Clinical trial NCT03635099
Conditions: Psoriasis
Sponsor: Boehringer Ingelheim
Start date: 2018-09-17; Completion date: 2021-05-26
Enrollment: 274 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is based on Week 12 co-primary endpoints of PASI (Psoriasis Area and Severity Index) 75 and sPGA (Static Physician's Global Assessment) 0/1, and overall safety Secondary objectives of Part 1 are to evaluate the efficacy and safety of BI 730357 through 24 weeks of treatment

Detailed description:

Arms: arm 1: Part I - Placebo matching BI 730357 taken orally once daily as a film-coated tablet in the morning while fasted for 12 weeks in period 1 followed by the same treatment for 12 weeks in period 2 (total treatment period of 24 weeks). Participants who failed to achieve a Psoriasis Area Severity Index score (PASI) 75 response at Week 12 were switched to a 200 mg dose, participants switching dose were imputed as failure for records after week 12, under original randomized treatment arm. arm 2: Part I - 25 milligram (mg) BI 730357 taken orally once daily as a film-coated tablet in the morning while fasted for 12 weeks in period 1 followed by the same treatment for 12 weeks in period 2 (total treatment period of 24 weeks). Participants who failed to achieve a Psoriasis Area Severity Index score (PASI) 50 response at Week 12 were switched to a 50 mg dose, participants switching dose were imputed as failure for records after week 12, under original randomized treatment arm. arm 3: Part I - 50 milligram (mg) BI 730357 taken orally once daily as a film-coated tablet in the morning while fasted for 12 weeks in period 1 followed by the same treatment for 12 weeks in period 2 (total treatment period of 24 weeks). Participants who failed to achieve a Psoriasis Area Severity Index score (PASI) 50 response at Week 12 were switched to a 100 mg dose, participants switching dose were imputed as failure for records after week 12, under original randomized treatment arm. arm 4: Part I - 100 milligram (mg) BI 730357 taken orally once daily as a film-coated tablet in the morning while fasted for 12 weeks in period 1 followed by the same treatment for 12 weeks in period 2 (total treatment period of 24 weeks). Participants who failed to achieve a Psoriasis Area Severity Index score (PASI) 50 response at Week 12 were switched to a 200 mg dose, participants switching dose were imputed as failure for records after week 12, under original randomized treatment arm. arm 5: Part I - 200 milligram (mg) BI 730357 taken orally once daily as a film-coated tablet in the morning while fasted for 12 weeks in period 1 followed by the same treatment for 12 weeks in period 2 (total treatment period of 24 weeks). arm 6: Part II - 4 film-coated tablets of matching Placebo were taken orally in the morning with a meal and 2 film-coated tablets of matching Placebo were taken orally in the evening with a meal for 12 weeks. arm 7: Part II - 4 film-coated tablets of 100 milligram (mg) BI 730357 (400 mg in total) were taken orally in the morning with a meal and 2 film-coated tablets of matching Placebo were taken orally in the evening with a meal for 12 weeks. arm 8: Part II - 2 film-coated tablets of 100 milligram (mg) BI 730357 were taken orally with a meal in the morning and evening (twice daily; total daily dosage: 400 mg) for 12 weeks.
Interventions: intervention 1: Placebo (fasted) intervention 2: BI 25 mg (fasted) intervention 3: BI 50 mg (fasted) intervention 4: BI 100 mg (fasted) intervention 5: BI 200 mg (fasted) intervention 6: Placebo (fed) intervention 7: BI 400 mg once daily (fed) intervention 8: BI 200 mg twice daily, 400 mg total (fed)
Intervention descriptions: intervention 1: Placebo matching BI 730357 taken orally once daily as a film-coated tablet in the morning while fasted for 12 weeks in period 1 followed by the same treatment for 12 weeks in period 2 (total treatment period of 24 weeks). intervention 2: 25 milligram (mg) BI 730357 taken orally once daily as a film-coated tablet in the morning while fasted for 12 weeks in period 1 followed by the same treatment for 12 weeks in period 2 (total treatment period of 24 weeks). intervention 3: 50 milligram (mg) BI 730357 taken orally once daily as a film-coated tablet in the morning while fasted for 12 weeks in period 1 followed by the same treatment for 12 weeks in period 2 (total treatment period of 24 weeks). intervention 4: 100 milligram (mg) BI 730357 taken orally once daily as a film-coated tablet in the morning while fasted for 12 weeks in period 1 followed by the same treatment for 12 weeks in period 2 (total treatment period of 24 weeks). intervention 5: 200 milligram (mg) BI 730357 taken orally once daily as a film-coated tablet in the morning while fasted for 12 weeks in period 1 followed by the same treatment for 12 weeks in period 2 (total treatment period of 24 weeks). intervention 6: 4 film-coated tablets of matching Placebo were taken orally in the morning with a meal and 2 film-coated tablets of matching Placebo were taken orally in the evening with a meal for 12 weeks. intervention 7: 4 film-coated tablets of 100 milligram (mg) BI 730357 (400 mg in total) were taken orally in the morning with a meal and 2 film-coated tablets of matching Placebo were taken orally in the evening with a meal for 12 weeks. intervention 8: 2 film-coated tablets of 100 milligram (mg) BI 730357 were taken orally with a meal in the morning and evening (twice daily; total daily dosage: 400 mg) for 12 weeks.

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c20414608-08
EudraCT No.:
2017-004659-21
BI Trial No.:
1407-0030
BI Investigational 
Product(s):
BI 730357
Title:
Phase II evaluation of safety, tolerability, and efficacy of 
BI 730357 in patients with moderate-to-severe plaque psoriasis
Lay Title:
This study is done in patients with plaque psoriasis and tests how 
well they tolerate BI 730357 and how effective it is. 
Clinical Phase:
II
Trial Clinical 
Monitor:
Phone:
, Fax: 
Coordinating 
Investigator:
Status:
Final Protocol (Revised Protocol (based on Global Amendment
7)
Version and Date:
Version:
Date:
8.0
24 August 2020
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Proprietary confidential information.
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Finished product name
N/A
Active ingredient name:
BI 730357
Protocol date
26 March 2018
Revision date
24 August 2020
Trial number
1407-0030
Title of trial:
Phase II evaluation of safety, tolerability, and efficacy of BI 730357 
in patients with moderate-to-severe plaque psoriasis
Coordinating 
Investigator:
Trial site(s):
Multi-centre trial conducted in approximately three countries
Clinical phase:
II
Trial rationale:
Favorable results of this trial will serve as a Proof of Clinical Concept 
in the treatment of PsO and for the refinement of Phase III dose 
selection.
Trial objective(s):
The primary objective is based on Week 12 co-primary endpoints of 
PASI 75 and sPGA 0/1, and overall safety.
Secondary objectives of Part 1 are to evaluate the safety of BI 730357 
through 24 weeks of treatment, and the effects of dose escalation and 
longer treatment duration on efficacy.
Trial endpoints
Co-primary endpoints:
≥ 75% reduction from baseline PASI score (PASI 75) at Week 12
sPGA score of clear or almost clear at Week 12
Secondary endpoints (endpoints beyond Week 12 apply only to Part 
1):
≥50% reduction from baseline PASI score (PASI 50) at Week 12 
≥90% reduction from baseline PASI score (PASI 90) at Week 12 
100% reduction from baseline PASI score (PASI 100) at Week 12
sPGA score of clear at Week 12
≥75% reduction from baseline in PASI score (PASI 75) at Week 
16, 20, 24


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sPGA score of clear or almost clear at Week 16, 20, 24 
Change from baseline in psoriasis symptoms evaluated using the 
total score on the Psoriasis Symptoms Scale at week 12 
Achievement of a Dermatology Life Quality Index score of 0 or 1 
at Week 12 
Trial design:
Two Part design (Part 1 and Part 2)
double-blind, randomised, placebo-controlled, parallel
Total number of patients 
randomized:
Part 1: 180
Part 2: 90
Number of patients on 
each treatment:
Part 1: 20 on Placebo, 40 on each of the 4 active treatment arms
Part 2: 10 on Placebo, 40 on each of 2 active treatment arms
Diagnosis :
Patients with moderate-to-severe plaque psoriasis
Main in- and exclusion 
criteria
Inclusion criteria:

Male or female patients. Women of childbearing potential1 must 
be ready and able to use a highly effective method of birth 
control. 

Age 18 to 75 (both inclusive) years at screening

BMI < 35

Diagnosis of chronic plaque psoriasis (with or without psoriatic 
arthritis) for at least 6 months before the first administration of 
study drug. 

Patients must be candidates for systemic psoriasis therapy

Moderate-to-severe plaque psoriasis:
a.
BSA ≥10%, and
b. PASI ≥12, and
c.
sPGA moderate or severe
Exclusion criteria:

Nonplaque forms of psoriasis, current drug-induced psoriasis, 
active ongoing inflammatory diseases other than psoriasis that 
might confound trial evaluations

Current enrolment in another investigational device or drug trial, 
or less than 30 days (from randomisation) since ending another 
                                                
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.
2Defined as a Child-Pugh Score of B or C.


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investigational device or drug trial(s), or receiving other 
investigational treatment(s)

Use of 
a.
any biologic agent within 12 weeks, or 
b. any anti-IL-23 biologic agent within 24 weeks prior to 
randomisation, or
c.
systemic anti-psoriatic medications or phototherapy within 
4 weeks prior to randomisation, or 
d. topical anti-psoriasis medications within 2 weeks prior to 
randomisation

Live vaccination ≤ 12 weeks prior to randomisation (visit 2), or 
any plan to receive a live vaccination during the conduct of this 
study

Relevant chronic or acute infections, including human 
immunodeficiency virus, viral hepatitis, candidiasis and 
tuberculosis.

Evidence of a current or previous disease (including known or 
suspected inflammatory bowel disease and cardiovascular 
disease) or medical finding that in the opinion of the investigator 
is clinically significant and would make the study participant 
unreliable to adhere to the protocol or to complete the trial, 
compromise the safety of the patient, or compromise the quality 
of the data

Chronic alcohol or drug abuse or any condition that, in the 
investigator’s opinion, makes them an unreliable trial patient or 
unlikely to complete the trial

Unwillingness to adhere to the rules of UV-light protection as 
described in section 4.2.2.3

Patients in Part 2: Moderate-to-severe hepatic impairment2
Test product(s):
BI 730357
dose:
Part 1: 25 mg, 50 mg, 100 mg, 200 mg BI 730357 once daily
Part 2: 400 mg BI 730357 once daily, 200 mg BI 730357 twice daily
mode of 
administration:
p.o.
Part 1: fasted
Part 2: fed
Comparator products:
Placebo to BI 730357
dose:
N.A.
mode of 
administration:
p.o.
Duration of treatment:
Part 1: 24 weeks


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Part 2: 12 weeks
Statistical methods:
Part 1: 
The primary objective includes demonstration of proof of clinical 
concept with respect to a non-flat dose response curve, 
characterization of the dose-response relationship within the 
therapeutic range, and selection of the dose range for phase III 
development. For this purpose, the primary analysis uses 
methodology for dose finding, employing both multiple comparison 
procedures and modelling techniques (MCPMod). 
Part 2:
A Bayesian borrowing approach will be implemented to estimate 
treatment effect; no hypothesis testing will be performed in the 
confirmatory sense. The primary endpoint is defined in section 2.1.2


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FLOW CHART, PART 1
Trial Periods
Screening
Treatment
Follow- up
Visit
1
2
3
4
5
6
7
8
9
10
EOT
FU 1
(EOO)
Week
-4 to -1
1
1
1
2
4
8
12
16
20
24
28
Day
-28 to -7
1
4
8
15
29
57
85
113 141
169
197
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consents1
x
Demographics 
x
Randomisation
x
Medical history
x
Smoking/alcohol history
x
Psoriasis therapy history
x
Psoriasis arthritis history
x
Baseline conditions
x
In-, ex-criteria, incl. 
infections 
x
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x
x
Body height 
x
Body weight
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
x
Physical examination
x
x
x
x
x
x
Resting 12 lead ECG
x
x
x
x
x
x
x
x
Pregnancy testing2
x
x
x
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
IRT call
x
x
x
x
x
x
x
x
Dispense study 
medication
x
x
x
x
x
x
Collect study medication
x
x
x
x
x
x
BSA3
x
PASI, sPGA assessment
x
x
x
x
x
x
x
x
x
x
x
NAPSI, PPASI, PSSI4
x
x
x
x
Pain VAS5
x
x
x
x
PSS 6
x
x
x
x
x
x
x
x
x
x
x
DLQI7
x
x
x
x
C-SSRS8
x
x
x
x
x
x
x
x
x
x
x
x
Safety lab samples
x
x
x
x
x
x
x
x
x
x
x
x
PG samples for 
Biobanking 
x
Biomarker samples 
(serum)
x
x
x
x
x
x
x
x
x
x
Whole blood (PBMC for 
flow cytometry), pre-dose
x
x
x
PK samples 9
x9
x
x
x
x9
x
x9
x
x
x
x
Optional skin 
Photographs10
x
x
x
Optional skin biopsies 11
x
x
x
x
Termination of trial 
medication12
x
Screening for LTE 13
x
Trial completion
x
Footnotes:


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1 Trial informed consent and informed consent about pharmacogenetics, skin photography and skin biopsies if applicable.
2 Serum pregnancy test at screening and if urine pregnancy test is positive. 
3 Assessment of Body Surface Area affected by plaques psoriasis
4Nail Psoriasis Severity Index, Palmoplantar Psoriasis Severity Index, Psoriasis Scalp Severity Index will be done if 
applicable
5 Only for patients with psoriatic arthritis
6 The Psoriasis Symptom Scale (PSS) will be completed by the patients during all clinic visits except V1.
7 Dermatology Life Quality Index 
8 C-SSRS, Columbia-Suicide Severity Rating Scale: Screening/Baseline version at Screening, Follow-up version at all other
visits.
9 PK-blood samples: Days 1, 29, and 85, full PK profiles (pre-dose, 0:15, 0:30, 1, 2, 3 post-dose) will be sampled; All other 
days should be pre-dose plasma samples only. 
10 Optional psoriasis skin lesions photographs. Only at sites in the US. Refer to the procedure in the ISF.
11 Optional skin biopsies will be taken from a subset of study participants. At baseline, two sets of lesional + non-lesional 
biopsies will be collected- one set for RNAseq and one set for IHC (immunohistochemistry) – in total four punches of four 
mm each. At the other timepoints two sets of lesional biopsies (2 punches) will be taken - one set for RNAseq and one set 
for IHC – in total two punches of four mm each. All biopsies should be completed pre-dose at each time point. Patients 
will be separately asked to consent for this procedure.
12 No administration of study medication at the EOT visit.
13 Patients who are completing Part 1 of this trial according to protocol will be offered to roll over into a long term extension 
trial (LTE).


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FLOW CHART, PART 2
Trial Periods
Screening
Treatment
Follow- up
Visit
1
2
3
4
5
6
7
EOT
FU 1 (EOO)
Week
-4 to -1
1
1
1
2
4
8
12
16
Day
-28 to -7
1
4
8
15
29
57
84
113
Visit window (days)
±1
±3
±3
±3
±3
±3
±7
Informed consents1
x
Demographics 
x
Randomisation
x
Medical history
x
Smoking/alcohol history
x
Psoriasis therapy history
x
Psoriasis arthritis history
x
Baseline conditions
x
In-, ex-criteria, incl. 
infections 
x
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
Body height 
x
Body weight
x
x
Vital signs
x
x
x
x
x
x
x
x
x
Physical examination
x
x
x
x
x
Resting 12 lead ECG
x
x
x
x
x
x
x
Pregnancy testing2
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
IRT call
x
x
x
x
x
Dispense study 
medication
x
x
x
Collect study medication
x
x
x
BSA3
x
PASI, sPGA assessment
x
x
x
x
x
x
x
x
NAPSI, PPASI, PSSI4
x
x
x
Pain VAS5
x
x
x
PSS 6
x
x
x
x
x
x
x
x
DLQI7
x
x
x
C-SSRS8
x
x
x
x
x
x
x
x
x
Safety lab samples
x
x
x
x
x
x
x
x
x
PG samples for 
Biobanking 
x
Biomarker samples 
(serum)
x
x
x
x
x
x
x
Whole blood (PBMC for 
flow cytometry), pre-dose
x
x
x
PK samples 9
x
x
x
x
x
x
x
Optional skin biopsies 10
x
x
x
Termination of trial 
medication11
x
Screening for LTE12
x
Trial completion
x
Footnotes:
1 Trial informed consent and informed consent about pharmacogenetics, skin photography and skin biopsies if applicable.
2 Serum pregnancy test at screening and if urine pregnancy test is positive. 
3 Assessment of Body Surface Area affected by plaques psoriasis


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4Nail Psoriasis Severity Index, Palmoplantar Psoriasis Severity Index, Psoriasis Scalp Severity Index will be done if 
applicable
5 Only for patients with psoriatic arthritis
6 The Psoriasis Symptom Scale (PSS) will be completed by the patients during all clinic visits except V1.
7 Dermatology Life Quality Index 
8 C-SSRS, Columbia-Suicide Severity Rating Scale: Screening/Baseline version at Screening, Follow-up version at all other
visits.
9 Trough PK-samples will be drawn at all visits from V2 through EOT. Details about PK-blood samples collection are 
provided in the PK blood sampling flow chart. 
10 Optional skin biopsies will be taken from a subset of study participants. At baseline, two sets of lesional + non-lesional 
biopsies will be collected- one set for RNAseq and one set for IHC (immunohistochemistry) – in total four punches of four 
mm each. At the other timepoints two sets of lesional biopsies (2 punches) will be taken - one set for RNAseq and one set 
for IHC – in total two punches of four mm each. All biopsies should be completed pre-dose at each time point. Patients 
will be separately asked to consent for this procedure.
11 Last administration of study medication at the EOT visit.
12 Patients completing the treatment period of this trial will be offered to roll over into a long term extension trial (LTE).


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PK BLOOD SAMPLING FLOW CHART FOR TROUGH SAMPLES 
AND POPULATION PK, SAMPLES COLLECTED FROM ALL 
PATIENTS IN PART 2
Visits
Week
Day
Time Relative to 
morning 
BI 730357 Dosing
Blood sampling 
for PK
2, 3, 4, 5, 6, 
7, EoT
1, 2, 4, 8, 
12
1, 4, 8, 
15, 29, 
57, 84
- 90 to - 5 minutes 
before start of morning 
dosing
X
2, 5, EoT
1, 2, 12
1, 15, 84
15 minutes to 1 hour 
after morning dose
X
2, 5, EoT
1, 2, 12
1, 15, 84
1:30 to 2:15 after 
morning dose
X
2, 5, EoT
1, 2, 12
1, 15, 84
2:45 – 3:30 after 
morning dose
X
PK BLOOD SAMPLING FLOW CHART FOR INTENSIVE PK 
SUBSTUDY, PART 2
(Participation will be optional and require a separate informed consent.)
Visits
Week
Day
Time to/after morning 
BI 730357 Dosing
Blood sampling 
for PK
2, EoT
1, 12
1, 84
- 90 to - 5 minutes before 
start of dosing
X
2, EoT
1, 12
1, 84
30 minutes ± 5 minutes
X
2, EoT
1, 12
1, 84
1:00 h ± 10 minutes
X
2, EoT
1, 12
1, 84
2:00 h ± 10 minutes
X
2, EoT
1, 12
1, 84
3:00 h ± 10 minutes
X
2, EoT
1, 12
1, 84
5:00 h ± 20 minutes
X
2, EoT
1, 12
1, 84
8:00 h ± 30 minutes
X
2, EoT
1, 12
2, 85
24:00 h*
X
EoT
12
86
48:00 h ± 2 hours**
X
EoT
12
87
72:00 h ± 2 hours**
X
*Day 2 sample must be taken within 30 min before next BI 730357 dosing.
** For patients continuing in the LTE the 48 hours and the 72 hours sampling will be omitted.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART, PART 1........................................................................................................6
FLOW CHART, PART 2........................................................................................................8
PK BLOOD SAMPLING FLOW CHART FOR TROUGH SAMPLES AND 
POPULATION PK, SAMPLES COLLECTED FROM ALL PATIENTS IN 
PART 2.................................................................................................................10
PK BLOOD SAMPLING FLOW CHART FOR INTENSIVE PK SUBSTUDY, PART 2
...............................................................................................................................10
TABLE OF CONTENTS ......................................................................................................11
ABBREVIATIONS................................................................................................................15
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................18
1.2.2
Clinical Experience in Humans .........................................................................20
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................22
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
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................29
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................31
3.3
SELECTION OF TRIAL POPULATION .......................................................31
3.3.1
Main diagnosis for trial entry ............................................................................31
3.3.2
Inclusion criteria .................................................................................................32
3.3.3
Exclusion criteria ................................................................................................32
3.3.4
Withdrawal of patients from treatment or assessments..................................34
3.3.4.1
Discontinuation of trial treatment .........................................................................34
3.3.4.2
Withdrawal of consent for trial participation........................................................34
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................35
4.
TREATMENTS...................................................................................................36


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4.1
INVESTIGATIONAL TREATMENTS ...........................................................36
4.1.1
Identity of the Investigational Medicinal Products..........................................36
4.1.2
Selection of doses in the trial..............................................................................36
4.1.3
Method of assigning patients to treatment groups...........................................37
4.1.4
Drug assignment and administration of doses for each patient......................38
4.1.5
Blinding and procedures for unblinding...........................................................39
4.1.5.1
Blinding.................................................................................................................39
4.1.5.2
Unblinding and breaking the code ........................................................................40
4.1.6
Packaging, labelling, and re-supply...................................................................40
4.1.7
Storage conditions...............................................................................................40
4.1.8
Drug accountability.............................................................................................40
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................41
4.2.1
Other treatments and emergency procedures..................................................41
4.2.2
Restrictions ..........................................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment ......................................................42
4.2.2.2
Restrictions on diet and lifestyle...........................................................................44
4.2.2.3
Restriction of UV-light exposure..........................................................................44
4.2.2.4
Contraception requirements..................................................................................45
4.3
TREATMENT COMPLIANCE........................................................................45
5.
ASSESSMENTS..................................................................................................46
5.1
ASSESSMENT OF EFFICACY........................................................................46
5.2
ASSESSMENT OF SAFETY.............................................................................46
5.2.1
Physical examination ..........................................................................................46
5.2.2
Vital signs.............................................................................................................46
5.2.3
Safety laboratory parameters ............................................................................46
5.2.4
Electrocardiogram ..............................................................................................48
5.2.5
Other safety parameters.....................................................................................49
5.2.5.1
Suicidality .............................................................................................................49
5.2.5.2
Major Adverse Cardovascular Event (MACE).....................................................50
5.2.6
Assessment of adverse events.............................................................................50
5.2.6.1
Definitions of adverse events................................................................................50
5.2.6.2
Adverse event collection and reporting ................................................................53
5.6
OTHER ASSESSMENTS...................................................................................58
5.6.1
Photography of skin lesions................................................................................58
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................59


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6.
INVESTIGATIONAL PLAN.............................................................................60
6.1
VISIT SCHEDULE.............................................................................................60
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................60
6.2.1
Screening period..................................................................................................61
6.2.2
Treatment period ................................................................................................61
6.2.3
Follow up period and trial completion..............................................................62
6.2.3.1
Early treatment and trial termination:...................................................................62
6.2.3.2
Trial completion....................................................................................................62
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................63
7.1
STATISTICAL DESIGN - MODEL.................................................................63
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................63
7.3
PLANNED ANALYSES.....................................................................................63
7.3.1
Primary endpoint analyses.................................................................................64
7.3.2
Secondary endpoint analyses .............................................................................67
7.3.4
Safety analyses.....................................................................................................67
7.4
INTERIM ANALYSES ......................................................................................69
7.5
HANDLING OF MISSING DATA ...................................................................69
7.6
RANDOMISATION ...........................................................................................70
7.7
DETERMINATION OF SAMPLE SIZE .........................................................70
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........73
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................73
8.2
DATA QUALITY ASSURANCE ......................................................................74
8.3
RECORDS...........................................................................................................74
8.3.1
Source documents ...............................................................................................74
8.3.2
Direct access to source data and documents.....................................................75
8.3.3
Storage period of records ...................................................................................75
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................76
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........76
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................76
8.6
TRIAL MILESTONES.......................................................................................77
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................77
9.
REFERENCES....................................................................................................79
9.1
PUBLISHED REFERENCES............................................................................79
9.2
UNPUBLISHED REFERENCES......................................................................81
10.
APPENDICES.....................................................................................................82
10.1
PASI SCORE DEFINITION AND USE...........................................................82
10.2
STATIC PHYSICIAN GLOBAL ASSESSMENT (SPGA) ............................82
10.3
NAPSI: NAIL PSORIASIS SEVERITY INDEX.............................................84


