Conditions: Psoriasis
Keywords: BI 655066 ABBV-066 risankizumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 182
Healthy volunteers: no

Brief summary:
This is a randomized double blind, double dummy, placebo controlled, parallel design study that is being performed to assess the safety and efficacy of BI 655066 (risankizumab).

Detailed description:
Participants were randomized to receive either placebo, risankizumab 75 mg, or risankizumab 150 mg in Part A. All participants received 2 injections to maintain the blind: the placebo arm received 2 injections of placebo, the risankizumab 75 mg arm received one injection of risankizumab 75 mg and one injection of placebo, and the risankizumab 150 mg arm received 2 injections of risankizumab 75 mg. Participants who received placebo in Part A switched to risankizumab in Part B; participants who received risankizumab (75 mg or 150 mg) in Part A continued to receive the same treatment (risankizumab 75 mg or 150 mg) in Part B.

Arms:
arm 1: Participants randomized to receive double-blind (DB) placebo for risankizumab by subcutaneous (SC) injection at Weeks 0 and 4 (Part A). arm 2: Participants randomized to receive double-blind (DB) risankizumab 75 mg by subcutaneous (SC) injection at Weeks 0 and 4 (Part A). arm 3: Participants randomized to receive double-blind (DB) risankizumab 150 mg by subcutaneous (SC) injection at Weeks 0 and 4 (Part A).

Interventions: intervention 1: risankizumab intervention 2: placebo for risankizumab
Intervention descriptions: intervention 1: Risankizumab pre-filled syringe, administered by subcutaneous (SC) injection intervention 2: Placebo for risankizumab pre-filled syringe, administered by subcutaneous (SC) injection

Protocol document:
Prot_002.pdf: 
001-MCS-40-106-RD-03 (13 0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
Document Number:
c08943535-02
BI Trial No.:
1311.38
BI Investigational 
Product:
risankizumab, BI 655066
Title:
A phase II/III, randomised, double-blind study to evaluate 
efficacy and safety of two different dose regimens of BI 655066 
(risankizumab) and placebo and maintenance of response of BI 
655066 (risankizumab) administered subcutaneously in 
Japanese patients with moderate to severe chronic plaque type 
psoriasis.
Lay Title:
BI 655066 (risankizumab) compared to placebo in Japanese 
patients with moderate to severe chronic plaque psoriasis
Clinical Phase:
Phase II/III
Trial Clinical 
Monitor:
Coordinating 
Investigator:
Status:
Final Protocol (Revised Protocol based on global amendment 
#1)
Version and Date:
Version: 2.0
Date: 08 Jun 2017
Page 1 of 80
Proprietary confidential information.
! 2017 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.
NCT03000075


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
risankizumab, BI 655066
Protocol date:
05 Sep 2016
Trial number:
1311.38
Revision date:
08 Jun 2017
Title of trial:
A phase II/III, randomised, double-blind study to evaluate efficacy 
and safety of two different dose regimens of BI 655066 
(risankizumab) and placebo and maintenance of response of BI 
655066 (risankizumab) administered subcutaneously in Japanese 
patients with moderate to severe chronic plaque type psoriasis.
Coordinating 
Investigator
Trial sites:
Multi-centre trial
Clinical phase:
II/III
Objectives:
The main objective of this study is to assess the efficacy and safety of 
two different dose regimens of BI 655066 (risankizumab) compared 
to placebo in patients with moderate to severe chronic plaque 
psoriasis.
Methodology:
Placebo controlled, double-blind, double-dummy, randomised, 
parallel-design comparison of two different dose regimens of BI 
655066 (risankizumab).
No. of patients:
total entered:
Approximately 168
each treatment:
BI 655066 (risankizumab) 75 mg: 56 patients
BI 655066 (risankizumab) 150 mg: 56 patients
placebo: 56 patients


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
risankizumab, BI 655066
Protocol date:
05 Sep 2016
Trial number:
1311.38
Revision date:
08 Jun 2017
Diagnosis :
Moderate to severe chronic plaque psoriasis
Main criteria
for inclusion:

Have a 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. 

Have stable moderate to severe chronic plaque psoriasis with or 
without psoriatic arthritis at both Screening and Baseline 
(Randomisation):
a.
Have an involved BSA ≥10% and
b. Have a PASI score ≥12 and
c.
Have an sPGA score of ≥3.

Age ≥20 years at screening
Test product:
BI 655066 (risankizumab)
dose:
75 mg (1 syringe and 1 placebo) or 150 mg (2 syringes, 75 mg each)
at Week 0, 4 and every 12 weeks
mode of 
administration:
subcutaneous
Comparator products:
placebo at Weeks 0 and 4
dose:
not applicable
mode of 
administration:
subcutaneous
Duration of treatment:
40 weeks


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
risankizumab, BI 655066
Protocol date:
05 Sep 2016
Trial number:
1311.38
Revision date:
08 Jun 2017
Endpoints
Primary endpoint:
- Achievement of ≥90% reduction from baseline PASI score (PASI 
90) at Week 16
Secondary endpoints:
•
Achievement of ≥90% reduction from baseline PASI score (PASI 
90) at Week 52
•
Achievement of an sPGA score of clear or almost clear at Week 
16
•
Achievement of an sPGA score of clear or almost clear at Week 
52
•
Achievement of ≥75% reduction from baseline PASI score (PASI 
75) at Week 16
•
Achievement of ≥75% reduction from baseline PASI score (PASI 
75) at Week 52
•
Achievement of 100% reduction from baseline PASI score (PASI 
100) at Week 16
•
Achievement of 100% reduction from baseline PASI score (PASI 
100) at Week 52
•
Achievement of American College of Rheumatology (ACR) 20
response at Week 16
•
Achievement of ACR 20 response at Week 52
Safety criteria:
Physical examination, vital signs, 12-lead electrocardiogram, 
laboratory tests, adverse events, serious adverse events, and local 
tolerability


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
risankizumab, BI 655066
Protocol date:
05 Sep 2016
Trial number:
1311.38
Revision date:
08 Jun 2017
Statistical methods:
Primary analysis: The achievement of PASI 90 at Week 16 is the 
primary endpoint and is binary variables with values of 0 or 1. The 
difference in proportion responding between the BI 655066
(risankizumab) arm and placebo arm will be estimated and tested 
using the Cochran-Mantel-Haenszel risk difference estimate stratified 
by the randomisation factors of concomitant disease of PsA at 
baseline (Yes versus No), and body weight (≤90 kg versus >90 kg) 
with weights proposed by Greenland & Robins. 
Secondary analysis: The same methods as the primary analyses will
be used to analyse all binary secondary. Change from baseline in
Psoriasis Symptoms Scale (PSS) at Week 16 will be analysed by the 
van Elteren test between the BI 655066 (risankizumab) arm and 
placebo arm.
In order to maintain the full significant level of 5%, two null 
hypotheses of each BI 655066 (risankizumab) arm vs Placebo will be 
tested using fixed-sequence method.


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FLOW CHART
Trial Periods
Screening
Randomised Treatment
Follow-Up
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
EOT FU1 FU2/
EOO
FU3/
EOO
Week
4
8
12
16
22
28
34
40
46
52
56
Day 
-42 to -14
1
29
57
85
113
155
197
239
281
323
365
393
Visit window 
(days)
±3
±7
±7
±3
±7
±7
±7
±7
±7
±7
±7
Informed consent
X
Demographics
X
Medical history
X
Smoking/alcohol 
history
X
Psoriasis therapy 
history
X
Psoriatic arthritis 
history
X
CASPAR1
X
In-/exclusion 
criteria
X
X
% BSA 
involvement
X
X
Height
X
Weight/waist 
circumference 2
X
X
X
Physical 
examination3
XC
XT
XT
XT
XT
XC
XT
XT
XT
XC
XT
XC
Vital signs4
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Infection 
screening5
X
X
X-ray5
X
X
Pregnancy testing6
X
X
X
X
X
X
X
X
Safety laboratory 
tests7
X
X
X
X
X
X
X
12 lead-ECG
X
X
X
X
X
X
X
PK sampling8
X
X
X
X
X
X
X
X
ADA sampling8
X
X
X
X
X
X
Biomarker 
sampling9
X
X
X
X
X
X
Local tolerability
X
X
X
X
X
X
X
X
PASI
X
X
X
X
X
X
X
X
X
X
X
X
sPGA
X
X
X
X
X
X


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Abbreviations: EOT=end of treatment, EOO=end of observation, FU= Follow-up, CASPAR=ClASsification of Psoriatic 
Arthritis, BSA= body surface area, ADA=anti-drug antibodies, HAQ-DI= Health Assessment Questionnaire Disability, 
PASI=Psoriasis Area and Severity Index, sPGA=static physician global assessment, TJC= Tender Joint Counts, SJC= 
Swollen Joint Counts, VAS= Visual Analog Scale, PSS= Psoriasis Symptoms Scale, DLQI= Dermatology Life Quality 
Index, V= Visit
1. At selected study sites, patients with a positive history of PsA or suspected to have PsA
will be evaluated via CASPAR (ClASsification of Psoriatic Arthritis) criteria for 
psoriatic arthritis (PsA). Refer to Appendix 10.3.
2. Refer to Section 5.3.1 for weight and waist circumference procedures.
3. Physical examination: C=complete, T=targeted. Refer to Section 5.3.1.
4. Vital signs should precede blood sampling and be assessed pre-dose at all dosing 
visits. Additional vital signs assessments at approximately 5 minutes post-dose (5 
minutes after last injection and 60 minutes post-dose (60 minutes after last injection) at 
Visit 2 and Visit 3. Monitor for signs and symptoms of hypersensitivity reactions for 
approximately 2 hours after the last injection at Visit 2 and for approximately 1 hour 
after the last injection at all other visits with drug administration. Refer to Section 5.3.2. 
5. The result of T-SPOT®, PPD, and X-ray will not be included in the clinical data base. 
Refer to Table 5.3.3: 1
Tender and 
Swollen Joint 
Counts (TJC 68, 
SJC 66)10
X
X
X
X
X
Physician’s global 
assessment of 
disease activity 
(VAS)10
X
X
X
X
X
PSS
X
X
X
X
X
DLQI
X
X
X
X
X
Patient’s 
assessment of 
pain (VAS)
X
X
X
X
X
Patient’s global 
assessment of 
disease activity 
(VAS)
X
X
X
X
X
HAQ-DI
X
X
X
X
X
Optional DNA 
banking
X
Randomisation
X
Contact IRT
X
X
X
X
X
X
X
Admin. of trial 
drugs
X
X
X
X
X
Termination of 
trial med.11
X
Trial completion12
X
X
Open label 
extension 13
X
Vital status14
X


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6. Serum pregnancy testing must be done at screening and if urine pregnancy test is 
positive. Urine pregnancy testing will be done prior to administration of study drug at 
all dosing visits and at Follow-Up (FU) Visit. 
7. Blood samples should be taken after patient has fasted for at least 8 hours (except 
screening visit). If not fasted mark on laboratory requisition form.
8. On dosing visits, pharmacokinetic (PK) and ADA samples should be taken 
approximately within 1 hour prior to administration of study drug. 
9. Biomarker sampling should be done prior to administration of study drug at dosing 
visits. Refer to Section 5.5.
10. At selected study sites, patients diagnosed with PsA by CASPAR criteria will 
perform PsA assessments as detailed in Appendix 10.3. 
11. Patients that terminate trial medication (med.) early should remain in the trial if possible 
and complete all remaining Treatment Period Visits, as well as FU1 and FU2 Visits.   
Termination of trial medication should be completed in the eCRF and treatment 
discontinuation registered in IRT. Refer to Section 6.2.3 for more details. 
12. Patients who finish the randomised treatment period, will complete either of the 
follow-up visit schedules dependent on extension trial participation (refer to Section 
6.2.3):
∀
Not participating in extension trial: FU1, FU2/EOO, FU3/EOO (final 1311.38
visit)
or
∀
Participating in extension trial: FU1, FU2/EOO (final 1311.38 visit), enter 
extension trial
13. Patients who have completed the study and who meet the eligibility criteria will be 
offered to participate in an extension trial. Refer to Section 6.2.3 and ISF.
14. For randomised patients leaving the study before the planned EOO, their vital status 
should be collected at Week 56.   


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................15
MEDICAL BACKGROUND.............................................................................15
1.1
DRUG PROFILE................................................................................................15
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....17
RATIONALE FOR PERFORMING THE TRIAL.........................................17
2.1
TRIAL OBJECTIVES........................................................................................17
2.2
BENEFIT - RISK ASSESSMENT.....................................................................17
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................19
OVERALL TRIAL DESIGN AND PLAN .......................................................19
3.1
3.1.1
Administrative structure of the trial .................................................................20
3.1.2
Data Monitoring Committee (DMC).................................................................20
3.1.3
MACE Adjudication Committee.......................................................................21
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUPS.........................................................................................21
SELECTION OF TRIAL POPULATION .......................................................21
3.3
3.3.1
Main diagnosis for trial entry ............................................................................21
3.3.2
Inclusion criteria .................................................................................................21
3.3.3
Exclusion criteria ................................................................................................22
3.3.4
Removal of patients from therapy or assessments...........................................23
Removal of individual patients .............................................................................23
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................24
3.3.4.2
4.
TREATMENTS...................................................................................................25
INVESTIGATIONAL TREATMENTS ...........................................................25
4.1
4.1.1
Identity of the Investigational Medicinal Products..........................................25
4.1.2
Selection of doses in the trial..............................................................................26
4.1.3
Method of assigning patients to treatment groups...........................................27
4.1.4
Drug assignment and administration of doses for each patient......................27
4.1.5
Blinding and procedures for unblinding...........................................................28
Blinding.................................................................................................................28
4.1.5.1
Unblinding and breaking the code ........................................................................28
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................29
4.1.7
Storage conditions...............................................................................................29
4.1.8
Drug accountability.............................................................................................29


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OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................30
4.2.1
Other treatments and emergency procedures..................................................30
4.2.2
Restrictions ..........................................................................................................30
Restrictions regarding concomitant treatment ......................................................30
4.2.2.1
Restrictions on diet and life style..........................................................................31
4.2.2.2
Restrictions regarding women of childbearing potential ......................................32
4.2.2.3
TREATMENT COMPLIANCE........................................................................32
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................33
TRIAL ENDPOINTS..........................................................................................33
5.1
5.1.1
Primary Endpoint ...............................................................................................33
5.1.2
Secondary Endpoints..........................................................................................33
5.1.3
Further Endpoints...............................................................................................33
ASSESSMENT OF EFFICACY........................................................................33
5.2
ASSESSMENT OF SAFETY.............................................................................34
5.3
5.3.1
Physical examination ..........................................................................................34
Waist circumference .............................................................................................34
5.3.1.1
Body Weight .........................................................................................................34
5.3.1.2
5.3.2
Vital Signs............................................................................................................34
5.3.3
Safety laboratory parameters ............................................................................35
5.3.4
Electrocardiogram ..............................................................................................37
5.3.5
Other safety parameters.....................................................................................38
5.3.6
Assessment of adverse events.............................................................................38
Definitions of AEs ................................................................................................38
5.3.6.1
Adverse event collection and reporting ................................................................41
5.3.6.2
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................43
5.4.1
Assessment of Pharmacokinetics.......................................................................43
5.4.2
Methods of sample collection .............................................................................43
Plasma sampling for pharmacokinetic analysis ....................................................43
5.4.2.1
Plasma sampling for ADA....................................................................................43
5.4.2.2
5.4.3
Analytical determinations ..................................................................................44
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................44
ASSESSMENT OF BIOMARKERS.................................................................44
5.5
5.5.1
Assessment of soluble protein biomarkers........................................................44
Methods of sample collection ...............................................................................44
5.5.1.1
Analytical determinations .....................................................................................44
5.5.1.2
5.5.2
Biomarker sample banking................................................................................44
5.5.3
DNA Banking.......................................................................................................45
Methods of sample collection ...............................................................................45
5.5.3.1
Analytical determinations .....................................................................................45
5.5.3.2
OTHER ASSESSMENTS...................................................................................45
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................45
5.7
6.
INVESTIGATIONAL PLAN.............................................................................46
VISIT SCHEDULE.............................................................................................46
6.1


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DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................46
6.2
6.2.1
Screening period..................................................................................................46
6.2.2
Treatment period ................................................................................................47
6.2.3
Follow-Up Period and Trial Completion ..........................................................48
Early treatment and trial termination ....................................................................48
6.2.3.1
Trial completion....................................................................................................48
6.2.3.2
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................49
STATISTICAL DESIGN - MODEL.................................................................49
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................49
7.2
PLANNED ANALYSES.....................................................................................49
7.3
7.3.1
Primary endpoint analyses.................................................................................50
7.3.2
Secondary endpoint analyses .............................................................................51
7.3.3
Further endpoint analyses..................................................................................51
7.3.4
Safety analyses.....................................................................................................52
7.3.5
Pharmacokinetic analyses ..................................................................................53
7.3.6
Pharmacodynamic analyses ...............................................................................53
7.3.7
Biomarker analyses.............................................................................................53
INTERIM ANALYSES ......................................................................................53
7.4
HANDLING OF MISSING DATA ...................................................................53
7.5
RANDOMISATION ...........................................................................................54
7.6
DETERMINATION OF SAMPLE SIZE .........................................................54
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................56
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................56
DATA QUALITY ASSURANCE ......................................................................57
8.2
RECORDS...........................................................................................................57
8.3
8.3.1
Source documents ...............................................................................................57
8.3.2
Direct access to source data and documents.....................................................58
8.3.3
Storage period of records ...................................................................................58
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................59
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........59
8.5
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................59
TRIAL MILESTONES.......................................................................................59
8.6
PROTOCOL VIOLATIONS .............................................................................60
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY..............................................................................60
9.
REFERENCES....................................................................................................61
PUBLISHED REFERENCES............................................................................61
9.1
UNPUBLISHED REFERENCES......................................................................63
9.2
10.
APPENDICES.....................................................................................................64
PASI DEFINITIONS AND USE........................................................................64
10.1


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STATIC PHYSICIAN GLOBAL ASSESSMENT (SPGA) ............................64
10.2
DIAGNOSIS AND ASSESSMENTS FOR PATIENTS WITH PSORIATIC 
10.3
ARTHRITIS ........................................................................................................66
10.3.1
psoriatic arthritis diagnosis at Screening..........................................................66
10.3.2
Psoriatic arthritis assessment.............................................................................67
10.3.3
ACR Response Criteria ......................................................................................70
PATIENT REPORTED OUTCOMES .............................................................70
10.4
10.4.1
Psoriasis Symptom Scale (PSS)..........................................................................70
10.4.2
Dermatology Life Quality Index (DLQI)..........................................................71
10.4.3
Health Assessment Questionnaire Disability Index (HAQ-DI) ......................73
10.4.4
pain VAS..............................................................................................................76
10.4.5
Patient’s global assessment VAS .......................................................................76
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................77


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ABBREVIATIONS
ACR
American College of Rheumatology
ADA
anti-drug antibodies
AE
adverse event
AESI
adverse event of special interest
AUC
area under the concentration-time curve of the analyte
BI
Boehringer Ingelheim
BSA
body surface area
CASPAR
CIASsification of Psoriatic Arthritis
CK
creatinine kinase
CI
confidence interval
CML
local clinical monitor 
CRA
clinical research associate
CRF
case report form
CRO
contract research organisation
CTP
clinical trial protocol
CTR
clinical trial report
DILI
drug induced liver injury
DLQI
Dermatology Life Quality Index
DMC
data monitoring committee
DNA
deoxyribonucleic acid
eCRF
electronic case report form
ECG
electrocardiogram/electrocardiography
eGFR
estimated glomerular filtration rate
EOO
end of observation
EOT
end of treatment
FAS
full analysis set
FU
follow-up
GCP
Good Clinical Practice
HAQ-DI
Health Assessment Questionnaire Disability
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IgG
immunoglobulin G
IRB
institutional review board
IRT
interactive response technology
ISF
investigator site file
i.v.
intravenous(ly)
LOCF
last observation carried forward
MACE
major adverse cardiovascular events
MedDRA
Medical Dictionary for Regulatory Activities
PASI
Psoriasis Area and Severity Index
PD
pharmacodynamics
PK
pharmacokinetics
PPD
purified protein derivative 


