Efficacy and Safety Comparison of Brodalumab Versus Guselkumab in Adult Subjects With Moderate-to-severe Plaque Psoriasis and Inadequate Response to Ustekinumab
Phase: PHASE4
Conditions: Plaque Psoriasis, Psoriasis Vulgaris, Psoriasis
Sponsor: LEO Pharma

 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Study title: Efficacy and safety comparison of brodalumab versus guselkumab in adult subjects with 
moderate -to -severe plaque psoriasis and inadequate response to ustekinumab; COBRA 
LEO Pharma number: LP0160-1510 
NCT number: NCT04533737 
Date: 10-Mar-2022 
 

CONFIDENTIAL 
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THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
 
Clinical Trial Protocol 
 
 
LP0160-1510 
 
 
 
Efficacy and safety comparison of brodalumab versus guselkumab in 
adult subjects with moderate -to -severe plaque psoriasis and inadequate 
response to ustekinumab; COBRA 
 
Phase 4 – efficacy trial 
A randomised, blinded, parallel-group, multi-site, clinical trial  
 
 
 
 
 
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, 
and the applicable regulatory requirement(s). 
LEO Pharma A/S 
Trial ID: 
LP0160-1510 
 
Date: 
 
10-Mar-2022 
 
EudraCT no: 
2019-004099-20 
 
Version: 
5.0 
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Clinical trial protocol statements 
Approval statement LEO Pharma A/S 
Electronic signatures made within LEO Pharma Clinical Vault are considered to be a legally 
binding equivalent of traditional handwritten signatures. The following persons have 
approved this clinical trial protocol by using electronic signatures as presented on the last 
page of this document: 
, MSc Eng, PhD  
 
Biostatistics lead, Medical Sciences  
 
 
 
, MD 
 
Vice president, Medical Sciences 
 
 
, PhD  
 
Global Head Clinical Operations Project, Clinical 
Project Management 
 
 
 
 
 
 
Approval statement signatory investigator 
The signatory investigator approves the clinical trial protocol by manually signing the 
signatory investigator clinical trial protocol approval form, which is a separate document 
appended to this document. 
The following person has approved this clinical trial protocol: 
, MD, PhD 
 
Signatory investigator 
 
 
Acknowledgement statement investigators  
Each participating investigator must agree to the approved clinical trial protocol by signing a 
clinical trial protocol acknowledgement form or similar document. 
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PPD
PPD
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Protocol amendment summary of changes table 
Document history 
Document 
Date 
Type of protocol amendment 
Amendment 3 
(substantial) 
10-Mar-2022 
Global 
Amendment 2 
(substantial) 
22-Jan-2021 
Global 
Amendment 1 
(substantial) 
19-Aug-2020 
Global 
Original protocol 
18-Jun-2020 
Not applicable 
 
Amendment 3 (10-Mar-2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
or subsequent regulation. 
Overall rationale for the amendment: 
The main reason for this amendment is to reduce the sample size and amend the eligibility 
criteria to ease recruitment.  
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it). 
Section no. 
and name 
Description of change 
Brief rationale 
3 Schematic of 
trial design 
Total number of subjects changed from 260 to 
240 subjects and in each treatment group from 
130 to 120 subjects. 
Sample size reduced 
from 260 to 
240 subjects. 
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Section no. 
and name 
Description of change 
Brief rationale 
4 Schedule of 
trial 
procedures 
QuantiFERON® test Tuberculosis test 
To allow tuberculosis 
test to be performed at 
local laboratory. 
4 Schedule of 
trial 
procedures, 
footnote 5 
Footnote 5: 
QuantiFERON® or purified protein derivative 
(PPD) test. The PPD test is only accepted if it 
is a requirement from local health authorities 
(see inclusion criterion 5). Tuberculosis test 
can be performed at the central laboratory. 
If a local laboratory test is performed to 
confirm this criterion, the local laboratory 
should be assessed before the local testing is 
performed. 
Footnote 6: 
PP-PASI and PP-IGA to be completed for 
all subjects at Visits 1 and 2. Subsequently, 
only subjects with palmoplantar psoriasis at 
baseline (Visit 2) will be followed using the 
separate tools PP-PASI and PP-IGA. 
Footnote 8: 
The DLQI, SF-36v2, and PHQ-8 
questionnaires should be completed by the 
subject prior to the investigator, safety, and C-
SSRS other assessments. For the sequence of 
assessments to be performed at each visit, 
please see Panel 8. 
Footnote 16: 
To allow tuberculosis 
test to be performed at 
local laboratory. 
 
 
 
 
 
To clarify when PP-
PASI and PP-IGA are to 
be performed. 
 
 
Order of assessments 
changed to ease the 
process at trial site. 
 
 
 
Correcting a clerical 
error 
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Section no. 
and name 
Description of change 
Brief rationale 
In case of abnormal dipstick results at baseline 
screening, a urine sample will be sent to the 
central laboratory for albumin-to-creatinine 
ratio. 
7.2 Number of 
subjects 
needed 
This trial will be conducted at approximately 
75 sites in Europe and Australia.  
Assuming a screening failure of 15 18%, 
approximately 306 293 subjects will be 
screened, and 260 240 eligible subjects will be 
randomised in a 1:1 ratio to treatment with 
either brodalumab or guselkumab. 
Removing Australia as 
a participating country 
and reducing the 
sample size to 
240 subjects. 
8.2 Inclusion 
criteria, 
inclusion 
criterion 4 
Subject has inadequately controlled plaque 
psoriasis currently treated with ustekinumab, 
and fulfils ALL of the following criteria:  
•  Ustekinumab administered at least 3 times 
at or higher than the approved dose or 
frequency before randomisation for at least 
24 weeks (Stelara® SmPC) (17). 
•  Investigator's Global Assessment (IGA) ≥2 
at screening and baseline. 
•  Absolute PASI >3 at screening and baseline. 
•  The last administration of ustekinumab was 
≥12 weeks before randomisation. 
To ease the 
identification of 
subjects who have not 
benefitted sufficiently 
from ustekinumab 
treatment. 
8.2 Inclusion 
criteria, 
inclusion 
criterion 5 
Subject has a negative test for tuberculosis at 
screening (negative QuantiFERON® test or 
purified protein derivative [PPD] test*). 
Subject without a history of Bacillus 
Calmette-Guérin (BCG) vaccination who has 
To allow tuberculosis 
test to be performed at 
local laboratory. 
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Section no. 
and name 
Description of change 
Brief rationale 
a positive PPD test or a positive or 
indeterminate QuantiFERON® test is allowed 
if the subject has ALL of the following: 
•  No symptoms or signs of tuberculosis as 
evaluated by the investigator. 
•  Documented prophylactic treatment of 
latent tuberculosis according to local standard 
of care initiated at least 1 month prior to first 
administration of IMP. 
•  No known exposure to a case of active 
tuberculosis after most recent prophylaxis. 
•  No evidence of active tuberculosis based on 
documented assessment by a pulmonologist or 
a tuberculosis specialist (phthisiologist).  
*The PPD test is only accepted if it is a 
requirement from local health authorities. 
Subject has no evidence of active 
tuberculosis according to local standard of 
care for patients requiring initiation of a 
biologic treatment. Subjects with 
adequately treated latent tuberculosis, 
according to local guidelines, are eligible. 
a.  A tuberculosis test can be performed at 
the central laboratory. 
b.  If a local laboratory test is performed to 
confirm this criterium, the local laboratory 
should be assessed before the local testing is 
performed.   
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Section no. 
and name 
Description of change 
Brief rationale 
8.3 Exclusion 
criteria, 
exclusion 
criterion 20 
Subject has previously received more than 1 
TNFα inhibitor. NOTE:  This exclusion 
criterion is not applicable in this version of 
the protocol. It is kept to avoid re-
numbering of the exclusion criteria. 
To ease the recruitment 
of subjects. 
8.4.2.2 Re-
screening 
All screening and laboratory assessments must 
be repeated except tuberculosis test 
QuantiFERON® test or the PPD test, if 
negative at first screening. 
To allow tuberculosis 
test to be performed at 
local laboratory. 
9.3 Treatment 
assignment 
Randomisation will be stratified by baseline 
(Visit 2) body weight (≤100 kg and >100 kg). 
For clarification. 
9.7 Prohibited 
medications 
and 
procedures, 
Panel 7 
Ustekinumab:  12 weeks prior to First 
administration of IMP 
To align with the 
revised inclusion 
criterion 4. 
9.10 Reporting 
product 
complaints 
Fax number: +45 6910 2468 7226 3287 
New fax number. 
11.1 Overview, 
Panel 8 
Order of assessments changed so PHQ-8 is 
performed together with DLQI and SF-36v2 
before all other assessments. 
To ease the assessment 
process at trial site. 
11.4.4.1 
Overview, 
Panel 15 
Tuberculosis test (if applicable) QuantiFERON® 
test (only at screening) PPD test (only at 
screening) 
 
Definition of PPD deleted from table footnote. 
To allow tuberculosis 
test to be performed at 
local laboratory. 
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Section no. 
and name 
Description of change 
Brief rationale 
12.1 Scientific 
rationale for 
trial design 
Inadequate response to ustekinumab is defined 
as IGA ≥2 after at least 3 doses at or higher 
than the approved dose or frequency and 24 
weeks of treatment, and this correlates well 
with the currently acceptable treatment goals. 
Evaluation of the eligible psoriatic subjects 
who have had at least 24 weeks of 
ustekinumab exposure will ensure the 
feasibility of the trial and the homogenous 
disease population.    
To align with the 
revised inclusion 
criterion 4. 
13.4.1 
Investigator 
reporting 
responsibilities 
Fax number: +45 6910 2468 7226 3287 
New fax number. 
14.1 Sample 
size 
Updated with description of new sample size 
calculation. 
To provide a rationale 
for the new sample size 
of 240 subjects. 
14.3.6 
Estimand 
strategy 
Procedures for multiple imputation in 
‘hypothetical’ strategies for addressing 
intercurrent events and in handling of missing 
data updated. Main analyses of primary 
estimands for binary and continuous endpoints 
clarified with regards to the combination of 
results from multiply imputed datasets. 
Prior TNF-α inhibitor use at baseline (≤1, >1) 
included as a factor in all analysis models. 
Scope of Sensitivity analysis 2 of the primary 
estimand for binary endpoints expanded to 
also assess robustness with respect to the 
assumption that the effect of treatment does 
not depend on prior TNF-α inhibitor use at 
baseline (≤1, >1). 
To align with other 
LP0160 protocols. 
 
 
 
To handle the change of 
eligibility criteria in the 
analysis. 
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Section no. 
and name 
Description of change 
Brief rationale 
14.3.7 
Analysis of 
efficacy 
endpoints 
For each binary endpoint it has been specified 
whether the underlying assessment will be 
considered on a continuous or ordinal scale. 
To aid in the 
specification of 
procedures for multiple 
imputation. 
Appendix 3C 
Subject and 
data 
confidentiality 
Processing of personal data on behalf of LEO 
Pharma requires a written agreement between 
LEO Pharma and the relevant party which 
covers collection, processing, and transfer of 
personal data in the clinical trial, as well as 
reporting obligations in the event of any 
data breach. 
For clarification. 
Appendix 3G 
Financial 
disclosure 
Investigators are responsible for providing 
information on financial interests and update 
this information, should any relevant 
change occur, during the course of the 
clinical trial and for 1 year after completion of 
the clinical trial, or for a longer period of time 
if required by local legislation. 
For clarification. 
Appendix 4 
Short version 
of eligibility 
criteria 
Aligned with revisions of inclusion criteria 5 
and exclusion criterion 20. 
PPD definition deleted from table footnotes. 
Alignment. 
Appendix 6 
COVID-19 
pandemic 
contingency 
plan 
Assessments will be performed via the use of 
a trial-specific mobile application on the 
subject’s own smartphone or via the use of 
other video software used by the trial site in 
their normal clinical practice and in 
agreement with the sponsor and following 
notification of the relevant ethics committee 
and by completing the PHQ-8 questionnaire 
To allow the use of 
already available 
software that the trial 
staff is familiar with. 
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Section no. 
and name 
Description of change 
Brief rationale 
via a webpage (hereafter termed ‘video 
visits’). 
Appendix 6 
COVID-19 
pandemic 
contingency 
plan 
Delivery of IMP to a subject may also be 
performed by the subject’s spouse or other 
relative or delegated person of trust who 
can pick up the IMP at the trial site and 
deliver to the subject. 
To make it easier to 
deliver IMP to the 
subject. 
Appendix 6 
COVID-19 
pandemic 
contingency 
plan 
Delivery of IMP to subjects and self-injection: 
2. Prepare and ship/hand out to 
subject’s relative or delegated 
person of trust (refer to trial product 
handling manual for instructions): 
o IMPs allocated via the IRT 
including instruction for use 
and other supplies. 
o Urine pregnancy test kits, if 
applicable. 
Care should be taken to keep blinded 
site staff from becoming unblinded 
while preparing the shipment/package 
for hand out to subject’s relative or 
delegated person of trust. 
3. Site staff are responsible for 
establishing contact with the subject as 
soon as he/she receives the IMP 
shipment. 
To make it easier to 
deliver IMP to the 
subject. 
Appendix 6 
COVID-19 
pandemic 
contingency 
plan 
Delivery of IMP to subjects and self-injection: 
4. At the date of self-injection, the 
unblinded site staff contacts the subject 
via the video function in the trial-
specific mobile application or other 
To allow the use of 
already available 
software that the trial 
staff is familiar with. 
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Section no. 
and name 
Description of change 
Brief rationale 
software used by the trial site in 
their normal clinical practice and 
completes the following: 
Throughout 
Minor editorial and document formatting 
revisions. 
Minor, have therefore 
not been summarised. 
 
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Table of contents 
Clinical trial protocol statements ............................................................................................ 2 
Protocol amendment summary of changes table ................................................................... 3 
Table of contents ..................................................................................................................... 12 
List of panels ........................................................................................................................... 16 
List of abbreviations ............................................................................................................... 18 
1 Protocol synopsis ................................................................................................................ 21 
2 Trial identification ............................................................................................................. 26 
3 Schematic of trial design ................................................................................................... 26 
4 Schedule of trial procedures ............................................................................................. 27 
5 Introduction and trial rationale ....................................................................................... 35 
5.1 Plaque psoriasis .......................................................................................................... 35 
5.2 Experience with investigational medicinal products .................................................. 35 
5.3 Trial rationale .............................................................................................................. 37 
5.4 Ethical considerations ................................................................................................. 38 
5.5 Benefit/risk assessment ............................................................................................... 39 
6 Trial objectives, endpoints, and estimands ...................................................................... 40 
7 Trial design ......................................................................................................................... 45 
7.1 Overall trial design ..................................................................................................... 45 
7.2 Number of subjects needed ......................................................................................... 46 
7.3 End-of-trial definition ................................................................................................. 46 
8 Trial population ................................................................................................................. 47 
8.1 Subject eligibility ........................................................................................................ 47 
8.2 Inclusion criteria ......................................................................................................... 47 
8.3 Exclusion criteria ........................................................................................................ 48 
8.4 Screening and screening failures ................................................................................ 51 
8.4.1 
Subject identification number ....................................................................... 51 
8.4.2 
Screening failures .......................................................................................... 52 
9 Treatments .......................................................................................................................... 53 
9.1 Trial product description ............................................................................................. 53 
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9.2 Administration of investigational medicinal product ................................................. 54 
9.3 Treatment assignment ................................................................................................. 55 
9.3.1 
Blinding ......................................................................................................... 55 
9.3.2 
Emergency unblinding of individual subject treatment ................................ 56 
9.4 Background treatment ................................................................................................. 57 
9.5 Rescue treatment ......................................................................................................... 57 
9.6 Concomitant medication and concurrent procedures ................................................. 57 
9.7 Prohibited medications and procedures ...................................................................... 58 
9.8 Treatment logistics and accountability ....................................................................... 60 
9.8.1 
Labelling and packaging of trial products ..................................................... 60 
9.8.2 
Storage of trial products ................................................................................ 60 
9.8.3 
Drug accountability ....................................................................................... 61 
9.8.4 
Treatment compliance ................................................................................... 61 
9.8.5 
Trial product destruction ............................................................................... 61 
9.9 Provision for subject care following trial completion ................................................ 62 
9.10 Reporting product complaints..................................................................................... 62 
10 Discontinuation and withdrawal ...................................................................................... 63 
10.1 General principles ....................................................................................................... 63 
10.2 IMP discontinuation rules ........................................................................................... 64 
10.2.1 Reasons for permanent discontinuation of IMP ............................................ 64 
10.2.2 Reasons for temporary discontinuation of IMP ............................................ 65 
10.3 Early termination assessments .................................................................................... 66 
10.4 Lost to follow-up ........................................................................................................ 67 
11 Trial assessments and procedures .................................................................................... 68 
11.1 Overview..................................................................................................................... 68 
11.2 Assessments performed only at screening/baseline .................................................... 69 
11.2.1 Demographics................................................................................................ 69 
11.2.2 Trial diseases (psoriasis, psoriatic arthritis or arthropathy, and other 
immunoinflammatory diseases) .................................................................... 69 
11.2.3 Trial disease treatment history ...................................................................... 69 
11.2.4 Medical history .............................................................................................. 70 
11.2.5 Substance use: tobacco and alcohol .............................................................. 70 
11.3 Efficacy assessments .................................................................................................. 70 
11.3.1 Psoriasis Area and Severity Index ................................................................. 70 
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11.3.2 Investigator’s Global Assessment ................................................................. 73 
11.3.3 Static Physician’s Global Assessment of genitalia ........................................ 74 
11.3.4 Patient-reported outcomes ............................................................................. 75 
11.4 Safety assessments ...................................................................................................... 77 
11.4.1 Vital signs ...................................................................................................... 77 
11.4.2 Physical examination..................................................................................... 78 
11.4.3 Body measurements ...................................................................................... 78 
11.4.4 Laboratory testing ......................................................................................... 78 
11.5 Other assessments: Patient-reported outcomes ........................................................... 81 
11.5.1 Overview ....................................................................................................... 81 
11.5.2 Columbia-Suicide Severity Rating Scale ...................................................... 81 
11.5.3 Patient Health Questionnaire-8 ..................................................................... 82 
11.6 End of trial .................................................................................................................. 83 
11.6.1 End-of-treatment form................................................................................... 83 
11.6.2 End-of-trial form ........................................................................................... 83 
11.7 Estimate of total blood volume collected ................................................................... 84 
11.8 Storage of biological samples ..................................................................................... 84 
12 Scientific rationale for trial design and appropriateness of assessments ..................... 85 
12.1 Scientific rationale for trial design ............................................................................. 85 
12.2 Appropriateness of assessments ................................................................................. 85 
12.2.1 Rationale for primary endpoint ..................................................................... 85 
12.2.2 Rationale for assessment of palmoplantar psoriasis ...................................... 86 
12.2.3 Rationale for assessment of genital psoriasis ................................................ 86 
13 Adverse events ................................................................................................................... 88 
13.1 Definition and classification of adverse events .......................................................... 88 
13.2 Collection of adverse event reports ............................................................................ 88 
13.3 Reporting of adverse events........................................................................................ 88 
13.4 Reporting of serious adverse events ........................................................................... 89 
13.4.1 Investigator reporting responsibilities ........................................................... 89 
13.4.2 LEO Pharma reporting responsibilities ......................................................... 90 
13.5 Other events that require expedited reporting ............................................................ 90 
13.5.1 Pregnancy ...................................................................................................... 90 
13.5.2 Adverse events of special interest ................................................................. 91 
13.6 Reporting of other events............................................................................................ 92 
13.6.1 Overdose........................................................................................................ 92 
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13.6.2 Medication error ............................................................................................ 93 
13.6.3 Misuse ........................................................................................................... 93 
13.6.4 Abuse ............................................................................................................. 93 
13.6.5 Aggravation of condition .............................................................................. 93 
13.7 Follow-up for final outcome of adverse events .......................................................... 94 
13.8 Handling of an urgent safety measure ........................................................................ 94 
14 Statistical methods ............................................................................................................. 95 
14.1 Sample size ................................................................................................................. 95 
14.2 Trial analysis sets ...................................................................................................... 100 
14.3 Statistical analysis ..................................................................................................... 100 
14.3.1 General principles ....................................................................................... 100 
14.3.2 Handling of missing values and imputation ................................................ 101 
14.3.3 Disposition of subjects ................................................................................ 102 
14.3.4 Demographics and other baseline characteristics........................................ 102 
14.3.5 Exposure and treatment compliance ........................................................... 102 
14.3.6 Estimand strategy ........................................................................................ 103 
14.3.7 Analysis of efficacy endpoints .................................................................... 123 
14.3.8 Testing strategy ........................................................................................... 127 
14.3.9 Analysis of safety ........................................................................................ 127 
15 References ......................................................................................................................... 131 
Appendix 1: Definitions of adverse events and serious adverse events ........................... 137 
Appendix 2: Classification of adverse events ..................................................................... 139 
Appendix 3: Trial governance considerations ................................................................... 142 
Appendix 3A: Regulatory and ethical considerations .............................................. 142 
Appendix 3B: Informed consent process ................................................................. 143 
Appendix 3C: Subject and data confidentiality ....................................................... 143 
Appendix 3D: Record keeping, quality control, and data handling ......................... 145 
Appendix 3E: Registration, reporting, and publication policy ................................ 148 
Appendix 3F: Insurance ........................................................................................... 149 
Appendix 3G: Financial disclosure .......................................................................... 149 
Appendix 3H: Committee structure ......................................................................... 150 
Appendix 3I: Trial and trial site closure ................................................................... 150 
Appendix 3J: Responsibilities .................................................................................. 151 
Appendix 4: Short version of eligibility criteria ................................................................ 152 
Appendix 5: Contact list ...................................................................................................... 155 
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Appendix 6: COVID-19 pandemic contingency plan........................................................ 156 
Appendix 7: Protocol amendment history ......................................................................... 162 
List of panels 
Panel 1: Trial design ................................................................................................................. 26 
Panel 2: Schedule of trial procedures – screening to Visit 11 (Week 16) ................................ 27 
Panel 3: Schedule of trial procedures – Visit 11 (Week 16) to Visit 17 (Week 28) .................. 31 
Panel 4: Objectives and endpoints ........................................................................................... 40 
Panel 5: Estimands ................................................................................................................... 42 
Panel 6: Identification of investigational medicinal products .................................................. 54 
Panel 7: Prohibited medications and procedures ...................................................................... 59 
Panel 8: Sequence of assessments ............................................................................................ 68 
Panel 9: Calculation of the PASI score .................................................................................... 71 
Panel 10: PASI severity score scale ......................................................................................... 72 
Panel 11: PASI area score scale ................................................................................................ 72 
Panel 12: PP-PASI score scale ................................................................................................. 73 
Panel 13: Investigator’s Global Assessment ............................................................................ 74 
Panel 14: Static Physician’s Global Assessment of genitalia ................................................... 75 
Panel 15: Clinical laboratory tests ............................................................................................ 79 
Panel 16: Adverse events of special interest ............................................................................ 92 
Panel 17: PASI response rates after the initiation of brodalumab 210 mg Q2W as rescue 
therapy among subjects initially randomised to ustekinumab in the 
AMAGINE-2 and -3 trials ................................................................................ 96 
Panel 18: Two-state alternating model used to simulate patient-level data, in order to power 
the trial .............................................................................................................. 97 
Panel 19: Approximate PASI 100 response rates for the guselkumab arm, reported in the 
NAVIGATE trial ............................................................................................... 98 
Panel 20: Estimated conjunctive power for rejecting the hypotheses associated with the 
primary and key secondary endpoints .............................................................. 99 
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Panel 21 Estimand strategies for addressing intercurrent events ........................................... 106 
Panel 22 ‘Hypothetical’ strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions and handling of missing data in the main analysis of the 
primary estimand for the primary endpoint .................................................... 110 
Panel 23 ‘Hypothetical’ strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions and handling of missing data in the main analysis of the 
first supplementary estimand for the primary endpoint ................................. 117 
Panel 24: Competing risks model describing the primary estimand for time-to-event endpoints
 ........................................................................................................................ 118 
Panel 25: Multi-state model for the sensitivity analysis accounting for the intermittent nature 
of the observation process .............................................................................. 120 
Panel 26 ‘Hypothetical’ strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions and handling of missing data in the main analysis of the 
primary estimand for ‘Absolute PASI at Week 16’ ........................................ 122 
Panel 27: Overview of the statistical analysis of efficacy endpoints ..................................... 124 
Panel 28: Hierarchical testing procedure to control the FWER for the pre-specified primary 
and key secondary endpoints .......................................................................... 127 
Panel 29 Schedule of minimum trial procedures to be performed under the COVID-19 
pandemic-related lockdown ........................................................................... 159 
 
 
 
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List of abbreviations 
ADA 
anti-drug antibody(ies) 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
APP 
Application 
AST 
aspartate aminotransferase 
BCG 
Bacillus Calmette-Guérin 
BSA 
body surface area 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CMO 
contract manufacturing organisation 
COVID-19 
Coronavirus disease 2019 
CRA 
clinical research associate 
CRO 
contract research organisation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTR 
clinical trial report 
DLQI 
Dermatology Life Quality Index 
eCRF 
electronic case report form 
eDiary 
electronic diary 
ePRO 
electronic patient-reported outcome 
FAS 
full analysis set 
FWER 
familywise error rate 
GCP 
Good Clinical Practice 
HCP 
healthcare professional 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification number 
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IE 
intercurrent event 
IEC 
independent ethics committee 
IGA 
Investigator’s Global Assessment 
IL 
Interleukin 
IL-17RA 
interleukin-17 receptor subunit A 
IL-23p19 
interleukin-23 subunit p19 
IMP 
investigational medicinal product 
IRT 
interactive response technology 
ITT 
intention-to-treat 
LS 
least square 
MACE 
major adverse cardiovascular events 
MAR 
missing at random 
MSM 
multi-state model 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRI 
non-responder imputation 
NRS 
numeric rating scale 
PASI 
Psoriasis Area and Severity Index 
PASI 75/90/100 75%/90%/100% improvement from baseline in PASI score 
PHQ-8 
Patient Health Questionnaire-8 
PP-PASI 
palmoplantar PASI 
PP-IGA 
palmoplantar IGA 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q8W 
every 8 weeks 
SAE 
serious adverse event 
SD 
standard deviation 
SF-36v2 
36-Item Short Form Health Survey version 2, acute recall 
SIB 
suicidal ideation and behaviour 
SmPC 
summary of product characteristics 
SOC 
system organ class 
sPGA 
static Physician’s Global Assessment 
sPGA-G 
sPGA of genitalia 
Th 
T-helper 
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TNF-α 
tumour necrosis factor-α 
TTE 
Time-to-event 
ULN 
upper limit of normal 
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1 Protocol synopsis 
Trial ID 
EudraCT no. 
LP0160-1510 
2019-004099-20 
Title of trial 
Efficacy and safety comparison of brodalumab versus guselkumab in adult 
subjects with moderate-to-severe plaque psoriasis and inadequate response to 
ustekinumab. 
Short title of trial 
Efficacy and safety of brodalumab compared with guselkumab in the treatment 
of plaque psoriasis after inadequate response to ustekinumab; COBRA. 
Main objectives 
and endpoints 
Objectives 
Endpoints 
Primary objective 
 
To compare the efficacy of 
brodalumab with guselkumab 
in adult subjects with 
moderate-to-severe plaque 
psoriasis and prior 
inadequate response to 
ustekinumab. 
 Primary endpoint 
• 
Having PASI1 100 response at 
Week 16. 
Secondary objectives 
 
To evaluate the efficacy of 
brodalumab compared with 
guselkumab while on 
treatment for up to 28 weeks 
in adult subjects with 
moderate-to-severe plaque 
psoriasis and prior 
inadequate response to 
ustekinumab. 
Key secondary endpoint 
• 
Time to PASI 100 response.  
Secondary endpoint 
• 
Time to PASI 90 response.  
To evaluate the efficacy of 
brodalumab compared with 
guselkumab through 
Week 28 in adult subjects 
with moderate-to-severe 
plaque psoriasis and prior 
inadequate response to 
ustekinumab. 
Secondary endpoints 
• 
Having PASI 100 response, assessed 
separately at Weeks 4, 8, and 28. 
• 
Having PASI 90 response, assessed 
separately at Weeks 4, 8, 16, and 28. 
• 
Having IGA2 of 0, assessed separately 
at Week 16 and Week 28.  
• 
Having IGA of 0 or 1, assessed 
separately at Week 16 and Week 28.  
• 
Having DLQI3 total score of 0 or 1, 
assessed separately at Weeks 4, 8, 12, 
16, 20, 24, and 28. 
• 
Change in SF-36v24 score from 
baseline, assessed separately at 
Weeks 4, 8, 16, and 28. 
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To evaluate the safety of 
brodalumab compared with 
guselkumab throughout the 
trial (28 weeks) in adult 
subjects with 
moderate-to-severe plaque 
psoriasis and prior 
inadequate response to 
ustekinumab. 
Secondary endpoints 
• 
Occurrence of treatment-emergent 
AEs from baseline to Week 28.  
Abbreviations: AE = adverse event; DLQI = Dermatology Life Quality Index; 
IGA = Investigator’s Global Assessment; PASI = Psoriasis Area and Severity 
Index; PASI 100 = 100% improvement from baseline in PASI score; PASI 
90 = 90% improvement from baseline in PASI score; SF-36v2 = 36-Item Short 
Form Health Survey version 2. 
1) The PASI is the most widely used tool in clinical trials to assess the severity and 
extent of psoriasis. It is a composite index with scores ranging from 0 to 72, with 
higher values indicating a more severe or more extensive condition. 
2) The IGA is an instrument used in clinical trials to rate the severity of psoriasis and 
is based on a 5-point scale ranging from 0 (clear) to 4 (severe). 
3) The DLQI is a validated questionnaire with content specific to those with 
dermatology conditions. It consists of 10 items and each item is scored on a 
4-point Likert scale (0 = ‘not at all/not relevant’; 1 = ‘a little’; 2 = ‘a lot’; 3 = ‘very 
much’). The total score is the sum of the 10 items (0 to 30); a high score is 
indicative of a poor quality of life. 
4) The SF-36v2 is a 36-item general health status assessment. Subjects will answer 
each question by selecting 1 of 3 to 6 categorical response options. The SF-36v2 
yields scores for 8 health domains (physical functioning, role physical, bodily 
pain, general health, vitality, social functioning, role emotional, and mental health) 
and 2 psychometrically derived summary scores (a physical component summary 
and a mental component summary). 
Final collection of 
data for the 
primary endpoint 
Week 16 
Trial design 
This is a phase 4, randomised, blinded (subject- and assessor-blinded, by 
dummy injections), parallel-group, multi-site, clinical trial consisting of a 2- to 
4-week screening period and a 28-week treatment period (comprised of a 
16-week induction period and a 12-week maintenance period). 
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Abbreviations: Q2W = every 2 weeks; Q8W = every 8 weeks; W = week. 
Main assessments 
The key efficacy assessments are Psoriasis Area and Severity Index (PASI) and 
Investigator’s Global Assessment (IGA). 
The patient-reported outcomes for efficacy include Dermatology Life Quality 
Index (DLQI) and 36-Item Short Form Health Survey version 2 (SF-36v2). 
The safety assessments include treatment-emergent adverse events (AE) 
reporting.  
Main criteria for 
inclusion 
• 
Subject is ≥18 years of age at the time of screening. 
• 
Subject has a diagnosis of plaque psoriasis for at least 6 months before 
the first administration of investigational medicinal product (IMP) as 
determined by the investigator. 
• 
Subject has inadequately controlled plaque psoriasis currently treated 
with ustekinumab, and fulfil ALL of the following criteria:  
o Ustekinumab administered at least 3 times at or higher than the 
approved dose or frequency before randomisation.  
o  IGA ≥2 at screening and baseline. 
o Absolute PASI >3 at screening and baseline. 
• 
Subject has no evidence of active tuberculosis according to local 
standard of care for patients requiring initiation of a biologic treatment.  
Subjects with adequately treated latent tuberculosis, according to local 
guidelines, are eligible. 
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Main criteria for 
exclusion 
• 
Subject was diagnosed with erythrodermic psoriasis, pustular psoriasis, 
guttate psoriasis, medication-induced psoriasis, or other skin 
conditions (e.g. eczema) that would interfere with evaluations of the 
effect of IMP on plaque psoriasis. 
• 
Subject has clinically important active infections or infestations, 
chronic, recurrent, or latent infections or infestations, or is 
immunocompromised (e.g. human immunodeficiency virus).  
• 
Subject has any systemic disease (e.g. renal failure, heart failure, 
hypertension, liver disease, diabetes, anaemia) considered by the 
investigator to be clinically significant and uncontrolled. 
• 
Subject has a known history of Crohn’s disease.  
• 
Subject has any active malignancy, including evidence of cutaneous 
basal or squamous cell carcinoma or melanoma. 
• 
Subject has a history of malignancy within 5 years, except for treated 
and considered cured cutaneous squamous or basal cell carcinoma, in 
situ cervical cancer, or in situ breast ductal carcinoma. 
• 
Subject has a known history of active tuberculosis. 
• 
Subject has a history of suicidal behaviour (i.e. ‘actual suicide 
attempt’, ‘interrupted attempt’, ‘aborted attempt’, or ‘preparatory acts 
or behaviour’) based on the Columbia-Suicide Severity Rating Scale 
(C-SSRS) questionnaire at screening or baseline. 
• 
Subject has any suicidal ideation of severity 4 or 5 (‘some intent to act, 
no plan’ or ‘specific plan and intent’) based on the C-SSRS 
questionnaire at screening or baseline.  
• 
Subject has a Patient Health Questionnaire-8 (PHQ-8) score of ≥10, 
corresponding to moderate-to-severe depression at screening or 
baseline. 
• 
Subject has previously been treated with any anti-interleukin (IL)-17A, 
anti-IL-17 receptor subunit A, or anti-IL-23 besides ustekinumab. 
• 
Subject has known or suspected hypersensitivity to any component(s) 
of the IMPs. 
Investigational 
medicinal 
products 
• 
Kyntheum® (210 mg brodalumab in 1.5 mL solution, 140 mg/mL) for 
subcutaneous injection.  
• 
Tremfya® (100 mg guselkumab in 1.0 mL solution, 100 mg/mL) for 
subcutaneous injection. 
• 
Placebo 1.0 mL (dummy 1 to mimic guselkumab: brodalumab solution 
without active ingredient) in 1.0 mL solution for subcutaneous 
injection. 
• 
Placebo 1.5 mL (dummy 2 to mimic brodalumab: brodalumab solution 
without active ingredient) in 1.5 mL solution for subcutaneous 
injection. 
Duration of trial 
participation 
A 2- to 4-week screening period and a 28-week treatment period. 
Number of 
subjects 
A total of 240 eligible subjects will be randomised in a 1:1 ratio to treatment 
with either brodalumab or guselkumab.  
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Number and 
distribution of 
trial sites 
Approximately 75 sites in Europe. 
Statistical 
methods 
Primary and key secondary endpoints 
 
The difference in response rates at Week 16 between the brodalumab and 
guselkumab arms will be analysed based on logistic regression, adjusted for 
baseline body weight (≤100 kg, >100 kg), prior TNF-α inhibitor use at 
baseline (≤1, >1) and baseline PASI score. Missing data will be assumed to 
be missing at random. In order to quantify the difference in the response rates, 
the odds ratio and risk difference, along with the associated 95% confidence 
intervals, will also be reported.  
 