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10.4
PPASI: PALMOPLANTAR PSORIASIS SEVERITY INDEX.....................84
10.5
PSORIASIS SCALP SEVERITY INDEX (PSSI)............................................85
10.6
DERMATOLOGY LIFE QUALITY INDEX (DLQI) ....................................86
10.7
PSORIASIS SYMPTOM SCALE (PSS)...........................................................86
10.8
PAIN VAS............................................................................................................87
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................88
11.1
GLOBAL AMENDMENT 1 ..............................................................................88
11.2
GLOBAL AMENDMENT 2 ..............................................................................89
11.3
GLOBAL AMENDMENT 3 ..............................................................................90
11.4
GLOBAL AMENDMENT 4 ..............................................................................92
11.5
GLOBAL AMENDMENT 5 ..............................................................................96
11.6
GLOBAL AMENDMENT 6 ..............................................................................97
11.7
GLOBAL AMENDMENT 7 ..............................................................................97


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AUC
Area under the Curve
BI
Boehringer Ingelheim
b.i.d.
bis in die (twice daily dosing)
BMI
Body Mass Index
BSA
Body Surface Area
CCDS
Company Core Data Sheet
CI
Confidence Interval
CML
Clinical Monitor Local
CNS
Central Nervous System
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Clinical Research Organisation
CRP
C-Reactive Protein
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450
DC
Dentritic Cell
DILI
DLQI
Drug Induced Liver Injury
Dermatology Life Quality Index
DMC
Data Monitoring Committee
ECG
ElectroCardioGraphy
EDC
Electronic Data Capture
ePRO
Electronic Patient Reported Outcome
EOO
End Of Observation
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
GCP
Good Clinical Practice
HIV 
Human Immunodeficiency Virus
IB
Investigator’s Brochure
IBD
Inflammatory Bowel Disease
IC
Inhibitory Concentration
ICH
International Conference on Harmonisation
IHC
ImmunoHistoChemistry
ILC
Innate Lymphoid Cell
IL
InterLeukin
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
iSTAT
independent Statistician


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i.v.
intravenous
LBD
Ligand Binding Domain
LoEE
List of Essential Elements
LPLT
Last Patient Last Treatment 
LTE
Long Term Extension trial
LXR
Liver X Receptor
MACE
Major Adverse Cardiovascular Event
MCT
Melanin Containing Tissue
MedDRA
Medical Dictionary for Drug Regulatory Activities
MST
Medical Sub Team
NMSC
Non-Melanoma Skin Cancer 
NOAEL
No Observed Adverse Effect Level
OPU
Operative Unit
PASI
Psoriasis Area and Severity Index
PBMC
Peripheral Blood Mononuclear Cell
Pbo
Placebo
PD
Pharmacodynamics
PG
PharmacoGenetic
PK
Pharmacokinetics
p.o.
per os (oral)
PoCC
Proof of Clinical Concept
PPASI
Palmoplantar Psoriasis Severity Index
PRO
Patient Reported Outcomes
PsA
Psoriatic Arthritis
PsO
(Plaque) Psoriasis
PSS
Psoriasis Symptom Scale
PXR
Pregnane X Receptor
q.d.
quaque die (once a day)
RAR
Retinoic Acid Receptor
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual Effect Period
ROR
RAR related Orphan Receptor
SAE
Serious Adverse Event
s.c.
subcutaneous
SMC
Safety Monitoring Committee
SmPC
Summary of Product Characteristics
sPGA
Static Physician’s Global Assessment
SUSAR
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TNF
Tumor Necrosis Factor
TSAP
Trial Statistical Analysis Plan
VAS
Visual Analogue Scale
VEGF
Vascular Endothelial Growth Factor
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 (<3%), moderate (3-10%), and severe (>10%) (P20-07441). 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).
The immunologic mechanism of PsO involves initial dendritic cell (DC) activation by 
cutaneous pathogens, leading to IL-23 secretion, promoting Th17 differentiation and 
stabilization. Keratinocytes are the principal target, in addition to DCs, dermal fibroblasts, 
and endothelial cells, for IL-17, resulting in the expression of numerous chemokines which 
direct chemotaxis and inflammation, and of defensin and S100A family peptides which alter 
expression of multiple genes involved in cell adhesion. The critical role of IL-17 in PsO 
pathogenesis has been extensively evaluated in IL-17-knockout animal models and confirmed 
in humans. Th17 cells, the majority of which are of memory phenotype, are enriched in the 
papillary dermis of psoriatic plaques. Disease severity has been shown to correlate directly 
with IL-17A level (R16-3073). The central role of IL-23 and IL-17 activity in the 
pathogenesis of disease has been proven unequivocally by the substantial clinical efficacy of 
biologic agents targeting these cytokines in the treatment of patients with moderate-to-severe 
plaque PsO. 
Mainstays of therapy for the treatment of PsO include topical agents, ultraviolet light-based 
therapies, traditional systemic agents (e.g., methotrexate, acitretin, cyclosporine), and more 
recently, targeted biologic and small-molecule therapies. Steroidal and non-steroidal topical 
agents (e.g., vitamin D analogues, retinoids, tar, anthralin, salicylic acid, tacrolimus) are 
efficacious, particularly for mild-to-moderate disease, but typically require long-term 
administration, and often provide only incomplete clearance. Long-term adherence to 
topically-prescribed therapies is often poor, and systemic absorption limits long-term usage 


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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.
Retinoic acid-related orphan receptor (ROR) γt is a nuclear hormone receptor/transcription 
factor expressed in Th17 cells and in distinct subsets of lymphoid cells, including NK cells, 
innate lymphoid cells (ILC), and T-cells. RORγt sits at a key focal point, integrating 
multiple signals, including T cell receptor engagement and cytokines (e.g., IL-1, IL-6, IL-23), 
and driving the expression of multiple genes (e.g., IL-17A, IL-17F, IL-22, IL-23R). Via 
sitting at this focal node integrating multiple signals and effecting multiple outputs, RORγt 
has the potential to have a broader effect in Th17-mediated diseased than individual cytokine 
blockades alone (e.g., IL-23 or IL-17).
1.2
DRUG PROFILE
Boehringer Ingelheim (BI) is developing the new chemical entity (NCE), RORγt antagonist
BI 730357, for the treatment of patients with plaque PsO and other Th17-mediated diseases. 
BI 730357 binds in the ligand-binding domain (LBD) of RORγt and inhibits co-activator 
peptide recruitment, thereby blocking the RORγt-mediated transcription of pro-inflammatory 
cytokines, and of IL-23R.
For a more detailed description of the profile of BI 730357 please refer to the current 
Investigator’s Brochure (IB) (c09228382).


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1.2.2
Clinical Experience in Humans
BI 730357 is currently in Phase II clinical development, targeting the treatment of adults with 
plaque PsO,
 
 Seven Phase I trials have been completed, and 3 Phase I 
or Phase II trials are currently ongoing, including this trial. The Investigator’s Brochure 
(c09228382) provides the most current and complete detail of BI 730357 clinical experience.
The most relevant details of Phase I clinical development to date are provided below.
Phase Ia first-in-human trial 1407.1 evaluated single-rising dose administration of BI 
730357 ranging from 2 mg through 800 mg, given as oral solution (2 mg and 8 mg) and film-
coated tablets (25 mg to 800 mg) to healthy male adult subjects aged 18 to 45 years. 
Approximately 84 subjects were to be entered into the trial; each group of 8 subjects was 
randomized (6 active:2 placebo) into sequential dose groups under fasting (2 mg, 8 mg, 25 
mg, 50 mg, 100 mg, 200 mg, and 400 mg), and fed conditions (400 mg, 800 mg). An 
additional 12 subjects were recruited into a 3-way crossover substudy, and administered 25 
mg BI 730357 as oral solution, tablet fasting, and tablet fed. In total, 66 male adult subjects 
received BI 730357.
Safety evaluations included physical examination, vital signs, ECG, laboratory tests, and 
adverse events (AEs). AEs, which generally reflected commonly-occuring 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. No serious AEs 
(SAEs) were reported. Overall, single-dose administration of BI 730357 was well tolerated 
by healthy male subjects in this clinical trial.
Phase Ib trial 1407-0002 evaluated MRD administration of BI 730357 ranging from 25 mg 
to 400 mg, given as film-coated tablets to healthy male adult subjects aged 18 to 45 years. 
Approximately 84 subjects were to be entered into the trial; each group of 12 subjects was 
randomized (9 active:3 placebo) into one of 4 sequential dose groups under fasting conditions 
(25 mg, 50 mg, 100 mg, 200 mg), and 3 sequential dose groups under fed conditions (50 mg, 
200 mg, and 400 mg). Subjects were dosed for 14 days (dose groups up to 100 mg) or 28 
days (200 mg and 400 mg dose groups).
Safety evaluations included physical examination, vital signs, ECG, laboratory tests, and 
AEs. No deaths, SAEs, or severe AEs were reported during the trial. Overall, administration 
of BI 730357 to healthy male subjects at doses up to 400 mg for up to 28 days was well 
tolerated.
The highest exposures observed in this study were substantially below the NOAEL exposures 
observed in the 4-week dog study.
In fasted individuals, exposure (Cmax and AUC) increased in a less than dose-proportional 
manner over the entire dosing range, both for single and multiple dosing. Steady state was 
attained by 7 days of multiple dosing, with an accumulation of approximately 2-fold for both 
Cmax and AUC. Under fed conditions, BI 730357 plasma exposures (AUC and Cmax) were 
observed to be higher compared with the same dose level under fasted conditions.


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Part 1 of this current and ongoing trial 1407-0030 was clinically completed Jan 2020. 
Primary analysis of data through Week 12 show that the overall frequency of patients with at 
least 1 treatment-emergent AE was 50.6% for patients receiving BI 730357 (range 47.5% to 
53.8%), vs. 55.0% of placebo recipients. No drug-related SAEs were reported. One severe 
AE, “psoriasis,” was reported; all other reported AEs were mild to moderate in severity. This 
was also the only reported an AE leading to discontinuation of trial drug. 
Overall, administration of BI 730357 to patients with moderate-to-severe plaque PsO at doses 
up to 200 mg for at least 12 weeks, under fasted conditions, has been well tolerated.
Results of the Week 12 primary analysis for trial 1407-0030 also demonstrate proof of
concept in the treatment of patients with moderate-to-severe plaque PsO for BI 730357 at the 
200 mg dose. PASI 75 was achieved by 12 (30.0%) of patients receiving 200 mg BI 730357, 
and sPGA of clear or almost clear was achieved by 11 (27.5%) of 200 mg recipients at Week 
12. 
Preliminary data on predose trough exposures in Part 1 of this trial show that exposure was 
higher in the patient population than healthy volunteers in previous studies.


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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.
RORγt has the potential to demonstrate substantial efficacy in the treatment of PsO, via a 
broader effect in Th17-mediated disease than provided by individual cytokine blockade alone 
(e.g., IL-23 or IL-17). The favorable preclinical data and acceptable safety, tolerability and 
PK demonstrated after single dose administration to healthy male volunteers in first-in-
human trial 1407.1 and in MRD trial 1407-0002 position BI 730357 favorably for 
advancement into a PoCC evaluation in adult patients with moderate-to-severe plaque PsO.
The aim of this Phase II trial is to investigate safety, tolerability, and efficacy of BI 730357 in 
patients with moderate-to-severe plaque PsO. Favorable results of this trial will serve as a 
PoCC in the treatment of PsO, for refinement of Phase III dose selection, and to support 
further development in other disease indications.


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Rationale for performing Part 2: 
Modelling of data from Part 1 of this trial indicates that the efficacy plateau of BI 730357 
may not have been reached with 200 mg dosed q.d. under fasted conditions, and that
exposures resulting from posologies dosing BI 730357 higher, under fed conditions, and/or 
twice daily may provide better efficacy. Part 2 of this trial therefore plans to evaluate the 
efficacy, safety, tolerability, and PK of 400 mg q.d. and 200 mg b.i.d. administration of BI 
730357, under fed conditions, to patients with moderate-to-severe plaque PsO.
It is anticipated that higher median BI 730357 exposures, as expected with 400 mg dosed 
q.d., and 200 mg dosed b.i.d. under fed conditions for 12 weeks will not exceed the NOAEL 
thresholds observed in 13 week general toxicity studies (see section 1.2.1). Treatment with 
doses of up to 400 mg q.d.under fed conditions to healthy volunteers for up to 28 days in 
Phase Ib MRD trial 1407-0002, and with doses of up to 200 mg q.d. under fasting conditions 
for more than 12 weeks thus far in Part 1 of this trial did not identify any safety signals (see 
section 1.2.2).
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 the trial will amount to 
approximately 350 mL (over 24 weeks in Part 1) and 250 mL (over 12 weeks in Part 2). In 
the optional intensive PK substudy, approxamitely an additional 60 mLwill be withdrawn. 
No health-related risk is expected from this blood withdrawal.
Drug-related risks and safety measures
As the nature of the target and the mechanism of action of BI 730357 are well understood, 
comparable compounds have been tested by other companies before, and the animal models 


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are believed to be predictive for the effects in humans, BI 730357 is not seen as a high risk 
compound.
The pharmacological effects of BI 730357 are dose dependent, and no evidence for prolonged 
or irreversible effects has been observed. Multiple dose administration of up to 200 mg 
BI 730357 q.d. fasted (over 24 weeks in Part 1) and of up to 400 mg q.d. fed (over 12 weeks 
in Part 2) is supported by pre-clinical, as well as clinical safety data from trial 1407.1 and 
trial 1407-0002 (see section 1.2.2). 
Since preclinical data indicate that BI 730357 has phototoxicity potential, subjects in this trial 
will be advised to apply protection measures as described in section 4.2.2.3. Solarium 
radiation, treatment with ultraviolet light (e.g., PUVA), and use of medication with known 
phototoxicity potential (e.g., doxycycline) are prohibited during this clinical trial until the end 
of the follow-up period.
BI 730357 is confirmed as a sensitive cytochrome P450 (CYP) 3A substrate, based on 
clinical drug-drug interaction (DDI) evaluation with itraconazole, a CYP3A inhibitor, in trial 
1407-0014. Drugs or foods that are known CYP3A inhibitors or strong or moderate CYP3A 
inducers should not be co-administered in clinical trials with BI 730357. Based on in vitro 
data, BI 730357 could potentially induce CYPs 1A2, 2B6, 2C8, 2C9, or 2C19 in human. 
Sensitive substrates of CYPs 1A2, 2B6, 2C8, 2C9, or 2C19 for which a reduction in exposure 
could present a potential patient risk should not be given together with BI 730357. 
Additionally, based on in vitro data, BI 730357 may inhibit a number of transporters in 
human; based on the magnitudes of the in vitro inhibition, it is recommended that substrates 
of P-gp, BCRP, OATP1B1, OATP1B3, OAT3, OCT2, MATE1, and MATE2-K for which an 
increase in exposure could present a potential patient risk should not be given together with 
BI 730357.
As with other immune-targeted therapies, impaired host defense is a theoretical target-related 
toxicity, potentially resulting in increased risk of infection and/or malignancy. Th17 cells 
play an important role in defense against extracellular bacteria and fungi at mucosal surfaces 
(R16-3166), (R16-3149). In some studies, IL-17-antagonists were associated with increased 
infections (R13-2643). Homozygous, but not heterozygous RORC knockout mice have a high
incidence of T cell lymphoma, thought to originate in the thymus (R16-2630). While the 
translatability of the knockout phenotype to pharmacological RORγ antagonism and to 
humans is unknown, this raises the hypothetical concern for clinical T cell lymphoma risk. 
The exact cause of T-cell lymphomas in RORC knockout mice is not fully understood, but 
changes in homeostasis in the thymus, such as thymocyte apoptosis and proliferation, are 
thought to play a role. No evidence of an increased risk of lymphoma development or 
changes preceding lymphoma development has arisen based on the BI 730357 toxicology 
studies in rat and dog of up to 26- and 39-week duration, respectively. AEs and SAEs 
consistent with malignancy, and specifically those representing lymphoma, are to be 
evaluated throughout the BI 730357 clinical development program. Thus far, no clinical 
signal regarding malignancy has been identified in BI 730357 clinical trials.
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into 
consideration when BI 730357 is administered.


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Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also section 5.2.6, adverse events of special interest.
Even though gastritis development is not expected in humans, AE consistent with gastric
intolerance or gastritis are designated as AEs of special interest (AESI) to ensure timely
characterization, monitoring, and reporting of any such effects in this study (see sections 
1.2.1 and 5.2.6.1).
Results of the Week 12 primary analysis from Part 1 of this trial demonstrate proof-of-
concept in the treatment of patients with moderate-to-severe plaque PsO for BI 730357 at the 
200 mg dose. Patients with plaque PsO receiving BI 730357 may therefore experience 
improvement in disease severity. Considering the data and modelling from the Part 1 Week 
12 primary analysis of this trial, higher efficacy may be observed in Part 2 of this trial with 
the expected higher BI 730357 exposures resulting from dosing posologies to be evaluated.
However, this is a newly-developed drug at an early stage of testing, therefore an individual 
benefit for patients cannot be guaranteed. In addition, patients may be randomized to placebo 
treatment and not see any potential benefit. Nonetheless, the results from toxicity and safety 
pharmacology studies demonstrated an acceptable profile for clinical trials with daily oral 
administration. The potential risks which are described above will be minimized by close 
monitoring and the involvement of an independent external DMC. These risks are considered 
manageable and outweighed by the potential benefits of the study drug.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
This is a Phase II evaluation of PoCC, based on the safety, tolerability, and efficacy of 
multiple doses of BI 730357 administered to patients with moderate-to-severe plaque PsO. 
This study will also serve the selection of doses for the further development of BI 730357.

The primary objective is based on Week 12 co-primary endpoints of PASI 75 and 
sPGA 0/1, and overall safety.

Secondary objectives of Part 1 are to evaluate the efficacy and safety of BI 730357 
through 24 weeks of treatment.
2.1.2
Primary endpoint(s)
The co-primary endpoints are:

Achievement of ≥ 75% reduction from baseline PASI score (PASI 75) at Week 12

Achievement of an sPGA score of clear or almost clear at Week 12
At the trial level, the co-primary endpoints will be the proportion of patients achieving 
PASI 75 and a sPGA score of clear or almost clear at Week 12 in each of the treatment
groups.
For descriptions and definitions of PASI and sPGA used in this trial, please refer to 
appendices 10.1 and 10.2 respectively.
2.1.3
Secondary endpoint(s)
Secondary endpoints beyond Week 12 apply only to Part 1. 

Achievement of ≥50% reduction from baseline in PASI score (PASI 50) at Week 12 

Achievement of ≥90% reduction from baseline in PASI score (PASI 90) at Week 12 

Achievement of 100% reduction from baseline in PASI score (PASI 100) at Week 12

Achievement of sPGA score of clear at Week 12

Achievement of ≥75% reduction from baseline in PASI score (PASI 75) at Week 16, 
20, 24

Achievement of an sPGA score of clear or almost clear at Week 16, 20, 24

Change from baseline in psoriasis symptoms evaluated using the total score on the 
Psoriasis Symptoms Scale (PSS) at Week 12 

Achievement of a Dermatology Life Quality Index (DLQI) score of 0 or 1 at Week 12 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a Phase II trial consisting of two parts.
Part 1:
Part 1 is a randomised, placebo-controlled, parallel-group, double-blind evaluation of 
approximately 180 male and female patients with moderate-to-severe plaque PsO.
Patients will be randomised 2:2:2:2:1 to one of 4 BI 730357 treatment groups A to D, of 
which A will receive the lowest and D the highest dose of BI 730357; treatment group E will 
receive placebo. 
At the Week 12 primary efficacy endpoint, non-responders will be reassigned to the next 
higher dose level or to the highest dose level, if they have been in the placebo arm (see Figure 
3.1: 1). Placebo recipients who achieve a PASI 75 response will remain on placebo through 
Week 24.
Figure 3.1: 1 Trial Design, part 1
Analysis for POCC
and
re-assignment of dose
2
4
6
8
10
12
week
14
16
18
20
22
24
D: 200 mg q.d. fasted BI 730357 (n=40)
A: 25 mg q.d. fasted BI 730357 
(n=40)
B: 50 mg q.d. fasted BI 730357 
(n=40)
E: Placebo (n=20)
100 mg BI 730357
200 mg BI 730357
50 mg BI 730357
50 mg BI 730357
25 mg BI 730357
C: 100 mg q.d. fasted BI 730357
(n=40)
200 mg BI 730357
100 mg BI 730357
Placebo
Week 4 
analysis 
Week24 
final 
analysis 


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Patients from dose groups A to C who fail to achieve a PASI 50 response at Week 12 will be 
switched to the next higher respective dose. Patients who have achieved a PASI 50 response 
will continue on their initial dose of BI 730357, in order to evaluate whether a greater 
response can be achieved with continued treatment. This design is intended to permit placebo 
recipients the opportunity to receive active study drug after Week 12 if they continue to 
experience substantial disease. Likewise, recipients of BI 730357 at lower dose levels (A 
through C) will be provided the opportunity to receive a higher dose of study drug. However, 
in order to fully evaluate the time-to-response curve in patients who demonstrate a partial 
response to BI 730357 at Week 12, the response threshold for BI 730357 recipients (PASI 
50) is set lower than for placebo recipients (PASI 75). Moreover, this reassignment will allow 
dose selection for Phase III based on efficacy evaluation over the full 24 weeks of treatment 
and obtain maximum safety information regarding the safety of high-dose exposure. It is 
anticipated that the best timing and the best cut-off for co-primary efficacy endpoint 
evaluation in Phase III studies will be refined based upon the results of this trial. Safety 
(physical examination, ECG, laboratory, AEs, and SAEs), efficacy, PK and target 
engagement are to be evaluated through Week 24.
Part 2: 
Part 2 is a randomised, placebo-controlled, parallel-group, double-blind evaluation of 
approximately 90 male and female patients with moderate-to-severe plaque PsO.
Patients will be randomised 4:4:1 to one of two BI 730357 treatment groups V (200 mg 
b.i.d.) or U (400 mg q.d.); treatment group W will receive placebo. In Part 2, the trial 
medication should be taken with a meal. The treatment will last for 12 weeks when the 
primary efficacy endpoint will be assessed (see Figure 3.1: 2).
Figure 3.1: 2 Trial Design, part 2
Primary Analysis
2
4
6
8
week
10
12
14
16
V: 200 mg b.i.d. fed BI 730357 
U: 400 mg q.d. fed BI 730357 
W: Placebo (n=10)
Follow-up 
Follow-up 
Follow-up 


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A randomised, double blind, placebo-controlled, parallel design has been chosen in order to 
evaluate safety, efficacy, PK, and PD of BI 730357 in patients with moderate-to-severe 
plaque PsO. A placebo control arm has been chosen to be included in order to evaluate the 
absolute effects of BI 730357 on safety and tolerability. This is acceptable, as the duration of 
the placebo treatment, if no spontaneous improvement of the disease occurs, will be limited 
to 12 weeks, and no intolerable disease progression is to be expected during this period.
Patients completing the treatment priod of the trial will be offered to roll over into an 
extension trial, in which they will continue receiving study medication. 
3.3
SELECTION OF TRIAL POPULATION
The trial is intended to provide PoCC of BI 730357 in the treatment of moderate-to-severe 
plaque PsO. Therefore, in Part 1 approximately 180 male and female patients suffering from 
this condition will be included at about 32 study sites. In Part 2, approximately 90 male and 
female patients will be included.
Screening of patients will be competitive, i.e., screening will stop at all sites once a sufficient 
number of patients have been screened. Investigators will be notified about screening 
completion, and will then not be allowed to screen additional patients for this trial.
A log of all patients enrolled into the trial (i.e., who have signed informed consent) will be 
maintained in the ISF at the investigational site, irrespective of whether they have been 
treated with investigational drug or not.
If a patient is randomised in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Male or female patients with moderate-to-severe plaque PsO.


