
 
 


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Urine sampling for pharmacokinetic analysis
5.3.2.3
BI894416
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 Charts and Appendix 
10.2 will be collected in 2 L polyethylene (PE) containers and stored at room temperature. 
Patients are told to empty their bladders at the end of each sampling interval.
Due to the known adsorption of the drug to the container wall, 10 mL of 10% Tween 20
solution will be added to each 2 L collection container prior to the start of urine sampling.
The weight of the empty container will be determined, thereafter 10 mL 10% Tween 20 will
be added and the weight of the container at the end of each sampling interval will be
determined.
The urine weight/volume for each collection interval will be documented (however, no 
correction for the specific gravity of urine is done; i.e., 1 L is defined to be equal to 1 kg). 
Two 0.5 mL aliquots will be stored in polypropylene (PP) tubes for bioanalytical 
measurements. If more than one collection container is used in an interval, the contents of all 
containers are to be mixed before aliquots are prepared. Mixing should be done by 
transferring the entire content of all collection containers into a single polyethylene) (PE)/PP 


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or glass container, and stirring the mixed fractions for about 1 min (manually or using a stir 
bar or other stirring device made of PE, PP, Teflon, or glass).
At a minimum, the sample tube labels should list BI trial number, patient number, visit, and 
planned collection time. Further information, such as matrix and analyte may also be 
provided.
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
approximately -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 approximately -20°C or below until analysis.
After completion of the trial, the urine samples may be used for further methodological 
investigations (e.g., for stability testing
 
 
 The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the CTR has been archived.
 
 
 
 
 
 
 


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5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Pharmacogenomic evaluation
5.6.1
Pharmacogenomics investigates genetic variations to explain and to predict an individual’s
response to drugs. Therefore, a blood sample for optional pharmacogenomic testing will be 
taken from each patient. In case of unexplainable variability of PK 
 parameters, DNA 
may be extracted from these samples and used for exploratory analysis of variants of the 
SYK gene and genes involved in Absorption, Distribution, Metabolism and Excretion 
(ADME) of drugs. It is not intended to include these data in the final report. However, the 
data may be part of the report if necessary.
Detailed instructions for pharmacogenomics sampling, including handling and shipment of
samples will be provided in the laboratory manual in the ISF.
Methods and timing of sample collection
5.6.1.1
One blood sample of 8.5 mL will be taken from an arm vein in a PAXgene blood DNA
drawing tube as indicated in the Flow Charts.
Analytical determinations
5.6.1.2
Genomic DNA will be extracted from blood samples according to standard molecular
genetics methods and analysed by Drug Metabolism Enzymes and Transporters (DMETTM)
analysis or other standard genotyping technologies.


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


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Charts. Each visit date 
(with its window) is to be counted from Day 1. If any visit has to be rescheduled, subsequent 
visits should follow the original visit date schedule. Additional visits for the purpose of re-
testing of laboratory parameters or AE monitoring may be included as deemed necessary by 
the investigator.
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 Charts.
If Screening Visit is performed on Day -3 (within 76 hours) prior to administration of trial 
drug, the ambulatory Visit 2 can be omitted.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK 
In the SRD part, the acceptable deviation from the scheduled time for vital signs, ECG, and 
laboratory tests will be ± 15 min for the first 4 h after trial drug administration, ± 30 min 
thereafter on Day 1 and ± 90 min on Day 2.
The acceptable deviation from the scheduled time for neurological tests in the SRD part is ± 
45 min on Day 1 and ± 90 min on Day 2.
Starting from 48 h post administration a time window of ±120 min will be allowed for all 
study activities (incl. PK 
 sampling) in the SRD part.
In the MRD part, the acceptable deviation from the scheduled time for vital signs, ECG, and 
laboratory tests will be ± 15 min for the first 4 h after trial drug administration on Day 1 and 
Day 9, ± 30 min thereafter on Day 1 and Day 9, ± 90 min on Day 2 and on Day 10 and ± 120 
min from Day 11 onwards.
The acceptable deviation from the scheduled time for neurological tests in MRD part is ± 45 
min on Day 1, and ± 90 min on Day 2.
From Day 3 until Day 8 and from 48 h post last administration on Day 9 a time window of 
±120 min will be allowed for all study activities (incl. PK 
 sampling) in the 
MRD part, except PK samples taken pre dose on Days 5, 7 and 8. Pre dose PK samples are 
taken within a time window of 15 min prior to drug administration.
If several activities are scheduled at the same time point in the Flow Charts, ECG should be 
the first and meal the last activity. Urine collection can be done prior to the ECG, if not 
within 5 min of the start of the ECG recording. Furthermore, if several measurements 


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including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the patient and possible influence on 
physiological parameters.
For planned individual plasma concentration sampling times and urine collection intervals 
refer to the Flow Charts. While the nominal times should be adhered to as closely as possible, 
the actual sampling times will be recorded and used for determination of pharmacokinetic 
parameters.
If a patient 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
6.2.1
Informed Consent

After having been informed in detail about the trial, all patients will provide written 
informed consent in accordance with GCP and local legislation prior to enrolment in 
the study. Patients will be asked to give Informed Consent to SRD, MRD, and to 
pharmacogenomics sampling (optional). 

The patient should be recorded on the enrolment log.

Upon obtaining Informed Consent the patient will receive a trial identification card.
Further Procedures at Visit 1

After the informed consent process is complete and written informed consent is 
obtained, the patients will be assessed for study eligibility including assessments 
summarized in the Flow Charts of SRD and MRD.

A preliminary check of in-/exclusion criteria is recommended at Screening to avoid to 
avoid unnecessary procedures and assessments in non-eligible patients.

Patients who fail screening following Visit 1 assessments should be registered as 
screen failures in eCRF. 1 Re-screening attempt is allowed.

For information regarding laboratory tests (including drug and virus screening), ECG, 
vital signs, medical examination, and neurological examination refer to Sections 5.2. 

Demographic data (inclusive height, weight (both measured at site), smoking and 
alcohol history), Medical history and baseline medication are to be obtained.

 

Reversibility Testing (please refer to Appendix 10.3)

Body plethysmography measurements will be conducted using the site’s own 
equipment [R98-1487]. Body plethysmography measurements will be taken as 
described in Flow Charts, Section 5.1.1 and in Appendix 10.4.

Echocardiography and echocardiography stress test after all other screening 
procedures have been completed.


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Treatment period
6.2.2
Each patient may participate in one SRD dose group and in one MRD dose group. In case of 
planned participation in the MRD part in this trial the previous participation in one dose 
group of the SRD part is allowed if BI 894416 has been administered more than 21 days prior 
to planned administration of BI 894416 in the MRD part (Participation in an SRD dose group 
after the patient has participated in the MRD part is not allowed).
Trial medication will be taken orally by each patient under direct supervision of the 
investigator or his designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
SRD: Study participants will be admitted to the trial site in the morning of Day 1 and kept 
under close medical surveillance for at least 34 h following drug administration. The patients 
will then be allowed to leave the trial site after formal assessment and confirmation of their 
fitness by the investigator or his designee. On all other study days, the study will be 
performed in an ambulatory fashion in the SRD part.
MRD: Study participants will be admitted to the trial site on Day -1 and kept under close 
medical surveillance until Day 10 (please refer to the Flow Chart). The patients will then be 
allowed to leave the trial site after formal assessment and confirmation of their fitness by the 
investigator or his designee. On all other study days, the study will be performed in an 
ambulatory fashion in the MRD part.
For details on time points and procedures for collection and processing of blood and urine 
samples for PK 
 analysis, refer to Section 5.3 or 5.4, respectively, to Appendix 10.2
and to the Flow Charts.
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 time points for all other trial procedures,
refer to the Flow Charts. AEs and concomitant therapy will be assessed continuously from
screening until the end of trial examination.
Follow-up period and trial completion
6.2.3
For AE assessment, laboratory tests, recording of ECG and vital signs, physical examination 
and neurological examination during the end of trial period, see Section 5.2.
Patients 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 judged 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 patient’s end of trial must be followed up 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained.


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The end of the trial as a whole is defined by the ‘last regular visit completed by last patient’ 
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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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objectives (refer to Section 2.1) of this trial will be assessed by calculating 
descriptive statistics for safety as well as for PK,
, which will be 
compared between the treatment groups.
As further analyses, PK endpoints will be explored regarding dose proportionality by the 
power model. Linear modelling will be used for exploring the attainment of steady state and 
for estimation of the linearity index.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in this study.
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the study; i.e., confidence intervals are considered as interval estimates for 
effects.
7.3
PLANNED ANALYSES
In general, the two trial parts (SRD and MRD) will be evaluated separately if not stated 
otherwise.
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all patients who were randomised and 
treated with at least one dose of study drug. The treatment assignment will be 
determined based on the first treatment the patients received. The treated set will be 
used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all patients in the 
treated set (TS) who provide at least one 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 patient will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.