The time to PASI 100 will be analysed according to Gray’s test, stratified by 
baseline body weight (≤100 kg, >100 kg). Gray’s test accounts for the 
occurrence of the competing risk, permanent discontinuation of IMP. Inference 
will be based on the estimated cumulative incidence of achieving a PASI 100 
response derived from the Aalen-Johansen estimator. The estimated cumulative 
incidence functions will be presented by treatment arm and baseline body 
weight (≤100 kg, >100 kg) along with 95% confidence bands. In addition, the 
estimated sub-distributional hazard ratio from a Fine and Gray model, stratified 
by baseline body weight (≤100 kg, >100 kg) and adjusted for prior TNF-α 
inhibitor use at baseline (≤1, >1) and baseline PASI score, will be presented 
along with the corresponding 95% CI.  
 
To control the familywise error rate, a hierarchical testing procedure, 
indicating the order in which the primary and key secondary endpoints are to 
be tested, has been pre-specified. 
Signatory 
investigator 
, MD, PhD 
 
 
 
Germany 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark 
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PPD

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2 Trial identification 
EudraCT number: 2019-004099-20. 
ClinicalTrials.gov number: NCT04533737. 
The clinical trial protocol will be registered in local registries if required by local legislation. 
3 Schematic of trial design 
Panel 1: Trial design  
 
 
Abbreviations: Q2W = every 2 weeks; Q8W = every 8 weeks; W = week.
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4 Schedule of trial procedures 
Panel 2: Schedule of trial procedures – screening to Visit 11 (Week 16) 
 
Screening 
Treatment (induction) period 
Early 
termination 
visit2 
As soon as 
possible 
within 
2 weeks after 
last IMP 
Unscheduled 
visit, if 
applicable3 
References 
(protocol 
section) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
(primary 
endpoint visit) 
Week 
-4/-2 to 0 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
Visit window (days)1 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Total population and eligibility 
Informed consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 
3B 
Subject eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
8.2 and 8.3 
Investigator assessments at screening/baseline only 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.1 
Trial disease(s) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.2 
Trial disease treatment history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.3 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.4 
Substance use: tobacco, alcohol 
X 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.5 
HIV, HBV, HCV tests 
X 
 
 
 
 
 
 
 
 
 
 
 
(X) 
11.4.4 
Tuberculosis test5 
X 
 
 
 
 
 
 
 
 
 
 
 
(X) 
11.4.4 
Treatments and randomisation 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
9.3 
Arm 1 
Administration of 
brodalumab 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
9.2 
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Screening 
Treatment (induction) period 
Early 
termination 
visit2 
As soon as 
possible 
within 
2 weeks after 
last IMP 
Unscheduled 
visit, if 
applicable3 
References 
(protocol 
section) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
(primary 
endpoint visit) 
Week 
-4/-2 to 0 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
Visit window (days)1 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Administration of 
dummy 1 
 
X 
 
 
X 
 
 
 
X 
 
 
 
(X) 
9.2 
Arm 2 
Administration of 
guselkumab 
 
X 
 
 
X 
 
 
 
X 
 
 
 
(X) 
9.2 
Administration of 
dummy 2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
9.2 
Concomitant medication/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
9.6 
Treatment compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
9.8.4 
Investigator assessments of efficacy 
PASI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.3.1.1 
IGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.3.2.1 
PP-PASI6 
X 
X 
 
 
X 
 
X 
 
 
 
X 
X 
(X) 
11.3.1.2 
PP-IGA6 
X 
X 
 
 
X 
 
X 
 
 
 
X 
X 
(X) 
11.3.2.2 
sPGA-G 7 
X 
X 
 
 
X 
 
X 
 
 
 
X 
X 
(X) 
11.3.3 
Subject assessments of efficacy and health-related quality of life 
DLQI8 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
(X) 
11.3.4.1 
SF-36v28 
X 
X 
 
 
X 
 
X 
 
 
 
X 
X 
(X) 
11.3.4.2 
eDiary device hand-out and training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
11.3.4 
Pruritus NRS9 
<=Daily at home during entire treatment period using an eDiary device => 
X10 
 
11.3.4.3 
Pain NRS9 
<=Daily at home during entire treatment period using an eDiary device => 
X10 
 
11.3.4.4 
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Screening 
Treatment (induction) period 
Early 
termination 
visit2 
As soon as 
possible 
within 
2 weeks after 
last IMP 
Unscheduled 
visit, if 
applicable3 
References 
(protocol 
section) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
(primary 
endpoint visit) 
Week 
-4/-2 to 0 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
Visit window (days)1 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
eDiary device return 
 
 
 
 
 
 
 
 
 
 
 
(X)11 
 
11.3.4 
Investigator assessments of safety 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.4.1 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
(X) 
11.4.2 
Body measurements12 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
(X) 
11.4.3 
Biochemistry13, 
haematology14,  
urinalysis (urine dipstick)15 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
(X) 
11.4.4 
Albumin-to-creatinine ratio 
(urinalysis)16 
(X) 
 
 
 
 
 
 
 
 
 
 
 
(X) 
11.4.4 
Urine pregnancy test17 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
(X) 
11.4.4 
Serum pregnancy test17 
X 
(X) 
 
 
(X) 
 
(X) 
 
(X) 
 
(X) 
(X) 
(X) 
11.4.4 
AEs and SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
13 
Patient-reported outcomes of safety  
C-SSRS18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.5.2 
PHQ-88 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.5.3 
Concluding forms in the eCRF 
End-of-treatment form19 
 
 
 
 
 
 
 
 
 
 
 
X 
 
11.6.1 
End-of-trial form20 
 
 
 
 
 
 
 
 
 
 
 
(X)20 
 
11.6.2 
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Footnotes to this panel are found below Panel 3. 
Abbreviations: AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; DLQI = Dermatology Life Quality Index; eCRF = electronic case report 
form; eDiary = electronic diary; eGFR = estimated glomerular filtration rate; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; IGA = Investigator’s Global Assessment; IMP = investigational medicinal product; NRS = numeric rating scale; PASI = Psoriasis 
Area and Severity Index; PHQ-8 = Patient Health Questionnaire-8; PP-IGA = palmoplantar IGA; PP-PASI = palmoplantar PASI; SF-36v2 = 36-Item Short 
Form Health Survey version 2; SAE = serious adverse event; sPGA-G = static Physician’s Global Assessment of genitalia. 
 
 
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Panel 3: Schedule of trial procedures – Visit 11 (Week 16) to Visit 17 (Week 28) 
 
Treatment (maintenance) period 
Early termination visit2 
As soon as possible 
within 2 weeks after last 
IMP 
Unscheduled 
visit, if 
applicable3 
References 
(protocol 
section) 
Visit 
12 
13 
14 
15 
16 
17 
Week 
18 
20 
22 
24 
26 
28 
Visit window (days)1 
±3 
±3 
±3 
±3 
±3 
±3 
Treatments 
Arm 1 
Administration of 
brodalumab 
X 
X 
X 
X 
X 
 
 
(X) 
9.2 
Administration of 
dummy 1 
 
X 
 
 
 
 
 
(X) 
9.2 
Arm 2 
Administration of 
guselkumab 
 
X 
 
 
 
 
 
(X) 
9.2 
Administration of 
dummy 2 
X 
X 
X 
X 
X 
 
 
(X) 
9.2 
Concomitant medication/procedures 
X 
X 
X 
X 
X 
X 
X 
(X) 
9.6 
Treatment compliance 
X 
X 
X 
X 
X 
 
 
(X) 
9.8.4 
Investigator assessments of efficacy 
PASI 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.3.1.1 
IGA 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.3.2.1 
PP-PASI6 
 
 
 
 
 
X 
X 
(X) 
11.3.1.2 
PP-IGA6 
 
 
 
 
 
X 
X 
(X) 
11.3.2.2 
sPGA-G7 
 
 
 
 
 
X 
X 
(X) 
11.3.3 
Subject assessments of efficacy and health-related quality of life 
DLQI8 
 
X 
 
X 
 
X 
X 
(X) 
11.3.4.1 
SF-36v28 
 
 
 
 
 
X 
X 
(X) 
11.3.4.2 
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Treatment (maintenance) period 
Early termination visit2 
As soon as possible 
within 2 weeks after last 
IMP 
Unscheduled 
visit, if 
applicable3 
References 
(protocol 
section) 
Visit 
12 
13 
14 
15 
16 
17 
Week 
18 
20 
22 
24 
26 
28 
Visit window (days)1 
±3 
±3 
±3 
±3 
±3 
±3 
Pruritus NRS9 
<= Daily at home during entire treatment period using an 
eDiary device => 
X10 
(X) 
11.3.4.3 
Pain NRS9 
<= Daily at home during entire treatment period using an 
eDiary device => 
X10 
(X) 
11.3.4.4 
eDiary device return 
 
 
 
 
 
X 
(X)11 
 
11.3.4 
Investigator assessments of safety 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.4.1 
Physical examination 
 
 
 
 
 
X 
X 
(X) 
11.4.2 
Body measurements12 
 
 
 
 
 
X 
X 
(X) 
11.4.3 
Biochemistry13, 
haematology14,  
urinalysis (urine dipstick)15  
 
 
 
 
 
X 
X 
(X) 
11.4.4 
Albumin-to-creatinine ratio 
(urinalysis)16 
 
 
 
 
 
 
 
(X) 
11.4.4 
Urine pregnancy test17 
 
X 
 
X 
 
X 
X 
(X) 
11.4.4 
Serum pregnancy test17 
 
(X) 
 
(X) 
 
(X) 
(X) 
(X) 
11.4.4 
AEs and SAEs 
X 
X 
X 
X 
X 
X 
X 
(X) 
13 
Patient-reported outcomes of safety 
C-SSRS18 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.5.2 
PHQ-88 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.5.3 
Concluding forms in the eCRF 
End-of-treatment form19 
 
 
 
 
 
X 
X 
 
11.6.1 
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Treatment (maintenance) period 
Early termination visit2 
As soon as possible 
within 2 weeks after last 
IMP 
Unscheduled 
visit, if 
applicable3 
References 
(protocol 
section) 
Visit 
12 
13 
14 
15 
16 
17 
Week 
18 
20 
22 
24 
26 
28 
Visit window (days)1 
±3 
±3 
±3 
±3 
±3 
±3 
End-of-trial form20 
 
 
 
 
 
X 
(X)20 
 
11.6.2 
Abbreviations: AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; DLQI = Dermatology Life Quality Index; eCRF = electronic case report 
form; ePRO = electronic patient-reported outcome; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IGA = Investigator’s Global Assessment; IMP = investigational medicinal product; NRS = numeric rating scale; PASI = Psoriasis Area and Severity Index; 
PHQ-8 = Patient Health Questionnaire-8; PP-IGA = palmoplantar IGA; PP-PASI = palmoplantar PASI; SF-36v2 = 36-Item Short Form Health Survey version 
2; SAE = serious adverse event; sPGA-G = static Physician’s Global Assessment of genitalia.  
 
Notes for Panel 2 and Panel 3 
1) If the date of a trial visit does not conform to the clinical trial protocol, subsequent visits should be planned to maintain the visit schedule relative to Visit 2 
(Week 0, baseline). Visits outside of the allowed visit window still need to be performed, taking into consideration that an interval of minimum 7 days to the 
subsequent, respective IMP administration must be maintained (visits 3 and 4 are exempt from the 7-day gap requirement). If the trial visit cannot be 
rescheduled to maintain a minimum of 7 days to the subsequent scheduled dose, the sponsor’s medical expert should be contacted. 
2) Subjects who discontinue IMP for any reason should attend an early termination visit as soon as possible and within 2 weeks after the last IMP. If a subject 
discontinues IMP or withdraws from the trial at a scheduled visit, then all assessments for an early termination visit must be performed at this particular visit 
(see Sections 10.3 and 11.6 for further instructions). The subjects who discontinue IMP prior to Week 16 will be asked to attend at least the primary endpoint 
visit at Week 16.  
3) An unscheduled visit can be performed by subject’s needs or at the discretion of the investigator for the following purposes: AE follow-up (and related 
concomitant medication/procedures, if applicable), administration of IMP after temporary discontinuation, re-collection of blood and/or urine samples due to 
sampling or testing errors or need for follow-up on specific laboratory abnormalities, or suspected pregnancy. Procedures are marked in brackets ‘(X)’ since 
they are optional depending on the reason for the unscheduled visit. 
4) The informed consent form (ICF) must be signed prior to performing any protocol-related procedures, including, but not limited to, screening evaluations and 
wash-out of disallowed medications. Screening evaluations may start at a later date than the ICF was signed.  
5) Tuberculosis test can be performed at the central laboratory. If a local laboratory test is performed to confirm this criterion, the local laboratory should be 
assessed before the local testing is performed. 
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6) PP-PASI and PP-IGA to be completed for all subjects at Visits 1 and 2. Subsequently, only subjects with palmoplantar psoriasis at baseline (Visit 2) will be 
followed using the separate tools PP-PASI and PP-IGA.  
7) Only subjects with genital psoriasis at baseline will be followed using the separate tool sPGA-G.  
8) The DLQI, SF-36v2, and PHQ-8 questionnaires should be completed by the subject prior to the investigator, safety, and C-SSRS assessments. For the sequence 
of assessments to be performed at each visit, please see Panel 8. 
9) To be completed daily by the subject from screening onwards. The subject must bring the device at Visit 2 (Week 0, baseline) for site to collect it from subjects 
who do not meet randomisation criteria (screening failures). The eDiary must be returned to the site at the last visit (e.g. final visit at Week 28 or early 
termination visit). 
10) Must be completed at the early termination visit, if not already done at home before the visit. 
11) The eDiary device return is marked ‘(X)’ since this is optional depending on the subject’s willingness to continue with all the remaining visits and assessments. 
12) Height and weight. Height is only measured at screening. 
13) Sodium, potassium, calcium, bicarbonate, albumin, blood urea nitrogen, creatinine, uric acid, total bilirubin, alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, C-reactive protein, cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, 
and glucose. At Visit 1 (screening), the biochemistry assessments must also include estimated glomerular filtration rate (eGFR). 
14) Red blood cell count, haemoglobin, haematocrit, platelets, white blood cell count, and differential (absolute count and %): neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils.  
15) Specific gravity, pH, occult blood, protein, glucose, leucocyte esterase, and ketones. In case of abnormal dipstick results, a urine sample will be sent to the 
central laboratory for microscopic examination (leukocytes, erythrocytes, and casts). 
16) In case of abnormal dipstick results at screening, a urine sample will be sent to the central laboratory for albumin-to-creatinine ratio. 
17) Only women of childbearing potential. At screening, a serum pregnancy test is always performed. For other visits, if a urine pregnancy test is positive, a serum 
pregnancy test must be done to confirm the result.  
18) The C-SSRS must be completed after all other assessments, but before administration of IMP. The ‘baseline’ paper version of the C-SRSS is used at screening 
and the ‘since last visit’ paper version is used at all subsequent visits. 
19) An end-of-treatment form must be completed in the eCRF for all randomised subjects, including subjects who permanently discontinue IMP. 
20) An end-of-trial-form must be completed in the eCRF for all randomised subjects, including subjects who permanently discontinue IMP or withdraw from the 
trial, at their last trial visit.  
 
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5 Introduction and trial rationale 
5.1 Plaque psoriasis 
Psoriasis is a chronic immune-mediated inflammatory disease characterised by patches of red, 
dry, itchy, and scaly skin, occurring in approximately 2% of the population worldwide. Plaque 
psoriasis is the most common type of psoriasis, corresponding to approximately 90% of all 
types (1).  
Current data revealed that the main pathophysiological driver is the interleukin-23 
(IL-23)/T-helper (Th) 17-cell axis. Th17 cells are activated by IL-23, thereby producing vast 
amounts of proinflammatory cytokines (e.g. IL-17A, tumour necrosis factor-α [TNF-α], 
IL-22, and IL-17F). IL-17A and IL-17F bind to the IL-17 receptor subunit A (IL-17RA), 
which generates the inflammatory response that causes keratinocytes to proliferate, leading to 
the formation of psoriatic plaques (2).  
Within the last decades, biologic therapies targeting different steps of the pathway have been 
introduced. This led to a revolution in the treatment paradigm of moderate-to-severe plaque 
psoriasis and made complete clearance of the skin a realistic treatment goal (3). 
Despite the improved treatment options, it is well recognised that patients may have an 
inadequate response to biologics due to a variety of reasons, including initial lack of efficacy 
(primary failures), loss of efficacy over time (secondary failures), and the advent of adverse 
events (AEs) or contraindications to the therapy. Hence, comparisons between therapies after 
a biologic failure could provide more data which can facilitate the physicians’ decisions.  
5.2 Experience with investigational medicinal products 
Brodalumab 
Brodalumab is a recombinant fully human monoclonal immunoglobulin G2 antibody that 
binds with high affinity to human IL-17RA, thereby blocking multiple cytokines from the 
IL-17 family. Blocking IL-17RA inhibits multiple IL-17 cytokine-induced inflammatory 
responses and results in reduced or normalised inflammation of the skin in patients with 
psoriasis. Brodalumab is approved in EU, Canada, Japan, Taiwan, Thailand, and the USA for 
the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for 
systemic therapy. 
 
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The approved dosage regimen of brodalumab for the treatment of moderate-to-severe plaque 
psoriasis in adult patients is 210 mg by subcutaneous injection at Weeks 0, 1, and 2 followed 
by 210 mg every 2 weeks (Q2W). 
Brodalumab efficacy: 
The efficacy of brodalumab for the treatment of psoriasis has been confirmed in 3 
placebo-controlled phase 3 trials, in which 2 of the trials also included an ustekinumab 
comparator arm. 
The overall benefit-risk profile of brodalumab was shown to be positive in treatment of 
subjects with moderate-to-severe plaque psoriasis regardless of baseline demographics and 
subpopulations studied.  
Brodalumab safety: 
The most commonly reported adverse reactions in brodalumab-treated subjects include 
arthralgia, headache, fatigue, diarrhoea, and oropharyngeal pain. There are no very common 
adverse reactions (see investigator’s brochure [IB]). 
During the 12-week placebo-controlled trial period in plaque psoriasis, infections were 
reported in 28.2% of subjects treated with Kyntheum® compared with 23.4% of subjects 
treated with placebo. The majority of infections consisted of nasopharyngitis, upper 
respiratory tract infection, pharyngitis, urinary tract infections, bronchitis, influenza, and 
sinusitis, which did not necessitate treatment discontinuation. Serious infections occurred in 
0.5% of subjects treated with Kyntheum® and in 0.1% of subjects treated with placebo. 
Higher rates of fungal infections, primarily non-serious skin and mucosal candida infections, 
were observed in Kyntheum® subjects (2.5%) compared with placebo subjects (1.0%; see the 
IB). 
Anti-drug antibodies (ADA) to brodalumab developed in 2.2% (88/3935) of subjects treated 
with Kyntheum® for up to 52 weeks in psoriasis clinical trials (0.3% of the subjects had ADA 
at baseline). Of these subjects, none had neutralising antibodies, and there was no evidence of 
any association between ADA development and altered pharmacokinetic profile, clinical 
response, or safety profile. For further details, please see the IB. 
Guselkumab 
Guselkumab is a fully human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody to 
the p19 subunit of IL-23 (IL-23p19). It is indicated for the treatment of moderate-to-severe 
plaque psoriasis in adults who are candidates for systemic therapy. The NAVIGATE trial 
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demonstrated that approximately 12% of subjects, who were randomised to guselkumab after 
inadequate response to ustekinumab, achieved complete clearance (100% improvement in 
Psoriasis Area and Severity Index score; PASI 100) after 12 weeks, 18% after 16 weeks, 22% 
after 28 weeks, and 20% after 36 weeks (4). 
The most common adverse reactions of guselkumab include upper respiratory tract infections, 
headache, injection site reactions, arthralgia, diarrhoea, gastroenteritis, fungal skin infections, 
and herpes simplex infections. 
For further details on guselkumab efficacy and safety, please see EU summary of product 
characteristics (SmPC) for Tremfya® (5). 
5.3 Trial rationale 
With increasing availability of novel biologics with new targets, the complexity of choosing 
the appropriate biologic treatment is ever more challenging for physicians. This applies not 
only to choosing the most efficacious treatment for the patient, but also to deciding on 
subsequent treatment options if the patient has inadequate response to a biologic treatment.  
Ustekinumab modulates proinflammatory signalling through the inhibition of IL-12 and 
IL-23. Several trials evaluating efficacy of more modern biologic treatments have 
demonstrated superiority of the newer agents (targeting IL-17A, IL-23p19, or IL-17RA) over 
ustekinumab (6-11).  
The efficacy of brodalumab for the treatment of psoriasis has been confirmed in 
3 placebo-controlled phase 3 trials, 2 of which included an ustekinumab comparator arm 
(AMAGINE-2 and -3). A subanalysis of these trials showed that rescue treatment with 
brodalumab improved skin outcomes among subjects with inadequate response to 
ustekinumab (9, 10, 12). 
The head-to-head trial of guselkumab versus ustekinumab in subjects inadequately treated 
with ustekinumab (NAVIGATE trial) has demonstrated increased psoriasis improvement in 
subjects randomised to guselkumab compared with those randomised to continue on 
ustekinumab (4). 
By comparing data from the AMAGINE and the NAVIGATE trials, it was concluded that 
brodalumab treatment would lead to significantly higher PASI 100 rates than guselkumab 
treatment after 16 weeks of treatment (34.7% vs. approximately 18%, respectively) (4, 12). 
No trials have, however, directly compared IL-17RA antagonism with IL-23p19 inhibition. 
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Therefore, the primary objective of this trial is to compare the efficacy of brodalumab versus 
guselkumab in adult subjects with moderate-to-severe plaque psoriasis and inadequate 
response to ustekinumab, thereby providing results that could support decision-making in the 
clinical setting. 
The primary endpoint is PASI 100 at Week 16. PASI 100 is chosen due to substantial evidence 
highlighting the importance of complete clearance from the patient’s perspective, improving 
quality of life and decreasing the disease burden (13). Moreover, PASI 100 allows better and 
most accurate differentiation between highly efficacious treatments available for the treatment 
of psoriasis today. 
5.4 Ethical considerations  
This trial will be conducted in accordance with the ethical principles that have their origins in 
International Council for Harmonisation Good Clinical Practice (ICH GCP) guidelines in 
compliance with the approved protocol and applicable regulatory requirements. 
In accordance with the current version of ICH GCP guidelines, qualified medical personnel 
employed by LEO Pharma will be readily available to advise on trial-related medical 
questions. Medical monitoring will be performed throughout the trial.  
In this trial, all subjects will be treated with biologic medications approved in EU for the 
treatment of moderate-to-severe plaque psoriasis. Since the trial has no placebo arm, any 
ethical considerations regarding withholdment of treatment do not apply. 
No children or other vulnerable subjects incapable of giving informed consent will be 
included in this clinical trial. Pregnant or breastfeeding women and women trying to conceive 
will not be included in the trial. Women of childbearing potential must agree to use a highly 
effective method of contraception to prevent pregnancy during the clinical trial and until 
12 weeks after discontinuation of treatment with investigational medicinal product (IMP). In 
addition, all women of childbearing potential will have a pregnancy test performed before, 
during, and after trial procedures to minimise the risk of foetuses being exposed to the IMPs. 
Suicidal ideation and behaviour (SIB), including completed suicide, have been reported in 
patients treated with brodalumab. The majority of patients with suicidal behaviour had a 
history of depression and/or suicidal ideation or behaviour. A causal association between 
treatment with brodalumab and increased risk of SIB has not been established (14). 
Since a history of prior depression and/or SIB are known risk factors for new SIB events (15), 
subjects with a recent history of depression (within 2 years), Patient Health Questionnaire-8 
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(PHQ-8) score ≥10, Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation level 
4 or 5, or any suicidal behaviour are excluded from participation in the trial. In addition, 
subjects will be continuously monitored for depression and SIB by the PHQ-8 and the 
C-SSRS. The investigator must discontinue subjects from IMP in case of C-SSRS suicidal 
ideation level 4 or 5, any suicidal behaviour, or a PHQ-8 score ≥15 corresponding to 
moderately severe-to-severe depression (16). 
The trial design chosen for this efficacy and safety trial is regarded as ethically justified and 
adherent with ethical requirements. 
5.5 Benefit/risk assessment 
Brodalumab and guselkumab are approved treatments for adult patients with 
moderate-to-severe plaque psoriasis who are candidates for systemic therapy. 
Data from this trial will provide more information on the efficacy and safety of the 
treatments to support the choice of treatment after inadequate response to ustekinumab.  
The risk to subjects in this trial will be minimised by fulfilment of all eligibility criteria and 
by close clinical monitoring. To ensure the safety and well-being of subjects participating in 
this trial, there will be ongoing monitoring of the subjects, reporting of any AEs, and 
well-defined IMP discontinuation criteria (Section 10).  
The subjects in this trial will be blinded by additional (dummy) injections due to differences 
in the volume and administration frequency between brodalumab and guselkumab. Additional 
(dummy) injections are not expected to increase the low risk normally associated with 
injections. Similarly, the blood sampling procedure poses the same low risk as normally 
associated with this procedure.  
Altogether, the risks associated with participating in this trial are considered low and are 
expected to be outweighed by the benefit of providing additional information for psoriasis 
patients and clinicians. 
 
