Conditions: Psoriasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12
Healthy volunteers: no

Brief summary:
The study will investigate the efficacy and safety compared to placebo and the safety compared to ustekinumab of brodalumab in adolescents with moderate to severe plaque psoriasis. The study will also investigate if brodalumab affects development of vaccination-induced immune responses.

The study will run over 62-64 weeks (including screening, treatment, and safety follow-up) for each participant, but with the primary endpoint measured at Week 12.

Detailed description:

Arms:
arm 1: Brodalumab for 52 weeks. The dose will be determined by the participant's body weight. arm 2: Ustekinumab for 52 weeks. The dose will be determined by the participant's body weight. arm 3: Placebo for the first 12 weeks and brodalumab for the following 40 weeks. The dose will be determined by the participant's body weight. arm 4: Placebo for the first 12 weeks and ustekinumab for the following 40 weeks. The dose will be determined by the participant's body weight.

Interventions: intervention 1: Brodalumab intervention 2: Ustekinumab intervention 3: Placebo
Intervention descriptions: intervention 1: Solution for subcutaneous injection. intervention 2: Solution for subcutaneous injection. intervention 3: The placebo solution is similar to the active brodalumab solution except that it does not contain any active substance.

Protocol document:
Prot_002.pdf: 
 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Study title: Efficacy and safety of brodalumab in adolescents from 12 to 17 years of age with moderate-
to-severe plaque psoriasis; EMBRACE 1 
LEO Pharma number: LP0160-1396 
NCT number: NCT04305327    
Date: 05-Oct-2021 
 


CONFIDENTIAL 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
 
Clinical Trial Protocol 
 
 
LP0160-1396  
 
Efficacy and safety of brodalumab in adolescents from 12 to 17 years of age with 
moderate-to-severe plaque psoriasis; EMBRACE 1 
Phase 3 – efficacy and safety trial including pharmacokinetics and vaccine response 
A phase 3, randomised, double-blind, multi-centre trial to evaluate the efficacy, 
safety, and tolerability of brodalumab treatment compared to placebo (blinded) and 
ustekinumab (open-label) in adolescent subjects (12–17 years of age) with  
moderate-to-severe plaque psoriasis 
 
 
 
 
 
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: 
LP0160-1396 
 
Date: 
 
05-Oct-2021 
 
EudraCT no: 
2019-001868-30 
 
Version: 
6.0 
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Clinical trial protocol statements 
Approval statement LEO Pharma A/S 
Electronic signatures made within eTMF LEO 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: 
 
 
 
 
 
Biostatistics lead, 
 
 
 
 
Medical lead, 
 
 
 
 
Clinical operations lead, 
 
 
 
 
 
 
Signatory investigator 
 
 
Acknowledgement statement investigator(s)  
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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Protocol amendment summary of changes table 
 Document history 
Document 
Date 
Type of protocol amendment 
Amendment 2 
(substantial) 
05-Oct-2021 
Global 
Amendment 1 
(substantial) 
10-Jun-2020 
Global 
Original protocol 
21-Jan-2020 
Not applicable 
 
Amendment 2 (05-Oct-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 
This amendment was written to:  
• Allow inactive or non-live vaccines, including COVID-19 vaccines, from Week 12. 
• Add voluntary photography as trial procedure at selected trial sites. 
• Update estimands strategy to account for COVID-19 pandemic restrictions impact on the 
trial conduct. 
The changes included in the amendment and a brief scientific rationale for each item are 
presented in the table below. 
Section no. and name 
Description of change 
Brief rationale 
Section 4 Schedule of 
trial procedures 
 
Visit window for Visit 3 and 4 changed from ±1 
to ±3. 
 
 
Added that visits outside the allowed visit 
window still need to be performed, taking into 
consideration that a minimum interval of 7 days 
must be kept between 2 administrations of 
brodalumab/placebo (except for Visit 3 and 
Visit 4, which are exempt from the 7-day gap 
requirement). 
To allow more flexibility for 
the investigator and the 
subject. 
 
For clarity. 
 
 
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Section no. and name 
Description of change 
Brief rationale 
Footnotes f and g Panel 2 and footnote f Panel 3 
deleted. 
 
New footnote e added to Panel 2 specifying that 
subjects must be randomised as soon as all 
inclusion and exclusion criteria are confirmed 
(including the central laboratory and ECG 
results from the screening visit). 
 
 
To align with the updated 
text. 
 
For better guidance for the 
investigator. 
Section 4 Schedule of 
trial procedures 
Section 7.1.2 Screening 
period (Week -4 to 
Week 0) 
 
The 14 days minimum prior to initiation of the 
treatment requirement deleted.  
To assure randomisation and 
initation of treatment as 
soon as subject´s eligibility 
is confirmed. 
Section 4 Schedule of 
trial procedures 
Section 11.7.2 
Photography (selected 
trial sites) 
 
New voluntary trial procedure added. 
The processing of photos is 
necessary for reasons of 
public interest in the area of 
public health, to ensure high 
standards of quality, and for 
scientific research purposes.  
Section 5.2 Experience 
with investigational 
medicinal product  
Section 5.5 Benefit/risk 
assessment 
 
List of countries where brodalumab is approved 
updated. 
To have an up-to-date 
country list. 
Section 5.5 Benefit/risk 
assessment 
 
Sentence regarding the need for subjects to be 
up-to-date with the vaccination program of their 
country of residence deleted. 
 