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PRO
patient reported outcome
PsA
psoriatic arthritis
PSS
Psoriasis Symptoms Scale
RCTC
Rheumatology Common Toxicity Criteria
REP
residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
serious adverse event
s.c.
subcutaneous(ly)
SOP
standard operating procedures
sPGA
static physician global assessment
VAS
Visual Analog Scale








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studies, the majority of patients receiving BI 655066 achieved 90% improvement of their 
disease. The most common AEs reported in these trials were mild nasopharyngitis, headache, 
back pain, and arthralgia, which showed no dose dependency. Local reactions following 
subcutaneous administration of BI 655066 were uncommon, and limited to redness, swelling 
or induration at the injection site. 
As with any immune modulating agent, BI 655066 may impair immune function resulting in 
a risk of infection. This will be monitored by collection of all AEs during the treatment and 
observation periods. Patients with clinically important active infection will not be included in 
the study. Patients with positive QuantiFERON® TB test, positive T-SPOT® test, or a positive 
PPD (purified protein derivative) skin test for tuberculosis must fulfil entry criteria as 
specified in Section 3.3.3, item 6. There is not enough information at this time to rule out a 
risk of cancer with BI 655066, but this risk is considered small with this type of compound as 
experience with the anti-IL-12/23 mAb ustekinumab has not suggested significant risk for 
cancer/serious infection. The investigators will perform physical examination at each visit
and will monitor for signs and symptoms of malignancy.
Increases in major adverse cardiovascular events (MACE) including myocardial infarction, 
cerebrovascular accident, and cardiovascular death, reported initially with anti-IL-12/23 
agents, such as ustekinumab, have not been observed in longer-term studies. In Phase I study 
and phase II study of BI 655066, 3 cases were considered to be possible MACE. While the 
likelihood of increased MACE with treatment by BI 655066 is small, all suspected 
cardiovascular events (serious or non-serious) observed in this study will be adjudicated by 
an independent MACE adjudication committee.
A patient will have an about 33% (1 in 3) chance in being randomised to the placebo arm. 
Patients assigned to placebo will not receive an active treatment through Week 16, but after 
that patients will receive BI 655066. The knowledge gained from the placebo treatment group 
in a relatively short period of time will be used to control for confounding factors for an 
unbiased estimate of effect size. The delay in starting treatment does not diminish the 
potential benefit of treatment because of active treatment. If the patient experiences an 
intolerable increase of psoriasis the patient will be discontinued from the trial to receive 
rescue treatment.
Patients will be monitored with study visits every 4 weeks through the end of the placebo 
period at Week 16.  
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 5.3.6.1.
In order to recognize any safety signals as early as possible, an independent data monitoring 
committee (DMC) will monitor all studies where patients are receiving BI 655066. 
In conclusion, the benefit-risk profile is considered appropriate for this stage of clinical 
development.  


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This randomised, double-blind, double-dummy, placebo controlled, parallel design study 
compares two different dose regiments of BI 655066 (risankizumab) with placebo. In total, 
approximately 168 patients with moderate to severe chronic plaque psoriasis will be 
randomised in this trial. 
Patients are included in the trial once they have signed the informed consent. Patients suitable 
after screening will be eligible to participate in the 40-week treatment period and will be 
randomised at a ratio of 2:2:1:1 to one of 4 treatment arms (BI 655066 75 mg, BI 655066
150 mg, placebo with BI 655066 75 mg, after Week 16, and placebo with BI 655066 150 mg
after Week 16) as shown in Figure 3.1: 1. Randomisation will be stratified by concomitant 
PsA at baseline (Yes versus No) and body weight (≤90 kg versus >90 kg) as listed in Section 
7.6.
Figure 3.1: 1 Trial design
Individual patient participation is concluded when the patient has completed the last planned 
visit. The “last-patient-last-visit-primary-endpoint” is the last scheduled primary endpoint 
visit at Week 16 completed by the last patient. 
Patients will be offered to roll over into an extension trial, if they have completed the study 
and meet the inclusion criteria for the extension trial. 
Patients who will not participate in the extension trial will be followed up for AE assessment 
16 weeks after having received their last dose.


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3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
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.
A coordinating investigator will be responsible to coordinate activities of investigators at 
different centres participating in this multi-centre trial. Tasks and responsibilities will be 
defined in a contract. Relevant documentation on the participating (principal) investigators 
and other important participants, including their curricula vitae, will be filed in the ISF.
Data management will be done by BI according to BI SOPs and Statistical Evaluation will be 
done by AbbVie according to AbbVie SOPs.
A central laboratory service and vendors for ECG, electronic clinical outcome assessment,
and IRT (interactive response technology) will be used in this trial. Details will be provided 
in the applicable manuals available in the ISF.
The organisation of the trial will be performed by the Nippon Boehringer-Ingelheim 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. A CML will be 
appointed responsible for coordinating the activities required in order to manage the trial in 
accordance with applicable regulations and internal SOPs in the countries covered by the 
respective BI Japan.  
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 Japanese information can be 
found in the ISF.
3.1.2
Data Monitoring Committee (DMC)
A project-based DMC, independent of the sponsor will be established to assess the progress 
of the clinical trial, including unblinded safety assessment at specified intervals, and to 
recommend to the sponsor whether to continue, modify, or stop the trial. Any efficacy data 
provided to the DMC will only be used for DMC's obligation to assess the full benefit-to-risk 
of the treatments. Thus, no statistical penalty will be imposed since efficacy analyses will not 
be the basis for any potential early trial termination. Measures are in place to ensure blinding 
of the sponsor and all other trial participants. The sponsor will remain blinded until after 
database lock. The tasks and responsibilities of the DMC will be specified in a charter. The 
DMC will maintain written records of all its meetings.


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3.1.3
MACE Adjudication Committee 
A project-based independent adjudication committee will be used to adjudicate all observed 
cardio- and cerebro-vascular events and thrombotic events reported during the conduct of the 
study to assure consistent assessment of MACE. This review will be blinded to treatment 
allocation; the events that are adjudicated and the adjudication process will be detailed in the 
MACE Adjudication Committee Charter.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUPS
This is a randomised, double-blind, double-dummy, placebo controlled, parallel design trial. 
The trial design is appropriate for assessing the efficacy and safety of two different dose 
regiments of BI 655066 compared to placebo in patients with moderate to severe chronic 
plaque psoriasis. While there is a low rate of response with placebo treatment, it is important 
to have a placebo control early in the study. In order to facilitate patient participation, the trial 
design will allow patients initially assigned to placebo to receive active treatment. Thus, only 
AEs reported during the first 16 weeks of the trial can be directly compared to placebo. 
SELECTION OF TRIAL POPULATION
3.3
A total of approximately 168 patients will be randomised in the current trial. A sufficient 
number of patients will be screened to meet this randomised goal. Patients will be recruited at 
multiple investigative sites. Recruitment will be competitive.  
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.
3.3.1
Main diagnosis for trial entry
Patients must have moderate to severe chronic plaque psoriasis.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1. Have a 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. 
2. Have stable moderate to severe chronic plaque psoriasis with or without psoriatic arthritis 
at both Screening and Baseline (Randomisation):
a.
Have an involved BSA ≥10% and
b.
Have a PASI score ≥12 and
c.
Have an sPGA score of ≥3.
3. Age ≥20 years at screening


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4. Male or female patients. Women of childbearing potential* must be ready and able to use 
highly effective methods of birth control per ICH M3(R2) that result in a low failure rate 
of less than 1% per year when used consistently and correctly. A list of contraception 
methods meeting these criteria is provided in the patient information.
*Women of childbearing potential are defined as:
•
having experienced menarche and are
•
not postmenopausal (12 months with no menses without an alternative 
medical cause) and are
•
not permanently sterilised (e.g., tubal occlusion, hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
5. Must be candidates for systemic therapy or phototherapy for psoriasis treatment, as 
assessed by the investigator 
6. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and Japanese legislation 
3.3.3
Exclusion criteria
1.
Patients with 
a.
non-plaque forms of psoriasis (including guttate, erythrodermic, or pustular)
b.
current drug-induced psoriasis (including an exacerbation of psoriasis from 
beta blockers, calcium channel blockers, or lithium)
c.
active ongoing inflammatory diseases other than psoriasis and psoriatic 
arthritis that might confound trial evaluations according to investigator’s 
judgment
2.
Previous exposure to BI 655066
3.
Currently enrolled in another investigational study or less than 30 days (from 
screening) since completing another investigational study (participation in 
observational studies is permitted)
4.
Use of any restricted medication as specified in Table 4.2.2.1: 1 or any drug 
considered likely to interfere with the safe conduct of the study  
5.
Major surgery performed within 12 weeks prior to randomisation or planned within 12 
months after screening (e.g., hip replacement, aneurysm removal, stomach ligation).  
6.
Known chronic or relevant acute infections including active tuberculosis, human 
immunodeficiency virus (HIV) or viral hepatitis based on infection screening; 
QuantiFERON® TB test, T-SPOT® test or PPD skin test. And X-ray will be 
performed. If the result is positive, patients may participate in the study if further 
work-up (according to Japanese practice/guidelines) establishes conclusively that the 
patient has no evidence of active tuberculosis. If presence of latent tuberculosis is 
established, then treatment should have been initiated and maintained according to 
local country guidelines.
7.
Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal or squamous cell 
carcinoma of the skin or in situ carcinoma of uterine cervix.
8.
Evidence of a current or previous disease, medical condition (including chronic 
alcohol or drug abuse) other than psoriasis, surgical procedure (i.e., organ transplant), 


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medical examination finding (including vital signs and ECG), or laboratory value at 
the screening visit outside the reference range that is 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.
9.
History of allergy/hypersensitivity to a systemically administered biologic agent or its 
excipients
10.
Women who are pregnant, nursing, or who plan to become pregnant while in the trial
11.
Previous enrolment in this trial
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
All patients have the right to withdraw from the study at any time without the need to justify
their decision. The investigator has the right to remove patients from the study for 
noncompliance, administrative, or other reasons. It should be clearly understood that an 
excessive rate of withdrawals can render the study results uninterpretable. The sponsor 
reserves the right to remove any study patient from the trial for non-compliance.
An individual patient is to be withdrawn from trial treatment if:
∀
The patient withdraws consent for trial treatment or trial participation, without the need to 
justify the decision.
∀
The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, AEs, other diseases, or pregnancy)
∀
Development of a toxicity or AE which warrants BI 655066 discontinuation including but 
not limited to SAEs or suspected unexpected serious adverse reactions (SUSARs).
∀
If prohibited treatment is used during the study for any indication, the patient must 
discontinue use of the prohibited treatment if he/she wishes to continue in the study. In 
case of undue safety risk for the patient, the patient should discontinue study treatment at 
the discretion of the investigator. If the patient received a live virus vaccination during the 
study, the patient must discontinue study treatment.
∀
If the patient experiences an intolerable increase of psoriasis during the course of the trial 
the patient will be discontinued from the trial to receive rescue treatment as deemed 
appropriate by the investigator.
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and CML, is not willing or able to stick to the 
trial requirements in the future.
Discontinuation of study medication should not lead to withdrawal from the study. If possible 
the patient should complete all study visits and procedures as initially planned.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow-up as outlined in the Flow Chart and Section 6.2.3. If a patient
becomes pregnant, refer to Section 5.3.6.2 for instructions.
Patients who discontinue the trial after receiving the first dose of study medication at Visit 2


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will not be replaced.
For randomised patients leaving the study before the planned end of observation (EOO), their 
vital status should be collected at Week 56.
For randomised patients the reason for withdrawal (e.g., AEs) must be recorded in the case 
report form (CRF). These data will be included in the trial database and reported.
Discontinuation of the trial by the sponsor
3.3.4.2
BI/AbbVie 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 that could significantly affect continuation 
of the trial, or any other administrative reason (e.g., discontinuation of development of BI 
655066)
3. Violation of Good Clinical Practice (GCP), the clinical trial protocol (CTP), or the 
contract disturbing the appropriate conduct of the trial
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
INVESTIGATIONAL TREATMENTS 
4.1
Two different dose regimens of BI 655066 (risankizumab) and placebo to match BI 655066 
will be administered subcutaneously. All products will be supplied by BI.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Description of test product BI 655066
Substance:
BI 655066
Pharmaceutical form:
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Chemical form:
Anti-human IL-23p19 mAb
Molecular weight
Approximately 148 kDa
Unit Strength:
75 mg BI 655066 in a pre-filled syringe, concentration 
90 mg/mL
Route of administration:
Subcutaneous injection
Posology:
Week 0, Week 4, then every 12 weeks
Duration of use:
40 weeks 




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In conclusion, above two doses (75 mg and 150 mg) are selected for this trial.
4.1.3
Method of assigning patients to treatment groups
Through the utilisation of IRT, patients will be randomised to receive BI 655066 75 mg, BI 
655066 150 mg, placebo (BI 655066 75 mg after Week 16), or placebo (BI 655066 150 mg 
after Week 16) in a ratio of 2:2:1:1 (See Section 3.1).  
After the eligibility criteria are confirmed, the investigator or designee will randomise the 
patient on Day 1 (Visit 2) through IRT call or website entry. At visits where study medication 
is to be administered, study sites will be required to complete the medication resupply 
module in the IRT. Details regarding the use of the IRT are described in the site-user manual 
available in the ISF.
4.1.4
Drug assignment and administration of doses for each patient
An IRT will be used to allocate medication to patients through medication numbers. These 
visits where study medication is to be administered are specified in the Flow Chart. 
At randomisation as well as subsequent medication administration visits, IRT will assign 
medication numbers. Site personnel will enter the medication numbers in the eCRF. 
Study drugs will be administered subcutaneously. Injections will be given in a double-
blind/double-dummy fashion with each patient receiving 2 injections at each dosing visit:  2 
injections of BI 655066, one injection of BI 655066 and one injection of matching placebo or 
2 injections of matching placebo depending on randomized dosing group. Syringes will be 
administered per Flow Chart schedule as assigned by IRT. 
The injections at each visit, including injections of placebo necessary in order to assure 
blinding are presented in Table 4.1.4: 1.   
BI 655066 and/or matching placebo will be administered as a subcutaneous injection in the 
abdomen, thighs, gluteal regions, or upper arms (contra-lateral to that used for PK/ADA
samples). Injections should be at least 2cm apart and should not be close to a vein. The 
injection sites should avoid sites of psoriasis involvement as well as sites where the skin is 
tender, bruised, erythematous, or indurated, and should be alternated to other areas for 
subsequent doses. The 2 injections at each dosing visit should be administered within 
approximately 5 minutes.  Further information regarding injection details will be provided in 
the ISF.


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Table 4.1.4: 1
Dosing schedule
Dosing 
Visit1
BI 655066 low
dose arm
BI 655066 high 
dose arm
Placebo arm
(BI 655066
low dose 
after Week 16)
Placebo arm
(BI 655066
high dose
after Week 16)
Day 1
(Visit 2)
1 x active BI
1 x placebo
2 x active BI
2 x placebo
2 x placebo
Week 4
(Visit 3)
1 x active BI
1 x placebo
2 x active BI
2 x placebo
2 x placebo
Week 16
(Visit 6)
1 x active BI
1 x placebo
2 x active BI
1 x active BI
1 x placebo
2 x active BI
Week 28
(Visit 8)
1 x active BI
1 x placebo
2 x active BI
1 x active BI
1 x placebo
2 x active BI
Week 40
(EOT Visit)
1 x active BI
1 x placebo
2 x active BI
1 x active BI
1 x placebo
2 x active BI
BI=BI 655066 (risankizumab), EOT= end of treatment
1 Each patient will receive a total of 2 injections per dosing visit.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
After randomisation at Visit2, patients, Investigators and everyone involved in trial conduct 
or analysis or with any other interest in this double-blind trial will remain blinded with regard 
to the randomised treatment assignments until after final database lock.
The randomization code will be kept secret by clinical trial support up to final database lock.
The randomisation codes will be provided to bioanalytics prior to last patient out to allow
them to exclude PK samples of placebo patients from the bioanalytical analyses. Bioanalytics 
will not disclose the randomisation code or the results of their measurements until the trial is 
officially unblinded. Serum drug levels and demographic data together with treatment 
assignments and dosing information may be made available to individuals outside of the trial 
team for the purpose of PK dataset generation and analysis in accordance with sponsor’s 
standard procedures.
The randomisation code will be unblinded to personnel involved in the interim analysis.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the principal 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 


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trial participants. Each principal investigator receives a manual from the IRT provider that 
contains instructions on how to unblind the treatment of a patient via the IRT. If the code 
break for a patient is accessed, the sponsor must be informed immediately. The reason for 
accessing the code break, together with the date, must be documented in the source 
documents and/or the appropriate eCRF page along with the date and the initials of the 
person who broke the code. In case third party needs to break the code, however, when the 
Investigator cannot be reached, the code can be opened by calling emergency code manager
(Refer trial identification card).
Due to the requirements to report SUSARs, it may be necessary for a representative from 
BI’s Pharmacovigilance group 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 storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the sponsor must be 
contacted immediately. Refer to ISF.
Trial medication must be securely stored, e.g., in a locked refrigerator or at a pharmacy. The 
medication may only be dispensed to trial patients according to the CTP by authorised 
personnel as documented in the trial staff list.
4.1.8
Drug accountability
The investigator/pharmacist who is documented in the trial staff list/investigational drug 
storage manager will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:
∀
Approval of the trial protocol by the institutional review board (IRB)
∀
Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site,
∀
Notification of the regulatory authority, e.g., competent authority,
∀
Availability of the curriculum vitae of the principal investigator,
∀
Availability of a signed and dated CTP,


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∀
Availability of the proof of a medical license for the principal investigator 
The investigator/pharmacist who is documented in the trial staff list/investigational drug 
storage manager 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 who is documented in the trial staff list/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 or appointed CRO, the investigator/pharmacist
who is documented in the trial staff list/investigational drug storage manager must verify that 
no remaining supplies are in the Investigator’s possession.
All unused medication must be returned to the sponsor.
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (See Section 3.3) are 
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 psoriasis, as deemed by the 
investigator, during the course of the trial the patient will be discontinued from the trial to 
receive rescue treatment. 
In case of AEs in need of treatment symptomatic therapy according to investigator judgment 
will be permitted. All concomitant and/or rescue therapies will be recorded on the appropriate 
pages of the eCRF. 
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
The medications (or classes of medications) listed in Table 4.2.2.1: 1 must not be taken for 
the time periods as specified.  


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Table 4.2.2.1: 1
Restricted medications 
Medication or class of medications
Restriction duration
(through EOO Visit)
guselkumab , tildrakizumab
not allowed prior or during trial 
participation
briakinumab, ustekinumab (sterala®), secukinumab 
(Cosentyx®)
6 months prior to randomisation
Brodalumab (Lumicef®), ixekizumab (Taltz®)
4 months prior to randomisation
adalimumab (Humira®) , infliximab (Remicade®)
investigational products for psoriasis (non-biologics)
12 weeks prior to randomisation
etanercept (Enbrel®) 
live virus vaccinations
6 weeks prior to randomisation
any investigational device or product (excludes 
psoriasis products)
other systemic immunomodulating treatments (e.g.,
methotrexate, cyclosporine A, corticosteroids1, 
cyclophosphamide, tofacitinib (Xeljanz®), 
apremilast)
other systemic psoriasis treatments (e.g., retinoids, 
fumarates, any other drug known to possibly benefit 
psoriasis)
photochemotherapy (e.g., PUVA)
30 days prior to randomisation
phototherapy (e.g., UVA, UVB)
topical treatment for psoriasis or any other skin 
condition (e.g., corticosteroids2, vitamin D 
analogues, vitamin A analogues, retinoids, 
salicylvaseline, salicylic acid, lactic acid, tacrolimus, 
tar, urea,α-hydroxy [fruit acids])
14 days prior to randomisation
1  No restriction on corticosteroids with only a topical effect for non-skin indications (e.g., inhalative 
corticosteroids to treat asthma or corticosteroid drops used in the eye or ear).  
2  Exception: Topical steroids of medium such as Locoid or weak such as prednisolone for use on the 
face, axilla, and/or genitalia with a restriction of use within 24 hours prior to trial visit in which PASI 
is assessed.
Restrictions on diet and life style
4.2.2.2
Patients should be fasted for at least 8 hours prior to collection of the safety laboratory 
samples, starting from Visit 2. Moisturizers/emollients containing retinoids and the use of 
tanning beds are not allowed during the study.