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6 Trial objectives, endpoints, and estimands 
Panel 4: Objectives and endpoints  
Objectives 
Endpoints 
Primary objective 
 
To compare the efficacy of 
brodalumab with guselkumab in adult 
subjects with moderate-to-severe 
plaque psoriasis and prior inadequate 
response to ustekinumab. 
 Primary endpoint 
• 
Having PASI 100 response at Week 16. 
Secondary objectives 
 
To evaluate the efficacy of 
brodalumab compared with 
guselkumab while on treatment for up 
to 28 weeks in adult subjects with 
moderate-to-severe plaque psoriasis 
and prior inadequate response to 
ustekinumab. 
Key secondary endpoint 
• 
Time to PASI 100 response.  
Secondary endpoint 
• 
Time to PASI 90 response.  
To evaluate the efficacy of 
brodalumab compared with 
guselkumab through Week 28 in adult 
subjects with moderate-to-severe 
plaque psoriasis and prior inadequate 
response to ustekinumab. 
Secondary endpoints 
• 
Having PASI 100 response, assessed separately at 
Weeks 4, 8, and 28. 
• 
Having PASI 90 response, assessed separately at 
Weeks 4, 8, 16, and 28. 
• 
Having IGA of 0, assessed separately at Week 16 
and Week 28.  
• 
Having IGA of 0 or 1, assessed separately at 
Week 16 and Week 28.  
• 
Having DLQI total score of 0 or 1, assessed 
separately at Weeks 4, 8, 12, 16, 20, 24, and 28. 
• 
Change in SF-36v2 from baseline, assessed 
separately at Weeks 4, 8, 16, and 28. 
Exploratory endpoints  
• 
Having IGA of 0 or 1 and at least a 2-grade 
improvement from baseline, assessed separately at 
Week 16 and Week 28. 
• 
Change from baseline in pruritus NRS 11 points 
(weekly average), assessed separately at Weeks 4, 
8, 16, and 28. 
• 
Improvement of at least 4 units in pruritus NRS 
11 points (weekly average), assessed separately at 
Weeks 4, 8, 16, and 28. 
• 
Change from baseline in pain NRS 11 points 
(weekly average), separately assessed at Weeks 4, 
8, 16, and 28.  
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Objectives 
Endpoints 
• 
Having absolute PASI ≤1, assessed separately at 
Weeks 4, 8, 16, and 28. 
• 
Having absolute PASI ≤2, assessed separately at 
Weeks 4, 8, 16, and 28. 
• 
Having absolute PASI ≥3, assessed separately at 
Weeks 4, 8, 16, and 28. 
• 
Having absolute PASI ≥5, assessed separately at 
Weeks 4, 8, 16, and 28. 
• 
Absolute PASI at Weeks 4, 8, 16, and 28. 
• 
Having PP-PASI 100 response, assessed separately 
at Weeks 4, 8, 16, and 28. 
• 
Having PP-IGA 0/1 response, assessed separately at 
Weeks 4, 8, 16, and 28. 
• 
Having sPGA-G 0/1 response, assessed separately 
at Weeks 4, 8, 16, and 28. 
To evaluate the safety of brodalumab 
compared with guselkumab 
throughout the trial (28 weeks) in 
adult subjects with moderate-to-severe 
plaque psoriasis and prior inadequate 
response to ustekinumab. 
Secondary endpoints 
• 
Occurrence of treatment-emergent AEs from 
baseline to Week 28.  
Abbreviations: AE = adverse event; DLQI = Dermatology Life Quality Index; IGA = Investigator’s Global 
Assessment; NRS = numeric rating scale; PASI = Psoriasis Area and Severity Index; PASI 100 = 100% 
improvement from baseline in PASI score; PASI 90 = 90% improvement from baseline in PASI score; PP-
PASI = palmoplantar PASI; PP-IGA = palmoplantar IGA; SF-36v2 = 36-Item Short Form Health Survey 
version 2; sPGA-G = static Physician’s Global Assessment of genitalia.
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Panel 5: Estimands 
Endpoint  
type 
Primary/ 
Supplementary1 
Estimand definition 
Population 
Treatment 
condition 
Variable 
Intercurrent 
events strategy2 
Population 
level 
summary3 
Binary based on 
investigator 
assessments 
Primary 
Subjects with 
an inadequate 
response to 
ustekinumab4 
Brodalumab 
vs. 
guselkumab  
Having a 
response without 
prior permanent 
discontinuation 
of IMP 
independent of 
pandemic 
restrictions 
‘Composite’, 
‘Hypothetical’, 
‘Treatment-
policy’ 
Odds ratio and 
LS-mean risk 
difference 
estimated by 
logistic 
regression 
Binary based on 
subject assessments 
Primary 
Subjects with 
an inadequate 
response to 
ustekinumab4 
Brodalumab 
vs. 
guselkumab 
Having a 
response without 
prior permanent 
discontinuation 
of IMP 
independent of 
pandemic 
restrictions 
‘Composite’, 
‘Hypothetical’, 
‘Hypothetical’ 
Odds ratio and 
LS-mean risk 
difference 
estimated by 
logistic 
regression 
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Endpoint  
type 
Primary/ 
Supplementary1 
Estimand definition 
Population 
Treatment 
condition 
Variable 
Intercurrent 
events strategy2 
Population 
level 
summary3 
Binary based on 
investigator 
assessments 
First supplementary 
Subjects with 
an inadequate 
response to 
ustekinumab4 
Brodalumab 
vs. 
guselkumab 
Having a 
response 
‘Treatment-
policy’, 
‘Hypothetical’, 
‘Treatment-
policy’ 
Odds ratio and 
LS-mean risk 
difference 
estimated by 
logistic 
regression 
Binary based on 
investigator 
assessments 
Second supplementary 
Subjects with 
an inadequate 
response to 
ustekinumab4 
Brodalumab 
vs. 
guselkumab 
Having a 
response without 
prior permanent 
discontinuation 
of IMP 
independent of 
pandemic 
restrictions 
‘Composite’, 
‘Hypothetical’, 
‘Hypothetical’ 
Odds ratio and 
LS-mean risk 
difference 
estimated by 
logistic 
regression 
Time-to-event 
Primary 
Subjects with 
an inadequate 
response to 
ustekinumab4 
Brodalumab 
vs. 
guselkumab 
Time to 
response prior to 
permanent 
discontinuation 
of IMP 
independent of 
pandemic 
restrictions 
‘While on 
treatment’, 
‘Hypothetical’, 
‘Treatment-
policy’ 
Aalen-Johansen 
estimate of the 
cumulative 
incidence 
function  
Continuous based on 
investigator 
assessments 
Primary 
Subjects with 
an inadequate 
response to 
ustekinumab4 
Brodalumab 
vs. 
guselkumab 
Endpoint  
‘Treatment-
policy’, 
‘Hypothetical’, 
‘Treatment-
policy’ 
Difference in 
LS-means 
estimated by 
ANCOVA  
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Endpoint  
type 
Primary/ 
Supplementary1 
Estimand definition 
Population 
Treatment 
condition 
Variable 
Intercurrent 
events strategy2 
Population 
level 
summary3 
Continuous based on 
subject assessments 
Primary 
Subjects with 
an inadequate 
response to 
ustekinumab4 
Brodalumab 
vs. 
guselkumab 
Endpoint 
‘Treatment-
policy’, 
‘Hypothetical’, 
‘Hypothetical’ 
Difference in 
LS-means 
estimated by 
ANCOVA  
Abbreviations: ANCOVA = analysis of covariance; IMP = investigational medicinal product; LS = least square.  
1) For primary and key secondary endpoints, the main analysis associated with the primary estimand is used to assess significance based on the proposed 
multiplicity control procedure (see Section 14.3.8). 
2) Refers to the strategies for handling occurrences of the intercurrent events permanent discontinuation of IMP independent of pandemic restrictions, permanent 
discontinuation of IMP due to pandemic restrictions, and unblinding of subjects, respectively, in the analysis. 
3) Refers to the population level summary, which forms the basis for making treatment comparisons.  
4) As defined in Sections 8.2 and 8.3. 
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7 Trial design 
7.1 Overall trial design 
This trial is a phase 4, randomised, blinded (subject and assessor), parallel-group, multi-site, 
clinical trial. The trial is designed to evaluate the efficacy and safety of standard 
administration of brodalumab compared with standard administration of guselkumab for the 
treatment of moderate-to-severe plaque psoriasis in adult subjects with inadequate response to 
ustekinumab.  
A schematic of the trial design is provided in Section 3. The total duration of the trial will be 
approximately 32 weeks and includes 3 periods: 
• Screening: Week -4/-2 to Week 0. 
• Induction: Week 0 to Week 16. 
• Maintenance: Week 16 to Week 28. 
Screening period (Week -4/-2 to Week 0) 
A screening visit will take place a maximum of 4 weeks and minimum of 2 weeks prior to the 
treatment period. The objective of the screening period is to enrol eligible and informed 
subjects. This entails wash-out of specified prohibited medication (Panel 7) and specified 
laboratory testing (Panel 15).  
Before any trial-related procedure is started, the subjects will receive the necessary written 
and verbal information and instructions, including the written subject information sheet and 
the informed consent form (ICF). Each subject will receive a unique subject number and the 
subject’s eligibility will be determined by clinical examination and confirmation of the 
eligibility criteria. 
Induction period (Week 0 to Week 16) 
The start of the treatment period is defined as Week 0 (baseline; Day 1). At this visit, 
eligibility will be confirmed by re-checking the eligibility criteria in subjects who were 
eligible based on previous examinations, review of sufficient wash-out of prohibited 
medication, and review of central laboratory results from the screening visit. If still eligible, 
the subject will continue in the trial and be randomised to either brodalumab or guselkumab 
treatment regimen as described below. 
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Arm 1 (brodalumab + dummy 1):  
• Brodalumab 210 mg (1.5 ml) subcutaneously at Weeks 0, 1, 2, and then Q2W until the 
end of trial (last administration of brodalumab at Week 26).  
• Dummy 1 (placebo 1.0 ml) subcutaneously at Weeks 0, 4, and then every 8 weeks 
(Q8W) until the end of trial (last administration of dummy 1 at Week 20). 
Arm 2 (guselkumab + dummy 2):  
• Guselkumab 100 mg (1.0 ml) subcutaneously at Weeks 0, 4, and then Q8W until the 
end of trial (last administration of guselkumab at Week 20). 
• Dummy 2 (placebo 1.5 ml) subcutaneously at Weeks 0, 1, 2, and then Q2W until the 
end of trial (last administration of dummy 2 at Week 26). 
The primary endpoint will be assessed at Week 16.  
Maintenance period (Week 16 to Week 28) 
The subjects will follow the treatment regimen described above. Last injections (brodalumab 
in Arm 1 and dummy 2 injection in Arm 2) will be given at Week 26. The subjects and 
assessors will be blinded throughout the trial.  
Baseline, efficacy, and safety assessments during the trial are described in Section 11. 
7.2 Number of subjects needed 
This trial will be conducted at approximately 75 sites in Europe.  
Assuming a screening failure of 18%, approximately 293 subjects will be screened, and 
240 eligible subjects will be randomised in a 1:1 ratio to treatment with either brodalumab or 
guselkumab. Randomisation will be stratified by body weight (≤100 kg, >100 kg).  
The statistical power considerations for this sample size are described in Section 14.1. 
7.3 End-of-trial definition 
A subject is considered to have completed the trial if having concluded all periods of the trial 
regardless of discontinuation of IMP. 
The end of the trial is defined as the date of the last visit of the last subject in the trial 
globally. 
Final collection of data for the primary endpoint occurs at Week 16 (Visit 11). 
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8 Trial population  
8.1 Subject eligibility 
The investigator should only include subjects who meet all eligibility criteria, are not put at 
undue risk by participating in the trial, and can be expected to comply with the protocol.  
The subject’s eligibility for the clinical trial must be verified according to the inclusion and 
exclusion criteria at visits specified in Section 4. It will be recorded in the electronic case 
report form (eCRF) if the subject has met all the inclusion criteria and none of the exclusion 
criteria. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in submission documentation to regulatory authorities and 
independent ethics committees (IECs), as applicable.  
8.2 Inclusion criteria 
For inclusion into this trial, subjects must fulfil all of the following criteria: 
1. Signed and dated informed consent has been obtained prior to any protocol-related 
procedures. 
2. Subject is ≥18 years of age at the time of screening. 
3. Subject has a diagnosis of plaque psoriasis for at least 6 months before the first 
administration of IMP as determined by the investigator. 
4. Subject has inadequately controlled plaque psoriasis currently treated with ustekinumab, 
and fulfils ALL of the following criteria:  
• Ustekinumab administered at least 3 times at or higher than the approved dose or 
frequency before randomisation (Stelara® SmPC) (17). 
• Investigator's Global Assessment (IGA) ≥2 at screening and baseline. 
• Absolute PASI >3 at screening and baseline. 
5. Subject has no evidence of active tuberculosis according to local standard of care for 
patients requiring initiation of a biologic treatment. Subjects with adequately treated latent 
tuberculosis, according to local guidelines, are eligible. 
a. A tuberculosis test can be performed at the central laboratory. 
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b. If a local laboratory test is performed to confirm this criterium, the local laboratory 
should be assessed before the local testing is performed. 
6. Subject who is a woman of childbearing potential* must have a negative serum pregnancy 
test at screening and a negative urine pregnancy test at baseline.  
* A woman is defined as being of childbearing potential if she is not postmenopausal (at 
least 12 months with no menses without an alternative medical cause prior to screening) 
and not surgically sterile (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy). 
7. Subject who is a woman of childbearing potential* must use a highly effective** form of 
birth control throughout the trial and at least for 12 weeks after last administration of IMP.  
** A highly effective method of birth control is defined as one which results in a low 
failure rate (less than 1% per year) such as bilateral tubal occlusion, intrauterine device, 
intrauterine hormone-releasing system, combined (oestrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation (oral, intravaginal, 
transdermal), progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable), sexual abstinence (when this is in line with the 
preferred and usual life style of the subject), or vasectomised partner (given that the 
subject is monogamous). 
8.3 Exclusion criteria 
Subjects must not enter the trial if they fulfil any of the following exclusion criteria:  
Skin disease-related 
1. Subject was diagnosed with erythrodermic psoriasis, pustular psoriasis, guttate psoriasis, 
medication-induced psoriasis, or other skin conditions (e.g. eczema) that would interfere 
with evaluations of the effect of IMP on plaque psoriasis. 
Other medical conditions 
2. Subject has a planned surgery, which in the opinion of the investigator will interfere with 
the planned IMP treatment (any planned surgery that will be performed during the trial 
period must be recorded).  
3. Subject has clinically important active infections or infestations, chronic, recurrent, or 
latent infections or infestations, or is immunocompromised (e.g. HIV). 
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4. Subject has a known history of hepatitis B, hepatitis C, or HIV. Positive hepatitis B 
surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core 
antibody (anti-HBc), hepatitis C virus antibody, or HIV antibody serology at screening. 
Subjects with positive anti-HBs are eligible provided that they have a negative HBsAg 
and negative HBc (blood pattern in vaccinated subjects). 
5. Subject has any systemic disease (e.g. renal failure, heart failure, hypertension, liver 
disease, diabetes, anaemia) considered by the investigator to be clinically significant and 
uncontrolled. 
6. Subject has a known history of Crohn’s disease.  
7. Subject had myocardial infarction, stroke, or unstable angina pectoris within the past 
12 months prior to the first administration of IMP. 
8. Subject has any active malignancy, including evidence of cutaneous basal or squamous 
cell carcinoma or melanoma. 
9. Subject has a history of malignancy within 5 years, except for treated and considered 
cured cutaneous squamous or basal cell carcinoma, in situ cervical cancer, or in situ breast 
ductal carcinoma. 
10. Subject has a known history of active tuberculosis. 
11. Subject has a history of suicidal behaviour (i.e. ‘actual suicide attempt’, ‘interrupted 
attempt’, ‘aborted attempt’, or ‘preparatory acts or behaviour’) based on the C-SSRS 
questionnaire at screening or baseline. 
12. Subject has any suicidal ideation of severity 4 or 5 (‘some intent to act, no plan’ or 
‘specific plan and intent’) based on the C-SSRS questionnaire at screening or baseline. 
13. Subject has a PHQ-8 score of ≥10, corresponding to moderate-to-severe depression at 
screening or baseline. 
14. Subject has a history of depressive disorder with severe episode(s) within the last 2 years.  
15. Subject has any concurrent medical condition that, in the opinion of the investigator, could 
cause the trial to be detrimental to the subject. 
Laboratory abnormalities 
16. Subject has laboratory abnormalities that, in the opinion of the investigator, will prevent 
the subject from completing the trial or interfere with the analysis of results, including:  
• White blood cell (WBC) count <3.00×109/L. 
• Absolute neutrophil count (ANC) <2.00×109/L. 
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• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2× the ULN 
(upper limit of normal). 
• Serum direct bilirubin ≥1.5 mg/dL (≥25.7 μmol/L). 
Wash-out and prohibited medications 
17. Subject has used potent topical steroids, topical anthralin/dithranol, topical calcipotriol, or 
any formulation or potency of topical therapy, within 7 days prior to first administration of 
IMP (exceptions are specified*). 
* Upper mid-strength or lower potency topical steroids on the face, axillae, and groin; 
bland emollients (without urea or alpha or beta hydroxy acids); and shampoo without 
steroids are permitted. 
18. Subject has used any of the following treatments* within 4 weeks prior to first 
administration of IMP. 
* Ultraviolet A light therapy (with or without psoralen); ultraviolet B light therapy; 
excimer laser; oral retinoids; methotrexate; cyclosporine; systemically administered 
calcineurin inhibitors; azathioprine; thioguanine; hydroxyurea; fumarates; apremilast; oral 
or parenteral corticosteroids including intramuscular or intraarticular administration; or 
any other immunomodulating therapy for psoriasis or any other indication (otic, nasal, 
ophthalmic, or inhaled corticosteroids within recommended doses are permitted).  
19. Subject has received any of the following biologic immunomodulating therapies prior to 
first administration of IMP: 
Approved agents:  
• Within 2 weeks for etanercept.  
• Within 4 weeks for adalimumab.  
• Within 10 weeks for certolizumab pegol.  
Other commercially available biologics: 
• Within 8 weeks for infliximab.  
Other experimental or commercially available biologic immunomodulators:  
• Within 4 weeks or 5 half-lives, whichever is longer. 
20. Subject has previously received more than 1 TNFα inhibitor.  NOTE:  This exclusion 
criterion is not applicable in this version of the protocol. It is kept to avoid re-numbering 
of the exclusion criteria. 
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21. Subject has previously been treated with any anti-IL-17A, anti-IL-17RA, or anti-IL-23 
besides ustekinumab. 
22. Subject received live vaccine(s) within 4 weeks of the first administration of IMP. 
23. Subject has received treatment with any non-marketed drug substance (that is, an agent 
which has not yet been made available for clinical use following registration) within 4 
weeks or 5 half-lives of the substance, whichever is longer, prior to screening. 
24. Subject is currently enrolled in another investigational device or drug trial or ended 
participation in one within 4 weeks or 5 half-lives of the IMP, whichever is longer, prior to 
screening. 
General 
25. Subject has known or suspected hypersensitivity to any component(s) of the IMPs. 
26. Subject is pregnant or lactating. 
27. Subject has a history of chronic alcohol or drug abuse within 12 months prior to 
screening, or any condition associated with poor compliance as judged by the investigator. 
28. Subject has previously been randomised in this clinical trial. 
29. Subject has a language barrier, mental incapacity, unwillingness, or lack of ability to 
understand the trial-related procedures.  
30. Subject is an employee of the trial site or any other individual directly involved with the 
planning or conduct of the trial, or immediate family member of such individual. 
31. Subject is legally institutionalised.  
8.4 Screening and screening failures 
8.4.1 Subject identification number 
Trial participation begins once written informed consent is obtained. Refer to Appendix 3B 
for details on the informed consent process. Once informed consent is obtained, a subject 
identification number (subject ID) will be assigned by a central interactive response 
technology (IRT) system and the screening evaluations to assess eligibility criteria may begin. 
The date of first screening activity could be on the same day or a later date than the informed 
consent form was signed. The subject ID will be used to identify the subject during the 
screening process and throughout trial participation. Subjects who have given written 
informed consent to participate in the trial and who have been assigned a subject ID are 
considered ‘screened’ subjects. 
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The investigator will maintain a log of all subjects considered for screening, whether they 
have provided written informed consent or not (screening log). This log will be anonymous 
and will include the reason(s) for not entering the trial, if applicable, or the allocated 
subject ID. In addition, the investigator will maintain a log of all consented subjects at the 
trial site (subject identification list). This log will include each subject’s identity, date of 
consent, and corresponding subject ID so that any subject may be identified if required for 
any reason. The log must not be copied or retained by LEO Pharma. 
8.4.2 Screening failures 
Screen failures are defined as subjects who consent to participate in the trial but are not 
subsequently randomised to trial treatment. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements (18) and to respond to 
queries from regulatory authorities. As a minimum, the following data must be collected in 
the eCRF for screen failures: 
• Date of informed consent(s). 
• Demographics (date of birth, age, sex, ethnicity, race). 
• Reason for screen failure. 
o Failure to meet eligibility criteria (specify which).  
o Lost to follow-up. 
o Withdrawal by subject. 
o Other (specification is required).  
• Date of screen failure. 
• Any AEs and serious AEs (SAEs). 
In case of any SAEs, these must be followed-up as described in Section 13.7. 
8.4.2.1 Re-sampling 
If a subject fails any eligibility criteria related to laboratory parameters, a re-sampling of 
failed parameter(s) is allowed within 28 days after the screening sampling date. If the 
laboratory parameter(s) normalises, the subject is allowed to be randomised and enter the 
trial. The subject will keep the assigned subject ID. 
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8.4.2.2 Re-screening 
Re-screening of screening failures is allowed only once within the limits of the trial’s 
recruitment period. However, re-screening is not allowed if the subject fails screening due to 
exclusion criteria no. 11, 12. 13, or 14. In the event of re-screening, a new informed consent 
must be obtained, and a new subject ID assigned. For re-screened subjects, the subject ID 
from the first screening will be recorded in the eCRF. All screening and laboratory 
assessments must be repeated except tuberculosis test, if negative at first screening. 
9 Treatments 
9.1 Trial product description 
All IMP will be packaged in individually numbered kits. Each pre-filled syringe is for single 
use only. Refer to Panel 6 for further details.  
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Panel 6: Identification of investigational medicinal products  
Investigational 
medicinal 
product 
Dosage form 
Active ingredient and 
concentration 
Pack size 
Source 
Brodalumab 
Trade name: 
Kyntheum® 
Solution for 
subcutaneous 
injection 
Brodalumab formulated at a 
nominal concentration of 
140 mg/mL including the 
following excipients: 
• 
Proline 
• 
Glutamate 
• 
Polysorbate 20 
• 
Water for injection 
Pre-filled 
syringe with 
210 mg 
brodalumab in 
1.5 mL 
solution 
Commercially 
available 
Guselkumab  
Trade name: 
Tremfya® 
Solution for 
subcutaneous 
injection 
Guselkumab formulated at a 
nominal concentration of 
100 mg/mL including the 
following excipients: 
• 
Histidine 
• 
Histidine 
monohydrochloride 
monohydrate 
• 
Polysorbate 80 
• 
Sucrose 
• 
Water for injection 
Pre-filled 
syringe with 
100 mg 
guselkumab in 
1 mL solution 
Janssen 
Biologics 
B.V. 
Commercially 
available; 
supplied by 
CMO 
Placebo 1.0 mL 
(dummy 1 to 
mimic 
guselkumab) 
Solution for 
subcutaneous 
injection 
The placebo solution is 
similar to the active 
brodalumab solution except 
that it does not contain any 
active substance 
Pre-filled 
syringe with 
1.0 mL 
solution 
San Diego, 
USA 
Placebo 1.5 mL 
(dummy 2 to 
mimic 
brodalumab) 
Solution for 
subcutaneous 
injection 
The placebo solution is 
similar to the active 
brodalumab solution except 
that it does not contain any 
active substance 
Pre-filled 
syringe with 
1.5 mL 
solution 
San Diego, 
USA 
Abbreviation: CMO = contract manufacturing organisation. 
 
9.2 Administration of investigational medicinal product 
An IRT system will assign the required kit number- for each subject at each IMP 
administration visit.  
IMP administration visits are shown in the schedule of trial procedures (Section 4). The first 
day of administration is considered Day 1 (Week 0, Visit 2). On administration visits, all other 
visit activities must be handled prior to administration of active IMP and/or dummy. The last 
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administration of active IMP under this protocol will occur at Week 26 for Arm 1 
(brodalumab) and Week 20 for Arm 2 (guselkumab). 
The IMPs and the dummies must be injected subcutaneously in the upper legs (thighs), 
stomach area (abdomen) or in the upper, outer arm by an unblinded healthcare professional 
(HCP). Injections should not be given into areas where the skin is tender, bruised, red, hard, 
thick, scaly, or affected by psoriasis. It is recommended that subsequent injections should be 
given on a different area or body region. It will be captured in the eCRF which region each 
injection is given and if it was on the right or left side. At Weeks 0, 4, 12, and 20, subjects will 
be injected with an active IMP and a dummy; it is recommended that these injections are 
given in the same area, at least 3 cm away from each other. 
Guselkumab must be administered according to the instructions for administration provided in 
the current EU SmPC Tremfya®(5).  
Instructions for use of the pre-filled syringes are provided in the investigator trial file; the IMP 
administration must be carried out according to these instructions. 
9.3 Treatment assignment  
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria will be randomised centrally at Week 0 (Visit 2) to receive either 
brodalumab or guselkumab treatment (see Section 3). Randomisation will be stratified by 
baseline (Visit 2) body weight (≤100 kg and >100 kg). Treatment assignment occurs based on 
a computer-generated randomisation scheme in a 1:1 ratio. 
The IRT system will be used to control randomisation and stratification factors, along with 
IMP supply chain and expiry tracking. The IRT system will assign the required kit number for 
each subject. 
Each investigator site will be supplied with sufficient IMP for the trial on an ongoing basis 
controlled by the IRT system. 
9.3.1 Blinding  
This is a subject- and assessor-blinded trial, in which the 2 active IMPs (brodalumab and 
guselkumab) are to be administered at different frequencies and in pre-filled syringes that are 
visually distinct from each other and contain different volumes of solution. They will be 
packaged open label. To obtain blinding, 2 dummies (both brodalumab placebo solutions) will 
be used to cover the different injection timepoints. Dummy 1 will be used in Arm 1 
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(brodalumab arm) to match guselkumab in Arm 2 (guselkumab arm). Dummy 1 is a 
brodalumab placebo solution and is matched for volume, but is not matched for viscosity, 
colour, or syringe to guselkumab. Dummy 2 will be used in Arm 2 (guselkumab arm) to 
match brodalumab in Arm 1 (brodalumab arm). Dummy 2 is matched for volume, viscosity, 
colour, and syringe to brodalumab. Furthermore, to ensure subjects stay blinded to treatment 
allocation, site staff should ensure that subjects are blindfolded during the administration of 
IMP. 
Neither the subjects nor any of the assessors will be aware of the treatment received. As the 
IMPs are packaged open-label, IMPs must be handled and administered by a qualified, 
unblinded HCP who is a member of site staff, not involved in any safety or efficacy 
assessments. The efficacy assessments will be performed by a designated assessor (see 
Section 11.1) who is blinded to the treatment allocation and not involved in the administration 
of IMP.  
The trial site will maintain a signature and delegation log detailing which staff members are 
unblinded or blinded and which staff members are maintaining and administering the IMPs. 
9.3.2 Emergency unblinding of individual subject treatment 
While the safety of a subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure a subject’s safety. An emergency unblinding request can be 
made by the investigators, HCPs who are not members of the trial staff, or authorised LEO 
Pharma personnel. 
Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator can unblind a subject’s treatment in the 
IRT system. For a requester who is not a member of the trial staff and who does not have 
access to the IRT system (e.g. a physician at an emergency room), a local contact number for 
the emergency unblinding contract research organisation (CRO) is provided on the subject 
card (see Appendix 3B) to be used if the investigator or delegated site staff cannot be reached. 
The requester will provide the trial ID and subject ID to the emergency unblinding CRO who 
will immediately reveal the individual treatment allocation. 
The emergency unblinding CRO will clarify that the requester requires immediate unblinding 
without further medical consultation. Should the requester wish to discuss whether unblinding 
is necessary, the emergency unblinding CRO will provide the requester with the LEO Pharma 
24/7 contact which will be diverted to the medical cover.  
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9.4 Background treatment 
Not applicable.  
9.5 Rescue treatment 
No rescue medication is allowed for the duration of the trial. It will be at the discretion of the 
investigator to ensure other treatment options for subjects who discontinue IMP or to ensure 
that the subjects are referred to other physician(s) according to standard practice. 
9.6 Concomitant medication and concurrent procedures 
Any medication or vaccine that the subject receives throughout the trial (including screening 
period) must be recorded in the subject’s medical record and the eCRF along with details such 
as: 
• Medication name. 
• Indication. 
• Start and stop date of administration (it will also be recorded if the medication is 
ongoing). 
• Dosage information, including dose, unit, and frequency. 
• Route of administration. 
Similarly, any concurrent procedure must also be recorded in the subject’s medical record and 
the eCRF. The following details will be recorded: 
• Procedure. 
• Body location (if relevant). 
• Indication. 
• Start and stop date (it will also be recorded if the procedure is ongoing). 
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 9.7. The 
sponsor’s medical expert should be contacted if there are any questions regarding concomitant 
or prior therapy. 
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The following concomitant medications related to psoriasis treatment are permitted 
throughout the trial (including the screening period): 
• Upper mid-strength or lower potency topical steroids on the face, axillae, and groin 
only. 
• Shampoos without steroids. 
• Bland emollients without urea or beta or alpha hydroxy acids. 
 
9.7 Prohibited medications and procedures 
The medications listed in Panel 7 are prohibited during the trial. In the case that any 
prohibited treatments are used during the trial, it must be recorded as a protocol deviation. 
The following circumstances require permanent discontinuation of IMP: 
• Use of any other biologic immunomodulating agent than IMPs. 
• Use of any prohibited medication that in combination with IMP results in a significant 
risk to the subject’s safety (as assessed by the investigator). 
• Administration of a live vaccine. 
If the prohibited medication does not require permanent discontinuation of IMP, then the 
investigator and the sponsor’s medical expert should discuss and consider to either 
discontinue the prohibited medication or discontinue the IMP.  
 