Biomarker set (BMS): This patient set includes all patients in the TS who provide at 
 
 


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Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be specified in the iQRMP, iPDs will be identified no later than in the 
Report Planning Meeting, and the iPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and Section 2.2 for drug BI 894416 will 
be calculated according to the relevant SOP of the Sponsor (001-MCS-36-472).
Plasma and urine concentration data and parameters of a patient 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 patient’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the patient received at least one dose of trial 
medication the patient was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine concentrations and/or parameters of a patient will be considered as non-
evaluable, if for example

The patient experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the patients 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
Plasma/urine concentration data and parameters of a patient which is flagged for exclusion 
will be reported with its individual values but will not be included in the statistical analyses.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report).
 
 
 
 


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Primary endpoint analyses
7.3.1
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards.
The analysis will be based on the treated set (TS) and will be descriptive in nature.
Secondary endpoint analyses
7.3.2
Primary analyses
The secondary efficacy endpoints (refer to Section 2.1.3) will be analysed descriptively based 
on the TS. 
The secondary PK endpoints (refer to Section 2.1.3) will be analysed descriptively based on 
the PKS. Analyses will be performed for the parent drug.
Further exploratory analyses
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-
∞, Cmax (SRD part) and AUCτ,ss, Cmax,ss (MRD part) of BI 894416 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 +    ∙ log (Dk) +  ekm ,
where 
ykm
logarithm of response (PK parameter) measured on patient m receiving dose k,
μ
the overall mean,
β
slope parameter of linear regression line,
D
level of dose k, k=1,…,K,
ekm
the random error associated with the mth patient who was administered dose k
(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.
As some small doses at the beginning and/or some doses at the upper end might not 
contribute to the linear relationship between dose and PK, dose proportionality over the entire 


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dose range investigated might not be shown. In that case an attempt will be made to identify a 
subrange of at least 3 consecutive doses where dose proportionality can be concluded.


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Safety analyses
7.3.4
Safety will be assessed as defined by the endpoints listed in Section 2.1.2 and 2.2.2 based on 
the treated set (TS). Safety analyses will be descriptive in nature and will be based on BI 
standards. All adverse events with an onset between start of treatment will be assigned to the 
on-treatment period for evaluation. For residual effect period (REP) information is listed in 
Section 1.2.2.
For all analyses the treatment actually administered (= treatment at onset) to the patient will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. The placebo group in the safety evaluation 
will consist of all patients treated with placebo, regardless of the dose group in which they 
were treated. The test treatment groups will be compared to the placebo group in a descriptive 
way. Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Measurements (such as ECGs, vital signs, or laboratory parameters) or AEs will be assigned 
to treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment-emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between the first trial medication intake and the 
trial termination date will be assigned to the treatment period. These assignments including 


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the corresponding time intervals will be defined in detail in the TSAP. Note that AEs 
occurring after the last per protocol contact but entered before database lock will be reported 
to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (called analysing treatments) may be defined in the 
TSAP in order to provide summary statistics for other than above periods, such as combined 
treatments, on-treatment totals, or periods without treatment effects (such as screening and 
post-study intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.6.1.4) and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as possibly clinically significant values will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
The ECG variables QT, HR, QTcF, QTcB, PR, QRS, and RR obtained from the centralised 
evaluation of 12-lead ECG recordings will be the basis for the derivation of quantitative and 
categorical ECG endpoints. These endpoints and their analyses will be described in the 
TSAP.
 
 
7.4
INTERIM ANALYSES
No official interim analysis of PK parameters will be done. A preliminary analysis of PK 
parameters (AUC0-24 and Cmax, single dose; AUCt,ss, AUC0-24,ss and Cmax, ss, multiple dose of
BI 894419), provided as individual values and geometric means per dose level, will be 
performed for each dose level before proceeding to the next level for SRD and MRD part.
AUC0-24,ss will be calculated from AUCt,ss after last dose.
Data from at least 6 actively dosed patients at the current dose level are required in order to
proceed to the next dose level.


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In contrast to the final PK calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows. Therefore, minor deviations may occur between preliminary and final results. 
The preliminary analysis will provide individual and mean concentration -time profiles and 
summary statistics of individual values without patient identification information. The 
preliminary results will be distributed to the investigator and the trial team. 
The pharmacokinetic parameters will be calculated according to the BI SOP 'Standards and 
processes for analyses performed within Clinical Pharmacokinetics/Pharmacodynamics' 
 The non-compartmental analysis will be performed using a validated software 
program such as
 
 A quality check of the 
preliminary data will be performed.
Modelling of all available data from the current trial and the previously performed SRD study 
in healthy volunteers (1371-0001) will be used as basis for prediction of exposure of next 
higher dose group. Further details are described in a separate analysis plan.
Depending on the results of available preliminary PK analyses and the tolerability and safety 
of the compound, changes to the dosing schedule (e.g., additional intermediate doses),) and 
additional PK/
preliminary analysis may be performed if requested by the Clinical Trial 
Leader, the investigator, or Trial Clinical Pharmacokineticist. Preliminary PK results will not 
be reported in the CTR.
No inferential statistical interim analysis is planned. However, after completion of each dose 
group the investigator (or his or her deputy) is allowed to postpone further dose progression 
until a preliminary analysis of the data has been performed.
7.5
HANDLING OF MISSING DATA
Safety
7.5.1
It is not planned to impute missing values for safety parameters.
Pharmacokinetics
7.5.2
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
The first 5 patients per dose level will not be randomised to maintain a treatment sequence of 
active-placebo-active-active-active due to safety reasons. The remaining 5 patients of each
dose level will be randomised in a 4:1 ratio (test treatment to placebo).


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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 patient replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 40 patients in each trial part (maximum 80 for the overall 
study). The planned sample size is not based on a power calculation. The size of 10 patients 
per dose group (8 on active treatment, and 2 on placebo) is commonly used in single- and 
multiple-rising dose studies of the present type and is in general considered as sufficient for 
the exploratory evaluation of single and multiple dose safety and pharmacokinetics.
Additional patients may be entered to extend the number of patients within a dose group or 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 in the respective 
trial part will not be exceeded. Thus, the actual number of patients entered may exceed 80 
(may exceed 40 per trial part) but is not to exceed 100 (is not to exceed 50 per trial part).
Based on amended CTP version 3.0, following SRD 2, an interim dose group (SRD 5) with 
additional 10 subjects was added, i.e. planned sample size is 50 in the SRD part (please refer 
to Section 4.1.2 and Figure 3.1:1).
Based on amended CTP version 5.0, following MRD 3, an interim dose group (MRD 5) with 
additional 10 subjects was added, i.e. planned sample size is 50 in the MRD part (please refer 
to Section 4.1.2 and Figure 3.1:1).


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the patient’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients 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.
Insurance Coverage: The terms and conditions of the insurance coverage are made available 
to the investigator and the patients, and are stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT 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 patient’s participation in the trial, written informed consent must be obtained from 
each patient (or the patient’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 patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or his 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.


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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 Clinical Research Associate appointed by Boehringer Ingelheim will visit the site at a 
regular basis and will support site staff in questions in first instance and will review medical 
records documented at trial site(s). Further, the medical records may be examined by other 
authorized monitors as Clinical Trial Managers, Site Monitoring Lead or Clinical Quality 
Assurance auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities.
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.
Training will be provided to investigators, coordinators and CRAs to ensure consistency and
accuracy of the data. The data will be source verified by the CRAs.
8.3
RECORDS
eCRFs for individual patients will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
Source documents
8.3.1
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial patient 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 eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests.
Before providing any copy of patients’ source documents to the sponsor, the investigator 
must ensure that all patient identifiers (e.g., patient’s name, initials, address, phone number,
and social security number) have properly been removed or redacted to ensure patient
confidentiality.


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If the patient is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the patient file.
For the eCRF, data must be derived from source documents, for example:

Patient identification: sex, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient
was informed)

Dates of patient’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 patient’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a patient 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 patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the patient eligible for the clinical trial.

Reversibility Test results

Body plethysmography results

and others (refer to Flow Chart)
Direct access to source data and documents
8.3.2
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all eCRFs 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
8.3.3
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 PATIENT PRIVACY
Individual patient 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 patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’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 
8.5.1
data
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.


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The end of the trial is defined as the ‘date of the last visit of the last patient in whole trial’
(‘Last Patient Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state.
A final report of the clinical trial data will be written only after all patients have completed 
the trial, so that all data can be incorporated and considered in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the 
 
, under the supervision of 
the Principal Investigator. Relevant documentation on the participating (Principal) 
Investigator(s) (e.g. their curricula vitae) will be filed in the ISF.
BI has appointed a Clinical Trial Manager, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local clinical monitors (CML), 
Clinical Research Associates, 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
 
 
).


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Analyses of BI 894416, 
l will be 
performed at 
 
.
 