To align with inclusion 
criteria. 
Section 5.5 Benefit/risk 
assessment 
Section 8.3 Exclusion 
criteria 
Section 9.7 Prohibited 
medication and 
procedures 
 
Specified that inactivated or non-live vaccine 
will be allowed from Week 12. 
To avoid putting subjects in 
an unjustified risk, the 
restriction for not allowing 
access to inactive and 
non-live vaccines including 
COVID-19 vaccines are 
limited to a minimum. 
Section 7.1.1 Overview 
of the trial design 
 
Added that it will be recorded in the eCRF if a 
visit was missed and whether the reason for the 
missed visit was related to pandemic 
restrictions. 
 
In order to perform the 
specified statistical analyses, 
data that is missing due to 
pandemic restrictions and 
data that is missing for other 
reasons need to be 
distinguished. 
 
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Section no. and name 
Description of change 
Brief rationale 
Section 8.2 Inclusion 
criteria 
῾As determined by the investigator’ added to 
inclusion criterion 2. 
Inclusion criterion 7 deleted. 
 
 
 
 
Inclusion criteria 9, 10, 11, and 12 deleted and 
replaced by new inclusion criterion ῾Subject has 
no evidence of active or latent tuberculosis 
according to local standard of care for patients 
requiring initiation of a biologic treatment’. 
For clarity. 
 
Exclusion criterion 4 is 
sufficient as the period for 
prohibited administration of 
inactivated and non-live 
vaccine is reduced from 
52 weeks to 12 weeks for 
placebo and brodalumab 
arms. 
 
To allow for more 
operational flexibility at site. 
 
Section 8.2 Inclusion 
criteria 
Throughout the document 
Definition of childbearing potential deleted as 
all female subjects will be considered of 
childbearing potential when entering the trial. 
Inclusion criterion 13 deleted accordingly and 
replaced by ῾Female subjects must have a 
negative pregnancy test at screening and at 
baseline’.  
To make the trial more 
operationally flexible. 
Section 8.3 Exclusion 
criteria 
 
Specified in exclusion criterion 18 that subjects 
with treated and considered cured cutaneous 
squamous or basal cell carcinoma, in situ 
cervical cancer, or in situ breast ductal 
carcinoma can be enrolled in the trial. 
For clarity. 
Section 9.1 Trial product 
description 
 
Panel 9 ῾Source’ column changed to 
 
 
 Name of the IMP corrected. 
   
For correctness and to 
clarify who is responsible 
for batch release. 
 
Section 9.2.1 
Administration of 
brodalumab, placebo, and 
ustekinumab  
 
Sentence ´Further details on IMP administration 
are provided in a trial product handling manual; 
the IMP administration must be carried out 
according to these instructions.´deleted. 
Details on the IMP 
administration are given in 
the protocol. 
Section 9.2.3 Reporting 
of IMP administration in 
eCRF 
 
Time of IMP administration will be recorded 
only at selected visits. 
Time of administration only 
needed at selected visits to 
create PK profiles. 
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Section no. and name 
Description of change 
Brief rationale 
Section 9.2.1.1 
Conditions requiring 
rescheduling of 
administration of 
brodalumab, placebo, or 
ustekinumab 
 
Specified that the 7-day gap requirement 
between administration of brodalumab/placebo 
does not apply to Visit 3 and Visit 4. 
Due to the change of the 
visit window for Visit 3 and 
4. 
Section 9.7 Prohibited 
medications and 
procedures 
Specified how to record prohibited medications 
and when a prohibited medication constitutes a 
protocol deviation. 
 
For clarity. 
Section 9.10 Reporting 
product complaints 
 
Specified that the product complaint must be 
immediately reported to the CRA by the site and 
that the CRA must contact Global Safety at 
LEO Pharma. 
 
To be in alignment with 
LEO Pharma´s procedures. 
Section 10.2.2 Reasons 
for temporary 
discontinuiation of IMP 
Specified that the IMP may be temporarily 
suspended in case of infection and other 
intercurrent illness and that it must be 
temporarily suspended in case of 
ANC ≥0.50x103/µL – ≤1.5x103/µL and fever or 
positive urine pregnancy test. 
 
For clarity. 
Section 11.1 Overview 
Sentence added explaining that the laboratory 
assessments can be completed anytime prior to 
´Patient-reported outcomes for safety 
assessments´. 
 
To make the trial more 
operationally flexible. 
 
Section 11.1 Overview 
Section 13.2 Collection 
of adverse event reports 
Appendix 3D 
 
Text regarding assessment of AEs updated. AEs 
will be assessed by a physician. 
To clarify responsibilities. 
Section 11.4.3 
Electrocardiogram 
 
Added that subjects should not be randomised 
before the evaluation report from the ECG 
service company of the ECG performed at 
Visit 1 is received at site. 
 
For better guidance. 
Section 11.4.5.1 
Overview of all 
laboratory tests 
 
PPD test and QuantiFERON® test replaced by 
῾Tuberculosis (only if applicable)’ in Panel 18. 
 
To align with new inclusion 
criterion 8. 
Section 11.4.5.1 
Overview of all 
laboratory tests 
 
Section 11.6.2 Blood 
sampling for analysis of 
IL-17 and other blood 
biomarkers  
 
Blood biomarkers changed to interleukin 
(IL)-17, IL-10, IL-6, CXCL9, CCL20, 
S100-A12, and Caspase-8. 
To match the serum 
biomarkers mentioned in the 
CTPs with the offerings of 
the preferred assay lab 
partner. 
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Section no. and name 
Description of change 
Brief rationale 
Section 11.9.1 End of 
treatment form 
Section 11.9.2 End of 
trial form 
 
Specification added to indicate that for subjects 
not completing the trial, it will be recorded if 
the reason for not completing the trial was 
related to pandemic restrictions. 
This information is needed 
to fully assess and report the 
impact of COVID-19 on the 
trial. 
Section 11.10 Storage of 
biological samples 
 
Storage time for blood samples corrected. 
For correctness. 
Section 13.3 Reporting of 
adverse events 
 
Specified that the duration of the AE must be 
reported by the start date and stop date of the 
event, unless the event is ongoing. If the event is 
ongoing, it will be marked as ongoing. 
 