 
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Panel 7: Prohibited medications and procedures 
Abbreviations: IL = interleukin; IMP = investigational medicinal product. 
1) Use requires permanent discontinuation of IMP. 
Prohibited medication/procedure 
Prohibited from 
Prohibited to 
Etanercept1 
2 weeks prior to first 
administration of IMP 
Week 28 
Adalimumab1 
4 weeks prior to first 
administration of IMP 
Week 28 
Infliximab1 
8 weeks prior to first 
administration of IMP 
Week 28 
Certolizumab pegol1 
10 weeks prior to first 
administration of IMP 
Week 28 
Ustekinumab1 
First administration of IMP 
Week 28 
Any other approved or experimental anti-IL-17 or anti-
IL-231 
Not allowed at any time 
Week 28 
Other experimental or commercially available biologic 
immunomodulator(s) 
4 weeks or 5 half-lives, 
whichever is longer, prior to 
first administration of IMP 
Week 28 
Any other non-marketed drug substance  
4 weeks or 5 half-lives, 
whichever is longer, prior to 
screening 
Week 28 
Ultraviolet A light therapy (with or without psoralen), 
ultraviolet B light therapy, excimer laser  
4 weeks prior to first 
administration of IMP 
Week 28 
Oral retinoids; methotrexate; cyclosporine; 
systemically administered calcineurin inhibitors; 
azathioprine; thioguanine; hydroxyurea; fumarates; 
apremilast; or oral or parenteral corticosteroids 
including intramuscular and intraarticular 
administration (with the exception that: otic, nasal, 
ophthalmic, or inhaled corticosteroids within 
recommended doses are permitted). 
4 weeks prior to first 
administration of IMP 
Week 28 
Topical therapies for psoriasis (e.g. calcineurin 
inhibitors and vitamin D analogues, super-potent or 
potent topical steroids) with the following exceptions: 
Upper mid-strength or lower potency topical steroids 
on the face, axillae, and groin only. 
Shampoos without steroids. 
Bland emollients without urea or beta or alpha hydroxy 
acids. 
7 days prior to first 
administration of IMP 
Week 28 
Use of live vaccines1 
4 weeks prior to first 
administration of IMP 
Week 28  
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9.8 Treatment logistics and accountability  
9.8.1 Labelling and packaging of trial products 
The IMP will be packaged in individually numbered kits. 
The labelling of IMPs will be in accordance with the EU Guidelines for good manufacturing 
practices for medicinal products for human and veterinary use, Annex 13 (19), local 
regulations, and trial requirements. Label text will be translated into local languages, as 
required.  
9.8.2 Storage of trial products  
All LEO Pharma supplied IMPs (Section 9.1) must be stored in a secure and restricted area 
under the conditions specified on the label and remain in the original container until 
dispensed. 
The IMPs must be stored at 2–8°C (and protected from light) at the trial site. Do not freeze 
the IMPs. The pre-filled syringes must not be shaken or heated.  
The temperature during storage should be monitored by a calibrated, stationary, and 
continuously monitoring system. Minimum requirement is a calibrated min/max thermometer. 
A temperature log must be kept to document the storage within the right temperature interval, 
unless the temperature recorder has back-up of data. Storage facilities should be checked at 
least every working day.  
Storage of IMP may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
Note that in the cases listed below, site staff should not use the affected IMP and should 
immediately quarantine the IMP (also change the status in the IRT system), and contact their 
clinical research associate (CRA) for further guidance: 
• Temperature excursion upon receipt or during storage at the trial site. 
• Damaged syringe or kit. 
Damaged IMP should be documented in the IRT system and reported as a product complaint 
to Global Safety, LEO Pharma (see Section 9.10). Damaged IMP may not be used. 
Further details regarding IMP storage (including handling of temperature excursions upon 
receipt or during storage at the trial site) and handling of damaged IMP (including kits 
damaged upon receipt) are provided in the trial product handling manual. 
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9.8.3 Drug accountability 
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and for documenting all transactions with them. 
Dispensing of IMPs may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
An individual drug accountability form must be kept of the IMP dispensed/administered to 
each subject randomised in the trial. This individual drug accountability form must be 
available during monitoring visits and will be checked by the CRA to verify correct 
dispensing of the IMP. Drug accountability information will be entered in the IRT system, 
where also inventory status of all IMP at the trial site will be maintained. Refer to the IRT 
manual for information on how to update the kit status in the IRT system. 
The trial site will maintain trial kit cartons from used kits until reconciliation has been 
checked by the CRA. Subsequently, the trial kit cartons from used kits may be discarded. 
All unused IMP (including packaging material) supplied by the contract manufacturing 
organisation (CMO) on behalf of LEO Pharma will be returned to the CMO. Prior to return, 
the IMP must be fully accounted for by the CRA with the help of site staff responsible for 
dispensing the IMP. Accountability must be documented in the IRT system. Please refer to the 
trial product handling manual for further details. 
9.8.4 Treatment compliance 
IMP injections will be performed by site staff. Site staff will also keep the accountability 
records up to date. Treatment compliance will be assessed by the site staff at the time points 
specified in Section 4. Any non-compliance (subject received partial dose; subject received no 
dose) and the reason for it must be recorded in the eCRF. 
9.8.5 Trial product destruction 
Used syringes can be destroyed at the trial site provided the trial site has procedures in place 
for such IMP destruction. Trial sites that do not have such IMP destruction procedures in 
place will dispose used IMP in sharps bins that will be returned to the CMO. For more 
information, see the trial product handling manual. 
Unused IMP and disposal containers with used syringes returned to the CMO will be 
destroyed by the CMO according to approved procedures and any local requirements. 
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9.9 Provision for subject care following trial completion  
To ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice. 
9.10 Reporting product complaints 
Any defects or issues with the IMP as well as any device deficiency (including malfunctions, 
use errors, and inadequate labelling) must be reported to Global Safety at LEO Pharma on the 
trial-specific complaint form (paper) within 3 days of first knowledge.  
Critical complaints (defined as any defect, issue, or device deficiency that has or potentially 
could have a serious impact for the subject, such as SAE or large particles in the syringe) 
must be reported to Global Safety, LEO Pharma within 24 hours.  
Complaint forms should contain a detailed description of the defect, issue, or device 
deficiency, including whether it led to an AE. (S)AEs which occur due to a defect or issue 
with the IMP or due to a device deficiency will be reported by the investigator as described in 
Sections 13.3 and 13.4.  
Refer to the trial product handling manual for information on how to update the kit status in 
the IRT system. 
During the investigation of the product complaint, the IMP or device must be stored at 
labelled conditions unless otherwise instructed; the trial site will be notified whether the IMP 
or device needs to be returned for further investigation or may be destroyed. 
Global Safety, LEO Pharma contact information for reporting product complaints: 
Fax number: +45 6910 2468  
E-mail address: drug.safety@leo-pharma.com 
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10 Discontinuation and withdrawal 
10.1 General principles 
A subject may withdraw from the trial (prior to first dose or during the treatment period) or 
permanently discontinue trial treatment at any time if the subject, the investigator, or LEO 
Pharma considers that it is not in the subject’s best interest to continue. 
To obtain the most representative efficacy and safety evaluation of brodalumab in the target 
population, the subject will be asked to remain in the trial and complete all the remaining 
visits and assessments after permanent discontinuation of IMP. It is key to assess the efficacy 
status of each subject at the planned primary endpoint visit (Week 16, see Section 4) 
irrespective of whether the subject has discontinued IMP or not. Therefore, the permanent 
discontinuation of IMP is evaluated as a separate occurrence that does not necessitate 
withdrawal from the trial.  
Permanent discontinuation of IMP and withdrawal from trial are considered 2 (potentially) 
separate occurrences: 
• Permanent discontinuation of IMP occurs when all further trial treatment is stopped. 
The subject will continue to participate in trial visit activities as outlined in 
Section 10.3. 
• Withdrawal from trial occurs when all further trial activities are stopped before the 
final visit at Week 28. This can happen either at the same time as permanent 
discontinuation of IMP or later. 
Medical reasons for discontinuation of IMP are given in Section 10.2.1. 
Reason(s) for discontinuation from IMP and/or withdrawal from the trial must be recorded in 
the medical records and the eCRF (lack of efficacy, AE, withdrawal by subject, lost to 
follow-up, death, pregnancy, or other, Sections 10.2.1 and 11.6.2). For subjects randomised to 
IMP, but not attending any post-baseline visits, it will be recorded whether any safety 
evaluations were performed after exposure to IMP. 
Subjects who withdraw from the trial and subjects who discontinue IMP will not be replaced. 
If a subject withdraws from the trial, he or she may request destruction of any samples taken 
and not tested, and the investigator must document this in the subject’s trial records. 
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10.2 IMP discontinuation rules 
10.2.1 Reasons for permanent discontinuation of IMP 
When discontinuing IMP, either at the scheduled end-of-treatment visit or IMP is discontinued 
prematurely, the subject should be treated at the discretion of the investigator (Section 9.9). 
Subjects will permanently discontinue IMP prematurely in the event of: 
• Having shown no response (efficacy) after 16 weeks of treatment. 
• Anaphylactic reaction or other severe systemic reaction to IMP injection. 
• An AE or deterioration of an AE that, in the opinion of the investigator or sponsor’s 
medical expert, contraindicates further IMP administration (e.g. Crohn’s disease). 
• Some cases of use of prohibited medication and treatment, see Section 9.7 for further 
details. 
• Diagnosis of a malignancy during the trial, excluding carcinoma in situ of the cervix, 
or localised squamous or basal cell carcinoma of the skin. 
• Evidence of pregnancy (positive serum pregnancy test). 
• Any infection that is opportunistic, such as active tuberculosis and other infections 
whose nature or course may suggest an immunocompromised status. 
• Any suicidal behaviour or suicidal ideation of category 4 or 5 according to the 
C-SSRS (the subject must be referred to a mental health professional). 
• A PHQ-8 score of ≥15 corresponding to moderately severe-to-severe depression 
(the subject must be referred to a mental health professional). 
• Any single measurement of ANC <0.50×103/µL. 
• Severe laboratory abnormalities:  
o ALT and/or AST values >3×ULN with total bilirubin >2×ULN (unless elevated 
bilirubin is related to Gilbert-Meulengracht Syndrome).  
o Confirmed ALT and/or AST >5×ULN (for more than 2 weeks). 
Refer to Section 10.3 for details on the handling of discontinuation of IMP or withdrawal of a 
subject, and to Section 4 for assessments to be performed in case of discontinuation of IMP. 
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Data to be recorded in the eCRF 
The primary reason for permanent discontinuation of IMP must be recorded in the medical 
records and on the end-of-treatment form in the eCRF where the following options are 
available:  
• Lack of efficacy. 
• Adverse event. 
• Withdrawal by subject. 
• Lost to follow-up. 
• Death. 
• Pregnancy. 
• Other. 
If ‘other’ is selected, a specification must be provided in the eCRF. If ‘adverse event’ is 
selected, the AE in question will be linked to the IMP discontinuation.  
‘Lack of efficacy’ should be assigned when a subject experiences 
aggravation/exacerbation/worsening of the trial disease, even when it is documented as an 
(S)AE according to Section 13.6.5. 
10.2.2 Reasons for temporary discontinuation of IMP 
Administration of IMP should be temporarily suspended in the event of: 
• An infection that requires parenteral treatment with antibiotic, antifungal, antiviral, 
anti-parasitic, or anti-protozoal agents. The administration of the IMP should be 
withheld until the infection has resolved in the opinion of the investigator. 
• Other major intercurrent illnesses or major surgery. The administration of the IMP 
should be withheld until the event has resolved in the opinion of the investigator. 
• ANC ≥0.50×103/µL to ≤1.5×103/µL and fever. The administration of the IMP should 
be withheld until the infection has resolved in the opinion of the investigator and ANC 
is >1.5×103/µL. 
• Positive urine pregnancy test. The administration of the IMP should be withheld until 
confirmation by serum pregnancy test. 
 
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A decision to discontinue IMP temporarily or to reinstitute IMP treatment must be discussed 
with sponsor’s medical expert. However, the investigator may suspend trial treatment at any 
time, even without consultation with sponsor’s medical expert if the urgency of the situation 
requires immediate action and if this is determined to be in the subject’s best interest. In such 
cases, sponsor’s medical expert should be informed as soon as possible. The schedule of 
planned visits should be maintained and all trial-related assessments should still be performed 
during the period of temporary discontinuation of IMP. 
If all assessments were performed prior to IMP administration, but a decision was made to 
temporarily discontinue IMP, the IMP should be administered at a rescheduled visit, which 
should be reported in the eCRF as an unscheduled visit. The subsequent IMP administration 
should be scheduled according to the schedule of the trial procedures with a minimum of 
7 days to the subsequent administration of the respective IMP (visits 3 and 4 are exempt from 
the 7-day gap requirement). When IMP is temporarily discontinued on a visit where 
2 injections are required, the 2 injections can be rescheduled independently due to the 
difference in administration frequencies (brodalumab/dummy 2: Q2W, 
guselkumab/dummy 1: Q8W). If the trial visit cannot be rescheduled to maintain a minimum 
of 7 days to the subsequent scheduled dose, the sponsor’s medical expert should be contacted. 
10.3 Early termination assessments 
Permanent discontinuation of IMP 
Unless the subject discontinues IMP due to withdrawal of consent, lost to follow-up, or death, 
subjects will be encouraged to continue in the trial for collection of scheduled efficacy and 
safety assessments, or at least attend an early termination visit and primary endpoint visit as 
indicated below (see Section 4 for data to be collected at these visits). The investigator will 
review any AEs which will be followed up according to Section 13.7, if the subject agrees. 
Subjects who permanently discontinue IMP prior to Week 16 (Visit 11) will be asked to attend 
at least: 
• Early termination visit, as soon as possible and within 2 weeks of the last IMP 
administration. 
• Primary endpoint assessment visit at nominal Week 16 (Visit 11). 
Subjects who permanently discontinue IMP at Week 16 (Visit 11) or hereafter will be asked to 
attend at least: 
• Early termination visit, as soon as possible and within 2 weeks of the last IMP 
administration. 
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Withdrawal from trial  
Subjects who withdraw from the trial for any reason will be asked to attend an early 
termination visit as soon as possible after last administration of IMP. See the schedule of trial 
procedures (Section 4) for data to be collected. The investigator will review any AEs which 
will be followed-up according to Section 13.7, if the subject agrees. 
10.4 Lost to follow-up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and if the trial site is not able to get in contact with the subject. The following actions 
must be taken if a subject fails to return to the trial site for a required visit: 
• The trial site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to continue in the trial. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record.  
• Should the subject continue to be unreachable, they will be considered to have 
withdrawn from the trial with a primary reason of lost to follow-up. 
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11 Trial assessments and procedures 
11.1 Overview 
Evaluations to be done at each visit are shown in the schedule of trial procedures in Section 4. 
Refer to Section 7.1 for further details on the trial design. 
Assessments and procedures at each trial visit should be performed as shown in Panel 8. 
Panel 8: Sequence of assessments 
 
Abbreviations: C-SSRS = Columbia-Suicide Severity Rating Scale; DLQI = Dermatology Life Quality Index; 
IMP = investigational medicinal product; PHQ-8 = Patient Health Questionnaire-8; SF-36v2 = 36-Item 
Short Form Health Survey version 2.  
 
Subjects participating in the trial will be under careful supervision of a principal investigator 
who must be a medically qualified physician. Investigators must be experienced in treating 
psoriasis and have documented experience and/or training in use of the assessments required 
by the protocol. The investigators performing the assessments must not be involved in the 
administration of IMP (Section 9.3.1). 
Site staff assessing PASI, IGA, palmoplantar IGA (PP-IGA), and static Physician’s Global 
Assessment of genitalia (sPGA-G) or reviewing the C-SSRS and PHQ-8 must be medically 
qualified physicians trained in the assessments. If adequately trained, other site staff may be 
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responsible for conducting the C-SSRS interview. The training certificate must be archived in 
the investigator trial file before any assessments.  
To reduce inter-rater variability, the same assessor should perform all the evaluations for a 
given subject throughout the entire trial period, if feasible. 
The site staff handling the IMP administration must not be involved in the efficacy 
assessments (Section 9.3.1). 
AEs must be assessed by medically qualified personnel (Section 13.2). 
11.2 Assessments performed only at screening/baseline 
11.2.1 Demographics  
The following demographic data will be recorded: 
• Date of birth (date, month, and year). If full date of birth is not allowed to be recorded, 
month and year of birth or only year of birth should be collected as per local 
legislation. In these cases, the subject’s age in years will also be recorded. 
• Sex: female, male. 
• Race: American Indian or Alaska native, Asian, Black or African American, native 
Hawaiian or other Pacific islander, White, other (‘other’ requires a specification to be 
provided). 
• Ethnic origin (self-reported by the subject): Hispanic or Latino, not Hispanic or 
Latino. 
11.2.2 Trial diseases (psoriasis, psoriatic arthritis or arthropathy, and other 
immunoinflammatory diseases) 
The duration of psoriasis will be recorded (to the nearest whole year). For subjects with 
‘current or previous psoriatic arthritis or psoriatic arthropathy’, the duration will be recorded 
(to the nearest whole year) together with the duration of any other immunoinflammatory 
diseases the subjects might have. 
11.2.3 Trial disease treatment history 
The subject’s psoriasis- and psoriatic arthritis-specific medication, and medication for other 
immunoinflammatory diseases, including biologic and non-biologic systemic therapy, 
phototherapy, and/or topical therapy at any time in the subject’s history will be recorded. For 
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these medications, the reason for discontinuation should be specified. If a treatment was given 
for both psoriasis and psoriatic arthritis, only the primary treatment indication should be 
recorded. It must be recorded if the subject has a contraindication to methotrexate, 
cyclosporine, phosphodiesterase-4 (PDE-4) inhibitors, Janus kinase (JAK) inhibitors, fumaric 
acid, or psoralen and ultraviolet A treatment (PUVA).  
11.2.4 Medical history 
Other relevant past and concurrent medical illnesses, based on subject interview, will be 
recorded in the eCRF. For each condition, diagnosis, treatment, start date, and stop date will 
be recorded; it will also be recorded if the condition, diagnosis, or treatment is ongoing. 
Please refer to Section 9.6 for recording of prior and concomitant medications. Relevant 
medical history also includes diseases which are specifically listed as exclusion criteria and 
diseases for which specific treatments are listed as exclusion criteria. 
11.2.5 Substance use: tobacco and alcohol 
The subject’s tobacco consumption will be recorded in the eCRF. It will be recorded if the 
subject has ever consumed tobacco, the type and amount of tobacco consumed, and the 
duration and frequency of the subject’s consumption will be recorded. 
The subject’s alcohol consumption will be recorded in the eCRF. It will be recorded if the 
subject consumes alcohol. If applicable, the average number of drinks and frequency of the 
consumption will be recorded.  
11.3 Efficacy assessments 
11.3.1 Psoriasis Area and Severity Index 
11.3.1.1 Psoriasis Area and Severity Index 
The PASI is the most widely used tool in clinical practice and clinical trials to assess the 
severity and extent of psoriasis (20). The PASI score will be assessed according to the 
schedule of trial procedures (Section 4). The assessment will be based on the condition of the 
disease at the time of evaluation and not in relation to the condition at a previous visit. 
The PASI is a composite index with scores ranging from 0 to 72, with higher values indicating 
a more severe or more extensive condition. 
The investigator will assess the severity of 3 psoriasis disease characteristics (redness, 
thickness, and scaliness) on each of the 4 body regions (head/neck, trunk, upper extremities, 
and lower extremities) according to the severity scale shown in Panel 10. It should be noted 
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that ‘upper extremities’ include arms and hands, ‘trunk’ includes the axillae and groin, and 
‘lower extremities’ include legs, buttocks, and feet. 
The investigator will assess the extent of psoriasis within each of the 4 body regions 
according to the area score scale shown in Panel 11. The assessment of extent is the 
percentage of the body region affected and not the percentage of the total body surface area 
(BSA) affected. For example, if one arm and hand are completely affected, and the other arm 
and hand are completely unaffected, the extent assessment for the upper extremities will be 
50%.  
For each body region, a combined score is calculated from the sum of severity scores 
multiplied by the area score and the weighting factor pertaining to that body region. The PASI 
score equals the sum of the combined scores for each body region (Panel 9). 
The investigator must evaluate subject eligibility in relation to inclusion criterion no. 4 for the 
PASI score at screening and baseline. The evaluation will be captured in the eCRF. 
Panel 9: Calculation of the PASI score 
Body region 
Redness 
(erythema) 
Thickness 
(induration) 
Scaliness 
(desquamation)  
Sum of severity 
scores 
Area score 
Weighting factor 
Body region  
score 
Head and neck 
(SS + 
  SS + 
  SS) = 
  SSS  
x AS 
x 0.1 
 
Trunk 
(SS + 
  SS + 
  SS) = 
  SSS  
x AS 
x 0.3 
 
Upper extremities 
(SS + 
  SS + 
  SS) = 
  SSS  
x AS 
x 0.2 
 
Lower extremities 
(SS + 
  SS + 
  SS) = 
  SSS  
x AS 
x 0.4 
 
The PASI score is the sum of the 4 body region scores (head, trunk, arms, and legs) 
(each calculated as SSS (SSredness + SSthickness + SSscaliness) x AS x weighting factor) 
 
(range 0-72) 
Abbreviations: AS = area score; PASI = Psoriasis Area and Severity Index; SS = severity score; SSS = sum of 
severity scores.  
Modified from (20). 
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Panel 10: PASI severity score scale 
Score 
Redness 
0 
None (no erythema) 
1 
Mild (faint erythema, pink to very light red) 
2 
Moderate (definite light red erythema) 
3 
Severe (dark red erythema) 
4 
Very severe (very dark red erythema) 
Score 
Thickness 
0 
None (no plaque elevation) 
1 
Mild (slight, barely perceptible elevation) 
2 
Moderate (definite elevation but not thick) 
3 
Severe (definite elevation, thick plaque with sharp edge) 
4 
Very severe (very thick plaque with sharp edge) 
Score 
Scaliness 
0 
None (no scaling) 
1 
Mild (sparse, fine scale, lesions only partially covered) 
2 
Moderate (coarser scales, most of lesions covered) 
3 
Severe (entire lesion covered with coarse scales) 
4 
Very severe (very thick coarse scales, possibly fissured) 
Abbreviation: PASI = Psoriasis Area and Severity Index. 
Modified from (20). 
Panel 11: PASI area score scale 
0 
0% affected area 
1 
1% to 9% affected area 
2 
10% to 29% affected area 
3 
30% to 49% affected area 
4 
50% to 69% affected area 
5 
70% to 89% affected area 
6 
90% to 100% affected area 
Abbreviation: PASI = Psoriasis Area and Severity Index. 
Modified from (20). 
 
11.3.1.2 Palmoplantar Psoriasis Area and Severity Index 
The palmoplantar PASI (PP-PASI) is a point-based system quantifying the area and severity 
of palmoplantar psoriasis. The PP-PASI measures erythema, induration, and desquamation on 
a scale of 0-4, with 4 being the most severe (Panel 12). The weighting factor for each palm is 
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20%, while that of each sole is 30%. The PP-PASI tool is widely used as a measure of 
improvement of palmoplantar psoriasis in clinical trials. 
Only subjects with palmoplantar psoriasis at baseline will be followed post randomisation 
using the PP-PASI tool. 
Panel 12: PP-PASI score scale 
Score 
Erythema (E) 
Induration (I) 
Desquamation 
(D) 
Area involved 
(%) 
0 
None 
None 
None 
0 
1 
Slight 
Slight 
Slight 
1-9 
2 
Moderate 
Moderate 
Moderate 
10-29 
3 
Severe 
Severe 
Severe 
30-49 
4 
Very severe 
Very severe 
Very severe 
50-69 
5 
--__ 
__ 
__ 
70-89 
6 
__ 
__ 
__ 
90-100 
The PP-PASI score is calculated as follows: [(E+I+D) × area × 0.2 – right palm] + [(E+I+D) × area 
× 0.2 – left palm] + [(E+I+D) × area × 0.3 – right sole] + [(E+I+D) × area × 0.3 – left sole] 
Abbreviation: PP-PASI = palmoplantar PASI. 
Modified from (21). 
 
11.3.2 Investigator’s Global Assessment 
11.3.2.1 Investigator’s Global Assessment  
The IGA is an instrument used in clinical trials to rate the severity of psoriasis and is based on 
a 5-point scale ranging from 0 (clear) to 4 (severe) (Panel 13). The IGA score will be assessed 
according to the schedule of trial procedures (Section 4). The assessment will be based on the 
condition of the disease at the time of evaluation and not in relation to the condition at a 
previous visit. The disease severity assessment score will be recorded in the eCRF. 
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Panel 13: Investigator’s Global Assessment 
Score 
Disease severity 
IGA morphological descriptors 
0 
Clear 
No signs of psoriasis; post-inflammatory hyperpigmentation may be 
present 
1 
Almost clear 
No thickening; normal to pink colouration; no to minimal focal 
scaling 
2 
Mild  
Just detectable to mild thickening; pink to light red colouration; 
predominantly fine scaling 
3 
Moderate  
Clearly distinguishable to moderate thickening; dull to bright red; 
clearly distinguishable erythema; moderate (mild to coarse) scaling 
4 
Severe  
Severe thickening with hard edges; bright to deep dark red 
colouration; severe/coarse scaling covering almost all or all lesions 
Modified from (22). 
 
11.3.2.2 Palmoplantar Investigator’s Global Assessment 
The PP-IGA tool assesses a combination of erythema and secondary features (plaque 
elevation and/or scaling); it is based on the above-mentioned IGA (22) specifically applied to 
the palms and soles. For the analysis of responses, the subject’s palmoplantar psoriasis is 
assessed as follows: 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe. 
Only subjects with palmoplantar psoriasis at baseline (Week 0; Visit 2) will be followed 
post randomisation using the PP-IGA tool. 
11.3.3 Static Physician’s Global Assessment of genitalia 
The sPGA-G score is based on a combination of erythema and secondary features (plaque 
elevation and/or scaling). For the analysis of responses, the subject’s genital psoriasis is 
assessed as follows: 0 = clear, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe, 5 = very 
severe.  
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Panel 14: Static Physician’s Global Assessment of genitalia 
Score 
Category 
Category description1 
0 
Clear 
Erythema: residual or no erythema. 
Plaque elevation: no elevation. 
Scaling: no scale. 
1 
Minimal 
Erythema: faint, light pink erythema. 
Plaque elevation: elevation is very slight and difficult to confirm. 
Scaling: some fine, white surface dryness.  
2 
Mild 
Erythema: mild, pink erythema. 
Plaque elevation: slight elevation with sloped edges. 
Scaling: fine scale on some or most lesions. 
3 
Moderate 
Erythema: moderate, red erythema. 
Plaque elevation: slight elevation with sloped edges. 
Scaling: coarse scale on most lesions. 
4 
Severe 
Erythema: severe, bright red erythema. 
Plaque elevation: substantial elevation, hard or sharp edges. 
Scaling: coarse, non-adherent scale on most or all lesions. 
5 
Very severe 
Erythema: very severe, deep red erythema. 
Plaque elevation: very significant elevation with hard and sharp edges. 
Scaling: very coarse, thick, and adherent scale completely or nearly 
completely covering most or all lesions. 
1) Severity is determined by a combination of 3 plaque characteristics (erythema, elevation, and scaling) based 
on descriptions of each characteristic. Erythema is the primary characteristic that should influence the rating, 
with plaque elevation and scaling considered as secondary. Assessment does not require all 3 characteristics 
to be present. 
Modified from (23).  
Only subjects with genital psoriasis at baseline (Week 0; Visit 2) will be followed 
post randomisation using the sPGA-G tool. 
11.3.4 Patient-reported outcomes 
The subjects will receive an electronic diary (eDiary) device and eDiary training at screening 
(Visit 1). The subject should bring the device once at baseline (Week 0, Visit 2). The eDiary 
should be returned at the last visit at the latest. 
Each subject will make individual assessments relating to their perception of the disease and 
quality of life. These assessments will be performed prior to the investigator performing any 
efficacy assessments. The investigator should not question the subject’s answers for any of the 
patient-reported outcomes (PROs). The investigator must review the data for timeliness and 
completeness. 
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Symptoms reported in the PROs will not be captured as AEs, unless they are specifically 
mentioned as an AE by the subject when they are asked the non-leading question: “How have 
you felt since I saw you last?” or as per the instructions given for C-SSRS and PHQ-8 
(Section 11.5).  
The PROs will be completed according to the schedule of trial procedures (Section 4). 
11.3.4.1 Dermatology Life Quality Index 
The DLQI is a validated questionnaire with content specific to those with dermatology 
conditions. It consists of 10 items addressing the subject’s perception of the impact of their 
skin disease on different aspects of their quality of life over the last week such as 
dermatology-related symptoms and feelings, daily activities, leisure, work or school, personal 
relationships, and the treatment (24). Each item is scored on a 4-point Likert scale (0 = ‘not at 
all/not relevant’; 1 = ‘a little’; 2 = ‘a lot’; 3 = ‘very much’). The total score is the sum of the 
10 items (0 to 30); a high score is indicative of a poor quality of life. 
The DLQI questionnaire will be filled out on a separate device. 
11.3.4.2 36-Item Short Form Health Survey  
The 36-Item Short Form Health Survey version 2 (SF-36v2; acute recall) is a 36-item general 
health status assessment. Subjects will be asked to answer each question by selecting 1 of 3 to 
6 categorical response options. The instrument instructions do not state a specific recall 
period; however, a recall period is defined within most items. The acute recall version, which 
asks subjects about the last week, will be used in this trial (25). 
The SF-36v2 (acute recall) yields scores for 8 health domains (physical functioning, role 
physical, bodily pain, general health, vitality, social functioning, role emotional, and mental 
health) and 2 psychometrically derived summary scores (a physical component summary and 
a mental component summary). 
The SF-36v2 questionnaire will be filled out on a separate device. 
11.3.4.3 Pruritus Numeric Rating Scale 
The pruritus NRS renders a quantitative symbolisation of itch. This validated scale is used by 
presenting the respondent with an ordered set from which to choose. Subjects will assess their 
worst itch over the past 24 hours using an 11-point NRS with 0 indicating ‘no itch’ and 10 
indicating ‘worst possible itch’. 
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The pruritus NRS will be completed daily by the subject at home on eDiary from screening 
onwards. 
11.3.4.4 Pain Numeric Rating Scale 
The pain NRS renders a quantitative symbolisation of pain. This validated scale is used by 
presenting the respondent with an ordered set from which to choose. Subjects will assess their 
worst pain over the past 24 hours using an 11-point NRS with 0 indicating ‘no pain’ and 10 
indicating ‘worst possible pain’. 
The pain NRS will be completed daily by the subject at home on eDiary from screening 
onwards. 
11.4 Safety assessments 
11.4.1 Vital signs 
Vital signs (resting blood pressure, pulse, and body temperature) must be assessed according 
to the schedule of trial procedures (Section 4). The subjects must relax in a supine position for 
>5 minutes before the measurements are done. 
If an abnormal vital sign at screening is considered to be clinically significant by the 
investigator, it will be at the discretion of the investigator to decide if the subject should be 
randomised into the trial.  
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later to verify the first measurement. Should the repeated measurement result in a 
normal value, the measurement must be repeated once more. If the third measurement verifies 
the second (normal) value, the first measurement should be considered false. If the third 
measurement confirms the first measurement (abnormal), the second measurement will be 
considered false. Only the last value measured and considered correct will be recorded in the 
eCRF. 
Reporting in eCRF 
Vital signs will be recorded in the eCRF. If vital signs were not assessed, a reason should be 
given. Clinically significant abnormal vital signs at the screening visit will be documented as 
medical history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom, or illness 
occurring after randomisation will be reported as an AE in accordance with Section 13.3. 
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11.4.2 Physical examination 
An abbreviated physical examination will be performed by the investigator according to the 
schedule of trial procedures (Section 4) and must include: 
• General appearance. 
• Lymph nodes. 
• Dermatologic examination of the skin. 
If an abnormal finding at screening or baseline is considered to be clinically significant by the 
investigator, it will be at the discretion of the investigator to decide if the subject should be 
randomised into the trial.  
Reporting in eCRF 
It will be recorded in the eCRF if a physical examination was performed and, if applicable, 
the investigator’s evaluation (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, 
clinically significant’); if a physical examination was not performed, a reason should be 
given. 
Clinically significant abnormal findings at the screening visit will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom, or illness 
occurring after randomisation will be reported as an AE in accordance with Section 13.3. 
11.4.3 Body measurements 
As part of the physical examination, the following must be measured and collected in the 
eCRF at the visits specified in the schedule of trial procedures (Section 4): 
• The subject’s height without shoes (only measured at screening). 
• The subject’s weight (in indoor clothing and without shoes). 
11.4.4 Laboratory testing 
11.4.4.1 Overview 
Blood and urine samples will be collected according to the schedule of trial procedures 
(Section 4). The tests shown in Panel 15 will be performed. 
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Panel 15: Clinical laboratory tests 
Biochemistry 
Haematology and differential 
Urine analysis 
Sodium 
Potassium 
Calcium 
Bicarbonate 
Albumin 
Blood urea nitrogen 
Creatinine 
Uric acid 
Total bilirubin1 
Alkaline phosphatase 
Aspartate aminotransferase 
Alanine aminotransferase 
C-reactive protein 
Cholesterol 
LDL cholesterol 
HDL cholesterol 
Triglycerides 
Glucose 
eGFR (only at screening) 
Red blood cell count 
Haemoglobin 
Haematocrit 
Platelets 
White blood cell count 
 
Differential (absolute count and 
%): 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Urine dipstick2: 
• 
Specific gravity 
• 
pH 
• 
Occult blood 
• 
Protein 
• 
Glucose 
• 
Leucocyte esterase 
• 
Ketones 
Urine pregnancy test3 
Albumin-to-creatinine ratio4  
Other 
Serum beta hCG3 
Tuberculosis test (if applicable) 
HIV, HBV, HCV (only at 
screening) 
 
Abbreviations: eGFR = estimated glomerular filtration rate; HBV = hepatitis B virus; HCV = hepatitis C virus; 
hCG = human chorionic gonadotropin; HDL = high density lipoprotein; HIV = human immunodeficiency 
virus; LDL = low density lipoprotein. 
 
1) If total bilirubin is above upper limit of normal, direct and indirect bilirubin will also be measured.  
2) Urine samples will be tested at the trial site (dipstick). In case of abnormal dipstick results, a urine sample 
will be sent to the central laboratory. 
3) Only women of childbearing potential. Urine pregnancy tests will be performed at the trial sites. If a urine 
pregnancy test is positive, a serum pregnancy test must be done to confirm the result. At screening, a serum 
pregnancy test is always performed. 
4) Only at screening, in case of abnormal dipstick result. 
 