 
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI 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
P05-12646
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et.al. 
ATS/ERS Task Force: Standardisation of Lung Function Testing. Eur 
Respir J. 2005. 26(5): 948-968.
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et.al. 
Standardisation of spirometry. Eur Respir J. 2005. 26(2): 319-338.
P08-01263
Expert panel report 3: guidelines for the diagnosis and management of 
asthma: full report 2007 (NIH publication no. 07-4051, revised August 
2007). http://www.nhlbi.nih.gov; Bethesda: U.S. Department of Health and 
Human Services, National Institutes of Health, National Heart, Lung and 
Blood Institute (2007).
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER). 2002. 
1-9.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005).
R08-1121
Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et.al. 
Standardisation of the measurement of lung volumes. Eur Respir J. 2005. 
26(3): 511-522.
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R13-1374
ZhuY, Herlaar E, Masuda ES, Burleson GR, Nelson AJ, Grossbard EB, 
Clemens GR. Immunotoxicity assessment for the novel Spleen tyrosine
kinase inhibitor R406. Toxicol Appl Pharmacol. 2007. 221(3): 268-277.
R13-5356
Elmore SA. Enhanced histopathology of the lymph nodes. Toxicol Pathol.
2006. 34(5): 634-647.
R14-4230
Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular 
approaches. Nature Med. 2012. 18(5): 716-725.
R15-0845
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright 
PL, Hankinson JL, Ip MSM, Zheng J, Janet Stocks on behalf of the ERS 
Global Lung Function Initiative. Multi-ethnic reference values for 
spirometry for the 3 – 95 year age range: the global lung function 2012 
equations: report of the Global Lung Function Initiative (GLI), ERS task 
force to establish improved lung function reference values. Eur Respir J. 
2012. 40(6): 1324-1343.
R15-4770
Blancato J, Graves A, Rashidi B, Moroni M, Tchobe L, Ozdemirli M, et.al. 
SYK Allelic Loss and the Role of Syk-Regulated Genes in Breast Cancer 
Survival. PloS ONE. 2014. 9(2): e87610.


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R15-5470
Mocsai A, Ruland J, Tybulewicz VLJ. The SYK tyrosine kinase: a crucial 
player in diverse biological functions. Nat Rev Immunol. 2010. 10(6): 387-
402.
R15-5888
Pelaia G, Vatrella A, Busceti MT, Gallelli L, Calabrese C, Terracciano R, 
Maselli R. Cellular mechanisms underlying eosinophilic and neutrophilic 
airway inflammation in asthma. Mediators Inflamm. 2015. 2015: 879783.
R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015).
R16-0945
Fahy JV. Type 2 inflammation in asthma - present in most, absent in many. 
Nat Rev Immunol. 2015. 15: 57-65.
R16-4459
Krisenko MO, Geahlen RL. Calling in SYK: SYK’s dual role as a tumor 
promoter and tumor suppressor in cancer. Biochim Biophys Acta Mol Cell 
Res. 2015. 1853(1): 254-263.
R16-5240
Boylan B, Gao C, Rathore V, Gill JC, Newman DK, Newman PJ. 
Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3
outside-in integrin signaling in human platelets. 2008. 112(7): 2780-2786.
R16-5298
Alsadeq A, Hobeika E, Medgyesi D, Klaesener K, Reth M. The role of the 
Syk/Shp-1 kinase-phosphatase equilibrium in B cell development and 
signaling. J Immunol. 2014. 193: 268-276.
R17-1830
Jameson SC. Maintaining the norm: T-cell homeostasis. Nat Rev Immunol. 
2002. 2(8): 547-556.
 
 
 
 
 
 
 
R18-1299
European Medicines Agency (EMA), Committee for Medicinal Products 
for Human Use (CHMP): guideline on strategies to identify and mitigate 
risks for first-in-human and early clinical trials with investigational 
medicinal products (20 July 2017).
R20-1374
Sung PS, Hsieh SL. CLEC2 and CLEC5A: Pathogenic Host Factors in 
Acute Viral Infections. Frontiers in Immunology. 2019. 10(2867): 1-9.


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R95-0013
Broom C. Design of first-administration studies in healthy man. Early 
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
R98-1487
Coates AL, Peslin R, Rodenstein D, Stocks J. Measurement of lung 
volumes by plethysmography. Eur Respir J. 1997. 10: 1415-1427.
9.2
UNPUBLISHED REFERENCES
 
c03536505
 Investigator Brochure: BI 894416 Asthma.
Current version.
n00240179
, BI 894416: 
Exploratory 15 day oral (gavage) toxicity study in male rats. Nonclinical 
Report. 13B105. 29 June 2015.
n00243171
 Assessment of pro-proliferative effects of the 
SYK inhibitor BI 1002494 on human breast cancer cell lines and in silico 
genetic evaluation of SYK for tumour suppressor characteristics using data 
from breast cancer patient databases. Nonclinical Report. 2016-i-r-resp3-
report1. 11 July 2016.
n00245394
 BI 894416: Dose Escalation in Dogs with Assessment of 
Electroencephalography and Nerve Conduction Velocity. Nonclinical 
Report. 15R160. 21 February 2017.


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10.
APPENDICES
10.1
RECRUITMENT, COHORT AND TIME-INTERVAL SCHEME
Figure 10.1: 1
Recruitment, Cohort and time-interval Scheme
The figure shows the recruitment plan, cohort schemes and time-intervals between cohorts 
and next dose group (interim doses are not shown but follow the same principle, please refer 
to Figure 3.1:1)


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10.2
TIME SCHEDULES FOR PHARMACOKINETIK (PK)
 
Table 10.2: 1
Time schedule for PK blood and urine samplings, 
 
– MRD part
Blood samples
Urine samples
Visit
Day
Time Point 
[hh:mm]/
event
eCRF 
Time/
PTM
BI 
894416
 
 
 
BI 
894416
 
3
1
Predose
-1:00
X
Predose
-0:05
X
BI 894416 
intake
0:00
▲
│
│
0:15
0:15
X
│
0:30
0:30
X
│
0:45
0:45
X
│
240 ml fluid 
intake
1:00
X
│
│
1:30
1:30
X
│
2:00
2:00
X
│
│
2:30
2:30
X
│
240 ml fluid 
intake
3:00
X
│
│
4:00
4:00
X
▼
▲
6:00
6:00
X
│
8:00
8:00
X
▼
▲
10:00
10:00
X
│
12:00
12:00
X
▼
▲
2
Predose
23:55
X
│
BI 894416 
intake
24:00
▼
5
Predose
95:55
X
BI 894416 
intake
96:00
7
Predose
143:55
X
BI 894416 
intake
144:00
8
Predose
167:55
X
BI 894416 
intake
168:00
Predose
175:55
X
BI 894416 
intake
176:00
Predose
183:55
X
BI 894416 
intake
184:00


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Table 10.2: 1 (cont.)
Time schedule for PK blood and urine samplings, 
 
– MRD part
Blood samples
Urine samples
Visit
Day
Time Point 
[hh:mm]/
event
eCRF 
Time/
PTM
BI 
894416
 
 
 
BI 
894416
 
9
190:30
190:30
X
Predose
191:55
X
BI 894416 
intake
192:00
▲
│
192:15
192:15
X
│
192:30
192:30
X
│
192:45
192:45
X
│
240 ml fluid 
intake
193:00
X
│
│
193:30
193:30
X
│
194:00
194:00
X
│
194:30
194:30
X
│
240 ml fluid 
intake
195:00
X
│
│
196:00
196:00
X
▼
▲
198:00
198:00
X
│
200:00
200:00
X
▼
▲
202:00
202:00
X
│
204:00
204:00
X
▼
▲
10
Discharge 
from site
216:00
X
│
▼
4
11
Ambula-tory 
Visit
240:00
X
5
12
Ambula-tory 
Visit
264:00
X
6
13
Ambula-tory 
Visit
288:00
X
10.3
REVERSIBILITY TESTING [P05-12782]
At the screening visit (Visit 1), following the completion of three acceptable 
prebronchodilator forced expiratory manoeuvres, salbutamol (albuterol) will be administered 
to each patient in order to document the degree of reversibility. Immediately after (within 10 
min) pre-bronchodilator forced expiratory manoeuvres and after a gentle and incomplete 
expiration, a dose of 100 μg of salbutamol (albuterol) is inhaled in one breath to total lung 
capacity (TLC). The breath is then held for 5–10 s before the patient exhales. Four separate 
doses (total dose 400 μg) are delivered at approximately 30-s intervals (this dose ensures that 
the response is high on the salbutamol [albuterol] dose–response curve). Three additional, 
acceptable post-bronchodilator forced expiratory manoeuvre tests are recorded ≥10 min and 
up to 15 min after the last dose of salbutamol (albuterol) is inhaled.


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Calculations will be based on Global Lung Function Initiative (GLI) formula [R15-0845].
10.4
BODY PLETHYSMOGRAPHY MEASUREMENT TECHNIQUE AND 
SPIROMETRY
The body plethysmography procedures will be performed in “linked” manoeuvers, i.e. 
without the patient coming off the mouthpiece prior to the completion of the manoeuvers.
The body plethysmography procedures will comprise (Figure 10.4: 1):
Figure 10.4: 1
Example of body plethysmography maneuver [R08-1121]

quiet tidal volume breathing, End-expiratory Lung Volume (EELV), followed by

shutter closing at EELV and panting with hands over cheeks, followed by

opening of the shutter and return to quiet tidal breathing (ensuring stable EELVs, 
which are at the same position as those prior to shutter closing), followed by

an Expiratory Reserve Volume (ERV) manoeuver, followed by a SVC/FVC 
manoeuvre (slow inspiration followed by a forced expiration)
Note:
The term “body plethysmography” is being used for specified measurements in the body box 
(MRD) or as well for “normal” spirometric measurements.
Spirometry (FEV1, FVC, 
 will be performed using the body box system or via a 
stand-alone spirometer.