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Restrictions regarding women of childbearing potential 
4.2.2.3
Female patients of childbearing potential should use the contraception methods described in 
Section 3.3.2 and the patient information.
TREATMENT COMPLIANCE
4.3
Study medication will be administered in accordance with the protocol by authorised study 
personnel (e.g., investigators and study nurse). The measured plasma concentrations will 
provide additional information about compliance.


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5.
VARIABLES AND THEIR ASSESSMENT
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The primary endpoints in this trial is the achievement of ≥90% reduction from baseline PASI 
score (PASI 90) at Week 16
5.1.2
Secondary Endpoints
Secondary Endpoints are:
•
Achievement of ≥90% reduction from baseline PASI score (PASI 90) at Week 52
•
Achievement of an sPGA score of clear or almost clear at Week 16
•
Achievement of an sPGA score of clear or almost clear at Week 52
•
Achievement of ≥75% reduction from baseline PASI score (PASI 75) at Week 16
•
Achievement of ≥75% reduction from baseline PASI score (PASI 75) at Week 52
•
Achievement of 100% reduction from baseline PASI score (PASI 100) at Week 16
•
Achievement of 100% reduction from baseline PASI score (PASI 100) at Week 52
•
Achievement of an American College of Rheumatology (ACR) 20 response at Week 16
•
Achievement of an ACR20 response at Week 52
5.1.3
Further Endpoints
The further endpoints are as follows:
•
Achievement of ≥50% reduction from baseline PASI score (PASI 50) at Weeks 16 and 52
•
Time until the first achievement of PASI 50, PASI 75, PASI 90, PASI 100 and sPGA 0 or 
1
•
Time until loss of PASI 75, PASI 90, PASI 100 and sPGA 0 or 1 response
•
Change from baseline in PASI score at Weeks 16 and 52
•
Percent change from baseline in PASI at Weeks 16 and 52
•
Absolute PASI of <3 at all visits collected
•
Achievement of an sPGA score of clear at Weeks 16 and 52
•
Change from baseline in psoriasis symptoms evaluated using the total score on the
Psoriasis Symptoms Scale (PSS) at Weeks 16 and 52
•
Achievement of a Dermatology Life Quality Index (DLQI) score of 0 or 1 at Weeks 16
and 52
•
Achievement of total score on the PSS of 0 at Weeks 16 and 52
•
Change from baseline in DLQI at all Weeks 16 and 52
ASSESSMENT OF EFFICACY
5.2
The skin condition will be assessed by using the PASI, sPGA, and other relevant scores as 
described in Section 5.1 and the ISF.  
Symptoms, quality of life, and physical function will be assessed by PSS and DLQI.
PsA assessment will be assessed by using ACR 20.
Details of the efficacy assessments are listed in Appendix 10.


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ASSESSMENT OF SAFETY
5.3
Safety will be assessed descriptively based on: 
•
Adverse events
•
Serious adverse events
•
Clinical laboratory values (haematology, clinical chemistry, and urinalysis) 
•
Intensity of AEs will be assessed by Rheumatology Common Toxicity Criteria (RCTC) 
version 2.0 (refer to ISF for details)
5.3.1
Physical examination
Complete and targeted physical examinations will be performed at visits as described in the 
Flow Chart. Complete physical examination will include vital signs assessment and general 
appearance as well as evaluation of all relevant organ systems. Targeted physical 
examination will include vital signs assessment and evaluation of organ systems associated 
with AE(s) symptoms or laboratory abnormalities.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
Waist circumference
5.3.1.1
Waist circumference measurements should be made around a patient’s bare midriff, after the 
patient exhales while standing without shoes and with both feet touching and arms hanging 
freely. The tape should be placed perpendicular to the long axis of the body and horizontal to 
the floor and applied with sufficient tension to conform to the measurement surface. Waist 
circumference should be determined by measuring the midpoint between the lowest rib and 
the iliac crest.
Body Weight
5.3.1.2
Body weight measurements should be done on the same scale for each patient. In order to get 
comparable body weight values, it should be performed in the following way:
∀
fasting (except for the screening visit)
∀
after the urine sampling (body weight after bladder voiding)
∀
shoes and coat/jackets should be taken off
∀
pockets should be emptied of heavy objects (i.e., keys, coins, etc.)
5.3.2
Vital Signs
Vital signs evaluations will be performed at visits as shown in the Flow Chart. This includes 
systolic/diastolic blood pressure, pulse rate, temperature, and respiratory rate. Blood pressure, 
pulse rate, and respiratory rate will be measured after patients have been sitting comfortably 
for at least five minutes. Measurement of vital signs should precede blood sampling to avoid 
the impact of blood sampling on the vital measurements. At dosing visits vital signs 


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evaluations will be performed pre-dose and at Visit 2 and Visit 3 additional evaluations will 
be taken at approximately 5 minutes post-dose (5 minutes after last injection) and 
approximately 60 minutes post-dose (60 minutes after last injection). 
Patients should be closely monitored for signs and symptoms of hypersensitivity reactions for 
approximately 2 hours after the last injection at Visit 2 and for approximately 1 hour after the 
last injection at all other visits with drug administration. Hypersensitivity reactions should be 
treated according to medical standards. Pre-medications for further injections might be 
considered and will be agreed on between investigator and BI clinical monitor.
5.3.3
Safety laboratory parameters
The laboratory tests listed in Table 5.3.3: 1 will be performed by the central laboratory 
service provider. A local laboratory may be used for selected tests in exceptional cases. 
Patients should be fasting for at least 8 hours prior to the blood sample being taken (except 
screening visit).
Instructions regarding sample collection, sample handling/processing, and sample shipping 
are provided in the Laboratory Manual in the ISF. For time points of laboratory sampling, see 
Flow Chart.
Laboratory results (i.e., all safety laboratory and clinical laboratory data relevant for current 
clinical practice) of the patients will be available in real time to the respective investigator 
(via laboratory reports) and to the sponsor (via the central laboratory website) and selected 
abnormal laboratory alerts will be flagged to the site and sent to sponsor in real time. 
Clinically relevant abnormal findings will be reported as baseline conditions or AE’s. A 
clinically relevant value may be either in or outside the reference range. Clinically relevant 
abnormal laboratory test results must be confirmed using an unscheduled visit laboratory kit 
and should be repeated until normalisation or stabilisation or until an alternative explanation 
has been found. Abnormal laboratory values will be also graded for intensity by using RCTC 
Version 2.0 criteria (R13-3515).  
Table 5.3.3: 1 
Laboratory tests
Category
Test name
Haematology
Hematocrit
Hemoglobin (Hb)
Glycosylated Hbc (HbA1c) 
Red Blood Cell Count/Erythrocytes
Reticulocyte Count
White Blood Cells/Leukocytes
Platelet Count/Thrombocytes
Differential 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)


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Table 5.3.3: 1 (continued)
Laboratory tests
Category
Test name
Differential Manual (if Diff erential 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)
Amylase
Lipase
Electrolytes
Calcium
Sodium
Potassium
Chloride
Bicarbonate
Substrates
Glucose
BUN
Uric acid
Creatinine
eGFR (estimated by CKD-EPI formula)
Bilirubin Total
Bilirubin Direct (if total is elevated)
Bilirubin Indirect (if total is elevated)
Troponin (reflex, in case of elevated CK)
Albumin
C-Reactive Protein (CRP) (high sensitivity)
Cholesterol, total
Triglycerides
LDL-Cholesterol
HDL-Cholesterol
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 T3and T4 in case of abnormal TSH) 
Autoantibodies (only at screening)
Rheumatoid Factor


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Table 5.3.3: 1 (continued)
Laboratory tests
Category
Test name
Urinalysis (dipstick)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/Erythrocytes
Urine WBC/Leukocytes
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
Albumin/creatinine ratio
Infection screening
Hepatitis B Surface Antigen (qualitative)1
Hepatitis B Surface Antibody (qualitative) 1
Hepatitis B Core Antibodies total (qualitative) 1
Hepatitis B Virus DNA (quantitative) 1, 2Hepatitis 
C Antibodies (qualitative)1 
HIV-1, and HIV-2 Antibody (qualitative)1,2
QuantiFERON®-TB3 (if appricable)
1 Hepatitis B, hepatitis C and HIV testing will be performed at screening and FU2/EOO Visit.
2 If Hepatitis B Surface Antigen is negative but Hepatitis B Core Antibodies total is positive and/or 
Hepatitis B Surface Antibody is positive, Hepatitis B Virus DNA will be quantified. If HBV DNA 
level is undetectable (<20 IU/mL) at screening, the patient can participate in this trial. However, 
HBV DNA level will be monitored at least every 6 months.
3 TB testing will be performed at screening and FU2/EOO Visit. QuantiFERON®, T-SPOT® or PPD 
skin test may be performed. T-SPOT® and PPD skin test will be performed at local laboratory.
5.3.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart.
ECGs will be recorded after the patients have rested for at least 5 minutes in a supine position 
and will always precede blood sampling. Six limb leads, as specified by Einthoven (I, II and 
III) and Goldberger (aVR, aVL, aVF), and six pre-cordial leads (V1–V6), according to 
Wilson, will be used. 
ECGs may be repeated for quality reasons and the repeat used for analysis. Additional ECGs 
may be collected for safety reasons. Clinically relevant, abnormal findings will be reported as 
AEs.
Information about the details of ECG collection and the parameters assessed will be provided 
in the ISF.


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ECGs will be read and evaluated by a central vendor. The study site will be informed about 
the results of the assessment of the ECG obtained at screening and if there are findings which 
would exclude the patient from study participation according to exclusion criterion in Section 
3.3.3.
The electronic version of the ECG is regarded as source data.
5.3.5
Other safety parameters
Local tolerability at the administration site of the subcutaneous injection will be assessed by 
the investigator according to “swelling”, “induration”, “heat”, “redness”, “pain”, or “other 
findings” at the specified visits as noted in the Flow Chart. This assessment should be done 
pre-dose.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any 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.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and
unintended. Response in this context means that a causal relationship between a medicinal
product and an AE is at least a reasonable possibility. Adverse reactions may arise from use 
of the product within or outside the terms of the marketing authorisation or from occupational 
exposure. Conditions of use outside the marketing authorisation include off-label use, 
overdose, misuse, abuse, and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:
∀
results in death,
∀
is life-threatening, this 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 
∀
prolongation of existing hospitalisation,
∀
results in persistent or significant disability or incapacity, or
∀
is a congenital anomaly/birth defect, or


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∀
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations
should be considered serious reactions, such as important medical events that might not be
immediately life threatening or result in death or hospitalisation but might jeopardise the
patient or might require intervention to prevent one of the other outcomes listed above.
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. Any suspected transmission via a medicinal product 
of an infectious agent is also considered a serious adverse reaction.
The following events will be handled as “deemed serious for any other reason”. 
An AE which possibly leads to disability will be reported as an SAE.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious
event regardless of the duration between discontinuation of the drug and the occurrence of the
cancer.
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 given above.
The latest list of “Always Serious AEs” can be found in the EDC-system. These events 
should always be reported as SAEs as given 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. 
AESI need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE. 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
•
marked peak 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.


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In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity 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
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterised by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge,
confounding factors such as concomitant medication, concomitant diseases and relevant
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship
could be:
• The event is consistent with the known pharmacology of the drug
• The event is known to be caused by or attributed to the drug class.
• A plausible time to onset of the event relative to the time of drug exposure.
• Evidence that the event is reproducible when the drug is re-introduced
• No medically sound alternative etiologies that could explain the event (e.g., preexisting 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 week 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).


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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 study drug treatment continues or remains
unchanged.
Adverse event collection and reporting
5.3.6.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate CRF by the investigator:
∀
From signing the informed consent onwards through the residual effect period (REP) until 
individual patient’s end of trial:
-
all AEs (serious and non-serious) and all AESIs.
However, if an individual patient discontinues trial medication prematurely but stays in 
the trial (i.e., if further visits including telephone visits, or vital status assessments are 
planned) from then on and until the individual patient’s end of the trial the investigator 
must report related SAEs and related 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 relevant SAEs and relevant AESIs of which the investigator may become aware of.
The REP is defined as 15 weeks after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment please see Section 7.3.4. Events which occurred after the REP will be considered as 
post treatment events.
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.
All SAEs and AESIs must be reported immediately to the head of the trial site.
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
CRF pages and the BI SAE form. The Investigator should determine the causal relationship
to the trial medication. 
The following should also be recorded as an (S)AE in the eCRF and SAE form (if 
applicable):
∀Worsening of the underlying disease or of other pre-existing conditions
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In the rare case pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (contact details will be provided in the ISF). The Pregnancy Monitoring 
Form for Clinical Trials (Part A) should be used. 
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 


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is to be completed. If there is an SAE and/or AESI associated with the pregnancy as an SAE 
form must be completed in addition. 
Adverse event(s) due to Medical device failure of trial medication
The investigator must report “Medical device failure” that leads to AEs or is judged as a 
potential cause for leading SAEs by the investigator, on the Product/Device Complaints 
Form to the sponsor, see the instruction in ISF. “Medical device failure” that lead to SAEs 
and/or AESIs or is judged as a potential cause for leading SAE must be reported to the 
sponsor’s Pharmacovigilance Department immediately.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
BI 655066 concentrations will be reported descriptively. No PK parameters will be calculated. 
PK data will be incorporated into a larger pharmacometric analysis with other trials of BI 
655066 project. The relationship between PK and selected efficacy endpoints, biomarkers,
and AEs may be assessed. PK and demographic data together with treatment assignments and 
dosing information may be made available to individuals outside of the trial team for the 
purpose of PK dataset generation in accordance with sponsor’s standard procedures.  
Detailed information on timing for dosing, PK and ADA sampling is provided in the Flow 
Chart. Date and exact clock time of drug administration and PK and ADA sampling will be 
recorded on eCRFs. These actual administration and sampling times will be used for 
determination of PK parameters. On visits with study medication dosing, PK and ADA 
sampling should occur prior to the drug administration.
5.4.2
Methods of sample collection
Plasma sampling for pharmacokinetic analysis 
5.4.2.1
For quantification of analyte plasma concentrations, approximately 3 mL of blood will be 
taken at the time points listed in the Flow Chart under PK sampling. For details on sample 
handling and logistics refer to the ISF (Laboratory Manual).  
After completion of the study, plasma samples may be used for further methodological 
investigations, e.g., stability testing. However, only data related to the analyte will be 
generated by these additional investigations.  
Plasma sampling for ADA
5.4.2.2
For ADA assessment, approximately 3 mL of blood will be taken at the time points listed in 
the Flow Chart under ADA sampling. For details on sample handling and logistics refer to the 
ISF (Laboratory Manual). Following the finalisation of the ADA bioanalytical report, 
selected ADA aliquots may be transferred to long term storage for possible additional ADA 
characterisation in the future.


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5.4.3
Analytical determinations
BI 655066 concentrations will be determined by a validated Enzyme Linked Immunosorbent 
Assay (ELISA).
The presence of ADA to BI 655066 will be assessed via a tiered approach using a validated 
electrochemiluminescence assay (screening, confirmatory, and titration analysis as 
appropriate). Samples that are confirmed positive may be further characterised in a validated 
neutralising antibody assay.
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Refer to Section 7.3.6.
ASSESSMENT OF BIOMARKERS 
5.5
5.5.1
Assessment of soluble protein biomarkers
Serum will be collected to assess changes in protein levels of disease specific markers such as 
but not limited to #-defensin 2, neutrophil gelatinase associated lipocalin-2 (NGAL), S-100 
A8 protein and adiponectin over time. In addition, changes in levels of biomarkers related to 
metabolic syndrome such as leptin, resistin, TNFa, IL-6 and VEGF will be explored.
Methods of sample collection
5.5.1.1
Approximately 8.5 ml of blood will be collected at time points indicated in the Flow Chart.
Samples should be collected prior to administration of study drug at dosing visits. For details
on sample handling and logistics refer to the ISF (Laboratory Manual).
Analytical determinations
5.5.1.2
These biomarkers are considered exploratory and respective assays will need to be qualified
to meet the required performance criteria.
5.5.2
Biomarker sample banking
After completion of the study any unused serum samples collected for biomarker sampling as 
listed in Section 5.5.1 may be used for further investigations (e.g., additional biomarkers for 
immunological & inflammatory diseases), if participation and the informed consent for 
biomarker sample banking is agreed upon by the patient. Declination to allow storage and use 
of these samples will not preclude participation in this study. The study samples will be 
stored for a maximum period of 15 years (under consideration of local legislation and if 
consented by the patient) upon archiving of the final study report after study completion.


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5.5.3
DNA Banking
Participation in the DNA banking sampling is voluntary and not a prerequisite for
participation in the trial. The patient must provide informed consent for participation in this
optional testing prior to any blood sampling used for DNA banking. The DNA banking
sample will be stored in accordance with local ethical and regulatory requirements.
Methods of sample collection
5.5.3.1
One blood sample for DNA banking will be taken at Visit 2. A maximum of 8.5 mL blood
will be collected per PaxGene DNA blood sampling tube. For details on sample handling and
logistics refer to the ISF (Laboratory Manual).
Analytical determinations
5.5.3.2
The DNA banking sample, derived from the original blood sample, will be stored at BI 
and/or AbbVie. The stored DNA may be retrospectively analysed, e.g., to identify whether 
there are other genetic factors that could contribute to a better therapeutic outcome or a 
higher risk of developing treatment-related adverse drug reactions.
OTHER ASSESSMENTS
5.6
Not applicable.
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements performed during this trial are standard measurements in psoriasis 
treatment trials and will be performed in order to monitor safety aspects or assess treatment 
response in an appropriate way.
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
All patients are to adhere to the visit schedule as specified in the Flow Chart. 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.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
Study procedures to be performed at each visit are listed in the Flow Chart and the respective 
protocol sections. Refer to Section 5 for explanations of procedures. Additional details on 
procedures at selected visits are provided below.
Measurement of vital signs should precede blood sampling and be assessed pre-dose at all 
dosing visits.  
Patient reported outcome (PRO)s should be completed by the patient on his/her own in the
pre-specified order (as programmed on the electronic device) 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 order of completion for PROs is as follows, as applicable for each PRO at relevant visits 
according to the Flow Chart:
(1) PSS
(2) DLQI
(3) HAQ-DI (for PsA assessments) 
(4) Pain visual analog scale (VAS) (for PsA assessments)
(5) Patient global assessment VAS (for PsA assessments)
6.2.1
Screening period
No trial procedures should be done unless the patient has consented to taking part in the trial.
Once consented, the patient is considered to be enrolled in the trial and has started screening. 
The patient number should be recorded on the enrolment log and registered in IRT as a 
screened patient.
Screening (Visit 1) should normally take place no more than 42 days before Visit 2 and be 
completed no less than 14 days prior to Visit 2. 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.


