Conditions: Healthy Psoriasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 83
Healthy volunteers: yes

Brief summary:
Phase Ib evaluation of the safety, tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) properties of Multiple Rising Dose (MRD) administration of BI 730357 to healthy volunteers for up to 28 days.

Detailed description:

Arms:
arm 1: Subjects were orally administered BI 730357 25 mg, film-coated tablet once daily over 14 days after a fasting period of at least 6 hours arm 2: Subjects were orally administered matching Placebo to BI 730357, film-coated tablet after a fasting period of at least 6 hours. arm 3: Subjects were orally administered matching Placebo to BI 730357, film-coated tablet after the intake of a standard continental breakfast. arm 4: Subjects were orally administered BI 730357 50 mg, film-coated tablet once daily over 14 days after a fasting period of at least 6 hours. arm 5: Subject was orally administered mixed treatment of BI 730357 50 mg and placebo, film-coated tablet once daily over 14 days after a fasting period of at least 6 hours arm 6: Subjects were orally administered BI 730357 50 mg, film-coated tablet once daily over 14 days after the intake of a standard continental breakfast. arm 7: Subjects were orally administered BI 730357 100 mg, film-coated tablet once daily over 14 days after a fasting period of at least 6 hours arm 8: Subjects were orally administered BI 730357 200 mg, film-coated tablet once daily over 28 days after a fasting period of at least 6 hours arm 9: Subjects were orally administered a microdose of midazolam 75 microgram (75 μg) solution for injection, orally on Day -1, and prior receiving BI 730357 on Days 3, and 14. Subjects were orally administered BI 730357 200 mg, film-coated tablet once daily over 28 days after the intake of a standard continental breakfast. arm 10: Subjects were orally administered a microdose of midazolam 75 microgram (75 μg) solution for injection, orally on Day -1, and prior receiving BI 730357 on Days 3, and 14. Subjects were orally administered BI 730357 400 mg, film-coated tablet once daily over 28 days after the intake of a standard continental breakfast.

Interventions: intervention 1: BI 730357 intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: BI 730357 film-coated tablet intervention 2: Placebo intervention 3: Once per day (QD) on Days -1, 3, and 14. Dose groups BI 730357 200 mg fed and BI 730357 400 mg fed

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c14109663-03
EudraCT No.:
2017-001653-14
BI Trial No.:
1407-0002
BI Investigational 
Product(s):
BI 730357
Title:
Phase Ib evaluation of the safety and tolerability and effect on 
midazolam metabolism of the administration of multiple rising 
doses of BI 730357 to healthy volunteers.
Lay Title:
This study tests how healthy men tolerate different doses of 
BI 730357 and how the metabolism of midazolam is affected by 
BI 730357. 
Clinical Phase:
Ib
Trial Clinical 
Monitor:
Phone: 
, Fax:
Principal 
Investigator :
Status:
Final Protocol (Revised Protocol based on Global Amendment  
2)
Version and Date:
Version:
Date:
3.0
12 January 2018
Page 1 of 80
Proprietary confidential information.
2018 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
Finished product name
N/A
Active ingredient name:
BI 730357
Protocol date
19 June 2017
Revision date
12 January 2018
Trial number
1407-0002
Title of trial:
Phase Ib evaluation of the safety and tolerability and effect on 
midazolam metabolism of the administration of multiple rising doses 
of BI 730357 to healthy volunteers
Principal Investigator:
Trial site(s):
Clinical phase:
Ib
Objective(s):
To evaluate the safety, tolerability, pharmacokinetic and 
pharmacodynamic properties of multiple rising doses of BI 730357
when administered to healthy volunteers.
Methodology:
Double-blind, randomised, placebo-controlled, MRD trial
Number of patients
entered: 
up to 84 healthy volunteers
Number of patients on 
each treatment:
12 per dose level; 9 on BI 730357, 3 on Placebo
Diagnosis:
Healthy volunteers


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Main in- and exclusion 
criteria
Inclusion criteria:

Healthy male volunteers 

Age ≥18 to 45 years at screening

BMI of 18.5 to 29.9 kg/m2
Exclusion criteria:

Currently enrolled in another investigational device or drug trial, 
or less than 30 days (from randomisation) since ending another 
investigational device or drug trial(s), or receiving other 
investigational treatment(s)

Live vaccination ≤ 12 weeks prior to randomisation (visit 2), or 
any plan to receive a live vaccination during the conduct of this 
study

Unwillingness to adhere to the rules of UV-light protection as 
described in section 4.2.2.3
Test product(s):
BI 730357
Midazolam
dose:
25 mg, 50 mg, 100 mg, 200 mg, 400 mg BI 730357
75 µg midazolam
mode of 
administration:
Oral
Comparator products:
Placebo to BI 730357
dose:
N/A
mode of 
administration:
Oral
Duration of treatment:
14 to 28 days
Endpoints
Primary

Safety: Number of subjects with drug-related AEs
Secondary
After the first dose:

AUCτ,1 (area under the concentration-time curve of the analyte 
in plasma over a uniform dosing interval τ after administration 
of the first dose)


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
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 over a uniform dosing interval τ)
Safety criteria:
Number of subjects with drug-related AEs
Statistical methods:
Descriptive statistics will be applied for all endpoints 
Dose proportionality of BI 730357 will be explored using a regression 
model. A 95% confidence interval (CI) for the slope will be 
computed.
Linearity index may be estimated using a linear model providing a 
two-sided 95% CI.
Attainment of steady state will be analysed by a repeated measures 
linear model for trough concentrations of BI 730357 with dose as an 
additional covariate if permissible.


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FLOW CHARTS
FLOW CHART 1: PROCEDURES, DOSE GROUPS WITH 14 DAYS 
TREATMENT
Trial periods
Randomisation and
Treatment Period
Follow up
Visit
1
2
3
4
5 to 
7
8
9
10
11
12 to 
14
15
(EOT)
16 
17
18
19
Study Day
-28 to -1
1
2
3
4 to 
6
7
8
9
10 
11 to 
13
14
15 
16
17
21
Informed consent 
x
Demographics, 
medical
history, baseline 
conditions
x
Randomisation
x
Concomitant 
therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Check of in-
/exclusion criteria
x
x
Body height/Body 
weight
x
Vital signs (blood 
pressure, pulse 
rate)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Physical 
examination
x
x
x
x
12-lead resting 
ECG3
x
x
x
x
x
x
x
Safety laboratory 
blood tests 
x
x
x
x
x
x
PK blood sampling
x
x
x
x
x
x
x
x
x
x
x
PK urine sampling
x
x
x
x
Biomarkers
(Whole Blood) 
x
x
x
x
x
x
x
Administration of 
BI 730357/Pbo5
x
x
x
x
x
x
x
x
x
x
Termination of 
study medication
x
Trial completion
x


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FLOW CHART 2: DRUG ADMINISTRATION AND ASSESSMENTS, 
DOSE GROUPS WITH 14 DAYS TREATMENT
Visit
Day
Planned 
Time
[h:min]
Clock time
For
actual day 
[h:min]
Event and 
comment
ECG3
Safety lab
BI 730357
PKblood 
PKurine
Biomarker 
sample
1
-28 to 
-1
Screening and informed 
consent
x
x
2
1
- 0:30
7:30
Randomisation & pre-
dose sampling
x
x4
x
x
0:00
8:00
BI 730357 admin5
x
x
↓
↓
x1,2
0:15
8:15
x
0:30
8:30
x
1:00
9:00
x
1:30
9:30
x
2:00
10:00
x
2:30
10:30
x
3:00
11:00
x
3:30
11:30
x
4:00
12:00
x
6:00
14:00
x
x
8:00
16:00
x
12:00
20:00
x
3
2
23:30
7:30
x
x
24:00
8:00
BI 730357 admin5
x
4
3
47:30
7:30
x2
48:00
8:00
BI 730357 admin5
5 to 7
4 to 6
8:00
BI 730357 admin5
8
7
143:30
7:30
x
x2
x
144:00
8:00
BI 730357 admin5
x
9
8
167:30
7:30
x
168:00
8:00
BI 730357 admin5
10
9
8:00
BI 730357 admin5
11
10
215:30
7:30
x
x2
216:00
8:00
BI 730357 admin5
x
12
11
239:30
7:30
x2
248:00
8:00
BI 730357 admin5
13
12
263:30
7:30
x2
264:00
8:00
BI 730357 admin5
14
13
287:30
7:30
x2
288:00
8:00
BI 730357 admin5
15
14
311:30
7:30
x
x4
x
x
312:00
8:00
BI 730357 admin5
x
x
↓
↓
312:15
8:15
x4
312:30
8:30
x4
313:00
9:00
x4
313:30
9:30
x4
314:00
10:00
x4
314:30
10:30
x4
315:00
11:00
x4
315:30
11:30
x4
316:00
12:00
x4
318:00
14:00
x4
x
320:00
16:00
x4
324:00
20:00
x4


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Visit
Day
Planned 
Time
[h:min]
Clock time
For
actual day 
[h:min]
Event and 
comment
ECG3
Safety lab
BI 730357
PKblood 
PKurine
Biomarker 
sample
16
15
335:30
7:30
x4
x1,2
x
17
16
359:30
7:30
x
18
17
383:30
7:30
x
EOO
21
End of observation
x
x
x
x


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FLOW CHART 3: PROCEDURES, DOSE GROUPS WITH 28 DAYS 
TREATMENT
Trial periods
screeni
ng
Treatment
Follow
-up
Visit
1
1.1
2
3
4
5 
to 
7
8
9
10
11
12
to 
14
15
16
17 
to 
18
19 
to
21
22
23 
to 
24
25
26 
to 
28
29
(EOT)
30
31
Study Day
-28 
to 
-1
-1
1
2
3
4 
to 
6
7
8
9
10
11 
to 
13
14
15
16 
to 
17
18 
to 
20
21
22 
to 
23
24
25 
to 
27
28
29
35
Informed 
consent 
x
Demographics, 
medical
history, baseline 
conditions
x
Randomisation
x
Concomitant 
therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Check of in-
/exclusion 
criteria
x
x
x
Body 
height/Body 
weight
x
Vital signs 
(blood pressure, 
pulse rate)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Physical 
examination
x
x
x
x
12-lead resting 
ECG3
x
x
x
x
x
x
x
Safety 
laboratory blood 
tests 
x
x
x
x
x
x
Midazolam
PK blood 
sampling
x
x
x
BI 730357
PK blood 
sampling
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PK urine 
sampling
x
x
x
x
Biomarkers 
(whole blood) 
x
x
x
x
x
x
x
x
x
x
Administration 
of Midazolam6
x
x
x
Administration 
of 
BI 730357/Pbo5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Termination of 
trial medication
x
Trial completion
x


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FLOW CHART 4: DRUG ADMINISTRATION AND ASSESSMENTS, 
DOSE GROUPS WITH 28 DAYS TREATMENT
Visit
Day
Planned Time
[h:min]
Clock time for 
actual day 
[h:min]
Event and 
comment
ECG3
Safety lab
BI 730357
PKblood 
Midazolam 
PKblood
PKurine
Biomarker 
sample
1
-28 to -2
Screening and 
informed consent
x
x
1.1
-1
-24:30
7:30
x
-24:00
8:00
Administration of 
Midazolam6
-23:45
8:15
x
-23:30
8:30
x
-23:00
9:00
x
-22:00
10:00
x
-21:30
10:30
x
-21:00
11:00
x
-20:00
12:00
x
-18:00
14:00
x
-16:00
16:00
x
2
1
- 0:30
7:305
Randomisation & pre-
dose sampling
x
x
x
x
0:00
8:00
Administration of 
BI 7303575
x
x
↓
↓
x1,2
0:15
8:15
x
0:30
8:30
x
1:00
9:00
x
1:30
9:30
x
2:00
10:00
x
2:30
10:30
x
3:00
11:00
x
3:30
11:30
x
4:00
12:00
x
6:00
14:00
x
x
8:00
16:00
x
12:00
20:00
x
3
2
23:30
7:30
x
x
x
24:00
8:00
BI 730357 admin5
4
3
47:30
7:30
x2
x
48:00
8:00 
Administration of 
Midazolam and 
BI 7303575
48:15
8:15
x
48:30
8:30
x
49:00
9:00
x
50:00
10:00
x
50:30
10:30
x
51:00
11:00
x
52:00
12:00
x
54:00
14:00
x
56:00
16:00
x
5 to 7
4 to 6
8:00
BI 730357 admin5
8
7
143:30
7:30
x
x2
x
144:00
8:00
BI 730357 admin5
x
9
8
167:30
7:30
x2
x


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Visit
Day
Planned Time
[h:min]
Clock time for 
actual day 
[h:min]
Event and 
comment
ECG3
Safety lab
BI 730357
PKblood 
Midazolam 
PKblood
PKurine
Biomarker 
sample
168:00
8:00
BI 730357 admin5
10 to 11
9 to 10
215:30
7:30
12
11
239:30
7:30
x2
240:00
8:00
BI 730357 admin5
13
12
263:30
7:30
x2
264:00
8:00
BI 730357 admin5
14
13
287:30
7:30
x2
288:00
8:00
BI 730357 admin5
15
14
311:30
7:30
x
x
x
x
x
312:00
8:00
Administration of 
Midazolam6 and
BI 7303575
x
x
↓
↓
↓
312:15
8:15
x
x
312:30
8:30
x
x
313:00
9:00
x
x
313:30
9:30
x
314:00
10:00
x
x
314:30
10:30
x
x
315:00
11:00
x
x
315:30
11:30
x
316:00
12:00
x
x
318:00
14:00
x
x
x
320:00
16:00
x
x
324:00
20:00
x
16
15
335:30
7:30
x
x
336:00
8:00
BI 730357 admin5
17
16
359:30
7:30
x2
360:00
8:00
BI 730357 admin5
18
17
383:30
7:30
x2
384:00
8:00
BI 730357 admin5
19 to 21
18 to 20
8:00
BI 730357 admin5
22
21
479:30
7:30
x2
x
480:00
8:00
BI 730357 admin5
23 to 24
22 to 23
8:00
BI 730357 admin5
25
24
551:30
7:30
x2
552:00
8:00
BI 730357 admin5
26 to 28
25 to 27
8:00
BI 730357 admin5
29
28
647:30
7:30
x
x
x
648:00
8:00
BI 730357 admin5
x
649:00
9:00
x
650:00
10:00
x
651:00
11:00
x
652:00
12:00
x
654:00
14:00
x
30
29
672:00
8:00
x
x
31
35
816:00
8:00
End of observation
x
x
x
x
Footnotes to flow charts 1 - 4
1 Last urine sampling belonging to the previous day 1 (24 hours). The following collection intervals should be used for urine 
collection: Pre-dose, 0-4, 4-8, 8-12, 12-24
2 Pre-dose samples
3 ECG should be recorded after drug administration


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4 Plasma samples for metabolite analysis will be taken in parallel to PK samples only for the 100 mg fasted dose group. 
5 In the fasted dose groups, on all visit days, breakfast should only be taken at least 30 min after the administration of study 
drug. In the fed dose groups, on all visit days, a standard continental breakfast should be taken after the first blood draw 
and before the intake of study drug.
6 Midazolam microdose will only be administered in the two highest dose groups