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11.4.4.2 Investigator evaluation of laboratory samples 
Central laboratory 
Chemistry, haematology, urinalysis (if applicable), serology, and serum pregnancy tests will 
be analysed by a central laboratory which will provide results to the trial sites. The 
investigator must evaluate all results outside the reference range (‘clinically significant’ or 
‘not clinically significant’) and sign and date the report for documentation of the review. The 
signed and dated version will be filed with the investigator’s trial documentation. Clinically 
significant abnormal tests must be repeated as soon as possible to confirm the abnormality. 
Subjects with clinically significant abnormal test results should be followed up at the 
discretion of the investigator.  
If a screening laboratory result is abnormal and of clinical significance, it will be at the 
investigator’s discretion to decide if the subject should be randomised into the trial. However, 
subjects meeting exclusion criterion no.16 (laboratory abnormalities) must not be randomised 
into the trial. 
A laboratory manual will be provided to the trial sites specifying the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information specific to this trial. 
Tests performed at the trial site 
Urine samples will be tested with a dipstick according to the schedule of trial procedures 
(Section 4). If a dipstick shows any abnormal reading, a urine sample must always be 
collected and sent to the central laboratory for further analysis, regardless of causality or 
investigator’s assessment of significance. 
Women of childbearing potential will have a urine pregnancy test performed at the trial site at 
baseline prior to randomisation. The test will be repeated every 4 weeks as shown in the 
schedule of trial procedures in Section 4. 
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Reporting in eCRF 
At each visit where samples must be taken, the site staff will record in the eCRF if a sample 
(urine/blood) was taken and the investigator’s assessment of the results (‘normal’, ‘abnormal, 
not clinically significant’, ‘abnormal, clinically significant’). 
It will be recorded in the eCRF if the subject is a woman of childbearing potential and if a 
urine pregnancy test was performed, if not, a reason should be provided. Also, the date and 
the outcome of the urine pregnancy test will be recorded in the eCRF (‘positive’, ‘negative’). 
Clinically significant abnormal laboratory results at the screening visit will be documented as 
medical history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition will be reported as an AE. Any new clinically significant abnormal 
laboratory values, sign, symptom, or illness occurring after randomisation will be reported as 
an AE in accordance with Section 13.3. 
11.5 Other assessments: Patient-reported outcomes 
11.5.1 Overview 
The C-SSRS must be completed after all other assessments have been performed at the trial 
visit, but prior to IMP administration. The investigator should not question the subject’s 
answers. The investigator must review the data for eligibility (at screening and at baseline), 
timeliness, and completeness, and take appropriate action (see below) before the subject 
leaves the trial site. 
11.5.2 Columbia-Suicide Severity Rating Scale 
The C-SSRS is a rater-administered, standardised, and validated instrument developed for the 
assessment of the severity and frequency of SIB (26, 27).  
The C-SSRS is divided into suicidal ideation (category 1 to 5), suicidal behaviour (category 6 
to 9), completed suicide (category 10), and non-suicidal self-injurious behaviour: 
Suicidal ideation 
• Category 1: Wish to be dead. 
• Category 2: Non-specific active suicidal thoughts. 
• Category 3: Active suicidal ideation with any methods (not plan) without intent to act. 
• Category 4: Active suicidal ideation with some intent to act, without specific plan. 
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• Category 5: Active suicidal ideation with specific plan and intent. 
Suicidal behaviour 
• Category 6: Preparatory acts or behaviour. 
• Category 7: Aborted attempts. 
• Category 8: Interrupted attempts. 
• Category 9: Actual attempts (non-fatal). 
Completed suicide 
• Category 10: Completed suicide. 
Non-suicidal self-injurious behaviour 
• Non-suicidal self-injurious behaviours. 
At all visits where the C-SSRS interview must be performed (see Section 4), it must be done 
after all other visit activities have been completed. However, the C-SSRS interview must be 
performed and the answers reviewed before the IMP administration. The C-SSRS takes 
approximately 3 to 10 minutes to complete.  
The investigator must evaluate the subject’s eligibility in relation to exclusion criteria no. 11 
and 12 for the C-SSRS components ‘history of suicidal behaviour’ and ‘suicidal ideation’ at 
screening (Visit 1) and baseline (Visit 2; Week 0).  
The ‘baseline’ paper version of the C-SRSS will be used at screening and the ‘since last visit’ 
paper version will be used at all subsequent visits. The C-SSRS assessments will be 
transcribed into the eCRF. 
Subjects with suicidal ideation of category 4 or 5 or any suicidal behaviour must be referred 
to a mental health professional and be discontinued from IMP. In addition, the event must be 
reported as an AE. 
11.5.3 Patient Health Questionnaire-8 
The PHQ-8 is a validated and widely used 8-item version of the Patient Health Questionnaire 
depression scale designed to clinically assess subjects for symptoms and signs of 
depression (16). 
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At all visits where the PHQ-8 must be completed (see Section 4), the answers must be 
reviewed by the investigator before the IMP administration. The PHQ-8 questionnaire will be 
filled out on a separate device and takes approximately 3 minutes to complete.  
For PHQ-8 scores ≥10, the subject must be referred to a mental health professional (score ≥10 
is cut-point for defining current depression), and the event must be reported as an AE (16). 
Subjects scoring ≥15 must in addition be discontinued from IMP. 
11.6 End of trial 
Both an end-of-treatment form and an end-of-trial form will be completed in the eCRF for all 
randomised subjects. 
11.6.1 End-of-treatment form 
An end-of-treatment form will be completed in the eCRF for all randomised subjects when 
they have had their last administration of IMP. This form will also be completed for subjects 
who permanently discontinue IMP and subjects who withdraw from trial (see Section 10.3 for 
early termination assessments). 
It will be recorded on the end-of-treatment form if the subject completed the treatment. If not, 
the primary reason for permanent discontinuation of IMP must be recorded (see 
Section 10.2.1). 
11.6.2 End-of-trial form 
An end-of-trial form must be completed in the eCRF for all randomised subjects. The 
following data will be collected:  
• Did the subject complete the trial. If not, the primary reason for early termination must 
be recorded. 
• Date of last contact. 
• Primary reason for withdrawal from trial (lack of efficacy, adverse event, withdrawal 
by subject, lost to follow-up, death, pregnancy, other). ‘Lack of efficacy’ should be 
assigned when a subject experiences aggravation/exacerbation/worsening of the trial 
disease, even when it is documented as an (S)AE according to Section 13.6.5. If 
‘other’ is selected, a specification must be provided in the eCRF. 
The end-of-trial form will be completed when the subject has had his/her last visit (that is, the 
final visit at Week 28, or earlier in case of early termination [see Section 10]).  
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11.7 Estimate of total blood volume collected 
Blood samples will be drawn for haematology, biochemistry, and serology. The total volume 
of blood to be drawn is approximately 60 mL, which is significantly less than the total volume 
of blood drawn during a blood donation (approximately 500 mL).  
11.8 Storage of biological samples 
Blood and urine samples are collected only for clinical laboratory tests in the trial 
(haematology, biochemistry, serology, and urinalysis). The storage of these biological samples 
will therefore follow the standard operating procedures at the sites and laboratories where the 
tests are conducted. Typically, samples are stored for no more than a few days after sample 
collection.  
 
 
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12 Scientific rationale for trial design and appropriateness of assessments 
12.1 Scientific rationale for trial design 
This is a phase 4, randomised, blinded (subject and assessor), parallel-group, multi-site, 
clinical trial. The parallel-group design is chosen as it is the only appropriate design to 
evaluate the trial objectives. Furthermore, randomisation provides the most reliable method 
removing selection bias between 2 groups of subjects. Additionally, the randomisation will be 
stratified by body weight to further ensure comparability of the treatment groups. The subjects 
and the assessors will be blinded, as it is the only design that can provide strong clinical 
evidence compared with the alternative designs, e.g. assessor-blinded only. Additionally, a 
blinded design is also expected to be a requirement from regulatory authorities. 
The duration of the trial is approximately 32 weeks including a screening period of 2 to 
4 weeks, and the primary endpoint is assessed at Week 16, ensuring a treatment duration long 
enough for efficacy and safety evaluations for both treatments during the induction period. 
Moreover, from the clinical perspective, it is also important to investigate if the treatment 
differences are sustained for a longer period. Therefore, an additional 12 weeks of active 
treatment are included, resulting in a total of 28 weeks of therapy, providing enough time to 
evaluate if efficacy is sustained for both treatments.  
The eligible trial population is described in detail in Section 8. Most criteria are defined 
according to the approved IB of Kyntheum® and EU SmPC of Tremfya®. Inadequate response 
to ustekinumab is defined as IGA ≥2 after at least 3 doses at or higher than the approved dose 
or frequency, and this correlates well with the currently acceptable treatment goals.  
This trial will provide a direct comparison of brodalumab and guselkumab on regimens 
according to the approved IB/SmPC. The data generated could support evidence-based 
decisions on sequencing and switching biologic treatments within psoriasis in the clinical 
setting. 
12.2 Appropriateness of assessments 
12.2.1 Rationale for primary endpoint 
PASI is the most thoroughly validated and the most extensively studied psoriasis clinical 
severity scoring tool, which assesses the extent of psoriasis at 4 anatomical regions with the 
signs of erythema, scale, and elevation (28). The efficacy endpoint, PASI 75, together with 
static Physician’s Global Assessment (sPGA) score of 1 or 0, are recommended by the 
European Medicines Agency (EMA) for assessment of clinical efficacy (29) and recognised 
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as important endpoints in clinical trials in psoriasis by regulatory authorities in the EU. 
However, with more effective treatments emerging, patients and physicians are increasingly 
looking for more ambitious response parameters. As this trial aims to compare 2 highly 
efficacious drugs, it is considered that PASI 100 is the most reliable and relevant response 
criterion to identify the differences in efficacy among the 2 treatments. 
12.2.2 Rationale for assessment of palmoplantar psoriasis 
Palmoplantar psoriasis is a variant of plaque psoriasis that develops on the palms and soles. It 
can be seen with or without psoriasis elsewhere on the body and affects approximately 3–4% 
of all psoriasis patients (30, 31).  
Treatment for palmoplantar psoriasis is often challenging, as the thick epidermal layers of the 
palms and soles prevent local action of topical treatments (32). However, randomised 
controlled trials on the efficacy and safety of biologics for treatment of palmoplantar psoriasis 
are still limited, because palmoplantar psoriasis patients usually do not have sufficiently high 
BSA involvement to meet the inclusion criteria (32-34).  
Less than 5% BSA is involved in palmoplantar psoriasis without involvement of other body 
areas. Despite this relatively small BSA involvement, subjects with palmoplantar psoriasis 
suffer from substantial impairment of health-related quality of life, having difficulty with 
daily activities involving hands and feet (34, 35).  
Therefore, palmoplantar psoriasis is a disease with significant quality-of-life issues, where 
more data from clinical trials are needed. The psoriasis patients with predominantly hands 
and/or feet involvement are able to participate in this trial due to lack of a BSA inclusion 
criterion. Hence, the PP-IGA and PP-PASI are included in this trial, as they are validated, 
reliable, and responsive assessments of palmoplantar psoriasis, which have been used in 
previous clinical trials (36-38). 
12.2.3 Rationale for assessment of genital psoriasis 
Traditionally, the genitals have been acknowledged as a vulnerable and difficult-to-treat area 
with topicals. Thus, there is an unmet need for effective and proven treatments of genital 
psoriasis. 
Questionnaire-based studies have shown a high prevalence of genital psoriasis among patients 
with plaque psoriasis (28.6–46%) (39, 40). A clinical observational study showed that the 
current prevalence of genital psoriasis was 38% and the lifetime prevalence of genital 
psoriasis was as high as 63% (41). While psoriasis in the genital area is often overlooked and 
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left untreated, it has been shown to have a significant impact on health-related quality of life 
and it is associated with a high disease burden (42).  
Previous tools for assessing genital psoriasis have not been widely accepted or used in clinical 
trials or in clinical practice. Recently, the sPGA-G was developed and validated for the 
assessment of genital psoriasis in clinical trials (23, 43). The tool has been accepted by the 
United States Food and Drug Administration (FDA).  
Taken together, genital psoriasis is an important and often overlooked manifestation of 
psoriasis in which data from clinical trials are needed. The sPGA-G is considered a relevant 
and feasible tool for the assessment of genital psoriasis and is therefore included as a clinical 
assessment in this trial. 
 
 
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13 Adverse events 
13.1 Definition and classification of adverse events 
AEs and SAEs are defined in Appendix 1. 
Classification of AEs in terms of severity, causality, and outcome is defined in Appendix 2. 
Causality assessment will be made for all IMPs (brodalumab, guselkumab, and dummies). 
13.2 Collection of adverse event reports 
AE data must be collected from time of first trial-related activity after the subject has signed 
the ICF until completion of the clinical trial (Section 7.3). 
AEs must be assessed by medically qualified personnel. 
At all visits, the subject will be asked a non-leading question by the investigator about AEs, 
for example: “How have you felt since I saw you last?” No specific symptoms should be 
asked for. It is important that the investigator also observes the subject for any changes not 
reported by the subject and records these changes. 
Refer to Sections 11.4.1 to 11.4.4 for principles of data entry in the eCRF with regard to vital 
signs and laboratory results (e.g. abnormal findings).  
13.3 Reporting of adverse events 
AEs reported by the subject or observed by the investigator must be recorded on the AE form 
of the eCRF and should be described in the following manner: 
The AE term must be in precise English medical terminology (that is, not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (for 
example ‘allergic contact dermatitis’). 
The duration of the AE must be reported by the start date and stop date of the event (if the 
event is ongoing, it will also be recorded). In addition, it will be recorded if the AE started 
prior to first administration of IMP. 
AEs must be classified in terms of severity, causality, and outcome according to the 
definitions in Appendix 2. 
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Action taken with IMP: any action taken with IMP as a consequence of the AE must be 
recorded (dose not changed, temporary discontinuation of IMP, permanent discontinuation of 
IMP, not applicable, unknown). 
Other action taken: any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concurrent procedure). 
Withdrawn from trial due to this AE: it must be recorded whether the AE led to withdrawal 
from the trial. 
13.4  Reporting of serious adverse events 
The criteria that define an AE as serious (that is, an SAE) are defined in Appendix 1. SAE 
criteria are also listed on the SAE form. 
13.4.1 Investigator reporting responsibilities 
Any SAE must be reported to LEO Pharma on the (paper) SAE form within 24 hours of first 
knowledge. This report should contain an assessment of available information on seriousness, 
severity, causal relationship to the IMPs, device, or trial procedure, the action taken, the 
outcome to date, and a narrative description of the course of the event. 
By signing and dating the SAE form, the investigator acknowledges that he/she is aware of 
the SAE and has assessed the causal relationship of the IMP(s) and any of the other 
medications to the SAE. 
The actual reporter, if not the investigator, should also sign and date the SAE report. 
The completed SAE form must be faxed or scanned and e-mailed to Global Safety at LEO 
Pharma using the e-mail address or fax number below: 
Global Safety at LEO Pharma 
E-mail address: drug.safety@leo-pharma.com  
Fax number: +45 6910 2468 
If relevant, the investigator will enclose other information with the SAE form, such as 
anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
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Additionally, Global Safety at LEO Pharma may request further information to fully assess 
the SAE. The investigator must forward such information to LEO Pharma upon request by fax 
or e-mail (see contact details above). 
The investigator must notify the local IEC(s) of SAEs, as required by current applicable 
legislation for the concerned country. 
SAEs occurring after the completion of the clinical trial should not be routinely sought or 
recorded. However, such events should be reported to Global Safety at LEO Pharma (see 
contact details above) if the investigator becomes aware of them. 
13.4.2 LEO Pharma reporting responsibilities 
Global Safety at LEO Pharma is responsible for assessing whether or not an SAE is expected. 
The relevant reference safety information documents for this clinical trial are:  
• For brodalumab, the IB Section 7.2, edition 13.0 and subsequent updates must be 
used.  
•  For Tremfya® (guselkumab) the current SmPC in the EU must be used. 
Global Safety at LEO Pharma will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries.  
The IEC(s) will be notified of SAEs according to the current applicable legislation for the 
concerned countries.  
All SAEs which are assessed as causally related to the IMP(s) by either the investigator or 
LEO Pharma (44), and which are unexpected (Suspected, Unexpected Serious Adverse 
Reactions [SUSARs]), are subject to expedited reporting to regulatory authorities and IEC(s) 
according to the current applicable legislation in the concerned countries. Investigators will be 
notified of the evolving safety profile of the IMP on an ongoing basis. 
13.5 Other events that require expedited reporting 
13.5.1 Pregnancy 
Any pregnancy occurring after first exposure to IMP and until the subject has completed the 
trial must be reported to LEO Pharma within 24 hours of first knowledge using the (paper) 
pregnancy form (part I). All pregnancies must be followed up until delivery or termination 
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and final outcome must be reported on the (paper) pregnancy form (part II) within 24 hours of 
first knowledge.  
The completed pregnancy forms must be faxed or scanned and e-mailed to Global Safety at 
LEO Pharma. Contact details are given in Section 13.4.1. 
Pregnant subjects must immediately discontinue IMP permanently (Sections 10.2.1 and 10.3). 
13.5.2 Adverse events of special interest 
The following AEs of special interest (AESIs) have been defined: SIB, serious infections (i.e. 
infections meeting the criteria of being an SAE), malignancy diagnosed after randomisation 
(except basal cell carcinoma, squamous cell carcinoma of the skin, and cervical carcinoma in 
situ), and major adverse cardiac events (MACE) defined as stroke, myocardial infarction, or 
cardiovascular death. These AESIs have been defined based on the known profile of 
brodalumab, emerging potential risks in the course of drug development, as well as other risks 
observed with other immunomodulating biologics used for psoriasis. AESIs must be reported 
to LEO Pharma as described in Panel 16. 
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Panel 16: Adverse events of special interest 
AESI 
Additional data to be collected 
SIB 
Any SIB event must be reported to LEO Pharma Global Safety 
(Section 13.4.1) on a specific SIB AE form within 24 hours of first 
knowledge, no matter whether the event is considered serious or non-
serious. 
For SIB events, the specific SIB AE form replaces the standard LEO 
Pharma SAE form. 
Serious infections 
Any serious infection must be reported to LEO Pharma Global Safety 
(Section 13.4.1) on the standard LEO Pharma SAE form within 24 hours 
of first knowledge. 
MACE 
Any MACE must be reported to LEO Pharma Global Safety 
(Section 13.4.1) on the standard LEO Pharma SAE form within 24 hours 
of first knowledge. 
Malignancy diagnosed 
after randomisation 
(except basal cell 
carcinoma, squamous 
cell carcinoma of the 
skin, and cervical 
carcinoma in situ) 
Any malignancy events that meet the criteria of being serious must be 
reported to LEO Pharma Global Safety (Section 13.4.1) on the standard 
LEO Pharma SAE form within 24 hours of first knowledge. The 
following should be included, if available: 
• 
Histology report. 
• 
Oncology assessment. 
• 
Treatment (surgery, radiation, chemotherapy, other). 
If a malignancy event does not meet the criteria of being serious, it should 
only be reported on the AE form in the eCRF as described in Section 13.3 
and reporting within 24 hours is not required. 
Abbreviations: AE = adverse event; eCRF = electronic case report form; MACE = major adverse cardiac 
events; SAE = serious adverse event; SIB = suicidal ideation and behaviour. 
13.6 Reporting of other events 
13.6.1 Overdose 
An overdose is defined as a subject receiving a quantity of IMP which is in excess of that 
specified in this protocol. An overdose is either accidental or intentional. An accidental 
overdose must be documented in the eCRF as a medication error as described in 
Section 13.6.2. An intentional overdose should be documented as misuse or abuse (see 
Sections 13.6.3 and 13.6.4). 
If the overdose is accidental and due to a device deficiency, the device deficiency must be 
reported as a product complaint as described in Section 9.10. 
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LEO Pharma does not recommend specific treatment for an overdose. The investigator will 
use clinical judgement to treat any overdose if necessary. 
13.6.2 Medication error 
Medication error refers to any unintentional error in the dispensing or administration of an 
IMP while in the control of the investigator or subject. Broadly, medication errors fall into 
3 categories: wrong medication, wrong dose (including overdose, form, concentration, 
amount), wrong route of administration. 
The medication error category must be documented on the other event form in the eCRF. In 
addition, AEs originating from a medication error must be recorded on the AE form as 
separate events. If the AE originating from the medication error qualifies as an SAE, 
expedited reporting is required (Section 13.4). 
If the medication error is due to a device deficiency, the device deficiency must be reported as 
a product complaint as described in Section 9.10. 
13.6.3 Misuse 
Misuse refers to situations where the IMP is intentionally and inappropriately used not in 
accordance with the protocol. 
The term ‘misuse’ must be recorded on the other event form in the eCRF. In addition, AEs 
originating from misuse must be recorded on AE form as separate events. If the AE 
originating from misuse qualifies as an SAE, expedited reporting is required (Section 13.4). 
13.6.4 Abuse 
Abuse relates to the sporadic or persistent, intentional excessive use of an IMP which is 
accompanied by harmful physical or psychological effects. 
The term ‘abuse’ must be recorded on the other event form in the eCRF. In addition, AEs 
originating from abuse must be recorded on the AE form as separate events. If the AE 
originating from abuse qualifies as an SAE, expedited reporting is required (Section 13.4). 
13.6.5 Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s) 
(including the trial disease), compared to screening, must be reported as an (S)AE in 
accordance with Sections 13.3 and 13.4.  
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In case the aggravation/exacerbation/worsening of the trial disease leads to permanent 
discontinuation of IMP or withdrawal from the trial, ‘lack of efficacy’ should be chosen as the 
primary reason for discontinuation of IMP / withdrawal from the trial in accordance with 
Section 10.2.1 and Section 11.6.2. 
13.7 Follow-up for final outcome of adverse events 
During the trial, the investigator should follow up for final outcome on all AEs (including 
SAEs). SAEs must be followed up until a final outcome has been established, that is, the 
follow up may continue beyond the end of the clinical trial. For SAEs which have stabilised 
and cannot be expected to recover during the trial, for example chronic or stabilised 
conditions, ‘not recovered’ is accepted as a final outcome. In addition, a statement that the 
SAE has stabilised or is chronic should be added to the narrative description of the SAE on 
the SAE form.  
13.8 Handling of an urgent safety measure 
An urgent safety measure is a measure taken to implement an action/protocol deviation under 
an emergency. This is defined as “…the occurrence of any new event relating to the conduct 
of the trial or the development of the investigational medicinal product where that new event 
is likely to affect the safety of the subjects, the sponsor and the investigator shall take 
appropriate urgent safety measures to protect the subjects against any immediate 
hazard.” (45). 
If the investigator becomes aware of information that requires an immediate change in a 
clinical trial procedure or a temporary halt of the clinical trial to protect clinical trial subjects 
from any immediate hazard to their health and safety, the investigator can do so without prior 
approval from LEO Pharma, regulatory authorities, or IECs. 
The investigator must immediately inform LEO Pharma – by contacting the clinical project 
manager or medical expert – of this change in a clinical trial procedure or of the temporary 
halt; the investigator will provide full details of the information and the decision-making 
process leading to the implementation of the urgent safety measure. 
LEO Pharma must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation. 
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14 Statistical methods 
14.1 Sample size 
The primary and key secondary endpoints for this trial are having PASI 100 response at 
Week 16 and the time from randomisation to PASI 100 response. Denoting the Week 16 
response rates by π and the sub-distribution hazard rates for having PASI 100 response at time 
t, measured in weeks, by 𝜆(𝑡), the null hypothesis for the primary endpoint, 
H0: πbroda – πgus ≤ 0, 
will be tested versus the 1-sided alternative, 
H1: πbroda – πgus > 0, 
  
while, for the key secondary endpoint, the null hypothesis, 
H0:λbroda(t)=λgus(t), 
will be tested versus the alternative, 
H1: λbroda(t)≠λgus(t). 
 
Panel 17 provides the estimated PASI 100 response rates based on an assessment of the 
124 subjects initially randomised to ustekinumab in the AMAGINE-2 and -3 trials, who 
received brodalumab 210 mg Q2W as rescue therapy starting at Week 16. To qualify for 
rescue medication in the AMAGINE-2 and -3 trials at Week 16, subjects must have had an 
sPGA ≥3 at Week 16 or an sPGA =2 for at least 4 weeks up to and including Week 16. In 
order to derive the estimates presented in Panel 17, missing data was imputed using 
non-responder imputation (NRI). 
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Panel 17: PASI response rates after the initiation of brodalumab 210 mg Q2W as rescue 
therapy among subjects initially randomised to ustekinumab in the 
AMAGINE-2 and -3 trials 
Week 
PASI 75 (%) 
PASI 90 (%) 
PASI 100 (%) 
# Imputed by NRI 
0 
23.4 
4.8 
0.0 
0 
2 
53.2 
19.4 
4.8 
2 
4 
67.7 
37.1 
13.7 
3 
8 
71.0 
52.4 
29.8 
1 
12 
73.4 
58.1 
35.5 
4 
16 
78.2 
61.3 
34.7 
9 
20 
79.0 
62.1 
42.7 
12 
24 
83.9 
62.9 
41.1 
11 
28 
79.8 
62.9 
41.1 
14 
32 
76.6 
63.7 
38.7 
15 
36 
71.8 
57.3 
35.5 
20 
Abbreviations: NRI = non-responder imputation; PASI = the Psoriasis Area and Severity Index; Q2W = every 2 
weeks. 
In order to power this trial, data were simulated from the two-state alternating continuous-
time Markov process displayed in Panel 18. The ‘two-state alternating model’ assumes that 
the transition intensity functions are constant over time. The benefit of the multi-state 
framework is that it naturally captures the correlation between the time from randomisation to 
PASI 100 response and the PASI 100 response status at Week 16. Estimates of the transition 
intensities for brodalumab were obtained by fitting the ‘two-state alternating model’ based on 
data from the AMAGINE-2 and -3 trials, among subjects receiving brodalumab 210 mg Q2W 
as rescue therapy after initially being randomised to ustekinumab. The model was fitted using 
the multi-state model (MSM) package in R, which accounts for the non-informative 
intermittent inspection process used to obtain the data. For guselkumab, the expected PASI 
100 response rates, based on the ‘two-state alternating model’, were derived from the 
Chapman-Kolmogorov equation, 
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πPASI100(t)=1 - [
λ10
λ10+λ01
+
λ01
λ10+λ01
e−(𝜆01+𝜆10)t] 
Panel 18: Two-state alternating model used to simulate patient-level data, in order to 
power the trial  
 
The estimated transition intensities for the guselkumab arm were then derived by minimising 
the mean squared error, based on the approximate observed rates extracted from the 
NAVIGATE trial shown in Panel 19. 
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Panel 19: Approximate PASI 100 response rates for the guselkumab arm, reported in the 
NAVIGATE trial 
Week PASI 100 (%) 
0 
0.0 
4 
3.2 
8 
7.6 
12 
11.3 
16 
18.0 
20 
23.2 
24 
21.0 
28 
22.4 
36 
20.3 
Abbreviations: PASI 100 = 100% improvement from baseline in the Psoriasis Area and Severity Index. 
Source: (4).  
Panel 20 provides the estimated marginal power for the primary and key secondary endpoints 
and the conjunctive power for rejecting the null hypotheses associated with the primary and 
key secondary endpoints, while controlling the familywise error rate (FWER) at the 
5% significance level (for 2-sided Fisher’s Exact and Gray’s tests). The power analysis is 
based on 100,000 simulations, from the alternating two-state model illustrated in Panel 18, 
assuming the underlying transition intensities for the brodalumab arm were, 
e) 𝜆broda,0,1 = 1.00 ∙𝜆̂broda,0,1 = 0.0333 and 𝜆broda,1,0 = 1.00 ∙𝜆̂broda,1,0 = 0.0272, 
l) 𝜆broda,0,1 = 0.98 ∙𝜆̂broda,0,1 = 0.0326 and 𝜆broda,1,0 = 1.02 ∙𝜆̂broda,1,0 = 0.0277 or 
u) 𝜆broda,0,1 = 1.02 ∙𝜆̂broda,0,1 = 0.0340 and 𝜆broda,1,0 = 0.98 ∙𝜆̂broda,1,0 = 0.0266, 
and assuming the underlying transition intensities for the guselkumab arm were 
e') 𝜆gus,0,1 = 1.00 ∙𝜆̂gus,0,1 = 0.0158 and 𝜆gus,1,0 = 1.00 ∙𝜆̂gus,1,0 = 0.0435, 
l') 𝜆gus,0,1 = 0.98 ∙𝜆̂gus,0,1 = 0.0155 and 𝜆gus,1,0 = 1.02 ∙𝜆̂gus,1,0 = 0.0444 or 
u') 𝜆gus,0,1 = 1.02 ∙𝜆̂gus,0,1 = 0.0162 and 𝜆gus,1,0 = 0.98 ∙𝜆̂gus,1,0 = 0.0427. 
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The scenarios described in bullet points l), u), l') and u') have been introduced for robustness 
of the resulting sample size with respect to small perturbations of the transition intensities. 
Panel 20: Estimated conjunctive power for rejecting the hypotheses associated with the 
primary and key secondary endpoints 
Sample 
size per 
arm 
Scenario for transition intensities 
Power for 
the primary 
endpoint 
Power for 
the key 
secondary 
endpoint 
Conjunctive 
power 
 
𝜆broda,0,1 𝜆broda,1,0 
 
𝜆gus,0,1 
𝜆gus,1,0 
N=110 e) 0.0333 
0.0272 
e') 0.0158 
0.0435 
83.3% 
96.8% 
82.5% 
N=110 e) 0.0333 
0.0272 
l') 
0.0155 
0.0444 
85.3% 
97.4% 
84.6% 
N=110 e) 0.0333 
0.0272 
u') 0.0162 
0.0427 
80.9% 
95.8% 
79.9% 
N=110 l) 
0.0326 
0.0277 
e') 0.0158 
0.0435 
80.7% 
95.8% 
79.7% 
N=110 l) 
0.0326 
0.0277 
l') 
0.0155 
0.0444 
82.5% 
96.4% 
81.6% 
N=110 l) 
0.0326 
0.0277 
u') 0.0162 
0.0427 
78.0% 
94.7% 
76.8% 
N=110 u) 0.0340 
0.0266 
e') 0.0158 
0.0435 
85.8% 
97.5% 
85.1% 
N=110 u) 0.0340 
0.0266 
l') 
0.0155 
0.0444 
87.5% 
98.0% 
86.9% 
N=110 u) 0.0340 
0.0266 
u') 0.0162 
0.0427 
83.8% 
96.9% 
83.0% 
N=120 e) 0.0333 
0.0272 
e') 0.0158 
0.0435 
87.0% 
97.8% 
86.4% 
N=120 e) 0.0333 
0.0272 
l') 
0.0155 
0.0444 
88.5% 
98.3% 
88.0% 
N=120 e) 0.0333 
0.0272 
u') 0.0162 
0.0427 
84.7% 
97.1% 
84.0% 
N=120 l) 
0.0326 
0.0277 
e') 0.0158 
0.0435 
84.1% 
96.9% 
83.3% 
N=120 l) 
0.0326 
0.0277 
l') 
0.0155 
0.0444 
86.0% 
97.6% 
85.3% 
N=120 l) 
0.0326 
0.0277 
u') 0.0162 
0.0427 
81.9% 
96.2% 
81.0% 
N=120 u) 0.0340 
0.0266 
e') 0.0158 
0.0435 
89.3% 
98.4% 
88.8% 
N=120 u) 0.0340 
0.0266 
l') 
0.0155 
0.0444 
90.6% 
98.7% 
90.2% 
N=120 u) 0.0340 
0.0266 
u') 0.0162 
0.0427 
87.2% 
97.9% 
86.6% 
Abbreviation: N = number of subjects. 
 