For clarity. 
Section 13.4.1 
Investigator reporting 
responsibilities 
A more detailed specification on the timing of 
reporting of SAEs added (i.e. immediately, 
without undue delay). 
To align with updated text in 
the EU CT regulation on 
reporting of SAEs. 
Section 13.4.2 LEO 
Pharma reporting 
responsibilities 
 
Specified that edition 13 of the Investigator´s 
Brochure should be used. 
To align with the newest 
edition of the Investigator´s 
Brochure. 
Section 13.6.5 
Aggravation of condition 
Added that plaque psoriasis is a fluctuating 
disease with possible periods of remission. In 
case of relapses/recurrences, only 
aggravations/exacerbations exceeding normal 
disease fluctuation or lesions appearing in a 
body area normally not affected by plaque 
psoriasis should be reported as an AE. 
 
To provide better guidance 
to the investigator. 
Section 13.7 Follow-up 
for final outcome of 
adverse events 
Specified that the final outcome of SAEs that 
have stabilised and from which the subject 
cannot be expected to recover during the trial 
should be reported as ‘recovering/resolving’ or 
‘not recovered/not resolved’ at the investigator´s 
discretion. In addition, a statement detailing 
why the subject cannot be expected to recover 
during the trial should be added to the narrative 
description of the SAE on the SAE form. 
 
For clarity. 
Section 14 Statistical 
methods 
Estimands updated with strategies to handle 
occurrences of permanent discontinuation of 
IMP due to pandemic restrictions. 
To provide estimand 
strategies in case COVID-19 
pandemic restrictions impact 
the trial conduct. 
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Section no. and name 
Description of change 
Brief rationale 
Section 14.3.6.1 
Estimand strategy for 
binary endpoints 
Sensitivity analysis 2 and 3 for primary 
estimand for binary endpoints removed. 
 
 
 
 
 
Missing data for reasons other than pandemic 
restrictions in secondary estimand for binary 
endpoints imputed assuming missing at random 
instead of imputed based on ‘control-based’ 
pattern mixture model, which was added as a 
sensitivity analysis. 
 
Sensitivity analysis for secondary estimand for 
binary endpoints using ‘retrieved-data’ pattern 
mixture model removed. 
 
 
 
 
Supplemental estimand: “hypothetical” 
estimand moved to 14.3.6.3 Estimand strategy 
for vaccine-related endpoints. 
The main analysis and the 
sensitivity analyses targeted 
different estimands. The 
sensitivity analyses were 
removed to follow the ICH 
E9 R1. 
 
 
To align with other LP0160 
protocols. 
 
 
 
 
 
It is expected that the rate of 
the intercurrent events will 
be low, and therefore there 
will not be sufficient 
retrieved data to inform this 
analysis. 
 
No longer recommended to 
use a purely hypothetical 
strategy for the primary and 
secondary endpoint. This is 
now reserved for the 
vaccine-related endpoints. 
Section 14.3.6.2 
Estimand strategy for 
continuous endpoints 
Primary analysis for primary estimand for 
continuous endpoints changed from MMRM to 
ANCOVA. 
 
Sensitivity analysis for primary estimand for 
continuous endpoints removed. 
 
 
Supplemental estimand: “hypothetical” strategy 
moved to 14.3.6.3 Estimand strategy for 
vaccine-related endpoints. 
To align the inferential 
models. 
 
Sensitivity analyses are 
reserved for primary and key 
secondary endpoints, which 
are all binary. 
 
No longer recommended to 
use a purely hypothetical 
strategy for the primary and 
secondary endpoint. This is 
now reserved for the 
vaccine-related endpoints. 
Section 14.3.6.3 
Estimand strategy for 
vaccine-related endpoints 
Primary analysis for the continuous vaccine-
related endpoints changed from MMRM to 
ANCOVA. 
To align the inferential 
models. 
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Section no. and name 
Description of change 
Brief rationale 
Section 14.3.9 Analysis 
of other endpoints 
Description of analysis of vaccine-related 
endpoints moved to section 14.3.6.3 Estimand 
strategy for vaccine-related endpoints. 
 
Exploratory analysis of itch based on the 
reversible illness-death model removed. 
For clarity. 
 
 
 
The main analysis of the itch 
data is considered sufficient 
to assess the effect of 
treatment. 
Section 14.3.10.6 Patient 
Health Questionnaire-A 
(PHQ-A) 
Exploratory analysis removed. 
The main analysis of the 
PHQ-A data is considered 
sufficient to summarise the 
observed data. 
Appendix 1 
Hospitalisation definition clarified. 
For clarity 
Appendix 6 
New appendix added containing the summary of 
the previous protocol amendment. 
To document the protocol 
amendment history, and to 
keep only the most recent 
amendment summary at the 
start of the protocol. 
Throughout the document 
Changed designated assessor to investigator. 
For consistency within the 
protocol. 
Throughout the document 
Removed Australia. 
Australia will not be 
participating in this trial. 
Throughout the document 
Minor editorial revisions. 
Minor, have therefore not 
been summarised. 
 