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHARTS......................................................................................................................5
FLOW CHART 1: PROCEDURES, DOSE GROUPS WITH 14 DAYS TREATMENT 5
FLOW CHART 2: DRUG ADMINISTRATION AND ASSESSMENTS, DOSE
GROUPS WITH 14 DAYS TREATMENT........................................................6
FLOW CHART 3: PROCEDURES, DOSE GROUPS WITH 28 DAYS TREATMENT 8
FLOW CHART 4: DRUG ADMINISTRATION AND ASSESSMENTS, DOSE 
GROUPS WITH 28 DAYS TREATMENT........................................................9
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS................................................................................................................16
1.
INTRODUCTION...............................................................................................18
1.1
MEDICAL BACKGROUND.............................................................................18
1.2
DRUG PROFILE................................................................................................19
1.2.1
Non-Clinical Studies ...........................................................................................19
1.2.2
Clinical Experience in Humans .........................................................................21
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................23
1.4
BENEFIT - RISK ASSESSMENT.....................................................................23
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................26
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........26
2.1.1
Main objectives....................................................................................................26
2.1.2
Primary endpoint(s)............................................................................................26
2.1.3
Secondary endpoint(s) ........................................................................................26
.........................26
.........................26
.........................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................28
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................28
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................32
3.3
SELECTION OF TRIAL POPULATION .......................................................32
3.3.1
Main diagnosis for trial entry ............................................................................32
3.3.2
Inclusion criteria .................................................................................................33
3.3.3
Exclusion criteria ................................................................................................33
3.3.4
Withdrawal of subjects from therapy or assessments.....................................34
3.3.4.1
Withdrawal from trial treatment ...........................................................................34
3.3.4.2
Withdrawal of consent for trial participation........................................................35


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3.3.4.3
Discontinuation of the trial by the Sponsor ..........................................................35
4.
TREATMENTS...................................................................................................37
4.1
INVESTIGATIONAL TREATMENTS ...........................................................37
4.1.1
Identity of the Investigational Medicinal Products..........................................37
4.1.2
Selection of doses in the trial..............................................................................38
4.1.3
Method of assigning subjects to treatment groups ..........................................42
4.1.4
Drug assignment and administration of doses for each subject .....................43
4.1.5
Blinding and procedures for unblinding...........................................................44
4.1.5.1
Blinding.................................................................................................................44
4.1.5.2
Unblinding and breaking the code ........................................................................44
4.1.6
Packaging, labelling, and re-supply...................................................................45
4.1.7
Storage conditions...............................................................................................45
4.1.8
Drug accountability.............................................................................................45
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................46
4.2.1
Other treatments and emergency procedures..................................................46
4.2.2
Restrictions ..........................................................................................................46
4.2.2.1
Restrictions regarding concomitant treatment ......................................................46
4.2.2.2
Restrictions on diet and life style..........................................................................46
4.2.2.3
Restriction of UV-light exposure..........................................................................46
4.2.2.4
Restrictions regarding WOCBP and men able to father a child ...........................46
4.3
TREATMENT COMPLIANCE........................................................................47
5.
ASSESSMENTS..................................................................................................48
5.1
ASSESSMENT OF SAFETY.............................................................................48
5.1.1
Physical examination ..........................................................................................48
5.1.2
Vital signs.............................................................................................................48
5.1.3
Safety laboratory parameters ............................................................................48
5.1.4
Electrocardiogram ..............................................................................................50
5.1.5
Other safety parameters.....................................................................................50
5.1.6
Assessment of adverse events.............................................................................50
5.1.6.1
Definitions of AEs ................................................................................................50
5.1.6.2
Adverse event collection and reporting ................................................................53
5.2
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................55
5.2.1
Assessment of pharmacokinetics .......................................................................55
5.2.2
Methods of sample collection .............................................................................55
5.2.2.1
Plasma sampling for pharmacokinetic analysis ....................................................55
5.2.2.2
Urine sampling for pharmacokinetic analysis.......................................................56
5.2.2.3
Plasma sampling for metabolism analysis ............................................................57
5.2.3
Analytical determinations ..................................................................................57
5.3.1.1
Methods of sample collection ...............................................................................58


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5.4
OTHER ASSESSMENTS...................................................................................59
5.5
APPROPRIATENESS OF MEASUREMENTS..............................................59
6.
INVESTIGATIONAL PLAN.............................................................................60
6.1
VISIT SCHEDULE.............................................................................................60
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................60
6.2.1
Screening and run-in period(s)..........................................................................60
6.2.2
Treatment period(s)............................................................................................60
6.2.3
Follow up period and trial completion..............................................................60
6.2.3.1
Early treatment and trial termination:...................................................................61
6.2.3.2
Trial completion....................................................................................................61
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................62
7.1
STATISTICAL DESIGN - MODEL.................................................................62
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................62
7.3
PLANNED ANALYSES.....................................................................................62
7.3.1
Primary endpoint analyses.................................................................................63
7.3.2
Secondary endpoint analyses .............................................................................63
................................................................................66
7.3.4
Safety analyses.....................................................................................................66
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................67
7.4
INTERIM ANALYSES ......................................................................................68
7.5
HANDLING OF MISSING DATA ...................................................................68
7.6
RANDOMISATION ...........................................................................................69
7.7
DETERMINATION OF SAMPLE SIZE .........................................................69
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........70
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ...........................................................................................................70
8.2
DATA QUALITY ASSURANCE ......................................................................71
8.3
RECORDS...........................................................................................................71
8.3.1
Source documents ...............................................................................................71
8.3.2
Direct access to source data and documents.....................................................71
8.3.3
Storage period of records ...................................................................................72
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................72
8.5
STATEMENT OF CONFIDENTIALITY........................................................72
8.6
TRIAL MILESTONES.......................................................................................72
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................73
9.
REFERENCES....................................................................................................74
9.1
PUBLISHED REFERENCES............................................................................74
9.2
UNPUBLISHED REFERENCES......................................................................76
10.
APPENDICES.....................................................................................................77


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................78
11.1
GLOBAL AMENDMENT 1 ..............................................................................78
11.2
GLOBAL AMENDMENT 2 ..............................................................................79


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AUC
Area under the Curve
CI
Confidence Interval
Cmax
Maximum measured concentration of BI 730357 in plasma
CML
Clinical Monitor Local
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DC
Dendritic cell
DG
Dose Group
DILI
Drug Induced Liver Injury
EDC
Electronic Data Capture
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
GCP
Good Clinical Practice
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
IV
intravenous
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRD
Multiple Rising Dose
MST
Medical Sub Team
NOAEL
No-observed-adverse-effect level
OPU
Operative Unit
PD
Pharmacodynamics
PK
Pharmacokinetics
p.o.
per os (oral)
PPASI
Palmoplantar Psoriasis Severity Index
PsA
Psoriatic Arthritis
PsO
Psoriasis
q.d.
quaque die (once a day)
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual Effect Period
SAE
Serious Adverse Event
SMC
Safety Monitoring Committee
SUSAR
Suspected Unexpected Serious Adverse Reaction
SRD
Single Rising Dose
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan


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WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Plaque psoriasis (PsO) is a chronic skin disease characterized by raised, well-demarcated, 
oval erythematous plaques covered in adherent silvery scale (R11-1257). Lesions are 
typically painful and/or itchy, and can be associated with a high degree of morbidity. PsO can 
affect extensive areas of skin; disease severity is in fact defined by body surface area (BSA) 
as mild (<5%), moderate (5-10%), and severe (>10%) (R11-1259). Approximately 25% of 
patients are classified as having moderate-to-severe disease. Disease severity correlates 
inversely with quality of life, as reported by patients with regard to symptom severity and 
disease impact on functionality and socialization (R16-4115, R11-1260, R03-1208, R16-
3072). Plaques on visible skin (e.g., scalp, face, hands) have particular impact on physical, 
sexual, psychosocial, and even economic status; disease severity is associated with reduced 
levels of employment and income (R16-3072). PsO is more than a superficial disease, with 
30% of patients having joint involvement, and a high correlation between PsO and obesity, 
diabetes, depression, metabolic syndrome, and cardiovascular risk (R16-4115). 
Affecting approximately 2% of the global population, including 25 million North American 
and European patients, PsO is the most prevalent immune-mediated skin disease (R08-1089).
Direct and indirect annual costs attributed to PsO in the US are estimated to be US $6,422 per 
patient on average, resulting in a total burden of US $35.2 billion. This cost is distributed, 
roughly in equal thirds, to medical costs, reduced quality of life, and productivity loss (R17-
1990). Across Germany, Italy, Spain, UK, and France the per-patient cost of PsO has been 
estimated to range from US $2,077 to $13,132 annually (R17-1989).
 
 
 
 
 
 
 
 
 
 
 
Mainstays of therapy for the treatment of PsO include topical agents, ultraviolet light-based 
therapies, traditional systemic agents (methotrexate, acitretin, cyclosporine), and more 
recently, targeted biologic and small-molecule therapies. Steroidal and non-steroidal (e.g., 
vitamin D analogues, retinoids, tar, anthralin, salicylic acid, tacrolimus) topical agents are 
efficacious, particularly for mild-to-moderate disease, but typically require long-term


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administration, and often provide only incomplete clearance. Long-term adherence to 
topically-prescribed therapies is often poor, and systemic absorption limits long-term usage
of topical corticosteroids, particularly for large surface areas and for facial and genital 
lesions. Ultraviolet light-based therapies, often combined with the photosensitizing agent 
psoralen, may be used to treat extensive areas of involved skin, but generally require long-
term therapy, and are associated with non-melanoma skin cancer (NMSC). Conventional 
systemic agents provide relatively inexpensive options to treat more severe or refractory 
disease, but long-term usage may be substantially limited by the risks of hepatotoxicity, bone 
marrow suppression, and pulmonary toxicity (methotrexate), teratogenicity (acetretin), and 
nephrotoxicity and hypertension (cyclosporine). During the past 15 years, antibodies 
targeting TNFα, and subsequently IL-12/23 and IL-17, have demonstrated substantial 
efficacy and indeed complete remission rates, with safety and tolerability superior to 
conventional therapies.
 
 
 
 
 
 
1.2
DRUG PROFILE
 
 
  
1.2.1
Non-Clinical Studies
Relevant non-clinical pharmacology, PK, and toxicology study results are summarized 
below. Further details are provided in the BI 730357 Investigator Brochure (IB).
 
 
 
 
 


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The disposition of BI 730357 is characterized in rat, dog and minipig by low clearance and 
moderate Vd. Moderate to high oral bioavailability was observed across species, which 
suggests that following oral administration, the bioavailability of BI 730357 in humans is 
likely to be moderate to high. The plasma protein binding of BI 730357 was high in all tested 
species (mouse, rat, dog, and human) and there was no preferential partitioning into red blood 
cells observed. In a quantitative whole body autoradiography study in male Long Evans 
(pigmented) rats, [14C]-BI 730357-derived radioactivity was readily absorbed and distributed 
to tissues. There was evidence of CNS exposure to drug-related material. Deposition of 
radioactivity into MCT of the ocular bulb was moderate to high and long lived.
When incubated with human hepatocytes, BI 730357 undergoes metabolism predominately 
via CYP3A4 to an oxidative metabolite. This metabolite was also observed following 
incubations with rat, dog, and minipig suspended hepatocytes. When BI 730357 was 
incubated with a selective inhibitor of CYP3A4 in a long-term human hepatocyte culture 
model, the overall metabolism was inhibited by ~90%, confirming that BI 730357 is mainly 
metabolized by CYP3A4. Therefore, if BI 730357 is primarily metabolically cleared, there is 
a high risk that coadministration with CYP3A inhibitors will significantly increase BI 730357
exposure and CYP3A inducers could decrease its exposure.
The propensities of BI 730357 to inhibit, inactivate, and/or induce CYP isoforms were
evaluated in vitro. BI 730357 was determined to be a potentially clinically-relevant CYP3A 
inactivator and an inducer of CYP1A2, CYP2B6, and CYP3A. The net effect of BI 730357
on a sensitive CYP3A substrate (midazolam) is an anticipated increase of the AUC by 1.8-
fold. Induction of CYP1A2 and CYP2B6 by BI 730357 at the projected dose and Cmax is also 
predicted to be potentially clinically relevant.
The toxicity profile of BI 730357 has been assessed in safety pharmacology, genetic toxicity,
and repeat-dose toxicity studies in rat and dog. In general BI 730357 appears to be well 
tolerated at clinically-relevant plasma exposure in toxicity studies. BI 730357 is considered 
non-genotoxic. Based on long half-lives of radioactivity in dermal tissues and results from an 
in vitro phototoxicity assay, BI 730357 has phototoxicity potential.
In summary, the non-clinical data of BI 730357 support clinical trials in male subjects with 
daily oral administration for up to 28 days. Human exposure up to those achieved at the no 


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observed adverse effect level (NOAEL) of 5 mg/kg/day in the 4 week dog study (Cmax 6,660 
nM, and AUC0-24 127,400 nM•h in males and females combined) is considered safe.
1.2.2
Clinical Experience in Humans
At the time of the submission of this Trial 1407-0002, preliminary results are available from
the Phase Ia first-in-human Trial 1407.1, conducted in Germany and comprising two parts. 
Part 1 was a randomised, single-blind, placebo-controlled trial to investigate safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single rising doses 
(SRD) of BI 730357 administered as oral solution (2 mg and 8 mg) and film-coated tablets 
(25 mg to 400 mg) to 56 healthy male adult subjects in the fasted state. Part 2 was a 
randomised, open label, single-dose, three-way crossover bioavailability comparison of 25 
mg of BI 730357 administered as oral solution, and tablet with or without food to 12 healthy 
male adult subjects.
The protocol was also amended to evaluate safety and drug exposure of single-dose 
administration up to 800 mg BI 730357, and to further evaluate food effect at 400 mg and 
800 mg doses. Three additional dose cohorts in the fed state were administered with 
BI 730357. A 400 mg dose cohort with standard diet and 400 and 800 mg cohorts with high-
fat diet were evaluated.
Safety evaluations included physical examination, vital signs, ECG, laboratory tests, and 
adverse events (AEs). AEs, which generally reflected commonly-occurring events of short 
duration, and were mostly mild or moderate in severity, were distributed without discernable 
trend among recipients of placebo and rising dose levels of BI 730357, whether administered 
under fasted or fed conditions. No serious AEs (SAEs) were reported.
Preliminary PK data were obtained with planned drug administration and sampling times
instead of actual times; therefore, final data may deviate from the preliminary data. A 
summary of the PK parameters of BI 730357 derived in this trial is given in Table 1.2.2:1 for 
oral solution and tablet.
Following administration of the tablet, BI 730357 was absorbed with a tmax between 
approximately 2 to 3 hours. Thereafter, plasma concentrations decreased rapidly in a mono-
or biphasic manner with an estimated terminal half-life (t1/2) ranging from approximately 20 
to 28 hours.