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Infection screening
Refer to exclusion criteria Section 3.3.3 with study participation directive for patients with a 
positive QuantiFERON®, T-SPOT®, or PPD skin test for TB.
Demographics
Informed consent date, sex, ethnicity and race will be collected and reported in the eCRF.
Medical History
Cardiovascular (CV) History and CV risk factors will be collected and reported in the 
Medical History eCRF page. 
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety laboratory tests, and any condition 
requiring therapy (excluding psoriasis) will be reported on the Baseline Condition CRF page.
Psoriatic Arthritis Diagnosis Assessment
At Visit 1, all patients with a positive medical history of psoriatic arthritis will be further 
evaluated for psoriatic arthritis (PsA) diagnosis based on CASPAR (ClASsification of 
Psoriatic Arthritis) criteria (R15-1001). See Appendix 10.3 for further details
IRT
All patients who are screened must be registered with IRT. If the patient results in a screen 
failure, IRT should be notified as soon as possible and within the 42-day screening period. 
Details of IRT procedures can be found in the IRT manual located in the ISF.
For the comprehensive list of the trial procedures required at the Screening Visit (Visit 1) 
please refer to Flow chart.
6.2.2
Treatment period
The treatment period is from Visit 2 to EOT Visit.  
Visits 2, 4, 6, 8, EOT, and FU2/EOO will be performed in fasted state (8 hours no food and 
only water). If a patient comes in non-fasted where a fasting condition is required, the visit 
should be performed, the non-fasted condition documented on the laboratory requisition, and 
the patient reminded about the expected conditions.
Urine pregnancy testing for all woman of child-bearing potential will be conducted on-site 
prior to every dosing and must be negative to further treat the patient. A positive urine test 
must be confirmed with a serum pregnancy test.
Randomisation via IRT and administration of study medication should be the last activity at 
Visit 2.
Venipuncture (i.e., safety laboratories, PK, ADA, biomarkers) should be the last procedure 
prior to study drug administration.


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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.
Early treatment and trial termination 
6.2.3.1
If study medication is discontinued prior to the planned Flow Chart EOT visit, every effort 
should be made to have the patient continue in the trial and complete all of the remaining 
Treatment Period Visits, as well as Follow-Up 1 and Follow-Up 2 Visits.  Trial termination 
should be completed at Follow-Up 2 Visit and Follow-Up 3 Visit should not be completed. 
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 Follow-Up 
3/End of Observation (FU3/EOO) Visit 16 weeks after last dose of study medication.
Patients who discontinue treatment early should be registered as withdrawn/discontinued in 
IRT will not have the option to participate in the extension trial.   
Trial completion
6.2.3.2
Patients who finish the randomised treatment period will return to the clinic for Follow-Up 1 
Visit (FU1) and Follow-Up 2 Visit (FU2). Completion is defined as a patient having reached 
the FU2 visit within the specified window per the Flow Chart. Patients who complete the 
randomised treatment period without early treatment discontinuation will have the option to 
participate in the extension trial.  
After FU1 Visit, the Flow Chart visit schedule is dependent on extension participation:
∀
Patient who will not participate in the extension trial will return to the clinic 
for FU2/EOO Visit and FU3/EOO Visit. Trial termination will be completed 
at FU3/EOO. The decision not to enter the extension trial will be registered in 
IRT at FU2/EOO Visit.
∀
Patients who participate in the extension trial will complete FU2/EOO as the 
final 1311.38 study visit. Trial termination will be completed at FU2/EOO and 
registered in IRT.  


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a confirmatory, multicentre, randomised, double-blind, double-dummy, placebo 
controlled study evaluating the efficacy and safety of two different dose regiments of BI 
655066 in patients with moderate to severe chronic plaque psoriasis. The primary objective of 
this trial is to assess the safety and efficacy of two different dose regiments of BI 655066 in 
comparison to placebo in patients with moderate to severe chronic plaque psoriasis.
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.
Randomisation will be stratified by concomitant disease of PsA at baseline (Yes versus No) 
and body weight (≤ 90 kg versus >90 kg). Based upon these design considerations and the 
binary nature of the primary endpoint of PASI 90, they will be analysed using the Cochran-
Mantel-Haenszel risk difference estimate stratified by the randomisation factors mentioned 
previously.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The primary hypotheses is that either BI 655066 150 mg or BI 655066 75 mg is superior to 
placebo in achieving ≥90% reduction from baseline in the PASI score (PASI 90) at Week 16 
in participants with moderate to severe chronic plaque psoriasis.
In order to maintain the full significant level of 5%, the following null hypotheses will be 
tested using fixed-sequence method in the following order, with two-sided alpha level of 
0.05.
1. BI 655066 150 mg is not different from placebo with respect to PASI 90 response at 
Week 16
2. BI 655066 75 mg is not different from placebo with respect to PASI 90 response at 
Week 16
PLANNED ANALYSES
7.3
The efficacy analyses will be based on the intent-to-treat principle, comprising all 
participants who were randomised. Efficacy analyses will be based on the planned treatment 
(i.e., the treatment assigned at randomisation); this set of patients is called the Intent-to-treat 
Population (ITT Population). Safety analyses will be performed on a Safety Population, 
comprising all randomized participants who received at least one dose of study drug. The 


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safety analysis will be performed based on the actual treatment received at the randomisation 
visit.
To evaluate the impact of protocol deviations on the primary endpoint, additional analyses 
will be performed on a Per-protocol (PP) Population.  The PP Population will include those 
who were most compliant with the protocol in ways that could impact the primary endpoint. 
Final results and the criteria for exclusion of subjects will be finalized prior to the blind 
break. 
The PP Population is defined as all subjects from the ITT Population who meet all the 
following criteria:
●
Subjects must receive at least 75% of planned study drug injections during the 
first 16 Week.  
●
Subjects must have a PASI assessment post-baseline.
●
Inclusion Criterion 2:  Subjects must have stable moderate to severe chronic 
plaque psoriasis at baseline:
○
Have an BSA ≥ 10% and
○
Have a PASI ≥ 12 and
○
Have an sPGA ≥ 3.
PP Populations will be analyzed by treatment group as randomized. 
7.3.1
Primary endpoint analyses
The achievement of PASI 90 at Week 16 is the primary endpoint and is a binary variable with 
values of 0 or 1. The difference in proportion responding between the BI 655066 arm and 
placebo arm will be estimated and tested using the Cochran-Mantel-Haenszel risk difference 
estimate stratified by the randomisation factors of concomitant disease of PsA at baseline 
(Yes versus No) and body weight (≤90 kg versus >90 kg) with weights proposed by 
Greenland & Robins, which is calculated as follows:
 = ∑

 ∙


∑




, 
ℎ
 = 

−

 ℎ     !" ,  = 1, ⋯, "

 =  ∙
 + 
 ℎ 
&ℎ  !" ,  = 1, ⋯, "
  ℎ "'  (! 
ℎ)  ! !" ,  = 1, ⋯, "
  ℎ "'  (! 
ℎ)  !* !" ,  = 1, ⋯, "
  ℎ "'  (!  ! !" ,  = 1, ⋯, "
  ℎ "'  (!  !* !" ,  = 1, ⋯, "
The estimated variance
is calculated as:
)!
+ ,- =
∑
.


(∑




)*


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ℎ . = ( −) 
1 + ( −) 
1
 ∙ ∙( + )*
,  = 1, ⋯, "
Assuming a normal distribution of 
, an approximate 95 % CI is given as follows, where 
z0.975 is the 97.5% quantile of the standard normal distribution:
23 = 4 ± 67.9:; ∙<)!
+ ,-=
Also, the approximate p-value can be calculated using the following:
()!>" = 2 ∙@
⎣
⎢
⎢
⎡
D > FF

<)!
+ ,-
FF
⎦
⎥
⎥
⎤
, 
ℎ D ~ K(0, 1)
If there is a stratum for a treatment group that has 0 patients in it, the 0 count will be replaced 
by 0.1 in order to prevent dividing by 0 in the above equations, as suggested in Greenland & 
Robins. Treatment versus placebo comparisons will include both a p-value and 95% 
confidence interval.
7.3.2
Secondary endpoint analyses
The same methods as discussed for the primary analyses will be used to analyse all binary
secondary endpoint at Week 16.
Secondary endpoints for Week 52 will be summarised descriptively.
7.3.3
Further endpoint analyses
Change from baseline in PSS at Week 16 will be analysed by the van Elteren test between the 
BI 655066 arm and placebo arm. The other further endpoints will be summarised 
descriptively, with number and proportion of responders for dichotomous endpoints and 
mean, median, SD and IQR presented for continuous variables.
Time to onset of Endpoint, the time to event will be calculated as: 
∀
Time to first onset (with observed event) = [date of first onset] – [date of first active 
treatment] + 1
∀
If a patient never attains Endpoint (e.g., PASI75 or PASI90), then that patient’s time 
to first onset will be censored at the last visit where the Endpoint was measured (e.g., 
PASI).
Time to Loss of Endpoint (from time of randomisation), defined using the following
algorithm:
a) Never attains Endpoint (Failure at time 0)
b) After achieving Endpoint, patient will be a failure if they subsequently do not
achieve Endpoint and either discontinue from the study or switch therapy


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while still not achieving Endpoint. Time to failure will be calculated using
date of first failure to achieve Endpoint.
c) Patients randomised to placebo will have Week 16 (i.e. when they begin
taking BI 655066) as Day 0 for determining Time to Loss of response.
d) Patients who maintain Endpoint throughout the study will be censored at their
last measurement
Time to Loss of Endpoint (from time of achieving Endpoint or from specific point in time) 
will be defined as above but only for those patients that have achieved Endpoint.
All Time to Event endpoints will be presented using Kaplan-Meier curves.
As sensitivity analysis, the primary and secondary endpoints will be analysed in the same 
way based on PP Population.
7.3.4
Safety analyses
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. Standard AbbVie summary tables and listings will be produced. All AEs with an 
onset between start of treatment and end of the REP, a period of 15 weeks after the last dose 
of trial medication, will be assigned to the 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 AbbVie standards. No hypothesis testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between start of treatment and end of the REP will be considered 
‘treatment-emergent’. The residual effect period is defined as 15 weeks after the last trial 
medication application. Adverse events 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 MedDRA.
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 highlighted in the 
listings. 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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7.3.5
Pharmacokinetic analyses
Descriptive statistics of BI 655066 concentration measurements by treatment group and visit 
will be provided.
PK data will be analysed using population PK approaches. For this purpose, data may also be 
combined with data from other trials and the results will be reported separately from the 
clinical trial report (CTR). Detail of the population PK analysis plan will be specified 
separately.
7.3.6
Pharmacodynamic analyses
No formal analysis of pharmacokinetic-pharmacodynamic relationships is planned. As the 
data from previous trials with BI 655066 suggest a PK- PD relationship for efficacy 
endpoints such as PASI, population PK-PD analyses will be performed. For this purpose, data 
may also be combined with data from other trials. Model based analyses will be planned and 
documented separately according to internal and external guidelines and SOPs. Other 
exploratory analyses of drug concentration, biomarker, or safety data may be performed using 
data obtained as part of this trial.
7.3.7
Biomarker analyses
Changes in serum protein biomarker levels over time will be described by treatment group. 
INTERIM ANALYSES
7.4
Before the submission to regulatory agencies with the long-term data, an interim report will 
be prepared for the submissions. An analysis will be conducted when the last patient 
completes the Week 28 visit. Primary endpoint (PASI 90 score at Week 16) for all patients 
will be included in the Week 28 analyses; hence no alpha adjustment is required at the Week 
28 analysis. For this analysis all efficacy endpoints and safety as well as PK and 
immunogenicity data will be analysed. As endpoints for Week 28, same analyses will be 
performed for the Week 52 endpoints defined in Section 5.
An independent team will be unblinded to perform this analysis. Unblinded treatment 
assignments will not be disseminated to the sites, investigators, or patients until the end of 
final database lock. 
HANDLING OF MISSING DATA
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 (No Response Imputation [NRI])


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-
If data at visits before and after, only impute as success if both visits are 
successes;
else impute as failure
Missing items from the PROs will be handled according to the respective measure
instructions (cf. Appendix 10.3). If there is no data for a particular visit, then it will be 
imputed following the same rules as described above.
Sensitivity analyses to assess the robustness of the hypothesis testing results will include:
∀
LOCF (for binary endpoints)
∀
Logistic regression
∀
MMRM (for continuous endpoints)
∀
Multiple imputation (for binary endpoints)
RANDOMISATION
7.6
Patients will be randomised in blocks to double-blind treatment, stratified by concomitant 
disease of PsA at baseline (Yes versus No) and body weight (≤90 kg versus >90 kg). Patients 
will be randomised to 4 sequences in a ratio of 1:1:2:2 within each level of stratification. 
Sequence 1: Weeks 0-16: Placebo, Weeks 16-52: BI 655066 75 mg
Sequence 2: Weeks 0-16: Placebo, Weeks 16-52: BI 655066 150 mg
Sequence 3: Weeks 0-16: BI 655066 75 mg, Weeks 16-52: BI 655066 75 mg
Sequence 4: Weeks 0-16: BI 655066 150 mg, Weeks 16-52: BI 655066 150 mg
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation lists 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 sizes will be documented in the CTR. Access to the codes will be 
controlled and documented.
DETERMINATION OF SAMPLE SIZE
7.7
The study is powered to show a benefit of BI 655066 over placebo in terms of PASI 90 
response at Week 16. Based on the outcome from the trial 1311.2, the PASI 90 response rate 
at Week 16 is assumed to be at least 65% in the BI 655066 arm. There is only minimal data 
available on placebo response in the BI 655066 program but the phase 3 results from 
ustekinumab and secukinumab indicate a response rate for PASI 90 of approximately 5% in 
the placebo arm. With 2-sided significance level 5%, based on these assumptions (65% vs 5% 
PASI 90 response rates), 17 patients in the BI 655066 arm and 17 in the placebo arm will 
provide 95% power for each comparison and an overall power of at least 90%.
For the Japanese submission, the safety data of at least 100 Japanese patients exposed to BI 
655066 at the registered dose(s) for 1 year or more is necessary for long team safety 
assessment as a result of the PMDA consultation meeting in 2015. This study will enrol a 
total of 168 patients, with 56 patients in each of the two BI 655066 arms and 56 patients in 
the placebo arm. It is expected that at least 68 patients exposed to BI 655066 75 mg and 68 


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patients exposed to BI 655066 150 mg will reach at least 1 year exposure to BI 655066 in this 
clinical trial or in the following extension study. Other global phase III trials where Japanese 
patients are to be enrolled will make up for the remaining safety data requirements. 


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
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 Harmonised Tripartite Guideline 
for GCP, relevant BI Standard Operating Procedures (SOPs), the Japanese GCP regulations 
(Ministry of Health and Welfare Ordinance No. 28, March 27, 1997) and other relevant 
regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in 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 subjects against any immediate hazard, and also of any serious breaches of 
the protocol, of ICH GCP, or the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997).
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor with regard 
to publication of the results of this trial are described in the contract with trial site. As a rule, 
no trial results should be published prior to finalisation of the CTR.
The rights of the Investigator/trial site and of the sponsor with regard to publication of the 
results of this trial are described in the Investigator contract/trial site’s contract. As a general 
rule, no trial results should be published prior to finalisation of the CTR.
The certificate of insurance cover is made available to the Investigator and the patients, and is 
stored in the ISF (Investigator Site File).
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB 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 Japan. 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 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 obtains written consent of the patient’s own free 


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will with the informed consent form after confirming that the patient understands the contents. 
The Investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, by IRB 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.
RECORDS
8.3
Case report forms 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 subject 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.
Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g., patient’s name, initials, address, phone number) have 
properly been removed or redacted to ensure patient confidentiality.
If the patient is not compliant with the protocol, any corrective action e.g., re-training must be 
documented in the patient file.
For the eCRF, data must be derived from source documents, for example:
∀
Patient identification: gender, date or year of birth


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∀
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 (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 on-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 on-site trial-related monitoring, audits, IRB review and 
regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g., PMDA). The CRA and auditor may review all eCRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol, ICH 
GCP, and Japanese GCP.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to the 
national or Japanese requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
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 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, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular
∀
A Quality Management System has been implemented to ensure the adherence with 
the Principles of GCP as outlined in 'Note For Guidance On Good Clinical Practice' 
(CPMP/ICH/13 5/95)
∀
The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by BI are regularly audited. The analytical groups and the banking facility
are therefore assessed to be qualified for the storage and use of biological samples and 
data collected in clinical trials.
∀
Samples and data are used only if an appropriate informed consent is available.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment pf the first patient in the whole 
trial.
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 Drug Discontinuation” (LPDD) date is defined as 
the date on which the last patient at an individual trial site ends trial medication (as scheduled 
per protocol or prematurely). Individual Investigators will be notified of SUSARs occurring 
with the trial medication until 30 days after LPDD at their site. Early termination of the 
trial is defined as the premature termination of the trial due to any reason before the end of 
the trial as specified in this protocol.


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Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
When the trial is completed, the Investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
sponsor of the completion in writing.
PROTOCOL VIOLATIONS
8.7
The Investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal Investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
R96-2379
Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. 
American College of Rheumatology. Preliminary definition of improvement in 
rheumatoid arthritis. Arthritis Rheum 1995. 38(6): 727-735
R96-3541
Fredriksson T, Pettersson U. Severe psoriasis - oral therapy with a new 
retinoid. Dermatologica 1978. 157: 238-244.
R05-2548
Finlay AY, 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 Jul 1993 Clin Exp Dermatol 1994. 19: 210-216
R08-1089
Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. 
Nature 2007. 445(7130): 866-873.
R11-1257
Nestle FO, Kaplan DH, Barker J. Mechanisms of disease: psoriasis. N Engl J 
Med 2009. 361(5): 496-509.
R11-1259
Menter A, Griffiths CEM. Psoriasis 2: current and future management of 
psoriasis. Lancet 2007. 370: 272-284.
R11-1547
Smith RLI, Warren RB, Eyre S, Ho P, Ke X, Young HS, et al. Polymorphisms 
in the IL-12beta and IL-23R genes are associated with psoriasis of early onset 
in a UK cohort. J Invest Dermatol 2008. 128: 1325-1327.
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, et al.
Standardizing assessment and reporting of adverse effects in rheumatology 
clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0. J 
Rheumatol 2007. 34(6): 1401-1414
R14-3559
Revicki DA, Jin Y, Wilson HD, Chau D, Viswanathan HN. Reliability and 
validity of the psoriasis symptom inventory in patients with moderate-to-
severe psoriasis. J Dermatol Treat 2014. 25(1): 8-14.
R14-3562
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 
2013. 24(5): 356-360.
R14-5159
Reich K, Puig L, Paul C, Kragballe K, Luger T, Lambert J, et al. One-year 
safety and efficacy of ustekinumab and results of dose adjustment after 
switching from inadequate methotrexate treatment: the TRANSIT randomised 
trial in moderate-to-severe plaque psoriasis. Br J Dermatol 2014. 170(2): 435-
444.


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R15-1001
Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H; 
CASPAR Study Group. Classification criteria for psoriatic arthritis: 
development of new criteria from a large international study. Arthritis Rheum 
2006. 54: 2665-73.
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 2013. 24(4): 255-260.
R15-1393
Davidovici BB, Sattar N, Joerg PC, Puig L, Emery P, Barker JN, et al;
Psoriasis Education and Learning Syllabus (PEARLS). Psoriasis and systemic 
inflammatory diseases: potential mechanistic links between skin disease and 
co-morbid conditions. J Invest Dermatol 2010. 130(7): 1785-1796.
R15-1410     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 2014. 53(6): 714-722.
R15-1411     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 2013. 16(6): 1014-1022.
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 2008. 159: 997-1035.
R15-3846
Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: a review of
its history, issues, progress, and documentation. J Rheumatol 2003. 30(1):
167-178.
R15-3849
The Health Assessment Questionnaire (HAQ) and the improved HAQ
(formerly called the PROMIS HAQ) (revised June 2009).
http://aramis.stanford.edu/downloads/HAQ%20Instructions%20(ARAMIS)%2
06-30-09.pdf (access date: 15 July 2015) ; Stanford: Stanford University
School of Medicine, Division of Immunology & Rheumatology 2009.
R15-5200
Langley RGB, Feldman SR, Nyirady J, Kerkhof P van de, Papavassilis C. The 
5-point Investigator's Global Assessment (IGA) scale: a modified tool for 
evaluating plaque psoriasis severity in clinical trials. J Dermatol Treat 2015. 
26(1): 23-31. 