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The following parameter will be determined/ calculated (in MRD part only) at screening, at 
Day -1, after 9 days of treatment and at Visit 8:

FEV1/FVC

FEV1: the highest FEV1 from an acceptable maneuver

FEF 25-75

Raw:
secondary (efficacy) endpoint
10.5
STANDARD CONVERSION TABLE FOR DIFFERENT ALCOHOL 
TYPES
For conversion of different alcohol types the electronical calculation by the validated system 
ClinBaseTM is used.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Number of global amendment
1
Date of CTP revision
18 June 2019
EudraCT number
2019-000805-60
BI Trial number
1371-0008
BI Investigational Product(s)
BI 894416
Title of protocol
Safety, tolerability, pharmacokinetics 
 
 of single rising oral doses and 
multiple rising oral doses of BI 894416 versus 
placebo in male patients with asthma 
 
 
(single-blind, randomised, 
placebo-controlled, parallel group design).
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
-
Title page
-
Synopsis
-
Flowchart SRD
-
Flowchart SRD/Timeschedule
-
Flowchart MRD
-
Flowchart MRD/Timeschedule
-
Flowcharts MRD+Midazolam
-
Section 1
-
Section 2.1.1
-
Section 2.2.2
-
Section 3.1
-
Section 3.3


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Number of global amendment
1
-
Section 3.3.3
-
Section 3.3.4.1
-
Section 3.3.4.4
-
Section 3.3.5
-
Section 4.1.1
-
Section 4.1.4
-
Section 4.1.6
-
Section 4.2.2
-
Section 5.1.2
-
Section 5.2.1
-
Section 5.2.5.2
-
Section 5.3.1
-
Section 5.3.2.1
-
Section 5.3.3.1
-
Section 6.1
-
Section 6.2.1
-
Section 7.3.3.1
-
Section 8.7
-
Section 9
-
Section 10.2
-
Section 10.6
Description of change
-
Title page: Title adapted
-
Synopsis: Title adapted, description of 
treatment adapted
-
Flowchart SRD and SRD/Timeschedule: 
Insertion of echocardiography assessment, 
extension of screening period to 4 weeks, 
addition of assessment at Follow-Up visit.
-
Flowchart MRD: addition of several 
screening assessments at FU visits and
insertion of echocardiography assessment, 
extension of screening period to 4 weeks
-
Flowchart MRD/Timeschedule: urine PK 
sampling at timepoint 191h removed, 
insertion of several screening assessments 
at FU visits and echocardiography 
assessment, extension of screening period 
to 4 weeks.
-
Flowchart MRD+
: deleted
-
Section 1, 2.2.2, 3.1; 4.1.1, 4.1.4, 4.1.6, 
4.2.2, 5.1.2, 5.3.2.1, 5.3.3.1, 6.1, 6.2.1, 
7.3.3.1, 8.7, 9, 10.2, and 10.6:
 
 
-
Section 1.4: insertion of benefit statement


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Number of global amendment
1
-
Section 1.4.1: Insertion of benefit-risk 
statement for patients with higher age and 
BMI
-
Section 1.4.2: insertion of risks related to 
echocardiography
-
Section 1.4.3.1: Insertion of risk statement
-
Section: 1.4.3.3: Insertion of 
echocardiography assessment
-
Section 2.1.1: clarification of main 
objectives
-
Section 3.3: clarification on selected study 
population
-
Section 3.3.3: EXCL 1, 5 and 12 adapted, 
addition of EXCL 6
-
Section 3.3.4.1: added treatment stopping 
rule
-
Section 3.3.4.4: reworded trial 
discontinuation stopping rule
-
Section 3.3.5: included maximum no of 
patients to be replaced
-
Section 5.2.1: Insertion of 
echocardiography assessment
-
Section 5.2.5.2: changed rule for storage 
of continuous ECG data
-
Section 5.3.1: deletion of ClinBase™
-
Section 6.2.1: addition of 
echocardiography
Rationale for change
-
Flowchart MRD/time schedule: correction 
as this assessment is not planned at this 
time point.
-
Section 5.3.1: correction
-
All other changes were made based on 
clarification letters from German 
Competent Authority (BfArM) and EC 
and after internal discussion to meet the 
requirements of the regulators.


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11.2
GLOBAL AMENDMENT 2
Number of global amendment
2
Date of CTP revision
22 November 2019
EudraCT number
2019-000805-60
BI Trial number
1371-0008
BI Investigational Product(s)
BI 894416
Title of protocol
Safety, tolerability, pharmacokinetics 
 
of single rising oral doses and 
multiple rising oral doses of BI 894416 versus 
placebo in male patients with asthma 
 
 
(single-blind, randomised, 
placebo-controlled, parallel group design).
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
-
Title page
-
Synopsis
-
Flowchart MRD/Timeschedule
-
Table 3.1: 1
-
Figure 3.1: 1
-
Section 3.3.1
-
Section 4.1.2
-
Table 4.1.2: 1
-
Table 4.1.4: 1
-
Section 7.7
-
Figure 10.1: 1
Description of change
-
Title page: document number, version 
number and date adapted
-
Synopsis: revision date adapted, insertion 
of interim dose 170mg


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Number of global amendment
2
-
Flowchart MRD/Timeschedule: correction 
(Vital signs at visit 2).
-
Table 3.1: 1: information on 170 mg dose 
added
-
Figure 3.1: 1: information on 170 mg dose 
added
-
Section 3.3.1: correction
-
Section 4.1.2: information on 170 mg dose 
added
-
Table 4.1.2: 1: information on 170 mg 
dose added, predicted PK parameters 
adapted
-
Table 4.1.4: 1: information on 170 mg 
dose added
-
Section 7.7: information on 170 mg dose 
added
-
Figure 10.1: 1: information on 170 mg 
dose added
Rationale for change
With the exception of the corrections, all changes 
were made based on the decision to reduce the 
dose of the next planned SRD 3 dose level 
according to the rules for dose reduction outlined 
in sections 3.1 and 4.1.2


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11.3
GLOBAL AMENDMENT 3
Number of global amendment
3
Date of CTP revision
23 January 2020
EudraCT number
2019-000805-60
BI Trial number
1371-0008
BI Investigational Product(s)
BI 894416
Title of protocol
Safety, tolerability, pharmacokinetics 
 
of single rising oral doses and 
multiple rising oral doses of BI 894416 versus 
placebo in male patients with asthma 
 
single-blind, randomised, 
placebo-controlled, parallel group design).
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
-
Title page
-
Flowchart SRD/Overview
-
Section 3.3.4.5
-
Section 4.1.2, Interim Dose Levels
-
Table 5.2.4: 1
-
Section 5.2.4
-
Section 5.2.6.2.2
-
Section 5.3.2.3, 
 
l
-
Section 6.2.1, Further Procedures at Visit 
1
-
Section 7.7
Description of change
-
Title page: document number, version 
number and date adapted
-
Flowchart SRD/Overview: subclause in 


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Number of global amendment
3
footnote 3 deleted
-
Section: 3.3.4.5: new discontinuation rule 
added
-
Section 4.1.2, Interim Dose Levels: 
wording added regarding escalation mode
-
Table 5.2.4: 1: new test added
-
Section 5.2.4: text deleted
-
Section 5.2.6.2.2: text in first paragraph 
adapted 
-
Section 5.3.2.3, 
 
-
Section 6.2.1, Further Procedures at Visit 
1: 3rd bullet point, text added 
-
Section 7.7: text added in the 3rd
paragraph
Rationale for change
-
Title page: adaptations regarding protocol 
amendment
-
Flowchart SRD/Overview/ Section 6.2.1, 
Further Procedures at Visit 1: changes to 
allow for one re-screening attempt
-
Section: 3.3.4.5: text added to allow to 
stop a study part in case escalation to the 
next dose group is possible but meaningful 
knowledge gain is not expected.
-
Section 4.1.2, Interim Dose Levels: 
wording added to describe the linkage 
between interim SRD5 and MRD3
-
Table 5.2.4: 1: assay added to allow for 
platelet function testing
-
Section 5.2.4: correction, obsolete text
-
Section 5.2.6.2.2: adapted text according 
to new BI standard to reflect, that fax 
transmissions are no longer supported in 
some countries.
-
Section 5.3.2.3, 
 
 clarification
-
Section 7.7: clarification


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11.4
GLOBAL AMENDMENT 4
Number of global amendment
4
Date of CTP revision
15 May 2020
EudraCT number
2019-000805-60
BI Trial number
1371-0008
BI Investigational Product(s)
BI 894416
Title of protocol
Safety, tolerability, pharmacokinetics 
 
s of single rising oral doses and 
multiple rising oral doses of BI 894416 versus 
placebo in male patients with asthma 
 