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3.3.2
Inclusion criteria
1.
Male or female patients. WoCBP1 must be ready and able to use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% 
per year when used consistently and correctly from date of screening until 4 weeks after 
last treatment in this trial. A list of contraception methods meeting these criteria is 
provided in the patient information. 
(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.)
2.
Age 18 to 75 years (both inclusive) at screening
3.
BMI < 35 kg/m2 at screening
4. Diagnosis of chronic plaque psoriasis (with or without psoriatic arthritis) for at least 6 
months before the first administration of study drug. Duration of diagnosis may be 
reported by the patient.
5.
Patients must be candidates for systemic PsO therapy. Moderate-to-severe plaque 
psoriasis:
a.
BSA ≥10%
and
b.
PASI ≥12
and
c.
sPGA moderate or severe
6. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
3.3.3
Exclusion criteria
1.
Nonplaque forms of PsO (including guttate, erythrodermic, or pustular), current drug-
induced PsO (including a new onset or exacerbation of PsO from, e.g., beta blockers, 
calcium channel blockers, lithium), active ongoing inflammatory diseases (including but 
not limited to inflammatory bowel disease (IBD)) other than PsO that might confound 
trial evaluations.
2.
Previous enrolment in this trial or previous exposure to BI 730357.
3.
Current enrollment in another investigational device or drug trial, less than 30 days (from 
randomisation) since ending another investigational device or drug trial(s), or receipt of
other investigational treatment(s). For antipsoriatic treatments, wash-out periods are 
provided in exclusion criterion 4 and in section 4.2.2.1.
4.
Use of 
a.
any biologic agent within 12 weeks, or
b. any anti IL-23 biologic agent within 24 weeks prior to randomisation, or


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c.
systemic anti-psoriatic medications or phototherapy within 4 weeks prior 
to randomisation, or
d. topical anti-psoriasis medications within 2 weeks prior to randomisation 
(c.f. section 4.2.2.1) 
(Exception: Topical steroids of US class 6 (mild, such as desonide) or US 
class 7 (least potent, such as hydrocortisone) will be permitted for use 
limited to the face, axilla, and/or genitalia with a restriction of use within 
24 hours prior to clinic visits where PASI is assessed)
5.
Receipt of a live vaccination within 12 weeks prior to randomisation (visit 2), or any plan 
to receive a live vaccination during the conduct of this trial 
6.
Patients who must or wish to continue the intake of restricted medications (see section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
7.
Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled.
8.
Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
the patient an unreliable trial participant or unlikely to complete the trial.
9.
Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to randomisation or planned within 12 months after screening, e.g., hip 
replacement
10. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
11. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately-treated basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, or in situ carcinoma of uterine cervix
12. Relevant chronic or acute infections including human immunodeficiency virus (HIV), 
viral hepatitis, candidiasis and tuberculosis. 
13. Evidence of a current or previous disease (including known or suspected IBD and 
cardiovascular disease), or medical finding that in the opinion of the investigator is 
clinically significant and would make the study participant unreliable to adhere to the 
protocol or to complete the trial, compromise the safety of the patient, or compromise the 
quality of the data.
14. Any suicidal ideation, including grade 4 or 5 in the Columbia Suicide Severity Rating 
Scale (C-SSRS) in the past 12 months (i.e., active suicidal thought with intent but 
without specific plan), or active suicidal thought with plan and intent in the past.
15. Unwillingness to adhere to the rules of UV-light protection as described in section 
4.2.2.3.
16. Any kind of photodermatosis.
17. Patients in Part 2: Moderate to severe hepatic impairment2.
(2 Defined as a Child-Pugh Score of B or C)


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Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications, please see sections 3.3.4.1 and 
3.3.4.2 below. Every effort should be made to keep the randomised patients in the trial: if 
possible on treatment, or at least to collect important trial data. Measures to control the 
withdrawal rate include careful patient selection, appropriate explanation of the trial 
requirements and procedures prior to randomization, 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. If the reason for 
discontinuation is death, this should be reported on the SAE form as well, regardless of 
causal relationship.
3.3.4.1
Discontinuation of trial treatment
An individual patient may be withdrawn from trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient 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 stick to the trial requirements in the future.

The patient needs to take concomitant drugs that interfere with the investigational product 
as listed in Table 4.2.2.1: 1.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).

The patient develops suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal 
thought with intent but without specific plan, or active suicidal thought with plan and 
intent). The patient should immediately be refered to a mental health professional for 
further work-up.

In addition to these criteria, the physician may discontinue subjects at any time based on 
his or her clinical judgment.
In case of a temporary reason, trial treatment should be restarted as early as possible if 
medically justified. Even if the trial treatment is permanently discontinued, the patient 
remains in the trial and, given his/her agreement, will undergo the procedures for early 
treatment discontinuation and follow up as outlined in the FLOW CHART, Part 1 and FLOW 
CHART, Part 2 and section 6.2.3. For all patients, 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.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time, without the need to 
justify the decision. If a patient wants to withdraw consent, the investigator should explain 
the difference between treatment withdrawal and withdrawal of consent for trial participation,


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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
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial
4. 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 third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 730357 and Placebo to match BI 730357.
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, 100 mg
Posology
q.d. or b.i.d.
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
q.d. or b.i.d.
Route of administration:
Per os
4.1.2
Selection of doses in the trial
The dose range for this trial is selected on the basis of the data obtained in first-in-human 
SRD trial 1407.1 and in MRD trial 1407-0002. In addition, for Part 2 dose selection, Week 12 
primary analysis data and modelling from Part 1 were considered. 
In the SRD trial, single dose levels of up to 800 mg, and in the MRD trial, multiple dose 
levels of up to 400 mg administered q.d. under fed conditions were well tolerated.


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Part 1: 
The doses of 25, 50, 100, and 200 mg q.d., administered fasted, are selected for Part 1 of this 
trial. The dose range for this trial was selected on the basis of the PK and safety data obtained 
in the SRD and MRD trials (1407.1 and 1407-0002, respectively) combined with the 
preclinical efficacy data.
The proposed BI 730357 dose selection strategy for PoCC evaluation in PsO patients was 
predicated upon the estimated whole blood BI 730357 IL-17 IC50 concentration in murine 
models, from which an anticipated human therapeutic trough exposure of 140 nM at steady 
state (Cmin,ss) was predicted (with a corresponding AUC0-24,ss of 5200 nM•h). The target Cmin,ss
in human was determined based on the effective plasma concentration required to reduce the 
tissue level of IL-17 by 80% in an IL-23 induced minicircle mouse model [c09228382].
Part 2: 
Modelling of data from Part 1 of this trial indicates that the efficacy plateau of BI 730357 
may not have been reached with 200 mg dosed q.d. under fasted conditions, and that 
exposures resulting from posologies dosing BI 730357 higher, under fed conditions, and/or 
twice daily may provide a better efficacy. Doses of 200 mg b.i.d. and 400 mg q.d.
administered under fed conditions are therefore selected for Part 2 of this trial (see section 
1.3). The higher BI 730357 exposures achieved with 200 mg b.i.d. and 400 mg q.d.
administered under fed conditions for 12 weeks are expected to be safe with regard to the 
NOAEL levels observed in 13 week general toxicity studies (see section 1.2.1). In addition,
treatment of patients with BI 730357 doses of up to 200 mg q.d. under fasted conditions for 
up to 24 weeks in part 1 of this trial, and administration of BI 730357 to healthy volunteers at 
doses of up to 400 mg q.d.under both fasted and fed conditions for up to 28 days in MRD 
trial 1407-0002 did not identify any safety signals (see section 1.2.2). 
In summary, the data generated in Part 2 of this trial will extend characterization of the dose-
response relationship within a wider therapeutic range, and enable selection of the dose range 
for Phase III development.
4.1.3
Method of assigning patients to treatment groups
In Part 1, during visit 2, eligible patients will be randomised in a 2:2:2:2:1 ratio to one of 4 
BI 730357 dose groups A to D, or placebo, in a blinded fashion via Interactive Response 
Technology (IRT). At the Week 12 primary efficacy endpoint, non-responders will be 
reassigned to the next higher dose level or to the highest dose level, if they have been in the 
placebo arm (see Figure 3.1: 1). Placebo recipients who achieve a PASI 75 response will 
remain on placebo through Week 24.
In Part 2, eligible patients will be randomised in a 4:4:1 ratio to one of 2 BI 730357 dose 
groups, or placebo, in a blinded fashion via Interactive Response Technology (IRT).
Treatment will be completed at Week 12.


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4.1.4
Drug assignment and administration of doses for each patient
Study medication will be dispensed at the investigational sites according to the FLOW 
CHART, Part 1 and FLOW CHART, Part 2. On days of scheduled patient visits, the study 
medication will be administered at the study site after the other visit procedures have been 
performed. On days with no scheduled study visit, the patient will take their medication at 
home.
In Part 1, patients will receive four tablets once per day. In Table 4.1.4: 1, the medication for
the first twelve weeks of treatment is listed. Part 1 treatment period is 24 weeks in total.
Table 4.1.4: 1
Trial medication during first twelve weeks of Part 1
25 mg/pbo tbl
50 mg/pbo tbl
100 mg/pbo tbl
A: 25 mg treatment group
1 active
1 pbo
2 pbo
B: 50 mg treatment group
1 pbo
1 active
2 pbo
C: 100 mg treatment group
1 pbo
1 pbo
1 active
1 pbo
D: 200 mg treatment group
1 pbo
1 pbo
2 active
E: Placebo (pbo) group
1 pbo
1 pbo
2 pbo
In Part 1, after twelve weeks treatment, patients may be assigned to a higher dose group,
depending on their response as assessed by PASI. 
In Part 1, from the start of the treatment period, patients will be instructed to take the trial 
medication once daily with a glass of water. Patients must take the study medication after at 
least 6 hours fasting and should not eat for 30 minutes after drug administration. The
medication should be taken in the morning at approximately the same time every day, to
ensure a dose interval of about 24 hours. If a dose is missed by more than 12 hours, that dose
should be skipped and the next dose should be taken as scheduled. No double doses should 
be taken.
In Part 2, patients will receive 6 tablets  per day: 4 tablets in the morning and 2 tablets in the 
evening. See Table 4.1.4: 2.
Table 4.1.4: 2
Trial medication in Part 2
Morning
Evening
U: 400 mg q.d.fed treatment group
4 active 100 mg
2 pbo
V: 200 mg b.i.d. fed treatment group
2 pbo
2 active 100 mg
2 active 100 mg
W: Placebo fed treatment group
4 pbo
2 pbo
In Part 2, treatment will be completed at Week 12.


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In Part 2, patients must take the trial medication with a meal. Patients should be instructed not
to take their medication on the morning of trial visits, as they will be dosed in the clinic. On 
days of trial visits, all visit procedures should be completed first before the patient has their 
meal and takes their morning dose.
In Part 2, the dosing interval should be approximately 12 hours. If a dose is missed by more 
than 6 hours, that dose should be skipped and the next dose should be taken as scheduled. No 
double doses should be taken.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators, and everyone involved in trial conduct or analysis will remain blinded 
with regard to the randomised treatment assignments until after database lock. 
The randomisation code will be kept secret by Clinical Trial Support up to database lock.
The randomisation codes will be provided to bioanalytics prior to last patient completed to 
allow for the exclusion from the analyses of PK samples taken from placebo patients. 
Bioanalytics will not disclose the randomisation code or the results of their measurements 
until the trial is officially unblinded.
A trial-independent statistician (iSTAT) will be assigned to prepare the summary reports for 
the DMC based on the agreed upon format and layout. All information, including adverse 
events, mortality, and laboratory parameters, will be provided in unblinded fashion. This will 
be accomplished by using coded labels and providing the DMC members with the decoding 
information separately.


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4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It 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 
 to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives and not be shared 
further. 
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). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
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 or designee 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 (for US sites).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics, if not site-to-site shipments are 
formally organized by the sponsor. Patients should be instructed to return unused 
investigational drug.


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The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the 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 patients. 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.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (cf. section 3.3) may be 
permissible. All concomitant medications should be carefully evaluated by the Investigator,
and the CML should be contacted when there are questions regarding concomitant 
medications.
In the event that a patient experiences an intolerable increase of PsO during the course of the 
trial, the trial medication will be discontinued and anti-psoriatic agents may be used as rescue 
medications.
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.
Severe infections according to RCTC grading, serious infections, and opportunistic or 
mycobacterial infections:
Treatment of the infection should be initiated promptly according to local standard of care. 
Treatment with trial medication should be discontinued.
Malignancies
In case of occurrence of malignant neoplasm other than appropriately treated basal cell 
carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix, the 
investigator should discontinue treatment with the trial medication, and notify the CTM. 
Diagnostics and treatment should be initiated according to local standard of care.
Suicidality
In case of signals of suicidal ideation the patient should be referred to psychiatric work up.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The medications, classes of medications, and foods listed in Table 4.2.2.1: 1 must not be 
taken for the time periods as specified. Classes of antipsoriatic medications listed in Table 
4.2.2.1: 1 are likewise restricted, however may be permitted as rescue treatment, at the 
investigator’s discretion, if a patient experiences an intolerable increase of PsO during the 
course of the trial. In such cases, the investigator must notify the BI CML and document the 
details of the drug used and reason in the eCRF.
A comprehensive list of restricted medications can be found in the ISF.


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Table 4.2.2.1: 1
Restricted medications and food 
Medication or class of medications
Specified restriction time 
Drugs with known phototoxic or photoallergic 
potential
(e.g., tetracyclines, fluorchinolones)
One week prior to randomisation 
until EOO 
Drugs or foods (e.g., seville oranges, grapefruit, 
paw paw and their products) which are known 
inhibitors or moderate or strong inducers of 
CYP3A, or are sensitive substrates of CYP1A2, or 
CYP2B6, or CYP2C8 , CYP2C9, or CYP2C19.
One week prior to randomisation 
until EOO
Drugs with narrow therapeutic windows which are 
substrates of P-gp, BCRP, OATP1B1, OATP1B3,
OAT3, OCT2, MATE1, and MATE2-K.
One week prior to randomisation 
until EOO
Investigational products (other than antipsoriatic 
drugs)
30 days prior to randomisation
through EOO (end of observation 
visit) 
Any drug known to interfere with or to aggravate 
PsO including but not limited to lithium and 
interferons
4 weeks prior to randomisation 
through EOO
BCG (Bacillus Calmette-Guérin) vaccine
1 year prior to randomisation 
through 1 year after last 
administration of study drug
Investigational antipsoriatic drugs
12 weeks prior to randomisation 
through EOO
Biologic agents (other than IL-23 antibodies)
within 12 weeks
12 weeks prior to randomisation 
through EOO
IL-23 antibody drugs (e.g., ustekinumab, 
guselkumab, tildrakizumab, risankizumab)
24 weeks prior to randomisation 
through EOO


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Table 4.2.2.1: 1
Restricted medications and food cont.
Investigational device or product (excludes
psoriasis products)
30 days prior to randomisation 
Other systemic immunomodulating treatments (e.g.,
methotrexate, cyclosporine A, corticosteroids1), 
apremilast (Otezla®1,cyclophosphamide, 
tofacitinib (Xeljanz))
Other systemic psoriasis treatments (e.g., retinoids, 
fumarates, any other drug known to possibly 
benefit psoriasis) 
Photochemotherapy (e.g., PUVA) 
Phototherapy (e.g., UVA, UVB) 
14 days prior to randomisation 
Topical treatment for psoriasis or any other skin 
condition (e.g. corticosteroids2, vitamin D 
analogues, vitamin A analogues, pimecrolimus, 
retinoids, salicylvaseline, salicylic acid, lactic acid, 
tacrolimus, tar, urea, andanthralin, α-hydroxy, fruit 
acids) 
1 No restriction on corticosteroids with only a topical effect (e.g. inhalant corticosteroids to treat asthma or corticosteroid 
drops used in the eye or ear).
2 Exception: Topical steroids of US class 6 (mild, such as Desonide) or US class 7 (least potent, such as hydrocortisone) will 
be permitted for use limited to the face, axilla, and/or genitalia with a restriction of use within 24 hours prior to clinic 
visits when PASI is assessed.
4.2.2.2
Restrictions on diet and lifestyle
In Part 1, the participants should take the medication after at least 6 hours fasting and should 
not eat for 30 minutes after drug administration.
In Part 2, the medication should be taken with a meal.
Foods which are known strong or moderate inhibitors of CYP 3A (e.g., seville oranges, 
grapefruit, paw paw and their products) should be avoided during the study participation.
Moisturizers/emollients containing retinoids and the use of tanning beds are not allowed 
during the study.
4.2.2.3
Restriction of UV-light exposure
Throughout their participation in the study, patients should avoid prolonged exposure to 
sunlight an artificial UV light. When exposed to direct 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. Patients should 
wear sun glasses when exposed to direct sun or other sources of UV-light. These protection
measures must be applied until the end of the follow-up periods.


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4.2.2.4
Contraception requirements 
Female patients: 
WoCBP (for the definition please refer to section 3.3.2) must use a highly effective method 
of birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year 
when used consistently and correctly during the study, and for a period of at least 28 days
after the last dose of study drug. 
Acceptable methods of birth control for this trial are: 

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal). 

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable). 

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion

Vasectomised sexual partner with documented absence of sperm. 
Or 

Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g., calendar, 
ovulation, symptothermal, post-ovulation methods, declaration of abstinence for the 
duration of exposure to study drug, and withdrawal are not acceptable.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on counts, treatment compliance will be calculated as shown in the formula below. 
Compliance will be verified by the CRA authorised by the sponsor.
Treatment compliance (%) =
Number of actually taken 100
     Number of which should have been taken
If the number of doses taken is not between 80-120%, site staff will explain to the patient the 
importance of treatment compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The skin condition will be assessed by using the PASI and sPGA as described in Appendix 
10.1 and 10.2 and the ISF. Further assessments will include NAPSI, PPASI and PSSI.
Symptoms and quality of life will be assessed by PSS and DLQI. Pain symptoms in patients 
with PsA will be assessed by the Pain VAS.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the FLOW 
CHART, Part 1 and FLOW CHART, Part 2. 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, Part 1 and FLOW CHART, Part 2.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the FLOW CHART, Part 1 and 
FLOW CHART, Part 2, 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. 
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. 
Blood samples for safety will be drawn prior to drug administration. In Part 2, patients do not 
have to be fasted for the blood sampling.
For the sampling time points please see FLOW CHART, Part 1 and FLOW CHART, Part 2.
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. 


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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 (please refer to section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see section 5.2.6.1 and the DILI Checklist provided in the ISF eDC
system. The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
Table 5.2.3: 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
Immunophenotyping of T cell subsets1
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


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Table 5.2.3: 1 
Safety laboratory tests cont.
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
C-Reactive Protein (CRP, High sensitivity)
Cholesterol, total1
Triglycerides1
LDL-Cholesterol /HDL-Cholesterol1
Urine Pregnancy test (only for female patients of 
childbearing potential - test done in clinic)
Human Chorionic Gonadotropin in the urine
Serum Pregnancy test (only for female patients of 
childbearing potential) at screening or if urine 
pregnancy test is positive) 
Human Serum Chorionic Gonadotropin 
Hormones (only at screening) 
TSH, (free T3 and T4 in case of abnormal TSH ) 
Autoantibodies (only at screening)
Rheumatoid Factor
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)2
HIV-1, and HIV-2 Antibody (qualitative)
QuantiFERON®-TB
1 only at screening and EOO-visit; 2A positive hep C antibody result should be confirmed by hep C-RNA PCR, before a 
patient is excluded.
5.2.4
Electrocardiogram
ECGs will be read and evaluated centrally. The 12-lead ECGs will be recorded as scheduled 
in the FLOW CHART, Part 1 and FLOW CHART, Part 2. ECGs may be repeated for quality 
reasons and the repeated recording used for analysis. 
If necessary, additional ECGs may be recorded for safety reasons. 


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The digital ECG recordings will be transmitted to a vendor for central evaluation and the 
results will be reported to the site. 
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.
5.2.5
Other safety parameters
5.2.5.1
Suicidality
Suicidal thoughts and behavior will be assessed by the Columbia-Suicide Severity Rating 
Scale (C-SSRS, R08-1147). 
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report. In this trial, paper forms will be used for the assessment of the C-SSRS®, and results 
will be transcribed into the e-CRF.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the Screening Visit/Visit 1 (using the ‘baseline/ screening’ version) with the 
aim to exclude patients with active moderate or severe symptomatology within a specified 
time prior to the screening or screening visit. The lifetime and the past year history of suicidal 
ideation and behavior will also be recorded.
After the screening visit, the assessment ‘since last visit’ version will be performed at each 
visit. The investigator is to review positive and negative reports for plausibility and clinical 
relevance. Doubtful reports may be repeated or reports may be validated by a consulting 
psychiatrist or other mental health professional expert. If there is a confirmed positive report 
of suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to 
immediately interview the patient, and/or is to consult a mental health professional. If the 
positive report is confirmed, appropriate actions for the patient’s safety have to be initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.
For ‘Self-injurious behavior, without suicidal intent’, standard AE / SAE reporting rules are 
to be applied.


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For each negative report (suicidal ideation type 1, 2 or 3) after the start of the trial, the 
investigator is to decide based on clinical judgment whether it represents an AE as defined in 
the protocol, and if it is considered an AE then it must be reported accordingly.
5.2.5.2
Major Adverse Cardovascular Event (MACE)
An independent adjudication committee will be used to adjudicate all observed cardio- and 
cerebro-vascular and thrombotic events reported during the conduct of the study, to assure 
consistent assessment of major adverse cardiovascular events (MACE). See section 8.7.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
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.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
requires inpatient hospitalisation or 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
-
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.


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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 
described in section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
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. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
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 (e.g., icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain) without lab results (e.g., 
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.


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Severe infections (according to RCTC grading)
Opportunistic and mycobacterial infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-
transplant lymphoproliferative disorder (EBV), progressive multifocal leucoencephalopathy, 
bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous mycobacterium, 
salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes 
zoster, strongyloides (hyperinfection syndrome and disseminated forms only), 
paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium species 
(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only), shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), HCV progression.
Gastric intolerance and gastritis:
Even though gastritis development is not expected in humans, AE consistent with gastric
intolerance or gastritis are designated as AE of special interest (AESI), to ensure timely
characterization, monitoring and reporting of any such events in this study (for details, please 
refer to section 1.2.1).
Not all gastrointestinal events will be considered AESI. Only events that are consistent with
the following definitions are considered AESI and will need to be reported accordingly:

Any AE of “nausea” or “vomiting” of moderate or worse severity (according to RCTC, 
OR of prolonged duration  (≥7 days), OR

Any AE of “gastritis” (regardless of duration or severity)
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.


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
A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g., Stevens-Johnson syndrome).

An indication of dose-response (i.e., greater effect size if the dose is increased, 
smaller effect size if dose is 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.
5.2.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient 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 eCRF.
Patients 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 patient’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


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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 conditions
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already 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 patient’s end of trial must be followed up until they have resolved, have been 
assessed as “chronic” or “stable”, or no further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, 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).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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5.6
OTHER ASSESSMENTS
5.6.1
Photography of skin lesions
In part 1 and at selected sites, participation is voluntary and not a prerequisite for 
participation in the trial. Photography of skin lesions will be performed optionally for 
additional documentation. Front and back trunk as well as target lesions photographs will be 
taken preferably as the time-points specified in the FLOW CHART, Part 1 per instructions in 
the ISF.
The patient’s consent must be obtained prior to take the photographs. Patients must be 
unrecognizable on the photos (refer to the procedure in the ISF).