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Based on the above assumptions and results, a sample size of 240 subjects would ensure a 
conjunctive power of at least 80% in order to reject the null hypotheses for both the primary 
and key secondary endpoints for all of the illustrated scenarios.  
14.2 Trial analysis sets 
All screened subjects will be accounted for in the clinical trial report (CTR). 
All randomised subjects will be included in the intention-to-treat (ITT) analysis set and will 
be analysed based on the planned (randomised) treatment allocation. The full analysis set 
(FAS) will consist of all randomised subjects with at least 1 post-baseline PASI assessment 
and be analysed based on the planned (randomised) treatment allocation.  
A safety analysis set will be defined as all subjects who received IMP and will be analysed 
according to the actual treatment received.  
14.3 Statistical analysis 
14.3.1 General principles 
Unless otherwise stated, significance tests will be 2-sided with a significance level of 5%; CIs 
will be presented with 95% degree of confidence; efficacy analyses will be based on FAS; 
safety analyses will be based on the safety analysis set; the presentation of supplementary 
estimands will be reserved for primary and key secondary endpoints only; and least square 
(LS)-mean estimates will be based on the observed margins.  
Inference based on multiple imputation methods will consist of n=1,000 imputed datasets to 
ensure that the between-imputation variance is estimated with adequate precision. For the 
analysis of binary endpoints relying on multiple imputation methods to address missing data, 
the risk differences and log odds ratios along with the associated standard errors will be 
pooled directly based on Rubin’s rules to quantify the potential treatment benefit. For the 
analysis of multiply-imputed datasets using analysis of covariance (ANCOVA), the estimated 
regression coefficients and associated standard errors will be pooled directly using Rubin’s 
rules.  
Tabulations of data by visit will explicitly account for missing data. Categorical data will be 
summarised by treatment arm, using the number and percentage of subjects in each category. 
Continuous data will be summarised using the mean, median, standard deviation (SD), 
minimum, and maximum values.  
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Any changes from the statistical analyses planned in this clinical trial protocol will be 
described and justified in either a protocol amendment, the SAP, and/or in the CTR depending 
on the ramifications of the proposed changes. 
14.3.2 Handling of missing values and imputation 
Likelihood methods, as well as single and multiple imputation methods will be implemented 
to account for the presence of missing data and to address occurrences of intercurrent events 
by ‘hypothetical’ strategies in the statistical analysis of the primary and secondary endpoints. 
For imputation-based methods, non-monotone missing data will be imputed based on a 
Markov Chain Monte Carlo method, assuming an underlying multi-variate normal 
distribution for continuous endpoints and the fully-conditional specification method for binary 
or ordinal endpoints. For imputation-based methods, monotone missing data will be imputed 
based on a monotone regression method for continuous endpoints and a fully-conditional 
specification logistic regression method for binary or ordinal endpoints. The variables used in 
the analysis model will be included in the imputation model. Here, the categorization into 
non-monotone and monotone missing data-patterns is based on all scheduled visits. 
Multiple imputation methods that will be implemented as part of the analyses of the primary 
and key secondary endpoints include the ‘delta-adjusted’ pattern-mixture model and the 
‘retrieved-data’ pattern-mixture model. The missing data methods are designed to assess the 
robustness of the results of the primary analysis, with respect to the assumptions made 
regarding missing data. 
The ‘delta-adjusted’ pattern-mixture model provides a convenient framework for assessing the 
impact of departures from the missing at random (MAR) assumption in instances where the 
‘control-based’ pattern-mixture model is not reasonable, e.g. when comparing 2 active 
treatments. For continuous endpoints, the ‘delta-adjusted’ pattern-mixture model assumes that 
within a given treatment arm, the mean response value among subjects no longer receiving 
treatment differs from the mean response among subjects remaining on treatment by a 
specified margin, denoted by Δ. For a given treatment arm at a specific timepoint, missing 
data are imputed based on the distribution of the conditional mean fitted to the observed data 
adjusted by the specified margin, Δ. When imputing missing binary data in the context of a 
logistic regression model, Δ is interpreted as the odds ratio of responding for withdrawals vs. 
completers. Similarly, for the imputation of missing time-to-event data based on a 
proportional hazards model, Δ is interpreted as the hazard ratio comparing withdrawals vs. 
completers.  
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The ‘retrieved-data’ pattern-mixture model assumes that within a given randomised treatment 
arm, the mean response value among subjects who withdraw from the trial, is given by the 
mean response among subjects who discontinue IMP but remain in the trial. Separate 
imputation models are therefore required for the trial populations defined by the randomised 
treatment allocation, along with discontinuation status.  
Endpoint-specific considerations regarding the implementation of multiple imputation 
algorithms will be specified in the SAP. 
14.3.3 Disposition of subjects 
An overall summary of subject disposition will be presented. The disposition summary will 
include information on the number of subjects screened, randomised, exposed, included in the 
FAS, permanently discontinuing IMP, and withdrawing from the trial by treatment arm and 
overall.  
Stacked cumulative incidence plots of the time to permanent discontinuation of IMP and 
withdrawal from trial will be presented separately for the ITT analysis set by treatment arm 
and reason. 
14.3.4 Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
the ITT analysis set by treatment arm and overall.  
Demographics include age, sex, race, and ethnicity. Baseline characteristics include height, 
weight, body mass index, smoking status, alcohol use, duration of psoriasis, and previous 
psoriasis therapy including prior biologic use. In addition to the above specified baseline 
characteristics, the following baseline measures of disease severity will be presented: PASI, 
IGA, PP-PASI, PP-IGA, sPGA-G, DLQI, SF-36v2, and the baseline weekly average pruritus 
and pain as assessed by the NRS. See Section 14.3.1 for further details of the presentation of 
categorical and continuous variables.  
14.3.5 Exposure and treatment compliance 
The cumulated dose administered to each subject will be determined and summarised 
descriptively. For subjects who withdraw from the trial, are lost to follow-up, or permanently 
discontinue IMP, their cumulated dose will be calculated up until the time of 
withdrawal/permanent discontinuation of IMP/loss to follow-up. 
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Treatment compliance will be presented from data listings. Subjects not receiving the 
scheduled dose will be listed by sites, sorted by treatment group, subject number, and visit. 
Subjects being administered IMP via remote visits will be listed by sites, sorted by treatment 
group, subject number, and visit. 
14.3.6 Estimand strategy 
14.3.6.1 Overview 
For each endpoint associated with a trial objective, a primary estimand will be pre-specified. 
Additional supplementary estimands will be used to further aid in the interpretation of the 
results. 
For each estimand, pre-specified sensitivity analyses will be conducted to assess the 
robustness of the results with respect to departures from the statistical assumptions supporting 
the associated models/estimators.  
Description of intercurrent events  
An intercurrent event refers to a post-randomisation event that either precludes the existence 
of or affects the interpretation of the measurements of an endpoint. For the purposes of this 
trial, we define the following 3 intercurrent events: 
Permanent discontinuation of IMP independent of pandemic restrictions: This event 
occurs when a subject permanently discontinues IMP for reasons not related to COVID-19 
pandemic restrictions. Permanent discontinuation of IMP due to sickness with COVID-19 
(an AE) will be interpreted as permanent discontinuation of IMP independent of pandemic 
restrictions. This event can occur either at the subject’s own initiative or at the 
investigator’s or sponsor’s discretion. The timing of the event will be taken as the date of 
permanent discontinuation of IMP recorded in the eCRF.  
Permanent discontinuation of IMP due to pandemic restrictions: This event occurs 
when a subject permanently discontinues IMP for reasons related to COVID-19 pandemic 
restrictions. Permanent discontinuation of IMP due to sickness with COVID-19 (an AE) 
will not be interpreted as permanent discontinuation of IMP due to COVID-19 pandemic 
restrictions. Examples of permanent discontinuation of IMP due to pandemic restrictions 
are quarantines, travel limitations, subject being unable or unwilling to travel to site due to 
personal pandemic-related reasons, site closures, reduced availability of site staff, and 
interruptions to supply chain of IMP. The timing of the event will be taken as the date of 
permanent discontinuation of IMP recorded in the eCRF. 
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Unblinding of subject: This event occurs at the first instance of either 
a) Subject self-injecting IMP at home as part of the COVID-19 pandemic 
contingency plan (Appendix 6), or 
b) Subject becoming accidentally unblinded 
Here, a) will be assumed to have occurred at the first instance, where a remote visit 
including dispensation of IMP is performed and b) will be taken to have occurred when 
accidental unblinding of a subject is reported in a protocol deviation. The timing of the 
intercurrent event will be taken as whichever comes first of the visit date of the first 
remote visit including dispensation of IMP as recorded in the eCRF or the date of 
accidental unblinding as reported for the subject in a protocol deviation. 
Note, there is a distinction between permanent discontinuation of IMP (an intercurrent event) 
and withdrawal from trial and/or loss to follow-up. Withdrawal from trial and loss to follow-
up, which are not intercurrent events, will be addressed when specifying methods and/or 
assumptions for handling missing data. The death of a subject has not been described above as 
an intercurrent event since occurrences of this event are considered unlikely in the setting of 
this trial. Should it happen that a subject die, then analyses will handle this using the same 
strategy as described below for addressing permanent discontinuation of IMP due to pandemic 
restrictions. 
Strategies for handling intercurrent events 
The ‘hypothetical’ strategy attempts to quantify the effect of treatment, in the hypothetical 
situation, where intercurrent events do not occur.  
The ‘treatment-policy’ strategy attempts to quantify the effect of the decision to treat subjects 
with the randomised treatment, thus ignoring the occurrence of intercurrent events.  
A ‘composite’ strategy accounts for the occurrence of intercurrent events, through the 
definition of a suitable composite endpoint, whose components include the aforementioned 
intercurrent events, as well as the endpoint of interest.  
A fourth strategy, for addressing intercurrent events, is the ‘while on treatment’ strategy. This 
strategy will be implemented to handle intercurrent events for time-to-event endpoints. Under 
the ‘while on treatment’ strategy, interest lies in assessing the treatment response prior to the 
occurrence of intercurrent events. The occurrence of intercurrent events can then be accounted 
for through the formulation of a competing risks model. 
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Depending on the strategy selected, the occurrence of an intercurrent event may lead to the 
exclusion of data observed after the occurrence of the event, be ignored, be accounted for in 
the definition of a composite endpoint, or restrict the relevant observation window to the time 
prior to the occurrence of the intercurrent event. Panel 21 provides an overview of the 
estimand strategies that will be used to address occurrences of the intercurrent events 
described above. 
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Panel 21 Estimand strategies for addressing intercurrent events 
Type of 
endpoint 
Estimand 
Strategy for addressing IE 
Permanent discontinuation of IMP 
independent of pandemic restrictions 
Permanent discontinuation of IMP 
due to pandemic restrictions 
Unblinding of subject 
Binary based on 
investigator 
assessments 
Primary 
‘Composite’: 
The IE is incorporated as a component 
in a composite variable with the 
endpoint of interest 
‘Hypothetical’: 
Data collected after occurrence of the 
IE will be excluded. Resulting missing 
data will be imputed from a controlled 
multiple imputation algorithm 
‘Treatment-policy’: 
Occurrences of the IE will be ignored 
Binary based on 
subject 
assessments 
Primary 
‘Composite’: 
The IE is incorporated as a component 
in a composite variable with the 
endpoint of interest 
‘Hypothetical’: 
Data collected after occurrence of the 
IE will be excluded. Resulting missing 
data will be imputed from a controlled 
multiple imputation algorithm 
‘Hypothetical’: 
Data collected after occurrence of the 
IE will be excluded. Resulting missing 
data will be imputed from a controlled 
multiple imputation algorithm 
Binary based on 
investigator 
assessments 
First 
supplementary 
‘Treatment-policy’: 
Occurrences of the IE will be ignored 
‘Hypothetical’: 
Data collected after occurrence of the 
IE will be excluded. Resulting missing 
data will be imputed from a controlled 
multiple imputation algorithm 
‘Treatment-policy’: 
Occurrences of the IE will be ignored 
Binary based on 
investigator 
assessments 
Second 
supplementary 
‘Composite’: 
The IE is incorporated as a component 
in a composite variable with the 
endpoint of interest 
‘Hypothetical’: 
Data collected after occurrence of the 
IE will be excluded. Resulting missing 
data will be imputed from a controlled 
multiple imputation algorithm 
‘Hypothetical’: 
Data collected after occurrence of the 
IE will be excluded. Resulting missing 
data will be imputed from a controlled 
multiple imputation algorithm 
Time-to-event 
Primary 
‘While on treatment’: 
The IE is accounted for as a competing 
risk in a competing risks model 
‘Hypothetical’: 
Occurrences of the IE will lead to right 
censoring, assumed to be non-
informative, in a competing risks 
model 
‘Treatment-policy’: 
Occurrences of the IE will be ignored 
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Type of 
endpoint 
Estimand 
Strategy for addressing IE 
Permanent discontinuation of IMP 
independent of pandemic restrictions 
Permanent discontinuation of IMP 
due to pandemic restrictions 
Unblinding of subject 
Continuous 
based on 
investigator 
assessments 
Primary 
‘Treatment-policy’: 
Occurrences of the IE will be ignored 
‘Hypothetical’: 
Data collected after occurrence of the 
IE will be excluded. Resulting missing 
data will be imputed from a multiple 
imputation algorithm based on the 
assumption of MAR within treatment 
arms 
‘Treatment-policy’: 
Occurrences of the IE will be ignored 
Continuous 
based on 
subject 
assessments 
Primary 
‘Treatment-policy’: 
Occurrences of the IE will be ignored 
‘Hypothetical’: 
Data collected after occurrence of the 
IE will be excluded. Resulting missing 
data will be imputed from a multiple 
imputation algorithm based on the 
assumption of MAR within treatment 
arms 
‘Hypothetical’: 
Data collected after occurrence of the 
IE will be excluded. Resulting missing 
data will be imputed from a multiple 
imputation algorithm based on the 
assumption of MAR within treatment 
arms 
Abbreviations: IE = intercurrent event, MAR = missing at random. 
 
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As seen in Panel 21 the strategy for addressing unblinding of subjects will depend on whether 
the endpoint of interest is based on subject assessments or investigator assessments. 
Unblinding of a subject will be considered as specifically having the potential to affect the 
interpretation of PROs and associated endpoints for that subject. Primary estimands for 
endpoints based on subject assessments will use a ‘hypothetical’ strategy for addressing 
unblinding of subjects. 
It is expected that unblinding of subjects will not affect the interpretation of those endpoints 
which are based on investigator assessments, since these assessments will be performed by 
investigators/assessors that are blinded to treatment allocation. Primary estimands for 
endpoints based on investigator assessments will use the ‘treatment-policy’ strategy for 
addressing unblinding of subjects. 
14.3.6.2 Estimand strategy for binary endpoints 
Primary estimand for binary endpoints 
For ease of explanation, we consider a specific binary endpoint based on investigator 
assessments, namely the primary endpoint of the trial: 
• Having PASI 100 response at Week 16 
The primary estimand associated with this endpoint can be seen to assess the difference in the 
rate of achieving PASI 100 response at Week 16 without permanently discontinuing IMP 
regardless of subjects becoming unblinded, if permanent discontinuation of IMP due to 
pandemic restrictions would not occur.  In the following, we elaborate on the estimand 
strategy specified in Panel 21 for this estimand, specifically the strategies for addressing the 
two intercurrent events related to permanent discontinuation of IMP. 
To elaborate on the ‘composite’ strategy for addressing permanent discontinuation of IMP 
independent of pandemic restrictions, we specify the composite variable to be used for 
analysis. This variable can take the values: 
• “1” if the subject is a PASI 100 responder at Week 16 and has not permanently 
discontinued IMP independently of pandemic restrictions by Week 16. 
• “0” if the subject is a PASI 100 non-responder or has permanently discontinued IMP 
independently of pandemic restrictions prior to Week 16. 
 
We now elaborate on the ‘hypothetical’ strategy for addressing permanent discontinuation of 
IMP due to pandemic restrictions. For subjects who have permanently discontinued IMP due 
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to pandemic restrictions prior to Week 16, data collected after permanent discontinuation of 
IMP will be excluded from analysis and replaced by model-based predictions. The purpose is 
to predict what value the estimand’s variable would take if the given subject would not 
permanently discontinue IMP due to pandemic restrictions. With this purpose in mind, two 
questions naturally arise because of the ‘composite’ strategy for addressing permanent 
discontinuation of IMP independent of pandemic restrictions: 
a) Would the subject still have been on treatment at Week 16 as opposed to having 
permanently discontinued IMP independently of pandemic restrictions beforehand? 
b) If yes, would the subject have been a PASI 100 responder at Week 16? 
In practice, both of these hypothetical questions will be addressed, although in reverse order, 
by carrying out the steps in Panel 22, each of which will be elaborated on further below. The 
steps are based on the envisaged hypothetical scenario where permanent discontinuation of 
IMP due to pandemic restrictions would not occur and subjects who have experienced this 
event would respond like similar subjects who have not experienced it. In addition to 
outlining the ‘hypothetical’ strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions, Panel 22 specifies the handling of missing data in the main analysis of 
the primary estimand. 
 
 
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Panel 22 ‘Hypothetical’ strategy for addressing permanent discontinuation of IMP due 
to pandemic restrictions and handling of missing data in the main analysis of 
the primary estimand for the primary endpoint 
Step no. 
Description 
Subjects in scope for imputation 
Purpose 
1 
Impute PASI 100 
response at Week 16 
under MAR 
assumptions 
Subjects who have permanently 
discontinued IMP due to pandemic 
restrictions prior to Week 16 
‘Hypothetical’ 
strategy 
Subjects who have not permanently 
discontinued IMP prior to Week 16 and 
whose PASI score at Week 16 is missing 
Handling of 
missing data 
2 
Impute treatment 
adherence status at 
Week 16 
Subjects who have permanently 
discontinued IMP due to pandemic 
restrictions prior to Week 16 
‘Hypothetical’ 
strategy 
Abbreviations: IMP = investigational medicinal product; MAR = missing at random; PASI = Psoriasis Area and 
Severity Index. 
 
When performing Step no. 1 in Panel 22, data collected after permanent discontinuation of 
IMP will be excluded from the imputation models, regardless of the reason for treatment 
discontinuation. This is well aligned with the ‘composite’ strategy described above for 
addressing permanent discontinuation of IMP independent of pandemic restrictions, where 
data collected after permanent discontinuation of IMP is irrelevant for the value of the 
estimand’s variable. 
For subjects who prior to Week 16 have permanently discontinued IMP due to pandemic 
restrictions, the values imputed in Step no. 1 may be thought of as PASI 100 responses at 
Week 16, conditional on treatment adherence, thereby addressing the hypothetical question b) 
stated above. Similarly, Step no. 2 in Panel 22 may be thought of as addressing the 
hypothetical question a) for these subjects. 
 
 
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Impute PASI 100 response at Week 16 under MAR assumptions 
Imputation of missing binary PASI 100 data at Week 16 will be done using multiple 
imputations of the underlying PASI scores Pwithin the 2 groups defined according to 
randomised treatment arm, assuming that data is missing at random within each group. The 
following will be done for each group: 
1. In each group, intermittent missing values will be imputed based on a Markov Chain 
Monte Carlo method, assuming an underlying multi-variate normal distribution, to obtain 
1000 copies of the dataset with a monotone missing data pattern (seed=645659, unless 
otherwise specified). 
2. An ANCOVA model will be fitted to the PASI score at Week 2. This is to be done in the 
context of a proper imputation model as implemented in PROC MI using the monotone 
regression method. The model will include effects of baseline body weight (≤100 kg, 
>100 kg), prior TNF-α inhibitor use at baseline (≤1, >1), and baseline PASI score. The 
estimated parameters, and their variances, will be used to impute missing PASI scores at 
Week 2 in each of the 1000 copies of the dataset generated above (seed=246673, unless 
otherwise specified). Negative imputed values will be replaced by 0, and imputed values 
larger than 72 will be replaced by 72, thereby ensuring that imputed PASI scores are 
within the range from 0 to 72. 
3. For each of the 1000 copies of the dataset, missing PASI scores at Week 4 will be imputed 
in the same way as for Week 2. The imputations will be based on an ANCOVA model with 
effects of baseline body weight (≤100 kg, >100 kg) and prior TNF-α inhibitor use at 
baseline (≤1, >1) together with the PASI scores at baseline and Week 2. The estimated 
parameters, and their variances, will be used to impute missing values at Week 4. Again, 
negative imputed values will be replaced by 0, and imputed values larger than 72 will be 
replaced by 72. 
4. This stepwise procedure will then be repeated sequentially for Weeks 6, 8, 10, 12, 14 and 
16 with the modification that only the PASI scores from the 2 preceding visits will be 
included as covariates, in addition to the effects of baseline body weight (≤100 kg, 
>100 kg) and prior TNF-α inhibitor use at baseline (≤1, >1). The missing binary PASI 100 
response at Week 16 will be derived from the corresponding underlying imputed PASI 
score. 
If the model does not converge, variables will be dropped one by one in the following order: 
• Prior TNF-α inhibitor use at baseline. 
• Baseline body weight. 
 
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Impute treatment adherence status at Week 16 
For each treatment arm, a Cox proportional hazards regression model will be fitted for the 
hazard rate of permanent discontinuation of IMP independent of pandemic restrictions. The 
models will be stratified by baseline body weight (≤100 kg, >100 kg) and will include prior 
TNF-α inhibitor use at baseline (≤1, >1) as a factor and baseline PASI score as a continuous 
covariate. The time to permanent discontinuation of IMP independent of pandemic restrictions 
will be measured in weeks and is assumed to not depend on the observed post-baseline PASI 
scores. Occurrences of permanent discontinuation of IMP due to pandemic restrictions will in 
this context be considered as right censorings assumed to be non-informative. For subjects 
experiencing such a censoring event prior to Week 16, say at time 𝑡, the model will provide an 
estimated probability 
𝑝̂(𝑡, treatment arm, baseline body weight, prior TNF-α inhibitor use, baseline PASI score) 
of being on treatment at Week 16 conditional on being on treatment at the earlier time 𝑡 in the 
scenario, where permanent discontinuation of IMP due to pandemic restrictions would not 
occur. The conditional probability 𝑝̂ will be calculated as the estimated survival function 
evaluated at Week 16 divided by the same function evaluated at time 𝑡. 
For each subject having permanently discontinued IMP prior to Week 16 due to pandemic 
restrictions and each of the 1000 copies of the dataset, a Bernoulli trial with the subject-
specific success probability  
𝑝̂(𝑡, treatment arm, baseline body weight, prior TNF-α inhibitor use, baseline PASI score). 
will be performed (seed=221576, unless otherwise specified) with 𝑡 denoting the time of 
treatment discontinuation due to pandemic restrictions. The results of the Bernoulli trials can 
be thought of as addressing the hypothetical question a).  
The imputed value of the estimand’s variable will be derived from the PASI 100 response at 
Week 16, conditional on treatment adherence, from Step no. 1 in Panel 22 and the result of the 
Bernoulli trial described above, in accordance with the ‘composite’ strategy for addressing 
permanent discontinuation of IMP independent of pandemic restrictions. 
The elaborations above are based on the primary endpoint, but the same principles will be 
applied for the primary estimand associated with other binary endpoints based on investigator 
assessments. Note here, that the PASI scale is considered as continuous when carrying out 
Step no. 1 in Panel 22. For e.g. the binary endpoint, 
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• having IGA of 0 at Week 16 
the underlying IGA score will be considered as ordinal rather than continuous, so Step no. 1 in 
Panel 22 will instead be carried out as outlined below for such an endpoint. 
Impute ‘having IGA of 0’ response at Week 16 under MAR assumptions 
Imputation of missing binary ‘having IGA of 0’ data at Week 16 will be done using multiple 
imputations of the underlying 5-point IGA values within the 2 groups defined according to 
randomised treatment arm, assuming that data is missing at random within each group. The 
following will be done for each group: 
1. In each group, intermittent missing values will be imputed based on fully conditional 
specification logistic regression to obtain 1000 copies of the dataset with a monotone 
missing data pattern (seed=151308, unless otherwise specified). 
2. An ordinal logistic regression model assuming proportional odds will be fitted to the IGA 
value at Week 2. This is to be done in the context of a proper imputation model as 
implemented in PROC MI using the monotone logistic method with the cumulative logit 
link function. The model will include effects of baseline body weight (≤100 kg, >100 kg), 
prior TNF-α inhibitor use at baseline (≤1, >1) and baseline IGA. The estimated 
parameters, and their variances, will be used to impute missing IGA values at Week 2 in 
each of the 1000 copies of the dataset generated above (seed=404677, unless otherwise 
specified). The imputations will be done based on the predicted probabilities associated 
with each of the values on the IGA scale at Week 2. 
3. For each of the 1000 copies of the dataset, missing values at Week 4 will be imputed in 
the same way as for Week 2. The imputations will be based on a proportional odds logistic 
regression model with effects of baseline body weight (≤100 kg, >100 kg) and prior TNF-
α inhibitor use at baseline (≤1, >1) together with the IGA values at baseline and Week 2. 
The estimated parameters, and their variances, will be used to impute missing values at 
Week 4. 
4. This stepwise procedure will then be repeated sequentially for Weeks 6, 8, 10, 12, 14 and 
16 with the modification that only the IGA values from the 2 preceding visits will be 
included as covariates, in addition to the effects of baseline body weight (≤100 kg, 
>100 kg) and prior TNF-α inhibitor use at baseline (≤1, >1). The missing binary ‘having 
IGA of 0’ response at Week 16 will be derived from the corresponding underlying imputed 
IGA value.  
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The primary estimand for binary endpoints based on subject assessments can be seen to assess 
the difference in rate of achieving response without permanently discontinuing IMP, if 
permanent discontinuation of IMP due to pandemic restrictions and unblinding of subjects 
would not occur. In accordance with Panel 21, this estimand will address unblinding of 
subjects by the same ‘hypothetical’ strategy as used for addressing permanent discontinuation 
of IMP due to pandemic restrictions. This means that the above elaboration on estimand 
strategy also applies to the primary estimand for binary endpoints based on subject 
assessments with the exception that unblinding of subjects will be handled just as permanent 
discontinuation of IMP due to pandemic restrictions. 
Main analysis  
For each of the 1000 complete datasets, the treatment effect will be estimated, along with the 
associated standard error, from a logistic regression model, adjusted for baseline body weight 
(≤100 kg, >100 kg), prior TNF-α inhibitor use at baseline (≤1, >1) and the baseline value of 
the underlying response variable. Based on Rubin’s rules, a combined estimate and standard 
error for the treatment effect will be calculated and the associated 𝑡 statistic will be used for 
testing the null hypothesis that the response rate for the brodalumab arm is less than or equal 
to the rate for the guselkumab arm, against the alternative that brodalumab is superior to 
guselkumab. In practice, the 𝑡 test will be carried out as a two-sided test at the 5% 
significance level, where the null hypothesis will only be rejected in favour of the stated 
alternative if the treatment effect estimate is in favour of brodalumab. This corresponds to a 
one-sided test at the 2.5% significance level. 
To quantify the magnitude of the potential treatment effect, estimates of the LS-mean risk 
difference and odds ratio will be presented along with the associated 95% confidence intervals 
(CIs), based on combining estimates and associated standard errors from the 1000 analyses 
using Rubin’s rules.  
Sensitivity analyses 
The following sensitivity analyses will be conducted based on the logistic regression model 
specified for the main analysis.  
• Sensitivity analysis 1 
These sensitivity analyses will assess the robustness of the results of the main analysis 
with respect to the MAR assumption. For subjects experiencing intercurrent events to 
be addressed by ‘composite’ or ‘hypothetical’ strategies cf. Panel 21, the data observed 
after the occurrence of such events will be excluded from the imputation models for 
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the following sensitivity analyses. Missing data will be imputed in separate sensitivity 
analyses based on each of the following imputation algorithms:  
o NRI. 
o ‘Delta-adjusted’ pattern-mixture model. 
Missing data arising after the occurrence of intercurrent events to be addressed by 
‘composite’ or ‘hypothetical’ strategies cf. Panel 21 will not be imputed by the 
algorithms mentioned above, as the value of the estimand’s variable will be 
determined by the strategy for addressing the intercurrent event.  
• Sensitivity analysis 2 
This sensitivity analysis will assess the robustness of the results of the main analysis 
with respect to the assumption that the effect of treatment does not depend on baseline 
body weight or prior TNF-α inhibitor use at baseline. To carry out this sensitivity 
analysis, an interaction term between baseline body weight (≤100 kg, >100 kg) and 
treatment arm, as well as an interaction term between prior TNF-α inhibitor use at 
baseline (≤1, >1) and treatment arm, will be included in the logistic regression model 
described in the main analysis. Backward elimination of the interaction terms will be 
used. The least significant interaction term that is not significant at the 5% 
significance level will be removed. Once an interaction term is removed from the 
model, it remains excluded. The process is repeated until all interaction terms in the 
model, if any, are significant at the 5% level. If the full model does not converge, the 
two separate models obtained by removing one of the interactions terms and keeping 
the other will be fitted. 
• Sensitivity analysis 3 
These sensitivity analyses will assess the robustness of the results of the main analysis 
with respect to the assumption that use of prohibited medication and procedures has no 
influence on the endpoint of interest among subjects not discontinuing IMP. This will 
be done by excluding data collected after use of prohibited medication and procedures. 
Missing data resulting from such exclusions will be imputed in separate sensitivity 
analyses based on each of the following imputation algorithms:  
o NRI. 
o ‘Delta-adjusted’ pattern-mixture model. 
Missing data arising after use of prohibited medication and procedures that have 
happened after the occurrence of intercurrent events to be addressed by ‘composite’ or 
‘hypothetical’ strategies cf. Panel 21 will not be imputed by the algorithms mentioned 
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above, as the value of the estimand’s variable will be determined by the strategy for 
addressing the intercurrent event. 
For subjects using prohibited medication and procedures or experiencing intercurrent 
events to be addressed by ‘composite’ or ‘hypothetical’ strategies cf. Panel 21 the data 
observed after the occurrence of such events will be excluded from the imputation 
models. 
Supplementary analysis 
To carry out this supplementary analysis, the main analysis will be performed only using 
investigator and subject assessments performed at on-site visits.  
First supplementary estimand 
The first supplementary estimand can be seen to assess the difference in response rates 
achieved regardless of permanent discontinuation of IMP and subjects becoming unblinded, if 
permanent discontinuation of IMP due to pandemic restrictions would not occur.  
In accordance with Panel 21, permanent discontinuation of IMP independent of pandemic 
restrictions will be addressed using the ‘treatment-policy’ strategy. Specifically, permanent 
discontinuation of IMP independent of pandemic restrictions will be ignored. The same 
strategies for addressing permanent discontinuation of IMP due to pandemic restrictions and 
unblinding of subjects will be used, and missing data will be handled in the same way as for 
the main analysis of the primary estimand, with the exceptions that: 
• Data collected from subjects who have permanently discontinued IMP independently 
of pandemic restrictions prior to Week 16 will be included when performing Step 
no. 1 of the multiple imputation method. 
• Step no. 2 of the multiple imputation method will not be carried out. 
These exceptions are introduced to align with the ‘treatment policy’ strategy for addressing 
permanent discontinuation of IMP independent of pandemic restrictions, which simply 
ignores treatment discontinuations of that nature. Panel 23 summarises the procedure. 
 
 
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Panel 23 ‘Hypothetical’ strategy for addressing permanent discontinuation of IMP due 
to pandemic restrictions and handling of missing data in the main analysis of 
the first supplementary estimand for the primary endpoint 
Step no. 
Description 
Subjects in scope for imputation 
Purpose 
1 
Impute PASI 100 
response at Week 16 
under MAR 
assumptions 
Subjects who have permanently 
discontinued IMP due to pandemic 
restrictions prior to Week 16 
‘Hypothetical’ 
strategy 
Subjects who have not permanently 
discontinued IMP due to pandemic 
restrictions prior to Week 16 and whose 
PASI score at Week 16 is missing 
Handling of 
missing data 
Abbreviations: IMP = investigational medicinal product; MAR = missing at random; PASI = Psoriasis Area and 
Severity Index. 
 
Inference will be based on the logistic regression model described in the main analysis of the 
primary estimand under the same assumptions.  
Additional sensitivity analyses of this estimand will assess the robustness of the imputation 
method for subjects with missing data. Imputation methods to be used for these analyses 
include: 
• ‘Retrieved-data’ pattern-mixture model (if sufficient data exist). 
• ‘Delta-adjusted’ pattern-mixture model. 
• NRI. 
Second supplementary estimand 
The second supplementary estimand can be seen to assess the difference in the rate of 
achieving response without permanently discontinuing IMP, if permanent discontinuation of 
IMP due to pandemic restrictions and unblinding of subjects would not occur. 
The second supplementary estimand associated with the primary endpoint will use the same 
strategies for addressing intercurrent events as the primary estimand for binary endpoints 
based on subject assessments. 
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Inference will be based on the logistic regression model described in the main analysis of the 
primary estimand under the same assumptions. 
14.3.6.3 Estimand strategy for time-to-event endpoints 
Primary estimand for time-to-event endpoints 
The primary estimand for time-to-event endpoints can be seen to assess the treatment 
response prior to permanent discontinuation of IMP regardless of subjects becoming 
unblinded, if permanent discontinuation of IMP due to pandemic restrictions would not occur. 
Panel 24 describes the competing risks model mentioned in Panel 21 as part of the strategy for 
addressing the two intercurrent events related to permanent discontinuation of IMP. 
Permanent discontinuation of IMP due to pandemic restrictions will be interpreted as right 
censoring, assumed to be non-informative, in the application of this model and data collected 
after the occurrence of such a censoring event will be excluded from analysis. This is thought 
of as a ‘hypothetical’ strategy, the envisaged scenario being that permanent discontinuation of 
IMP due to pandemic restrictions would not occur and that subjects who have experienced 
this event would respond like similar subjects who have not experienced it. 
Panel 24: Competing risks model describing the primary estimand for time-to-event 
endpoints 
 
Abbreviations: IMP = investigational medicinal product. 
 