 
(single-blind, randomised, 
placebo-controlled, parallel group design).
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
-
Title page
-
Protocol Synopsis
-
Flow Chart SRD - Overview
-
Flow Chart MRD – Overview
-
Flow Chart MRD – Time Schedule
-
Section 1.4.4 and 1.4.5
-
Section 3.1 – Part 2 (MRD Portion)
-
Figure 3.1: 1
-
Table 3.1: 2
-
Section 3.3.4.1
-
Section 4.1.2
-
Table 4.1.2: 1
-
Table 4.1.2: 2
-
Table 4.1.2: 3
-
Table 4.1.2: 4


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Number of global amendment
4
-
Table 4.1.4: 2
-
Table 5.2.4: 1
-
Section 5.2.4
-
Section 5.3.2.2
-
Section 6.1
-
Section 7.7
-
Section 8.7
-
Appendix 10.2 – Table 10.2 : 1
Description of change
-
Title page: document number, version 
number and date adapted
-
Protocol Synopsis: addition of interim 
dose group, administrative changes
-
Flow Chart SRD and MRD/Overviews:
addition of cotinine test and SARS-CoV-2 
test
-
 
-
Section 1.4.4 and 1.4.5: risk section added
-
Section 3.1 – Part 2 (MRD Portion): 
changed wording
-
Figure 3.1: 1: updated study design
-
Table 3.1: 2: new values added 
-
Section 3.3.4.1: new discontinuation rule 
added
-
Section 4.1.2: Interim Dose Levels: 
wording added regarding escalation mode
-
Table 4.1.2: 1 and 4.1.2: 3: new values 
added
-
Table 4.1.2: 2 and Table 4.1.2: 4: new 
tables added
-
Table 4.1.4: 2: updated table
-
Table 5.2.4: 1: updated table
-
Section 5.2.4: text regarding additional 
tests/test lab added
-
Section 5.3.2.2: new dose group added
-
Section 6.1: new wording describing the 
order of assessments
-
Section 7.7 added text regarding MRD5
-
Section 8.7: added text regarding use of 
laboratory
-
Appendix 10.2 – Table 10.2 : 1: new 
information regarding test mode
Rationale for change
-
Title page: adaptations regarding protocol 
amendment
-
Protocol Synopsis: interim dose group 


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Number of global amendment
4
based on descriptions in Section 3.1 – Part 
2 (MRD Portion)
-
Flow Charts SRD/MRD Overview: new 
safety measures re SARS-Cov-2 pandemic 
and supportive lab value for exclusion of 
current smokers.
-
 
-
Section 1.4.4 and 1.4.5: description of 
risks and safety measures related to
SARS-CoV-2 and COVID-19
-
Section 3.1 – Part 2 (MRD Portion): 
clarification regarding exposures from 
SRD covering exposures from MRD dose 
groups
-
Figure 3.1: 1: addition of MRD5
-
Table 3.1: 2: information for new MRD 5 
(60 mg tid) interim dose added
-
Section 3.3.4.1: rule regarding 
discontinuation of SARS-CoV-2 positive 
patients
-
Section 4.1.2, Interim Dose Levels: 
wording added to describe the linkage 
between interim SRD and MRD
-
Table 4.1.2: 1 and 4.1.2: 3 values were 
updated based on the latest predictions 
including all completed dose groups
-
Table 4.1.2: 2 and Table 4.1.2: 4: new 
values for obtained PK parameters added 
from all completed dose groups
-
Table 4.1.4: 2: information for new dose 
group added
-
Table 5.2.4: 1: new test for SARS-CoV-2 
added
-
Section 5.2.4: addition of the lab 
responsible for SARS-CoV-2 testing and 
change of the lab for PFA. Description of 
additional tests for cotinine and SARS-
CoV2.
-
 
-
Section 6.1: wording to allow urine 
sampling prior to ECG


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Number of global amendment
4
-
Section 7.7: description of changed 
samples size due to MRD5
-
Section 8.7: information on 2nd site of 
local laboratory added
-
 
 


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11.5
GLOBAL AMENDMENT 5
Number of global amendment
5
Date of CTP revision
14 October 2020
EudraCT number
2019-000805-60
BI Trial number
1371-0008
BI Investigational Product(s)
BI 894416
Title of protocol
Safety, tolerability, pharmacokinetics 
 
 of single rising oral doses and 
multiple rising oral doses of BI 894416 versus 
placebo in male patients with asthma 
 
 
single-blind, randomised, 
placebo-controlled, parallel group design).
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
-
5.3.2.1 Blood sampling for 
pharmacokinetic analysis
Description of change
-
 
Rationale for change
-
Expand the use of PK plasma samples


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21616656
6.0
clinical-trial-protocol-version-06
Safety, tolerability, pharmacokinetics 
 of single rising oral
doses and multiple rising oral doses of BI 894416 versus placebo in male patients
with asthma (single-blind, randomised, placebo-controlled, parallel group design).
Approval-Therapeutic Area Head
15 Oct 2020 14:46 CEST
Approval-Clinical Trial Leader
15 Oct 2020 15:39 CEST
Author-Trial Statistician
16 Oct 2020 08:15 CEST
Approval-Team Member Medicine
19 Oct 2020 03:57 CEST
Author-Clinical Pharmacokineticist
19 Oct 2020 10:38 CEST
Verification-Paper Signature
Completion
26 Oct 2020 14:13 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21616656
6.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c31207422-01
BI Trial No.:
1371-0008
Title:
Safety, tolerability, pharmacokinetics 
 of 
single rising oral doses and multiple rising oral doses of BI 894416 
versus placebo in male patients with asthma (singleblind, 
randomised, placebo-controlled, parallel group design).
(including Protocol Amendments No.1-5 [c21616656-06])
Investigational
Product:
BI 894416
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
10 FEB 2021 SIGNED
Version:
1
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS..........................................................................................................9
5.1
PRIMARY ENDPOINT........................................................................................9
5.2
SECONDARY ENDPOINTS ...............................................................................9
5.2.1
Key secondary endpoint........................................................................................9
5.2.2
Secondary endpoints .............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................15
6.3
SUBJECT SETS ANALYSED ...........................................................................16
6.5
POOLING OF CENTRES..................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................20
7.
PLANNED ANALYSIS ......................................................................................25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........27
7.2
CONCOMITANT DISEASES AND MEDICATION......................................27
7.3
TREATMENT COMPLIANCE ........................................................................27
7.4
PRIMARY ENDPOINT......................................................................................27
7.5
SECONDARY ENDPOINTS .............................................................................27
7.5.1
Key secondary endpoints ....................................................................................27
7.5.2
Secondary endpoints ...........................................................................................27
7.7
EXTENT OF EXPOSURE .................................................................................32
7.8
SAFETY ANALYSIS..........................................................................................32
7.8.1
Adverse Events ....................................................................................................32
7.8.2
Laboratory data...................................................................................................34
7.8.3
Vital signs.............................................................................................................34
7.8.4
ECG ......................................................................................................................34
7.8.5
Others ...................................................................................................................36
8.
REFERENCES ....................................................................................................38


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10.
HISTORY TABLE..............................................................................................43


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR – SRD part ......................................13
Table 6.1: 2
Labels for treatments for use in the CTR – MRD part .....................................14
Table 6.2: 1
Handling of iPDs ..............................................................................................16
Table 6.3: 1
Subject sets analysed ........................................................................................19
Table 6.7: 1
Time schedule of 12-lead ECG recordings – SRD part....................................22
Table 6.7: 2
Time schedule of 12-lead ECG recordings – MRD part ..................................23
Table 10: 1
History table .....................................................................................................43


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
website: glossary
Term
Definition / description
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
 
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ
BLQ
Below limit of quantification
BMI
Body mass index
BMS
Biomarker Set
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state
CSD
Company standard displays
CV
Arithmetic Coefficient of Variation
DBLM
Database Lock Meeting
DILI
Drug induced liver injury
ECGPCS
ECG Pharmacokinetic Concentration Set
FEF 25-75
Forced Expiratory Flow at 25-75%
FEV1
Forced Expiratory Volume (Pressure) in 1 second
FVC
Forced (expiratory) Vital Capacity
gCV
Geometric Coefficient of Variation


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Term
Definition / description
gMean
Geometric Mean
LI
Linearity Index
LLOQ
Lower limit of quantification
LLT
Lower Level Term
IQRMP
Integrated Quality and Risk Management Plan
Max
Maximum
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PEF
Peak Expiratory Flow
PKS
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile
RAGe
Report Appendix Generator system
RV
Residual Volume
SD
Standard Deviation
sd
Single dose
SVC
Slow Vital Capacity
 
TS
Treated Set
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary


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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 
endpoints and other data.
This trial statistical analysis plan (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, randomisation.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
 
The statistical analyses will be performed within the validated working environment CARE, 
including SAS® (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number of 
SAS®-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP.
In addition, an enrolled set (ES) and an ECG pharmacokinetic concentration set (ECGPCS) 
have been introduced. The ECGPCS is used for the ECG exposure response analysis.
Additionally, the linearity index will be determined in the MRD part (see section 7.6 for 
details).
In CTP Section 7.5.1 it is stated that it is not planned to impute missing values for safety 
parameters. Nevertheless, according to BI standards, missing or incomplete AE dates as well 
as missing baseline laboratory parameters will be imputed. Standards for ECG endpoint 
calculations are also applied (refer to section 6.6 for details). 
 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Section 2.1.2 of the CTP: Primary endpoint to assess safety and tolerability of BI 894416 is 
the percentage of patients with drug-related adverse events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
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:
Efficacy Endpoints: (for lung function and small airway assessment) from MRD part:

Airway resistence (Raw) after 7 days of t.i.d. treatment
Pharmacokinetic Endpoints for BI 894416:
SRD part: 

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)
MRD part:
After the first dose:

AUC0-8 (area under the concentration-time curve of the analyte in plasma over the
time interval 0 to 8h)

Cmax (maximum measured concentration of the analyte in plasma)
After the last dose:

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)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatments and 
selection of doses, please see CTP, Section 4.
The study will be performed as randomised, placebo-controlled, single-blind, parallel group 
study with two parts (SRD part and MRD part) in patients with mild asthma. 
If not otherwise stated, the two trial parts (SRD and MRD) will be evaluated separately.
It is planned that 50 patients will be treated with a single dose of BI 894416 or Placebo in the 
SRD part of the trial and 50 patients will be treated up to 7 days with tid dosing and 2 days
with qd dosing of BI 894416 or Placebo in the MRD part of the trial. Both trial parts consist 
of 5 dose groups comprising a planned number of 10 patients per group (8 on active 
treatment, 2 on Placebo).
Table 6.1: 1
Labels for treatments for use in the CTR – SRD part
Dose 
group
Sort 
order
Treatment
Short label
1
P+
Matching Placebo tablet q.d.
Placebo sd
1
2
A
75 mg BI 894416 tablet q.d.
BI 75mg sd
2
3
B
125 mg BI 894416 tablet q.d.
BI 125mg sd
5
4
K
170 mg BI 894416 tablet q.d.
BI 170mg sd
3
5
C
175 mg BI 894416 tablet q.d.
BI 175mg sd
4
6
D*
225 mg BI 894416 tablet q.d.
BI 225mg sd
*The dosage may be reduced to a dose >175 mg and <225 mg in case that preliminary PK analysis predict 
that a dose lower than 225 mg is needed to not exceed the limits of exposure
+The placebo group in the safety evaluation will consist of all patients treated with placebo, regardless of 
the dose group in which they were treated.
The SRD part was stopped after dose group BI 170mg single dose (sd) as exposure limits 
outlined in the CTP were reached. Dose groups BI 175mg sd and BI 225mg sd were not 
performed.


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Table 6.1: 2
Labels for treatments for use in the CTR – MRD part
Dose 
group
Sort 
order
Treatment
Short label
1
R+
Matching Placebo tablet t.i.d.
Placebo tid
1
2
F
10 mg BI 894416 tablet t.i.d.
BI 10mg tid
2
3
G
25 mg BI 894416 tablet t.i.d.
BI 25mg tid
3
4
H
50 mg BI 894416 tablet t.i.d.
BI 50mg tid
5
5
L
60 mg BI 894416 tablet t.i.d.
BI 60mg tid
4
6
I*
70 mg BI 894416 tablet t.i.d.
BI 70mg tid
+The placebo group in the safety evaluation will consist of all patients treated with placebo, regardless of 
the dose group in which they were treated.
*The dosage may be reduced to a dose >50 and <70 mg tid in case that preliminary PK analysis predict that 
a dose lower than 70 mg tid is needed to not exceed the limits of exposure (CTP Section 4.1.2) or to not 
exceed the exposure covered by the SRD part of the trial with predicted gMean Cmax,ss and AUC0-24,ss
values.
With CTP version 5.0, an interim dose group (dose group 5) of 60 mg tid is inserted between 
dose group 3 and 4. Dose group BI 70mg tid was not performed.
Section 1.2.2 of the CTP: …the individual patient’s end of trial is 14 days following last 
dosing with BI 894416 or placebo at the earliest.
All AEs reported between administration of BI 894416 and the individual patient’s end of
trial will be counted as on-treatment AEs.
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00h (midnight) on day of informed consent until first 
administration time of study drug (BI 894416 or Placebo))

On treatment
o
BI/Placebo treatment (separately for each treatment, ranging from the time of 
first administration of BI 894416/Placebo until 0:00h (midnight) on the day after 
trial completion date)
The following AE displays will be provided in the report:
Section 15.3 (separately for SRD and MRD part) and Appendix 16.1.13.1.8 (for 
ClinicalTrials.gov and EudraCT only but combined for SRD and MRD part) 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 will not be included in this analysis. 
The following totals will be provided in section 15.3 in addition:

a total over all on-treatment phases ("Total") 

a total over all on-treatment phases involving BI 894416 ("BI Total")


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The following totals will be provided in section 16.1.13.1.8 in addition:

a total over all on-treatment phases ("Total") 

a total over all on-treatment phases ("Total - SRD part") 

a total over all on-treatment phases ("Total - MRD part") 

a total over all on-treatment phases involving BI 894416 ("BI Total") 

a total over all on-treatment phases involving BI 894416 ("BI Total – SRD part") 

a total over all on-treatment phases involving BI 894416 ("BI Total – MRD part") 
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays the screening period will be 
included and no totals will be provided.
Tables of vital signs and laboratory values will present results by the above mentioned on-
treatment phase.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated patients.
Section 7.3 of the CTP: Important protocol deviation (iPD) categories will be specified in 
the iQRMP, iPDs will be identified no later than in the Report Planning Meeting, and the iPD 
categories will be updated as needed.
Consistency check listings (for identification of deviations of 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 and database lock meeting
(RPM/DBLM). At this meeting, all manual deviations identified at the sites by the CRAs and 
deviations too complex to program will be reviewed by the trial team to decide which are 
considered important. For definition of important protocol deviations (iPD), and for the 
process of identification of these, refer to the Boehringer Ingelheim (BI) SOP "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 RPM/DBLM minutes and decision log as well as an accompanying Excel spreadsheet (3). 
Categories which are considered to be iPDs in this trial are defined in the integrated quality 
and risk management plan (IQRMP). If the data show other iPDs, the definition in the 
IQRMP will be supplemented accordingly by the time of the Report Planning Meeting.
The iPDs will be summarised and listed.
Table 6.2: 1 below specifies which kind of iPDs could potentially lead to exclusion from 
which analysis set. The decision on exclusion of patients from analysis sets will be made at 
the latest at the Report Planning Meeting, after discussion of exceptional cases and 
implications for analyses.


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Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief Description
Excluded from which analysis set
iPD B1 
Informed consent not available/not 
done
All
iPD B2 
Informed consent too late
None
iPD B3
Wrong informed consent form signed
All
iPD A
In-/Exclusion Criteria Not Met
PKS, BMS, ECGPCS
iPD C1
Incorrect trial medication taken
PKS, BMS, ECGPCS
iPD C2
Randomisation not followed
PKS, BMS, ECGPCS
iPD C3
Wrong dosage schedule
PKS, BMS, ECGPCS
iPD C4
Incorrect intake of trial medication
PKS, BMS, ECGPCS
iPD D1
Prohibited medication use
PKS, BMS, ECGPCS
iPD D2
Improper washout of concomitant 
medication
PKS, BMS, ECGPCS
iPD E1
Certain violations of procedures used 
to measure primary or secondary data
PKS, BMS, ECGPCS
iPD F1
Certain violations of time schedule 
used to measure primary or secondary 
data
PKS, BMS, ECGPCS
iPD G1
PDs affecting efficacy, safety and 
rights
PKS, BMS, ECGPCS
iPD G2
Certain deviations of time schedule 
with respect to nutrition
PKS, BMS, ECGPCS
iPD Q1
Missed examination
PKS, BMS, ECGPCS
iPD Q2
Missed visit
PKS, BMS, ECGPCS
iPD Q3
Drug shipment
PKS, BMS, ECGPCS
6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP: Statistical analyses will be based on the following analysis sets:

Enrolled Set (ES):
This subject set includes all patients who were enrolled in the study regardless of 
whether they were treated or not. The ES is used for the disposition table / listing.

Treated set (TS): The treated set includes all patients who were randomised and 
treated with at least one dose of study drug. The treatment assignment will be 


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determined based on the first treatment the patients received. The treated set will be 
used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all patients in the 
treated set (TS) who provide at least one 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 patient will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.

 
 
 
 

ECG Pharmacokinetic Concentration Set (ECGPCS):
This subject set includes all patients from the TS who provide at least one pair of a 
valid drug plasma concentration of BI 894416 and a corresponding (i.e. time-matched) 
ECG endpoint to be used in the exposure-response analyses. For placebo patients, the 
plasma concentration is set to zero and hence always considered as valid. The decision 
whether a time deviation between PK blood sampling and ECG recording is 
acceptable (and thus whether the pair of values will be used) is to be made no later 
than at the RPM before data base lock.
All ECG analyses are performed on the TS, except for the exposure-response analyses, 
which are performed on the ECGPCS.
Pharmacokinetics
Plasma and urine concentration data and parameters of a patient 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 patient’s data will be 
documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the patient received at least one dose of trial 
medication the patient was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine concentrations and/or parameters of a patient will be considered as 
nonevaluable, if for example


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
The patient experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the patients 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
Plasma/urine concentration data and parameters of a patient which is flagged for 
exclusion will be reported with its individual values but will not be included in the 
statistical analyses.
Only concentration values within the validated concentration range and actual sampling 
times will be used for the calculation of pharmacokinetic parameters. Concentrations 
used in the pharmacokinetic calculations will be in the same format as in the bioanalytical 
report (that is to the same number of decimal places provided in the bioanalytical report).
 