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In Part 2, no skin photos will be taken.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial except from the skin biopsies and photos are 
standard measurements in PsO treatment trials and will be performed in order to monitor 
safety aspects or assess treatment response in an appropriate way.
Skin biopsies, although not standard, are also widely used in PsO trials and indispensable for 
the understanding of the disease pathophysiology and effects of the treatments which are 
investigated. Only a subset of patients will be asked for skin biopsies. A separated informed 
consent will be obtained from these patients. 
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 patients 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 CHART, Part 1 and 
FLOW CHART, Part 2. 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 CHART, Part 1 and 
FLOW CHART, Part 2 and the respective protocol sections. Additional details on procedures 
at selected visits are provided below.
Assessments – as applicable to the respective visit - should be performed in the following 
order:

Informed consent

Demographics, medical history and baseline conditions

Concomitant therapies or changes in concomitant therapies

Height

Weight

Vital signs

Physical examination

12-Lead ECG, local assessment

Pregnancy test (in females of childbearing potential)

Safety laboratory (blood samples)

Biomarkers (blood samples)

PK sampling (for intensive PK sampling, please refer to flowchart)

Assessment of eligibility criteria

Breakfast or light dinner (for patients in the pk sub-study who take their evening dose at 
the site)

Dispensation/administration of study medication
(In Part 1, no study medication should be dispensed/administered at the EOT visit. In Part 
2, last drug administration is at EOT)
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
PROs should be completed by the patient on his/her own in the pre-specified order in a quiet 
area/room before any other visit assessments or treatments, and, if possible, before any 
interaction with the investigator or other members of the study team.
The PSS will be completed by the patient at all visits, except V1, on a paper form.
The order of completion for PROs is as follows, as applicable for each PRO at relevant visits
according to the FLOW CHART, Part 1 and FLOW CHART, Part 2:


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(1) PSS 
(2) DLQI
(3) Pain VAS (for patients with concomitant PsA)
The Baseline/screening scale of the C-SSRS will be administered for eligibility confirmation 
and the follow-up scale at all visits for assessement of suicidality.
6.2.1
Screening period
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 patient should be recorded on the enrolment log. The patient should be 
registered in IRT as a screened patient.Screening procedures may be extended to more than 
one physical visit, if needed.
Re-screening will not be permitted. Patients who fail screening following Visit 1 assessments 
should be registered as a screen failure in IRT.
Re-testing for certain eligibility criteria can be performed once for abnormal laboratory, 
results.  
After the informed consent process is complete and written informed consent is obtained, the 
subjects will be assessed for study eligibility including laboratory assessments as indicated in 
section 5.2.6.
All other assessments will also be performed as summarized in the study FLOW CHART, 
Part 1 and FLOW CHART, Part 2. Patients will be asked to continue their background 
medication without changes and to adhere to their administration algorithm.
All subsequent visits should be scheduled.
6.2.2
Treatment period
The treatment period starts with Visit 2 and ends with the EOT visit. Randomisation will
occur at Visit 2 using IRT.
The patients will return to the clinic for regularly scheduled visits as specified in the FLOW 
CHART, Part 1 and FLOW CHART, Part 2. At these visits, the occurrence of safety and 
efficacy endpoints, trial medication compliance, concomitant therapy or intervention will be 
assessed.
At all treatment visits, the order of assessments (as applicable) should be followed:

Completion of the questionnaires

Physical examination, urine pregnancy and vital signs

ECG 

Laboratory samples
All assessments must be performed before the medication is taken. Patients in Part 2 should 
have a meal within 30 minutes prior to taking their medication.


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6.2.3
Follow up period and trial completion
For all randomised patients termination of trial medication and trial completion must be 
recorded on the corresponding eCRFs.
6.2.3.1
Early treatment and trial termination:
If study medication is discontinued prior to the planned FLOW CHART, Part 1 and FLOW 
CHART, Part 2 EOT visit, every effort should be made to have the patient continue in the 
trial and complete all of the remaining Treatment Period Visits and FU Visit. Trial 
termination should be completed at the FU Visit. If a patient cannot or will not continue in 
the trial, the patient should complete EOT visit procedures instead of the planned treatment 
period visit and return to the clinic for FU/EOO Visit 4 weeks after last dose of study 
medication.
6.2.3.2
Trial completion
Patients who finish the randomised treatment period will return to the clinic for Follow-up 
Visit. Trial completion is defined as patients having reached the FU visit within the specified 
window per the FLOW CHART, Part 1 and FLOW CHART, Part 2. Patients who complete 
the randomised treatment period without early treatment discontinuation will have the option 
to participate in a long term extension (LTE) trial, if their psoriasis has improved and if they 
have well tolerated the study treatment. In Part 2, patients may also be offered participation in 
the LTE, if they feel that they have benefited from the trial treatment.
After the EOT Visit, the visit schedule is dependent on LTE participation:

Patient who will not participate in the LTE study will return to the clinic for FU/EOO 
Visit. Trial termination will be completed at FU/EOO. The decision not to enter the LTE
will be registered in IRT at the EOT Visit.

Patients who participate in the LTE will complete the EOT visit as the final 1407-0030
study visit.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
Part 1:
The primary trial objective includes demonstration of PoCC with respect to a non-flat dose 
response curve, characterization of the dose-response relationship within the therapeutic 
range, and selection of the dose range for phase III development. See section 2.1.1 for details 
on the objective of this trial. For this purpose, the primary analysis uses methodology for 
dose finding employing both multiple comparison procedures and modelling techniques 
(MCPMod). The co-primary endpoints are defined in section 2.1.2.
Part 2:
A Bayesian borrowing approach will be implemented to estimate treatment effect by PASI 75 
and sPGA. No hypothesis testing will be performed. The primary endpoint is defined in 
section 2.1.2
Baseline refers to the measurement recorded at randomisation (Visit 2); if data at Visit 2 is 
missing, then data from Visit 1 will be considered baseline. The percent reduction from 
baseline is calculated by % PASI reduction from baseline = ((PASI at baseline - PASI at Visit 
X) / PASI at baseline) * 100, at all follow up visits. Achieving an x% or larger reduction from 
baseline PASI score is denoted as PASI X.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Part 1:
The co-primary endpoints are based on Week 12 PASI 75 and sPGA 0/1 response. The null 
hypothesis is that there is a flat dose response curve comparing the placebo and the 
BI 730357 dose groups. The alternative hypothesis is that there is a non-flat dose response 
curve indicating a benefit of BI 730357 over placebo. 
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, whilst protecting the overall probability of Type I error (one sided α of 
5%). The pre-specified models and their parameters used for this test are outlined in section 
7.3.1.
Part 2:
The co-primary endpoints are based on Week 12 PASI 75 response and sPGA 0/1. PASI 75 
at week 12 will be analysed based on a Bayesian borrowing approach.
7.3
PLANNED ANALYSES
The following patient analysis sets are defined:

The efficacy analyses will be based on the intent-to-treat principle, comprising all 
participants who were randomised and received at least one dose during the trial. The 


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efficacy analyses will be based on the planned treatment; this set of patients is called 
the Full Analysis Set (FAS).

Safety analyses will be based on the actual treatment received; this set of patients is 
called the Treated Set (TS).
Specifications of important protocol violations will be provided in the TSAP.
7.3.1
Primary endpoint analyses
Part 1:
The achievement of PASI 75 at Week 12 is the first co-primary endpoint, and is a binary 
variable with values of 0 or 1. The achievement of a sPGA score of clear or almost clear at 
Week 12 is the second co-primary endpoint and is a binary variable with values of 0 or 1. 
After the last patient reaches Week 12, the analyses for PoCC and dose-finding will be 
performed on each co-primary endpoint using multiple comparison and modelling techniques 
(MCPMod) [R10-1424, R15-1961] for binary data whereby several possible dose response 
models (patterns) will be evaluated, while keeping full control of the type I error at 5%, one-
sided, to identify the best-fitting model or subset of models.
A non-flat dose-response relationship is established if for each co-primary endpoint, the null 
hypothesis of no dose effect (i.e., a flat dose response curve) is rejected for at least one of the 
pre-specified models with respect to the alpha chosen.
For the sample size calculation, the maximum effect size is assumed to be 50%, with the
placebo effect size assumed to be 10% for PASI 75 at Week 12. The maximum effect size is 
assumed to be 50% with the placebo effect size assumed to be 10% for sPGA (0/1) at Week 
12. Further details are given in section 7.7.
The following models shapes have been selected as the candidate set of possible dose 
response patterns (Figure 7.3.1:1) based on current expectation. Assuming the following dose 
groups will be tested: placebo, active BI 730357 25 mg, 50 mg, 100 mg, and 200 mg.

Linear: no assumptions needed

Emax 1: 30% of the maximum effect is achieved at 50 mg

Emax 2: 80% of the maximum effect is achieved at 50 mg

Exponential: 5% of the maximum effect is achieved at 25 mg

Logistic: 10% of the maximum effect is achieved at 25 mg
   
   80% of the maximum effect is achieved at 100 mg
Note that the actual shapes and assumptions on proportion of maximum effect are applied on 
the logit scale for binary data, e.g. linear model. For interpretation convenience, dose 
response curves in Figure 7.3.1: 1 are converted to original scale of PASI 75 and sPGA 0/1
probability.


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Figure 7.3.1: 1 Shape of the models within the candidate set
PoCC is established if for each co-primary endpoint, at least one model is statistically 
significant, rejecting the null hypothesis of a flat dose response relationship for each of the 
candidate dose response models with a contrast test controlled for the family–wise type I 
error rate at one sided α = 5%. 
If PoCC is established, the statistically significant (best fitting) model(s) from the above 
candidate set are refitted to the data to generate new estimates for all model parameters from 
the data. The final model will be obtained via model averaging across the significant models 
based on Akaike Information Criterion (AIC). The target dose(s) can be estimated from that 
model by incorporating information on the minimum clinically relevant effect and accounting 
for safety. Only doses within the dose range investigated (0 to 200 mg) will be considered 
although the actual modelling will be performed on a broader range of doses including 
extrapolation.
If considered necessary and for the purpose of further model refinement, MCPMod might be
repeated on the primary endpoint but with an extended set of shapes including the original 
candidates.
Comparisons between treatment groups will be exploratory in nature. Comparisons between 
treatment groups regarding the co-primary endpoints will also be performed using the Chi-
square test for each of the four active treatments versus placebo. In addition, unadjusted 
absolute risk differences of the response rates at Week 12 between BI 730357 arms and the 
placebo group will be analysed. The proportion of responders in each arm, the risk difference 


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between each BI 730357 arm and placebo with 95% exact confidence intervals will be 
displayed. This is considered the secondary analysis for the primary endpoint(s). More details 
on the above analyses as well as additional sensitivity analyses will be given in the TSAP.
For the PoCC analysis, the analyses will be performed by BI personnel independent of the 
trial team in order to prevent potential introduction of operational bias. A logistics plan 
prepared and approved in accordance with Sponsor’s specific procedures will detail 
procedures used to ensure that all members of the trial team remain blinded. The logistics 
plan will also contain a detailed list of functions that need to be unblinded to perform this 
analysis.
Part 2:
The achievement of PASI 75 at Week 12 will be summarized in the form of proportion of 
patients achieving PASI 75 at Week 12 as an outcome measure so as to perform the primary 
analysis. 
The primary analysis on PASI 75 at week 12 will be based on a Bayesian borrowing 
approach. For the placebo control group, an informative prior is based on historical data 
whereas the prior for the BI 730357 group is non-informative. The derivation of the 
informative prior is based on a meta-analytic predictive (MAP) prior approach which is 
additionally robustified against prior-data conflicts by adding a vaguely informative 
component to the prior.
A Bayesian approach with an informative mixture beta prior for the placebo group will be 
used. The prior is a combination of a mixture of informative beta priors derived from 
historical trials and a vaguely informative beta prior. The weight on the vaguely informative 
beta prior is 50%. The prior considered is: 0.388 * Beta (8.269, 132.315) + 0.112 * Beta 
(2.546, 27.521) + 0.5 * Beta (0.07, 0.93). Non-informative beta prior Beta(1, 1) is used for BI 
active treatment arms.The actual prior may be updated based on additional historical 
information being available, including result from part I. The final prior will be documented 
in the TSAP.
The primary analysis for sPGA clear or almost clear at week 12 will be analysed by 
summarizing the proportion of responders in each arm with 95% exact confidence intervals.
If considered necessary, same approach as PASI 75 based on Bayesian borrowing approach.
The proportions of 200 mg b.i.d. and 400 mg q.d. recipients who achieve PASI 75 
improvement criteria at Week 12., will be respectively compared with that of placebo 
recipients. For that purpose, the posterior probability distribution for the risk difference will 
be evaluated and compared to specific boundary values. The dual criteria will be assessed to 
evaluate the effect of BI 730357: (1) significance: a posterior probability of at least 90% that 
the PASI 75 response rate for patients on BI 730357 is higher than that for patients on 
placebo; and (2) relevance: a posterior probability of at least 50% that the PASI 75 response 
rate for patients on BI 730357 is higher than that for patients on placebo by various boundary 
values. If at least one dose satisfy both criteria, it is considered as “pass”. If neither doses 
have significance or relevance criteria been met, it is considered as “not pass”. Otherwise it is 
in the “consider” zone, where sPGA 0/1 at week 12 will be jointly evaluated.


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7.3.2
Secondary endpoint analyses
Part 1:
If considered necessary, a MCPMod approach will also be applied to selected secondary
endpoints.
The same methods as discussed for the secondary analysis for the primary endpoints will be 
used to analyse clinical binary secondary endpoints, if applicable.
For binary endpoints after Week 12, two analysis strategies will be considered as following:

The analysis will be done based on the original treatment assignment at randomisation. 
Non-responders at Week 12 will be imputed as failure for binary endpoints after 
Week 12.

For non-responders at Week 12, analysis based on the escalated treatment they 
received at Week 12 will also be considered.
For PSS total score at Week 12, point estimates and two-sided 95% confidence intervals for 
mean reduction from baseline and difference between each BI 730357 arm and placebo will 
be provided.
Part 2:
For PSS total score at Week 12, point estimates and two-sided 95% confidence intervals for 
mean reduction from baseline in each arm will be provided.
For other binary secondary endpoints, the proportion of responders in each arm with 95% 
exact confidence intervals will be displayed.
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 


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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.
All treated patients 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 
adverse events 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 patients 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.


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7.4
INTERIM ANALYSES
Part 1:
When the last patient completes the 4 Week visit, there will be an administrative interim 
analysis for the purpose of internal planning other indications of BI 730357. An independent 
team will be formed to perform this analysis. Details will be specified in an interim analysis 
logistic plan. As the trial will continue unchanged irrespective of the results, no statistical 
adjustment for the primary endpoint is required.
When the last patient completes the Week 12 visit (timepoint of primary endpoint), the 
primary analysis will be performed. In order to support the further double-blinded conduct of 
the trial until the Week 24 visit, the Trial Team will be kept blinded on the individual patients’ 
treatment group assignment. A separate team will be formed to perform this analysis. Details 
will be specified in the logistic plan.
In summary, Part 1 of this trial will be double-blinded until the final analysis when the last 
patient completes Week 24. More details about the analyses will be specified in the TSAP.
Part 2:
No interim analysis is planned for the Part 2 of this trial.
For both trial parts, an independent DMC will follow the DMC charter and be responsible for 
reviewing safety data periodically to ensure patient safety and to monitor the conduct of the 
trial and the integrity of the data. Refer to section 8.7 for more information for DMC.
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.
The following rules will be used to impute for missing data:
- For all non-binary endpoints, LOCF (Last Observation Carried Forward) will be used to 
impute missing values 
- For all binary endpoints (i.e., endpoints that are either 1 (patient responded) or 0 (patient did 
not respond)):
- If no data after that visit*, then impute as failure (NRI [No Response Imputation])


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- If data at visits* before and after, only impute as success if both visits are successes; 
else impute as failure.
* Patients that take prohibited medications to treat PsO will be treated the same as those that 
discontinued from the trial, i.e., subsequent visits following start of prohibited medication 
will be considered as failure for binary endpoints. 
Missing items from the Quality of Life questionnaires will be handled according to the 
measure instructions (cf. Appendix 10.6). If there is no data for a particular visit, then it will 
be imputed following the same rules as described above.
More details will be included in the TSAP, if needed.
7.6
RANDOMISATION
An IRT will be used for the assignment of subjects to treatment groups. 
Part 1:
Patients will be randomised in blocks to double-blind treatment. Patients will be randomised 
to one of 4 BI 730357 dose groups and placebo in a 2:2:2:2:1 ratio. In total, approximately 40 
patients will be allocated to each BI 730357 active dose group, and approximately 20 patients 
to placebo. Refer to section 3.1 for the details.
Part 2:
Patients will be randomised to the 200 mg b.i.d., 400 mg q.d. BI 730357 dose group or 
placebo in a 4:4:1 ratio. In total, approximately 40 patients will be allocated to BI 730357 200 
mg b.i.d. dose group, 40 patients will be allocated to BI 730357 400 mg q.d. dose group and 
approximately 10 patients to placebo. Refer to section 3.1 for the details.
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
Part 1:
Sample size calculation is mainly driven by safety considerations.
Based on an assumed maximum treatment effect size of BI 730357 vs. placebo for the PASI 
75 endpoint, as well as on the pre-specified models listed in section 7.3.1, the power is 
provided in the Table 7.7: 1 for different scenarios for one of the co-primary endpoint PASI 
75. The maximum treatment benefit is assumed to be 50% compared to placebo (60% vs 
10%) for PASI 75 at Week 12. 


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The maximum treatment benefit is assumed to be 50% compared to placebo (60% vs 10%) 
for sPGA 0/1 at Week 12. The same dose- response assumptions are made for the sPGA 
(0/1). As PASI 75 and sPGA (0/1) are highly correlated, a sample size of about 180 
(=40:40:40:40:20 to 4 BI 730357 active dose groups and placebo, refer to section 3.1) 
evaluable patients will have an overall power > 90% to show a significant non-flat dose-
response curves across the different doses and placebo using MCPMod approach with 
parameters as listed in section 7.3.1.
Table 7.7: 1
Power of MCPMod for each candidate set model and min, max, 
average power for PASI 75
Model
Assumption A
(e.g., maximum 
treatment 
effect=0.5, 
allocation 
40:40:40:40:20)
Assumption B
(e.g., maximum 
treatment 
effect=0.4, 
allocation 
40:40:40:40:20)
Assumption C
(e.g., maximum 
treatment 
effect=0.01, 
allocation 
40:40:40:40:20)
Assumption D
(e.g., maximum 
treatment 
effect=0.3, 
allocation 
40:40:40:40:20)
Linear
99.9%
99.4%
6.6%
95%
Emax 1
99.7%
98.0%
6.5%
90.2%
Emax 2
94.5%
85.9%
6.1%
70.5%
Logistic
99.7%
99.7%
6.8%
96.9%
Exponential 
99.9%
99.8%
6.6%
97.1%
Min
94.5%
85.9%
6.1%
70.5%
Max
99.9%
99.9%
6.8%
97.1%
Average
98.8%
96.6%
6.6%
90.0%
Assumptions considered:

A: Main scenario reflecting assumption listed in section 7.3.1. Assuming PASI 75 
response rate is 10% (placebo), 60% for the 200 mg dose group. Sample size 
considered is 180 patients with 2:2:2:2:1 allocation ratio. 

B: Similar scenario as A, but response rate at 200 mg dose group is lower at 50%.

C: Scenario reflection almost no treatment benefit. 

D: Same scenario as A and B, but with a lower maximum treatment benefit.
The calculations for the PoCC step have been performed using DoseFinding R-package [R15-
2001]. Calculations were performed using R version 3.4.2. The R codes for the sample size 
calculations as well as the analyses using the MCPMod approach will be provided in the 
TSAP.
Part 2:
Posterior probabilities are evaluated based on assumed response rates of 7% on placebo and 
52% on BI 730357 200 mg b.i.d. and 400mg q.d., respectively, when assuming sample sizes 
for BI 730357 200 mg b.i.d., 400 mg q.d. and placebo group are 40, 40 and 10, respectively, 
and the prior specified in Section 7.3.1. Dual criteria for establishing an overall “pass” are 


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used. For example, under the dual criterion 1) significance P( BI – PBO > 0 | Data) > 0.95; 
and 2) relevance P( BI – PBO > 0.40 | Data) > 0.5, if there is a truly treatment difference of 
40% in response rates, the given sample size provides a chance of >90% to detect the 
treatment benefit in at least one active dose group. A “passed” indicates at least one dose 
satisfies both significance and relevance criteria; A “not passed” indicates neither dose 
satisfies either of these two criteria. Table 7.7: 2 presents the probabilities of decisions under 
different cases. 
Table 7.7: 2
Posterior probabilities for each scenario under different significance 
and relevance criteria settings
Significance 
criterion
Relevance 
criterion
Assumed PASI 75 
response rate
200 b.i.d., 400 q.d., 
PBO
P(Passed#)
P(Not 
passed# )
P(Consider#)
P( BI – PBO > 0 
| Data) > 0.9
P( BI- PBO > 
0.35 | Data) > 
0.5
7% , 7% vs. 7%
0
66%
34%
52%, 52% vs. 7%
99%
0
1%
52%, 52% vs 15%
92%
3%
5%
P( BI – PBO > 0 
| Data) > 0.9
P( BI- PBO > 
0.4 | Data) > 
0.5
7% , 7% vs. 7%
0
66%
34%
52%, 52% vs. 7%
94%
0
6%
52%,52% vs 15%
82%
3%
15%
P( BI – PBO > 0 
| Data) > 0.9
P( BI- PBO > 
0.45 | Data) > 
0.5
7% , 7% vs. 7%
0
66%
34%
52%, 52% vs. 7%
82%
0
18%
52%, 52% vs 15%
66%
3%
31%
P( BI – PBO > 0 
| Data) > 0.95
P( BI- PBO > 
0.35 | Data) > 
0.5
7% , 7% vs. 7%
0
84%
16%
52%, 52% vs. 7%
99%
0
1%
52%,52% vs 15%
92%
5%
3%
P( BI – PBO > 0 
| Data) > 0.95
P( BI- PBO > 
0.4 | Data) > 
0.5
7% , 7% vs. 7%
0
84%
16%
52%, 52% vs. 7%
94%
0
6%
52%,52% vs 15%
82%
5%
12%
P( BI – PBO > 0 
| Data) > 0.95
P( BI- PBO > 
0.45 | Data) > 
0.5
7% , 7% vs. 7%
0
84%
16%
52%, 52% vs. 7%
82%
0
18%
52%, 52% vs 15%
66%
5%
29%
# - Passed: At least one dose satisfied both criteria. 
- Not passed: neither dose has either relevance or significance criteria satisfied
- Consider: all other scenarios
sPGA 0/1 at week 12 will be supportive if the trial result based on PASI 75 falls into 
“consider” zone.
The calculations for the Bayesian posterior probability calculation are based on R-package 
RBesT using R version 3.5.1.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a 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 patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the 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 patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or
delegate must sign (or place a seal on) and date the informed consent form. 


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If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients 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 patient. 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.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial, and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.


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During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see section 8.3.2). The investigator must ensure that all patient identifiers 
(e.g., patient’s name, initials, address, phone number, social security number) have properly 
been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
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.
8.3.3
Storage period of records
Trial site(s):


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The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF


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8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Out”).
The Last Patient Last Treatment (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT 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.
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 patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
Two separate reports will be written for Part 1 and Part 2 of this trial.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of each part of the clinical trial, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be established. Members of the DMC are 
independent of BI, they are physicians experienced in the treatment of the disease under 
investigation and a statistician. 
The DMC will evaluate safety data, efficacy data and results of interim analyses. The DMC 
will receive notification of urgent significant safety concerns including severe infections, 
suicidality reports, MACE and DILI cases for immediate evaluation. While DMC members 


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may be unblinded, measures are in place to ensure the blinding for everyone else involved in 
the trial. Regular DMC meetings will be held at specified intervals. The DMC will 
recommend continuation, modification or termination of the trial as detailed in the DMC 
charter. DMC recommendations as well as the final BI decision will be reported to the 
appropriate RAs/HAs, IRBs/ECs, and to investigators as requested by local law. The tasks 
and responsibilities of the DMC are specified in a charter.
MACE adjudication committee
An independent adjudication committee will be used to adjudicate all observed cardio- and 
cerebro-vascular and thrombotic events reported during the conduct of the study to assure 
consistent assessment of major adverse cardiovascular events (MACE).This review will be 
blinded to treatment allocation; the events that are to be adjudicated and the adjudication 
process will be detailed in the MACE Adjudication Committee Charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the (Investigator Site File) ISF. The investigators will have access to the 
BI clinical trial portal 
 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,
-
ensure appropriate training and information of Local Clinical Monitors (CML), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, a central ECG service and an IRT vendor will be used in this 
trial. Details will be provided in the IRT Manual, the ECG instructions and Central 
Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P20-07441
Menter A, Gelfand JM, Connor C, et al. Joint American Academy of 
Dermatology. National Psoriasis Foundation guidelines of care for the 
management of psoriasis with systemic nonbiologic therapies. J Am Acad 
Dermatol. 2020. 82: 1445-1486.
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NPF psoriasis score. Psoriasis Forum. 8:2. 2002
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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.
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Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. 
Nature. 445:7130. 866-873. 2007.
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Posner K. State of the science: measurement of suicidal adverse events and the 
Columbia Suicide Severity Rating Scale. 47th NCDEU Ann Mtg, Boca Raton, 
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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.
R11-1260
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.
R14-3559 
Revicki DA, Jin Y, Wilson HD, Chau D, Viswanathan HN. Reliability and 
validity of the psoriasis symptom inventory in patients with moderate-tosevere 
psoriasis. J Dermatol Treat 25(1): 8-14. 2014.