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Table 1.2.2:1 Preliminary geometric mean (geometric CV%) PK parameters of BI 730357
(SRD Part)
Fasted, Solution
Fasted, Tablet
Fed, Tablet
Dose
2 mg
Solution
N=6 
8 mg
Solution
N=6
25 mg
Tablet
N=6
50 mg
Tablet
N=6
100 mg
Tablet
N=6
200 mg
Tablet
N=6
400 mg
Tablet
N=6
400 mg
Std. diet 
N=6
400 mg
High Fat
N=5
800 mg
High Fat
N=6
AUC
0-24
[nM*hr]
224
(19.9)
928
(23.6)
1431
(26.5)
2623
(42.3)
4142
(37.5)
6346
(16.0)
9453
(26.0)
17864
(21.6)
22520
(35.6)
33849
(27.2)
AUC
0-24/D 
[nM*hr/mg]
112
(19.9)
116
(23.6)
57.2
(26.5)
52.5
(42.3)
41.4
(37.5)
31.7
(16.0)
23.6
(26.0)
44.7
(26.0)
56.3
(35.6)
42.3
(27.2)
C
max
[nM]
32.9
(39.4)
154
(28.9)
103
(31.7)
173
(41.9)
284
(30.7)
433
(27.6)
755
(37.4)
1268
(17.5)
1898
(30.2)
2466
(15.7)
C
max/D 
[nM/mg]
16.5
(39.4)
19.2
(28.9)
4.12
(31.7)
3.47
(41.9)
2.84
(30.7)
2.17
(27.6)
1.89
(37.4)
3.17
(17.5)
4.75
(30.2)
3.08
(15.7)
C
24
[nM]
4.83
(31.7)
18.6
(35.0)
50.5
(26.4)
104
(49.9)
160
(44.3)
289
(21.2)
360
(32.6)
618
(32.4)
649
(55.7)
1060
(31.2)
t
1/2
[hr]
24.3
(29.1)
24.0
(33.9)
26.6
(29.3)
25.6
(37.0)
23.8
(34.9)
20.0
(29.4)
28.1
(26.8)
29.1
(36.9)
25.8
(50.1)
25.9
(32.3)
t
max
[hr}
0.95
(36.7)
0.85
(46.1)
2.96
(17.4)
2.90
(41.3)
2.42
(41.8)
2.02
(55.4)
2.77
(38.0)
4.80
(27.5)
3.00
(55.4)
4.40
(38.5)
These preliminary trial data suggest that the exposure (AUC0-24) to BI 730357 increased in a 
dose-proportional manner for solution between 2 and 8 mg and for tablet up to 50 mg, and 
thereafter increased in a less-than-dose-proportional manner, with approximately 1.5-fold 
increase in exposure with each 2-fold increase in dose up to 400 mg. The highest exposures 
observed in the fasted state (Cmax of 755 nM and AUC0-24 of 9453 nM*hr) at the 400 mg dose 
level were substantially below (approximately 9- and 13-fold lower, respectively) the 
NOAEL exposures in the 4-week dog study (Cmax of 6,660 nM, and AUC0-24 of 127,400 
nM*hr). A comparison of exposures (for the tablets in the fasted state) showed that with an 8-
fold and 16-fold increase in dose from 25 to 200 and 400 mg, the AUCs increased by 4.4 fold 
and 6.6 fold, respectively.
Comparing 400 mg dose cohorts in the fasted and fed state, the exposures with standard and 
high-fat diets were approximately 90% and 140% higher, respectively, than the exposure in 
the fasted state, confirming a positive food effect. Thus, the exposure of BI 730357 when 
taken with food (standard breakfast) approximately doubled (AUC0-24 of 9453 vs 
17864 nM*hr) when compared to fasted state at the 400 mg dose level.
The highest exposure in the SRD study was observed at the 800 mg dose cohort when 
administered with a high-fat diet. This exposure (AUC0-24 of 33849 nM*hr) was 
approximately 1.5-fold higher than the exposure at the 400 mg dose with high-fat diet (AUC0-
24 of 22520 nM*hr) in comparison to a 2-fold increase in dose. However, this highest 
exposure was still approximately 4-fold lower when compared to the NOAEL exposures in 
the 4-week dog study.


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1.3
RATIONALE FOR PERFORMING THE TRIAL
As described in section 1.1, the treatment of patients with moderate-to-severe plaque PsO has 
been greatly enhanced by the introduction of biologic agents, and more options may be added 
to the armamentarium in the near future. However, these antibody drugs must be 
administered by subcutaneous injections, and long-term therapeutic effect may be limited by 
the formation of antidrug antibodies. There remains a medical need for the introduction of 
new, efficacious oral treatment options.
 
 
 
 
 
The aim of Phase Ib Trial 1407-0002 is to investigate the safety, tolerability, and PK of 
BI 730357 in healthy male volunteers. 
As BI 730357 was determined to be a substrate, an inactivator, and an inducer of CYP3A4, 
which could potentially result in clinically-relevant drug-drug interactions (DDI), a DDI 
assessment is being conducted in this trial, whereby a microdose of midazolam will be 
administered to volunteers at two of the highest dose groups of BI 730357. A microdose 
results in a low enough concentration of midazolam as to not be pharmacologically active 
and, thus, will not interfere with examination of BI 730357. Furthermore, this assessment will 
inform us regarding potential DDIs with medications that are CYP3A4 substrates and allow 
us to determine whether or not to exclude such drugs from subsequent trials.
1.4
BENEFIT - RISK ASSESSMENT
Study participants are exposed to the risks of the study procedures and the risks related to the 
exposure to the trial medication.
Procedure-related risks
Blood sampling by venipuncture or through an indwelling venous catheter 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 total volume of blood withdrawn per subject during this trial will not exceed the volume 
of a normal blood donation (500 mL). No health-related risk is expected from this blood 
withdrawal.


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Drug-related risks and safety measures
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.


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Special precautions
The following safety measures will be applied in order to minimize the risk for healthy 
volunteers:

Dose selection is based on a sound preclinical package, and safety, tolerability and 
PK data from SRD administration of BI 730357 up to 400 mg in healthy volunteers.

Progression from one dose group to the next would only be allowed after a safety 
interim analysis of the results from the precedent dose group. This safety analysis 
will be performed by a Safety Monitoring Committee (SMC). Further details about 
the composition of the SMC are provided in section 8.7.

If 2/3 of subjects in a dose group (6 of 9 subjects) experience an AE assessed as 
≥Grade 2 according to Rheumatology Common Toxicity Criteria (RCTC v 2), dose 
escalation will be suspended until SMC review and agreement to proceed.

Extensive safety laboratory monitoring will be performed.

Each dose group of 12 subjects will be divided into 3 cohorts of 4 subjects each. Start 
of dosing for 1st patient of each cohort will be separated by at least 24 hours. Subjects 
will stay at the trial site for at least 24 hours after their first study drug 
administration.

Start of dosing for the 1st patient of each dose group will be separated by at least 1 
week from completion of dosing the previous dose group.

All subjects will be closely monitored by physical examinations, and safety 
laboratory and ECG evaluations.

Individual stopping rules as described in section 3.3.4.1 will be applied.

UV-light protection measures as described in section 4.2.2.3 will be required until the 
end of the follow-up period.

The potential risks which are described above will be minimized by close monitoring 
and the involvement of a SMC
Based upon preclinical data for BI 730357 and clinical data from SRD Trial 1407.1, as well 
as the implemented safety measures described above, healthy subjects will not be exposed to 
undue risks in relation to the important information expected from this trial as a basis for 
further clinical development of this compound. Healthy volunteers are not expected to have 
any direct benefit from participation in this clinical trial. Considering the medical need of the 
development of a better tolerated and more effective oral treatment for patients with PsO, the 
Sponsor considers that the benefit outweighs the potential risks and justifies exposure of 
healthy human volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
Phase Ib evaluation of the safety, tolerability, PK, and PD properties of MRD administration
of BI 730357 to healthy volunteers for up to 28 days.
2.1.2
Primary endpoint(s)

Safety: Number of subjects with drug-related AEs, measured by the percentage of 
patients with drug related AEs within 7 days of treatment, which covers more than the 
residual effect period defined by 5 half-lifes of the study drug.
2.1.3
Secondary endpoint(s)
After the first dose:

AUCτ,1 (area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose)

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 
over a uniform dosing interval τ)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This Phase Ib (MRD) study 1407-0002 will evaluate 5 dose levels of BI 730357 administered 
to healthy volunteers for 14 days or 28 days, in fasted or fed state.
Approximately 84 subjects are to be entered into the study and allocated to one out of up to 7 
dose groups; each dose group of 12 subjects is to be randomised (9 active:3 placebo) in 3
sequential cohorts, each composed of 3 subjects receiving active study drug and one subject 
receiving placebo. Subjects are to be evaluated for safety (physical examination, ECG and 
laboratory studies, AEs, and SAEs) and PK during once-daily study drug treatment for 14
days or 28 days, and for approximately one week after completion of treatment (Figure 
3.1.1:2). Twenty-eight day evaluation of the higher dose groups is intended to more 
thoroughly evaluate BI 730357 safety and tolerability prior to longer term administration to 
patients with moderate-to-severe plaque PsO in future clinical trials. Dose cohorts are 
planned in both the fasted and fed states to confirm and further evaluate, after multiple dose 
administration, the positive food effect that was observed in the SRD trial. Moreover, the fed 
cohorts will also provide safety data at higher exposures in the fed state, in the event subjects 
take BI 730357 with food.
Additionally, the potential for DDI with a CYP3A substrate will be assessed in the 2 highest 
dose groups. This will be conducted in parallel to the multiple dose assessments, using a 
microdose of midazolam (a sensitive CYP3A substrate) administered at 3 different time 
points (baseline, Day 3 and Day 14) to examine potential CYP3A inactivation and induction 
effects of BI 730357.
Decision on dose groups and dose escalation
The dose groups will be investigated consecutively in ascending order of doses or expected
exposures, maintaining a time interval of at least 7 days between the last drug administration 
in the previous dose group and the first drug administration of the subsequent dose group. 
The decision to proceed to the next dose group will be based upon evaluation of the safety, 
tolerability and all available PK data of the preceding dose groups. The next dose will only be 
given if, in the opinion of the Investigator and SMC, no safety concerns arose in the 
preceding dose group (i.e., no dose-limiting events occurred) and if none of the pre-specified 
trial-specific stopping criteria were met (refer to section 3.3.4.2).
A dose-escalation decision tree for the trial is shown below in Figure 3.1.1:1.


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Figure 3.1.1:1  Dose-escalation decision tree
Bolded arrows and boxes = preferred pathway. Dotted lines = alternative pathway.
25 mg 
fasted 
50 mg 
fasted 2W
100 mg 
fasted 2W
50 mg 
fed 2W
200 mg 
fasted 4W
200 mg 
fed 4W
100 mg 
fed 4W
400 mg 
fed 4W
200 mg 
fed 4W
no safety 
concerns
major safety 
concerns
STOP
minor/monitorable 
safety concerns 
SMC
SMC
SMC
SMC
SMC
SMC


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A SMC will be held after 14 days of dosing of DG 4 (200 mg fasted) to evaluate safety and 
PK data and decide if either the 200 mg fed cohort (if no safety concerns observed) or the 100 
mg fed cohort (e.g., if minor and monitorable safety concerns observed) will be conducted.   
Figure 3.1.1: 2 Trial Design
*Subjects in the two highest dose groups will receive a microdose of midazolam prior to the initiation 
of study drug and at pre-specified time points during the treatment period.
** SMCs will be held after each dose group and after 14 days of the 200 mg fasted dose group to 
decide on the treatment of the next dose groups.
The various planned dose groups are listed in Table 3.1.1:1. However, of the 8 listed dose 
groups, a maximum of 7 dose cohorts will be evaluated. The Sponsor may also decide to 
conclude this trial without testing a 400 mg dose group upon evaluation of PK and safety data 
from prior dose groups, thus limiting dosing in subsequent trials to ≤200 mg.
1
2
3
4
5
6
7
8
9
10
11
12
13
14 15 16 17
18
19
20
21
22
23
24
weeks
25 mg 
fasted
F
U
50 mg 
fasted
F
U
100 mg 
fasted
200 mg fed*
50 mg 
fed
400 mg fed*
200 mg fasted
100 mg fed*
or
200 mg fed*
F
U
F
U
F
U
F
U
F
U
F
U
F
U
SMC**
25 26
27
28


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Table 3.1.1:1 Planned dose groups
Dose Group
1
2
3
4
5
6*
7
8*
Daily dose (mg)
25
50
100
200
50
100
200
400
Status
fasted
fasted
fasted
fasted
fed
fed
fed
fed
Treatment duration 
(days)
14
14
14
28
14
28
28
28
Number of subjects
12
12
12
12
12
12
12
12
Subjects receiving 
placebo
3
3
3
3
3
3
3
3
Subjects receiving 
active drug
9
9
9
9
9
9
9
9
*In total, 7 dose groups will be evaluated. Testing of either DG 6 or DG 8 will be decided by 
the SMC. 


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial employs MRD design with a double-blind, placebo control and a 3:1 active:
placebo randomisation. Additionally, a DDI assessment will be conducted in the 2 highest 
dose groups using a fixed-sequence design (midazolam administered alone, followed by 
midazolam administered with BI 730357 on two separate occasions) 
For MRD trials, the design described in section 3.1 is viewed favourably under the provision 
not to expose the subjects involved to undue risks since the main study objective is to 
investigate safety and tolerability of BI 730357.
With the rising dose design, double-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects and investigators. The disadvantage of this trial design is a possible 
observer bias with regard to the dose-depending effects as well as time effects, but it has the 
virtue of minimizing subject risk by sequentially studying ascending doses. As time-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 trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety and tolerability. Each dose group consists of 12 subjects, with 9 on 
active treatment and 3 on placebo. The placebo control group includes all subjects of all dose 
groups treated with placebo. 9 subjects per active treatment group are in general considered 
as sufficient for the exploratory evaluation of PK.
A SMC together with the Principal Investigator will review the emerging safety data after 
completion of each dose group and decide on whether to proceed to the next higher dose.
A CYP3A DDI evaluation using a microdose of midazolam is considered acceptable, as a 
microdose of midazolam is not expected to have any pharmacological or PD effects, thus, 
subjects are not exposed to undue risks and the evaluation of the investigational drug should 
not be influenced. This assessment will allow for better judgement regarding acceptable co-
medications in Phase III development. 
3.3
SELECTION OF TRIAL POPULATION
This trial will be conducted in healthy male volunteers.
As the treatment duration in this study is limited to 14 to 28 days, the potential benefit for 
patients with PsO is considered very low. The potential indirect benefit is limited to the 
development of an efficacious drug for patients with PsO.
3.3.1
Main diagnosis for trial entry
Healthy male volunteers


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3.3.2
Inclusion criteria
1. Healthy male subjects according to the assessment of the Investigator, based on a 
complete medical history, physical examination, vital signs (blood pressure, pulse rate), 
12-lead ECG, and clinical laboratory tests 
2. Subjects with a partner who is a woman of childbearing potential (WOCBP1) must be 
willing to use male contraception (condom or sexual abstinence) from the first 
administration of trial medication until 30 days after last administration of trial 
medication
3. Age of 18 to 45 years (incl.) at screening
4. BMI of 18.5 to 29.9 kg/m2 (incl.) at screening
5. Signed and dated written informed consent prior to admission to the study in accordance 
with ICH-GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including blood pressure, pulse rate or ECG) 
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
4. Any evidence of a concomitant disease judged as clinically relevant by the Investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract (except appendectomy and 
simple hernia repair) that could interfere with the PK of the trial medication 
7. Diseases of the CNS (including but not limited to any kind of seizures or stroke), and 
other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or acute infections which are of relevance in the opinion of the Investigator
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e., fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
13. Tobacco usage (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Alcohol abuse (consumption of more than 30 g per day)
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. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome) 
19. Subject is assessed as unsuitable for inclusion by the Investigator; for instance, is 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
20. Unwillingness to adhere to the rules of UV-light protection as described in section 
4.2.2.3.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.4
Withdrawal of subjects from therapy or assessments
Subjects may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”), as described in sections 3.3.4.1 and 3.3.4.2 below. Every effort 
should be made to keep the randomised subjects in the trial: if possible on treatment, or at 
least to collect important trial data. Measures to control the withdrawal rate include careful 
participant selection, appropriate explanation of the trial requirements and procedures prior to 
randomisation, as well as the explanation of the consequences of withdrawal. The decision to 
withdraw from trial treatment or from the whole trial as well as the reason must be 
documented in the patient files and CRF.
3.3.4.1
Withdrawal from trial treatment
An individual subject is to be permanently withdrawn from trial treatment if:

the subject wants to withdraw from trial treatment, without the need to justify the 
decision.

the subject needs to take concomitant drugs that interfere with the investigational 
product.

the subject can no longer be treated with trial medication for other medical reasons 
(such as surgery, AEs, other diseases, or pregnancy).