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UNPUBLISHED REFERENCES
9.2
c01569420
Investigator’s Brochure BI 655066, Psoriasis, Crohn’s Disease, Ankylosing 
Spondylitis, Asthma, Psoriatic Arthritis 1311.P1/1311.P2/1311.P3/1311.P4/ 
1311.P5, Current Version.
c02434648
Summary report of analysis, Trial 1311.1. 26 Mar 2015. 
c03272682
Summary report of interim analysis at Week 48, Trial 1311.2. 05 May 2015.


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10.
APPENDICES
PASI DEFINITIONS AND USE
10.1
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 summarised 
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
STATIC PHYSICIAN GLOBAL ASSESSMENT (SPGA)
10.2
This sPGA 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) (R15-5200). 
The assessment is considered “static” which refers to the patients disease state at the time of 
the assessments, without comparison to any of the patient’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)


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3
Definite red coloration (Dull to bright red)
4
Bright to Deep red coloration of lesions
Induration (plaque elevation)
0
None
1
Just detectable (possible 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


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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
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
DIAGNOSIS AND ASSESSMENTS FOR PATIENTS WITH PSORIATIC 
10.3
ARTHRITIS
10.3.1
psoriatic arthritis diagnosis at Screening
At Visit 1 at selected study site, patients with a positive history of PsA or suspected to have 
PsA will be further evaluated for PsA diagnosis based on CASPAR criteria (R15-1001). To 
be classified has having PsA, a patient must have inflammatory articular disease (joint, spine, 
or entheseal) with at least 3 points total from the 5 categories in Table 10.3.1: 1. All trial 
participants will have 2 points assigned due to evidence of current psoriasis per trial entry 
criteria and require at least one additional point for diagnosis of PsA. 


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Table 10.3.1: 1
CASPAR criteria
Category
Point assignment
Evidence of current psoriasis, a personal history of psoriasis, or a 
family history of psoriasis
2 points
Typical psoriatic nail dystrophy, including onycholysis, pitting, or 
hyperkaratosis observed on current physical examination
1 point
A negative test result for rheumatoid factor by any method except 
latex
1 point
Either current dactylitis, defined as swelling of an entire digit, or a 
history of dactylitis recorded by a rheumatologist
1 point
Radiographic evidence of juxta-articular new bone formation 
appearing as ill-defined ossification near joint margins (but excluding 
osteophyte formation) on plain radiographs of the hand or foot
1 point
10.3.2
Psoriatic arthritis assessment
Visit 2
If a diagnosis of PsA is confirmed and the patient meets all study entry criteria for 
participation, the following will be performed at Visit 2:
∀
HAQ-DI (refer to Appendix 10.4.3)
∀
Patient’s assessment of pain VAS (refer to Appendix 10.4.4) 
∀
Patient global assessment VAS (refer to Appendix 10.4.5)
∀
Tender and Swollen Joint Counts as listed in Table 10.3.2: 1
∀
Physician’s global assessment of disease activity (VAS)
Visit 6, Visit 8, EOT, and FU2/EOO
For patients with swollen or tender joint count ≥3 at Visit 2, the following will be performed 
at Visit 6, 8, EOT, and FU2/EOO Visit:
∀
HAQ-DI (refer to Appendix 10.4.3)
∀
Patient’s assessment of pain VAS (refer to Appendix 10.4.4) 
∀
Patient global assessment VAS (refer to Appendix 10.4.5)
∀
Tender and Swollen Joint Counts as listed in Table 10.3.2: 1
∀
Physician’s global assessment of disease activity (VAS)




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Table 10.3.2 : 1 (continued) Tender and Swollen Joint Counts
Joint
Left
Right
Tender
Swollen
Tender
Swollen
MTP1
MTP2
MTP3
MTP4
MTP5
IP of great toe
PIP of toes 2
PIP of toes 3
PIP of toes 4
PIP of toes 5
* Hip will only be assessed for TJC (tender joint counts), not for SJC (swollen joint count).
Joint counts will be performed by assessor(s) who must be well trained and part of the site 
personnel. Whenever possible, the same evaluator should perform these assessments at all 
visits.
Number of tender joints:
The 68 joints assessed for tenderness include the 2 temporomandibular, 2 sternoclavicular, 2 
acromioclavicular joints, 2 shoulders, 2 elbows, 2 wrists, 10 metacarpophalangeal, 10 
proximal interphalangeal, 8 distal interphalangeal joints of the hands, the 2 hips, 2 knees, 2 
ankles2 mid-tarsal, 10 metatarsophalangeal, and 10 proximal interphalangeal joints of the 
feet. 
Joints are be scored as either tender (1) or not tender (0)
Number of swollen joints:
The 66 joints to be examined for swelling are the same as those examined for tenderness, 
however excluding both hip joints.
Joints are to be scored as either swollen (1) or not swollen (0).
Synovial fluid and/or soft tissue swelling but not bony overgrowth represents a positive result 
for swollen joint count. Dactylitis of a digit in the hand or the foot counts as one tender and 
swollen joint.
Data will be recorded for tender and swollen joints (right or left side), i.e., a box (no, yes or 
not applicable) needs to be ticked for all joints. 


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10.3.3
ACR Response Criteria
ACR 20 (R96-2379):
•
At least 20% improvement in SJC* compared to baseline AND
•
At least 20% improvement in TJC* compared to baseline AND
•
At least 20% improvement in at least 3 out of the following 5 variables 
1. Patient’s assessment of pain on VAS 
2. Patient’s global assessment of the disease on VAS
3. Physician’s global assessment of the disease on VAS
4. Patient’s assessment of disability on HAQ
5. Acute phase reactants (serum CRP)
* SJC and TJC are evaluated according to the complete joint count (see Appendix 10.3.2).
Physician’s global assessment of disease activity
The physician’s global assessment of disease activity will be performed using 100 mm VAS 
ranging from no disease activity to maximal disease activity, after the question "Considering 
all the ways the Subjects psoriatic arthritis affects them, how would you rate the way they felt 
over the past week? Place a vertical mark ( | ) on the line to indicate how they felt”. To 
enhance objectivity, the physician must not be aware of the specific patient’s global 
assessment of disease activity, when performing his own assessment on that subject.
PATIENT REPORTED OUTCOMES
10.4
10.4.1
Psoriasis Symptom Scale (PSS)
The PSS will be self-administered by the patient at visits indicated in the Flow Chart.
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 
as a daily diary, using a 5-point Likert-type 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, click on the circle that best describes the severity of your symptoms during the 
past 24 hours. Please answer every question.


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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
-
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
10.4.2
Dermatology Life Quality Index (DLQI)
The DLQI will be self-administered by the patient at visits indicated in the Flow Chart.
The DLQI is a patient-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) and 1 (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 patient’s life, 2-5 = small effect, 6-10 = moderate effect, 11-
20 = very large effect, and 21-30 = extremely large effect on patient’s life. The higher the 
score, the more the quality of life is impaired. A 5-point change from baseline is considered a 
clinically important difference.
The DLQI has been extensively used in clinical trials and has a large evidence base 
supporting reliability and validity (R15-3845).


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10.4.3
Health Assessment Questionnaire Disability Index (HAQ-DI)
The HAQ-DI will be self-administered by the patient at visits indicated in the Flow Chart.
The HAQ-DI is a twenty-item patient reported outcome instrument that assesses current 
physical function/disability. The HAQ-DI covers eight categories (dressing and grooming, 
hygiene, arising, reach, eating, grip, walking and common daily activities). There are four 
response options, ranging from 0 (no difficulty) to 3 (unable to do). HAQ-DI score is 
reported as a mean score between 0 and 3 by dividing the total score by the number of items 
answered (R15-3849).
The HAQ-DI has been the most-widely used instrument to assess physical function clinical 
trials of treatments for rheumatoid and psoriatic arthritis and has extensive evidence of its 
validity and other psychometric properties in this context (R15-3846). 
The HAQ-DI will be self-administered by the patient at visits indicated in the Flow Chart.


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10.4.4
pain VAS
The pain-VAS will be self-administered by the patient at visits indicated in the Flow Chart.
The patient’s assessment of pain will be performed using a horizontal 100 mm VAS, ranging 
from 0 (no pain) to 100 (severe pain) after the question:
“Please indicate with a vertical mark ( | ) through the horizontal line the most pain you had 
from your psoriatic arthritis in the past week”.
10.4.5
Patient’s global assessment VAS
The patient global assessment VAS will be self-administered by the patient at visits indicated 
in the Chart.
The patient’s global assessment of disease activity will be performed using a horizontal 
100 mm VAS, ranging from 0 (very well) to 100 (very poor) after the question:
"Considering all the ways psoriatic arthritis affects you, please indicate with a vertical mark ( 
| ) through the horizontal line how well you are doing in the past week”.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1.0
Date of CTP revision
08 Jun 2017
BI Trial number
1311.38
BI Investigational Product(s)
risankizumab, BI 655066
Title of protocol
A phase II/III, randomised, double-blind study to 
evaluate efficacy and safety of two different dose 
regimens of BI 655066 (risankizumab) and placebo 
and maintenance of response of BI 655066
(risankizumab) administered subcutaneously in 
Japanese patients with moderate to severe chronic 
plaque type 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
Protocol synopsis
Description of change
Changed multiple testing procedure
Rationale for change
To decrease type II error and newly planned 
procedure also controls family-wise type I error of 
less than 5%.
Section to be changed
Flowchart
Description of change
Added “X” for sPGA at Visit 1
Rationale for change
sPGA entry criteria collected on the electronic
device was added to Flow Chart as a clarification
Section to be changed
Section 2.3
Description of change
Changed a item number
Rationale for change
To correct typo error
Section to be changed
Section 3.1.1
Description of change
Added text to specify Data Manage will be done by 


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BI and Statistical Evaluation will be done by 
AbbVie according to each SOPs.
Rationale for change
In February 2016, AbbVie entered into a license
agreement with BI related to risankizumab, and in
October 2016, the US IND for risankizumab
transitioned from BI to AbbVie. To modify study 
conduct responsibilities as a result of that license 
agreement.
Section to be changed
Section 3.3.4.2
Description of change
Updated text to “BI/AbbVie reserves the right to 
discontinue the trial overall or at a particular trial 
site at any time for the following reasons”.
Rationale for change
In February 2016, AbbVie entered into a license
agreement with BI related to risankizumab, and in
October 2016, the US IND for risankizumab
transitioned from BI to AbbVie. To modify study 
conduct responsibilities as a result of that license 
agreement.
Section to be changed
Table 4.2.2.1: 1
Description of change
Changed a lank of topical steroid from “mild” to 
“medium”
Rationale for change
To correct description
Section to be changed
Section 5.5.3.2
Description of change
Specified DNA banking sample storage
Rationale for change
In February 2016, AbbVie entered into a license
agreement with BI related to risankizumab, and in
October 2016, the US IND for risankizumab
transitioned from BI to AbbVie. To modify study 
conduct responsibilities as a result of that license 
agreement.
Section to be changed
Section 7.2
Description of change
Changed multiple testing procedure
Rationale for change
To decrease type II error and newly planned 
procedure also controls family-wise type I error of 
less than 5%.
Section to be changed
Section 7.3
Description of change
Changed analysis populations : 
FAS to ITT Population
SAF to Safety Population
PPS to PP Population
Rationale for change
All changes were made under blinding prior Data 


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base lock.
FAS to ITT Population: ITT analysis is more 
conservative approach.
SAF to Safety Population: Terminology changes
PPS to PP Population: New definition is based on 
more concrete definition.
Section to be changed
Section 7.3.1
Description of change
Changed confidence interval
Rationale for change
It corresponds to changes in 7.2.
Section to be changed
Section 7.3.3
Description of change
Corrected typo
Changed Definition of Loss of Endpoint
Rationale for change
To correspond to changes in 7.3 and it was based 
on ITT principle.
Section to be changed
Section 7.3.4
Description of change
Changed text to specify that AbbVie summary
tables and listings will be produced and analyses
based on AbbVie standards
Rationale for change
In February 2016, AbbVie entered into a license
agreement with BI related to risankizumab, and in
October 2016, the US IND for risankizumab
transitioned from BI to AbbVie. To modify study 
conduct responsibilities as a result of that license 
agreement.
Section to be changed
Section 7.5
Description of change
Changed missing data handling
Rationale for change
To correspond to changes in 7.3 and it was based 
on ITT principle.
Section to be changed
Section 7.7
Description of change
Changed of comparison-wise significance level and 
assumption for statistical powers
Rationale for change
To correspond to changes in 7.2.
Section to be changed
Section 10.3.3
Description of change
Add the description of Physician’s global 
assessment of disease activity.
Rationale for change
To clarify a procedure for the assessment.
Section to be changed
Section 10.4.4
Description of change
Changed text from “today” to “in the past week”
Rationale for change
To clarify a period for the assessment.


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Section to be changed
Section 10.4.5
Description of change
Changed text from “today” to “in the past week”
Rationale for change
To clarify a period for the assessment.


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
c08943535
2.0
clinical-trial-protocol-version-02
A phase II/III, randomised, double-blind study to evaluate efficacy and safety of two
different dose regimens of BI 655066 (risankizumab) and placebo and maintenance
of response of BI 655066 (risankizumab) administered subcutaneously in Japanese
patients with moderate to severe chronic plaque type psoriasis.
09 Jun 2017 07:43 CEST
12 Jun 2017 03:32 CEST
12 Jun 2017 04:02 CEST
12 Jun 2017 10:32 CEST
16 Jun 2017 22:19 CEST
19 Jun 2017 04:42 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08943535
2.0

SAP_003.pdf: 
Risankizumab
M16-004 – Statistical Analysis Plan
Version 1.0 – 10 Jan 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M16-004 (1311.38)
A Phase II/III, Randomized, Double-blind Study to 
Evaluate Efficacy and Safety of Two Different Dose 
Regimens of Risankizumab and Placebo and 
Maintenance of Response of Risankizumab 
Administered Subcutaneously in Japanese Patients 
With Moderate to Severe Chronic Plaque Type 
Psoriasis
Date:  10 Jan 2018
Version 1.0
NCT03000075


Risankizumab
M16-004 – Statistical Analysis Plan
Version 1.0 – 10 Jan 2018
2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Design Diagram ..................................................................................... 6
4.3
Sample Size............................................................................................ 7
4.4
Interim Analysis..................................................................................... 7
5.0
Analysis Populations and Stratification...............................8
5.1
Analysis Populations .............................................................................. 8
5.2
Variables Used for Stratification of Randomization .............................. 10
6.0
Analysis Conventions .......................................................... 10
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............16
7.1
Demographic and Baseline Characteristics ........................................... 16
7.2
Medical History.................................................................................... 18
7.3
Previous Treatment and Concomitant Medications ............................... 18
7.4
Protocol Deviations .............................................................................. 19
8.0
Patient Disposition............................................................... 19
9.0
Study Drug Exposure and Compliance.............................. 20
10.0
Efficacy Analysis .................................................................21
10.1
General Considerations......................................................................... 21
10.1.1
Analyses of Categorical Variables ........................................................ 22
10.1.2
Analyses of Continuous Variables ........................................................ 23
10.1.3
Analyses of Time-to-Event Variables ................................................... 24
10.1.4
Missing Data Imputations..................................................................... 25
10.1.5
Analysis of Psoriasis Symptoms Scale (PSS)........................................ 26
10.2
Primary Efficacy Analysis.................................................................... 27
10.3
Secondary Efficacy Analyses ............................................................... 28
10.3.1
Further Efficacy Analysis..................................................................... 29
10.4
Handling of Multiplicity....................................................................... 30


Risankizumab
M16-004 – Statistical Analysis Plan
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10.5
Efficacy Subgroup Analysis ................................................................. 31
11.0
Safety Analysis.....................................................................31
11.1
General Considerations......................................................................... 31
11.2
Analysis of Adverse Events.................................................................. 32
11.2.1
Treatment-Emergent Adverse Events.................................................... 32
11.2.2
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 40
11.2.3
Safety Subgroup Analysis..................................................................... 40
11.3
Analysis of Laboratory Data................................................................. 41
11.3.1
Variables and Criteria Defining Abnormality........................................ 41
11.3.2
Statistical Methods ............................................................................... 43
11.4
Analysis of Vital Signs and Weight ...................................................... 46
11.4.1
Variables and Criteria Defining Abnormality........................................ 46
11.4.2
Statistical Methods ............................................................................... 47
11.5
Analysis of ECG Parameters ................................................................ 48
11.6
Local Tolerability................................................................................. 48
12.0
Pharmacokinetic Analysis...................................................49
13.0
Biomarkers Analysis ...........................................................49
14.0
Summary of Changes .......................................................... 49
14.1
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP ................................................................................... 49
14.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP .................................................................. 49
15.0
Appendix.............................................................................. 49
16.0
References............................................................................49
17.0
List of Tables, Figures, and Data Listings to Be 
Programmed........................................................................49
List of Tables
Table 1.
Notation for Treatment Groups............................................................... 9
Table 2.
Visit Windows for Analysis of PASI, Vital Signs, and Local 
Tolerability in Part A (ITT/PP/Safety Populations)............................... 13


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M16-004 – Statistical Analysis Plan
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4
Table 3.
Visit Windows for Analysis of Safety Laboratory Tests in Part A 
(Safety Population)............................................................................... 13
Table 4.
Visit Windows for Analysis of ECG in Part A (Safety Population) ....... 13
Table 5.
Visit Windows for Analysis of sPGA, PSS, DLQI, HAQ-DI, Pain 
VAS, Investigator's Global Assessment VAS, Patient's Global 
Assessment VAS, CRP as an ACR 20 Component, SJC, and TJC 
in Part A (ITT Population).................................................................... 14
Table 6.
Visit Windows for Analysis of PASI, Vital Signs, and Local 
Tolerability in Part B (ITT/Safety Population) ...................................... 14
Table 7.
Visit Windows for Analysis of sPGA, PSS, DLQI, HAQ-DI, Pain 
VAS, Investigator's Global Assessment VAS, Patient's Global 
Assessment VAS, SJC, TJC, Laboratory Tests, and ECG in Part B 
(ITT/Safety Population)........................................................................ 15
Table 8.
Visit Windows for Summary of Study Drug Injections in Part A .......... 15
Table 9.
Visit Windows for Summary of Study Drug Injections in Part B .......... 15
Table 10.
Areas of Safety Interest ........................................................................ 36
Table 11.
Clinical Laboratory Tests ..................................................................... 42
Table 12.
Criteria for Potentially Clinically Important Chemistry Values ............. 44
Table 13.
Criteria for Potentially Clinically Important Hematology Values .......... 44
Table 14.
NCI CTCAE Grading........................................................................... 45
Table 15.
Criteria for Potentially Clinically Important Vital Sign Findings........... 47
List of Figures
Figure 1.
Study Design Schematic......................................................................... 6


Risankizumab
M16-004 – Statistical Analysis Plan
Version 1.0 – 10 Jan 2018
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3.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analysis to be completed by 
the AbbVie Clinical Statistics Department for risankizumab study Protocol M16-004 (BI 
Study 1311.38) dated 05 September 2016 and the protocol amendment dated 
07 June 2017.
This SAP will provide details to further elaborate statistical methods as outlined in the 
Protocol of Study 1311.38.
Analyses will be performed using SAS® version 9.4 (SAS. Institute, Inc., Cary, NC 
27513) or higher using the UNIX operating system.
SAP will not be updated in case of future administrative or minor amendments to the 
protocol unless the changes have any impact on the analysis of the study data.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The objectives of this study are to assess the efficacy and safety of two different dose 
regimens of risankizumab compared to placebo in patients with moderate to severe 
chronic plaque psoriasis.  The primary efficacy evaluation will be performed at Week 16 
and an assessment of maintenance of response will be performed at Week 52.
In the subset of enrolled patients with concomitant psoriatic arthritis, the signs and 
symptoms of psoriatic arthritis will be evaluated to assess improvement during the trial.
This trial will assess PK and the emergence of anti-drug antibodies (ADA) and their effect 
on efficacy and safety.  Moreover, it will be explored how the use of risankizumab may 
influence protein expression levels and disease specific protein markers.  These analyses 
will not be covered in this SAP.