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Bushnell DM, Martin ML, McCarrier K, Gordon K, Chiou CF, Huang X,et al. 
Validation of the Psoriasis Symptom Inventory (PSI), a patient-reported 
outcome measure to assess psoriasis symptom severity. J Dermatol Treat. 
24(5): 356-360. 2013
R15-1219
Martin ML, McCarrier KP, Chiou CF, Gordon K, Kimball AB, Voorhees AS 
van, et al.. Early development and qualitative evidence of content validity for 
the Psoriasis Symptom Inventory (PSI), a patient-reported outcome measure of 
psoriasis symptom severity. J Dermatol Treat 24(4): 255-260. 2013.
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Lebwohl M, Swensen AR, Nyirady J, Kim E, Gwaltney CJ, Strober BE. The 
psoriasis symptom diary: development and content validity of a novel patient 
reported outcome instrument. Int J Dermatol 53(6): 714-722. 2014.
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Strober BE, Nyirady J, Mallya UG, Guettner A, Papavassilis C, Gottlieb AB, 
et al. Item-level psychometric properties for a new patient-reported psoriasis 
symptom diary. Value Health 16(6): 1014-1022. 2013.
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.
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Bornkamp B, Pinheiro J, Bretz F. Package 'DoseFinding' (February 19, 2015). 
Cran rproject org web packages DoseFinding DoseFinding pdf. 
Comprehensive R Archive Network. 2015.
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.
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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.
R16-2630
Ueda E, Kurebayashi S, Sakaue M, Backlund M, Koller B, Jetten AM. High 
incidence of T-cell lymphomas in mice deficient in the retinoid-related orphan 
receptor RORgamma. Cancer Res 2002. 62(3):901-909.
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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.
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Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of 
interleukin-17 function in disease. Immunology. 129. 311-321. 2010.


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R16-3150
Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, et al. Chronic 
mucocutaneous candidiasis in humans with inborn errors of interleukin-17 
immunity. Science. 332. 65-68. 2011.
R16-3160
Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M, et al. 
Impairment of immunity to Candida and Mycobacterium in humans with bi-
allelic RORC mutations. Science. 349: 6248. 606-613. 2015.
R16-3166
Miossec P. Clinical implications of Th17/IL-17: diseases that may benefit 
from manipulating the Th17 pathway. Eur J Immunol. 39. 667-669. 2009.
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.
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
 and 
 Prediction of BI 730357 Pharmacokinetics and 
Therapeutic Dose in Human. Current version.
s00083382-01 BI 730357 Development Safety Update Report (DSUR). No. 03. 27 Jan 2020.


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10.
APPENDICES
10.1
PASI SCORE DEFINITION AND USE
The PASI score is an established measure of clinical efficacy for psoriasis medications (R96-
3541).
The PASI is a tool which provides a numeric scoring for patients overall psoriasis disease 
state, ranging from 0 to 72. It is a linear combination of percent of surface area of skin that is 
affected and the severity of erythema, infiltration, and desquamation over four body regions.
The endpoints used are based on the percent reduction from baseline, generally summarized 
as a dichotomous outcome based on achieving over an X% reduction (or PASI X), where X is 
50, 75, 90 and 100.
To calculate the PASI score, the four main body areas are assessed: head (h), trunk (t), 
upper extremities (u) and lower extremities (l). These correspond to 10, 30, 20 and 40% of 
the total body area respectively.
The area of psoriatic involvement of these four areas (Ah, At, Au, and Al) is given a 
numerical value: 0 = no involvement, 1 = <10%, 2 = 10 to <30%, 3 = 30 to <50%, 4 = 50 to 
<70%, 5 = 70 to <90%, and 6 = 90 to 100% involvement.
The signs of severity, erythema (E), infiltration (I) and desquamation (D) of lesions are 
assessed using a numeric scale 0-4 where 0 is a complete lack of cutaneous involvement and 
4 is the severest possible involvement; scores are made independently for each of the areas, h, 
t, u and l and represents a composite score for each area. An illustration of judging erythema 
follows: 0 = no erythema, 1 = slight erythema, 2 = moderate erythema, 3 = striking erythema, 
and 4 = exceptionally striking erythema.
The PASI score is calculated according to the following formula:
PASI = 0.1(Eh+Ih+Dh)Ah + 0.3(Et+It+Dt)At + 0.2(Eu+Iu+Du)Au + 0.4(El+Il+Dl)Al
10.2
STATIC PHYSICIAN GLOBAL ASSESSMENT (SPGA)
The sPGA used in this trial is a 5 point score ranging from 0 to 4, based on the physician’s 
assessment of the average thickness, erythema, and scaling of all psoriatic lesions (Table 
10.2: 1) (!"# $#%&&
' . The assessment is considered “static” which refers to the patients 
disease state at the time of the assessments, without comparison to any of the subject’s 
previous disease states, whether at Baseline or at a previous visit.
A lower score indicates less body coverage, with 0 being clear and 1 being almost clear.
The Investigator (or qualified site personnel) scores the erythema, induration and scaling of 
all psoriatic lesions from 0 - 4 based on the following descriptors:
Erythema
0 Normal (post-inflammatory hyper/hypopigmentation may be present)
1 Faint, diffuse pink or slight red coloration 
2 Mild (light red coloration)
3 Definite red coloration (Dull to bright red)
4 Bright to Deep red coloration of lesions


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Induration (plaque elevation)
0 None
1 Just detectable (slight elevation above normal skin) 
2 Mild thickening (slight but definite elevation, typically edges are indistinct or sloped)
3 Clearly distinguishable to moderate thickening (marked definite elevation with rough 
or sloped edges)
4 Severe thickening with hard edges (marked elevation typically with hard or sharp 
edges)
Scaling 
0 No scaling
1 Minimal focal scaling (surface dryness with some desquamation)
2 Predominately fine scaling (fine scale partially or mostly covering lesions)
3 Moderate scaling (coarser scale covering most or all of the lesions)
4 Severe /coarse scaling covering almost all or all lesions (coarse, non-tenacious scale 
predominates)
Scoring: a composite score is generated from the above data and the final sPGA is 
determined from this composite score as follows:
Clear 
0 = 0 for all three
Almost clear 1 = mean >0, <1.5
Mild 
2 = mean >= 1.5, <2.5
Moderate 
3 = mean >= 2.5, <3.5
Severe 
4 = mean >= 3.5
Table 10.2: 1
sPGA Rating Scale for Overall Psoriatic Disease
Score
Short description
Detailed description
0
clear
No signs of psoriasis. Post-inflammatory hyperpigmentation 
may be present
1
almost clear
Normal to pink coloration
Just detectable (possible slight elevation above normal skin)
No to minimal focal scaling
2
mild
Pink to light red coloration
Mild thickening (slight but definite elevation, typically 
edges are indistinct or sloped)
Predominantly fine scaling


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Table 10.2: 1
sPGA Rating Scale for Overall Psoriatic Disease cont.
3
moderate
Dull to bright red coloration
Clearly distinguishable to moderate thickening
Moderate scaling
4
severe
Bright to deep dark red coloration;
Severe thickening with hard edges
Severe coarse scaling covering almost all or all lesions
10.3
NAPSI: NAIL PSORIASIS SEVERITY INDEX
The NAPSI assesses how much of the fingernail is affected with psoriasis with scores ranging 
from 0 to 80.
If a patient has nail psoriasis, the physician will assess the nail psoriasis at each protocol 
defined time point. Fingers (5) on each hand will be individually examined for two distinct 
assessments and are graded as follows:

Nail Matrix Assessment:
0 = None
1 = present in 1 quadrant of nail
2 = present in 2 quadrants of nail
3 = present in 3 quadrants of nail
4 = present in 4 quadrants of nail

Nail Bed Assessment:
0 = None
1 = present in 1 quadrant of nail
2 = present in 2 quadrants of nail
3 = present in 3 quadrants of nail
4 = present in 4 quadrants of nail
The sum of the scores will be added resulting a range of 0 to 80. If an individual finger 
assessment is missing (not done), the average of the remaining measured digits will be 
imputed and added to the sum. If < 50% of the finger assessments are missing the imputation 
will be performed. If more than 50% of the assessments are missing then the sum of the 
scores will be left as missing.
10.4
PPASI: PALMOPLANTAR PSORIASIS SEVERITY INDEX
The PPASI provides a numeric scoring for psoriasis affecting the hands and feet with scores 
ranging from 0 to 72. It is a linear combination of percent of surface area of hands and feet 
that are affected and the severity of erythema, induration, and desquamation.
If a patient has palmoplantar psoriasis, the physician will assess the psoriasis at each protocol 
defined time point. Both palms and soles on each hand and foot will be individually assessed 
for erythema, induration, desquamation and percentage of area affected as follows:

Erythema, Induration and Desquamation:


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0 = None
1 = Slight
2 = Moderate
3 = Severe
4 = Very Severe

Percent of Palm and Sole Area Covered:
0 = Clear
1 = <10%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
The PPASI is a composite score and will be computed for each palm and sole, left and right 
and is derived from the sum of the scores for erythema (E), induration (I) and desquamation 
(D) multiplied by the score recorded for the extent of palm and sole area involved.
PPASI is calculated as follows: (sum of scored for E+I+D)*Area *0.2(location: right palm) + 
(sum of scored for E+I+D)*Area *0.2(location:left palm) + (sum of scored for 
E+I+D)*Area*0.3(location: right sole) +(sum of scores for E+I+D)*Area *0.3(location: left
sole). The range is 0 to 72.
10.5
PSORIASIS SCALP SEVERITY INDEX (PSSI)
If a patient has scalp psoriasis, the physician will assess the erythema (redness), induration 
(hardness), desquamation (shedding of skin) and percent of scalp covered at each protocol 
defined time point.

Erythema, Induration and Desquamation:
0 = None
1 = Slight
2 = Moderate
3 = Severe
4 = Very Severe

Percent of Scalp Covered:
1 = <10%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
The PSSI is a composite score derived from the sum of the scores for erythema, induration 
and desquamation multiplied by the score recorded for the extent of scalp area involved. The 
range is 0 to 72.


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10.6
DERMATOLOGY LIFE QUALITY INDEX (DLQI)
The DLQI is a subject-administered, ten-question, quality of life questionnaire that covers six 
domains including symptoms and feelings, daily activities, leisure, work and school, personal 
relationships and treatment (R05-2548). The DLQI has a one-week recall period. Item scores 
range from 0 (not relevant/not at all) to 3 (very much). Question 7 is a “yes”/ “no” question 
where “yes” is scored as 3.
DLQI total score is calculated by summing the scores of each question resulting in a range of 
0 to 30 where 0-1 = no effect on subject’s life, 2-5 = small effect, 6-10 = moderate effect, 11-
20 = very large effect, and 21-30 = extremely large effect on subject’s life. The higher the 
score, the more the quality of life is impaired. A 4-point change from baseline is considered a 
clinically important difference.
10.7
PSORIASIS SYMPTOM SCALE (PSS) 
The PSS will be completed by the patients during all clinic visits except V1.
The PSS is a four-item patient-reported outcome (PRO) instrument that assesses the severity 
of psoriasis symptoms in patients with moderate to severe psoriasis. The symptoms included 
are: pain, redness, itching and burning from psoriasis. Current symptom severity is assessed 
for a 24 hour recall periodusing a 5-point verbal rating scale ranging from 0 (none) to 4 (very 
severe). The PSS was developed based on published evidence supporting the development of 
two similar, proprietary patient-reported outcome instruments: the Psoriasis Symptom 
Inventory and the Psoriasis Symptom Diary. These measures were developed in accordance 
with FDA PRO Guidance and have published evidence of reliability, validity, and ability to 
detect change (R14-3562, R14-3559, R15-1219, R15-1410, R15-1411). 
Psoriasis Symptom Scale 
Listed below are a set of problems that people with psoriasis have said are important. For 
each question, tick the box that best describes the severity of your symptoms during the past 
24 hours. Please answer every question. 
1. How severe was your pain from your psoriasis during the past 24 hours? 
- None 
- Mild 
- Moderate 
- Severe 
- Very severe 
2. How severe was the redness from your psoriasis during the past 24 hours? 
- None 
- Mild 
- Moderate 
- Severe 
- Very severe 
3. How severe was your itching from your psoriasis during the past 24 hours? 
- None 


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- Mild 
- Moderate 
- Severe 
- Very severe 
4. How severe was your burning from your psoriasis during the past 24 hours? 
- None 
- Mild 
- Moderate 
- Severe 
- Very severe 
10.8
PAIN VAS
The Pain VAS will be self-administered by the patient (for PsA patients) at visits indicated in 
the FLOW CHART, Part 1 and FLOW CHART, Part 2. 
The patient’s assessment of pain will be performed using a horizontal 100 mm visual analog 
scale (VAS), ranging from 0 (no pain) to 100 (severe pain) after the question:
“How much pain have you had because of your psoriatic arthritis in the past week? 
Place a vertical (│) mark on the line to indicate the severity of the pain.” 


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
05 July 2018
EudraCT number
EU number
2017-004659-21
BI Trial number
1407-0030
BI Investigational Product(s)
BI 730357
Title of protocol
Phase II evaluation of safety, tolerability, and 
efficacy of BI 730357 in patients with moderate-
to-severe plaque psoriasis
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
COMMENT: The first version of this protocol has never been submitted to any regulatory 
authority. This revision is the first protocol version which is used outside of BI.
Section to be changed
1.2.1
Non-clinical studies
Description of change
Inclusion of data from non-clinical safety data.
Rationale for change
Results from additional animal toxicology studies 
have become available (embryofetal toxicology, 
39 week chronic toxicity in beagle dogs
Section to be changed
1.2.2.
Clinical Experience in Humans
Description of change
Final results from the SRD study and interim data 
from the MRD study were included. 
Rationale for change
Final report of the SRD study and interim date 
from the MRD up to for weeks dosing with 200 
mg BI 730357 have become available.
Section to be changed
3.3.2
Inclusion criteria
Description of change
added:
# 4: Diagnosis of chronic plaque psoriasis (with 
or without psoriatic arthritis) for at least 6 months 
before the first administration of study drug. 
Duration of diagnosis may be reported by the 
patient
#5: Patients must be candidates for systemic PsO 
therapy.
Rationale for change
To further specify the target patient population 
for this study.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
15 Nov 2018
EudraCT number
EU number
2017-004659-21
BI Trial number
1407-0030
BI Investigational Product(s)
BI 730357
Title of protocol
Phase II evaluation of safety, tolerability, and 
efficacy of BI 730357 in patients with 
moderate-to-severe plaque psoriasis
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Flowchart
Description of change
Added: Assessment of body weight at Visit 8.
Rationale for change
To obtain information on possible weight 
change after 12 weeks of study treatment.
Section to be changed
3.3.2
Inclusion criteria
Description of change
Added: upper age limit of 75 years inclusive.
Rationale for change
To adjust the age range to standards of Phase 2 
trials in this indication.
Section to be changed
3.3.3
Exlusion criteria
Description of change
Deleted from ex criterion #3: “or previous 
enrolment in this trial”
Rationale for change
Avoid duplication as this is already stated in
ex-criterion #2.
Section to be changed
3.3.3
Exlusion criteria
Added: 16. Any kind of photodermatosis.
For clarification
Section to be changed
Table 
4.2.2.1:1
Restricted Medications
Description of change
“or photoallergic” added to “Drugs with known 
phototoxic potential
Rationale for change
For clarification. 
Section to be changed
Table 
4.2.2.1:1
Restricted Medications
Description of change
Added: Biologic agents (other than IL-23 
antibodies) should not be taken within 12 


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weeks prior to randomisation through EOO
Rationale for change
For clarification. Biologics were already 
excluded by exclusion-criterion #4a.
Section to be changed
6.1 
Visit Schedule and Flowchart footnotes
Description of change
Added: no study medication should be 
dispensed/administered at the EOT visit
Rationale for change
For clarification
Section to be changed
8.1
Trial approval, patient information, informed 
consent
Description of change
Added to “the investigator”: …or delegate
obtains written consent …”. 
Added to “The investigator”: “…or 
 
delegate must sign …”
Rationale for change
Administrative change to include delegation of 
informed consenting in countries where this is 
allowed by local regulations.
11.3
GLOBAL AMENDMENT 3
Date of amendment
18 February 2019
EudraCT number
EU number
2017-004659-21
BI Trial number
1407-0030
BI Investigational Product(s)
BI 730357
Title of protocol
Phase II evaluation of safety, tolerability, and 
efficacy of BI 730357 in patients with 
moderate-to-severe plaque psoriasis
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
1.2.1
1.4
Non-clinical studies
benefit-risk assessment
Description of change
Information added that no drug-drug 
interactions of CYP3A4 substrates and 
BI 730357 as a perpetrator are to be expected
Rationale for change
To include results from a recently completed 
clinical multiple rising dose study with a 
midazolam micro-dose sub study.
Section to be changed
3.3.2
4.2.2.4
Inclusion criteria
contraception requirements
Description of change
Deleted from inclusion criterion #1: 
Requirement for contraception in male study 
participants.


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Rationale for change
Based on nonclinical data (no genotoxicity 
demonstrated or suspected human 
teratogenicity/fetotoxicity at therapeutic 
systemic exposure levels) no measures are 
needed for contraception in male trial 
participants with a partner that is a WoCBP.
Section to be changed
3.3.3
4.2.2.1
Exclusion criteria
Restricted medications
Description of change
Explanatory corrections to exclusion criterion 
#3 and to table 4.2.2.1:1.
CYP3A4 substrates deleted from the list of 
restricted medications. Otherwise, more details 
and examples were added but no basically new 
information.
Rationale for change
For clarification
Section to be changed
4.2.1
5.2.6.1
Other treatments and emergency procedures
Definition of AEs
“Mycobacterium tuberculosis” replaced by “all 
mycobacterial infections”.
To include and cover a more complete picture 
of opportunistic infections in the definition.
Section to be changed
Description of change
Rationale for change
Section to be changed
7.3
Planned analyses
Description of change
-
“treated set” will be used instead of “safety 
set”
-
Point estimates instead of Wilcoxon rank test 
for the analysis of Psoriasis Symptom Scale
-
Wilcoxon rank test will not be used for 
analysis of Dermatology Life Quality Index 
Rationale for change
Statistical considerations
Section to be changed
7.3.4
Safety analysis
Description of change
Residual effect period reduced from 28 days to 
7 days.
Rationale for change
Correction. 


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The follow-up period after end of treatment will 
remain at 28 days.
11.4
GLOBAL AMENDMENT 4
Date of amendment
27 March 2020
EudraCT number
EU number
2017-004659-21
BI Trial number
1407-0030
BI Investigational Product(s)
BI 730357
Title of protocol
Phase II evaluation of safety, tolerability, and 
efficacy of BI 730357 in patients with 
moderate-to-severe plaque psoriasis
Global Amendment due to urgent safety reasons
no
Global Amendment
Yes
COMMENT: The main purpose of this amendment is the addition of two active and one 
placebo group to the trial.
A PK intensive substudy was added to provide understanding of how exposure is impacted by 
high doses and by food.
Section to be changed
Synopsis
Description of change
Information clarified for Part 1 and added Part 
2 in the following sections:

Trial objectives

Trial endpoints

Trial design

Total number of patients randomized

Number of patients on each treatment

Test Product – Dose

Mode of administration

Duration of treatment

Statistical methods
Criteria for Pharmacokinetics added
Section to be changed
Flow 
chart
Description of change
A separate flow chart for Part 2 has been 
included.
Rationale for change
To reflect the procedures of the second part of 
this trial.
Section to be changed
Flow 
chart
Description of change
Flowcharts for collection of PK samples have 
been added.


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Section to be changed
Table of 
Contents
Description of change
Flow Charts added to TOC.
Section 11.4 added to reference Global 
Amendment 4.
Section to be changed
1.2.1.
Non-Clinical Studies
Description of change
Information about preclinical data has been 
updated.
Rationale for change
To reflect the latest status of information and 
align with current IB.
Section to be changed
1.2.2.
Clinical Experience in Humans
Description of change
Replace interim results from Phase 1 trials by 
final results.
Addition of information about interim results 
from ongoing trial 1407-0030.
Rationale for change
Provide most recent available information and 
align with current IB.
Section to be changed
1.3
Rationale for performing the trial
Description of change
Rationale for extending this trial by Part 2 
added.
Rationale for change
To provide justification for performing Part 2.
Section to be changed
1.4 
Benefit-Risk Assessment
Information on blood-volume to be collected 
during Part 2 added.
Information on new dose groups added.
Section to be changed
1.4
Benefit-Risk Assessment
Description of change
Information on DDI potential has been updated.
Rationale for change
To reflect the latest results from DDI trials.
Section to be changed
2.
Trial Objectives and Endpoints
Description of change
Objectives and endpoints for Parts 1 and 2 were 
specified.
Pharmacokinetic endpoints added for intensive 
PK subset.
Rationale for change
To provide clarification on objectives and 
endpoints.
Section to be changed
3.1
Overall Trial Design and Plan
Description of change
Information on Part 2 design added.
Rationale for change


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Section to be changed
3.2
Discussion of trial design
Section to be changed
3.3
Selection of trial population
Description of change
Information on Part 2 added
Rationale for change
To provide total number of new patients 
included in Part 2.
Section to be changed
3.3.3
Exclusion criteria
Description of change
Added exclusion of hepatic impairment for Part 
2.
Rationale for change
To exclude patients with higher grade hepatic 
impairment.
Section to be changed
4.1.2
Selection of doses in the Trial
Description of change
Justification of doses used in Part 2 added.
Section to be changed
4.1.3
Method of assigning patients to treatment 
groups
Description of change
Information on randomisation ratio of Part 2 
added.
In Part 2, patients will have to take their study 
medication with a meal.
Rationale for change
Food will increase the exposure to the 
study.drug.
Section to be changed
4.1.4
Drug assignment and administration
Description of change
Details about dose groups and dosing 
instructions for Part 2 added.
Rationale for change
In Part 2 higher doses will be used. Study drug 
will be taken either once or twice daily and 
with a meal.
Section to be changed
4.1.5
Blinding and procedures for unblinding
Description of change
Details added on DMC review of PK summary 
report for Part 2.
Rationale for change
To provide clarification on how PK information 
will be reviewed.
Section to be changed
4.2.2.1
Restrictions regarding concomitant treatment
Description of change
Table 4.2.2.1: 1 was updated.
Rationale for change
To reflect latest results from DDI studies and 
take into account the higher study drug doses 


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used in Part 2.
Section to be changed
4.2.2.2
Restrictions on diet and life-style
Description of change
Information added for Part 2.
Rationale for change
To remain consistent with all protocol 
amendment changes.
Section to be changed
5.2.3
Table 5.2.3: 1 Safety laboratory tests
Description of change
Removed requirement for patients to be fasted 
for blood sample collections.
Footnote added that a positive hep C antibody 
test should be confirmed by PCR.
Rationale for change
For clarification.
Section to be changed
5.3.1
Assessment of pharmcokinetics
Description of change
Information on pk assessments in Part 2 added.
Section to be changed
5.3.2
Method of pharmacokinetic sample collection
Description of change
Information on pk assessment in Part 2 added
Rationale for change
To clarify procedure requirements for PK 
assessment.
Section to be changed
5.6.1
Photography of skin lesions
Description of change
In Part 2, no photos will be taken.
Rationale for change
Sufficient number of photos have been 
collected in Part 1.
Section to be changed
6.1
Visit schedule
Description of change
Information added, that in Part 2 study 
medication should be taken with a meal.
Rationale for change
To find out about the influence of food on drug 
exposure.
Section to be changed
6.2.2
Treatment period 
Description of change
Information about taking medication in Part 2 
added.
Rationale for change
To clarify medication must be taken with a 
meal.
Section to be changed
6.2.3.2
Trial completion
Description of change
Information added, that patients who complete 
Part 2 will not be able to roll over into the long 
term extension trial.
Rationale for change
Currently, the LTE trial does not offer doses 
above 200 mg per day, so patients would have 
to reduce doses when rolling over.