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
the subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the Investigator and sponsor representative, is not willing 
or able to adhere to the trial requirements for the remainder of the study.

!"#$%& '() *+"#,) +- '#).'/)%' '() ,"01)*' )23)#$)%*), *.#!$+4.,*"5.# +# ()/.'+5+&$* 
.!4)#,) )4)%' 6$%*5"!$%& 
5.0+#.'+#7 .0%+#/.5$'$),89 :$'( Rheumatology Common 
Toxicity Criteria (RCTC) Version 2.0 Grade 2 +# ($&()#;In addition to these criteria, 
the physician may discontinue subjects at any time based on his or her clinical 
judgment.
Given the subject’s agreement, the subject will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Charts (FC) and section 6.2.3.
For all participants, the reason for withdrawal from trial treatment (e.g., AE) must be 
recorded in the CRF. These data will be included in the trial database and reported.
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique study subject number, and will 
be assigned to the same treatment as the subject he/she replaces.
3.3.4.2
Withdrawal of consent for trial participation
Subjects may withdraw their consent for trial participation at any time without the need to 
justify the decision. This will however mean that no further information may be collected for 
the purpose of the trial and negative implications for the scientific value may be the 
consequence. Furthermore, it may mean that further follow up on safety cannot occur.
If a subject wants to withdraw consent, the Investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see section 3.3.4.1
above.
3.3.4.3
Discontinuation of the trial by the Sponsor
BI, the Sponsor, reserves the right to discontinue the trial overall or at a particular trial site at 
any time for the following reasons:
1. New toxicological findings or SAEs invalidate the earlier positive benefit-risk-
assessment. 
2. More specifically, a dose group will be stopped if more than 50% of the subjects in this
dose group show drug-related and clinically relevant AEs of moderate or severe intensity, 
or if at least one drug-related SAE is reported in this dose group that is considered to be 
unacceptable.
3. Also the trial will be terminated if more than 50% of the subjects in the trial show drug-
related and clinically relevant AEs of moderate or severe intensity, or if more than one 
drug-related SAE is reported that is considered to be unacceptable.
4. The expected enrolment goals overall or at a particular trial site are not met


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5. Violation of GCP, or the CTP or the contract with BI by a trial site or Investigator, 
disturbing the appropriate conduct of the trial
6. The Sponsor decides to discontinue the further development of the investigational 
product.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the fifth reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Multiple doses of BI 730357, and Placebo to match BI 730357.
Microdoses of Midazolam in Dose Groups 4 and 5.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Test product 1:
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
25 mg, 50 mg
Posology
QD
Route of administration:
Per os
Substance:
Placebo to match BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
--
Posology
QD
Route of administration:
Per os


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Table 4.1.1: 2
Probe drug:
Substance:
Midazolam (Midazolam-ratiopharm®)
Pharmaceutical formulation:
Solution for injection
Source:
Ratiopharm GmbH, Germany
Unit strength:
5 mg/ 5 mL diluted to 50 µg/mL*1.5 mL (75 µg)
Posology
QD on Days -1, 3, and 14
Route of administration:
Per os
4.1.2
Selection of doses in the trial
The primary objective of this trial is to investigate the safety, tolerability, and PK of 
BI 730357 in healthy male subjects following fasting oral MRD administration of 25 mg, 
50 mg, and 100 mg q.d. over 14 days, and doses between 100mg and 400 mg q.d. over 28
days. Study medication will be taken either after a fasting period of at least 6 hours or after 
the intake of a standard continental breakfast, to investigate food effect on BI 730357 
exposure. A relatively broad dose range is selected in order to evaluate likely subtherapeutic, 
therapeutic and supratherapeutic dose levels, without jeopardizing the subjects’ safety, and 
determine whether there is a meaningful safety threshold for this new drug.
The dose range for this trial was selected on the basis of the data obtained in the first-in-
human SRD Trial 1407.1. In this study, dose levels up to 800 mg were well tolerated. 
As described in section 1.2.1, an anticipated human therapeutic exposure was predicted based 
on a Cmin,ss of 140 nM. In Trial 1407.1 this projected trough level at 24 h (C24h) was exceeded
for subjects in dose group ≥ 100 mg after SRD BI 730357 administration. Therefore, 
evaluation of a dose range spanning above and below 100 mg in this trial is appropriate. 
Evaluation of higher dose levels is further justified for this novel mechanism since it is 
possible that a Cmin,ss more than the 140 nM may be necessary (i.e., > IC50) to reach the 
optimal efficacy.
SRD Trial 1407.1 demonstrated that BI 730357 was safe and well tolerated up to the 800 mg 
dose. Given that BI 730357 had a half-life of approximately 20 to 28 hours, higher exposures 
will be expected following MRD administration of comparable doses. Assuming the PK
properties remain consistent with single rising dose data after once daily dosing, 
accumulation of BI 730357 in plasma upon multiple dosing is expected to be 3.0 fold and 2.7
fold compared to simulated single dose AUC and Cmax, respectively. These accumulation 
factors are based on the population pharmacokinetic model developed using the interim Trial 
1407.1 data (2-compartment PK model with first order absorption and elimination, to and 
from central compartment) which was used to simulate typical profiles at Day 1 and Day 14. 


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These simulated steady-state exposures assume linear PK and can be considered as the upper 
bound for exposures, given that exposures were less than linear at higher single doses in the 
SRD study. This would also allow a safety comparison to the NOAEL exposures.
Table 4.1.2: 1
Plasma exposures of BI 730357 in SRD Trial 1407.1 (preliminary 
G.Mean) and expected exposures (fasted state) following MRD
administration (expected maximum G.Mean, steady-state exposure 
based on simulations assuming dose-proportional and linear kinetics)
Dose  
(fasted)
Observed exposures
in Trial 1407.1    
(see Table 1.2.2:1)
Expected maximum steady state 
exposures in 1407.2 following 
MRD administration in fasted state
Cmax
(nM)
AUC0-24
(nM*hr)
Ctrough,ss
(nM)
Cmax,ss
(nM)
AUCss
(nM*hr)
25 mg
103
1413
102
235
3376
50 mg
173
2623
233
488
7296
100 mg
284
4142
462
968
14509
200 mg
433
6346
938
1958
29513
400 mg
755
9453
1940
4016
59931
The starting dose of 25 mg q.d. was well tolerated in SRD Trial 1407.1, and considered to be 
safe. The predicted Ctrough,ss level at this dose is expected to be below the projected IC50
required for efficacy (sub-therapeutic dose). The subsequent doses of 50,100, 200 and 400 
mg are expected to achieve steady state trough levels greater than the IC50 value. The highest 
dose level of 400 mg was set to provide a sufficient safety margin for patients in subsequent 
clinical trials. An additional 14 days of administration at the two highest doses (i.e., 200 mg 
and 400 mg) will allow assessment of safety for the longer duration in subsequent trials.
Figure 4.1.2:1 and Figure 4.1.2:2 show that with the selected doses, BI 730357 administered 
under multiple dose conditions (G.Mean) will not exceed the NOAEL exposures.
The Cmax at the NOAEL in dogs is depicted in the figure below, and is 6660 nM which would 
be ~ 1.7-fold the human estimated G.Mean Cmax, ss at 400 mg, the maximum dose used in this 
trial.


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Figure 4.1.2: 1              Predictions of Cmax,SS based on exposure with BI 730357 in the SRD 
trial and comparison to NOAEL exposures
Footnote: The boxplots show the predicted distribution of Cmax,SS of 500 simulated subjects. The predictions are based upon 
a linear population pharmacokinetic model that was developed using interim PK data of the SRD portion of the 
1407.1 study. The bottom and top of the box are the first and third quartiles, and the band inside the box is the 
second quartile (the median) and outliers are represented by open circles. The whiskers are the lowest datum still 
within 1.5 IQR of the lower quartile, and the highest datum still within 1.5 IQR of the upper quartile. The dotted 
red line represents the mean Cmax at the NOAEL in dogs of 6660 nM. G.Mean values denotes geometric mean of 
the predicted Cmax,SS at each dose level and % Above denotes the percent of individuals above the NOAEL levels.


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Figure 4.1.2: 2              Predictions of AUCSS based on exposure with BI 730357 in the SRD 
trial and comparison to NOAEL exposures
Footnote: The boxplots show the predicted distribution of AUCSS of 500 simulated subjects. The predictions are based upon 
a linear population pharmacokinetic model that was developed using interim PK data of the SRD portion of the 1407.1 
study. The bottom and top of the box are the first and third quartiles, and the band inside the box is the second quartile (the 
median) and outliers are represented by open circles. The whiskers are the lowest datum still within 1.5 IQR of the lower 
quartile, and the highest datum still within 1.5 IQR of the upper quartile. The dotted red line represents the mean AUC at the 
NOAEL in dogs of 127400 nM*h. G.Mean values denotes geometric mean of the predicted AUCSS at each dose level and % 
Above denotes the percent of individuals above the NOAEL levels.
Based on non-clinical data, it is predicted that BI 730357 can be safely administered to 
humans at dose levels achieving exposures of approximately 6660 nM (Cmax) and 127,400 
nM·h (AUC0-24). At the highest dose of 400 mg to be used in this trial, there remains a 
multiple of exposure (MoE) of 1.7- and 2.1-fold to the estimated Cmax, ss and AUCss, 
respectively. 
The dose rationale for the proposed fed cohorts of 50, 100, 200 and 400 mg is to provide 
safety and PK data at the expected higher exposures in the fed state based on the positive 
food effect observed in the SRD study (1407.1). This will provide safety coverage in the 
event that subjects inadvertently take BI 730357 with food in subsequent clinical trials with a 
fasted-state dose administration schedule. The proposed fed cohorts will also provide the 
necessary data if BI 730357 needs to be administered with food in future clinical trials.
In order to estimate the exposures of the fed cohorts in 1407.2, an exposure multiple of 2-fold
(realistic) to 5-fold (maximum-case scenario) was applied to the SRD exposure (see Table 


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1.2.2:1) at the 400 mg fed (standard-diet) cohort. The exposures at the lower fed doses (which 
were not tested in 1407.1) were calculated assuming dose-proportional kinetics. The 
projected exposures are shown in Table 4.1.2:2, below.
Table 4.1.2: 2
Expected plasma exposures of BI 730357 following MRD 
administration in fed state (expected G.Mean, steady-state exposure 
assuming dose-proportional kinetics to 400 mg fed exposure from 
1407.1 and a 2-fold to 5-fold exposure multiple)
Dose  
(fed state 
std. diet)
Observed exposures 
in Trial 1407.1    
(see Table 1.2.2:1)
Expected steady state exposures in 1407.2 
following MRD administration in fed state
2-fold accumulation
5-fold accumulation
Cmax
(nM)
AUC0-24
(nM*hr)
Cmax,ss
(nM)
AUCss
(nM*hr)
Cmax,ss
(nM)
AUCss
(nM*hr)
400 mg
1268
17864
2536
35728
6340
89320
200 mg
Not tested
1268
17864
3170
44660
100 mg
634
8932
1585
22330
50 mg
317
4466
793
11165
Based on the projected exposures listed above, even with a 5-fold accumulation ratio (highly 
unlikely, but assuming a maximum scenario), the highest Cmax,ss and AUCss are still below the 
NOAEL exposures of 6660 nM (Cmax) and 127,400 nM·h (AUC0-24). However, it is more 
likely that the accumulation ratio would be in the 2-3 fold range and, thus, lower exposures 
are expected.
The dose of midazolam used for the DDI evaluation at two of the highest BI 730357 doses
was chosen to be 75 µg, which is within the definition of a microdose (1/100th of the 
therapeutic dose or 100 µg, whichever is smaller). Since midazolam PK is dose proportional 
over the microdose to therapeutic dose range, the microdose should still be able to accurately 
predict CYP3A DDI liability, while remaining below a pharmacologically active 
concentration. An IV solution has been chosen for administration as an oral solution, as an IV
solution is meant to be diluted and, thus, there is data available regarding the stability and 
compatibility of a diluted solution. Furthermore, the IV solution contains midazolam in 
isotonic saline solution, while the oral solution has added excipients, making it a less than 
ideal for such a dilution. Additionally, there is the aspect of feasibility, whereby the oral 
solution would need to be diluted 1:400, which may not be possible to accurately achieve, 
while the IV solution would only require a dilution of 1:200. The IV solution has been 
successfully diluted and administered orally as a microdose in previous clinical studies 
without any reports of AEs.
4.1.3
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be assigned sequentially to dose 


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groups, and likewise to cohorts within each dose group. Allocation of subjects will thereby
not be influenced by trial personnel, rather will be determined only by the subjects’ temporal 
availability.
The list of subject and medication numbers will be provided to the trial site in advance. The
allocation of subjects to study subject numbers will be performed prior to the first 
administration of trial medication. For this purpose, the subjects will be allocated to a study 
subject number by drawing lots. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.
4.1.4
Drug assignment and administration of doses for each subject
The trial medication will be administered to the subjects as an oral dose together with about 
240 mL of water under supervision of the investigating physician or an authorised designee. 
The so-called four-eye principle (two-person rule) should be applied for administration of 
trial medication, if correct dosage cannot be ensured otherwise. On study days one and 14, 
visit procedures including blood draws will be performed following an overnight fast, which 
is to start no later than 8 hours before the scheduled dosing. On other days, in the fasted dose 
groups, the fasting period prior to the withdrawal of blood samples should be at least 6 hours. 
To ensure a dosing interval of 24 hours, the administration of trial medication should take 
place at the same time every day. In the fed dose groups, a standard continental breakfast (see
table 4.1.4:1) should be taken after blood sampling and before the study drug administration.
In the fasted dose groups, the intake of food should not occur earlier than 30 minutes after the 
drug administration.
The medication phase will be followed by a 7 day follow-up and wash-out period.
Table 4.1.4: 1
Composition of the standard continental breakfast
Ingredients
kcal
1 bread roll
164
15 g butter 
113
1 slice of Gouda cheese (approximately 40g)
146
1 slice of meat (approximately 20g)
33
1 cup of decaffeinated coffee or tea (without sugar)
2
Sum1
458
1
The total caloric content is supplied approximately as following: 88 kcal as protein, 133 kcal 
as carbohydrate, and 237 kcal as fat.
Components may be substituted to accommodate for dietary requirements (i.e. vegetarian, gluten intolerance, etc.). The 
composition regarding calories, fat, protein and carbohydrates should, however, remain similar.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This trial is designed double-blind with regard to the subjects and the Investigators (as well as 
the research staff at the trial site) in order to eliminate observer or performance bias. This 
means avoiding systematic differences in assessments regarding the subject’s treatment 
(active or placebo). According to the rising dose design, the current dose level will be known 
to subjects and investigators.
At the trial site, access to the randomisation schedule is restricted to unblinded pharmacists 
and pharmacy staff members. Access to the codes will be controlled and documented by a 
signed confidentiality statement, which will be stored in the TMF. Persons directly involved 
in the clinical conduct of the trial will not have access to the treatment allocation prior to 
database lock. 
The subjects, Investigators and study site staff will not be aware of the treatment allocation 
(i.e., active vs placebo) from the time of randomisation at Day 1 until database lock. See also 
section 3.1 for information on study design and blinding. 
Regarding the Sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical monitor, data manager, 
statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug metabolism scientist, as
well as dedicated contract research organisation (CRO) personnel). The objective of the trial 
is not expected to be affected.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the Investigator by an emergency code break 
envelope. Unblinding information will also be centrally available at ESMS Global Ltd 
(Emergency Scientific and Medical Services), London, United Kingdom. ESMS can be 
reached by telephone at any time and is able to provide information on the assigned treatment 
by the subject ID number.
Unblinding must only be used in an emergency situation when the identity of the trial drug 
must be known to the Investigator in order to provide appropriate medical treatment or 
otherwise assure safety of trial participants. The reason for unblinding must be documented in 
the source documents and/or appropriate CRF page along with the date and the initials of the 
person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual subjects during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives and not be shared 
further. 