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4.2
Design Diagram
This randomized, double-blind, double-dummy, placebo controlled, parallel design study 
compares two different dose regiments of risankizumab with placebo.  In total, 
approximately 168 patients with moderate to severe chronic plaque psoriasis will be 
randomized in this trial.
Patients are randomized at a ratio of 2:2:1:1 to one of 4 treatment arms (risankizumab 
75 mg, risankizumab 150 mg, placebo switching to risankizumab 75 mg after Week 16, 
and placebo switching to risankizumab 150 mg after Week 16) as shown in Figure 1.
Randomization will be stratified by concomitant PsA at baseline (Yes versus No) and 
body weight (≤ 90 kg versus > 90 kg). 
Patients will be offered to roll over into an extension trial, if they have completed the 
study and meet the inclusion criteria for the extension trial.
Figure 1.
Study Design Schematic
BI 655066 is risankizumab.


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4.3
Sample Size
For the Japanese submission, the safety data of at least 100 Japanese patients exposed to 
risankizumab at the registered dose(s) for 1 year or more is necessary for long team safety 
assessment as a result of the PMDA consultation meeting in 2015.  This study will enroll 
a total of 168 patients, with 56 patients in each of the two risankizumab arms and 
56 patients in the placebo arm.  It is expected that at least 68 patients exposed to 
risankizumab 75 mg and 68 patients exposed to risankizumab 150 mg will reach at least 
1 year exposure to risankizumab in this clinical trial or in the following extension study.  
Other global phase 3 trials where Japanese patients are to be enrolled will make up for the 
remaining safety data requirements.
Based on the outcome from the Trial 1311.2, the PASI 90 response rate at Week 16 is 
assumed to be at least 65% in each of the risankizumab arm.  The phase 3 results from 
ustekinumab and secukinumab indicate a response rate for PASI 90 of approximately 5% 
in the placebo arm.  With hieratical order of testing the 150 mg risankizumab vs placebo 
followed 75 mg risankizumab vs placebo, the above sample size will provide more than 
90% power to detect the superiority of both risankizumab arms vs placebo.
4.4
Interim Analysis
Before the submission to regulatory agencies with the long-term data, an interim report 
will be prepared for the submissions analysis pertaining to Part A.  Primary endpoint 
(PASI 90 score at Week 16) for all patients will be included in the Week 28 analyses, 
which is the only and final analysis for the primary endpoint; hence no alpha adjustment is 
required.  For this analysis all efficacy endpoints and safety as well as PK and 
immunogenicity data will be analysed.  As endpoints for Week 28, same analyses will be 
performed for the Week 52 endpoints defined in Section 10.3.
AbbVie Data and Statistical Sciences will be unblinded to perform this analysis.  
Unblinded treatment assignments will not be disseminated to BI, the sites, investigators, 
or patients until the end of final database lock.


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5.0
Analysis Populations and Stratification
5.1
Analysis Populations
In this SAP, Part A refers to Week 0 to Week 16, and Part B refers to Week 16 and after.
Intent-to-Treat (ITT) Population:  The ITT Population is defined as all subjects who 
are randomized at Week 0.  ITT Population will be used for the efficacy analyses in 
Part A and Part B, as well as efficacy across the entire study (cross-period) for subjects 
who are randomized to risankizumab arms.  Subjects who are randomized to placebo in 
Part A and do not continue into Part B will be excluded from the analysis in Part B. 
ITT Population will be analyzed by treatment group as randomized. 
Per-Protocol (PP) Population:  To evaluate the impact of protocol deviations on the 
primary endpoint, additional efficacy analyses will be performed on a PP Population.  The 
PP Population will include those who were most compliant with the protocol in ways that 
could impact the primary endpoints.  Final results and the criteria for exclusion of subjects 
will be finalized prior to database lock. 
The PP Population is defined as all subjects from the ITT Population who meet all the 
following criteria:
●
Subjects must receive at least 75% of planned study drug injections (including 
dummy placebo injections) in Part A (prior to Week 16). 
●
Subjects must have at least one PASI assessment post-baseline.
●
Inclusion Criterion 2:  Subjects must have stable moderate to severe chronic 
plaque psoriasis at baseline:
○
Have an BSA ≥ 10% and
○
Have a PASI ≥ 12 and
○
Have an sPGA ≥ 3.


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Version 1.0 – 10 Jan 2018
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Final results and the criteria for exclusion of subjects will be finalized prior to the interim 
database lock.
PP Populations will be analyzed by treatment group as randomized. 
Safety Population:  Safety analyses will be performed on a Safety Population, 
comprising all randomized participants who received at least one dose of study drug in 
Part A.  The safety analysis will be performed based on the actual treatment received at 
the randomization visit.  Subjects who do not continue into Part B will be excluded from 
the Part B specific safety analysis.  All safety analyses will be conducted on the Safety 
Population.
All Risankizumab Treated (ALL RZB) Population:  The ALL_RZB Population is 
defined as subjects who receive at least one dose of risankizumab in the study.  Key safety 
summaries will be provided on the ALL_RZB Population.
Table 1.
Notation for Treatment Groups
Population
Treatment Code
Definition
ITT/Safety 
(Part A)
RZB_75
Subjects who randomized to risankizumab 75 mg.
RZB_150
Subjects who randomized to risankizumab 150 mg. 
PBO
Subjects who randomized to either of the two placebo arms.
ITT/Safety 
(Part B)
RZB_75/RZB_75
Subjects who randomized to risankizumab 75 mg.
RZB_150/RZB_150
Subjects who randomized to risankizumab 150 mg. 
PBO/RZB_75
Subjects who randomized to placebo and then risankizumab 
75 mg entered Part B
PBO/RZB_150
Subjects who randomized to placebo and then risankizumab 
150 mg entered Part B
ITT/Safety 
(entire study)
RZB_75/RZB_75
Subjects who randomized to risankizumab 75 mg.
RZB_150/RZB_150
Subjects who randomized to risankizumab 150 mg.
ALL_RZB
ALL_RZB
Subjects who received at least one dose of risankizumab 
75/150 mg.


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5.2
Variables Used for Stratification of Randomization
Randomization will be stratified by concomitant PsA at baseline (Yes versus No) and 
body weight (≤ 90 kg versus > 90 kg).
6.0
Analysis Conventions
Definition of Baseline
The last non-missing observation collected on or before the date of the first dose of study 
drug injection will be used as Baseline for summary of demographics and disease 
characteristics, safety and efficacy analyses, with the exception that:
●
The last evaluation on or prior to the date of first dose of risankizumab will be 
used for the safety analyses in Part B among subjects randomized to placebo at 
Week 0, and the safety analyses in the ALL_RZB Population.
●
For all vital sign assessments, only assessments prior to first dose time will be 
considered, since vital signs are to be assessed both pre- and post-dose in some 
visits. 
Entry of Part B is defined as the last non-missing observation collected on or before the 
date of the first dose of study drug in Part B for PBO/RZB_75 and PBO/RZB_150 arms 
and last non-missing observation collected on or before the date of Week 16 visit for 
RZB_75/RZB_75 and RZB_150/RZB_150 arms.
Definition of Final Observation (Applicable to Safety Analyses)
Final observation in Part A is defined as the last non-missing observation collected within 
105 days following the last dose of study drug in Part A for those who do not enter Part B, 
and on or before the first dose date of study drug injection in Part B for subjects who 
entered Part B.  For vital sign assessments, only assessments prior to the first dose of 
study drug injection in Part B will be included in the analysis for Part A. 
Final observation for Part B is defined as the last non-missing observation collected 
within 105 days following the last dose in Part B.


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Final observation for the entire study analyses is defined as the last non-missing 
observation collected within 105 days following the last dose of study drug.
Final observation for ALL_RZB Population is defined as the last non-missing observation 
collected within 105 days following the last dose of risankizumab.
Definition of Rx Days in Each Period (Days Relative to the Date of First Dose of 
Study Drug in Each Period)
Rx Days are calculated for each time point relative to the date of first dose of study drug.  
They are defined as the number of days between the day of the first dose of study drug 
and the specific time point.  Rx Days are negative values when the time point of interest is 
prior to the first study drug dose day.  Rx Days are positive values when the time point of 
interest is on or after the first study drug dose day.  The day of the first dose of study drug 
is defined as Rx Day 1, while the day prior to the first study drug dose is defined as Rx 
Day –1 (there is no Rx Day 0). 
Rx Days for Part A and entire study will be defined relative to the date of first dose of 
study drug.  Rx days for Part B will be defined relative to the date of the date of the 
first study drug injection on or after Week 16. 
Definition of Analysis Windows 
All time points and corresponding time windows are defined based on Rx Days.  The visit 
schedule with accompanying details can be found in Flow Chart and Section 6.1 of the 
protocol.
For efficacy analyses, local tolerability, ECG, laboratory parameters, and vital sign 
variables, analysis windows are constructed using the following algorithm:
●
Determine the nominal Rx day for each visit (e.g., Week 4 [4 weeks after 
Baseline visit] equals Rx Day 29).
●
In order to include all post baseline data, the first post-baseline interval starts 
on the first day after the first dose of study drug (Rx Day 2).


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●
Determine the window around a specific nominal Rx day by adding or 
subtracting half of the interval between adjacent visits (e.g., days between 
Week 4 and Week 8 is 28).  The threshold between adjacent visits is 
determined by splitting the interval evenly between the visits.  If the resulting 
split is between Rx days, then the threshold is determined as the midpoint 
between the adjacent visits.  If the resulting split is on an Rx day, then the 
threshold is determined as being between that Rx day and the Rx day prior to it 
(e.g., the split between Week 4 and Week 8 would be between Rx Days 43 and 
44).
●
If more than one assessment is included in a time window the assessment 
closest to the nominal day will be used.  If there are two observations 
equidistant to the nominal day, the later one will be used in analyses.  If more 
than one assessment is included on the same day, then the worst assessment on 
that day will be used in analyses, except those specified in Section 11.0.
The following analysis windows have been specified for the analysis of efficacy, 
laboratory parameters, and vital signs, etc. for each analysis period.  In order to include all 
post baseline data, the first post baseline interval starts on the day after the date of 
first study drug injection in each period (Rx Day 2) for all efficacy variables.
For subjects who were randomized and not dosed date of randomization will be used for 
determining window definitions.


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Table 2.
Visit Windows for Analysis of PASI, Vital Signs, and Local 
Tolerability in Part A (ITT/PP/Safety Populations)
Window Label
Target Day
Interval
Baseline
1
≤ 1a
Week 4
29
[2, 43]
Week 8
57
[44, 71]
Week 12
85
[72, 99]
Week 16
113
[100, 127b]
Rx Day calculated relative to first dose date of study drug.  For subjects randomized but not dosed, Rx Day calculated 
relative to Randomization.
a.
There is no baseline for local tolerability measurements.  If time is collected in vital signs, restrict to records prior 
to the first dose of study drug.
b.
The minimum of upper bound and the day of the first dose date in Part B (and within 105 days of last dose for 
safety analyses).
Table 3.
Visit Windows for Analysis of Safety Laboratory Tests in Part A 
(Safety Population)
Window Label
Target Day
Interval
Baseline
1
≤ 1
Week 8
57
[2, 85]
Week 16
113
[86, 141*]
Rx Day calculated relative to first dose date of study drug.
*
The minimum of upper bound, the day of the first dose date in Part B, and 105 days of last dose.
Table 4.
Visit Windows for Analysis of ECG in Part A (Safety Population)
Window Label
Target Day
Interval
Baseline
1
≤ 1
Week 4
29
[2, 71]
Week 16
113
[72, 155*]
Rx Day calculated relative to first dose date of study drug.
*
The minimum of upper bound, the first dose date in Part B, and the last dose + 105 days.


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Table 5.
Visit Windows for Analysis of sPGA, PSS, DLQI, HAQ-DI, Pain 
VAS, Investigator's Global Assessment VAS, Patient's Global 
Assessment VAS, CRP as an ACR 20 Component, SJC, and TJC in 
Part A (ITT Population) 
Window Label
Target Day
Interval
Baseline
1
≤ 1
Week 16
113
[2, 225*]
Rx Day calculated relative to first dose date of study drug.  For subjects randomized but not dosed, Rx Day calculated 
relative to Randomization.
*
The minimum of upper bound and the day of the first dose date in Part B.
Table 6.
Visit Windows for Analysis of PASI, Vital Signs, and Local 
Tolerability in Part B (ITT/Safety Population)
Window Label
Target Day
Interval
Entry of Part B
1
≤ 1a
Week 22  
43
[2, 64]
Week 28
85
[65, 106]
Week 34 
127
[107, 148]
Week 40 
169
[149, 190]
Week 46 
211
[191, 232]
Week 52 
253
[233, 267]
Week 56 
281
[268, 295b]
Rx Day calculated relative to the first dose date on or after Week 16 for PBO/RZB_75 and PBO/RZB_150 arms, and 
relative to the date of Week 16 visit for RZB_75/RZB_75 and RZB_150/RZB_150 arms.  PASI only evaluated from 
Week 22 to 52.  Local tolerability only evaluated from Week 22 to 40.
a.
If time is collected for vital sign, restrict to records prior to the first dose of study drug in Part B.
b.
The minimum of upper bound and 105 days after the last dose.
Subjects who enter the Open Label Extension Study 1311.31 will not have Week 56 evaluations.


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Table 7.
Visit Windows for Analysis of sPGA, PSS, DLQI, HAQ-DI, Pain 
VAS, Investigator's Global Assessment VAS, Patient's Global 
Assessment VAS, SJC, TJC, Laboratory Tests, and ECG in Part B 
(ITT/Safety Population)
Window Label
Target Day
Interval
Entry of Part B
1
≤ 1
Week 28 
85
[2, 127]
Week 40 
169
[128, 211]
Week 52 
253
[212, 294a]
Rx Day calculated relative to the first dose date on or after Week 16 for PBO/RZB_75 and PBO/RZB_150 arms, and 
relative to the date of Week 16 visit for RZB_75/RZB_75 and RZB_150/RZB_150 arms.
a.
The minimum of upper bound and 105 days after the last dose.
Table 8.
Visit Windows for Summary of Study Drug Injections in Part A
Window Label
Target Day
Time Window
Week 0 
1
≤ 1
Week 4
29
[2, 57a]
Rx Day calculated relative to the first dose date of study drug.
a.
Before the first dose date on or after Week 16.
Table 9.
Visit Windows for Summary of Study Drug Injections in Part B
Window Label
Target Day
Time Window
Week 16 
1
≤ 1
Week 28
85
[2, 127]
Week 40
169
[128, 211]
Rx Day calculated relative to the date of first dose date on or after Week 16.
Definition of Missing Data Imputation
No global imputation is taking place at the database level.  Efficacy related imputations 
are outlined in Section 10.0.  There is no imputation for missing values in the safety 
analyses.


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Rounding of Numeric Results
Rounding will be performed for presentation of results.  No rounding will be performed 
before or during analyses.  The ROUND function of SAS will be used to round results. 
When dichotomizing continuous variables from single observations, associated 
continuous variables will be rounded to 9 decimal points before applying the cutoff point 
to determine the response status (for example, percent change from baseline in PASI score 
will be rounded to 9 decimal places before comparing to 90%).
The mean and median will be rounded for presentation to 1 decimal more than the data 
entered into the database.  The standard deviation will be rounded to 2 decimal places 
more than the data entered into the database.  The minimum and maximum values will be 
presented as entered into the database.
Probabilities will be rounded to 3 decimal places before assignment of statistical 
significance and will be presented in rounded format.  Probabilities that round to zero or 
are reported by SAS as zero will be presented as "< 0.001."  Probabilities that round to 1 
or are reported by SAS as 1 will be presented as "> 0.999."
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized for each arm and for overall 
of the ITT population.  The number of observations, mean, standard deviation, median, 
minimum and maximum will be summarized for continuous variables; and treatment 
groups will be compared using a one-way analysis of variance (ANOVA) model with 
treatment as the independent factor.  Categorical or discrete variables will be summarized 
via counts and percentages; and treatment groups will be compared using a two-sided 
Pearson's Chi-Square test (or an appropriate exact test if expected cell count < 5).
The following demographic and baseline parameters will be summarized. 


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Subject Demographics
●
Sex (male, female)
●
Age (years), defined as the number of years from date of birth to date of 
first drug
●
Age (< 40 years, ≥ 40 – < 65 years, ≥ 65 years)
●
Body weight (kg)
●
Body weight category (≤ 90 kg versus > 90 kg).
●
Height (cm)
●
BMI (kg/m2)
●
BMI (normal:  < 25, over weight:  ≥ 25 – < 30, obese:  ≥ 30);
●
concomitant PsA at baseline 
General Baseline Characteristics
●
PASI (Psoriasis Area and Severity Index)
●
sPGA categories
●
BSA (Body Surface Area)
●
PSS
●
Dermatology Life Quality Index (DLQI)
●
HAQ-DI (HAQ Disability Index)
●
Pain VAS (Visual Analog Scale)/Patient Global Assessment (PtGA) VAS 
(Visual Analog Scale)
●
TJC/SJC (Tender/Swollen Joints)
●
Investigator's Global Assessment VAS
●
Serum CRP 
Psoriasis and Cardiovascular History
●
Psoriatic arthritis (diagnosed, suspected, no) 
●
Cardiovascular Diseases (myocardial infarction, angina pectoris, transient 
ischemic attack, stroke, deep vein thrombosis)


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●
Cardiovascular Risk Factors (hypertension, hyperlipidemia, diabetes mellitus, 
obesity)
General Use
●
Smoking history (Never-smoked, Ex-smoker, Currently smokes)
●
Alcohol History (Non-drinker, drinks – no interference to study participation, 
drinks – possible interference to study participation)
Prior Treatment:
●
Psoriasis TNF antagonist and Other Biologic Usage History – by Response to 
Treatment
●
Psoriasis Treatment – by Therapy Type (topical therapy, phototherapy, 
photochemotherapy, non-biologic systemic therapy, TNF antagonist, other 
biologic)
Physical Exam, Infection screening and Pregnancy Test will be presented in listing 
format.
7.2
Medical History
Medical history will be summarized using body systems and condition/diagnosis as 
captured on the eCRF.  The body systems will be presented in alphabetical order and the 
conditions/diagnoses will be presented in alphabetical order within each body system.  
The number and percentage of subjects with a particular condition/diagnosis will be 
summarized for each treatment arm.  Subjects reporting more than
one condition/diagnosis within a body system will be counted only once for that body 
system.
7.3
Previous Treatment and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken at the time of entry into the study and prior 


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to the first dose of study drug.  A concomitant medication is defined as any medication 
that started prior to the first dose of study drug and continued to be taken after the 
first dose of study drug or any medication that started after the first dose of study drug, 
but not after the last dose of study drug plus 21 days.  The number and percentage of 
subjects who had taken medications will be summarized by generic drug name assigned 
by the World Health Organization (WHO) for both prior and concomitant medications.
7.4
Protocol Deviations
Number and percentage of subjects who reported at least one of the following protocol 
deviation categories will be provided.
●
Subject entered into the study even though she/he did not satisfy entry criteria
●
Subject who developed withdrawal criteria during the study and was not 
withdrawn
●
Subject who received wrong treatment or incorrect dose
●
Subject who received excluded or prohibited concomitant treatment
8.0
Patient Disposition
The number of subjects for each of the following categories will be summarized, for 
overall and for each treatment group in the ITT population:
●
Number of subjects randomized
●
Number of subjects treated 
●
Number of subjects who completed the study
●
Number of subjects who discontinued the study drug
●
Number of subjects who prematurely discontinued study
In addition, the reasons for premature discontinuation will be summarized with 
frequencies and percentages. 