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Section to be changed
7.
Statistical Methods and Determination of 
Sample Size
Description of change
Wording about statistical plans for Part 2 
added.
Section to be changed
8.6
Trial Milestones
Description of change
Wording added to reference Part 1 and Part 2.
Rationale for change
For clarification.
Section to be changed
Entire document
Description of change
Typos and formatting adapted according BI 
Style Guide.
Rationale for change
BI Style Guide.
Section to be changed
9.2
Unpublished References
Description of change
Reference DSUR s00083382-01 added
Rationale for change
11.5
GLOBAL AMENDMENT 5
Date of amendment
12 May 2020
EudraCT number
EU number
2017-004659-21
BI Trial number
1407-0030
BI Investigational Product(s)
BI 730357
Title of protocol
Phase II evaluation of safety, tolerability, and 
efficacy of BI 730357 in patients with 
moderate-to-severe plaque psoriasis
Global Amendment due to urgent safety reasons
Global Amendment
Yes 
Section to be changed
1.2.1
Non-Clinical Studies
Description of change
Information on gastritis finding in beagle dogs 
added.
Rationale for change
Include update information
Section to be changed
1.4
Benefit-Risk Assessment
Description of change
Added: “AE consistent with gastric
intolerance or gastritis are designated as AE of 
special interest (AESI).
Rationale for change
To provide background on why gastric AEs are 
added to AESIs.
Section to be changed
5.2.6.1
Assessment of Adverse Events
Description of change
AE consistent with gastric intolerance or 


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gastritis are designated as AE of special interest
Rationale for change
To ensure timely characterisation, monitoring 
and reporting of such effects.
11.6
GLOBAL AMENDMENT 6
Date of amendment
01 July 2020
EudraCT number
EU number
2017-004659-21
BI Trial number
1407-0030
BI Investigational Product(s)
BI 730357
Title of protocol
Phase II evaluation of safety, tolerability, and 
efficacy of BI 730357 in patients with 
moderate-to-severe plaque psoriasis
Global Amendment due to urgent safety reasons
Global Amendment
Yes 
Section to be changed
4.1.4
Drug assignment and administration
Description of change
Details on dosage regimen for Part 2 updated.
Rationale for change
To reflect changes to drug packaging for Part 2.
11.7
GLOBAL AMENDMENT 7
Date of amendment
24 August 2020
EudraCT number
EU number
2017-004659-21
BI Trial number
1407-0030
BI Investigational 
Product(s)
BI 730357
Title of protocol
Phase II evaluation of safety, tolerability, and 
efficacy of BI 730357 in patients with 
moderate-to-severe plaque psoriasis
Global Amendment due to urgent safety reasons
Global Amendment
Yes 
COMMENT: The main purpose of this amendment is to allow patients 
completing Part 2 to continue treatment in a long term extension trial.
Section to be changed
Synopsis
Main in- and exclusion criteria
Description of change
“and men able to father a child” was deleted 
from contraception requirement.
Rationale for change
To correct the discrepancy to the protocol body.
Section to be changed
FC Part 2
Flow Chart, Part 2
Description of change
An additional row and footnote was included to 
explain that patients completing the treatment 
period of this trial will be offered to roll over 


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into a long term extension trial (LTE).
Rationale for change
Section to be changed
PK FC
PK BLOOD SAMPLING FLOW CHART FOR 
INTENSIVE PK SUBSTUDY, PART 2
Description of change
Footnote added to explain that for patients 
continuing in the LTE the 48 hours and the 72 
hours sampling will be omitted.
Rationale for change
The 48 h and 72 h samples are meant for the 
assessment of the trial drug wash-out kinetics. 
They do not make sense, if the patient 
continues taking study medication.
Section to be changed
1.2.1 
Non Clinical Studies
Description of change
Section was updated
Rationale for change
To reflect the current state of knowledge and 
align with the latest version of the Investigators 
Brochure.
Section to be changed
1.2.2 
Clinical Experience in Humans
Description of change
Section was updated.
Rationale for change
To reflect the current status of clinical trials 
with BI 730357 and align with the latest 
version of the Investigators Brochure.
Section to be changed
4.1.2
Selection of Doses in the Trial
Description of change
Section was updated.
Rationale for change
To reflect the current state of knowledge and 
align with the latest version of the Investigators 
Brochure.
Section to be changed
6.2.3.2
Trial Completion
Description of change
Added: “In Part 2, patients may also be offered 
participation in the LTE, if they feel that they 
have benefited from the trial treatment.“
Rationale for change
In Part 1, both investigators and patients 
frequently asked if continuation in the LTE was 
possible, even though the objective threshold of 
50% PASI improvement had not been achieved. 
They stated that symptoms, which are not 
captured by PASI (e.g. itching) and subjective 
wellbeing had improved. In addition, Part 1 
results indicate that 12 week treatment may not 
achieve maximal response and further 
improvement may be seen after extended 
treatment with the study drug.


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Section to be changed
9.1
References
Description of change
Reference R11-1259 was deleted. New 
reference added. P20-07441.
Rationale for change
To reflect the current state of knowledge and 
align with the latest version of the Investigators 
Brochure.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c20414608
8.0
clinical-trial-protocol-version-08
Phase II evaluation of safety, tolerability, and efficacy of BI 730357 in patients with
moderate-to-severe plaque psoriasis
Author-Clinical Trial Leader
25 Aug 2020 13:06 CEST
Approval-Clinical Pharmacokinetics
25 Aug 2020 15:22 CEST
Approval-Biostatistics
26 Aug 2020 17:33 CEST
Approval-
 Medicine
28 Aug 2020 10:23 CEST
Approval-Team Member Medicine
03 Sep 2020 16:17 CEST
Verification-Paper Signature
Completion
03 Sep 2020 20:14 CEST


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(Continued) Signatures (obtained electronically) 
 
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c25658163-02
BI Trial No.:
1407-0030
Title:
Phase II evaluation of safety, tolerability, and efficacy of BI 730357 
in patients with moderate-to-severe plaque psoriasis
BI Investigational
Product(s):
  BI 730357
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
06 SEPT 2019 SIGNED 
Version:
Final
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINTS.....................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoints......................................................................................8
5.2.2
Secondary endpoints.............................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................10
6.1
TREATMENTS...................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATION......................................................11
6.3
SUBJECT SETS ANALYSED...........................................................................13
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.6.1
Efficacy data........................................................................................................15
6.6.2
Safety data and other data .................................................................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........19
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................19
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINTS...................................................................................20
7.4.1 
Primary Analysis.................................................................................................20
7.4.2 
Secondary analyses .............................................................................................21
7.5
SECONDARY ENDPOINTS.............................................................................22
7.5.1
Key secondary endpoints....................................................................................22
7.5.2
(Other) Secondary endpoints.............................................................................22


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7.7
EXTENT OF EXPOSURE.................................................................................26
7.8
SAFETY ANALYSIS..........................................................................................26
7.8.1
Adverse events.....................................................................................................26
7.8.2
Laboratory data ..................................................................................................28
7.8.3
Vital signs.............................................................................................................29
7.8.4
ECG......................................................................................................................30
7.8.5
Others...................................................................................................................30
8.
REFERENCES....................................................................................................31
10.
HISTORY TABLE..............................................................................................34


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LIST OF TABLES
Table 6.1: 1
Definition of treatment periods.........................................................................10
Table 6.2: 1
Important protocol deviations...........................................................................11
Table 6.7: 1
Time windows for assignment of on-treatment efficacy, safety lab, vital 
signs, and biomarker measurements to visits for statistical analysis................17
Table 7.4: 1
MCPMod contrast coefficient (design stage) ...................................................21
Table 7.8.1: 1 Other special groupings of adverse events .......................................................27
Table 10: 1
History table .....................................................................................................34


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP
Term
Definition / description
AE
Adverse Event
BRPM
Blinded Report Planning Meeting
BES
Biopsy Evaluable Set
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DM&SM
Boehringer Ingelheim Data Management And Statistics Manual
DRA
Drug Regulatory Affairs
DMG
Dictionary Maintenance Group
EDC
Electronic Data Capture
EMEA
European Agency For The Evaluation Of Medicinal Products
FAS
Full Analysis Set
ICH
International Conference On Harmonisation
IPD
Important Protocol Deviation
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary For Regulatory Activities
MCPMod
Multiple Comparison Procedure and Modelling
MQRM
Medical Quality Review Meeting
MMRM
Mixed Effect Model Repeated Measurement
PASI
Psoriasis Area Severity Index
PK
Pharmacokinetics
PKS
Pharmacokinetics Set
PPS
Per Protocol Set
PSTAT
Project Statistician
PT
Preferred Term
PV
Protocol Violation
Q1
Lower Quartile
Q3
Upper Quartile
REP
Residual Effect Period


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Term
Definition / description
SA
Statistical Analysis
SD
Standard Deviation
SMQ
Standardised MedDRA Query
SOC
System Organ Class
sPGA
Static Physician’s Global Assessment
TOM
Trial Oversight Meeting
ToC
Table of Contents
TS
Treated Set
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.
The trial data is stored in the BI Rave (BRAVE) database system.
SAS® Version 9.4 will be used for analyses.
R version 3.3.2 or later with “DoseFinding” package (9) will be used for MCPMod analysis.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The co-primary endpoints are:

Achievement of ≥75% reduction from baseline PASI score (PASI 75) at Week 12

Achievement of a sPGA score 0 or 1 at Week 12
The co-primary endpoints are the proportion of patients achieving PASI 75 and sPGA 0/1 at 
Week 12 by treatment group.
Details for scoring Psoriasis Area and Severity Index (PASI) and static Physician Global 
Assessment (sPGA) are described in Section 10.1 and 10.2 of the CTP. 
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol
5.2.2
Secondary endpoints

Achievement of ≥50% reduction from baseline in PASI score (PASI 50) at Week 12 

Achievement of ≥90% reduction from baseline in PASI score (PASI 90) at Week 12 

Achievement of 100% reduction from baseline in PASI score (PASI 100) at Week 12

Achievement of sPGA score 0 at Week 12

Achievement of ≥75% reduction from baseline in PASI score (PASI 75) at Week 16, 
20, 24

Achievement of an sPGA score 0 or 1 at Weeks 16, 20, and 24 

Change from baseline in psoriasis symptoms evaluated using the total score on the 
Psoriasis Symptoms Scale (PSS) at Week 12 

Achievement of a Dermatology Life Quality Index (DLQI) score of 0 or 1 at Week 12 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Patients will be randomised 2:2:2:2:1 to one of 4 BI 730357 treatment groups A to E, of
which A will receive the lowest and D the highest dose of BI 730357; treatment group E will
receive placebo.
At Week 12, patients will remain in their treatment group or be reassigned depending on the 
primary efficacy endpoint result:

Non-responders will be reassigned to the next higher dose level or to the highest dose 
level based on the original treatment assignment at randomization.

Placebo recipients (group E) who achieve a PASI 75 response will remain on placebo 
through Week 24. Otherwise, they will be assigned with the highest dose level starting 
from Week 12. 

200 mg recipients will not be titrated at week 12.
For example, patients from dose groups A to C who fail to achieve a PASI 50 response will 
be switched to the next higher respective dose. Patients who have achieved a PASI 50 
response will continue on their initial dose of BI 730357. Patients from dose group D will 
remain on the dose group D through Week 24.
Patients will be analyzed according to the treatment to which they were randomized. The 
following study periods based on actual start and stop dates of study treatment administration 
are defined: 
Table 6.1: 1
Definition of treatment periods
Analysing Treatment 
Period
Start Date (including)
Stop Date (excluding)
Screening
Date of informed consent
Date of medication 
randomization -1 day
On-treatment period
Date of medication 
randomization
Date of last study 
medication intake + 7 days
Follow-up
Date of last study medication 
intake +8 days
Last contact date
For the main safety analyses, Adverse Events (AEs) will be classified to one of the following 
time periods: “screening”, “on-treatment”, or “follow-up”. Section 7.3.4 of the protocol 
specifies that, all AEs and laboratory assessments 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 for this trial, will be assigned to the “on-treatment” period for evaluation.
Detailed rules for assigning AEs to these time periods are listed below:

If date of informed consent ≤AE onset date and <date of first drug administration, then 
the AE is assigned to “screening”


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
If date of first drug administration ≤AE onset date ≤date of last intake +7 days, then 
the AE is assigned to “on-treatment”

If AE onset date > date of last drug administration+7 days, then the AE is assigned to 
“follow-up”
AE will be reported for first and second 12 weeks separately. If an AE onsets on the day of 
week 12 visit, actual time of AE and time of drug administration on week 12 visit will be 
compared to determine under which period such AE will be reported.
6.2
IMPORTANT PROTOCOL DEVIATION
A protocol deviation (PD) is important if it affects the rights or safety of the study subjects, or 
if it can potentially influence the primary outcome measurement(s) in a non-negligible way. 
Patients with important PDs that could potentially impact the evaluation of the primary 
endpoint(s) will be excluded from PPS, if applicable).
A list of important PDs (IPDs) is given in Table 6.2: 1. Important PDs will be reviewed at 
Medical Quality Review Meetings (MQRMs) conducted periodically during the trial. A list of 
protocol deviation will be discussed at the Blinded Report Planning Meetings (BRPMs).
If the data show other important PDs, this table will be supplemented accordingly at BRPMs 
or through team review of the manual PD log. The decision whether a subject will be 
excluded from the analysis will be made at the final BRPM prior to Database Lock (DBL).
Table 6.2: 1
Important protocol deviations
Category / 
Code
Description
Requirements
Excluded from
(if applicable)
Automatic/
Manual
A
A1
Entrance criteria not met
Inclusion criteria not met 
as specified in the protocol
A1.1
Demographic or pregnancy 
testing inclusion criterion
not met
Inclusion criteria 1,2,3 not 
met
None
Automatic
A1.2
Psoriasis inclusion criterion 
not met
Inclusion criteria 4 not met
PPS
Automatic
A1.3
Patient does not meet
the specified moderate to 
severe plaque-type psoriasis
Inclusion criteria 5 not met
PPS
Automatic 
and Manual
A2
Exclusion criteria not met
Exclusion criteria not met 
as specified in the protocol
A 2.1
Patient has active/past 
clinically important 
diseases, has significant 
laboratory values, or 
pregnancy-related
exclusion criteria met
Exclusion criteria 1, 
9,10,11,12,13 not met
None
Automatic 
A 2.2
Patient has participated in
another clinical trial
within 30 days before
the randomization or 
previously enrolled in trial
Exclusion criteria 2,3 not 
met
PPS
Automatic
and Manual


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Table 6.2: 1 (Cont’d) Important protocol deviations 
Category / 
Code
Description
Requirements
Excluded from
(if applicable)
Automatic/
Manual
A 2.3
Patient has not sufficient 
wait time since last intake 
of restricted medication or 
must or wish to continue the 
intake of restricted 
medications
Exclusion criteria 4,6 not 
met
PPS 
Automatic 
and Manual
A 2.4
Patient has received
a live vaccine
Exclusion criteria 5 not 
met
None
Automatic/
Manual
A 2.5
Patient has chronic 
alcohol/drug abuse 
Exclusion criteria 8 not 
met
None
Automatic
A 2.6
Patient has suicidal ideation
Exclusion criteria 14 not 
met
None
Automatic
B
Informed consent
B1
Informed consent missing
Informed consent not 
available/not done
All
B2
Date of informed consent 
was after the date of any 
study related procedure, or 
the patient signed the wrong 
version of ICF
Informed consent late
PPS if ICF after 
procedure (A). 
None if wrong 
version. (M)
Automatic 
and Manual
C
Trial medication and 
randomisation
C1.1
Incorrect trial medication 
taken prior to week 12 
Medication kit assigned 
not matching treatment 
patient was randomised to 
(cross-treatment1) and/or 
not matching IVRS 
assignment
PPS
Automatic 
and manual
C1.2
Incorrect trial medication 
taken after week 12
Medication kit assigned 
not matching treatment 
patient was randomised to 
(cross-treatment1) and/or 
not matching IVRS 
assignment
None
Automatic 
and manual
C2
Non-compliance
Overall compliance <80% 
or >120%
Non-compliance caused by 
treatment cessation due to 
a cardiovascular procedure 
should not be classified as 
a protocol violation.
PPS
Automatic
C3
PASI score entered in IRT 
entry error at week 12
PASI score entered in IRT 
not the same as entered in 
CRF page at 
randomization and week 
12
None
Automatic 
and Manual


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Table 6.2: 1 (Cont’d) Important protocol deviations 
Category / 
Code
Description
Requirements
Excluded from
(if applicable)
Automatic/
Manual
C4
Medication code broken 
inappropriately
Medication code broken 
inappropriately - reason for 
medication code break 
None
D
Concomitant medication
D 1.1
Prohibited medication use 
potential impact patient 
safety2 in first 12 weeks
Prohibited medication used 
may impact patient safety 
profile in first 12 weeks of 
treatment
None
Manual
D 1.2
Prohibited medication use 
potential impact patient 
safety2 in second 12 weeks 
Prohibited medication used 
may impact patient safety 
profile in second 12 weeks 
of treatment
None
Manual
D 1.3
Prohibited medication use 
potential impact patient 
efficacy3 in first 12 weeks
Prohibited medication used 
may impact patient efficacy 
profile in first 12 weeks of 
treatment
PPS
Manual
D 1.4
Prohibited medication use 
potential impact patient 
efficacy3 in second 12 weeks
Prohibited medication used 
may impact patient efficacy 
profile in second 12 weeks 
of treatment
None
Manual
E
Study Specific
E 1
Dispense expired drug
None
1 cross-treatment means actual treatment received is different from randomized or IRT assigned treatment type.
2 Prohibited medication use potential impact patient safety are manually reviewed in MQRM or TOM. Decision 
are documented in related meeting minutes and final BRPM minutes.
3 Prohibited medication use potential impact patient efficacy includes all pre-treatment PsO therapy not meet 
washout period or concomitant use during study conduct specificied in CTP table 4.2.2.1:1.
6.3
SUBJECT SETS ANALYSED
There are five patient sets defined in this trial:

Randomised Set (RS)
The RS includes all patients who signed the informed consent form and were also 
randomised, regardless whether the patient was treated with trial medication or not.

Treated Set (TS)
The TS includes all patients in the RS who received at least 1 dose of trial medication and 
is based on the actual treatment received at randomization visit and week 12 visit, if 
applicable.

Full Analysis Set (FAS)
The FAS includes all patients in the RS who received at least 1 dose of trial medication 
and provided baseline and at least 1 post-randomisation measurement of PASI. 

Per Protocol Set (PPS)
The PPS, a subset of FAS, includes all patients who did not have an IPD affecting the 
primary efficacy endpoint or patients safety (see Table 6.2: 1 for details).


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Patient disposition will be based on randomized set. 
The FAS will be used for the analyses of demographics, baseline characteristics and all 
efficacy endpoints. The efficacy analyses will follow the intention-to-treat (ITT) principle in 
assigning patients to treatment groups, i.e., efficacy analyses will be analysed as randomised 
using the FAS. 
The TS will be used for the analyses of concomitant medication use, medical history, PsO
therapy history, treatment exposure, compliance, and safety (including adverse events, 
laboratory measurements, vital signs, and ECG). Safety analyses will assign patients to the 
treatment group based on the actual treatment received. 
PPS for sensitivity analysis will be considered if necessary. Decision will be documented in 
BRPM minutes.
If a patient erroneously receives the wrong dose of trial drug, the patient’s efficacy data will 
be analysed in the randomized treatment group and the patient’s safety data will be analysed 
in the actual treatment group. If a patient receives placebo instead of  randomized BI730357 
study medication, this will be noted as an IPD.


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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
General imputation rules for continuous and binary endpoints are described in protocol 
section 7.5. 
Missing data imputations at the interim analysis at completion of both week 4 and week 12, 
will be performed using all available on-treatment data observed up to the respective analysis 
cut-off date.
6.6.1
Efficacy data
If at any time a patient uses an inappropriate concomitant medication, then all future data will 
be treated as failure for binary variables and LOCF (using the last on-treatment observation 
prior to inappropriate concomitant medication use) for continuous variables. As part of the 
LOCF technique, baseline values will be carried forward if no post-baseline value is available.
If a patient is missing items from a questionnaire measured at a visit, these will be handled 
according to the instructions given in Section 10.11 of the protocol specific to each 
questionnaire.
For the NAPSI, PSSI, and PPASI assessment, if the CRF is marked as “No” indicating that 
the patient does not have nail, scalp, palmo-plantar disease, then the total score will be set as 
zero (0) for that assessment in the analysis dataset.
For efficacy endpoints which are continuous in nature, a restricted maximum likelihood 
(REML)-based mixed model repeated measures (MMRM) approach will be used for 
inferential analysis, if applicable. No imputation will be performed for data used in MMRM.


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6.6.2
Safety data and other data
In general, missing data will not be imputed and only observed values will be analyzed. 
Missing or incomplete AE dates will be imputed according to BI standards (see DM&SM) 
“Handling of missing and incomplete AE dates”). (1)
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For efficacy endpoints, baseline is defined as the pre-treatment observation at Visit 2. If Visit 
2 is missing, then Visit 1 will be used for baseline.
For laboratory safety measurements, the last measurements taken prior to the treatment start 
will be considered as baseline.
In general, measurements reported with a date only (and no time) and taken on the day of first 
administration of trial treatment will also be considered pre-treatment values.
The visit schedule with accompanying details can be found in Flow Chart 1. Measurements 
taken after start of treatment will be considered either on- or off-treatment values based on 
definition in Table 6.1: 1.
On-treatment measurements for EOT and EOS visit for early discontinued patients will be 
allocated to visits by means of time windows with the limit between adjacent windows half-
way between the planned dates for the visits; the middle day is counted to the window of the 
later visit. Mutually exclusive relative day windows are defined below to provide derived 
visits that correspond to the post-baseline time points. For example, Visit 6 is planned on Day 
29 and Visit 7 is planned on Day 57. Therefore, the window of Visit 6 reaches until Day 42 
while the window of Visit 7 starts on Day 43. The visit schedule with corresponding windows 
is given in Table 6.7: 1.


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Table 6.7: 1
Time windows for assignment of on-treatment efficacy, safety lab, vital signs, 
and biomarker measurements to visits for statistical analysis
Window No.
Window label
Nominal visit
Nominal day
Interval
0
Baseline
VISIT 2
1
N/A
1
Week 1
VISIT 3
4
[2,4]
2
Week 1
VISIT 4
8
[5,11]
3
Week 2
VISIT 5
15
[12,21]
4
Week 4
VISIT 6
29
[22,42]
5
Week 8
VISIT 7
57
[43,70]
6
Week 12
VISIT 8
85
[71,98]
7
Week 16
VISIT 9
113
[99,126]
8
Week 20
VISIT 10
141
[127,154]
9
Week 24
EOT
169
[155,182]
10
Week 28
EOS
197
[183,∞]
If there are multiple values for an efficacy endpoint in one window (visit), use the one from 
scheduled visit. If value from scheduled visit is not present, the visit closest to the nominal 
day will be selected for assessing endpoints at a particular visit and for by-visit displays. If the 
visits are equidistant from the nominal day, then the earlier visit will be selected. All 
measured values will be stored in analysis datasets. 
The same visit windows will be used for safety laboratory and vital sign assessments. If there 
are multiple safety or laboratory values in one time window on treatment, the worst value will 
be selected for the by-visit analyses.
Analysis of AE data, concomitant medication or non-drug therapies, as well as use of rescue 
medication will not be based on visits. Frequency tables for these data will be using on-
treatment data only. Therefore, no assignment to time windows will be necessary for such 
data.
While the nominal times listed in this section should be adhered to as closely as possible, the 
actual sampling times will be recorded and used for determination of pharmacokinetic 
parameters.
For visits without an assigned value based on time windows, a value will thereafter be 
imputed as defined in Section 6.6. LOCF imputation of efficacy endpoints, when applicable, 
will be performed based on all available observations obtained during the on-treatment period, 
irrespective of whether the observation was selected in any time window.


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7.
PLANNED ANALYSIS
According to CTP Section 7.4, there are two interim analyses planned for this study. 
1)
An administrative interim analysis for the purpose of internal planning other 
indications of BI 730357 will be performed when the last patient completes the 4 
week follow-up visit
a.
Output will comprise only baseline summaries, key efficacy endpoints( i.e. 
PASI, sPGA) and key adverse events tables
b. No separate report is planned to be written for this analysis
2)
The interim for the primary analysis (at an interim time point) will be performed 
when the last patient completes the 12 week follow-up visit
For each interim analysis, the trial team will perform a blinded analysis and an independent 
team will perform unblinded analyses. In order to support the further double-blinded conduct 
of the trial until the week 24 visit, the trial team are kept blinded on the individual patients’ 
treatment group assignment. Details of each interim analysis are specified in the trial interim 
analysis logistic and access plan for week 4 and week 12 separately.
The analysis of the entire efficacy, safety, and biomarker data collected through the full 28 
weeks of follow-up will be performed once all entered patients have completed the trial (up to
EOT/Week 28 Visit); at that time point, a final database lock will be done and all on-
treatment data through week 28 will be reported.
General remarks:
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of clinical trials and project summaries” (6).
For EoT tables, the set of summary statistics is: N / Mean / SD / Min / Median / Max.
For appendix tables, the set of summary statistics is: N / Mean / SD / Min / Q1 (lower
quartile) / Median / Q3 (upper quartile) / Max.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
“missing” will be displayed only if there are actually missing values. Percentages will be 
based on all patients in the respective patient set no matter whether they have non-missing 
values or not.
Planned treatment for first 12 weeks of treatment is defined as treatment patient assigned from 
IVRS at randomization visit (visit2). Planned treatment for second 12 weeks of treatment is 
defined as the treatment patient assigned from IVRS at week 12 visit (V8).
Subject data listings of data used in the analyses (i.e. demographic and baseline characteristics 
and key efficacy endpoints) will also be provided and included in Appendix 16.2 of the CTR.