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4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP).
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where 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 immediately contacted.
4.1.8
Drug accountability
The Investigator will receive the investigational drugs delivered by 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,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. The Investigator or pharmacist must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the use by 
each patient, and the return to the sponsor or warehouse / drug distribution centre or 
alternative disposal of unused products. If applicable, the sponsor or warehouse / drug 
distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial participants. 
The Investigator / pharmacist / investigational drug storage manager will maintain records 
that document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor< and/or >appointed CRO, the Investigator / pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant treatments are allowed. 
In case of AEs in need of treatment, symptomatic therapy according to investigator judgment 
will be permitted. All concomitant and/or rescue therapies will be recorded on the appropriate 
pages of the eCRF. 
4.2.2.2
Restrictions on diet and life style
On Days 1 and 14 with intensive PK sampling, participants should be fasted for at least 8
hours prior to administration of study medication. 
In the fasted dose groups, at all other visits, the participants should take the medication after 
at least 6 hours fasting and at least 30 minutes before taking food.
In the fed dose groups, a standard continental breakfast (see table 4.1.4:1) should be taken 
after the first blood draw and before the administration of medication.
Foods which are known strong or moderate inhibitors of CYP 3A (e.g., fruit juices from star 
fruit, paw paw, grapefruit) should be avoided during the study participation.
The use of tanning beds is not allowed during the study.
4.2.2.3
Restriction of UV-light exposure
Throughout their participation in the study, participants should avoid sunbathing. When 
exposed to sunlight study participants should protect skin areas not covered by clothes by 
using sun-protection creams and lip balms with sun protection factor 30 or higher with 
protection against UV-A and UV-B. 
These protection measures must be applied until the end of the follow-up period.
4.2.2.4
Restrictions regarding WOCBP and men able to father a child
Participants able to father a child must use the contraception methods described in section 
3.3.3 and in the subject information.


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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 will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see section 3.3.4).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF SAFETY
5.1.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow
Charts. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. 
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart.
The results must be included in the source documents available at the site. 
5.1.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Charts, prior to blood 
sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. 
5.1.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.1.3:1. For the sampling time 
points please see the Flow Charts.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the Investigator. It is the responsibility of the 
Investigator to evaluate the laboratory reports. Clinically-relevant abnormal findings as 
judged by the Investigator will be reported as AEs.
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see the DILI Checklist provided in the ISF. The amount of blood taken 
from the subject concerned will be increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.


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Table 5.1.3:1 
Safety laboratory tests
Category
Test name
Haematology
Hematocrit (Hct)
Hemoglobin (Hb)
Glycosylated Hbc (HbA1c)1
Red Blood Cell Count/ Erythrocytes
Reticulocyte Count
White Blood Cells / Leucocytes
Platelet Count/ Thrombocytes
Diff. Automatic
Neutrophils (relative and absolute count)
Eosinophils (relative and absolute count)
Basophils (relative and absolute count)
Monocytes (relative and absolute count)
Lymphocytes (relative and absolute count)
Diff. Manual (if Diff Automatic is abnormal)
Neutrophils, bands (Stabs)
Neutrophils, polymorphonuclear (PMN)
Eosinophils
Basophils
Monocytes
Lymphocytes
Coagulation
Activated Partial Thromboplastin Time (aPTT)
Prothrombin time (INR)
Fibrinogen
Enzymes
AST(GOT)
ALT(GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Lipase
Amylase
Electrolytes
Calcium
Sodium
Potassium
Chloride
Bicarbonate
Substrates
Glucose
BUN
Uric acid
Creatinine
eGFR (estimated by CKD-EPI formula)
Bilirubin Total
Bilirubin Direct (if total is elevated)
Bilirubin Indirect (if total is elevated)
Troponin (reflex in case of elevated CK)
Albumin
Cholesterol, total1
Triglycerides1
LDL-Cholesterol /HDL-Cholesterol1
1 only at screening and EOO-visit


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Table 5.1.3:1 
Safety laboratory tests cont.
Category
Test name
Hormones (only at screening) 
TSH, (free T3 and T4 in case of abnormal TSH ) 
Urinalysis (dipstick)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/ Erythrocytes
Urine WBC/ Leucocytes
Urine pH
Urine-Sediment (microscopic examination, only if 
urine analysis abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells
Urine Sed. Crys., Unspecified
Urine Sediment RBC/ Erythrocytes
Urine Sediment WBC/ Leucocytes
Urine
Albumin (quantitative)
Creatinine
Infections screening
(only at the screening visit)
Hepatitis B Surface Antigen (qualitative)
Hepatitis C Antibodies (qualitative)
HIV-1, and HIV-2 Antibody (qualitative)
QuantiFERON®-TB
1 only at screening and EOO-visit
5.1.4
Electrocardiogram
The 12-lead ECGs will be recorded as scheduled in the Flow Charts. The Investigator or a 
designee will evaluate whether the ECG is normal or abnormal and whether it is clinically 
relevant, if abnormal. ECGs may be repeated for quality reasons and the repeated recording 
used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in subject’s medical record.
Clinically-relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
5.1.5
Other safety parameters
N/A
5.1.6
Assessment of adverse events
5.1.6.1
Definitions of AEs 
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.


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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A 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 or 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
“AE Collection” and AE reporting to Sponsor and timelines”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI 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. These events should 
always be reported as SAEs as described above.


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Adverse events of special interest (AESIs)
The term 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 above.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

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 these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity grading of AEs will be performed according to Rheumatology Common 
Toxicity Criteria (RCTC) Version 2.0 developed by OMERACT (R13-3515). Refer to ISF 
for intensity/severity classification. Intensity options are:  
Grade 1 
mild
Grade 2 
moderate
Grade 3 
severe
Grade 4 
life –threatening
Causal relationship of AEs
Medical judgement 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).


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
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 diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g., after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g.,
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.1.6.2
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in the subject files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
•
From signing the informed consent onwards until the individual subject’s end of trial: 
-all AEs (serious and non-serious) and all AESIs.
•
After the individual subject’s end of trial: 
the Investigator does not need to actively monitor the subject for AEs but should only 
report related SAEs and related AESIs of which the Investigator may become aware of by 
any means of communication, e.g., phone call. Those AEs should however, not be 
reported in the CRF.


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Figure 5.1.6.2: 1
Trial periods for collection of AEs
Participants, who discontinue trial medication prematurely and agree to be contacted further,
should be followed up as described in section 3.3.4.1, withdrawal from trial treatment. From 
then on until the individual subject’s end of the trial the Investigator must report all 
deaths/fatal AEs regardless of relationship, related SAEs and related AESIs of which the 
Investigator becomes aware.
AE reporting to Sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The Investigator should determine the causal 
relationship to the trial medication and any possible interactions between the trial medication
and a Non-Investigational Medicinal Product (NIMP) / Auxiliary Medicinal Product (AMP).
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing 
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.


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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. All (S)AEs, including those 
persisting after individual subject’s end of trial must be followed up until they have resolved, 
have been assessed as “chronic” or “stable”, or no further information can be obtained.
Pregnancy
.
Potential drug exposure during pregnancy must be reported if a partner of a male trial
participant becomes pregnant. This requires 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 B).
The pregnancy is not to be reported as an AE.
5.2
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.2.1
Assessment of pharmacokinetics
PK parameters for exposure and disposition will be calculated as stated in sections 2.1.3 and 
2.2.2. Other standard single and multiple dose PK parameters will be calculated and further 
specified in the TSAP.
5.2.2
Methods of sample collection
5.2.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 730357 and CD 6975 (Metabolite) plasma concentrations, 2.7 mL of 
blood will be taken from an antecubital or forearm vein into a K-EDTA (tripotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 minutes at about 
2000 g to 4000 g and at 4 to 8 °C or at room temperature. Two plasma aliquots will be 
obtained and stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL 
plasma the second aliquot should contain the remaining plasma. The process from blood 
collection until transfer of plasma aliquots into the freezer should be completed within 
120 minutes, with interim storage at room temperature. For each aliquot the time when the 
sample was placed in the freezer will be documented. Until transfer on dry ice to the 
analytical laboratory, the aliquots will be stored upright at about -20°C or below at the trial 
site. The second aliquot will be transferred to the analytical laboratory after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory the plasma samples 
will be stored at about -20°C or below until analysis.


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For quantification of midazolam plasma concentrations, 4 mL of blood will be taken from an 
antecubital or forearm vein into a K2-EDTA-anticoagulant blood drawing tube at the times 
indicated in the Flow Chart. Blood will be withdrawn by means of either an indwelling 
venous catheter or by venipuncture with a metal needle. The EDTA-anticoagulated blood 
samples will be centrifuged for about 10 minutes at about 2000 g to 4000 g and at 4 to 8 °C. 
Two plasma aliquots will be obtained and stored in polypropylene tubes. The first aliquot 
should contain at least 1.0 mL plasma the second aliquot should contain the remaining 
plasma. The process from blood collection until transfer of plasma aliquots into the freezer 
should be completed within 120 minutes, with interim storage on crushed ice or in an ice-
water bath. For each aliquot the time when the sample was placed in the freezer will be 
documented. Until transfer on dry ice to the analytical laboratory, the aliquots will be stored 
upright at about -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory the plasma samples will be stored at about -20°C or below until 
analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information, such as matrix and 
analyte, may also be provided. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations, e.g., for stability testing, assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the final study 
report has been signed.
5.2.2.2
Urine sampling for pharmacokinetic analysis
A blank urine sample will be collected before administration of trial medication (within the 3 
hours before drug dosing) and two 0.5 mL aliquots will be retained to check for analytical
interference by concomitant or rescue medication.
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in
2 L polyethylene (PE) containers and stored at room temperature. Subjects are told to empty
their bladders at the end of each sampling interval.
The urine weight/volume for each collection interval will be documented (however, no
correction for the specific gravity of urine is done, i.e., 1 L is defined to be equal to 1 kg).
Two 0.5 mL aliquots will be stored in polypropylene (PP) tubes for bioanalytical
measurement. In case 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 PE/PP or glass
container, and stirring the mixed fractions for about 1 minute (manually or using a stir bar or


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other stirring device out of PE, PP, Teflon or glass). If required further details on urine
sampling will be described in a study-specific lab manual.
At minimum, the sample tube labels should list at least the following information: BI trial
number, subject number, visit, and planned collection time. Further information such as
matrix and analyte may also be provided.
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at about 
-20°C or below at the trial site. The second aliquot will be transferred after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory the plasma samples 
will be stored at about -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, assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations, but not later than 5 years after the final study report has been signed.
5.2.2.3
Plasma sampling for metabolism analysis
Additional K3-EDTA plasma samples for the identification of drug metabolites will be 
investigated in the 100 mg fasted dose group. Based on the knowledge gained during the trial 
conduct, e.g., from preliminary PK results, the dose group may be changed to a different one. 
The change will be implemented via a non-substantial CTP Amendment.
The blood samples will be drawn in parallel to PK samples on Day 14 at the time points 
indicated in the Flow Chart (time points for metabolism analysis are the same as for PK). At 
each of these time points, 2.7 ml blood will be needed for metabolite analysis. Details of 
sample processing will be described in a study-specific laboratory manual, see ISF. Data 
from MIST samples will not be transferred into the database.
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
the drug metabolism will be reported separately but not included in the CTR of this trial. The 
study samples will be discarded after completion of the experiments, but not later than 5 
years after the final study report has been signed. 
5.2.3
Analytical determinations
BI 730357 and CD 6975 concentrations in plasma and BI 730357 concentration in urine will 
be determined by a validated LC-MS/MS (liquid chromatography tandem mass spectrometry) 
assay. Midazolam concentrations in plasma will be determined by a validated LC-MS/MS
assay. All details of the analytical methods will be available prior to the start of sample 
analysis.


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5.3.1.1
Methods of sample collection
For the assessment of mRNA expression from whole blood, 4.3 mL blood will be collected 
from an antecubital or forearm vein into a sodium citrate blood drawing tube at the times 
indicated in the Flow Chart and treated within 60 minutes with stimulation conditions 
described in 5.4.1.
For the assessment of IL-17A protein in plasma, 4.5 mL blood will be collected from an 
antecubital or forearm vein in a lithium heparin-anticoagulant blood drawing tube at the times 
indicated in the Flow Chart and treated within 60 minutes with stimulation conditions 
described in 5.4.1.
Sampling times and periods may be adapted during the trial based on information obtained 
during trial conduct (e.g., preliminary PK data), including addition of samples and visits, as 
long as the total blood volume taken from each subject does not exceed 500 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
Detailed instructions for sampling, handling and shipment of samples are provided in the ISF 
/ Lab Manual.
After completion of the study the samples may be used for further biomarker investigations. 
The study samples will be discarded after completion of any additional investigations but not 
later than 3 years after the end of the trial.


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5.4
OTHER ASSESSMENTS
 
 
 
5.5
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial except from the skin biopsies are standard 
measurements in multiple rising dose trials and will be performed in order to monitor safety 
aspects in an appropriate way.
Therefore, the appropriateness of all measurements applied in this trial is given.
Information about race should be obtained from all study participants as allowed by local 
regulations. This is because the prevalence and characteristics of psoriasis differ widely 
between subjects of different racial origin. It will thus be worthwhile to assess if patients of 
different race will respond differently to the study treatment.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All subjects 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.
Study procedures to be performed at each visit are listed in the Flow Charts and the 
respective protocol sections. Additional details on procedures at selected visits are provided 
below.
Measurement of vital signs should precede blood sampling and be assessed pre-dose at all 
dosing visits. All blood samplings on all visits which are not intensive PK-days should occur 
prior to the intake of medication.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
No trial procedures should be done unless the subject has consented to taking part in the trial.
Once consented, the subject is considered to be enrolled in the trial and have started 
screening. The subject should be recorded on the enrolment log. Screening procedures may 
be extended to more than one physical visit, if needed.
Re-screening will not be permitted. Subjects who fail screening following Visit 1 assessments 
should be registered as a screen failure.
After the informed consent process is complete and written informed consent is obtained, the 
subjects will be assessed for study eligibility including laboratory assessments.
All other assessments will also be performed as summarized in the study Flow Charts. 
All subsequent visits should be scheduled.
6.2.2
Treatment period(s)
Please refer to Flow Charts 1 to 4.
6.2.3
Follow up period and trial completion
For all randomised subjects termination of trial medication and trial completion must be 
recorded on the corresponding eCRFs.