 
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Table of contents 
Table of contents ..................................................................................................................... 10 
List of panels ........................................................................................................................... 15 
List of abbreviations ............................................................................................................... 17 
1 Protocol synopsis ................................................................................................................ 20 
2 Trial identification ............................................................................................................. 26 
3 Schematic of trial design ................................................................................................... 26 
4 Schedule of trial procedures ............................................................................................. 27 
5 Introduction and trial rationale ....................................................................................... 37 
5.1 Plaque psoriasis .......................................................................................................... 37 
5.2 Experience with investigational medicinal product .................................................... 38 
5.3 Trial rationale and justification for dose ..................................................................... 41 
5.3.1 
Trial rationale ................................................................................................ 41 
5.3.2 
Justification for dose ..................................................................................... 42 
5.4 Ethical considerations ................................................................................................. 42 
5.5 Benefit/risk assessment ............................................................................................... 46 
6 Trial objectives and endpoints .......................................................................................... 49 
7 Trial design ......................................................................................................................... 52 
7.1 Overall trial design ..................................................................................................... 52 
7.1.1 
Overview of the trial design .......................................................................... 52 
7.1.2 
Screening period (Week -4 to Week 0) .......................................................... 53 
7.1.3 
Treatment phase (Week 0 to Week 52) .......................................................... 53 
7.1.4 
Safety follow-up period (Week 52 to Week 60) ............................................ 54 
7.2 Number of subjects needed ......................................................................................... 55 
7.3 End of trial definition.................................................................................................. 55 
8 Trial population ................................................................................................................. 56 
8.1 Subject eligibility ........................................................................................................ 56 
8.2 Inclusion criteria ......................................................................................................... 56 
8.3 Exclusion criteria ........................................................................................................ 57 
8.4 Screening and screening failures ................................................................................ 61 
8.4.1 
Subject identification number ....................................................................... 61 
8.4.2 
Screening failures .......................................................................................... 61 
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9 Treatments .......................................................................................................................... 63 
9.1 Trial product description ............................................................................................. 63 
9.1.1 
Brodalumab and placebo ............................................................................... 63 
9.1.2 
Ustekinumab.................................................................................................. 64 
9.1.3 
Vaccines ......................................................................................................... 65 
9.2 Administration of IMP ................................................................................................ 66 
9.2.1 
Administration of brodalumab, placebo, and ustekinumab........................... 66 
9.2.2 
Administration of vaccine ............................................................................. 67 
9.2.3 
Reporting of IMP administration in eCRF .................................................... 68 
9.3 Treatment assignment ................................................................................................. 69 
9.3.1 
Blinding ......................................................................................................... 69 
9.3.2 
Emergency unblinding of individual subject treatment ................................ 70 
9.4 Background treatment ................................................................................................. 70 
9.5 Rescue treatment ......................................................................................................... 70 
9.6 Concomitant medication and concurrent procedures ................................................. 71 
9.7 Prohibited medications and procedures ...................................................................... 72 
9.8 Treatment logistics and accountability ....................................................................... 74 
9.8.1 
Labelling and packaging of trial products ..................................................... 74 
9.8.2 
Storage of trial products ................................................................................ 74 
9.8.3 
Drug accountability ....................................................................................... 75 
9.8.4 
Treatment compliance ................................................................................... 76 
9.8.5 
Trial product destruction ............................................................................... 76 
9.9 Provision for subject care following trial completion ................................................ 76 
9.10 Reporting product complaints..................................................................................... 76 
10 Discontinuation and withdrawal ...................................................................................... 78 
10.1 General principles ....................................................................................................... 78 
10.2 IMP discontinuation rules ........................................................................................... 79 
10.2.1 Reasons for permanent discontinuation of IMP ............................................ 79 
10.2.2 Reasons for temporary discontinuation of IMP ............................................ 80 
10.3 Early termination assessments .................................................................................... 81 
10.4 Lost to follow-up ........................................................................................................ 82 
11 Trial assessments and procedures .................................................................................... 83 
11.1 Overview..................................................................................................................... 83 
11.2 Assessments performed only at screening/baseline .................................................... 84 
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11.2.1 Demographics................................................................................................ 84 
11.2.2 Trial disease (psoriasis, psoriatic arthritis, psoriatic arthropathy, and 
other immunoinflammatory diseases) ........................................................... 84 
11.2.3 Trial disease treatment history ...................................................................... 85 
11.2.4 Medical history .............................................................................................. 85 
11.2.5 Substance use: tobacco and alcohol .............................................................. 85 
11.3 Efficacy assessments .................................................................................................. 85 
11.3.1 Psoriasis Area and Severity Index ................................................................. 85 
11.3.2 Static Physician’s Global Assessment ........................................................... 88 
11.3.3 Body surface area involvement ..................................................................... 89 
11.3.4 Patient-reported outcomes for efficacy and health-related quality of life ..... 89 
11.4 Safety assessments ...................................................................................................... 91 
11.4.1 Vital signs ...................................................................................................... 91 
11.4.2 Physical examination..................................................................................... 92 
11.4.3 Electrocardiogram ......................................................................................... 92 
11.4.4 Body measurements: height and weight........................................................ 93 
11.4.5 Laboratory testing ......................................................................................... 93 
11.4.6 Blood sampling for analysis of vaccine antibodies ....................................... 96 
11.4.7 Blood sampling for analysis of ADA ............................................................ 96 
11.5 Pharmacokinetic assessments ..................................................................................... 96 
11.5.1 Blood sampling for analysis of brodalumab concentration for PK 
assessments ................................................................................................... 96 
11.6 Pharmacodynamics ..................................................................................................... 97 
11.6.1 Overview ....................................................................................................... 97 
11.6.2 Blood sampling for analysis of IL-17 and other blood biomarkers .............. 97 
11.6.3 Blood sampling for analysis of T- and B-lymphocyte subsets ...................... 97 
11.7 Other assessments ....................................................................................................... 98 
11.7.1 Patient-reported outcomes for safety assessments ........................................ 98 
11.7.2 Photography (selected trial sites) ................................................................ 100 
11.8 Estimate of total blood volume collected ................................................................. 101 
11.9 End of trial ................................................................................................................ 101 
11.9.1 End of treatment form ................................................................................. 101 
11.9.2 End of trial form .......................................................................................... 101 
11.10 Storage of biological samples ................................................................................... 102 
12 Scientific rationale for trial design and appropriateness of assessments ................... 103 
12.1 Scientific rationale for trial design ........................................................................... 103 
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12.2 Appropriateness of assessments ............................................................................... 104 
13 Adverse events ................................................................................................................. 107 
13.1 Definition and classification of adverse events ........................................................ 107 
13.2 Collection of adverse event reports .......................................................................... 107 
13.3 Reporting of adverse events...................................................................................... 107 
13.4 Reporting of serious adverse events ......................................................................... 108 
13.4.1 Investigator reporting responsibilities ......................................................... 108 
13.4.2 LEO Pharma reporting responsibilities ....................................................... 109 
13.5 Other events that require expedited reporting .......................................................... 109 
13.5.1 Pregnancy .................................................................................................... 109 
13.5.2 Adverse events of special interest ............................................................... 110 
13.6 Reporting of other events.......................................................................................... 111 
13.6.1 Overdose...................................................................................................... 111 
13.6.2 Medication error .......................................................................................... 112 
13.6.3 Misuse ......................................................................................................... 112 
13.6.4 Abuse ........................................................................................................... 112 
13.6.5 Aggravation of condition ............................................................................ 113 
13.7 Follow-up for final outcome of adverse events ........................................................ 113 
13.8 Handling of an urgent safety measure ...................................................................... 113 
14 Statistical methods ........................................................................................................... 115 
14.1 Sample size ............................................................................................................... 115 
14.2 Trial analysis sets ...................................................................................................... 116 
14.3 Statistical analysis ..................................................................................................... 117 
14.3.1 General principles ....................................................................................... 117 
14.3.2 Handling of missing values ......................................................................... 118 
14.3.3 Disposition of subjects ................................................................................ 120 
14.3.4 Demographics and other baseline characteristics........................................ 121 
14.3.5 Exposure and treatment compliance ........................................................... 121 
14.3.6 Estimand strategy ........................................................................................ 122 
14.3.7 Testing Strategy ........................................................................................... 134 
14.3.8 Analysis of efficacy endpoints .................................................................... 134 
14.3.9 Analysis of other endpoints ......................................................................... 137 
14.3.10 Analysis of safety ........................................................................................ 138 
14.3.11 Anti-drug antibodies .................................................................................... 142 
14.3.12 Pharmacokinetics ........................................................................................ 142 
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14.3.13 Interim analysis ........................................................................................... 143 
15 References ......................................................................................................................... 144 
Appendix 1: Definitions of adverse events and serious adverse events ........................... 151 
Appendix 2: Classification of adverse events ..................................................................... 153 
Appendix 3: Trial governance considerations ................................................................... 157 
Appendix 3A: Regulatory and ethical considerations .............................................. 157 
Appendix 3B: Informed consent process ................................................................. 157 
Appendix 3C: Subject and data confidentiality ....................................................... 159 
Appendix 3D: Record keeping, quality control, and data handling ......................... 160 
Appendix 3E: Registration, reporting, and publication policy ................................ 163 
Appendix 3F: Insurance ........................................................................................... 165 
Appendix 3G: Financial disclosure .......................................................................... 165 
Appendix 3H: Data monitoring committee structure ............................................... 165 
Appendix 3I: Trial and site closure .......................................................................... 166 
Appendix 3J: Responsibilities .................................................................................. 167 
Appendix 4: WHO model prescribing information for classification of topical 
corticosteroids .................................................................................................................. 168 
Appendix 5: Contact list ...................................................................................................... 169 
Appendix 6: Protocol amendment history................................................................................ 170 
 