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Disposition of the patient population participating in the trial will be summarised by 
presentation of the frequency of patients screened, entered, screened but not entered, treated, 
entered but not treated. Within treated patients, data will be summarized by treatment periods 
(period 1 - first 12 weeks of treatment and period 2 – second 12 weeks of treatment) for 
treatment ongoing patients, patients complete planned treatment period and patients who are 
prematurely discontinued, by reason. Disposition will be listed by country.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Demographic parameters 
collected and to be presented include, but are not limited to, the following:

Gender (Male, Female)

Race and ethnicity (as defined in the eCRF)

Age [years]

Height [cm]

Weight [kg] (continuous)

Weight Group (>100kg vs. < 100 kg)

Body mass index [kg/m2] (defined as weight [kg]/(height [cm]/100)2)

Body mass index [kg/m2] (>30 vs. <30)

Smoking history (Never-smoked, Ex-smoker, Currently smokes)

Alcohol History (Non-drinker, drinks – no interference, drinks – possible interference)

Region

PsA history (diagnosed, suspected, no PsA)

Prior biologic use for psoriasis (Yes/No)
Baseline disease characteristic to be presented include, but are not limited to, the following: 

BSA (Visit 1)

PASI score

sPGA

NAPSI, PPASI, PSSI

Pain VAS

PSS total score

DLQI
For NAPSI, PPASI, PSSI and pain-VAS, report is only based on patients are applicable to the 
measurement per protocol, e.g. pain VAS only for patients with psoriatic arthritis.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
A table of the number (%) of patients with concomitant diagnoses from baseline condition by 
system organ class (SOC) and preferred term (PT) will be included along with a supporting 
listing. Concomitant diagnoses will be coded with the most recent version of MedDRA in 
effect at database lock.


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Concomitant medication will be described as a table of number (%) of patients with on-
treatment medication use. On-treatment is defined as medication with a stop date after or on 
the day of first trial drug intake and before last trial drug intake + 7 days.
Number (%) of patients with psoriasis therapy history will be summarized, including both 
non-topical drug therapy and non-drug therapy.
7.3
TREATMENT COMPLIANCE
Treatment compliance will be reported from baseline to Week 24 based on calculation as 
described in CTP section 4.3. Only descriptive statistics are planned for this section of the 
report. Treatment non-compliance is defined as any randomized patients having taken at least 
one dose of study medication with an overall compliance rate not between 80% and 120% 
inclusive. Overall compliance is calculated based on unweighted average of study drug 
compliance rate at each visit during the treatment period. For the patients who discontinued 
the study treatment prematurely only the visits on or before premature discontinuation will be 
used for the calculation of overall compliance.
Only descriptive statistics are planned for this section of the report. Summary statistics of 
compliance in the treated set will be given for the number of subjects as well as the 
corresponding percentage with compliance in the categories <80%, 80% - 120%, >120%, 
missing.
7.4
PRIMARY ENDPOINTS
7.4.1 
Primary Analysis
After the last patient reaches Week 12, the primary analyses of the primary endpoints will be 
performed in all randomized patients who receive at least one dose of treatment based on 
randomised treatment (FAS) using the Multiple Comparison Procedures and Modelling 
(MCP-Mod) approach (7, 8). 
First, the response rate for co-primary endpoints at week 12 of each dose group will be 
estimated using a logistic regression model. The model will include the fixed effect of 
treatment (categorical dose) and baseline PASI score as covariate. SAS procedure “proc 
logistic” will be used to fit the logistic regression model. 
	
 =  + 
i ~  subject, j ~  treatment

= the response variable for primary endpoints

= the baseline measurement of subject i (=1,2,…)

= coefficient of baseline effect

= the effect of treatment j (= 1, ..,Y)
The adjusted mean estimates of response at logit scale for each dose groups, as well as the 
estimated variance-covariance matrix will then be analysed using MCPMod for dose-response 
analysis. 


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The multiple comparison procedure will be implemented using of optimal contrast tests which 
control the family-wise type I error rate at one-sided α = 0.05. The optimal contrasts 
corresponding to the candidate models are calculated as in the trial design stage and shown in 
Table 7.4:1. The actual analysis contrast coefficients will be based on using the estimated 
variance-covariance matrix from the data.
Table 7.4: 1
MCPMod contrast coefficient (design stage)
Contract coefficients for dose
Model
0
25 mg
50 mg
100 mg
200 mg
Linear
-0.179
-0.350
-0.301
-0.037
0.868
Emax1
-0.248
-0.467
-0.272
0.214
0.774
Emax2
-0.553
-0.458
0.048
0.388
0.575
Logistic
-0.210
-0.429
-0.403
0.341
0.702
Exponential model
-0.133
-0.264
-0.261
-0.231
0.889
If at least one dose-response model is statistically significant, rejecting the null hypothesis of 
a flat dose-response curve indicates a benefit of BI 730357 over placebo. Test statistics and p-
values will be displayed for different dose response models.
Once the significance of a dose-response signal is established, the selected dose-response 
model(s) will be re-fitted to the data without any parameter assumptions to generate a set of 
new estimates of the model parameters from the data. The final dose-response model will be 
estimated by averaging significant model(s) based on their Akaike Information Criterion 
(AIC) (the smaller the AIC value the better model fit). Fitted response rate and difference to 
placebo for all investigated dose-response models will be tabulated at each dose along with 
logistic regression estimate and the weighted AIC estimate.
Fitted dose-response curve(s) for significant model(s) will be graphically presented with 95% 
confidence band across investigated dose range (0 to 200mg).
The adjusted mean estimates from the logistic regression and fitted MCPMod estimates of 
response rate are both on the logit scale. The absolute and difference in proportions will be 
calculated by transforming the estimate back to the probability scale. More details please refer 
to Section 9.4.
7.4.2 
Secondary analyses
For both co-primary endpoints, the point estimate and two-sided 90% and 95% exact
confidence intervals for proportion of responder will be displayed for each treatment group. 
The unadjusted absolute difference in proportion between active groups and placebo group 
regarding the co-primary endpoints will be estimated with 90% and 95% Pearson-Clopper 


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exact confidence intervals and p-value calculated by Chi-square test. This is considered the 
secondary analysis for the primary endpoint(s). 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoints
If considered necessary, a MCPMod approach will also be applied to selected secondary 
endpoints.

PASI 75 at week 16
The same methods as discussed for the secondary analysis for the primary endpoint will be 
used to analyse clinical binary secondary and further endpoints for each treatment group as 
well as treatment comparison.
For the convenience of writing and reviewing, all PASI and sPGA endpoints at different time 
points (secondary and further clinical endpoints) are described in this section.
For the analysis of binary efficacy endpoints after week 12 based on non-responder 
imputation, patients switch treatment at week 12 will be imputed as failure for records after 
week 12, under original randomized treatment arm. 
Psoriasis Area and Severity Index (PASI)
Treatment comparison for unadjusted absolute difference in proportion between active groups 
and placebo group will be performed for achievement of 50% (PASI50), 75% (PASI75), 
100% (PASI 100) at week 12 and 75% (PASI 75) at Week 16, 20 and 24.
Descriptive statistics of total PASI score and PASI total score change from baseline, PASI 
total score percentage change from baseline and the percentage of patients who achieve a 
PASI score of at least 50% (PASI 50), 75% (PASI 75), 90% (PASI90) and 100% (PASI100) 
reductions from baseline will be tabulated by treatment over time. Additionally, these will be 
graphically represented by line plots over time.


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Static Physician's Global Assessment (sPGA)
The sPGA is scored using the following levels of assessment:
0 - clear 1 - almost clear 2 - mild 3 - moderate 4 - marked 5 - severe
Details for scoring sPGA and its components are described in Section 10.2 of the CTP.
Treatment comparison for unadjusted absolute difference in proportion between active groups 
and placebo group will be performed for sPGA equals to 0 at week 12 and sPGA clear or 
almost clear at week 12, 16, 20 and 24.
The number and proportion of patients who achieve a sPGA score of 1 (clear) or 2(almost 
clear) over time will be tabulated for each treatment group. 
Additionally, the proportion of patients shifting from their baseline sPGA values to different 
values over time will be tabulated for each treatment group.
PSS total score change from baseline at week 12
For change from baseline in PSS total score at Week 12 and treatment comparison, a 
restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) 
approach will be used. The analyses will include the fixed, categorical effects of treatment, 
visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline 
PSS total score and baseline PASI score-by-visit interaction. Patient will be considered as a 
random effect.  An unstructured covariance structure for within subject variation will be used.
The number and proportion of patients who PSS total score 0 over time will be tabulated for 
each treatment group. 
Additionally, the proportions of patients shifting from their baseline PSS values to different 
values over time will be tabulated for each treatment group for each individual domain (pain, 
redness, itching, burning).
DLQI score of 0 or 1 at week 12
Achievement of a Dermatology Life Quality Index (DLQI) score of 0 or 1 at week 12 will 
analysed by treatment comparison of unadjusted absolute difference in proportion between 
active groups and placebo group with 90% and 95% exact confidence intervals. This is 
considered the secondary analysis for the primary endpoint(s).
For DLQI, if one question is left unanswered this is scored 0 and the total score is summed 
and expressed as usual out of a maximum of 30;


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7.7
EXTENT OF EXPOSURE
Exposure will be presented as categorized period of “1-28”, “29-56”, “57-84” and 
“>85” days based on dose received for total study medication intake. Exposure will be 
summarized and presented separately for first 12 weeks and second 12 weeks of 
treatment. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
7.8.1
Adverse events
The analyses of adverse events will be descriptive in nature. All analyses of AEs will be based 
on the number of patients with AEs (not the number of AEs).
Multiple overlapping or adjacent recordings (AE occurrences) of the same AE are collapsed 
into one AE event if all AE attributes are identical as defined in (3, 4).
Two AE occurrences are considered to be time-overlapping if the start date of the second, 
later occurrence is earlier or equal to the end date of the first occurrence.
Two AE occurrences are considered to be time-adjacent if the start date of the second, later 
occurrence is one day later than the end date of the first occurrence. The default definition for 
the gap of one day may be changed on the project level.


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If multiple overlapping (AE occurrences) of the same AE have different attributes, the AEs 
will be queried to confirm whether they are in fact one occurrence or to correct the end date of 
the first occurrence to match the start date of the second occurrence.
After this process of collapsing the events to remove duplication and clarify any 
inconsistencies, the resulting data will form the basis for all reporting of AEs in the listings, 
tables, and figures.
For further details on summarization of AE data, please refer to the guideline 'Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries' (3, 4).
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug administration and 
within 7 days of last drug administration will be assigned to the assigned treatment. All 
adverse events occurring before first drug intake will be assigned to ‘screening’.
The severity of AEs will be summarised by the maximum intensity of the events each patient had 
(as indicated by the recorded RCTC version 2 grade). This will show the number and percent of 
patients who had at most mild, moderate, severe, and life threatening events. Severe adverse 
event is defined as an AE with RCTC grade equals to 3 (severe) or 4 (life threatening).
Groupings of adverse events and adverse events of special interest (AESI)
The AESI have been defined in the protocols as hepatic injury defined by the following 
alterations of liver parameters:

For patients with normal liver function at Baseline: 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.
See Section 7.3.2 for a description of the assessment of potential Hy’s Law cases.
Other user-defined special adverse event grouped term for BI 730357 specified in Table 
7.8.1:1 will be reported.
Table 7.8.1: 1 Other special groupings of adverse events
N
AESI
Term
Definition#
1
Yes
Drug Induced 
Liver Injury* 
SMQ Drug related hepatic disorders –
comprehensive search (20000006)
2
Yes
Opportunistic 
infections*
BIcMQ “Opportunistic infections” BIcMQ 
(30000108)
3
Yes
Tuberculosis*
BIcMQ “Tuberculosis” BIcMQ (30000107)
4
Yes
Severe 
infections*
SOC “Infections and infestations” with CRF 
grade >=3


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Table 7.8.1:1
Other special groupings of adverse events
5
No
Cardiovascular, 
Cerebrovascular, 
events (including 
MACE)

SOC ‘cardiac disorders’ (fatal cases only)

SOC ‘vascular disorders’ (fatal cases only)

SMQ Myocardial Infarction (20000047)

SMQ Haemorrhagic central nervous 
system vascular conditions (20000064)

SMQ Ischaemic central nervous system 
vascular conditions (20000063)
PTs: cardiac death, sudden cardiac death, 
sudden death
*: adverse event of special interest (AESI). AESI will be collected according to eCRF
The following periods will be defined for assessing adverse events:

First 12 weeks of treatment

Second 12 weeks of treatment
For AE occurs on day of week 12 visit, actual AE onset time will be compared with first drug 
administration time to determine AE period. The treatment label for second 12 weeks will be 
a combination of actual treatment in first 12 weeks of treatment and second 12 weeks of 
treatment.  
AE summaries
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarized by treatment, primary system organ class and preferred 
term according to MedDRA. Separate tables will be provided for patients with:

Drug-related AEs

AESIs

AEs leading to discontinuation

Serious AEs

Severe AEs (RCTC grade 3 or 4)

Investigator defined drug related SAE

Other significant AEs 

AE by worst RCTC intensity

Investigator defined drug-related serious AEs

Special AE grouped term
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards.  For lab descriptive, two separate tables for first 12 weeks of treatment and entire 
study period will be provided. For the entire period table, a new treatment label for each 
patient: start with treatment received at randomization and be updated if the patient have 
switched the treatment during the course of trial (by concatenating the second treatment after 
the first treatment) will be derived.


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The number and percent of patients with possibly clinically significant on-treatment
abnormalities as identified by use of clinically significant ranges for each laboratory
parameter collected will be presented. The patients with possibly clinically significant
abnormalities will be identified within the initial on-treatment period by study treatment.
Each laboratory value will be graded using the RCTC (version 2.0) grading of laboratory 
abnormalities. A summary table of the Baseline grade compared with the last available on-
treatment grade will display the number and percent of each type of transition in grade by
laboratory parameter within each treatment period, and treatment group. A second table will 
show the number and percent of patients with each type of transition from Baseline to their 
worst on-treatment grade parameter within each treatment period, and treatment group. For 
these shift tables, only the double blind period will be considered. Parameters using
categorised values, such as the urinalysis parameters, will show the shift table among those 
values in a similar manner to the RCTC graded values. Last and worst value will be 
considered with respect to each period. For example, if patient have entered the second 12 
weeks of treatment, then the last value for first 12 weeks table is considered as the last value 
measured before week 12 reassignment.
A graphical summary highlighting potential cases of Hy’s Law within each treatment
group will be presented. The maximum on-treatment values of total bilirubin and ALT 
will be plotted each on a scale as multiples of the upper limit of normal. The figure will
show areas that meet the criteria of cholestasis (total bilirubin > 2x ULN), Temple’s 
corollary (ALT > 3 x ULN) and Hy’s Law as the combination of these two factors. A 
similar figure using maximum AST values in place of ALT will be constructed. An 
accompanying listing will show by sample date and study day the full course of the total 
bilirubin, ALT, AST and alkaline phosphatase values for patients whose total bilirubin 
are > 2xULN or AST or ALT values > 3 x ULN at any time during the study (all
treatment periods). The listing will indicate where the value meets the criteria, either
falling in the cholestasis range, that for Temple’s corollary or where the combination 
meets that for Hy’s Law itself.
Laboratory measurements taken up to the residual effect period of 7 days after the last 
administration of randomized study drug will be considered as on-treatment.
Study visits will be presented by the Visit labels in Table 6.7.1.
7.8.3
Vital signs
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(see DM&SM: Display and Analysis of Laboratory Data) (5).
Listing and descriptive statistics of laboratory values over time as well as median and 
interquartile range (IQR) of changes between baseline and extreme abnormal value on 
treatment will be provided. Baseline is understood as the last available measurement before 
study drug administration. Extreme abnormal value on treatment is understood as the on 
treatment laboratory value which is most significantly away from the reference range.


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Frequency of patients with transitions relative to reference range and listing of patients with 
significant abnormal laboratory values will be presented as well.
In cases of repeated measurements performed for the same visit the last observation will be 
used for tabulations.
7.8.4
ECG
Not applicable.
7.8.5
Others
CSS-R
The individual items and categories of suicidal ideation and behavior from the C-SSRS will 
be summarized through descriptive statistics.


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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.
5.
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.
7.
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding studies combining 
multiple comparisons and modeling procedures. J Biopharm Stat. 2006; 16:5. 639-
656.[R10-1424]
8.
Pinheiro J, Bomkamp B, Glimm E, et al. Model-based dose finding under model 
uncertainty using general parametric models. Stat Med 2014; 33 (10): 1646-1661 [R15-
4293]
9.
Bornkamp B, Pinheiro J, Bretz F. Package 'DoseFinding' (February 19, 2015).
Comprehensive R Archive Network. 2015 [R15-2001]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
08-Nov -2018
None
This is the initial TSAP with necessary 
information for trial conduct
Final
06-Sept-2019
None
This is the final TSAP, approved
before unblinding of the week 4 interim 
analysis. It is also intended to
be the TSAP for primary analysis at 
week 12 and final database lock.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25658163
2.0
8-01-tsap-core
Phase II evaluation of safety, tolerability, and efficacy of BI 730357 in patients with
moderate-to-severe plaque psoriasis
Approval-Biostatistics
06 Sep 2019 20:08 CEST
Approval-Biostatistics
06 Sep 2019 20:28 CEST
Approval-Medical Writer
09 Sep 2019 07:55 CEST
Approval-Clinical Trial Leader
09 Sep 2019 11:14 CEST
Approval-Team Member Medicine
09 Sep 2019 22:02 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25658163
2.0


001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c35536779-01
BI Trial No.:
1407-0030 Part 2
Title:
  Phase II evaluation of safety, tolerability, and efficacy of BI    
730357 in patients with moderate-to-severe plaque psoriasis
Including revised protocol amendment (c20414608-08)
Investigational
Product(s):
BI 730357
Responsible trial 
statistician(s):
  
  
  Phone: 
Fax: 
Date of statistical 
analysis plan:
12 May 2021 SIGNED 
Version:
1
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2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS(S).....................................................................................................8
5.1
PRIMARY ENDPOINT(S)...................................................................................8
5.2
SECONDARY ENDPOINT(S).............................................................................8
5.2.1
Key secondary endpoint(s) ...................................................................................8
5.2.2
Secondary endpoint(s)...........................................................................................8
5.4.5 
Variables related to safety ..................................................................................11
6.
GENERAL ANALYSIS DEFINITIONS...........................................................12
6.1
TREATMENT(S) ................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED ...........................................................................13
6.5
POOLING OF CENTRES..................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................15
6.6.1
Efficacy data ........................................................................................................15
6.6.2
Safety data and other data..................................................................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................16
7.
PLANNED ANALYSIS ......................................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........19
7.2
CONCOMITANT DISEASES AND MEDICATION......................................20
7.3
TREATMENT COMPLIANCE ........................................................................21
7.4
PRIMARY ENDPOINT(S).................................................................................21
7.4.1
Primary analysis of the primary endpoint(s)....................................................21
7.4.2 
Secondary analyses for the co-primary endpoints ...........................................22
7.4.4 
Sensitivity analyses for the co-primary endpoints............................................23
7.5
SECONDARY ENDPOINT(S)...........................................................................25
7.5.1
Key secondary endpoint(s) .................................................................................25


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7.5.2
(Other) Secondary endpoint(s)...........................................................................25
7.7
EXTENT OF EXPOSURE .................................................................................29
7.8
SAFETY ANALYSIS..........................................................................................29
7.8.1
Adverse Events ....................................................................................................29
7.8.2
Laboratory data...................................................................................................31
7.8.3
Vital signs.............................................................................................................32
7.8.4
ECG ......................................................................................................................32
7.8.5
Others ...................................................................................................................32
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............33
9. 
REFERENCES ....................................................................................................34
11.
HISTORY TABLE..............................................................................................43


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LIST OF TABLES
Table 6.1: 1
Definition of treatment periods.........................................................................12
Table 6.7: 1
Time windows for assignment of on-treatment efficacy, safety lab, vital 
signs, and biomarker measurements to visits for statistical analysis................17
Table 7.8.1:1 Other user-defined special groupings of adverse events....................................30
Table 11: 1
History table .....................................................................................................43


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2.
LIST OF ABBREVIATIONS
A list of all abbreviations used in this TSAP
Term
Definition / description
AE
Adverse Event
BRPM
Blinded Report Planning Meeting
BES
Biopsy Evaluable Set
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DM&SM
Boehringer Ingelheim Data Management And Statistics Manual
DRA
Drug Regulatory Affairs
DMG
Dictionary Maintenance Group
EDC
Electronic Data Capture
EMEA
European Agency For The Evaluation Of Medicinal Products
FAS
Full Analysis Set
ICH
International Conference On Harmonisation
IPD
Important Protocol Deviation
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary For Regulatory Activities
MQRM
Medical Quality Review Meeting
MMRM
Mixed Effect Model Repeated Measurement
PASI
Psoriasis Area Severity Index
PK
Pharmacokinetics
PKS
Pharmacokinetics Set
PPS
Per Protocol Set
PSTAT
Project Statistician
PT
Preferred Term
PV
Protocol Violation
Q1
Lower Quartile
Q3
Upper Quartile
REP
Residual Effect Period
SA
Statistical Analysis


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Term
Definition / description
SD
Standard Deviation
SMQ
Standardised MedDRA Query
SOC
System Organ Class
sPGA
Static Physician’s Global Assessment
TOM
Trial Oversight Meeting
ToC
Table of Contents
TS
Treated Set
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan


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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. To be precise, this trial statistical analysis plan intends to describe 
the statistical analysis strategy for the part 2 of study 1407-0030 in detail.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.
SAS® Version 9.4 will be used for analyses.
R Version 4.0.1 (2020-06-06) with “RBesT” package (Version 1.6.1) will be used for the 
Bayesian analysis.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
A fast-track approach will be taken in order to expedite decision making and for preparation 
of the planned phase III trials, see more details in Section 8.
Details surrounding the assessment of the impact of the COVID-19 pandemic on the
trial, are specified in Section 10.1.
5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The co-primary endpoints are:

Achievement of ≥75% reduction from baseline PASI score (PASI 75) at Week 12

Achievement of a sPGA score 0 or 1 at Week 12
The summary measures for the co-primary endpoints are the proportion of patients achieving 
PASI 75 at Week 12 and achieving sPGA 0/1 at Week 12, respectively, by treatment group.
Details for scoring Psoriasis Area and Severity Index (PASI) and static Physician Global 
Assessment (sPGA) are described in Section 10.1 and 10.2 of the CTP. 
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
5.2.2
Secondary endpoint(s)

Achievement of ≥50% reduction from baseline in PASI score (PASI 50) at Week 12 

Achievement of ≥90% reduction from baseline in PASI score (PASI 90) at Week 12 

Achievement of 100% reduction from baseline in PASI score (PASI 100) at Week 12

Achievement of sPGA score 0 at Week 12

Change from baseline in psoriasis symptoms evaluated using the total score on the 
Psoriasis Symptoms Scale (PSS) at Week 12 

Achievement of a Dermatology Life Quality Index (DLQI) score of 0 or 1 at Week 12


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5.4.5 
Variables related to safety
In this trial, no endpoint of safety will be analyzed. However, safety and tolerability will be
assessed in a descriptive way based on:

Vital signs (blood pressure (BP), pulse rate (PR), body weight)

Clinical laboratory tests (hematology, clinical chemistry and urinalysis)

Suicidality (as captured in the Columbia-Suicide Severity Rating Scale(C-SSRS))

Adjudicated cerebrocardiovascular events 

Adverse events (note that clinically significant physical examinations and 
pathological ECG findings are reported as AE/SAE)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
Patients will be randomised 4:4:1 to one of two BI 730357 treatment groups V (200 mg
b.i.d.) or U (400 mg q.d.); treatment group W will receive placebo. In Part 2, the trial
medication should be taken with a meal.
Patients will be analyzed according to the treatment to which they were randomized. The 
following study periods based on actual start and stop dates of study treatment administration 
are defined: 
Table 6.1: 1
Definition of treatment periods
Analysing Treatment 
Period
Start Date (including)
Stop Date (excluding)
Screening
Date of informed consent
Date of medication 
randomization -1 day
On-treatment period
Date of medication 
randomization
Date of last study 
medication intake + 7 days
Follow-up
Date of last study medication 
intake +8 days
Last contact date
For the main safety analyses, Adverse Events (AEs) will be classified to one of the following 
time periods: “screening”, “on-treatment”, or “follow-up”. Section 7.3.4 of the protocol 
specifies that, all AEs and laboratory assessments 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 for this trial, will be assigned to the “on-treatment” period for evaluation.
Detailed rules for assigning AEs to these time periods are listed below:

If date of informed consent ≤AE onset date  <date of first drug administration, then the 
AE is assigned to “screening”;

If date of first drug administration ≤AE onset date ≤date of last intake +7 days, then 
the AE is assigned to “on-treatment”;

If AE onset date > date of last drug administration+7 days, then the AE is assigned to 
“follow-up”.
Section 7.3.4 of the protocol specifies that adverse events that start before first drug intake 
and deteriorate under treatment will also be considered as ‘treatment emergent’. Worsening 
will be determined by a more severe grade according to Rheumatology Common Toxicity 
Criteria (RCTC) Version 2.0.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation (PD) is important if it affects the rights or safety of the study subjects, 
or if it can potentially influence the primary outcome measurement(s) in a non-negligible 
way. Handling of iPDs in analysis is included in the DV domain specifications and stored 
within the Trial Master File (TMF) in the electronic Document Management System (eDMS). 
6.3
SUBJECT SETS ANALYSED
The following patient analysis sets are defined:

Screened set:
   This screened set includes all patients who signed the informed consent form.