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In addition to patient disposition, number of screening failures and reasons for screening 
failure will also be summarized among all screened subjects in a subject screening status 
table.
The summaries will be provided for Part A and Part B.
9.0
Study Drug Exposure and Compliance
Summary of study drug treatment duration and compliance will be provided for each 
treatment arm in each treatment period under the ITT Population.
Study drug treatment duration (days) will be summarized using the sample size, mean, 
standard deviation, minimum, median and maximum.  In addition cumulative exposure of 
RZB (including total patient years) will also be summarized in the ALL_RZB Population.  
Study drug treatment duration will be summarized as follows:
Study Drug Exposure (in Days) in Each Period:
Part A:
●
For subjects who did not continue into Part B:
○
Date of last injection in Part A – Date of first injection in Part A + 84 days.
●
For subjects who continued into Part B: 
Minimum of
○
Date of first injection in Part B – Date of first injection in Part A 
○
Date of last injection in Part A – Date of first injection in Part A + 84 days.
Part B:
Date of last injection in Part B – Date of first injection in Part B + 84 days.
ALL_RZB:
For study drug exposure during the administration of risankizumab in the ALL_RZB 
Population:


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●
Date of last injection of risankizumab – Date of first injection of risankizumab 
+ 84 days.
A data cutoff date (December 15, 2017) will be applied during the interim analysis, and 
the duration of study drug exposure will be defined up to this cutoff date.
Compliance
There will be a summary of the number of subjects receiving study drug and dose at each 
study drug administration visit.  This will be repeated on the cumulative number of doses.  
When computing compliance at each study drug administration visit, the denominator will 
include all subjects in each analysis population who have not prematurely discontinued 
the study drug prior to the scheduled study drug injection.  Subjects who have 
prematurely discontinued the study drug but have not prematurely discontinued the study 
are not used in the denominator.
10.0
Efficacy Analysis
10.1
General Considerations
When the last patient completes the Week 28 visit, the Primary Analysis will be 
performed including all efficacy endpoints pertaining to Part A.  This is the only and final 
analysis for these endpoints, hence no alpha adjustment is required.  For this primary 
analysis, all endpoints will be analysed up to Week 28, with the following exception:
●
Categorical endpoints related to PASI and sPGA, using the LOCF method, 
will be analysed up to the last visit that at least one subject has observed PASI 
and sPGA measurements, respectively.
The treatment effect will be evaluated based on a two-sided significance level of 0.05 
(when rounded to three decimal places).


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The ITT population will be used for the analyses of efficacy endpoints.  The following 
treatment periods will be analyzed:
●
Part A (up to Week 16) 
●
Part B (Week 16 and after) 
Time-to-event analysis will be performed across the entire study for subjects who are 
randomized to risankizumab or placebo arms in addition to the analyses in Part A.
Primary variable will also be analyzed for the per-protocol populations using primary 
approach to handle missing data as described in Section 10.1.4.
Subjects' actual Concomitant PsA at baseline (Yes: Diagnosed or Suspected; versus: No)
and body weight (≤ 90 kg versus > 90 kg) will be used as the strata in the stratified 
analyses.
10.1.1
Analyses of Categorical Variables
For categorical variables, frequencies and percentages will be summarized.  Treatment 
comparison will be conducted using a Cochran-Mantel-Haenszel (CMH) test with 
stratification factors as strata for the analysis.  The CMH test will use weights proposed 
by Greenland & Robins, which is calculated as follows:
 =
∑

 ∙


∑




 , where
 = 

 − 

  denotes the risk difference in stratum &, & = 1, ⋯, )

 =  ∙
 + 
  denotes the weight of stratum &, & = 1, ⋯, )
 denotes the number of subjects with event in treatmentin stratum i, & = 1, ⋯, )
 denotes the number of subjects with event in treatment/in stratum i, & = 1, ⋯, )


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 denotes the number of subjects on treatmentin stratum i,& = 1, ⋯, )
 denotes the number of subjects on  treatment/in stratum i, & = 1, ⋯, )
The estimated variance of  is calculated as:
012
3 45 =
∑
6


(∑




)/
where 6 = ( −) 
9 + ( −) 
9
 ∙ ∙( + )/
 , & = 1, ⋯, )
Assuming a normal distribution of , an approximate 95% CI is given as follows, 
where :;.=>?is the 97.5% quantile of the standard normal distribution:
@A =  B  ± :;.=>? ∙D012
3 45E
Also, the approximate p-value can be calculated using the following:
pvalue =  2 ∙Pr
⎣
⎢
⎢
⎡
M > OO

D012
3 45
OO 
⎦
⎥
⎥
⎤
 , where M ~ T(0, 1)
If there is a stratum for a treatment group that has 0 subjects in any cell in the contingency 
table, all cells from the stratum will be added by 0.1 in order to prevent dividing by 0 in 
the above equations, as suggested in Greenland & Robins.
10.1.2
Analyses of Continuous Variables
Change from baseline in PSS will be analyzed by stratified van Elteren test.  For other 
continuous variables, the model based mean and standard error will be presented.  The 
Baseline and visit means will also be presented for each treatment group for subjects who 


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have both Baseline and post Baseline visit values.  The treatment groups will be compared 
using ANCOVA with treatment group, Baseline value, and stratification factors in the 
model.
10.1.3
Analyses of Time-to-Event Variables
Time-to-event analysis will be done for RZB_75, RZB_150, PBO treatment arms for 
Part A, and all RZB_75/ RZB_75, RZB_150/ RZB_150 treatment arms for the entire 
study.
For the time to first achievement of Endpoint, the time to event will be calculated as:
●
Time to first achievement (with observed event) = [date of first achievement] –
[date of first study drug] + 1
●
If a subject never attains an endpoint, then that subject's time to 
first achievement will be censored at the last visit where variable was 
measured.  Censoring will be done within Part A for the analyses in Part A, 
and over the entire study for cross-period analyses.  For example, if the 
first time a PASI 90 response is achieved in Part B, then PASI 90 will be 
censored for Part A analysis only.
Time to loss of response will be evaluated from the time of achievement of the same 
endpoint, and defined using the following algorithm:
●
Never attains Endpoint (Failure at time 0)
●
After achieving Endpoint, subjects will be a considered loss of response if they 
subsequently lost the response or discontinue from the study due to AE of 
"Worsening of disease under study."
●
Subjects will be censored at their last assessment if they do not lose the 
endpoint or discontinue from the study due to reasons other than AE of 
"Worsening of disease under study."  Time to failure will be calculated starting 
from date of first achievement of the endpoint.


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Time to event will be analyzed using Kaplan-Meier estimates for each treatment group.  
Treatments comparisons will be performed using stratified Log-rank test.
10.1.4
Missing Data Imputations
Missing data will be imputed using the following methods for the efficacy analyses:
●
Non-Responder Imputation (NRI):  The NRI analysis will categorize any 
subject who has missing value at a specific visit as non-responder for that visit.  
The only exception is when if the subject is a responder both before and after 
this specific visit window, then the subject will be categorized as a responder 
for the visit.  The NRI will be the primary approach in the analysis of 
categorical variables.  Of note, this before- and after-window imputation will 
utilize visits across Part A and B for the risankizumab arms.
●
Last Observation Carried Forward (LOCF):  The LOCF analyses will use the 
completed evaluation from the previous visit for efficacy measures assessed to 
impute missing data at later visits.  For observations in RZB_75/RZB_75, and 
RZB_150/RZB_150 arms in Part B, LOCF is continued across Part A and 
Part B.  LOCF will be applied to the observations in PBO/RZB_75, and 
PBO/RZB_150 arms within the analysis period.  Baseline values will not be 
carried forward.  LOCF will be the primary approach in the analyses of 
continuous variables, and the secondary approach in the analyses of categorical 
variables.
●
As-observed:  The as-observed analysis will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit will be excluded from the as observed analysis for that visit.  As-observed 
analysis will be the secondary approach in the analysis of continuous variables.
●
Multiple Imputation (MI):  The MI will be used as sensitivity approach to 
impute missing data in primary endpoints. The variables to be included in the 
imputation model are listed below.  If MI is not applicable due to the nature of 
our data (e.g., MCMC algorithm does not converge), logistic regression or 
mixed effect model repeat measurement (MMRM) methods will be applied as 
sensitivity approach, whichever applicable.


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The Multiple Imputation analysis will be carried out in three steps.
●
Imputation of missing data.  The imputation will be generated for each efficacy 
endpoint measurement.  The variables to be included in the imputation model 
are:  concomitant disease of Baseline disease severity (PASI and sPGA), 
Baseline weight, treatment group, Concomitant PsA at baseline (Yes: 
Diagnosed or Suspected; versus: No), and measurements at each visit from 
randomization up to the end of the analysis period.  For each endpoint, 
20 'complete' datasets will be generated using SAS PROC MI.  The imputed 
post-baseline measurements will be rounded to the same precision as the 
observed data before the determination of responder status (e.g., PASI90).
●
Analysis of imputed data sets.  A CMH test, stratified by stratification factors, 
will be used to analyze categorical endpoints in each imputed dataset.
●
Synthesis of imputation and analysis results.  SAS PROC MIANALYZE will 
be used to generate the final inferences of the risk difference between 
treatment groups.
Of note, subjects who discontinued due to AE of "worsening of disease under study" will 
be counted as non-responders in all subsequent visits in the NRI and MI analyses, and will 
have their last observation prior to discontinuation carried forward in the LOCF analyses.  
For Observations in RZB_75/RZB_75, and RZB_150/RZB_150 arms in Part B, LOCF is 
continued across Part A and Part B.  LOCF will not carry forward from Period A to 
Period B for PBO/RZB_75, and PBO/RZB_150 arms.
10.1.5
Analysis of Psoriasis Symptoms Scale (PSS)
The 4-item PSS was designed to measure patient-reported psoriasis symptoms.  Subjects 
are requested to rate the severity of each of their symptoms related to pain, redness, 
itching, and burning, in the last 24 hours from "0 = none" to "4 = very severe," with total 
scores, which is the sum of the four item responses, ranging from 0 to 16 with higher 
scores indicating worse symptoms.  If one or more of the four items are missing then the 
total score for that day will be set to missing.


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PSS will be completed on Day 1 and the Week 16 visit in Part A.  Total Score from Day 1 
will be used as the baseline value.  Change from baseline in PSS will be analyzed by the 
van Elteren test between the risankizumab arms and placebo arm using the stratification 
factors of Concomitant PsA at baseline (Yes: Diagnosed or Suspected; versus: No) and
body weight (≤90 kg versus > 90 kg).  An example of the SAS code for this is as follows:   
proc freq data = indata; 
  tables strata * treatmnt * aval1 / cmh2 scores=modridit noprint;
where "strata" is numbered 1 – 4 based on the row order, "treatment" is dichotomous 
(Arm A or Arm B), and "aval1" is the PSS change from baseline at Week 16.  In the 
output from this code, the p-value is the "Prob" for statistic 2 – "Row Mean Scores 
Differ."
PSS will be completed by the subject during clinic visits at Week 28, Week 40 and 
Week 52 in Part B.  The PSS change from baseline will be summarized for these visits for 
each treatment arm.
In addition to the PSS total score, the four individual components, pain, redness, itching, 
and burning, will be analyzed using the same methodology.
10.2
Primary Efficacy Analysis
The primary hypotheses is that either risankizumab 150 mg or risankizumab 75 mg is 
superior to placebo in achieving ≥ 90% reduction from baseline in the PASI score 
(PASI 90) at Week 16 in participants with moderate to severe chronic plaque psoriasis.
In order to maintain the full significant level of 5%, the following null hypotheses will be 
tested in rank order, with two-sided alpha level 0.05.
1.
Risankizumab 150 mg is not different from placebo with respect to PASI 90 
response at Week 16


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2.
Risankizumab 75 mg is not different from placebo with respect to PASI 90 
response at Week 16
The difference in proportion of subjects achieving PASI 90 between treatment arms will 
be estimated and tested using the Cochran-Mantel-Haenszel risk difference estimate 
stratified by the stratification factors of Concomitant PsA at baseline (Yes: Diagnosed or 
Suspected; versus: No)  and body weight (≤ 90 kg versus > 90 kg).
The primary analysis will be carried out in the ITT Population and the PP Population.  
Non-responder imputation will be used as the primary approach for missing values.  
LOCF and MI will be performed as sensitivity analyses.
10.3
Secondary Efficacy Analyses
Secondary endpoints will be analysed in the ITT Population.  The same methods as 
discussed for the primary analyses will be used to analyze all binary secondary endpoint 
at Week 16.
Secondary endpoints for Week 52 will be summarized descriptively.
Secondary Efficacy Endpoints are:
●
Achievement of PASI 90 at Week 52
●
Achievement of an sPGA score of clear or almost clear  at Week 16
●
Achievement of an sPGA score of clear or almost clear  at Week 52
●
Achievement of ≥ 75% reduction from baseline PASI score (PASI 75) at 
Week 16
●
Achievement of PASI 75 at Week 52
●
Achievement of 100% reduction from baseline PASI score (PASI 100) at 
Week 16
●
Achievement of PASI 100 at Week 52


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●
Achievement of an American College of Rheumatology (ACR) 20 response at 
Week 16, among subjects with confirmed diagnosis of PsA using CASPAR 
criteria and with baseline total TJC and SJC counts ≥ 3 at selected study sites 
●
Achievement of an ACR 20 at Week 52, among subjects with confirmed 
diagnosis of PsA using CASPAR criteria and with baseline total TJC and SJC 
counts ≥ 3 at selected study sites
10.3.1
Further Efficacy Analysis
Further exploratory endpoints below will be analyzed among the ITT Population at all 
visits collected:
●
Achievement of PASI 50/75/90/100
●
Achievement of sPGA of clear and sPGA of clear or almost clear
●
Time until the first achievement of PASI 50, PASI 75, PASI 90, PASI 100, 
sPGA of clear and sPGA of clear or almost clear
●
Time until loss of PASI 75, PASI 90, PASI 100, sPGA of clear and sPGA of 
clear or almost clear response
●
Change from baseline in PASI score 
●
Percent change from baseline in PASI 
●
Achievement of absolute PASI of < 3 
●
Change from baseline in psoriasis symptoms evaluated using the total score on 
the Psoriasis Symptoms Scale (PSS) 
●
Achievement of a Dermatology Life Quality Index (DLQI) score of 0 or 1 
●
Achievement of total score on the PSS of 0 
●
Change from baseline in DLQI 
●
Change from baseline in HAQ-DI, among subjects with confirmed diagnosis 
of PsA using CASPAR criteria and with baseline total TJC and SJC counts ≥ 3 
at selected study sites
●
Change from baseline in Pain VAS, among subjects with confirmed diagnosis 
of PsA using CASPAR criteria and with baseline total TJC and SJC counts ≥ 3 
at selected study sites


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●
Change from baseline in Patient's Global Assessment VAS, among subjects 
with confirmed diagnosis of PsA using CASPAR criteria and with baseline 
total TJC and SJC counts ≥ 3 at selected study sites 
●
Change from baseline in Investigator's Global Assessment VAS, among 
subjects with confirmed diagnosis of PsA using CASPAR criteria and with 
baseline total TJC and SJC counts ≥ 3 at selected study sites
●
Achievement of an ACR 20, among subjects with confirmed diagnosis of PsA 
using CASPAR criteria and with baseline total TJC and SJC counts ≥ 3 at 
selected study sites
●
Investigator's global assessment among subjects with confirmed diagnosis of 
PsA using CASPAR criteria and with baseline total TJC and SJC counts ≥ 3 at 
selected study sites
●
Change from baseline in CRP, among subjects with confirmed diagnosis of 
PsA using CASPAR criteria and with baseline total TJC and SJC counts ≥ 3 at 
selected study sites
●
Change from baseline in TJC and SJC, among subjects with confirmed 
diagnosis of PsA using CASPAR criteria and with baseline total TJC and SJC 
counts ≥ 3 at selected study sites
In addition, the proportion of subjects achieving PASI 90, PASI 100, sPGA of clear, and 
sPGA of clear or almost clear at each visit in Part B will be summarized among those who 
had PASI 90, PASI 100, sPGA of clear, and sPGA of clear or almost clear, respectively, 
at the entry of Part B.
10.4
Handling of Multiplicity
The statistical comparisons for the primary efficacy will be carried out in the hierarchical 
order:
1.
The risankizumab 150 mg groups vs the placebo group.
2.
The risankizumab 75 mg groups vs the placebo group.


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The statistically significant results (p-value ≤ 0.05) for the comparison in the higher rank 
are necessary to initiate the testing of the next comparison in the lower rank.  Since a step-
down procedure is used, each comparison will be tested at a significance level of 0.05 and 
overall alpha level of 0.05 will be preserved.
10.5
Efficacy Subgroup Analysis
To evaluate the consistency of the efficacy on the primary endpoint of PASI 90 at 
Week 16 over demographic and other baseline characteristics, summaries and analyses 
will be performed for the following subgroups.
●
Age (< 40 years, ≥ 40 – < 65 years, ≥ 65 years)
●
Sex (male, female)
●
Smoking (current, ex or never)
●
BMI (normal:  < 25, over weight:  ≥ 25 – < 30, obese:  ≥ 30);
●
Body weight (≤ 90 kg versus > 90 kg)
●
Body weight (≤ median versus > median)
●
Baseline PASI score (by median); 
●
Baseline sPGA (3, 4)
●
concomitant PsA at baseline (Yes:  baseline total TJC and SJC counts ≥ 3 
versus No:  otherwise) among the subjects at the selected sites
●
Psoriasis Therapy History (Phototherapy or Photochemotherapy, TNF 
Antagonist, Other biologics, Non-biologic systemic therapy, All biologics, 
Naïve to all)
11.0
Safety Analysis
11.1
General Considerations
Safety analyses will include adverse events, laboratory, local tolerability, ECG, and vital 
sign measurements.  Safety summaries will be provided using the safety population as 
defined in Section 5.1.  Pairwise comparisons of risankizumab vs placebo will be 


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performed in the Safety Population.  Continuous variables will be analyzed using one-way 
ANOVA and categorical variables will be analyzed using Fisher's exact test.  For analyses 
of AEs, only P values ≤ 0.100, when rounded to three digits, will be presented.
Missing safety evaluations will not be imputed.
11.2
Analysis of Adverse Events
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as any event with an onset that 
is after the first dose of study drug and with an onset date within 105 days after the last 
dose of study drug in the analysis period, or prior to the first dose in the subsequent period 
for subjects who entered in to the subsequent period.  Events where the onset date is the 
same as the study drug start date are assumed to be treatment-emergent, unless the adverse 
event start time is prior to the study drug start time.  If an incomplete onset date is 
collected for an adverse event, the event will be assumed to be treatment-emergent unless 
there is other evidence that confirms that the event is not treatment-emergent (e.g., the 
event end date is prior to the study drug start date).
The data cutoff date (December 15, 2017) will be applied to TEAEs during the interim 
analysis, in accordance to the duration of study drug exposure defined up to this cutoff 
date.
Summary tables will be presented as follows:
1.
Adverse Event Overview
The number and percentage of subjects experiencing treatment-emergent adverse 
events will be summarized for the following adverse event categories.  
●
Any AE
●
Any AE that was assessed as related to study drug by the investigator
●
Any severe AE
●
Any serious AE (SAE)


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●
Any SAE that was assessed as related to study drug by the investigator
●
Any AE leading to discontinuation of study drug.
●
Any AE leading to death.
●
Any deaths
●
Areas of Safety Interest
2.
Adverse Events by System Organ Class and Preferred Term
TEAEs will be summarized and presented using primary Medical Dictionary for 
Regulatory Activities (MedDRA) system organ classes (SOCs) and preferred terms 
(PTs).  The SOCs will be presented in alphabetical order, and the PTs will be 
presented in alphabetical order within each SOC.
Subjects reporting more than one adverse event for a given MedDRA preferred 
term will be counted only once for that term (most severe incident for the severity 
tables and most related incident for the relationship tables).  Subjects reporting 
more than one type of adverse event within a SOC will be counted only once for 
that SOC.  Subjects reporting more than one type of adverse event will be counted 
only once in the overall total. 
In addition, the number and percentage of adverse events with causal relationship 
between the events and the study drug will be summarized using the same 
conventions described above.
3.
Adverse Events by Maximum Severity
The severity grading of AEs follows Rheumatology Common Toxicity Criteria 
(RCTC).  
●
Grade 1 – mild
●
Grade 2 – moderate
●
Grade 3 – severe
●
Grade 4 – life threatening
Adverse events will be summarized by maximum severity.  If a subject has an 
adverse event with unknown severity, then the subject will be counted in the 


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severity category of "unknown," even if the subject has another occurrence of the 
same event with a severity present.  The only exception is if the subject has another 
occurrence of the same adverse event with the most extreme severity (life 
threatening).  In this case, the subject will be counted under the "life threatening" 
category.
4.
Adverse Events by Maximum Relationship
Adverse events will be summarized by maximum relationship to study drug, as 
assessed by the investigator.  Relationship of an AE to study drug is assessed by 
the investigator and collected in the CRF as 'Yes' or 'No.'  If a subject has an 
adverse event with unknown relationship, the subject will be counted in the 
relationship category of "unknown," even if the subject has another occurrence of
the same event with a relationship of "No."  If the subject has another occurrence of 
the same adverse event with a relationship assessment of "Yes," the subject will be 
counted under the "yes" category. 
A listing of all pretreatment (i.e., events start prior to the first study drug injection) serious 
adverse events will be provided. 
The following tables are planned.
Treatment-emergent adverse events will be summarized as follows:
●
Grouped by SOC and PT
●
Grouped by SOC, PT and maximum relationship to study drug
●
Grouped by SOC, PT and maximum severity
Treatment-emergent SAEs will be summarized as follows:
●
Grouped by SOC and PT
●
A by-subject listing will be provided


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Pre-treatment SAEs will be summarized as follows:
●
A by-subject listing will be provided
Treatment-emergent adverse events leading to death or premature discontinuation 
of study drug will be summarized as follows:
●
Grouped by SOC and PT
●
Separate listings by subject for deaths and premature terminations of study 
drug due to adverse events will be provided.
Treatment-emergent areas of safety interest will be summarized as follows:
●
Grouped by SOC and PT
●
A listing by subject will be provided.
Areas of Safety Interest
Areas of Safety Interest groupings are listed in Table 10.  These events are of interest due 
to a higher rate in the moderate to severe psoriasis population, or of interest for all 
immunoglobulin products or products in general.
The final list will be based on the most updated final version of risankizumab Product 
Safety Statistical Analysis Plan, which is consistent to the most updated risankizumab 
Risk Management Plan.