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List of panels 
Panel 1: Trial design ................................................................................................................. 26 
Panel 2: Schedule of trial procedures for screening and induction period ............................... 27 
Panel 3: Schedule of trial procedures for maintenance and safety follow-up periods ............. 32 
Panel 4: Simulated systemic exposure (AUC at Week 10-12 dosing Q2W+1) across observed 
body weight quintiles by dosing regime .......................................................... 39 
Panel 5: Week 12 sPGA response by quintiles of predicted AUCweek 10-12 for the phase 3 
population studied for 210 mg Q2W+1 brodalumab ....................................... 40 
Panel 6: Summary of mean PASI improvement from baseline (LOCF) at Week 12 by weight 
class and treatment (full analysis set) ............................................................... 41 
Panel 7: Primary objective and endpoints supporting the primary objective ........................... 49 
Panel 8: Secondary objectives and endpoints supporting the secondary objectives ................ 50 
Panel 9: Identification of brodalumab and placebo .................................................................. 63 
Panel 10: Identification of ustekinumab ................................................................................... 64 
Panel 11: Identification of the vaccines ................................................................................... 65 
Panel 12: Prohibited medications and procedures .................................................................... 73 
Panel 13: Sequence of assessments .......................................................................................... 83 
Panel 14: PASI severity score scale ......................................................................................... 87 
Panel 15: PASI area score scale ............................................................................................... 87 
Panel 16: Calculation of the PASI score .................................................................................. 88 
Panel 17: sPGA severity score scale ........................................................................................ 89 
Panel 18: Laboratory tests ........................................................................................................ 94 
Panel 19: Adverse events of special interest .......................................................................... 111 
Panel 20: Estimated one-sided 95% upper confidence limit for the precision of the estimated 
difference in vaccine response between the brodalumab dosing regimen and 
placebo arms assuming the probability of vaccine response is equal in the 2 
arms ................................................................................................................ 116 
Panel 21: Overview of estimands and handling of missing data ............................................ 124 
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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 primary analysis of 
the primary estimand for binary endpoints .................................................... 126 
Panel 23: Hypothetical strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions and handling of missing data in the primary analysis of 
the secondary estimand for binary endpoints ................................................. 129 
Panel 24: Hypothetical strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions and handling of missing data in the sensitivity analyses 
of the secondary estimand for binary endpoints ............................................. 130 
Panel 25: Hypothetical strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions and handling of missing data in the primary analysis of 
the primary estimand for continuous endpoints ............................................. 132 
Panel 26: Hypothetical strategy for addressing permanent discontinuation of IMP and rescue 
treatment and handling of missing data in the analysis of the secondary 
estimand for continuous secondary endpoints ............................................... 133 
Panel 27: Hierarchical testing procedure to control the familywise error rate for the pre-
specified primary and key secondary endpoints ............................................ 134 
Panel 28: Overview of statistical analyses ............................................................................. 135 
Panel 29: Search criteria for AESI ......................................................................................... 140 
 