 
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Main analysis 
The null hypothesis,  
H0:𝜆𝑏𝑟𝑜𝑑𝑎(𝑡) = 𝜆𝑔𝑢𝑠(𝑡), ∀ 𝑡∈(0,28), 
where λ(𝑡) denotes the sub-distribution hazard rate associated with the time-to-event endpoint 
at time t, measured in weeks, will be tested against the alternative,  
H1:𝜆𝑏𝑟𝑜𝑑𝑎(𝑡) ≠𝜆𝑔𝑢𝑠(𝑡) 
based on Gray’s test, stratified by baseline body weight (≤100 kg, >100 kg). 
To quantify the magnitude of the potential treatment effect, the estimated cumulative 
incidence functions for the competing risks model displayed in Panel 24 will be presented for 
the groups defined by treatment arm and randomisation strata, based on the Aalen-Johansen 
estimator, along with 95% confidence bands. Additionally, the estimated sub-distributional 
hazard ratios comparing treatment arms and corresponding 95% CIs for the 2 competing risks 
based on fitting Fine and Gray models, stratified by baseline body weight (≤100 kg, >100 kg) 
and adjusted for prior TNF-α inhibitor use at baseline (≤1, >1) and the baseline PASI score 
will be presented.  
It is important to note that for endpoints that are only assessed at trial visits, e.g. PASI score, 
the above specified analysis implicitly ignores the intermittent inspection process. The time to 
achieving the endpoint, e.g. PASI 100 response, is imputed based on the trial visit where the 
response is first observed.  
Sensitivity analysis assessing the robustness with respect to the intermittent follow-up 
For a given subject in the main analysis, the time to response while remaining on treatment – 
interpreting permanent discontinuation of IMP due to pandemic restrictions as right censoring 
– is imputed using the scheduled timing of the visit where the desired response is first 
observed. In order to assess the robustness of the results of the primary analysis with respect 
to this imputation strategy, the probability of achieving a response prior to discontinuation of 
IMP independent of pandemic restrictions will be estimated based on the MSM illustrated in 
Panel 25. For this analysis, the intermittent nature of the follow-up will be taken into account 
by formulating the individual contributions to the likelihood with respect to the transition 
probability matrix, as in Kalbfleisch and Lawless, 1985 (46). The estimated state occupation 
probabilities and expected duration of time spent in the response state will also be estimated. 
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Panel 25: Multi-state model for the sensitivity analysis accounting for the intermittent 
nature of the observation process 
 
Abbreviations: IMP = investigational medicinal product. 
 
Proportional transition intensity regression models, assuming the baseline transition 
intensities are piecewise constant, will also be fit to the MSM in Panel 25. The models will 
adjust for baseline PASI score, prior TNF-α inhibitor use at baseline (≤1, >1), and baseline 
body weight (≤100 kg, >100 kg) to quantify the magnitude of the potential treatment effect, 
while accounting for the intermittent nature of the inspection process.  
Sensitivity analysis with respect to the assumption of non-informative censoring 
In addition to ignoring the intermittent nature of the observation process, the primary analysis 
assumes non-informative censoring, i.e. the censoring and event processes are independent. In 
order to assess the sensitivity of the results of the primary analysis with respect to the 
assumption of non-informative censoring, the piecewise constant proportional hazards 
‘delta-adjusted’ pattern-mixture model of Lipkovich et al., 2016 (47), will be generalised to 
the competing risks setting in order to impute censored event times, for causes other than 
administrative censoring.  
Details regarding the formulation, specification, and estimation for the models that will be fit 
as a part of the sensitivity analyses will be provided in the SAP.  
Supplementary analysis 
Proportional hazard regression models will be fit for the cause-specific hazard rates of 
achieving a PASI 100 response and permanent discontinuation of IMP independent of 
pandemic restrictions. The models will be stratified by body weight (≤100 kg, >100 kg) and 
will include prior TNF-α inhibitor use at baseline (≤1, >1) and baseline PASI score as 
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covariates. The estimated cause-specific hazard ratios comparing treatment arms will be 
presented along with 95% CIs. 
14.3.6.4 Estimand strategy for continuous endpoints 
Primary estimand for continuous endpoints 
For ease of explanation, we consider a specific continuous endpoint based on investigator 
assessments: 
• Absolute PASI at Week 16 
The primary estimand associated with this endpoint can be seen to assess the LS-mean 
difference in absolute PASI at Week 16 regardless of permanent discontinuation of IMP and 
subjects becoming unblinded, if permanent discontinuation of IMP due to pandemic 
restrictions would not occur. In the following, we elaborate on the estimand strategy specified 
in Panel 21 for this estimand, specifically the ‘hypothetical’ strategy for addressing permanent 
discontinuation of IMP due to pandemic restrictions. 
The hypothetical scenario envisaged is that permanent discontinuation of IMP due to 
pandemic restrictions would not occur and that subjects who have experienced this event 
would respond like similar subjects who have not experienced it. Data collected after 
permanent discontinuation of IMP due to pandemic restrictions will be excluded. The 
‘hypothetical’ strategy and the handling of missing data in the main analysis are outlined in 
Panel 26. 
 
 
 
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Panel 26 ‘Hypothetical’ strategy for addressing permanent discontinuation of IMP due 
to pandemic restrictions and handling of missing data in the main analysis of 
the primary estimand for ‘Absolute PASI at Week 16’ 
Step no. 
Description 
Subjects in scope for imputation 
Purpose 
1 
Impute PASI 
score at Week 
16 under MAR 
assumptions 
Subjects who have permanently 
discontinued IMP due to pandemic 
restrictions prior to Week 16 
‘Hypothetical’ 
strategy 
Subjects who have not permanently 
discontinued IMP due to pandemic 
restrictions prior to Week 16 and whose 
score at Week 16 is missing 
Handling of 
missing data 
Abbreviations: IMP = investigational medicinal product; MAR = missing at random; PASI = Psoriasis Area and 
Severity Index. 
 
The imputation of PASI scores at Week 16 will be carried out as specified for the primary 
estimand for the primary endpoint. The elaborations above are based on the endpoint 
‘Absolute PASI at Week 16’, but the same principles will be applied for the primary estimand 
associated with other continuous endpoints based on investigator assessments. 
The primary estimand for continuous endpoints based on subject assessments can be seen to 
assess the LS-mean difference in the continuous endpoint regardless of permanent 
discontinuation of IMP, if permanent discontinuation of IMP due to pandemic restrictions and 
unblinding of subjects would not occur. In accordance with Panel 21, this estimand will 
address unblinding of subjects by the same ‘hypothetical’ strategy as used for addressing 
permanent discontinuation of IMP due to pandemic restrictions. This means that the above 
elaboration on estimand strategy also applies to the primary estimand for continuous 
endpoints based on subject assessments with the exception that unblinding of subjects will be 
handled just as permanent discontinuation of IMP due to pandemic restrictions. 
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Main analysis 
Each of the 1000 imputed datasets will be analysed based on an ANCOVA model, including 
baseline body weight (≤100 kg and >100 kg), prior TNF-α inhibitor use at baseline (≤1, >1) 
and treatment arm as factors and adjusting for the baseline value of the endpoint as a 
covariate. The pooled estimate of the difference in the LS-mean between the brodalumab and 
guselkumab arms, along with the associated 95% CIs and nominal p-values, will be presented 
based on applying Rubin’s rules to the estimates and standard errors from the aforementioned 
ANCOVA analysis of the imputed datasets.  
Sensitivity analyses  
Rather than assuming missing data are MAR, the sensitivity analyses will impute missing data 
based on the following algorithms: 
• ‘Delta-adjusted’ pattern-mixture model. 
• ‘Retrieved-data’ pattern-mixture model (if sufficient data exist). 
Missing data arising after the occurrence of intercurrent events to be addressed by a 
‘hypothetical’ strategy cf. Panel 21 will not be imputed by the algorithms mentioned above, as 
the value of the estimand’s variable will be determined by the strategy for addressing the 
intercurrent event. 
14.3.7 Analysis of efficacy endpoints 
Panel 27 provides an overview of the statistical analysis of the primary, key secondary, 
secondary, and exploratory efficacy endpoints. As stated in Section 14.3.1, the analysis of 
efficacy endpoints will be based on the FAS. 
 
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Panel 27: Overview of the statistical analysis of efficacy endpoints 
Endpoint 
Type of 
endpoint 
Primary estimand 
Primary endpoint 
PASI 100 response at Week 16 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Key secondary endpoint(s) 
Time to PASI 100 response 
TTE 
Primary estimand for TTE endpoints 
Secondary and exploratory endpoints 
Time to PASI 90 response 
TTE 
Primary estimand for TTE endpoints 
Having PASI 100 response at Week 4 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having PASI 100 response at Week 8 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having PASI 100 response at Week 28 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having PASI 90 response at Week 4 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having PASI 90 response at Week 8 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having PASI 90 response at Week 16 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having PASI 90 response at Week 28 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having IGA of 0 at Week 16 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Having IGA of 0 at Week 28 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Having IGA of 0 or 1 at Week 16 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Having IGA of 0 or 1 at Week 28 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Having DLQI total score of 0 or 1 at Week 4 
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Having DLQI total score of 0 or 1 at Week 8 
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Having DLQI total score of 0 or 1 at Week 12 
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Having DLQI total score of 0 or 1 at Week 16 
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Having DLQI total score of 0 or 1 at Week 20 
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Having DLQI total score of 0 or 1 at Week 24 
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Having DLQI total score of 0 or 1 at Week 28 
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Having IGA of 0 or 1 and at least a 2-grade 
improvement from baseline at Week 16 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
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Endpoint 
Type of 
endpoint 
Primary estimand 
Having IGA of 0 or 1 and at least a 2-grade 
improvement from baseline at Week 28 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Change in SF-36v2 from baseline at Week 4  
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Change in SF-36v2 from baseline at Week 8 
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Change in SF-36v2 from baseline at Week 16  
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Change in SF-36v2 from baseline at Week 28 
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Change from baseline in the weekly average 
pruritus NRS at Week 4 
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Change from baseline in the weekly average 
pruritus NRS at Week 8 
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Change from baseline in the weekly average 
pruritus NRS at Week 16 
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Change from baseline in the weekly average 
pruritus NRS at Week 28 
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Improvement of at least 4 units in the weekly 
average pruritus NRS at Week 4  
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Improvement of at least 4 units in the weekly 
average pruritus NRS at Week 8  
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Improvement of at least 4 units in the weekly 
average pruritus NRS at Week 16  
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Improvement of at least 4 units in the weekly 
average pruritus NRS at Week 28  
Binary 
Primary estimand for binary endpoints based 
on continuous subject assessments 
Change from baseline in weekly average pain 
NRS at Week 4 
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Change from baseline in weekly average pain 
NRS at Week 8 
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Change from baseline in weekly average pain 
NRS at Week 16 
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Change from baseline in weekly average pain 
NRS at Week 28 
Continuous 
Primary estimand for continuous endpoints 
based on subject assessments 
Having absolute PASI ≤1 at Week 4 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≤1 at Week 8 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≤1 at Week 16 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≤1 at Week 28 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≤2 at Week 4 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≤2 at Week 8 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≤2 at Week 16 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
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Endpoint 
Type of 
endpoint 
Primary estimand 
Having absolute PASI ≤2 at Week 28 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≥3 at Week 4 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≥3 at Week 8 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≥3 at Week 16 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≥3 at Week 28 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≥5 at Week 4 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≥5 at Week 8 
Binary 
Primary estimand for binary endpoints based 
in continuous investigator assessments 
Having absolute PASI ≥5 at Week 16 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having absolute PASI ≥5 at Week 28 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Absolute PASI at Week 4 
Continuous 
Primary estimand for continuous endpoints 
based on investigator assessments 
Absolute PASI at Week 8 
Continuous 
Primary estimand for continuous endpoints 
based on investigator assessments 
Absolute PASI at Week 16 
Continuous 
Primary estimand for continuous endpoints 
based on investigator assessments 
Absolute PASI at Week 28 
Continuous 
Primary estimand for continuous endpoints 
based on investigator assessments 
Having PP-PASI 100 response at Week 4 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having PP-PASI 100 response at Week 8 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having PP-PASI 100 response at Week 16 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having PP-PASI 100 response at Week 28 
Binary 
Primary estimand for binary endpoints based 
on continuous investigator assessments 
Having PP-IGA 0/1 at Week 4 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Having PP-IGA 0/1 at Week 8 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Having PP-IGA 0/1 at Week 16 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Having PP-IGA 0/1 at Week 28 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Having sPGA-G 0/1 response at Week 4 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Having sPGA-G 0/1 response at Week 8 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Having sPGA-G 0/1 response at Week 16 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
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Endpoint 
Type of 
endpoint 
Primary estimand 
Having sPGA-G 0/1 response at Week 28 
Binary 
Primary estimand for binary endpoints based 
on ordinal investigator assessments 
Abbreviations: DLQI = Dermatology Life Quality Index; IGA = Investigator’s Global Assessment; 
NRS = numeric rating scale; PASI = Psoriasis Area and Severity Index; PASI 100 = 100% improvement in 
PASI score; PASI 90 = 90% improvement in PASI score; PP-PASI = palmoplantar PASI; PP-
IGA = palmoplantar IGA; SF-36v2 = 36-Item Short Form Health Survey version 2; sPGA-G = static 
Physician’s Global Assessment of genitalia; TTE = time-to-event. 
 
14.3.8 Testing strategy 
To control the FWER of the analysis of the pre-specified primary and key secondary 
endpoints, the hierarchical testing procedure illustrated in Panel 28 has been defined. The test 
of the null hypotheses will be based on the pre-specified main analysis of the primary 
estimands. The initial weight allocated to each hypothesis test is specified in Panel 28. 
Initially, 100% of the weight is allocated to the hypothesis test of the primary endpoint. If the 
null hypothesis associated with the primary endpoint is rejected, the key secondary endpoint 
will be assessed. 
Panel 28: Hierarchical testing procedure to control the FWER for the pre-specified 
primary and key secondary endpoints 
 
Abbreviations: FWER = familywise error rate; PASI = Psoriasis Area and Severity Index; TTPASI100 = time to 
PASI 100. 
 
14.3.9 Analysis of safety 
The analysis of safety will be based on the safety analysis set. 
14.3.9.1 Adverse events 
AEs will be coded during the course of the trial according to Medical Dictionary for 
Regulatory Activities (MedDRA). AEs will be presented by preferred term and primary 
system organ class (SOC). 
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For AEs, missing values will be treated as missing, except for causality, intensity, seriousness, 
and outcome of AEs. A worst-case approach will be used: if causality is missing, the AE will 
be regarded as related to the IMP; if the intensity of an AE is missing, the AE will be regarded 
as severe; if seriousness is missing, the AE will be regarded as serious; if onset date is 
missing, it will be assumed to be the first day of administration of IMP; if outcome is missing, 
and no date of outcome is present, the outcome is regarded as ‘not recovered’. 
Treatment-emergent AEs will be summarised; however, all AEs recorded during the course of 
the trial will be included in subject data listings. An event will be considered treatment-
emergent if the onset occurred after the first administration of IMP or if the event started prior 
to the first administration of IMP and worsened in severity after the first administration of 
IMP. The tabulations described in the following will only include the treatment-emergent 
events reported prior to or at the Week 28 visit. In each of the tabulations, AEs are defined by 
MedDRA preferred terms within primary SOC. Tabulations of treatment-emergent AEs will 
be presented for the following 2 scenarios: 
• ‘While exposed to IMP’, defined as AEs occurring within 5 half-lives after the most 
recent date of IMP administration.  
• ‘While in trial’, defined as all AEs observed during the duration of the trial.  
An overall summary of the number and percentage of subjects reporting the event, along with 
the number of events and the event rate per 100 subject-years for any treatment-emergent 
AEs, deaths, SAEs, AEs leading to permanent discontinuation of IMP or withdrawal from 
trial, treatment-related AEs, and severe AEs will be presented.  
The severity for each type of AE will be tabulated by treatment arm.  
The causal relationship to IMP for each type of AE will be tabulated by treatment arm. 
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to IMP as ‘not related’. The number of events, subjects and the event rate per 
100 subject-years for each type of related AE will be tabulated and presented.  
SAEs will be evaluated separately and a narrative for each will be given. AEs leading to 
withdrawal from trial or permanent discontinuation of IMP will be tabulated and listed. 
14.3.9.2 Adverse events of special interest 
The AESIs for the trial are classified as important identified and important potential risks 
(Section 13.5.2). The AESI will be tabulated and listed by treatment arm according to the 
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safety analysis set for the ‘while exposed to IMP’ and ‘while on trial’ scenarios. The search 
criteria for AESIs will be specified in the SAP.  
14.3.9.3 Vital signs  
The change in vital signs (resting blood pressure, pulse, and body temperature) from baseline 
will be summarised by visit and treatment arm as mean, SD, median, minimum, and 
maximum values for the safety analysis set. 
14.3.9.4  Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline will be summarised by visit 
and treatment arm as mean, SD, median, minimum, and maximum values for the safety 
analysis set. 
Laboratory parameters will be classified as ‘low’, ‘normal’, or ‘high’, depending on whether 
the value is below, within, or above the reference range, respectively. A shift table will be 
produced showing the categories at baseline against those at the end of treatment. Subjects 
with laboratory parameters outside the reference range will be listed. Reference ranges will be 
listed in the SAP. 
14.3.9.5  Columbia-Suicide Severity Rating Scale  
The most severe C-SSRS response observed for each subject over the relevant time periods 
will be summarised by the number and percentage of subjects, as well as by treatment arm 
based on the safety analysis set. This includes the time periods ‘while exposed to IMP’, ‘while 
in trial’, ‘while exposed to IMP and blinded’, and ‘while in trial and blinded’. The severity of 
the response will be ranked in the following order, from least to most severe: 
1. Wish to be dead. 
2. Non-specific active suicidal thoughts. 
3. Active suicidal ideation with any methods (not plan) without intent to act. 
4. Active suicidal ideation with some intent to act, without specific plan. 
5. Active suicidal ideation with specific plan and intent. 
6. Preparatory acts or behaviour. 
7. Aborted attempt. 
8. Interrupted attempt. 
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9. Actual attempt (non-fatal). 
10. Completed suicide. 
Additionally, the number and percentage of subjects reporting the following composite events 
will be presented by treatment arm: 
• Any suicidal ideation or behaviour during the trial.  
• Suicidal ideation with intent to act (4-5). 
• Suicidal behaviour.  
• Suicidal ideation (4-5) and suicidal behaviour.  
• Suicidal ideation (4-5) or suicidal behaviour.  
• Self-injurious behaviour without suicidal intent. 
14.3.9.6  Patient Health Questionnaire-8 
The most severe PHQ-8 total score observed for each subject over the relevant time periods 
will be summarised by the number and percentage of subjects, as well as by treatment arm for 
the safety analysis set. This includes the time periods ‘while exposed to IMP’, ‘while in trial’, 
‘while exposed to IMP and blinded’, and ‘while in trial and blinded’. The summaries will be 
based on the following categories: 
• 0-4 (none - minimal). 
• 5-9 (mild). 
• 10-14 (moderate). 
• 15-19 (moderately severe). 
• 20-24 (severe). 
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32. 
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Gupta SR, Valdecantos WC, Bagel J. Adalimumab for treatment of moderate to severe 
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AB, Van Voorhees AS, Edson-Heredia E, Gelfand JM. Palmoplantar psoriasis is 
associated with greater impairment of health-related quality of life compared with 
moderate to severe plaque psoriasis. J Am Acad Dermatol. 2014;71(4):623-632. 
 
36. 
Goldblum O, Thomason D, Yang M, Sundaram M. Validation of the physician's global 
assessment of psoriasis of the hands and/or feet as a clinical endpoint. Journal of the 
American Academy of Dermatology. 2013;68(4):AB218. 
 
37. 
Gottlieb A, Sullivan J, van Doorn M, Kubanov A, You R, Parneix A, Hugot S, 
Milutinovic M. Secukinumab shows significant efficacy in palmoplantar psoriasis: 
Results from GESTURE, a randomized controlled trial. Journal of the American 
Academy of Dermatology. 2017;76(1):70-80. 
 
38. 
Menter A, Warren RB, Langley RG, Merola JF, Kerr LN, Dennehy EB, Shrom D, 
Amato D, Okubo Y, Reich K. Efficacy of ixekizumab compared to etanercept and 
placebo in patients with moderate-to-severe plaque psoriasis and non-pustular 
palmoplantar involvement: results from three phase 3 trials (UNCOVER-1, 
UNCOVER-2 and UNCOVER-3). J Eur Acad Dermatol Venereol. 2017;31(10):1686-
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Meeuwis KA, de Hullu JA, Massuger LF, van de Kerkhof PC, van Rossum MM. 
Genital psoriasis: A systematic literature review on this hidden skin disease. Acta 
Derm Venereol. 2011;91(1):5-11. 
 
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40. 
Meeuwis KA, de Hullu JA, de Jager ME, Massuger LF, van de Kerkhof PC, van 
Rossum MM. Genital psoriasis: a questionnaire-based survey on a concealed skin 
disease in the Netherlands. J Eur Acad Dermatol Venereol. 2010;24(12):1425-1430. 
 
41. 
Ryan C, Sadlier M, De Vol E, Patel M, Lloyd AA, Day A, Lally A, Kirby B, Menter A. 
Genital psoriasis is associated with significant impairment in quality of life and sexual 
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42. 
Meeuwis KA, van de Kerkhof PC, Massuger LF, de Hullu JA, van Rossum MM. 
Patients' experience of psoriasis in the genital area. Dermatology. 2012;224(3):271-
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43. 
Ryan C, Menter A, Guenther L, Blauvelt A, Bissonnette R, Meeuwis K, Sullivan J, 
Cather JC, Yosipovitch G, Gottlieb AB, et al. Efficacy and safety of ixekizumab in a 
randomized, double-blinded, placebo-controlled phase IIIb study of patients with 
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European Parliament Union, European CoT. Directive 2001/20/EC of the European 
Parlament and of the Council of 4 April 2001 on the approximation of the laws, 
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Lipkovich L, Ratitch B, O'Kelly M. Sensitivity to censored-at-random assumption in 
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48. 
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Pharmaceuticals for Human Use: Clinical Safety Data Management. Definitions and 
Standards for Expected Reporting (E2A), Step 4; 27-Oct. 1994. 
 
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49. 
WMA. World Medical Association. Declaration of Helsinki – ethical principles for 
medical research involving human subjects. Amended by the 64th WMA General 
Assembly, Fortaleza, Brazil. 2013. 
 
50. 
CIOMS. International Ethical Guidelines for Health-related Research Involving 
Humans. Council for International Organizations of Medical Sciences. 4th. Geneva. 
2016. 
 
 
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Appendix 1: Definitions of adverse events and serious adverse events 
Adverse event definition 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily 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 (investigational) product, whether or not related to the medicinal 
(investigational) product. (48) 
This definition includes: 
• Accidental injuries. 
• Events related to trial procedures. 
• Reasons for any unfavourable and unplanned change in medication (drug 
and/or dose). 
• Clinically significant worsening of pre-existing conditions. 
• Reasons for admission to hospital or surgical procedures unless these were 
planned before the subject consented to trial participation. 
• AEs commonly observed and anticipated based on the pharmacological effect 
of the IMP.  
• Any laboratory abnormality assessed as clinically significant by the 
investigator (see Section 11.4.4.2). 
Serious adverse event definition 
An SAE is any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening – at risk of death at the time of the SAE (not an event that 
hypothetically might have caused death if more severe). 
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• Requires inpatient hospitalisation or prolongation of existing hospitalisation. 
Planned hospitalisation or planned prolonged hospitalisation do not fulfil the 
criteria for being an SAE but should be documented in the subject’s medical 
record. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is a medically important condition. Events that may not be immediately 
life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require intervention to prevent one of the other outcomes listed 
in the definition above. Examples are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias, and convulsions 
that do not result in hospitalisation, development of drug dependency, or drug 
abuse. 
AESIs are described in Section 13.5.2. 
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Appendix 2: Classification of adverse events 
Severity 
The severity of the AE should be described in terms of mild, moderate, or severe according to 
the investigator’s clinical judgement.  
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
If the severity of an AE worsens, a new AE should be recorded. 
Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probably, 
possibly, or not related according to the investigator’s clinical judgement.  
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
 
Could not be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
 
Follows a known pattern of response to the IMP. 
 
Disappears or decreases on cessation or reduction in dose of the IMP. 
 
Reappears or worsens upon re-challenge. 
Possibly 
related 
 
Follows a reasonable temporal sequence from the administration of the 
IMP. 
 
Could also be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
 
Follows a known pattern of response to the IMP. 
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Not related 
 
Does not follow a reasonable temporal sequence from administration of the 
IMP. 
 
Is better explained by other factors like the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
 
Does not reappear or worsen upon re-challenge. 
 
Does not follow a known pattern of response to the IMP. 
 
Outcome 
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below. 
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing.  
Recovered/  
resolved with 
sequelae 
The event has reached a state where no further changes are expected and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
 
The stop date of the event must be recorded. In case of a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
 