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Table 10.
Areas of Safety Interest
ASI Grouping
Categories 
(ASI)
Search Criteria
Terms to Display
Include 
in AE 
Overview 
(Y/N)
Adjudicated CV 
Events
MACE
Adjudicated 
events
Display underlined terms 
defined by the following 
adjudicated terms:
!
CV Death which includes 
CETERM values:  Fatal 
CV, Fatal PE, Fatal Non-
Cardiac/Non-Neuro Arterial 
Thrombosis/Thromboembol
ism, Undetermined Death, 
Not assessable death 
(cardiac/neuro/thrombotic), 
Fatal Stroke
!
Myocardial infarction
!
Stroke
Y
Extended 
MACE
Adjudicated 
events
Display underlined terms from 
MACE and underlined terms 
below:
!
Hospitalization for Unstable 
Angina
!
Coronary Revascularization 
Procedures
N


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Table 10.
Areas of Safety Interest (Continued)
ASI Grouping
Categories 
(ASI)
Search Criteria
Terms to Display
Include 
in AE 
Overview 
(Y/N)
Adjudicated CV 
Events 
(continued)
Other CV 
events
Adjudicated 
events
Display underlined terms 
defined by the following 
adjudicated terms:
!
Thrombotic events which 
includes CETERM values:  
Deep Vein Thrombosis, 
TIA, Pulmonary Embolism, 
Non-fatal Non-
Cardiac/Non-Neurological 
Arterial Thrombosis/ 
Thromboembolism, Other 
Venous Thrombosis, 
specified (non-fatal)
!
Cardiac arrhythmia which 
includes CETERM of:  
Clinically Significant 
Arrhythmia
!
Congestive heart failure
which includes CETERM of 
Heart Failure
!
Hypertensive emergency
N
Serious 
infections, TB, 
fungal and 
opportunistic 
infections 
(including 
herpes zoster)
Serious 
infections
Serious PTs of 
the CMQ 
(company 
MedDRA query) 
Infections 
(CMQ 80000018)
PTs
Y
TB
Tuberculosis 
(including 
Investigations) 
CMQ 
(code 80000033)
PTs
Y
Opportunistic 
infections
Opportunistic 
infections CMQ 
(code 80000073)
PTs
N


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Table 10.
Areas of Safety Interest (Continued)
ASI Grouping
Categories 
(ASI)
Search Criteria
Terms to Display
Include 
in AE 
Overview 
(Y/N)
Serious 
infections, TB, 
fungal and 
opportunistic 
infections 
(including 
herpes zoster) 
(continued)
Fungal 
infections
Fungal infections 
CMQ 
(code 80000063)
PTs
N
Herpes Zoster
Herpes zoster 
CMQ 
(code 80000175)
PTs
N
Malignancies
All possible 
malignancies
Narrow –
Malignancies 
(SMQ 20000090) 
PTs
N
Malignant 
Tumours
Narrow –
Malignant 
tumours 
(SMQ 20000194)
PTs
Y
Non-melanoma 
skin cancer 
(NMSC)
Broad – Skin 
malignant 
tumours 
(SMQ 20000204) 
excluding terms 
identified by the 
Melanoma CMQ 
(code 80000119)
PTs
N
Malignant 
Tumours 
excluding 
NMSC
'Malignant 
Tumours 
excluding 
NMSC' is 
identified by the 
'Malignant 
Tumours' search 
excluding terms 
identified by the 
'Non-melanoma 
skin cancer 
(NMSC) search.
PTs
Y


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Table 10.
Areas of Safety Interest (Continued)
ASI Grouping
Categories 
(ASI)
Search Criteria
Terms to Display
Include 
in AE 
Overview 
(Y/N)
Hypersensitivity 
Reaction
Hypersensitivity
Narrow –
Hypersensitivity 
(SMQ 20000214)
PTs
Y –
serious 
events 
only
Anaphylactic 
Reaction
Narrow –
Anaphylactic 
reaction 
(SMQ 20000021)
PTs
N
Hepatic Events
Hepatic Events
Broad – Hepatic 
failure, fibrosis 
and cirrhosis and 
other liver 
damage-related 
conditions 
(SMQ 20000013) 
Broad –
Hepatitis, non-
infectious 
(SMQ 20000010) 
Broad –
Cholestasis and 
jaundice of 
hepatic origin 
(SMQ 20000009) 
Broad – Liver 
related 
investigations, 
signs and 
symptoms 
(SMQ 20000008) 
Narrow – Liver-
related 
coagulation and 
bleeding 
disturbances 
(SMQ 20000015)
PTs
N


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Adverse Event per 100 Patient-Years of Exposure
AEs occurring during the entire study will be presented by event rate per 
100 patient years.  These will be presented for any TEAEs, serious adverse events, Areas 
of Safety Interest. 
AEs per 100 patient-years of exposure is defined as the number of AEs divided by the 
total exposure in 100 patient-years.  Note that one event per preferred term per day per 
subject will be counted in the calculation of the number of AEs (i.e., a preferred term will 
not be counted twice on the same day for the same subject).  See the calculation method 
below.
where total patient years is defined as the sum of the study drug exposure (defined as date 
of last dose – date of first dose + 105 days (5 half-lives)) of all subjects normalized by 
365.25, and rounded to one decimal place.
11.2.2
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
Deaths and all SAEs will be presented in listing format.  In addition, SAEs will be 
summarized by System Organ Class and MedDRA Preferred Term.
11.2.3
Safety Subgroup Analysis
The AE overview and AE by SOC and preferred term in each period will also be analyzed 
with respect to the actual values of:
●
concomitant PsA at baseline (Yes:  baseline total TJC and SJC counts ≥ 3 
versus No:  otherwise) among the subjects at the selected sites
●
Dichotomous body weight (≤ 90 kg versus > 90 kg)
●
Dichotomous body weight (≤ median versus > median)
Years
Patient 
Total
TEAEs
of
Number 
100 ∀


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11.3
Analysis of Laboratory Data
For the assessments of laboratory data, values observed more than 105 days after the last 
dose of study drug will be excluded.
Listing and descriptive statistics of laboratory values over time, change from baseline, and 
extreme abnormal value on treatment will be provided.  Extreme abnormal value is the 
value which is most significantly away from the reference range.  Frequency of subjects 
with transitions relative to reference range and listing of subjects with significant 
abnormal laboratory values will be presented as well.
11.3.1
Variables and Criteria Defining Abnormality
Clinical laboratory tests performed by central laboratory service provider are listed below. 


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Table 11.
Clinical Laboratory Tests
Category
Test Name
Haematology
Hematocrit (Hct)
Hemoglobin (Hb)
Glycosylated Hbc (HbA1c)
White Blood Cells/Leukocytes
Platelet Count/Thrombocytes
Diff. Automatic
Neutrophils (relative and absolute count) 
Eosinophils (relative and absolute count) 
Lymphocytes (relative and absolute count) 
Enzymes
AST (GOT) 
ALT (GPT) 
Alkaline Phosphatase (AP) 
Creatine Kinase (CPK) 
Gamma-Glutamyl Transferase (GGT/γ-GT) 
Lactic Dehydrogenase (LDH) 
Amylase 
Lipase 
Electrolytes
Calcium 
Sodium 
Potassium 
Substrates
Glucose 
BUN 
Uric acid 
Creatinine 
eGFR (estimated by CKD-EPI formula) 
Bilirubin Total 
Albumin 
C-Reactive Protein (CRP) (high sensitivity) 
Cholesterol, total 
Triglycerides 
LDL-Cholesterol 
HDL-Cholesterol
Urinalysis (dipstick)
Urine Glucose


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11.3.2
Statistical Methods
All analyses will be conducted in the Safety Population.  Table for potentially clinically 
important lab values will also be summarized in the ALL_RZB Population.
Analysis of Continuous Laboratory Parameters
Though the protocol indicates utilizing the Rheumatology Common Toxicity Criteria 
(RCTC) scale for grading laboratory values, given that the NCI National Cancer Institute 
Common Toxicity Criteria for Adverse Event (CTCAE) scale includes a more 
comprehensive list of laboratory values; therefore, the lab analyses based on the NCI 
CTCAE scale will be presented.  Change from Baseline to each scheduled visit and to the 
final value in continuous laboratory parameters will be summarized with the mean, 
standard deviation and median.  The Baseline and visit/final value means will also be 
presented for subjects who have both the Baseline and visit/final values (see Section 6.0
for the definition of Baseline and final values).  If there are multiple post-baseline 
measurements on the same day, the average value will be used. 
Shift Tables
Shift tables for changes from Baseline according to the normal range will be provided for 
each hematology and clinical chemistry parameter.  Shifts from Baseline to the following 
endpoints will be considered:  minimum value, maximum value and final value.  
Categories of "low or normal" and "high or normal" will be included at Baseline in 
addition to the categories of "low," "normal," "high" and "missing."  If there are multiple 
measurements on the same day, the last value will be used.
Potentially Clinically Important Laboratory Values
Frequencies and percentages of subjects with post Baseline lab values meeting the 
following criteria will be summarized.  Of note, a post baseline value must be more 
extreme than the baseline value to be considered a potentially clinically important finding. 


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Table 12.
Criteria for Potentially Clinically Important Chemistry Values
Chemistry Variables
Units
Definition of Potentially Clinically Important Current 
(Version 4) NCI CTCAE Grade 3 or Greater
Very Low
Very High
TBL
mcmol/L
> 3.0 × ULN
SGOT/AST
U/L
> 5.0 × ULN
SGPT/ALT
U/L
> 5.0 × ULN
Albumin
g/L
< 20
Glucose
mmol/L
< 2.2
> 13.9
Triglycerides
mmol/L
> 5.7
Creatinine
mcmol/L
> 3.0 × ULN
Sodium
mmol/L
< 130
> 155
Potassium
mmol/L
< 3.0
> 6.0
Calcium
mmol/L
< 1.75
> 3.1
CPK
U/L
> 5.0 × ULN
Total Cholesterol
mmol/L
> 10.34
GGT
> 5.0 × ULN
ALP
> 5.0 × ULN
Lipase
> 5.0 × ULN
Amylase
> 5.0 × ULN
Table 13.
Criteria for Potentially Clinically Important Hematology Values
Hematology Variables
Units
Definition of Potentially Clinically Important Current 
(Version 4) Grade 3 or Greater
Very Low
Hemoglobin
g/dL
< 8.0
Platelets count
109/L
< 50.0
WBC count
109/L
< 2.0
Neutrophils
109/L
< 1.0
Lymphocytes
109/L
< 0.5
A separate listing will be provided that presents all of the subjects and values that are NCI 
CTCAE toxicity grade 3 or above.  For each of these subjects, the whole course of the 


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respective parameter will be listed.  The NCI CTCAE grading is shown in Table 14
below:
Table 14.
NCI CTCAE Grading
Test
Grade 1
Grade 2
Grade 3
Grade 4
SGPT/ALT 
increased
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
SGOT/AST 
increased
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
GGT increased
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
ALP increased
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
TBL increased
> ULN – 1.5 × ULN
> 1.5 – 3.0 × ULN
> 3.0 – 10.0 × ULN
> 10.0 × ULN
Creatinine 
increased
> ULN – 1.5 × ULN
> 1.5 – 3.0 × ULN
> 3.0 – 6.0 × ULN
> 6.0 × ULN
CPK increased
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 10.0 × ULN
> 10.0 × ULN
Hemoglobin 
decreased
< LLN – 100.0 g/L
< 100.0 – 80.0 g/L
< 80.0
Neutrophil count 
decreased
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
WBC decreased
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Lymphocyte 
count decreased
< LLN – 0.8 × 109/L
< 0.8 – 0.5 × 109/L
< 0.5 – 0.2 × 109/L
< 0.2 × 109/L
If there are multiple post-baseline measurements on the same day, the worst value will be 
used.
Liver Function Tests
Additional summaries will be presented for liver function tests including ALT or serum 
glutamic-pyruvic transaminase (SGPT), AST or serum glutamic-oxaloacetic transaminase 
(SGOT), alkaline phosphatase, and total bilirubin.  Each laboratory value will be 
categorized as follows:
●
< 1.5 × ULN
●
≥ 1.5 × ULN – < 3.0 × ULN


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●
≥ 3.0 × ULN – < 5.0 × ULN
●
≥ 5.0 × ULN – < 10.0 × ULN
●
≥ 10.0 × ULN – < 20.0 × ULN
●
≥ 20.0 × ULN
Shift tables of Baseline to the maximum (relative to the normal range, i.e., the largest 
multiple relative to the upper limit of normal) values, and from Baseline to final value will 
be presented using these categories.  A listing of potentially clinically important liver 
function laboratory values will be provided.  The listing will include all subjects who met 
any of the following four criteria:
●
ALT ≥ 3 × ULN, or
●
AST ≥ 3 × ULN, or
●
Alkaline phosphatase ≥ 1.5 × ULN, or
●
Total bilirubin ≥ 2 × ULN.
A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions will be provided:  
●
ALT > 3 × ULN or AST > 3 × ULN
●
Associated with an increase in bilirubin ≥ 2 × ULN 
●
Alkaline phosphatase < 2 × ULN.
11.4
Analysis of Vital Signs and Weight
11.4.1
Variables and Criteria Defining Abnormality
The following vital sign parameters will be assessed:  Systolic blood pressure [mmHg], 
Diastolic blood pressure [mmHg], Pulse [beats per minute], Respiratory rate [breaths per 
minute], Temperature [°C], Weight [kg].  The following table presents the Criteria for 
Potentially Clinically Important Vital Sign Findings.  Of note, a post baseline value must 


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be more extreme than the baseline value to be considered a potentially clinically important 
finding.
Table 15.
Criteria for Potentially Clinically Important Vital Sign Findings
Vital Sign
Category
Criteria for Potential Clinically Important Vital Signs
Systolic Blood Pressure
Low Value
≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High Value
≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic Blood Pressure
Low Value
≤ 50 mmHg and decrease ≥ 15 mmHg from Baseline
High Value
≥ 105 mmHg and increase ≥ 15 mmHg from Baseline
Pulse
Low Value
≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High Value
≥ 120 bpm and increase ≥ 15 bpm from Baseline
11.4.2
Statistical Methods
Changes from Baseline to each visit and to the final value in vital sign parameters will be 
summarized with the mean, standard deviation and median.  The Baseline and final value 
means will also be presented for subjects who have both the Baseline and final values (see 
Section 6.0 for the definition of Baseline and final values).
For baseline, if there are multiple measurements on the same day, the last measurement 
prior to the first dose of study drug will be used as the Baseline vital sign value.  If there 
are multiple post-baseline measurements on the same day, average value will be used.
For systolic blood pressure, diastolic blood pressure and pulse, a listing of all subjects 
with any vital sign value meeting criteria for potentially clinically important values will be 
provided.  For each of these subjects, the whole course of the respective parameter will be 
listed.  The number and percentage of subjects who have at least one value meeting 
criteria for potentially clinically important values will be provided for each selected vital 
sign parameter.
All analyses will be conducted in the Safety Population.  Table for potentially clinically 
important vital signs will also be summarized in the ALL_RZB Population.


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11.5
Analysis of ECG Parameters
The ECG parameters will be assessed as scheduled in the study protocol.
Summary statistics for mean change from baseline for corrected QT interval (QTc) using 
Bazett (QTcB) and Fridericia (QTcF) corrections, aggregated, will be provided by 
analysis visits.
●
Values for both QTcF and QTcB interval measurements will be categorized 
into the following:  ≤ 450 ms, > 450 ms, > 480 ms, > 500 ms, or missing.  For 
the scheduled visits, as well as baseline, the number and percentage of subjects 
within each category will be presented.  Additionally, for each category, the 
number and percentage of subjects with a maximum QTcF interval falling into 
the category will be presented; a similar summary will be presented for QTcB 
intervals.
●
For QTcF and QTcB intervals, the changes from baseline will be categorized 
into the following:  < 30 ms, 30 ≤ – < 60 ms, ≥ 60 or missing.  For the 
scheduled visits, the number and percentage of subjects within each category 
will be presented.  Additionally, for each category, the number and percentage 
of subjects with a maximum change from baseline in the QTcF interval falling 
into the category will be presented; a similar summary will be presented for 
QTcB intervals.
Analyses will be conducted in the Safety Population.
11.6
Local Tolerability
Local tolerability at the administration site of the subcutaneous injection will be assessed 
by the investigator in the measurements of "swelling," "induration," "heat," "redness," 
"pain," or "other findings." 
Proportion of subjects reporting each condition will be analyzed.  The overall rate (with at 
least one occurrence) during Part A and B will also be presented.
Analyses will be conducted in the Safety Population in Part A and in Part B. 


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12.0
Pharmacokinetic Analysis
Pharmacokinetic analysis is not covered in this SAP.
13.0
Biomarkers Analysis
Biomarkers Analysis is not covered in this SAP.
14.0
Summary of Changes
14.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
14.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP
15.0
Appendix
None.
16.0
References
None.
17.0
List of Tables, Figures, and Data Listings to Be 
Programmed
To be provided in a separate document.