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List of abbreviations 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AS 
area score 
AST 
aspartate aminotransferase 
aTTA 
anti-tetanus toxoid antibodies 
AUC 
area under the curve 
AUCW10-12 
area under the serum concentration-time curve at Week 10-12 
BCG 
Bacillus Calmette-Guérin 
BSA 
body surface area 
Ctrough 
trough (pre-dose) serum concentrations 
CW10 
serum concentration sampled during Week 10 
CDISC 
clinical data interchange standards consortium 
CDLQI 
Children Dermatology Life Quality Index 
CMH 
Cochran-Mantel-Haenszel 
CI 
confidence interval 
CMO 
contract manufacturing organisation 
CONSORT 
consolidated standards of reporting trials 
COVID-19 
coronavirus disease 19 
CRA 
clinical research associate 
CRO 
contract research organisation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTR 
clinical trial report 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
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ePRO 
electronic patient-reported outcome 
EU 
European Union 
FAS 
full analysis set 
FDA 
United States Food and Drug Administration 
FDLQI 
Family Dermatology Life Quality Index 
GCP 
Good Clinical Practice 
GEE 
generalised estimating equation 
HPV 
human papillomavirus 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification number 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
IL 
interleukin 
IMP 
investigational medicinal product 
IRT 
interactive response technology 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
LS 
least squares 
MACE 
major adverse cardiac events 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effect model for repeated measures 
MSM 
multi-state model 
NRI 
non-responder imputation 
NRS 
numeric rating scale 
PASI 
Psoriasis Area and Severity Index 
PASI 75 
at least 75% improvement in PASI score 
PDCO 
paediatric committee 
PHQ-A 
Patient Health Questionnaire-9 modified for adolescents, without question 
number 9 
PK 
pharmacokinetics 
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PPD 
purified protein derivative 
PT 
preferred term 
Q2W+1 
Weeks 0, 1, 2, and every 2 weeks thereafter 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDTM 
standard data tabulation model 
SIB 
suicidal ideation and behaviour 
SmPC 
summary of product characteristics 
SMQ 
standardised MedDRA queries 
SOC 
system organ class 
SS 
severity score 
SSS 
sum of severity scores 
sPGA 
static Physician’s Global Assessment 
Td 
combined tetanus toxoid and diphtheria toxoid vaccine 
Tdap 
combined tetanus toxoid, diphtheria toxoid, and acellular pertussis vaccine 
TEAE 
treatment-emergent adverse event 
Th 
T-helper 
TT 
tetanus toxoid 
UK 
United Kingdom 
ULN 
upper limit of normal 
UAE 
United Arab Emirates 
USA 
United States of America 
WBC 
white blood cell 
WHO 
World Health Organization 
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1 Protocol synopsis 
Trial ID 
EudraCT no. 
LP0160-1396 
2019-001868-30 
Title of trial 
A phase 3, randomised, double-blind, multi-centre trial to evaluate the efficacy, 
safety, and tolerability of brodalumab treatment compared to placebo (blinded) 
and ustekinumab (open-label) in adolescent subjects (12–17 years of age) with  
moderate-to-severe plaque psoriasis 
Short title of trial 
Efficacy and safety of brodalumab in adolescents from 12 to 17 years of age 
with moderate-to-severe plaque psoriasis; EMBRACE 1 
Primary objective 
To determine the efficacy of subcutaneous administration of brodalumab 
compared with placebo in treating adolescents with moderate-to-severe plaque 
psoriasis. 
Primary endpoint, 
key secondary 
endpoints, and 
secondary 
endpoint for the 
primary objective 
Primary endpoint: 
• 
Having at least 75% improvement in Psoriasis Area and Severity Index 
(PASI) score from baseline (PASI 75 response), assessed at Week 12. 
Key secondary endpoints: 
• 
Static Physician’s Global Assessment (sPGA) score of 0 or 1, assessed at 
Week 12. 
• 
sPGA score of 0, assessed at Week 12. 
• 
PASI 90 response, assessed at Week 12. 
• 
PASI 100 response, assessed at Week 12. 
• 
Children’s Dermatology Life Quality Index (CDLQI) total score of 0 or 1, 
assessed at Week 12. 
Secondary endpoint: 
• 
Family Dermatology Life Quality Index (FDLQI) total score of 0 or 1, 
assessed at Week 12. 
Final collection of 
data for the 
primary endpoint 
Week 12. 
Trial design 
This trial is designed as a clinical phase 3, multi-centre, randomised, placebo-
controlled (double-blind until Week 12) and comparator-controlled (open-label 
ustekinumab) trial in which adolescents with moderate-to-severe plaque 
psoriasis will be treated with brodalumab, ustekinumab, placebo followed by 
brodalumab, or placebo followed by ustekinumab. 
The brodalumab arm and the 2 placebo arms will be double-blinded until 
Week 12 and the ustekinumab arm will be open-label throughout the entire 
trial. The trial will be unblinded after Week 12, but the efficacy assessments 
will be performed by an investigator who is blinded to the treatment allocation 
of all arms throughout the entire trial. 
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The trial consists of a screening period of 2 to 4 weeks (Week -4/-2 to Week 0), 
an induction period of 12 weeks (Week 0 to Week 12), a maintenance period of 
40 weeks (Week 12 to Week 52), and a safety follow-up period of 8 weeks 
(Week 52 to Week 60). 
Induction period from Week 0 to Week 12 
Subjects randomised at Week 0 to brodalumab or any of the 2 placebo arms 
will receive injections at Weeks 0, 1, 2, 4, 6, 8, and 10. The dose will be 
determined by the subject’s body weight at Week 0 (Day 1): 
• 
Subjects weighing 30 to <70 kg will receive 140 mg brodalumab (in a 
1.0 mL syringe) or 1.0 mL brodalumab placebo. 
• 
Subjects weighing ≥70 kg will receive 210 mg brodalumab (in a 1.5 mL 
syringe) or 1.5 mL brodalumab placebo. 
Subjects randomised at Week 0 to ustekinumab will receive injections at 
Weeks 0 and 4. The ustekinumab dose will be determined by the subject’s body 
weight at each dosing visit: 
• 
Subjects weighing 30 to <60 kg will receive 0.75 mg ustekinumab per kg 
body weight. 
• 
Subjects weighing ≥60 and ≤100 kg will receive 45 mg ustekinumab. 
• 
Subjects weighing >100 kg will receive 90 mg ustekinumab. 
Vaccination 
Subjects randomised at Week 0 to brodalumab or any of the 2 placebo arms 
will receive 1 dose of 0.5 mL of non-live T-cell-dependent tetanus toxoid (TT)-
containing vaccine at Week 8. The vaccine response will be evaluated at 
Week 12 and vaccine-related safety assessments will be evaluated throughout 
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the trial. Subjects randomised to ustekinumab only will not receive the 
vaccination.  
Maintenance period from Week 12 to Week 52 
Subjects randomised at Week 0 to either brodalumab or ustekinumab will 
continue on the allocated treatment until Week 52:  
• 
Subjects on brodalumab treatment will receive injections every 2 weeks 
from Week 12 to Week 50.  
• 
Subjects on ustekinumab treatment will receive injections at Weeks 16, 28, 
and 40. 
Subjects randomised to placebo followed by brodalumab will switch to 