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6.2.3.1
Early treatment and trial termination:
If a subject cannot or will not continue in the trial, he should complete EOT visit procedures 
instead of the planned treatment period visit and return to the clinic for FU/EOO Visit 1 week 
after last dose of study medication.
6.2.3.2
Trial completion
Participants who finish the treatment period will return to the clinic for Follow-up Visits. 
Trial completion is defined as subjects having reached the FU visit within the specified 
window per the Flow Chart.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
The primary objective of this trial is to investigate the safety and tolerability of BI 730357 by 
using descriptive statistics for all endpoints comparing active dose groups to placebo. The 
primary endpoint is defined in section 2.1.2. Inferential statistics is not planned (as explained 
in section 7.2).
The secondary objective is the exploration of the PK and PD of BI 730357. Endpoints as 
specified in section 2.1.3 and section 2.2.2 will be analysed by descriptive statistics. 
Secondary endpoints as defined in section 2.1.3 will be subjected to analysis of dose 
proportionality by use of the power model. Trough concentration values will be analysed 
regarding attainment of steady state as a pre-requisite for calculation of steady state 
parameters. Additionally, the linearity index will be estimated. Furthermore, the relative 
bioavailability of midazolam in the presence and absence of BI 730357 at the highest dose(s)
will be evaluated and the relationship between trough exposure and IL-17 inhibition will be 
explored. Refer to section 7.3 further details.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of up to 7 different dose groups of BI 730357 are to be determined on 
the basis of the investigated parameters in comparison to placebo. It is not planned to test any
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will
be described in their entirety and evaluated by descriptive statistical methods.
The analysis of PK and PD data will also be descriptive. Confidence intervals will be 
computed and will have to be interpreted in the perspective of the exploratory character of the 
study, i.e., confidence intervals are considered as interval estimates for effects.
7.3
PLANNED ANALYSES
All individual data will be listed.
All treated subjects (that is, all subjects who received at least one dose of study drug), will be
included in the treated set. 
The primary endpoint will be analysed only descriptively on the treated set. For more details
see section 7.3.4. Safety analyses will be based on the actual treatment received at 
randomisation.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited
concomitant medication, completeness and consistency of data) will be checked. Important


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protocol violations (IPVs) will be identified no later than in the Blinded Report Planning
Meeting and provided in the TSAP.
Specifications of important protocol violations will be provided in the TSAP.
7.3.1
Primary endpoint analyses
Analysis of safety and tolerability is described in section 7.3.4.
7.3.2
Secondary endpoint analyses
The secondary parameters (refer to section 2.1.3) will be calculated according to the 
BIStandard Operating Procedure (SOP) ‘Standards and processes for analyses performed 
within Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472, current version). 
Reasons for exclusion of single PK parameters may be:

The subject experiences emesis at or before two times median tmax. Median tmax is to 
be determined for the test product excluding the subjects experiencing emesis

The subject experiences emesis at any time during the labelled dosing interval

Time deviations

Use of restricted medications
The subject set for the evaluation of PK endpoints (PKS) will include all treated subjects that 
provide at least one observation for at least one secondary endpoint without important
protocol violations relevant for the evaluation of PK endpoints. Whether a protocol violation 
is relevant will be decided no later than in the Blinded Report Planning Meeting.
Excluded subjects will be listed with their individual plasma concentrations and individual
PK parameters, however, they will not be included in descriptive statistics for plasma 
concentrations, PK parameters or other statistical assessment.
Only the fasted dose groups will be used for the assessments of dose proportionality, 
lineartity index, and the attainment of steady state.


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Assessment of dose proportionality
Dose proportionality will be assessed using the PK endpoints as specified in section 2.1.3.
The basic model for the investigation of dose proportionality will be a power model that 
describes the functional relationship between the dose and PK endpoints.
The model consists of a regression model applied to log-transformed data. The corresponding 
ANCOVA model includes the logarithm of the dose as a covariate. 
Together with 
and 
, taking natural logarithms converts this model 
to a linear form as follows:
Where
logarithm of the PK endpoint for subject j at dose level i; where i = 1, 2, 
…, 4-5, j = 1, 2, …, 9;

intercept parameter;
slope parameter;
logarithm of dose i;
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model.
Based on the estimate for slope parameter (β), a 2-sided 95% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of a 
linear relationship between the log-transformed PK endpoint and the log-transformed dose 
will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
Linearity index
Linearity with respect to multiple administration will be explored using the linearity index 
(LI) that will be computed as follows:



0
,
AUC
AUC
LI
ss

In order to construct a confidence interval for LI, a statistical model using AUCτ,ss and AUC 
0-∞will be set up: A linear model on the logarithmic scale including effects for 'subject' and 
'AUC type' can be applied, where 'subject' is a random and 'AUC type' a fixed effect.
[1]
 =  + 
 + s + e , where
ij
i
ij
ε
)
X
exp(
)
exp(Y







)
exp(


)
exp(
ε
ij
ij



ij
i
ij
ε
X
β
α
Y




ij
Y
β
i
X
ij
ε


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
logarithm of the response (AUC after first dose, AUC after last dose) for subject j
and AUC type i; where i = 1 (after first dose) or 2 (after last dose) and j=1, 2,…, n

the overall mean


the AUC type i
s
the effect associated with subject j (random effect)
e
random error associated with subject j at AUC type i (assumed to be independent 
and identically normally distributed).
A pairwise comparison of both areas via the log transformed difference
log(
,
) = log(,) - log()
will then be performed including calculation of a 2-sided 95% CI. The back transformed 
point estimate then represents the estimate of LI. Perfect linearity with respect to multiple 
administrations holds true if this index equals unity.
Generally, this model will be applied to each dose level separately. If there is evidence that 
the areas are comparable across dose levels, they can be analysed simultaneously. The 
corresponding model will then include the log transformed dose as (additional) covariate.
Attainment of steady state
Attainment of steady state will be explored by using the trough concentrations of BI 730357
between days 2 and 14 or 28 respectively and the concentrations taken directly at the end of 
the first and the last dosing interval (Cτ,1, Cτ,14/28) for each dose level. Pairwise comparisons 
of concentrations are performed using 2-sided 95% CIs based on the t-distribution. The 
calculation is based on a repeated measures linear model on the logarithmic scale.
 =  + 
 + s + e , where

logarithm of the concentrations for subject j at time i, i = 1, 2, … and
j=1, 2,…, n

the overall mean,


the effect associated with time point i (repeated effect),
s
(random) effect of subject j, j=1, 2, ..., n
e
random error associated with subject j at time i (assumed to be independent
and identically normally distributed).
Dose can be included as an additional covariate if there is evidence that the trough 
concentration profiles are comparable across dose levels.
The model will be used to explore the time to steady state by pairwise comparing 
concentrations from different time points: log-transformed differences between all 
subsequent time points (log(Cpre,i/Cpre,j) = log(Cpre,i) - log(Cpre,j), where j>i) will be compared 
and adjusted means (Least Squares Means) as well as 2-sided 95% CIs will be calculated. 


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Thereafter, these quantities will be back-transformed by exponentiation to give the 
corresponding (adjusted) ratio and CI.
Comparisons which reveal CIs (for the adjusted ratio) not including 100% will be inspected 
to determine if the differences between time points are resulting from not yet attaining 
steady-state. 
For further details refer to the TSAP (such as selection of covariance structure and 
comparison of time points).
Graphical displays
To support the analyses of dose proportionality, linearity and attainment of steady state, 
graphical representations of the data might be created. These might include (but are not 
limited to) individual time-courses of trough plasma concentrations and the (geometric) mean 
plasma concentration time profiles.
Further details will be given in the TSAP if needed.
7.3.4
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Standard BI summary tables and listings will be produced. All AEs with an onset between 
start of treatment and end of the residual effect period (REP), a period of 7 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.


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All treated subjects will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs, i.e., all 
AEs occurring between start of treatment and end of the residual effect period. AEs that start 
before first drug intake and deteriorate under treatment will also be considered as ‘treatment-
emergent’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA) at the database lock.
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 values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of subjects with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
The PK parameters listed in sections 2.1.3, 2.2.1 and 2.2.2 will be calculated according to the 
relevant BI internal procedures.
Only concentration values within the validated concentration range and actual sampling times
will be used for the calculation of PK parameters. Concentrations used in the PK calculations 
will be in the same format provided in the bioanalytical report, (that is, to the same number of 
decimal places provided in the bioanalytical report).
The following descriptive statistics will be calculated for plasma concentrations and PK
parameters: number (N), arithmetic mean, standard deviation, minimum, median, maximum,
arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation.
The exception to this is tmax, where only median, minimum and maximum will be calculated. 
The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. Thereafter, the individual values, as well as the descriptive
statistics, will be reported with three significant digits in the clinical trial report.
For handling of missing data, please refer to section 7.5.
Analyses will be carried out using Phoenix® WinNonlin® 6.3 (or later) and/or SAS® 
software, Version 9.4 (or later).


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7.4
INTERIM ANALYSES
No inferential statistical interim analysis is planned. However, after each dose group the 
Investigator (or 
 deputy) is allowed to postpone further dose progression until a 
preliminary analysis of the data already obtained has been performed. Refer to section 8.7 for 
more information.
7.5
HANDLING OF MISSING DATA
Every effort should be made to collect complete data at all visits.
With respect to safety evaluations, it is not planned to impute missing values.
Missing PK data will be handled as follows:
Plasma concentration - time profiles
Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not 
analysed), and BLQ (below the limit of quantification) will be ignored and not replaced by 
zero at any time point (applies also to the lag phase). Descriptive statistics of concentrations 
at specific time points will be calculated only when at least 2/3 of the individuals have 
concentrations within the validated concentration range. The overall sample size to decide 
whether the “2/3 rule” is fulfilled will be based on the total number of samples intended to be 
drawn for that time point (i.e., BLQ, NOR, NOS, NOA are included).
Pharmacokinetic parameters
In the non-compartmental analysis, concentration data identified with NOS, NOR, and NOA 
will not be considered. BLQ values in the lag phase will be set to zero. The lag phase is 
defined as the period between time zero and the first time point with a concentration above 
the quantification limit. All other BLQ values of the profile will be ignored. 
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case-to-case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis.

If a concentration is only excluded from half-life determination, it will be used for all 
other calculations (e.g., descriptive statistics) and for graphical presentation.

If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter 
determination. However, the excluded concentration itself will be listed in the tables in 
Section 15 of the clinical trial report associated with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time is not 
recorded or is missing for a certain time point, the planned time will generally be used for this 
time point instead. Pharmacokinetic parameters which cannot be determined will be 
identified by "not calculated" (NC).
More details will be included in the TSAP, if needed.


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7.6
RANDOMISATION
Subjects will be randomised within each dose group in a 3:1 ratio, which reflects the ratio of 
subjects receiving active drug to placebo.
The Sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
More details can be found in section 4.1.5.
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of up to 84 subjects in this trial depending on the number of 
dose groups as described in section 3.1. The planned sample size is not based on a power 
calculation. The size of 12 subjects per dose group (9 on active treatment, and 3 on placebo) 
is commonly used in multiple-rising dose studies of the present type and is in general 
considered as sufficient for the exploratory evaluation of multiple dose safety and 
pharmacokinetics [R95-0013].
Additional subjects may be entered to allow testing of additional intermediate doses within 
the planned dose range on the basis of experience gained during trial conduct (e.g.,
preliminary PK data), i.e., the actual number of subjects entered may exceed 84.


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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 Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The BI 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 
rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the subjects, and 
is stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to subject participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH / GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.”
The subject must be given sufficient time to consider participation in the trial. The 
Investigator obtains written consent of the subject’s own free will with the informed consent 
form after confirming that the subject understands the contents. The Investigator must sign 
(or place a seal on) and date the informed consent form. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent. Re-consenting may become necessary when new relevant information 
becomes available and should be conducted according to the sponsor’s instructions. The 
consent and re-consenting process should be properly documented in the source 
documentation.


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The subject must be informed that his/her personal trial-related data will be used by
Boehringer Ingelheim in accordance with the local data protection law. The level of
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the Sponsor. See section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
8.3.2
Direct access to source data and documents
The Sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g., FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
Sponsor will also monitor compliance with the protocol and GCP.


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8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject data obtained as a result of this trial is considered confidential, and 
disclosure to third parties is prohibited with the exceptions noted below. Subject privacy will 
be ensured by using subject identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the Sponsor’s
representatives, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial
(“Last Subject Out”).
The “Last Subject Drug Discontinuation” (LPDD) date is defined as the date on which the 
last subject at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial
medication until 30 days after LPDD at their site. Early termination of the trial is defined 
as the premature termination of the trial due to 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.


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Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data 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 subject
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
This trial is sponsored by BI.
A SMC composed of Principal Investigator, members of the BI Trial Team and a trial 
independent member will be established, to review individual and aggregated safety data at 
the conclusion of dosing for each dose group, to determine the acceptability of safety and 
tolerability, and recommend next dose level/does escalation. Details of the SMC 
responsibilities and procedures are described in the SMC Charter.
Relevant documentation on the participating (Principal) Investigators (e.g., their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required 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,
.
Data Management and Statistical Evaluation will be conducted 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.
A central laboratory service vendor will be used in this trial. Details will be provided in the 
Central Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R03-1208
NPF psoriasis score. Psoriasis Forum. 8:2. 2002
R05-2548
Finlay AQ, Khan GK. Dermatology Life Quality Index (DLQI) – a simple 
practical measure for routine clinical use. Joint Ann Mtg of the British 
Association of Dermatologists and the Canadian Dermatology Association , 
Oxford, 6-10 July 1993. Clin Exp Dermatol. 19. 210-216. 1994.
R08-1089
Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. 
Nature. 445:7130. 866-873. 2007.
R10-1424
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures. J Biopharm 
Stat.16:5. 639-656. 2006.
R11-1257
Nestle FO, Kaplan DH, Barker J. Mechanisms of disease: psoriasis. N Engl J 
Med. 361:5. 496-509. 2009.
R11-1259
Menter A, Griffiths CEM. Psoriasis 2: current and future management of 
psoriasis. Lancet. 370. 272-284. 2007.
R11-1260
Griffiths CEM, Baker JNWN. Psoriasis 1: pathogenesis and clinical features 
of psoriasis. Lancet. 370. 263-271. 2007.
R13-2643
Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, 
Higgins PDR, et.al. Secukinumab in Crohn´s Disease Study Group. 
Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to 
severe Crohn´s disease: unexpected results of a randomised, double-blind 
placebo-controlled trial. Gut. 61:12. 1693-1700. 2012.
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, Tsuji W, 
et.al. Standardizing assessment and reporting of adverse effects in 
rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria 
v.2.0. J Rheumatol 34:6. 1401-1414. 2007.
R15-1961
European Medicines Agency. Qualification Opinion of MCP-Mod as an
efficient statistical methodology for model-based design and analysis of Phase
II dose finding studies under model uncertainty. 23 January 2014.
R15-2001
Bornkamp B, Pinheiro J, Bretz F. Package 'DoseFinding' (February 19, 2015). 
Cran rproject org web packages DoseFinding DoseFinding pdf.
Comprehensive R Archive Network. 2015.