Randomised set (RS):
The RS includes all patients who signed the informed consent form and were also 
randomised, regardless whether the patient was treated with trial medication or not.

Treated set(TS):
The TS includes all patients in the RS who were documented to have taken at least 1 
dose of trial medication. Patients will be grouped based on the actual treatment 
received at the randomization visit and week 12 visit, if applicable.

Full analysis set (FAS):
The FAS includes all patients in the RS who received at least 1 dose of trial 
medication and provided baseline and at least 1 post-randomisation measurement of 
PASI. Patients will be grouped according to the treatment to which they were 
randomized by IRT at the start of the trial.


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The FAS will be used for the analyses of demographics, baseline characteristics and all 
efficacy endpoints. The efficacy analyses will follow the intention-to-treat (ITT) principle in 
assigning patients to treatment groups, i.e., efficacy analyses will be analysed as randomised 
using the FAS. 
The TS will be used for the analyses of concomitant medication use, medical history, PsO 
therapy history, treatment exposure, compliance, and safety (including adverse events, 
laboratory measurements, vital signs, and ECG). Safety analyses will assign patients to the 
treatment group based on the actual treatment received. 
If a patient erroneously receives the wrong dose of trial drug, the patient’s efficacy data will 
be analysed using the randomized treatment group and the patient’s safety data will be 
analysed using the actual treatment group.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Efficacy data
General imputation rules for continuous and binary endpoints are described in protocol 
section 7.5. Every effort should be made to collect complete data at all visits.
The following rules will be used to impute for missing data:

For all non-binary endpoints, LOCF (Last Observation Carried Forward) will be 
used to impute missing values.

For all binary endpoints (i.e., endpoints that are either 1 (patient responded) or 0 
(patient did not respond)):
                - If no data after that visit*, then impute as failure (NRI [No Response 
Imputation])
                - If data at visits* before and after, only impute as success if both visits are 
successes; else impute as failure.
* Patients that take prohibited medications to treat PsO will be treated the same as those 
that discontinued from the trial, i.e., subsequent visits following start of prohibited 
medication will be considered as failure for binary endpoints.
If at any time a patient uses an inappropriate concomitant medication, then all future data will 
be treated as failure for binary variables and LOCF (using the last on-treatment observation 
prior to inappropriate concomitant medication use) for continuous variables. As part of the 
LOCF technique, baseline values will be carried forward if no post-baseline value is available.
If a patient is missing items from a questionnaire measured at a visit, these will be handled 
according to the instructions given in Section 10 of the protocol specific to each 
questionnaire. Missing items from the Quality of Life questionnaires will be handled 
according to the measure instructions (cf. CTP Appendix 10.6). If there is no data for a 
particular visit, then it will be imputed following the same rules as described in the protocol.
For the NAPSI, PSSI, and PPASI assessment, if the CRF is marked as “No” indicating that 
the patient does not have nail, scalp, palmo-plantar disease, then exclude such patients from 
the analysis for NAPSI, PSSI, and PPASI.
For efficacy endpoints which are continuous in nature, a restricted maximum likelihood 
(REML)-based mixed model repeated measures (MMRM) approach will be used for 
inferential analysis, if applicable. No imputation will be performed for data used in MMRM.
6.6.2
Safety data and other data
With respect to safety evaluations, it is not planned to impute missing values; and only 
observed values will be analysed.


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Missing or incomplete AE dates will be imputed according to BI standards “Handling of 
missing and incomplete AE dates” (2).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For efficacy endpoints, baseline is defined as the pre-treatment observation at Visit 2. If Visit 
2 is missing, then Visit 1 will be used for baseline.
For laboratory safety measurements, the last measurements taken prior to the treatment start 
will be considered as baseline.
In general, measurements reported with a date only (and no time) and taken on the day of first 
administration of trial treatment will also be considered pre-treatment values.
The visit schedule with accompanying details can be found in Flow Chart 1 in the protocol. 
Measurements taken after start of treatment will be considered either on- or off-treatment 
values based on definition in Table 6.1: 1.
On-treatment measurements for EOT and EOS visit for early discontinued patients will be 
allocated to visits by means of time windows with the limit between adjacent windows half-
way between the planned dates for the visits; the middle day is counted to the window of the 
later visit. Mutually exclusive relative day windows are defined below to provide derived 
visits that correspond to the post-baseline time points. For example, Visit 6 is planned on Day 


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29 and Visit 7 is planned on Day 57. Therefore, the window of Visit 6 reaches until Day 42 
while the window of Visit 7 starts on Day 43. The visit schedule with corresponding windows 
is given in Table 6.7: 1.
Table 6.7: 1
Time windows for assignment of on-treatment efficacy, safety lab, vital signs, 
and biomarker measurements to visits for statistical analysis
Window No.
Window label
Nominal visit
Nominal day
Interval
0
Baseline
VISIT 2
1
N/A
1
Week 1
VISIT 3
4
[2,5]
2
Week 1
VISIT 4
8
[6,11]
3
Week 2
VISIT 5
15
[12,21]
4
Week 4
VISIT 6
29
[22,42]
5
Week 8
VISIT 7
57
[43,70]
6
Week 12
VISIT 8/EOT 
visit
84
[71,98]
7
Week 16
EOS
113
[99,∞]
If there are multiple values for an efficacy endpoint in one window (visit), use the one from 
scheduled visit. If value from scheduled visit is not present, the visit closest to the nominal 
day will be selected for assessing endpoints at a particular visit and for by-visit displays. If the 
visits are equidistant from the nominal day, then the earlier visit will be selected. All
measured values will be stored in analysis datasets. 
The same visit windows will be used for safety laboratory and vital sign assessments. If there 
are multiple safety or laboratory values in one time window on treatment, the worst value will 
be selected for the by-visit analyses.
Analysis of AE data, concomitant medication or non-drug therapies, as well as use of rescue 
medication will not be based on visits. Frequency tables for these data will be using on-
treatment data only. Therefore, no assignment to time windows will be necessary for such 
data.
While the nominal times listed in this section should be adhered to as closely as possible, the 
actual sampling times will be recorded and used for determination of pharmacokinetic 
parameters.
For visits without an assigned value based on time windows, a value will thereafter be 
imputed as defined in Section 6.6. LOCF imputation of efficacy endpoints, when applicable, 


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will be performed based on all available observations obtained during the on-treatment period, 
irrespective of whether the observation was selected in any time window.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. For appendix tables, the set of summary statistics is: N / Mean / SD / Min / Q1 (lower
quartile) / Median / Q3 (upper quartile) / Max.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
“missing” will be displayed only if there are actually missing values. Percentages will be 
based on all patients in the respective patient set no matter whether they have non-missing 
values or not.
Planned treatment is defined as the treatment to which one patient has been assigned by IVRS 
at randomization visit (visit2). 
Subject data listings of data used in the analyses (i.e. demographic and baseline characteristics 
and key efficacy endpoints) will also be provided and included in Appendix 16.2 of the CTR.
Disposition of the patient population participating in the trial will be summarised by 
presentation of the frequency of patients screened, entered, screened but not entered, treated, 
entered but not treated. Within treated patients, data will be summarized by treatment ongoing 
patients, patients complete planned treatment period and patients who are prematurely 
discontinued, by reason. Disposition will be listed by country.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Demographic parameters 
collected and to be presented include, but are not limited to, the following:

Gender (Male, Female)

Race and ethnicity (as defined in the eCRF)

Age [years]

Height [cm]

Weight [kg] (continuous)

Weight Group (>100kg vs. < 100 kg)

Body mass index [kg/m2] (defined as weight [kg]/(height [cm]/100)2)

Body mass index category (>30 kg/m2 vs. <30 kg/m2)

Smoking history (Never-smoked, Former-smoker, Currently smokes)

Alcohol History (Never-drinker, Former-drinker, Current-drinker)

Region and country

Prior biologic use for psoriasis (Yes/No)
Baseline disease characteristic to be presented include, but are not limited to, the following: 


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
BSA (Visit 1)

PASI score

sPGA

NAPSI, PPASI, PSSI

Pain VAS

PSS total score

DLQI

Duration of Psoriasis [years]

PsA history (diagnosed, suspected, no PsA)
For NAPSI, PPASI, PSSI and pain-VAS, report is only based on patients who have such 
applicable measurements per protocol, e.g. pain VAS is reported only among patients with 
psoriatic arthritis.
Number (%) of patients with psoriasis therapy history will be summarized, including both 
non-topical drug therapy and non-drug therapy.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report, based on the treated set.
A table of the number (%) of patients with concomitant diagnoses from baseline condition by 
system organ class (SOC) and preferred term (PT) will be included. Concomitant diagnoses 
will be coded with the most recent version of MedDRA in effect at database lock.
Concomitant medication will be described as a table of number (%) of patients. Depending on 
if concomitant medication stops before trial treatment starts or not, medication information
collected from eCRF pages will be classified as historical medication or on-treatment 
concomitant medication, and a summary table will be provided for each of the two categories.
Historical medication is defined as medication taken prior to the start of trial treatment and 
stopped before trial treatment starts. There are two scenarios for on-treatment concomitant 
medications:

Scenario 1: medication start date or stop date is between first dose of trial treatment 
and last dose of trial treatment plus 7-day REP;
or

Scenario 2: medication stop date is after ‘last dose of trial treatment plus 7-day REP’, 
and medication start date is before ‘last dose of trial treatment plus 7-day REP’.


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7.3
TREATMENT COMPLIANCE
Treatment non-compliance, as one type of important protocol deviations (iPDs), is defined as 
any randomized patients having taken at least one dose of study medication with an overall 
compliance rate not between 80% and 120% inclusive. Overall compliance rate is calculated 
based on unweighted average of study drug compliance rate across all visits during the 
treatment period. For patients who discontinued the study treatment prematurely, only the 
visits on or before premature discontinuation will be used for the calculation of overall 
compliance rate.
Treatment compliance will be reported from baseline to Week 12 based on calculation as 
described in CTP section 4.3. When presenting the compliance rate of study medication by 
visit, if patients discontinue treatment prematurely, then their compliance data collected at 
EOT visit is mapped to the next originally planned visit per protocol for reporting. For 
example, if one patient prematurely discontinues the study treatment at Week 10 and comes to 
site for EOT visit, then his/her compliance data collected at EOT visit is mapped to Week 12 
for reporting purpose. That compliance rate should be interpreted as the compliance rate for 
his/her participation days in the window between planned Week 8 and Week 12.
Only descriptive statistics are planned for this section of the report. Summary statistics of 
compliance in the treated set will be given for the number of subjects as well as the 
corresponding percentage with compliance in the categories <80%, 80% - 120%, >120%, 
missing.
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
The co-primary endpoint ‘achievement of PASI 75 at Week 12’ will be summarized in the 
form of proportion of patients achieving PASI 75 at Week 12 as an outcome measure so as to 
perform the primary analysis.
For Part 2 of 1407-0030, the primary analysis on PASI 75 at week 12 will be based on a 
Bayesian borrowing approach. An informative prior is derived for the placebo control group 
based on historical placebo data. The derivation of the informative prior is based on a meta-
analytic predictive (MAP) prior approach which is additionally robustified against prior-data 
conflicts by adding a vaguely informative component to the prior.
A Bayesian approach with an informative mixture beta prior for the placebo group will be
used. The prior is a combination of a mixture of informative beta priors derived from


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historical trials and a vaguely informative beta prior. The weight on the vaguely informative
beta prior is 50%. The prior mentioned in the protocol is now updated based on additional 
historical information being available to: 
Non-informative beta prior Beta(1, 1) is used for BI 730357 active treatment arms. 
The proportions of 200 mg b.i.d. and 400 mg q.d. recipients who achieve PASI 75
improvement criteria at Week 12, will be respectively compared with that of placebo
recipients. For that purpose, the posterior probability distribution for the risk difference will
be evaluated and compared to specific boundary values. The dual criteria will be assessed to
evaluate the effect of BI 730357: (1) significance: a posterior probability of at least 90% that
the PASI 75 response rate for patients on BI 730357 arm is higher than that for patients on
placebo arm; and (2) relevance: a posterior probability of at least 50% that the PASI 75 
response rate for patients on BI 730357 arm is higher than that for patients on placebo arm by 
various boundary values. If at least one dose satisfies both criteria based on PASI 75 response 
rate, it is considered as “pass”. If neither doses have significance or relevance criteria been 
met, it is considered as “not pass”. Otherwise it is in the “consider” zone. When falling in 
‘consider zone’ based on PASI 75 response rate, sPGA 0/1 at week 12 will be jointly 
evaluated.
The calculations for the Bayesian posterior probability calculation are based on R-package
RBesT Version 1.6.1 and R version 4.0.1(2020-06-06).
The primary analysis for sPGA clear or almost clear at week 12 will be summarizing the 
proportion of responders in each arm together with 90% and 95% exact confidence intervals.
7.4.2
Secondary analyses for the co-primary endpoints
The secondary analyses for PASI 75 at week 12 include:

summarizing the proportion of responders in each arm together with 90% and 95% 
exact confidence intervals.

Calculating the unadjusted absolute difference in proportion between active treatment 
group and placebo group, 90% and 95% confidence intervals together with a 
corresponding p-value to investigate if the active treatment group has a different
response rate from the placebo group based on Chi-square distribution;
The secondary analysis for sPGA clear or almost clear at week 12 is calculating the 
unadjusted absolute difference in proportion between active treatment group and placebo 
group, 90% and 95% confidence intervals together with a corresponding p-value to 
investigate if the active treatment group has a different response rate from the placebo group 
based on Chi-square distribution.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
The same methods as discussed previously for the secondary analyses for the summary 
measure of the co-primary endpoint ‘PASI 75 at week 12’ will be used to analyse clinical 
binary secondary endpoints for each treatment group as well as treatment comparison.
Psoriasis Area and Severity Index (PASI)
Treatment comparison for unadjusted absolute difference in proportion between active groups 
and placebo group will be performed for achievement of 50% (PASI50), 90% (PASI90), 
100% (PASI 100) at week 12.
Static Physician's Global Assessment (sPGA)
The sPGA is scored using the following levels of assessment:
0 – clear;
1 - almost clear;
2 – mild;
3 – moderate;
4 -  severe
Details for scoring sPGA and its components are described in Section 10.2 of the CTP.
Treatment comparison for unadjusted absolute difference in proportion between active groups 
and placebo group will be performed for sPGA equals to 0 at week 12.
PSS total score change from baseline at week 12
For change from baseline in PSS total score at Week 12 and treatment comparison, a 
restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) 
approach will be used. The analyses will include the fixed, categorical effects of treatment,
visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline 
PSS total score and baseline PSS score-by-visit interaction. Patient will be considered as a 
random effect.  An unstructured covariance structure for within subject variation will be used.
DLQI score of 0 or 1 at week 12


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For DLQI, if one question is left unanswered, this is scored 0 and then the total score is 
summed and expressed as usual out of a maximum of 30.
Achievement of a Dermatology Life Quality Index (DLQI) score of 0 or 1 at week 12 will be 
analysed by treatment comparison of unadjusted absolute difference in proportion between 
active groups and placebo group with 90% and 95% confidence intervals.


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7.7
EXTENT OF EXPOSURE
Exposure will be presented as categorized period of “1-28”, “29-56”, “57-84” and 
“>85” days based on dose received for total study medication intake. Exposure will be 
summarized and presented for first 12 weeks of treatment. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse Events
The analyses of adverse events will be descriptive in nature. All analyses of AEs will be based 
on the number of patients with AEs (not the number of AEs).
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug administration and 
within 7 days after last drug administration will be assigned to the assigned treatment. Section 
7.3.4 of the protocol specifies that adverse events that start before first drug intake and 
deteriorate under treatment will also be considered as ‘treatment emergent’. Worsening will 
be determined by a more severe grade according to Rheumatology Common Toxicity Criteria 
(RCTC) Version 2.0.
All adverse events occurring before first drug intake will be assigned to ‘screening’ and all 
AEs occurring after last drug intake + 7 days will be assigned to ‘follow-up’ (for listings 
only).
According to ICH E3 (6), in addition to Deaths and serious adverse events, ‘other significant’ 
AEs need to be listed in the clinical trial report. These will be any non-serious
adverse event that led to an action taken with study drug (e.g. discontinuation or dose
reduced or interrupted). An overall summary of adverse events will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ
class and PT using the version of MedDRA at the database lock. Separate tables will be
provided for subjects with SAEs, AEs leading to treatment discontinuation and related AEs.
The system organ classes will be sorted by default by decreasing frequency and PTs will be


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sorted by decreasing frequency within SOC.
For further details on summarization of AE data, please refer to the guideline 'Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries' (7).
The severity of AEs will be summarised by the maximum intensity of the events each patient had 
(as indicated by the recorded RCTC version 2 grade). This will show the number and percent of 
patients who had at most mild, moderate, severe, and life-threatening events. “Severe adverse 
event” is defined as an AE with RCTC grade equals to 3 (severe) or 4 (life threatening).
Groupings of adverse events and adverse events of special interest (AESI)
The term “adverse events of special interest (AESI)” relates to any specific AE that has 
been identified at the project level as being of particular concern for prospective safety 
monitoring and safety assessment within this trial, e.g., the potential for AEs based on 
knowledge from other compounds in the same class.
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the 
same timeframe that applies to SAEs.
The AESI have been defined in section 5.2.6.1 of the protocol.
Other user-defined special adverse event grouped term for BI 730357 specified in Table 
7.8.1:1 will be reported.
Table 7.8.1:1 Other user-defined special groupings of adverse events
N
Term
Definition #
1
SMQ Drug Related Hepatic 
Disorders
SMQ Drug related hepatic disorders –
comprehensive search (20000006)
2
SMQ Opportunistic infections
MedDRA SMQ Opportunistic Infections (narrow -
20000235)
3
Tuberculosis related terms
BIcMQ “Tuberculosis related terms” BIcMQ 
(30000107)(broad)
4
Severe infections
SOC “Infections and infestations” with eCRF 
severity grade >= Rheumatology Common Toxicity 
Criteria (RCTC) Grade 3 – MedDRA (soc code 
10021881 mppath=1)
5
Gastritis related terms 
•
BIcMQ Gastritis (broad) [32008061]
6
Malignancies including all sub-
SMQs
-
SMQ broad (20000090)
Merge medbase by mptcd to all HLT terms
# This column indicates whether the Term(s) provided in the first column are MedDRA 


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preferred terms (PT), Standardised MedDRA Queries (SMQ) or BI customised 
MedDRA Queries (BIcMQ).
In addition, the adjudication outcome of Cerebro-cardiovascular events from the vendor, 
, will be summarized by indication,  treatment, primary system organ class and 
preferred term.
  
AE summaries
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarized by treatment, primary system organ class and preferred 
term according to MedDRA. Separate tables will be provided for patients with:

Investigator defined drug-related AEs

Investigator defined drug-related serious AEs

AESIs

AEs leading to discontinuation

Serious AEs

Other significant AEs 

AE by worst RCTC intensity

Special AE grouped term (or called “user-defined AE category”) specified in Table 
7.8.1:1
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards.  
The number and percent of patients with possibly clinically significant on-treatment
abnormalities as identified by use of clinically significant ranges for each laboratory
parameter collected will be presented. The patients with possibly clinically significant
abnormalities will be identified within the initial on-treatment period by study treatment.
Each laboratory value will be graded using the RCTC (version 2.0) grading of laboratory 
abnormalities. A summary table of the Baseline grade compared with the last available on-
treatment grade will display the number and percent of each type of transition in grade by
laboratory parameter within each treatment period, and treatment group. A second table will 
show the number and percent of patients with each type of transition from Baseline to their 
worst on-treatment grade parameter within each treatment period, and treatment group. For 
these shift tables, only the double blind period will be considered. Parameters using
categorised values, such as the urinalysis parameters, will show the shift table among those 
values in a similar manner to the RCTC graded values. 
A graphical summary highlighting potential cases of Hy’s Law within each treatment


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group will be presented. The maximum on-treatment values of total bilirubin and ALT 
will be plotted each on a scale as multiples of the upper limit of normal. The figure will
show areas that meet the criteria of cholestasis (total bilirubin > 2x ULN), Temple’s 
corollary (ALT > 3 x ULN) and Hy’s Law as the combination of these two factors. A 
similar figure using maximum AST values in place of ALT will be constructed. An 
accompanying listing will show by sample date and study day the full course of the total 
bilirubin, ALT, AST and alkaline phosphatase values for patients whose total bilirubin 
are > 2xULN or AST or ALT values > 3 x ULN at any time during the study (all
treatment periods). The listing will indicate where the value meets the criteria, either
falling in the cholestasis range, that for Temple’s corollary or where the combination 
meets that for Hy’s Law itself.
Laboratory measurements taken up to the residual effect period of 7 days after the last 
administration of randomized study drug will be considered as on-treatment.
Study visits will be presented by the Visit labels in Table 6.7:1.
Listing and descriptive statistics of laboratory values over time as well as median and 
interquartile range (IQR) of changes between baseline and extreme abnormal value on 
treatment will be provided. Baseline is understood as the last available measurement before 
study drug administration. Extreme abnormal value on treatment is understood as the on 
treatment laboratory value which is most significantly away from the reference range.
Frequency of patients with transitions relative to reference range and listing of patients with 
significant abnormal laboratory values will be presented as well.
In cases of repeated measurements performed for the same visit the last observation will be 
used for tabulations.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
Relevant findings at baseline were reported as baseline conditions, and other findings on 
ECGs were reported as AEs and analyzed accordingly.
7.8.5
Others
C-SSRS
The individual items and categories of suicidal ideation and behaviour from the C-SSRS will 
be summarized through descriptive statistics.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
Fast-track approach:
Once the last patient has completed their End-of-Treatment (EOT) visit and all corresponding 
data has been entered and cleaned to the level documented in the “Data Delivery Request” 
(DDR) form, the data will be declared ready to be unblinded via the “Data Ready to be 
Unblinded and/or Final Trial Closure Notification” (RUN) form. Then the treatment 
information will be released for analysis.
The data collection for the off-treatment residual effect period until the End-of-Study (EoS)/ 
Follow-Up visit will continue into the unblinded trial database. Once trial data collection has 
been completed and all data has been entered and cleaned as documented on the RUN form, a 
final data lock will be performed.
After the release of treatment information, it is expected that only trial data related to the off-
treatment residual effect period will be entered and changed. Therefore, after the timepoint of 
release of treatment information, all changes affecting trial data up to the End-of-Treatment 
(EoT) visit will be documented and summarized in the CTR.


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9.
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.
4.
Bias reduction of maximum likelihood estimates. Firth, D. Biometrika.
1993; 80 (1): 27-38. [R20-2291]      
5.
Ge, M., Durham, L. K., Meyer, R. D., Xie, W., & Thomas, N. (2011). Covariate-
adjusted difference in proportions from clinical trials using logistic regression and 
weighted risk differences. Drug information journal: DIJ/Drug Information Association, 
45(4), 481-493  [R16-5360]
6.
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, EMA webpage.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
Author
Sections 
changed
Brief description of change
1 
12-May-2021
None
This is the final TSAP