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
ES
TS
PKS
BMS
ECGPCS
Analysis of PK endpoints
X
ECG endpoints and plasma 
concentrations used in exposure-
response analysis
X
Safety parameters
X
Demographic/baseline  parameters
X
Important protocol deviations
X
Disposition
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
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035 (4)).
Missing data and outliers of PK/
data are handled according to BI standards (see 001-
MCS-36-472_RD-01) (5).
Missing baseline laboratory values will be imputed by the respective values from screening.
Unscheduled measurements of laboratory data or vital signs 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. Adherence to time windows will be 
checked via the consistency check listings at the RPM/DBLM.
If single cardiac cycles of an ECG (out of the generally four) are missing, the arithmetic mean 
for this single ECG will be computed with the reduced (1, 2 or 3) number of cardiac cycles.
If all cardiac cycles of an ECG are missing, no imputation will be done.


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If replicate ECG recordings are missing, the arithmetic means per time point will be computed 
with the reduced number (1 or 2) of recordings.
For the classification of the on-treatment QTc/QT intervals into “no new onset” / “new onset”
categories, a missing value is obtained only in case that
(i) all on-treatment values are missing and
(ii) the baseline value is less than or equal to 500 msec, or missing.
If condition (i) is fulfilled but the baseline value is greater than 500 msec, this case will be
categorized as ‘no new onset’. If baseline is missing and the maximum on-treatment QTc 
interval is greater than 450 msec (or 500 msec for QT interval, respectively), this is classified 
as a ‘new onset’ in the respective category. If baseline is missing and the maximum QTc 
interval is less than or equal to 450 msec (or 500 msec for QT interval, respectively), this will 
be categorized as ‘no new onset’. If baseline is missing, a QTc/QT interval > 500 msec at any 
time on treatment will be a notable finding.
For placebo patients the missing plasma concentration values will be replaced by 0 for the
exposure response analysis. For patients on active drug, missing plasma concentration values
with ‘BLQ’ in the comment field will not be replaced.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before first administration of BI 894416 
(SRD part: value at V3, ptm -3:00, MRD part: value at V3, ptms -17:00, -1:00, -0.05 ). 
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 Charts.
If Screening Visit is performed on Day -3 (within 76 hours) prior to administration of trial
drug, the ambulatory Visit 2 can be omitted.
Study measurements and assessments scheduled to occur ‘before’ trial medication
administration on Day 1 are to be performed and completed within a 3 h-period prior to the
trial drug administration (including blank values for PK and biomarkers).
In the SRD part, the acceptable deviation from the scheduled time for vital signs, ECG, and
laboratory tests will be ± 15 min for the first 4 h after trial drug administration, ± 30 min
thereafter on Day 1 and ± 90 min on Day 2.
The acceptable deviation from the scheduled time for neurological tests in the SRD part is 
± 45 min on Day 1 and ± 90 min on Day 2.
Starting from 48 h post administration a time window of ±120 min will be allowed for all
study activities (incl. PK and biomarker sampling) in the SRD part.
In the MRD part, the acceptable deviation from the scheduled time for vital signs, ECG, and
laboratory tests will be ± 15 min for the first 4 h after trial drug administration on Day 1 


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and Day 9, ± 30 min thereafter on Day 1 and Day 9, ± 90 min on Day 2 and on Day 10 and 
± 120 min from Day 11 onwards.
The acceptable deviation from the scheduled time for neurological tests in MRD part is 
± 4 min on Day 1, and ± 90 min on Day 2.
From Day 3 until Day 8 and from 48 h post last administration on Day 9 a time window of
± 120 min will be allowed for all study activities (incl. PK and biomarker sampling) in the
MRD part, except PK samples taken pre dose on Days 5, 7 and 8. Pre dose PK samples are
taken within a time window of 15 min prior to drug administration.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.
If Visit 2 is omitted because Visit 1 was performed within 76 hours prior to the trial drug 
administration, the Visit 1 ECG data were transferred as Visit 2 data.
There will be a centralised evaluation of the 12-lead ECG recordings at the time points and 
for the ECG recordings specified in the Table 6.7: 1 and the Table 6.7:2 below:


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Table 6.7: 1
Time schedule of 12-lead ECG recordings – SRD part
Visit
Day
Planned time 
[hh:mm]
(relative to drug 
administration)
Study phase
Central evaluation
1
-28 to 
-3
Screening
NA
2
-3 to -1
-72:00
-71:45
-71:30
(separated by at least 
15minutes)
Pre-treatment
All three ECGs of the triplicate
Pre-treatment
All three ECGs of the triplicate
Pre-treatment
All three ECGs of the triplicate
3
1
-3:00
Baseline 
All three ECGs of the triplicate
0:30
On treatment
first single ECG of the triplicate
1:00
On treatment
first single ECG of the triplicate
1:30
On treatment
first single ECG of the triplicate
2:00
On treatment
first single ECG of the triplicate
2:30
On treatment
first single ECG of the triplicate
3:00
On treatment
first single ECG of the triplicate
4:00
On treatment
first single ECG of the triplicate
6:00
On treatment
first single ECG of the triplicate
8:00
On treatment
first single ECG of the triplicate
12:00
On treatment
first single ECG of the triplicate
2
24:00
On treatment
first single ECG of the triplicate
34:00
On treatment
NA
4
3
48:00
On treatment
NA
5
4
72:00
On treatment
NA
8
15-17
End of trial 
examination
NA
At Visit 1 single ECGs will be recorded.
At Visit 2 and Visit 3 (up to planned time 24:00h) triplicate ECGs will be recorded. For the 
four pre-dose triplicate ECGs all three single ECGs will be evaluated. For the other triplicate 
ECGs only the first single ECG will be evaluated.
At Visit 3 (planned time 34:00h) and Visits 4-8, single ECGs will be recorded.


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Table 6.7: 2
Time schedule of 12-lead ECG recordings – MRD part
Visit
Day
Planned time [hh:mm]
(relative to drug 
administration)
Study phase
Central evaluation
1
-28 to 
-3
Screening
NA
3
-1
-17:00
-16:45
-16:30
(separated by at least 
15minutes)
Pre-treatment
All three ECGs of the triplicate
Pre-treatment
All three ECGs of the triplicate
Pre-treatment
All three ECGs of the triplicate
-1:00
Baseline 
All three ECGs of the triplicate
3
1
0:30
On treatment
first single ECG of the triplicate
1:00
On treatment
first single ECG of the triplicate
1:30
On treatment
first single ECG of the triplicate
2:00
On treatment
first single ECG of the triplicate
2:30
On treatment
first single ECG of the triplicate
3:00
On treatment
first single ECG of the triplicate
4:00
On treatment
first single ECG of the triplicate
6:00
On treatment
first single ECG of the triplicate
8:00
On treatment
first single ECG of the triplicate
12:00
On treatment
first single ECG of the triplicate
2
24:00
On treatment
first single ECG of the triplicate
2
34:00
On treatment
NA
3
47:00, 56:00, 58:00
On-treatment
NA
4
70:30, 80:00
On-treatment
NA
5
104:00
On-treatment
NA
6
128:00
On treatment
NA
7
152:00
On treatment
NA
8
176:00
On treatment
NA
9
191:55
On treatment
first single ECG of the triplicate
192:30
On treatment
first single ECG of the triplicate
193:00
On treatment
first single ECG of the triplicate
193:30
On treatment
first single ECG of the triplicate
194:00
On treatment
first single ECG of the triplicate
194:30
On treatment
first single ECG of the triplicate
195:00
On treatment
first single ECG of the triplicate
196:00
On treatment
first single ECG of the triplicate
198:00
On treatment
first single ECG of the triplicate


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Table 6.7: 2
Time schedule of 12-lead ECG recordings – MRD part - continued
Visit
Day
Planned time [hh:mm]
(relative to drug 
administration)
Study phase
Central evaluation
200:00
On treatment
first single ECG of the triplicate
204:00
On treatment
first single ECG of the triplicate
10
216:00
On treatment
first single ECG of the triplicate
4
11
240:00
On treatment
NA
5
12
264:00
On treatment
NA
6
13
288:00
On treatment
NA
7
16
-
On treatment
NA
8
23-30
-
On treatment
NA
For the four pre-dose triplicate ECGs all three single ECGs will be evaluated. For the other 
triplicate ECGs only the first single ECG will be evaluated. 
Section 5.2.5.1 of the CTP: Central ECG lab evaluation will be performed (during the study 
and/or after the study) for the first of three replicate ECGs per time point. For baseline, all 
three ECGs of the triplicate ECG on Day 1 pre-dose will be evaluated. For the three 
triplicate ECGs on Day -3 to -1 all ECGs will be evaluated. This will include the 
determination of cardiac QRSaxis as assessed by the ECG machine’s algorithm as well as the 
intervals RR, PR, QRS and QT measured semi-automatically. Heart rate (HR) and the QT 
interval corrected for HR (QTc e.g. QTcF and QTcB) will be determined by the sponsor.
For the exposure response analyses, pairs of ECG variables and corresponding plasma
concentrations will be built using the same planned time points, e.g. HR change from baseline 
and the plasma concentration measured at planned time 1:00 will build one pair.
Whether a time deviation between PK blood sampling time and corresponding ECG recording 
is too big and the pair has to be excluded from the analysis will be decided no later than at the 
RPM. This critical time deviation depends on the PK properties. When plasma concentrations 
are expected to change only little around a given time point, the acceptable time deviation 
between ECG recording and PK blood sampling may be bigger.