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R15-3845
Basra MKA, Fenech R, Gatt RM, Salek MS, Finlay AY. The Dermatology 
Life Quality Index 1994-2007: a comprehensive review of validation data and 
clinical results. Br J Dermatol. 159. 997-1035. 2008.
R15-5200
Langley RGB, Feldman SR, Nyirady J, Kerkhof P van de, Papavassilis C. The 
5-point Investigator's Global Assessment (IGA) scale: a modified tool for 
evaluating plaque psoriasis severity in clinical trials. J Dermatol Treat. 26:1.
23-31. 2015.
 
 
R16-3072
Horn EJ, Fox KM, Patel V, Chiou CF, Dann F, Lebwohl M. Association of 
patient-reported psoriasis severity with income and employment. J Am Acad 
Dermatol. 57:6. 963-971. 2007.
R16-3073
Lynde CW, Poulin Y, Vender R, Bourcier M, Khalil S. Interleukin 17A: 
toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol. 
71:1. 141-150. 2014.
R16-3149
Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of 
interleukin-17 function in disease. Immunology. 129. 311-321. 2010.
 
R16-4115
Mattei PL, Corey KC, Kimball AB. Cumulative life course impairment: 
evidence for psoriasis. Curr Probl Dermatol. 44. 82-90. 2013.
R17-1989
Burgos-Pol R, Martinez-Sesmero JM, Ventura-Cerda JM, Elias I, Caloto MT, 
Casado MA. The cost of psoriasis and psoriatic arthritis in 5 European 
countries: a systematic review. Actas Dermos Sifiliogr. Engl. Ed. 107:7. 577-
590. 2016.
R17-1990
Vanderpuye-Orgle J, Zhao Y, Lu J, et al. Evaluating the economic burden of 
psoriasis in the United States. J Am Acad Dermatol. 72:6. 961-967. 2015.
R95-0013
Broom C. Design of first-admistration studies in healthy man. In: O´Grady J, 
Linet Ol, editors. Early Phase Drug Evaluation in Man. London. Macmillan 
Press. 206-213. 1190.
R96-3541
Fredriksson T, Pettersson U. Severe psoriasis – oral therapy with a new 
retinoid. Dermatologica. 157. 237-244. 1978.


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c09228382
Investigators´s Brochure. BI 730357. Psoriasis (ankylosing spondylitis, 
psoriatic arthritis, asthma, inflammatory bowel disease). Current version.
n00250111
 Prediction of BI 730357 Pharmacokinetics and
Therapeutic Dose in Human. Current version.


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10.
APPENDICES
No appendices included in this protocol.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Number of global amendment
1
Date of CTP revision
06 October 2017
EudraCT number
2017-001653-14
BI Trial number
1407-0002
BI Investigational Product(s)
BI 730357
Title of protocol
Phase Ib evaluation of the safety and tolerability 
and effect on midazolam metabolism of the 
administration of multiple rising doses of 
BI 730357 to healthy volunteers
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
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
Change #1:
Section to be changed
All sections of the protocol
Description of change
Removal of all sections and text referring to Part 
2 (Phase II, proof of concept in patients with 
plaque psoriasis) of the previous protocol 
version.
Rationale for change
Separate the two parts of the protocol and make 
the Phase I multiple rising dose in healthy 
volunteers a self-contained trial.
Change #2:
Section to be changed
3.3.2
Inclusion criterion #3
Description of change
“Age of 18 to 50 years (incl.) at screening” 
changed to “Age of 18 to 45 years (incl.) at 
screening”
Rationale for change
Adapt age range to Phase I standard as requested 
by health authority (BfArM)
Change #3
Section to be changed
3.3.4.1
Withdrawal from trial treatment
Description of change
Addtion of individual stopping rule:
An individual subject is to be permanently 
withdrawn from trial treatment if “during the 
course of treatment the subject experiences 
cardiovascular or hematologic adverse event 
(including laboratory abnormalities), with 
Rheumatology Common Toxicity Criteria 


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(RCTC) Version 2.0 Grade 2 or higher.”
Rationale for change
Adhere to respective EMA guideline and FDA 
request.
11.2
GLOBAL AMENDMENT 2
Number of global amendment
2
Date of CTP revision
12 January 2018
EudraCT number
2017-001653-14
BI Trial number
1407-0002
BI Investigational Product(s)
BI 730357
Title of protocol
Phase Ib evaluation of the safety and tolerability 
and effect on midazolam metabolism of the 
administration of multiple rising doses of 
BI 730357 to healthy volunteers
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
Change #1:
Section to be changed
1.2
Drug profile
Description of change
Rationale for change
Clarification
Change #2:
Section to be changed
1.2.2
Clinical Experience in Humans
Description of change
Include updated results from SRD trial
Rationale for change
Update and provide justification for change #3.
Change #3:
Section to be changed
3.1
4.1.2
4.1.4
4.2.2
7.3.2
Flow charts #2 and #4
Overall trial design
Selection of doses
Drug assignment
Restrictions
Secondary endpoint analyses
Description of change
Addition of fed dose groups 50 mg, 200 mg and 
either 100 or 400 mg. Removal of 400 mg fasted 
dose group. Number of subjects increased from 
60 to up to 84.
Decision tree added.
Rationale for change
To assess the effect of food on drug exposure
Change #4


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Section to be changed
4.1.4
Drug assignment
Description of change
Contents of continental breakfast added
Rationale for change
Change #5:
Section to be changed
4.1.1
Identity of the investigational medicinal products
Table 4.1.1:2.
Description of change
5 mg/ 5 mL diluted to 5 µg/mL*15 mL (75 µg)
Changed to:
5 mg/ 5 mL diluted to 50 µg/mL*1.5 mL (75 µg)
Rationale for change
Correction of editorial error
Change #6:
Section to be changed
5.2.2
5.2.3
Methods of sample collection
Analytical determinations
Description of change
Addition of drug metabolites to be tested for
Rationale for change
New metabolites identified
Change #7:
Section to be changed
5.3.1.3
5.3.1.4
Methods of sample collection
Analytical determinations
Description of change
Sections were removed 
Rationale for change
Editorial change: Sections were duplicates of 
sections 5.3.1.1 and 5.3.1.2


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c14109663
3.0
clinical-trial-protocol-version-03
Phase Ib evaluation of the safety and tolerability and effect on midazolam
metabolism of the administration of multiple rising doses of BI 730357 to healthy
volunteers
Author-Trial Statistician
12 Jan 2018 14:01 CET
Author-Clinical Monitor
12 Jan 2018 15:03 CET
Approval-Team Member Medicine
14 Jan 2018 21:56 CET
Author-Trial Clinical
Pharmacokineticist
15 Jan 2018 10:54 CET
Approval-Therapeutic Area 
16 Jan 2018 11:22 CET
Verification-Paper Signature
Completion
16 Jan 2018 13:28 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c14109663
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c26150818-01
BI Trial No.:
1407-0002
Title:
Phase Ib evaluation of the safety and tolerability and effect on 
midazolam metabolism of the administration of multiple rising 
doses of BI 730357 to healthy volunteers.
Investigational
Product:
BI 730357
Responsible trial 
statisticians:
Phone:
Fax:
Phone:
Fax:
Date of statistical 
analysis plan:
12 OCT 2018 SIGNED
Version:
Final
Page 1 of 32
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2018 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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
...................................................................................9
.................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................15
....................................................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........19
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................19
7.3
TREATMENT COMPLIANCE........................................................................19
7.4
PRIMARY ENDPOINTS...................................................................................19
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoints....................................................................................20
7.5.2
Secondary endpoints...........................................................................................20
...................................................................................24
7.7
EXTENT OF EXPOSURE.................................................................................26
7.8
SAFETY ANALYSIS..........................................................................................26
7.8.1
Adverse events.....................................................................................................26
7.8.2
Laboratory data ..................................................................................................28
7.8.3
Vital signs.............................................................................................................28
7.8.4
ECG......................................................................................................................29
7.8.5
Others...................................................................................................................29
8.
REFERENCES....................................................................................................30
............................................................................31
10.
HISTORY TABLE..............................................................................................32


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LIST OF TABLES
Table 6.1: 1    Dose Groups .....................................................................................................11
Table 6.1: 2
Treatments and labels used in the analysis.......................................................12
Table 6.2: 1
Important protocol deviations ..........................................................................14
Table 6.3: 1
Subject sets analysed........................................................................................15
Table 7.5.2: 1 Available trough concentrations Dose Groups 1, 2, and 3...............................22
Table 7.5.2: 2 Available trough concentrations Dose Group 4 ...............................................23
Table 10: 1
History table .....................................................................................................32


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
λz
Terminal rate constant in plasma
ADS
Analysis Dataset
Aet1-t2
Amount of analyte that is eliminated in urine from the time interval t1 to t2
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANOVA
Analysis of Variance
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUCτ,1
Area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ
BI
Boehringer Ingelheim
BMI
Body Mass Index
BWU
Bioavailability/Bioequivalence, Within-Subject Design, uncontrolled
Cmax(,ss)
Maximum measured concentration of the analyte in plasma (at steady state)
Cpre,N
Predose concentration of the analyte in plasma immediately before 
administration of the Nth dose and after N-1 doses were administered
CI
Confidence Interval
CLR, t1-t2
Renal clearance of the analyte in plasma from the time point t1 to t2
CL/F
Apparent clearance of the analyte in the plasma after extravascular 
administration
CRF
Case Report Form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation


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Term
Definition / description
DBLM
Database Lock Meeting
ECG
Electrocardiogram
fet1-t2
Fraction of given drug excreted unchanged in urine from time point t1 to t2
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
ICH
International Conference On Harmonisation
IL-17A
Interleukin 17A
iPD
Important Protocol Deviation
LI
Linearity Index
LLT
Lower Level Term
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
MRD
Multiple Rising Dose
mRNA
Messenger Ribonucleic Acid
MRTpo
Mean residence time of the analyte in the body after oral administration
PD
Pharmacodynamic(s)
PDS
PD Parameter Analysis Set
PK
Pharmacokinetic(s)
PKS
PK Parameter Analysis Set
POC
Percent of Control
PT
Preferred Term
PTF
Peak-Trough Fluctuation
QD
Quaque die, once daily
RA, AUC
Accumulation ratio based on AUCτ
RA, Cmax
Accumulation Ratio based on Cmax,ss
RAGe
Report Appendix Generator system
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual Effect Period
RPM
Report Planning Meeting
SAS®
Statistical Analysis System


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Term
Definition / description
SD
Standard Deviation
SOC
System Organ Class
SP
Sample Point
t1/2
Terminal half-life of the analyte in plasma
tmax(,ss)
Time from dosing to maximum measured concentration of the analyte in 
plasma (at steady state)
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WHO-DD
World Health Organization- Drug Dictionary
XPKISTAT
SAS® Macro for analysis of PK data


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This 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 will be stored in a trial database within the RAVE EDC system.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or later, Certara USA Inc., Princeton, NJ, USA).
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 SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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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, dose proportionality will not only be assessed for fasted dose groups as described 
in the CTP but also separately for fed dose groups.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP: 
Safety: Number of subjects with drug-related AEs, measured by the percentage of patients 
with drug related AEs within 7 days of treatment, which covers more than the residual effect 
period defined by 5 half-lifes of the study drug.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP:
After the first dose:

AUCτ,1 (area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose)

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 
over a uniform dosing interval τ)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment sequences 
and selection of doses, please see CTP, Sections 3 and 4.
The study was performed as a double-blind, randomised, placebo-controlled, MRD trial with 
7 dose groups. It was planned to assign 12 healthy volunteers in each dose group, 9 to be 
randomised to BI 730357, and 3 to be randomised to Placebo.
Table 6.1: 1                       Dose Groups
Dose Group
1
2
3
4
5
7
8
Daily dose (mg)
25
50
100
200
50
200
400
Status
fasted
fasted
fasted
fasted
fed
fed
fed
Treatment duration (days)
14
14
14
28
14
28
28
Number of subjects
12
12
12
12
12
12
12
Subjects receiving placebo
3
3
3
3
3
3
3
Subjects receiving active drug
9
9
9
9
9
9
9
For details of dosage and formulation see Table 6.1: 2.
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00 h on day of informed consent until first administration 
time of study drug (BI)

On treatment
o
Including residual effect period (REP); i.e. ranging from the time of first 
administration of BI 730357/Placebo until 7 days after the last administration of
BI 730357/Placebo)

Follow-Up (ranging from end of on-treatment phase until end of follow-up)


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Table 6.1: 2
Treatments and labels used in the analysis
Treatment as received2,3
Short label
H
BI 730357, tablet, 25 mg, qd
BI 25mg
I
BI 730357, tablet, 50 mg, qd
BI 50mg
J
BI 730357, tablet, 2*50mg, qd
BI 100mg
K
BI 730357, tablet, 4*50mg, qd, std continental breakfast 
+ 3 times Midazolam, 75µg, po, qd
BI 200mg fed
L
BI 730357, tablet, 8*50mg, qd, std continental breakfast
+ 3 times Midazolam, 75µg, po, qd
BI 400mg fed
M
BI 730357, tablet, 4*50mg, qd
BI 200mg
O
BI 730357, tablet, 50mg, qd, std continental breakfast
BI 50mg fed
Z
Placebo to match BI 730357 (DG 1-4)
Placebo fast
Y/Z1
Placebo to match BI 730357 (+ Midazolam) (DG 5,7,8)
Placebo fed
Y/Z1
Placebo to match BI 730357 (+ Midazolam)
Placebo total
1As Midazolam is only provided in a micro-dose with no therapeutic effect, groups Y and Z are combined to one 
Placebo group for all analyses.
2All analyses will be performed by treatment as received, i.e. if a subject did not receive the correct treatment, 
the subject will be counted towards the treatment group of the treatment that was received.
3Subjects who received a mixture of drugs due to administration errors will be analyzed as separate groups.
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT) of the CTR 
displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening and follow-up will not be included in this 
analysis. 
The following totals will be provided in addition (Section 15.3 only):
a total over all on treatment phases involving BI treatment (“BI total on treatment”)
a total over all on treatment phases included in this analysis ("Total on treatment")
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:


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Screening 
On treatment (labelled with the name of the study treatment (short label))
Follow-up BI
Follow-up Placebo
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:
a total over all study phases after BI treatment (“BI total”)
a total over all study phases ("Total")
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 Data Reviewers guide. 
6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all randomised 
subjects.
Listings of protocol deviations and of unresolved discrepancies will be provided to be 
discussed at the combined report planning and database lock meeting (RPM/DBLM), e.g. 
deviations in drug administration, in blood sampling etc. At this meeting, it will be decided 
whether the discrepant data can be used as they are or whether the data have to be corrected
in the clinical database.
Each protocol deviation must be assessed to determine whether it is an important protocol 
violation. A protocol deviation is considered an important protocol deviation (iPD) if it 
affects the rights or safety of the study subjects or if it can potentially influence the primary 
outcome measure(s) for the respective subjects in a way that is neither negligible nor in 
accordance with the study objectives. This last category of iPD forms the basis for the 
decision of whether a subject does or does not belong to an analysis set. Protocol deviations
that do not influence the subject's rights and safety or the evaluability of the subjects for the 
main study objectives are not considered to be iPDs. These are only considered when 
checking the trial quality in general.
If any iPDs are identified, they are to be summarized into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet [BI-KMED-COPS-TMP-
0001] (2). The following table contains the categories which are considered to be important 
protocol deviations in this trial. If the data show other iPDs, this table will be supplemented 
accordingly by the time of the RPM/DBLM.