brodalumab treatment during the maintenance period and receive brodalumab 
injections at Weeks 12, 13, 14, and then every 2 weeks until Week 50. The 
brodalumab dose will be determined by the subject’s body weight at Week 0: 
• 
Subjects weighing 30 to <70 kg at Week 0 will receive 140 mg 
brodalumab. 
• 
Subjects weighing ≥70 kg at Week 0 will receive 210 mg brodalumab. 
Subjects randomised to placebo followed by ustekinumab will switch to 
ustekinumab treatment during the maintenance period and will receive 
ustekinumab injections at Weeks 12, 16, 28, and 40. The ustekinumab dose will 
be determined by the subject’s body weight at each dosing visit: 
• 
Subjects weighing 30 to <60 kg will receive 0.75 mg ustekinumab per kg 
body weight. 
• 
Subjects weighing ≥60 and ≤100 kg will receive 45 mg ustekinumab. 
• 
Subjects weighing >100 kg will receive 90 mg ustekinumab. 
Rescue treatment 
From Week 4 and after, rescue treatment with topical corticosteroids (class I to 
IV, according to World Health Organization [WHO] classification of topical 
corticosteroids, as deemed appropriate by the investigator) is allowed in all 
4 treatment arms in subjects with an increase of ≥25% in PASI score from 
baseline (Week 0).  
Safety follow-up period from Week 52 to Week 60 
The subjects will be followed until Week 60. The 8-week follow-up period 
covers 5 half-lives of brodalumab and is appropriate for short-term safety 
evaluation after the treatment is completed.   
Main assessments 
Investigator efficacy assessments 
• 
PASI score. 
• 
sPGA score. 
Patient-reported outcomes for efficacy 
• 
CDLQI score. 
• 
FDLQI score. 
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Main criteria for 
inclusion 
• 
Subject was diagnosed with chronic plaque psoriasis at least 6 months 
before randomisation. 
• 
Subject has a diagnosis of moderate-to-severe plaque psoriasis as defined 
by PASI ≥12, sPGA ≥3, and body surface area ≥10% at screening and at 
baseline. 
• 
Subject, in whom topical therapy is not adequate, and who is a candidate 
for systemic therapy.  
• 
Subject’s immunisations are up-to-date according to national immunisation 
programme schedule as specified by country-specific paediatric health 
authorities. Missing an adolescent dose of combined tetanus, diphtheria, 
and pertussis (Tdap) or combined tetanus and diphtheria (Td) vaccine is 
accepted. 
• 
Subject has no evidence of active or latent tuberculosis according to local 
standard of care for patients requiring initiation of a biologic treatment.  
Main criteria for 
exclusion 
• 
Subject is diagnosed with erythrodermic psoriasis, pustular psoriasis, 
guttate psoriasis, medication-induced psoriasis, or other skin conditions 
(e.g., eczema). 
• 
Subject has been vaccinated with a TT-containing vaccine ≤18 months 
prior to first dose of investigational medicinal product (IMP). 
Subject has been vaccinated with a TT-containing vaccine within 5 years 
prior to the first dose of IMP - applicable for countries in EU + UK.  
• 
Subject has developed or experienced either Guillian-Barre syndrome, 
encephalopathy, Arthus-type hypersensitivity, or severe allergic reactions 
in connection with previous Tdap or Td vaccine. 
• 
Subject with chronic or recurrent infections, or active infection, 
systemically treated within 4 weeks prior to first dose of IMP.  
• 
Subject has a known history of Crohn’s disease.   
• 
Subject has any active malignancy or a history of any malignancy within 
5 years. 
• 
Subject has a history of suicidal behaviour and has suicidal ideation with 
some intent to act or specific plan and intent. 
• 
Subject has a history of depressive disorder with severe episode(s) within 
the last 2 years.   
• 
Subject has received anti-IL-12/23p40 for less than 12 months prior to the 
first dose of IMP or has previously no response to anti-IL-12/23p40 
therapy.  
• 
Subject has previously received anti-IL-17 therapy. 
Investigational 
medicinal 
products 
Brodalumab 
• 
Brodalumab is a recombinant fully human monoclonal immunoglobulin G 
(IgG)2 antibody that binds with high affinity to the human interleukin-17 
receptor A (IL-17RA) and blocks the interaction with IL-17A, IL-17E, and 
IL-17F. 
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• 
Active substance and concentration: brodalumab, 140 mg/mL. 
• 
Dosage form: solution for injection. 
• 
Method of administration: subcutaneous administration. 
Placebo 
• 
The brodalumab placebo solutions are similar to the active brodalumab 
solutions except that they do not contain any active substance. 
Ustekinumab 
• 
Ustekinumab is a human IgG1ĸ monoclonal antibody against the p40 
subunit of the IL-12 and IL-23 cytokines.  
• 
Active substance and concentration: ustekinumab, 90 mg/mL. 
• 
Dosage form: solution for injection. 
• 
Method of administration: subcutaneous administration. 
Tdap; vaccine including pertussis  
• 
A combined TT, diphtheria toxoid, and acellular pertussis vaccine 
(adsorbed, reduced antigen content). Each 0.5 mL dose is formulated to 
contain TT ≥20 IU, diphtheria toxoid ≥2 IU, pertussis toxoid 20 µg. 
• 
Dosage form: suspension for injection. 
• 
Method of administration: intramuscular administration. 
Td; vaccine not including pertussis  
• 
A combined TT and diphtheria toxoid vaccine (adsorbed, reduced antigen 
content). Each 0.5 mL dose is formulated to contain TT ≥20 IU and 
diphtheria toxoid ≥2 IU. 
• 
Dosage form: suspension for injection. 
• 
Method of administration: intramuscular administration. 
Duration of 
treatment 
The duration of the treatment phase for each subject is planned for 52 weeks 
including a 12-week induction period and a 40-week maintenance period. 
Number of 
subjects 
A total of 120 eligible subjects randomised in a 2:2:1:1 ratio to brodalumab 
(52 weeks of treatment), ustekinumab (52 weeks of treatment), placebo 
followed by brodalumab (brodalumab placebo the first 12 weeks of treatment 
and brodalumab the last 40 weeks), or placebo followed by ustekinumab 
(brodalumab placebo the first 12 weeks of treatment and ustekinumab the last 
40 weeks). 
Number and 
distribution of 
trial sites 
Approximately 75 sites mainly in Europe and Russia. 
Statistical 
methods 
Primary and key secondary endpoints 
The difference in response rates at Week 12 between the brodalumab arm and 
the pooled placebo arms will be analysed based on the Cochran-Mantel-
Haenszel (CMH) test stratified by baseline body weight (<70 kg, ≥70 kg). 
Missing data at Week 12 will be imputed using non-responder imputation. 
Additionally, subjects satisfying the requirements for rescue treatment prior to 
Week 12, will be defined as non-responders. Inference will be based on the p-
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value obtained from the CMH test. In order to quantify the difference in 
response rates, the common risk difference and associated 95% confidence 
interval, based on the CMH test, will also be reported.   
In order to control the familywise error rate, a hierarchical testing procedure, 
indictaing the order in which the primary and key secondary endpoints are to be 
tested, has been pre-specified.    
Signatory 
investigator 
 