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7.
PLANNED ANALYSIS
In general, the two trial parts (SRD and MRD) will be evaluated separately if not stated
otherwise.
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.5.2) will also be performed 
by 
 and will be presented in Section 15.5 of the CTR and in 
Appendix 16.1.13.3.
Descriptive data analysis of PK parameters and concentrations will be performed by the 
department 
 and will be 
presented in Section 15.6 of the CTR.
Descriptive data analysis of gene expression data will also be performed by the department 
 
 
Descriptive data analysis of the efficacy endpoints will be performed by 
 
and will be presented in Section 15.2 of the CTR and in Appendix 16.2.6.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (6)) with the exception of those generated for PK-calculations (7).
The individual values of all patients will be listed, sorted by dose group, patient number, and 
visit. 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations and PK parameters, the following descriptive statistics will 
additionally be calculated:
CV 
arithmetic coefficient of variation


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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 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 (%) for each dose
group. Percentages will be rounded to one decimal place and will be based on all patients in 
the respective subject set whether they have non-missing values or not. The category 'missing' 
will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
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 or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’, the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’, the value can be used for further analyses based on actual times. If ACEXCO 
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (11).


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by dose group and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the latest version of the coding system of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded 
using the latest version of the World Health Organization Drug Dictionary (WHO-DD). The 
coding version number will be displayed as a footnote in the respective output.
The diagnoses and medications will be listed. Patients without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK/biomarker analysis will be 
decided no later than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured sample concentrations will provide additional confirmation of compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINT
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of
BI 894416.
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
Primary analyses:
Section 7.3.2 of the CTP:
The secondary efficacy endpoints (refer to Section 5.2.2 and Section 5.4) will be analysed 
descriptively based on the TS.
Boxplots by time-point and treatment group will be provided (for absolute values and changes 
from baseline).


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Airway resistance includes ‘Total airways resistance’, ‘Total specific airways resistance’, 
‘Effective airway resistance’ and ‘Effective specific airway resistance’.
The secondary PK endpoints (refer to Section 5.2.2) will be analysed descriptively based on
the PKS. Analyses will be performed for the parent drug.
Further exploratory analyses:


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each patient.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by dose group.
The safety data for treated patients who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
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 and will be based on BI standards as 
presented in “Analysis and Presentation of Adverse Event Data from Clinical Trials – Display 
Template” [BI-KMED-BDS-HTG-0041] (8).
The standard AE analyses will be based on the number of patients with AEs (and not on the 
number of AEs). 


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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.
According to the clinical study protocol, adverse events of special interest (AESI) will be 
analysed:
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:
o
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
According to ICH E3 (9), 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).
An overall summary of AEs (including number of patients with any AE, drug related AEs, 
AESIs, serious AEs and drug related serious AEs) will be presented. 
The frequency of patients with AEs will be summarized by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for patients with serious 
AEs, for patients with drug-related AEs, for patients with drug related serious adverse events 
and for patients with AESIs. In addition, the frequency of subjects with AEs will be 
summarised by treatment, worst intensity, primary system organ class (SOC) and preferred 
term (PT).
The SOC and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of patients with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.


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For disclosure of adverse events on EudraCT additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[BI-KMED-BDS-HTG-0042] (10). In addition to the standard descriptive tables, line graphs 
(mean values and standard deviation over time) of absolute values, changes from baseline and 
percent changes from baseline will be provided for the normalised laboratory parameters.
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possible 
clinically significant will be flagged in the data listings. 
Clinically relevant findings in laboratory data will be reported as adverse events if judged 
clinically relevant by the investigator, and will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significant 
abnormal or not (at the RPM/DBLM at the latest).
Descriptive statistics of laboratory data including change from baseline will be calculated by 
visit based on the worst value of the patient at that visit.
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate).
7.8.4
ECG
Continuous ECG monitoring (SRD part only)
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.
Continuous safety ECG monitoring (by investigator)
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.


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12-lead ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator.  
The descriptive evaluations of ECG data will be based on the TS.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
For all patients with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding time profiles will be shown.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time of QTcF, QT, HR, PR and QRS. The time profiles of mean and SD for the 
changes from baseline on treatment will be displayed graphically by treatment.
For QTcF and HR changes from baseline, the relationship to the corresponding plasma
concentrations will be evaluated using a random coefficient model. For patients in the
ECGPCS, all time points with available ECG endpoints and valid time-matched drug plasma
concentrations will be included. For the handling of missing values, see Section 6.6.
The response variable will be the change from baseline in QTcF (ΔQTcF). The placebo
patients will be included in the analysis, setting their plasma concentrations to zero.
As a first step, it is investigated if there is a potential delayed or accelerated (e.g. due to
metabolites) effect of the drug on QTcF. A general visual impression is provided by
overlaying time profiles of plasma concentrations and QTcF changes from baseline (ΔQTcF).
These figures will be generated for each patient (presented in Statistical Appendix of the
CTR), as well as for means per active treatment (presented in the End-of-Text part of the
CTR).
The relationship between BI 894416 plasma concentrations and QTcF changes from baseline 
will be investigated in an exploratory manner using a random coefficient model to estimate 
the difference in means between BI 894416 and placebo of QTcF change from baseline and 
its 90% confidence interval at the geometric mean of the Cmax (SRD part) / Cmax,ss (MRD part)
for each dose. Additionally, the estimated overall slope with its 90% confidence interval will 
be provided. The used random coefficient model is based on a white paper from Garnett et al. 
(12) with ΔQTcF as response variable, centered baseline QTc and plasma concentration as 


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continuous covariates, treatment and time as fixed categorical effects, and a random intercept 
and slope for each patient. For more details refer to Section 9.3.
For visualization, a scatterplot of the BI 894416 plasma concentration against the following
individual QTcF values will be provided: For each patient on active treatment and each time
point, subtract the mean value of all individual observed ΔQTcF values from the placebo
group for this time point from the individual observed ΔQTcF value for this patient and time
point. This results in estimates for “individual ΔΔQTcF” values, which should only be used
for plotting purposes. The corresponding regression line and its pointwise confidence bands
as well as and the geometric mean of Cmax (SRD part) / Cmax,ss (MRD part) for each dose will 
additionally be displayed in the plot.
To check model assumptions, the conditional residuals will be plotted and presented in the
Statistical Appendix of the CTR. In case of non-linearity or if there is evidence for a delayed
effect, further models will be explored in order to better characterise the PK-ECG relationship 
(e.g. effect compartment models, non-linear models, etc.).
All of the above described graphical and statistical analyses will be also performed for HR in
place of QTcF.
Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval (values log-transformed using the natural 
logarithm) will be estimated by applying the random coefficient model described in 
Section 9.1 using all time points. A scatterplot of QTcF vs RR including the overall 
regression line will be included in the Statistical Appendix of the CTR. The resulting (fixed 
effect) slope together with two-sided 95% confidence intervals will be included in the 
footnote for this plot.
7.8.5
Others
Physical examination
Physical examination findings, including general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities, and skin will be reported as relevant medical history/baseline 
condition (i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.
Neurological examination
Neurological examination findings, including general level of arousal, orientation, eye 
movement, pupil size and pupil reactivity, reflexes, assessment of muscle strength, gait, 
romberg test, tremor, point-to-point movements and sensitivity will be reported as relevant 


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medical history/baseline condition (i.e., a condition already existent before intake of study 
drug) or as AE and will be summarised as such. 
No separate listing or analysis of neurological examination findings will be prepared.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON
3.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, version 1.6, KMED.
4.
BI-KMED-BDS-HTG-0035: "Handling of Missing and Incomplete AE Dates", current 
version; KMED.
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies”, current version; IDEA for CON.
6.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project 
Summaries”, current version; KMED.
7.
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
8.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
9.
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
10. BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; KMED.
11. 001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
12. Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. J Pharmacokin Pharmacodyn 2017 [R18-0143]
13. Ring A. Statistical models for heart rate correction of the QT interval. Stat Med 2010 
[R10-2920]
14. U.S. Department of Health and Human Services. Common terminology criteria for 
adverse events (CTCAE) version 5.0 (published: November 27, 2017).
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v 
5_Quick_Reference_8.5x11.pdf#search=%22CTCAE%22 (access date: 9 April 2017); 
U.S.Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute 2017 [R18-1357]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1 
10-FEB-21
None
This is the final TSAP