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Table 6.2: 1
Important protocol deviations
Category
/Code
Description
A
Entrance criteria not met
A1
Inclusion criteria 1, 2, 3, 4, or 5 not met
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available / not done
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomization order not followed
C3
Wrong dosage schedule
C4
Non-compliance
C5
Medication code broken inappropriately
D
Concomitant medication
D1
Prohibited medication use
D2
Mandatory medication not taken
E
Missing data 
E1
Certain deviations of procedures used to measure primary or secondary data
F
Incorrect timing1
F1
Certain deviations of time schedule used to measure primary and secondary 
endpoints
G
Other trial specific important violations
G1
PDs affecting safety and rights
1 Time deviations will only be flagged as important PD, when leading to exclusion of the entire subject from an analysis set
Source: ‘Protocol Violation Handling Definitions’ [001-MCS-50-413_RD-01] (3).


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6.3
SUBJECT SETS ANALYSED

Treated set (TS):
This subject set includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for safety 
analyses.

PK parameter analysis set (PKS):
This subject set includes all subjects from the TS who provide at least one evaluable 
secondary PK endpoint that does not have an important deviation relevant for the 
evaluation of PK.  Thus, a subject will be included in the PKS, even if he contributes 
only one PK endpoint value for one treatment period to the statistical assessment.
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.

PD parameter analysis set (PDS): 
This subject set includes all subjects from the TS who provide at least one evaluable 
secondary or further PD endpoint that does not have an important deviation relevant for 
the evaluation of PD.  Thus, a subject will be included in the PDS, even if he contributes 
only one PD endpoint value for one treatment period to the statistical assessment.
Table 6.3: 1
Subject sets analysed
Analysis set
Class of endpoint
TS
PKS
PDS
Safety endpoints and primary endpoints
X
PK endpoints 
X
PD endpoints
X
Demographic/baseline endpoints
X
Important PVs
X
Disposition
X


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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 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study day will be calculated relative to the date and time of the first dose of randomized 
treatment. The day prior to the start of randomized treatment will be ‘Day -1’ and the day of 
the start of randomized treatment will be ‘Day 1’; therefore, ‘Day 0’ will not exist.
Baseline refers to the measurement recorded at randomization (Visit 2); if data at Visit 2 is 
missing, then data from Visit 1 will be considered baseline. 
Time windows are defined in the CTP; the following time windows are planned:
- Screening: 1 to 28 days before drug administration
- Dose groups 1, 2, 3, and 5 treatment period: starts at first day of drug administration (day 1) 
and ends at last day of drug administration (day 14)
- Dose groups 4, 7, and 8 treatment period: starts at first day of drug administration (day 1) 
and ends at last day of drug administration (day 28)
- Dose groups 1, 2, 3, and 5 follow up period: starts at 1 day after last drug administration and 
ends at day 21
- Dose groups 4, 7, and 8 follow up period: starts at 1 day after last drug administration and 
ends at day 35
- Dose groups 1, 2, 3, and 5 end of study: Day 22 onwards
- Dose groups 4, 7, and 8 end of study: Day 36 onwards
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.


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7.
PLANNED ANALYSIS
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 Sections 7.5.2 and 7.6) 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 ClinPK 
at BI and will be presented in Section 15.6 of the CTR.
Inferential statistical analyses of PD endpoints (refer to Sections 7.5.2 and 7.6) will be 
performed by
and will be presented in Section 15.7 of the CTR 
and in Appendix 16.1.13.6. Descriptive statistical analyses of PD endpoints will be performed 
by ClinPK and will be presented in the same sections.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations.
The analysis of PD parameters, as well as the tables and graphs, will follow the definitions of 
the BI standard procedure “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics” [001-MCS-36-472] (7).
The individual values of all subjects will be listed, sorted by treatment group, subject 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
In general, means, medians, and percentiles are presented to one more decimal place than the
raw data and SDs are presented to two more decimal places than the raw data. Minima and
maxima are presented to the same number of decimal places as the raw data.
For analyte concentrations, as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean


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gCV
geometric coefficient of variation
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 
treatment group. Percentages will be rounded to one decimal place and will be based on all 
subjects 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]).
If applicable, conversion from days to weeks, months and years will be as follows:

weeks = days ÷ 7

months = 12 × days ÷ 365.25

years = days ÷ 365.25.
All p-values will be displayed to four decimal places (or “<.0001” if appropriate).
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.


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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” (8). PD parameters will be 
handled accordingly.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only standard descriptive statistics and summary tables are planned for this section of the 
report, based on the TS. The data will be summarised by treatment group and a “total” 
column will be included in the summary table. The following variables will be displayed: 
gender, ethnicity, race, age, height, weight, etc.
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 coding system of the Medical Dictionary for
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects 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 will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
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 plasma 
concentrations and/or urinary excretion 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 ENDPOINTS
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 730357.


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable, as no key secondary endpoints have been specified in the 
protocol.
7.5.2
Secondary endpoints
Assessment of dose proportionality
Dose proportionality of the PK endpoints AUCτ,1 and Cmax in plasma after the first dose of 
BI 730357 and AUCτ,ss and Cmax,ss in plasma after the dose at day 14 of BI 730357 will be 
explored using the power model that describes the functional relationship between dose and 
PK endpoints. The basic model consists of a regression model applied to log-transformed 
data. The corresponding ANCOVA (Analysis of Covariance) model includes the logarithm of 
the dose as a covariate.
The model is described by the following equation:
Section 7.3.2 of the CTP: 
Yij = α + β*Xi + εij
where
Yij
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, …,4, j = 1, 2, …, 9, 
α
intercept parameter;
β 
slope parameter;
Xi
logarithm of dose i;
εij
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model.
Based on the estimate for slope parameter (β), a 2-sided 95% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of 
a linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed. 


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Modelling will be performed twice: Once for all fasted dose groups (groups 1, 2, 3, and 4) 
and once for all fed dose groups (5, 7, 8).
This analysis will be accomplished by using the XPKISTAT macro (design DB), based on 
the PKS.
To support the analyses of dose proportionality, a regression plot will be performed, where 
the logarithm of dose is depicted versus logarithm of PK endpoint, including the estimated 
regression line from the power model and reference line of perfect proportionality (β=1). 
Linearity index
Only the fasted dose groups will be used for assessment of linearity index.
Linearity with respect to multiple administration will be explored for BI 730357 using the 
linearity index (LI) that will be computed as follows:
AUC
AUC ss
LI



0
,

Section 7.3.2 of the CTP: In order to construct a confidence interval for LI, a statistical 
model using AUCτ,ss and AUC0-∞will be set up: A linear model on the logarithmic scale 
including effects for ‘subject’ and ‘AUC type’ can be applied, where ‘subject’ is a random 
and ‘AUC type’ a fixed effect.
Yij = μ + τi  + sj + eij, where
Yij
logarithm of the response (AUC after first dose, AUC after last dose) for subject j and 
AUC type i; where i=1 (after first dose (day 1)) or 2 (after last dose (day 14 for DG 
4)) and j=1,2,…,n
μ
the overall mean
τi
the AUC type i (fixed effect)
sj
the effect associated with subject j (random effect)
eij
random error associated with subject j at AUC type i (assumed to be independent and 
identically normally distributed)
The covariance matrix is chosen to be an unstructured matrix to allow for different variances 
for the two AUC types. In case the model does not converge (due to the unstructured 
covariance matrix), a compound symmetry structure can be chosen instead.
A pairwise comparison of both areas via the log transformed difference


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)
log(
)
log(
)
log(
0
,
0
,






AUC
AUC
ss
ss
AUC
AUC


will then be performed including calculation of a 2-sided 95% CI. The back transformed 
point estimate then represents the estimate of LI. Perfect linearity with respect to multiple 
administrations holds true if this index equals unity.
Generally, this model will be applied to each dose level separately. If there is evidence that 
the areas are comparable across dose levels, they can be analysed simultaneously. The 
corresponding model will then include the log transformed dose as (additional) covariate.
The following SAS code will be used to fit the model: 
PROC MIXED DATA=indata; 
CLASS AUCtype subject; 
MODEL logkp = AUCtype / DDFM=KR; 
REPEATED AUCtype / subject=subject TYPE=UN; 
LSMEANS AUCtype / PDIFF CL ALPHA=0.05; 
RUN;
Attainment of steady state
Only the fasted dose groups will be used for assessment of attainment of steady state.
Attainment of steady state will be explored by using the trough concentrations of BI 730357
between days 2 and 14 or 28 respectively and the concentrations taken directly at the end of
the first and the last dosing interval (Cτ,1, Cτ,14/28) for each dose level.
The following table summarises the available trough concentrations:
Table 7.5.2: 1 Available trough concentrations Dose Groups 1, 2, and 3
Day
2
3
7
10
11
12
13
14
15
Planned 
time [h]
23:30
47:30
143:30
215:30
239:30
263:30
287:30
311:30
335:30
PK 
Parameter
Cτ 
Cpre,3
Cpre,7
Cpre,10
Cpre,11
Cpre,12
Cpre,13
Cpre,14
Cτ,ss


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Table 7.5.2: 2 Available trough concentrations Dose Group 4
Day
2
3
7
8
11
12
13
14
15
Planned 
time [h]
23:30
47:30
143:30
167:30
239:30
263:30
287:30
311:30
335:30
PK 
Parameter
Cτ
Cpre,3
Cpre,7
Cpre,8
Cpre,11
Cpre,12
Cpre,13
Cpre,14
Cpre,15
Day
16
17
21
24
28
29
Planned 
time [h]
359:30
383:30
479:30
551:30
647:30
671:30
PK 
Parameter
Cpre,16
Cpre,17
Cpre,21
Cpre,24
Cpre,28
Cτ,ss
Individual time-courses of trough plasma concentrations and the (geometric) mean plasma 
concentration time profile will be plotted by dose group. 
The attainment of steady state will be explored by dose group by using a repeated measures 
linear model on the logarithmic scale including ‘time’ as a repeated effect and 'subject' as 
random effect. 
CTP Section 7.3.2: The calculation is based on a repeated measures linear model on the 
logarithmic scale.
Yij = μ + i + sj + eij
where
Yij
logarithm of the concentrations for subject j at time i, i=1, 2, … I and 
j=1, 2,…, n

the overall mean,
i
the effect associated with time point i (repeated effect),
sj
(random) effect of subject j, j=1, 2,…,n
eij
random error associated with subject j at time i (assumed to be independent 
and identically normally distributed).
Dose can be included as an additional covariate if there is evidence that the trough
concentration profiles are comparable across dose levels.
The model will be used to explore the time to steady state by pairwise comparing
concentrations from different time points: log-transformed differences between all


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subsequent time points (log(Cpre,i/Cpre,j) = log(Cpre,i) - log(Cpre,j), where j>i) will be compared
and adjusted means (Least Squares Means) as well as 2-sided 95% CIs will be calculated.
Thereafter, these quantities will be back-transformed by exponentiation to give the
corresponding (adjusted) ratio and CI.
Comparisons which reveal CIs (for the adjusted ratio) not including 100% will be inspected
to determine if the differences between time points are resulting from not yet attaining steady-
state.
As default, the structure of the covariance matrix will be unstructured (type=UN or UNR). In 
case an unstructured covariance matrix does not work, the following covariance structures 
will be chosen, in the pre-defined order: Toeplitz or AR1. A Compound Symmetry structure 
should not be considered, as this structure already postulates a steady-state. For the 
approximation of the degrees of freedom the Kenward and Roger method is recommended.
The following SAS code will be used to fit the model: 
PROC MIXED DATA=indata; 
CLASS subject time; 
MODEL logkp = time / DDFM=KR; 
REPEATED time / TYPE=UN SUBJECT=subject; 
LSMEANS time / DIFF CL ALPHA=0.05;
RUN;


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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 subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS and performed in accordance with BI 
standards. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyze 
continuous (quantitative) data.
The individual values of all subjects will be listed, sorted by treatment, subject number and
visit.
The safety data for treated subjects 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 the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (9).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 


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The intensity grading of AEs will be performed according to Rheumatology Common 
Toxicity Criteria (RCTC) Version 2.0 developed by OMERACT (10).
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence)
For further details on summarization of AE data, please refer to [001-MCG-156] (9).
The analysis of AEs will be based on the concept of treatment emergent adverse events. That
means that all adverse events occurring between the date of the first administration of trial
treatment till the date of the last administration of trial treatment + residual effect period will
be assigned to the on-treatment period label with the trial treatment assigned on Day 1 of the
first treatment cycle. All AEs occurring before the first administration of trial treatment will
be assigned to ‘screening’ and all AEs occurring after the residual effect period will be 
assigned to ‘follow-up’. For details on the treatment definition, see Section 6.1.
Adverse events of special interest (AESIs)
Section 5.1.6.1 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 and/ or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/ or AST) elevations ≥10 fold ULN
Other significant AE (according to ICH E3)
According to ICH E3 (11), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review
Meeting.
An overall summary of AEs (including AESIs) will be presented.


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The frequency of subjects with AEs will be summarized by treatment, primary system organ 
class (SOC) and preferred term (PT). This table will also be shown by RCTC grade (All, 
Grade 1, Grade 2 or higher). Separate tables by treatment and RCTC grade will be provided 
for subjects with other significant AEs according to ICH E3 (11), for subjects with serious 
AEs, for subjects with drug-related AEs, for subjects with drug related serious adverse 
events, for subjects with AESIs, for subject with AEs leading to treatment discontinuation, 
and for subjects with AEs leading to death.
The SOC and PTs will be sorted by frequency (within system organ class). The MedDRA 
version number will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
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 [001-MCG-157] (12). Summary statistics will be based on normalized 
laboratory values. Both converted and normalized laboratory values will be listed.
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 clinically 
relevant will be highlighted in the data listings.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the CRF or at the RPM/DBLM at the latest. It is the 
investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study.
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate). In the listing the difference from baseline will also be 
displayed.
Clinically relevant findings in vital signs will be reported as AEs.


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7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as adverse events 
(when they occurred during treatment).
7.8.5
Others
Physical examination
Physical examination findings 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.


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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.
BI-KMED-COPS-TMP-0001: “iPD log”, current version; KMED
3.
001-MCS-50-413_RD-01: “Protocol Violation Handling Definitions”, current version, 
IDEA for CON.
4.
001-MCG-156_RD-01: "Handling of Missing and Incomplete AE Dates", current 
version; IDEA for CON.
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic
Analyses of Clinical Studies”, current version; IDEA for CON.
6.
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current version; 
IDEA for CON.
7.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
8.
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
9.
001-MCG-156: “Analysis and Presentation of Adverse Event Data from Clinical Trials”, 
current version; IDEA for CON.
10. Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, Tsuji W, et.al. 
Standardizing assessment and reporting of adverse effects in rheumatology clinical trials 
II: the Rheumatology Common Toxicity Criteria v.2.0. J Rheumatol 34:6. 1401-1414. 
2007.
11. 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
12. 001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
12-OCT-18
None
This is the final TSAP without any 
modification