LEO Pharma definitions versus CDISC definitions 
Note that as per the above definition, LEO Pharma uses “recovered/resolved” only if an event 
has actually stopped. According to the Clinical Data Interchange Standards Consortium 
(CDISC) definition, the category “recovered/resolved” also includes events which have 
improved. However, following the LEO Pharma definitions above, such an improved event 
will instead be classified as “not recovered/not resolved” or “recovering/resolving”. 
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Similarly, it should be noted that as per the above definition, LEO Pharma uses 
“recovered/resolved with sequelae” only if an event has reached a state where the residual 
symptoms are assumed to persist. According to CDISC, an event is considered “with 
sequelae”, if it has “retained pathological conditions”. Consequently, it is likely that some of 
the events classified by LEO Pharma with the outcome “recovered/resolved with sequelae” 
could have been classified with the outcome “recovered/resolved” according to the CDISC 
definition. 
In summary, the definitions used by LEO Pharma are more conservative than those used by 
CDISC. 
Serious adverse events 
For SAEs which have stabilised and from which the subject cannot be expected to recover 
during the trial or the safety follow-up periods, for example chronic illnesses, the final 
outcome should be reported as ‘not recovered’; in addition, a statement that the SAE has 
stabilised or is chronic should be added to the narrative description of the SAE on the SAE 
form.  
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Appendix 3: Trial governance considerations 
Appendix 3A: Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including 
the current version of the Declaration of Helsinki (49) and Council for 
International Organizations of Medical Sciences (CIOMS) International 
Ethical Guidelines (50). 
• Current version of applicable ICH GCP Guidelines (44). 
• EU General Data Protection Regulation 2016/679 of 27 April 2016. 
• Applicable laws and regulations. 
The appropriate regulatory authorities must be notified of/approve the clinical trial as 
required. 
Any documents that the IEC may need to fulfil its responsibilities (such as the trial protocol, 
protocol amendments, IB, subject information sheet and ICF, or advertisements) will be 
submitted to the IEC. These documents must be reviewed and approved by the IEC before the 
trial is initiated. 
Any amendments to the protocol must be approved by/receive favourable opinion from 
relevant regulatory authorities and IECs, as required, prior to implementation. 
The principal investigator will be responsible for the following, if required by local 
legislation: 
• Providing written summaries of the status of the trial to the IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IEC. 
• Notifying the local IEC of SAEs or other significant safety findings as required 
by IEC procedures. 
• Providing oversight of the conduct of the trial at the trial site and ensuring 
adherence to applicable national and international legislation. 
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Appendix 3B: Informed consent process  
Subjects will receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 
The subject’s signed and dated informed consent to participate in the clinical trial will be 
obtained prior to any clinical trial-related procedure being carried out in accordance with 
ICH GCP and all applicable laws and regulations. The authorised person obtaining the 
informed consent must also sign the ICF. 
Subjects will be re-consented to the most current version of the ICF(s) during their 
participation in the trial, if required.  
A copy of the ICF(s) must be provided to the subject.  
Subject card 
At screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff including the number for the investigator in case of emergency situations. The 
subject card also includes a local telephone number for the emergency unblinding CRO to be 
used if the investigator or delegated site staff cannot be reached or if unblinding in the IRT 
system cannot be performed. 
Appendix 3C: Subject and data confidentiality 
This clinical trial protocol as well as all other information, data, and results relating to this 
clinical trial and/or to the IMP is confidential information of LEO Pharma and shall not be 
used by the investigator for purposes other than this clinical trial. 
The investigator agrees that LEO Pharma may use any and all information, data, and results 
from this clinical trial in connection with the development of the IMPs and, therefore, may 
disclose and/or transfer information, data and/or results to other investigators, regulatory 
authorities, and/or commercial partners. 
Trial subjects will be assigned a unique identifier (subject ID) by LEO Pharma. Any subject’s 
records or datasets that are transferred to LEO Pharma will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred.  
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Trial subjects must be informed that their personal trial-related data will be used by LEO 
Pharma in accordance with local data protection law.  
Trial subjects must be informed and consent to that their medical records may be examined by 
clinical quality assurance auditors or other authorised personnel appointed by LEO Pharma, 
by appropriate IEC members, and by inspectors from regulatory authorities. 
Trial subjects must be informed that LEO Pharma might keep their trial-related data for as 
long as they are useful for developing treatments for the disease or other diseases and future 
research. 
Processing of personal data 
This protocol specifies the personal data on trial subjects (for example race, ethnicity, age, 
sex, health condition, medical history, test results, etc.) which shall be collected as part of the 
clinical trial and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO Pharma, and third parties acting on behalf of LEO Pharma. 
Processing of personal data on behalf of LEO Pharma requires a written agreement between 
LEO Pharma and the relevant party which covers collection, processing, and transfer of 
personal data in the clinical trial, as well as reporting obligations in the event of any data 
breach. In certain cases, an agreement on transfer of personal data may also be required. 
Investigators and LEO Pharma must ensure that collection, processing and transfer of 
personal data are in compliance with applicable legislation on data protection and privacy, 
including but not limited to the EU General Data Privacy Regulation. 
Subjects must be asked to consent to the collection, processing, and transfer of their personal 
data to EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorisations for products/services, marketing of products/services 
and other related activities. 
LEO pharma has obtained the necessary authorisations for the processing of personal data 
collected in the trial. 
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Appendix 3D: Record keeping, quality control, and data handling 
Source data at trial sites 
For all data recorded, the source document must be defined in a source document agreement 
or similar document at each trial site. There must only be 1 source defined at any time for any 
data elements. 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed and dated by medically qualified investigators. 
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 
• Subject ID. 
• The fact that the subject is participating in a clinical trial in psoriasis including 
treatment with brodalumab or guselkumab for 28 weeks. 
• Other relevant medical information. 
Trial monitoring 
During the course of the trial, CRA(s) will visit the trial site. These visits have the following 
objectives: (i) to continually verify source data to confirm that data entered into the eCRF by 
authorised site personnel are accurate, complete, and verifiable from source documents; (ii) to 
confirm that the safety and rights of subjects are being protected; and (iii) to confirm that the 
trial is being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements. 
A risk-based monitoring approach will be applied. The monitoring visit intervals will depend 
on the trial site’s recruitment rate and the compliance of the trial site with the protocol and 
ICH GCP. The level of source data verification, data checks, and visit intervals will be 
specified in the monitoring guideline.  
In addition to on-site monitoring, pre-specified trial data will undergo central monitoring as 
specified in the trial’s data review plan.  
In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, for example, medical records, laboratory 
reports, appointment books, etc. If the electronic medical record does not have a visible audit 
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trail, the investigator must provide the CRA with signed and dated printouts. In addition, 
relevant site staff should be available for discussions at monitoring visits and between 
monitoring visits (e.g. by telephone). 
Protocol compliance 
Protocol deviations will be documented and notified to the investigator. Protocol deviations 
will be assessed by LEO Pharma and major deviations described in the CTR. 
Sponsor audits, IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO Pharma or inspections from 
domestic or foreign regulatory authorities or from IECs. Audits and inspections may take 
place during or after the trial. The investigator and the site staff as well as LEO Pharma staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving 
auditors and inspectors direct access to all source documents and other documents at the trial 
site relevant to the clinical trial. This includes permission to examine, verify, and reproduce 
any records and reports that are important to the evaluation of the trial. 
If the trial site is contacted for an inspection by competent authorities, LEO Pharma must be 
notified immediately. 
Data handling 
Data will be collected by means of electronic data capture unless transmitted electronically to 
LEO Pharma or designee (e.g., laboratory data). The investigator or staff authorised by the 
investigator will enter subject data into the eCRF. Data recorded in the eCRF will be 
accessible to the trial site and LEO Pharma personnel immediately after entry. The eCRF must 
be maintained in an up-to-date state by the trial site at all times. 
The investigator must verify the correctness of the data entered by the site by electronically 
dating and signing all eCRF used. This signature information will be kept in the audit trail and 
cannot be altered. Any correction(s) made by the investigator or authorised site staff to the 
eCRF after original entry will be documented in the audit trail. Changes to data already 
approved will require re-signature by the investigator. The person making the change to the 
data, and the date, time, and reason for the change will be identified in the audit trail. 
Subject data should be entered into the eCRF no later than 5 working days after each visit, 
unless a different deadline is stated in the clinical trial agreement. Queries for discrepant data 
will be generated automatically by the system upon entry or manually by the CRA, sponsor’s 
medical expert, or the data manager. All queries will be raised electronically within the 
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electronic data capture system. This systematic validation will ensure that a clean and 
consistent database is provided for the statistical analysis. 
An electronic PRO (ePRO) solution will be used to capture patient-reported data (data from 
questionnaires completed at the trial site and eDiary data). By the use of an ePRO, data will 
be available immediately after data entry and available for CRAs and site personnel, including 
the investigator, with reader access only. The ePRO system is a separate application from the 
eCRF and data captured from the eCRF and the ePRO will be stored on different servers 
during data capture. Data from both systems will be included in the final trial database. 
External data transfers from vendors to LEO Pharma will be transmitted and handled via a 
secure file transfer protocol site.  
Transmissions of data are documented in more detail in a data flow plan which is part of the 
trial master file. 
Software used 
CDISC controlled terminology version 30-Mar-2018 was used for definition of controlled 
terminology used throughout this protocol and will be used for statistical programming and 
output. Standard data tabulation model (SDTM) version 3.2 will be used for data tabulations. 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file (44). Essential trial documents must be stored 
until LEO Pharma informs the investigator that the documents are no longer to be retained, or 
longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (for 
example in case of an inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
No documents may be destroyed during the retention period without the written approval of 
LEO Pharma. No documents may be transferred to another location or party without written 
acceptance from LEO Pharma. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
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For archiving purposes, each investigator will be supplied with an electronic copy of the 
eCRFs and ePRO data for all screened subjects at the trial site. This is done after completion 
of the trial and before access to the eCRF/ePRO is revoked. Audit trail information will be 
included. eCRFs and ePRO data must be available for inspection by authorised 
representatives from LEO Pharma, from regulatory authorities and/or IECs. 
Appendix 3E: Registration, reporting, and publication policy 
Trial disclosure 
LEO Pharma is committed to be transparent with respect to its clinical trials. 
Basic information of this clinical trial will be registered in the global data registry, 
www.ClinicalTrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Results of this clinical trial will be posted on the corporate website of LEO Pharma in 
accordance with our Position on Public Access to Clinical Trial Information no later than 
12 months after trial completion. Trial results may also become reported in 
www.ClinicalTrials.gov, www.clinicaltrialsregister.eu and national data registries in 
accordance with applicable law and regulations after clinical trial completion or premature 
termination.  
LEO Pharma may also provide researchers access to anonymised patient-level data for further 
research. Publication and access will be in accordance with the Position on Public Access to 
Clinical Trials which can be found on the LEO Pharma website. Moreover, LEO Pharma may 
re-use the same patient-level data for other projects within the same purpose as the trial.  
Publications 
The investigator shall be entitled to make publications of the results generated by the 
investigator in accordance with the process described here. 
A multi-site publication will be submitted for publication within 18 months after the clinical 
trial has been completed or terminated at all trial sites and all data have been received, defined 
as database lock of the clinical trial. After such multi-site publication is made public, or if no 
multi-site publication has been submitted with the above-described deadline, the investigator 
shall have the right to publish the results from the clinical trial generated by the investigator, 
subject to the following notice requirements: 
Prior to submission for publication or presenting a manuscript relating to the clinical trial, the 
investigator shall provide to LEO Pharma a copy of all such manuscripts and/or presentations. 
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LEO Pharma shall have rights to review and comment. The investigator shall consider 
comments provided by LEO Pharma but is not required to modify the manuscript and/or 
presentation based on such comments, provided, however, that the investigator upon the 
request of LEO Pharma remove any confidential information (other than results generated by 
the investigator) prior to submitting or presenting the manuscripts. The investigator shall, 
upon the request of LEO Pharma withhold the publication or presentation to allow LEO 
Pharma to protect its inventions and other intellectual property rights described in any such 
manuscripts.  
In case no multi-site publication has been made public at the time of investigator’s 
notification of an independent publication to LEO Pharma, LEO Pharma and the writing 
group may also delay the publication or presentation if the manuscript is deemed to harm the 
ongoing multi-site publication. 
In case of publications made by the investigator after the first multi-site publication has been 
published, the above-mentioned requirements must still be followed. 
Any publication must comply with Good Publication Practice (GPP3) standards. 
LEO Pharma complies with GPP3 standards and the recommendations from the International 
Committee of Medical Journal Editors. LEO Pharma complies with the positions of the 
International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), 
European Federation of Pharmaceutical Industries and Associations (EFPIA), Japan 
Pharmaceutical Manufacturers Association (JPMA), Pharmaceutical Research and 
Manufacturers of America (PhRMA), and the joint position statement by the American 
Medical Writers Association (AMWA), the European Medical Writers Association (EMWA), 
and the International Society for Medical Publication Professionals (ISMPP) on disclosure of 
information about clinical trials, trial results, and authorship. LEO Pharma also follows the 
CONSORT reporting guidelines (18). 
Appendix 3F: Insurance 
LEO Pharma has taken out relevant insurances covering the subjects in the present clinical 
trial in accordance with applicable laws and regulations. 
Appendix 3G: Financial disclosure 
Investigators will provide LEO Pharma with sufficient, accurate financial information as 
requested to allow LEO Pharma to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
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for providing information on financial interests and update this information, should any 
relevant change occur, during the course of the clinical trial and for 1 year after completion of 
the clinical trial, or for a longer period of time if required by local legislation. 
Appendix 3H: Committee structure 
No data monitoring committee or other trial committee is planned for in this trial. 
Appendix 3I: Trial and trial site closure 
Premature termination of trial or trial site 
LEO Pharma, the investigator, the IECs, or competent authorities may decide to stop the 
clinical trial, part of the trial, or a trial site at any time, but agreement on procedures to be 
followed must be obtained. 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO Pharma must promptly inform IECs and 
provide a detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
Reasons for the early closure of a trial site by LEO Pharma or investigator may include but 
are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IEC or local health authorities, LEO Pharma procedures, or GCP guidelines. 
• Inadequate recruitment of subjects by the investigator. 
Completion of trial 
Investigators will be informed when subject recruitment is to cease. Screening activities will 
be stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number. 
Trial sites will be closed upon trial completion. LEO Pharma will undertake arrangements for 
the collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
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When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 
Appendix 3J: Responsibilities 
The signatory investigator is responsible for the approval of the clinical trial protocol and 
the CTR on behalf of all clinical trial investigators and as agreed to in a signatory investigator 
agreement. 
The national coordinating investigators are responsible for national issues relating to the 
clinical trial as agreed to in a national coordinating investigator agreement. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a clinical trial agreement.  
 
 
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Appendix 4: Short version of eligibility criteria 
Inclusion criteria 
No. 
Short version 
1 
Signed and dated informed consent has been obtained prior to any protocol-related procedures. 
2 
Subject is ≥18 years of age at the time of screening. 
3 
Subject has a diagnosis of plaque psoriasis for at least 6 months before the first administration of IMP as determined by the investigator. 
4 
Subject has inadequately controlled plaque psoriasis currently treated with ustekinumab, and fulfils the criteria specified in the protocol.  
5 
Subject has no evidence of active tuberculosis according to local standard of care for patients requiring initiation of a biologic treatment.  Subjects with 
adequately treated latent tuberculosis, according to local guidelines, are eligible.  
6 
Subject has a negative serum pregnancy test during screening and a negative urine pregnancy test at baseline (for women of childbearing potential).  
7 
Subject uses a highly effective form of birth control throughout the trial and at least for 12 weeks after last administration of IMP (for women of 
childbearing potential). 
Abbreviations: IMP = investigational medicinal product; PASI = Psoriasis Area and Severity Index. 
 
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Exclusion criteria 
No. 
Short version 
1 
Subject diagnosed with erythrodermic/pustular/guttate/medication-induced psoriasis, or other skin conditions (e.g. eczema) that would interfere with 
evaluations of the effect of IMP. 
2 
Subject has a planned surgery, which in the opinion of the investigator will interfere with the planned IMP treatment. 
3 
Subject has clinically important active infections or infestations, chronic, recurrent, or latent infections or infestations, or is immunocompromised (e.g. 
HIV). 
4 
Subject has a known history of hepatitis B, hepatitis C, or HIV. Positive hepatitis B, hepatitis C, or HIV test results at screening (hepatitis B vaccinated 
subjects are eligible). 
5 
Subject has any systemic disease (e.g. renal failure, heart failure, hypertension, liver disease, diabetes, anaemia) considered by the investigator to be 
clinically significant and uncontrolled. 
6 
Subject has a known history of Crohn’s disease. 
7 
Subject had myocardial infarction, stroke, or unstable angina pectoris within the past 12 months prior to the first administration of IMP. 
8 
Subject has any active malignancy, including evidence of cutaneous basal or squamous cell carcinoma or melanoma. 
9 
Subject has a history of malignancy within 5 years, except for treated and considered cured cutaneous squamous or basal cell carcinoma, in situ cervical 
cancer, or in situ breast ductal carcinoma. 
10 
Subject has a known history of active tuberculosis. 
11 
Subject has a history of suicidal behaviour based on the C-SSRS questionnaire at screening or at baseline. 
12 
Subject has any suicidal ideation of severity 4 or 5 (‘some intent to act, no plan’ or ‘specific plan and intent’) based on the C-SSRS questionnaire at 
screening or baseline. 
13 
Subject has a PHQ-8 score of ≥10, corresponding to moderate-to-severe depression at screening or baseline. 
14 
Subject has a history of depressive disorder with severe episode(s) within the last 2 years. 
15 
Subject has any concurrent medical condition that, in the opinion of the investigator, could cause the trial to be detrimental to the subject. 
16 
Subject has laboratory abnormalities that, in the opinion of the investigator, will prevent the subject from completing the trial or interfere with the 
analysis of results. 
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17 
Subject has used potent topical steroids, topical anthralin/dithranol, topical calcipotriol, or any formulation or potency of topical therapy within 7 days 
prior to first administration of IMP. 
18 
Subject has used any of the following treatments within 4 weeks prior to first administration of IMP (Ultraviolet A therapy, ultraviolet B light therapy, 
excimer laser, oral retinoids, etc.; the full list is available in the protocol). 
19 
Subject has received any of the following biologic immunomodulating therapies prior to first administration of IMP (within 2 weeks for etanercept, 
within 4 weeks for adalimumab, etc.; the full list is available in the protocol). 
20 
Subject has previously received more than 1 TNF-α inhibitor. NOTE: This exclusion criterion is not applicable in this version of the protocol. It is kept 
to avoid re-numbering of the exclusion criteria. 
21 
Subject has previously been treated with any anti-IL-17A, anti-IL-17RA, or anti-IL-23 besides ustekinumab. 
22 
Subject received live vaccine(s) within 4 weeks of the first administration of IMP. 
23 
Subject has received treatment with any non-marketed drug substance within the 4 weeks or 5 half-lives of the substance, whichever is longer, prior to 
screening. 
24 
Subject is currently enrolled in another investigational device or drug trial or ended participation in one within 4 weeks or 5 half-lives of the IMP, 
whichever is longer, prior to screening. 
25 
Subject has known or suspected hypersensitivity to any component(s) of the IMPs. 
26 
Subjects is pregnant or lactating. 
27 
Subject has a history of chronic alcohol or drug abuse within 12 months prior to screening, or any condition associated with poor compliance as judged 
by the investigator. 
28 
Subject has previously been randomised in this clinical trial. 
29 
Subject has a language barrier, mental incapacity, unwillingness, or lack of ability to understand the trial-related procedures.  
30 
Subject is an employee of the trial site or any other individual directly involved with the planning or conduct of the trial, or immediate family member of 
such individual. 
31 
Subject is legally institutionalised.  
Abbreviations: C-SSRS = Columbia-Suicide Severity Rating Scale; HIV = human immunodeficiency virus; IL = interleukin; IMP = investigational medicinal 
product; PHQ-8 = Patient Health Questionnaire-8 TNF-α = tumour necrosis factor-α.  
 
 
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Appendix 5: Contact list 
Contact details for the clinical project manager, appointed CRA, and sponsor’s medical expert 
are provided to the trial sites as a separate contact list. 
Sponsor 
LEO Pharma A/S (referred to as ‘LEO Pharma’ or ‘the sponsor’ in this clinical trial protocol) 
is the sponsor of the clinical trial: 
LEO Pharma A/S  
Industriparken 55 
DK-2750 Ballerup 
Denmark 
 
Coordinating investigator 
Signatory investigator:  
, MD, PhD 
 
 
 
Germany 
 
 
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Appendix 6: COVID-19 pandemic contingency plan 
In case local restrictions due to a COVID-19 pandemic outbreak prevents a subject from 
attending the site, the site must contact the CRA to allow for implementation of contingency 
measures mentioned in this appendix based on mutual agreement. 
This contingency plan provides a possibility to perform minimum safety and efficacy 
assessments followed by self-injection of IMP. Assessments will be performed via the use of a 
trial-specific mobile application on the subject’s own smartphone or via the use of other video 
software used by the trial site in their normal clinical practice and in agreement with the 
sponsor and following notification of the relevant ethics committee and by completing the 
PHQ-8 questionnaire via a webpage (hereafter termed ‘video visits’). 
Both brodalumab and guselkumab are approved treatments in several countries worldwide 
and subjects may self-inject the IMPs when deemed appropriate by a health care professional. 
Therefore, no safety issues are expected regarding self-injection of IMP in this trial.  
Separate informed consent forms (A and B) are available, and intended for: 
• Conduct of trial assessments via video visits (form A). 
• Delivery of IMP to the subject and self-injection (form B). 
Consent must be obtained from the subject before the respective contingency activities are 
performed. Investigators are encouraged to inform subjects about the contingency plan and to 
obtain informed consent from the subject in advance of a potential COVID-19 outbreak. 
Delivery of IMP to a subject is possible only if the subject consents to ICF form A. If a 
subject does not consent to ICF form A, treatment with IMP must be temporarily discontinued 
until on-site visits are possible. However, trial staff should remain in contact with the subject 
via phone to ensure subject safety. Delivery of IMP to a subject may also be performed by the 
subject’s spouse or other relative or delegated person of trust who can pick up the IMP at the 
trial site and deliver to the subject. 
1. Visits 
• Screening (Week -4/-2 to 0) and baseline (Week 0) visits should be performed as 
physical on-site visits. If a site is unable to perform these visits on-site, screening and 
randomisation of new subjects at that site should be on hold until on-site visits are 
possible. 
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• Panel 29 indicates the minimum requirements for procedures that should be performed 
during a lockdown; but sites should always try to follow the procedures outlined in 
Panel 2 and Panel 3 (original schedules of trial procedures) to the extent possible.  
• All minimum assessments and procedures of a visit do not need to be performed on 
the same day but should be completed within the time window of the visit. 
• Without compromising the safety of subjects and site personnel, it is expected that all 
efforts are made to secure attendance at sites for the primary endpoint visit (Week 16) 
and the final visit (Week 28). If the visits at Week 16 and Week 28 cannot be 
performed either on-site or via a video visit within the given visit window, the visit 
window for the assessments can be extended for up to 10 days. 
Remote completion of the PHQ-8 questionnaire 
After site staff has activated the remote set up of the subject, using either the subject’s e-mail 
address or phone number, the subject should complete the PHQ-8 questionnaire on a 
computer via a webpage. 
Delivery of IMP to subjects and self-injection 
After ensuring that the outcomes of the C-SSRS and PHQ-8 assessments do not indicate that 
IMP administration should be discontinued, the following procedures should be performed by 
unblinded site staff: 
1. Allocation of IMP for the subject using IRT (can be performed by blinded staff).  
2. Prepare and ship/hand out to subject’s relative or delegated person of trust (refer to 
trial product handling manual for instructions): 
• IMPs allocated via the IRT including instruction for use and other supplies. 
• Urine pregnancy test kits, if applicable. 
Care should be taken to keep blinded site staff from becoming unblinded while 
preparing the shipment/package for hand out to subject’s relative or delegated person 
of trust. 
3. Site staff are responsible for establishing contact with the subject as soon as he/she 
receives the IMP. This is to ensure that: 
• The subject is reminded of IMP storage instructions.  
• The date for self-injection is agreed on keeping in mind that it should be 
performed at the earliest possible timepoint.  
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• If applicable, female subject is reminded to perform a urine pregnancy test prior to 
the date of IMP self-injection. 
• The subject is instructed to not inform the site staff (except from unblinded site 
staff) about the identity of the IMPs received. 
4. At the date of self-injection, the unblinded site staff contacts the subject via the video 
function in the trial-specific mobile application or other video software used by the 
trial site in their normal clinical practice and completes the following: 
i. 
Obtain result of the urine pregnancy test before self-injection, if applicable. 
ii. 
Instruct subject in self-injection. 
iii. 
Self-injection may be performed under supervision of the unblinded site staff. 
iv. 
Information about the kit numbers administrated, date of injection, injection 
site, and whether the doses were fully or partly injected is provided by the 
subject to the unblinded site staff, who records the information on the IMP 
administration checklist. If the subject is comfortable with handling the 
injections, the supervision can be omitted during future self-injections. In that 
case, the subject must be instructed in contacting the unblinded site staff at the 
earliest possible time after self-injection to provide the above-mentioned 
information. 
5. The subject should be instructed to keep the IMP cartons, while the IMP syringes are 
disposed of in the sharp-bin container provided to the subject. The IMP cartons should 
be returned to the site in a non-transparent bag. 
2. Trial procedures 
• Local laboratories can be used for biochemistry, haematology, albumin-to-
creatinine ratio, and serum pregnancy test, if deemed necessary by the investigator, 
if on-site visits are not possible or in case of temporary lockdown of the central 
laboratory. Only findings meeting the definition for an AE (refer to Appendix 1) 
should be reported in the eCRF. 
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Panel 29 Schedule of minimum trial procedures to be performed under the COVID-19 pandemic-related lockdown 
 
Treatment period 
Early 
termination 
visit3 
 
Unschedule
d visit, if 
applicable4 
References 
(protocol 
section) 
Visit 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Week 
1 
2 
4 
6 
8 
10 
12 
14 
162 
18 
20 
22 
24 
26 
282 
Visit window (days)1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Treatment via trial-specific mobile application, when needed 
Arm 1 
Administration of 
brodalumab 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
9.2 
 
Administration of 
dummy 1 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
9.2 
Arm 2 
Administration of 
guselkumab 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
9.2 
 
Administration of 
dummy 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
9.2 
Concomitant 
medication/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
9.6 
Treatment compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
(X) 
9.8.4 
Investigator assessments of efficacy via trial-specific mobile application 
PASI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.3.1.1 
IGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.3.2.1 
Subject assessments of efficacy and health-related quality of life 
Pruritus NRS5 
<=Daily at home during entire treatment period using an eDiary device => 
X6 
 
11.3.4.3 
Pain NRS5 
<=Daily at home during entire treatment period using an eDiary device => 
X6 
 
11.3.4.4 
Investigator assessments of safety via trial-specific mobile application 
Urine pregnancy test7 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
(X) 
11.4.4 
AEs and SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
13 
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Treatment period 
Early 
termination 
visit3 
 
Unschedule
d visit, if 
applicable4 
References 
(protocol 
section) 
Visit 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Week 
1 
2 
4 
6 
8 
10 
12 
14 
162 
18 
20 
22 
24 
26 
282 
Visit window (days)1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Patient-reported outcomes of safety  
C-SSRS  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.5.2 
PHQ-8 (website) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
11.5.3 
Concluding forms in the eCRF 
End-of-treatment form8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
11.6.1 
End-of-trial form9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
(X)9 
 
11.6.2 
Abbreviations: AE = adverse event; COVID-19 = Coronavirus disease 2019; C-SSRS = Columbia-Suicide Severity Rating Scale; eCRF = electronic case report 
form; eDiary = electronic diary; IGA = Investigator’s Global Assessment; IMP = investigational medicinal product; NRS = numeric rating scale; 
PASI = Psoriasis Area and Severity Index; PHQ-8 = Patient Health Questionnaire-8; SAE = serious adverse event. 
1) If the date of a trial visit does not conform to the clinical trial protocol, subsequent visits should be planned to maintain the visit schedule relative to Visit 2 
(Week 0, baseline). 
2) The primary endpoint visit (Week 16) and the final visit (Week 28) are in grey as these visits are critical and should be conducted at the site, if possible. 
3) Subjects who discontinue IMP for any reason should attend an early termination visit as soon as possible and within 2 weeks after the last IMP. If a subject 
discontinues IMP or withdraws from the trial at a scheduled visit, then all assessments for an early termination visit must be performed at this particular visit 
(see Sections 10.3 and 11.6 for further instructions). The subjects who discontinue IMP prior to Week 16 will be asked to attend at least the primary endpoint 
visit at Week 16. A virtual early termination visit can be conducted. However, a visit at site should be conducted once the restrictions related to COVID-19 
pandemic are lifted. 
4) An unscheduled visit can be performed by subject’s needs or at the discretion of the investigator. Procedures are marked in brackets ‘(X)’ since they are optional 
depending on the reason for the unscheduled visit. 
5) To be completed daily by the subject. 
6) Must be completed at the early termination visit, if not already done at home before the visit. 
7) Only women of childbearing potential. 
8) An end-of-treatment form must be completed in the eCRF for all randomised subjects, including subjects who permanently discontinue IMP. 
9) An end-of-trial-form must be completed in the eCRF for all randomised subjects, including subjects who permanently discontinue IMP or withdraw from the 
trial, at their last trial visit.
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3. Blinding 
The 2 active IMPs (brodalumab and guselkumab) are packaged open-label and are visually 
distinct from each other, containing different volumes of solution. Therefore, the subject will 
be unblinded if the subject self-injects the IMPs.  
The subject must be instructed to keep blinding for other staff, i.e. other site staff including 
the investigator. 
To protect trial integrity, dummy injections must be self-administered as this will reduce the 
risk of unblinding the site staff. 
4 eCRF recording 
It must be recorded in the eCRF if the visit or given assessment was conducted remotely or 
not. If not conducted, it will be recorded in the comments log if this was due to the COVID-
19 pandemic. 
All IMP self-injections and missed doses must be documented in the eCRF with ‘COVID-19 
pandemic’ written in the comments log for the visit in scope. 
For all information pertaining to remote visits, assessments, and IMP related information to be 
recorded in the eCRF, please refer to the eCRF completion guidelines.  
5 Statistical methods 
Statistical considerations related to COVID-19 pandemic restrictions are presented in 
Section 14 of the main protocol. 
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Appendix 7: Protocol amendment history 
The protocol amendment summary of changes table for the current amendment is located 
directly before the table of contents.  
Amendment 2 (22-Jan-2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
or subsequent regulation. 
Overall rationale for the amendment: 
The main reason for this amendment is to provide a possibility to perform minimum safety 
and efficacy assessments via the use of electronic communications followed by delivery of 
IMP to subjects for self-injections in case of emergency COVID-19 pandemic restrictions.  
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it). 
Section no. 
and name 
Description of change 
Brief rationale 
4 Schedule of 
trial 
procedures 
Visits outside of the allowed visit window still 
need to be performed, taking into 
consideration that an interval of minimum 
7 days to the subsequent, respective IMP 
administration must be maintained (visits 3 
and 4 are exempt from the 7-day gap 
requirement). 
To clarify that a gap of 
7 days between IMP 
administrations is not 
expected for visits 3 
and 4. 
Footnote revised: 
8) The DLQI and SF-36v2 questionnaires 
must should be completed by the subject prior 
to any other visit-related trial procedures. the 
investigator, safety, and other assessments. 
To clarify that DLQI 
and SF-36v2 
questionnaires should 
be completed prior to 
all other assessments 
except the laboratory 
assessments and to 
provide a visual 
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Section no. 
and name 
Description of change 
Brief rationale 
For the sequence of assessments to be 
performed at each visit, please see Panel 8. 
presentation of the 
sequence to 
assessments to be 
performed during visits. 
6 Trial 
objectives, 
endpoints, and 
estimands 
Panel 5 updated with strategies to handle 
occurrences of permanent discontinuation of 
IMP due to pandemic restrictions and 
unblinding of subjects.  
To provide estimand 
strategies in case of 
COVID-19 pandemic 
restrictions. 
9.2 
Administration 
of 
investigational 
medicinal 
product 
Instructions for use of the pre-filled syringes 
are provided in a trial product handling 
manual the investigator trial file; the IMP 
administration must be carried out according 
to these instructions. 
To correct the location 
where the instructions 
for use is provided. 
9.3.1 Blinding 
Furthermore, to ensure subjects stay 
blinded to treatment allocation, site staff 
should ensure that subjects are blindfolded 
during the administration of IMP. 
To clarify the procedure 
for how IMP will be 
administered to subjects 
in order to maintain the 
blind. 
10.2.2 Reasons 
for temporary 
discontinuation 
of IMP 
The subsequent IMP administration should be 
scheduled according to the schedule of the 
trial procedures with a minimum of 7 days to 
the subsequent administration of the 
respective IMP (visits 3 and 4 are exempt 
from the 7-day gap requirement). 
To clarify that a gap of 
7 days between IMP 
administrations is not 
expected for visits 3 
and 4. 
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Section no. 
and name 
Description of change 
Brief rationale 
11.1 Overview 
Sequence of assessments reordered to indicate 
that laboratory assessments could be 
performed at any time during the visit but 
should be completed prior to performing 
‘Other assessments’. Also, the investigator 
and safety assessments were merged in one 
box. 
To enable the trial to be 
operationally more 
flexible. 
13.4.2 LEO 
reporting 
responsibilies 
For brodalumab, the IB Section 7.2, edition 
12.0 13.0 and subsequent updates must be 
used. 
To reflect the latest IB 
version. 
14 Statistical 
methods 
Updated to limit introduction of bias for 
evaluation of the treatment effect of 
brodalumab and guselkumab due to 
COVID-19 pandemic restrictions and 
unblinding of subjects. 
To provide strategies in 
case of COVID-19 
pandemic restrictions. 
Appendix 6 
COVID-19 pandemic contingency plan to 
provide an opportunity for remote assessments 
and delivery of IMP and pregnancy tests to 
subjects that are unable to attend site visits 
due to COVID-19 restrictions.  
To ensure the 
possibility of continued 
treatment despite 
restricted site access 
caused by the 
COVID-19 pandemic. 
Throughout 
Minor editorial and document formatting 
revisions. 
Minor, have therefore 
not been summarised. 
 
Amendment 1 (19-Aug-2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
or subsequent regulation. 
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Overall rationale for the amendment: 
The main reasons for this amendment, based on input provided during the Voluntary 
Harmonisation Procedure in EU, are: 
• to add the discontinuation criterion for subjects who show no response after 16 weeks 
of treatment. 
• to add an evaluation by a specialist in case of a positive QuantiFERON® test. 
• to add an additional sensitivity analysis to assess the robustness of the results of the 
primary analysis with respect to the use of prohibited medication and procedures 
among subjects not discontinuing IMP.  
Furthermore, capturing of ‘lack of efficacy’ in case of aggravation/exacerbation/worsening of 
the trial disease has been clarified, and albumin-to-creatinine test at screening was changed to 
only be performed in case of abnormal urine dipstick test.  
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it). 
Section no. 
and name 
Description of change 
Brief rationale 
4 Schedule of 
trial 
procedures 
The row for serum pregnancy test has been 
moved under Investigator assessments of 
safety and (X) has been added to the schedule. 
To make the procedure 
visible in the panels to 
highlight the need of 
this test in case of 
positive urine 
pregnancy test. 
Albumin-to-creatinine ratio will only be 
performed for subjects with abnormal urine 
dipstick results. The row for albumin-to-
creatinine ratio has been moved under 
Investigator assessments of safety and 
replaced with (X).  
To minimise the 
unessential procedure.  
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Section no. 
and name 
Description of change 
Brief rationale 
This change has also been reflected in 
Section 11.4.4 Laboratory testing Panel 15.  
(X) has been added to treatment 
administration for unscheduled visit. 
To allow for 
administration of IMP 
on unscheduled visits. 
8.2 Inclusion 
criteria 
Revised bullet point: 
No evidence of active tuberculosis based on 
documented assessment by a pulmonologist 
or a tuberculosis specialist (phthisiologist) 
on chest radiograph within 3 months prior to 
the first administration of IMP, if any chest 
radiograph is available. 
To exclude active 
tuberculosis in patients 
who had a positive 
QuantiFERON® or PPD 
test result. 
10.2.1 Reasons 
for permanent 
discontinuation 
of IMP 
Added bullet point: 
Having shown no response (efficacy) after 
16 weeks of treatment. 
To discontinue IMP 
administration for 
subjects who show no 
response after 16 weeks 
of treatment.  
Added clarification: 
‘Lack of efficacy’ should be assigned when 
a subject experiences 
aggravation/exacerbation/worsening of the 
trial disease, even when it is documented as 
an (S)AE according to Section 13.6.5. 
To consistently capture 
permanent 
discontinuation of IMP 
or withdrawal from trial 
due to ‘lack of 
efficacy’. 
11.6.2 
End-of-trial 
form 
Added clarification: 
‘Lack of efficacy’ should be assigned when 
a subject experiences 
aggravation/exacerbation/worsening of the 
To consistently capture 
permanent 
discontinuation of IMP 
or withdrawal from trial 
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Section no. 
and name 
Description of change 
Brief rationale 
trial disease, even when it is documented as 
an (S)AE according to Section 13.6.5. 
due to ‘lack of 
efficacy’. 
13.6.5 
Aggravation of 
condition 
Added clarification: 
In case the 
aggravation/exacerbation/worsening of the 
trial disease leads to permanent 
discontinuation of IMP or withdrawal from 
the trial, ‘lack of efficacy’ should be chosen 
as the primary reason for discontinuation 
of IMP / withdrawal from the trial in 
accordance with Section 10.2.1 and 
Section 11.6.2. 
To consistently capture 
permanent 
discontinuation of IMP 
or withdrawal from trial 
due to ‘lack of 
efficacy’. 
14.3.6.2 
Estimand 
strategy for 
binary 
endpoints 
An additional sensitivity analysis (sensitivity 
analysis 3) was added.  
To assess the robustness 
of the results of the 
primary analysis with 
respect to the use of 
prohibited medication 
and procedures among 
subjects not 
discontinuing IMP. 
Throughout 
Minor editorial and document formatting 
revisions. 
Minor, have therefore 
not been summarised. 
 
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