 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark. 
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2 Trial identification 
EudraCT number: 2019-001868-30. 
The clinical trial protocol will be registered in local registries if required by local legislation. 
3 Schematic of trial design 
Panel 1: Trial design 
 
 
 
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a) 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 randomisation/baseline at 
Day 1. Visits outside the allowed visit window still need to be performed, taking into consideration that a minimum interval of 7 days must be kept between 2 administrations of 
brodalumab/placebo (except for Visit 3 and Visit 4, which are exempt from the 7-day gap requirement). 
b) All subjects who permanently discontinue IMP prematurely will be asked to attend an early termination visit, a safety follow-up visit (8 weeks after last IMP), and the subsequent 
primary and secondary endpoints visits (at Week 12, Week 16, and Week 52). The subjects will also be asked to continue in the trial and attend other than primary and secondary 
endpoints visits, if the subjects wish. Refer to Section 10 for further information. 
c) Unscheduled visit(s) may occur if subjects need to make a visit in between the scheduled visit dates e.g., due to an adverse event, difficulty complying with the trial protocol 
requirements, or a significant change in their disease state.  
d) The informed consent/assent form(s) must be signed prior to performing any protocol-related procedures. If the subject reaches legal age during the trial, the subject will be 
consented to the most current version of the informed consent form if required by national laws or regulations. 
e) Subjects must be randomised as soon as all inclusion and exclusion criteria are confirmed (including the central laboratory and ECG results from the screening visit). 
f) Assessed daily by the subject. Completion of the eDiary will be initiated at the latest 1 week prior to baseline at Day 1. The eDiary will be returned at the last visit. 
g) Only subjects randomised to either brodalumab or placebo. 
h) Only female subjects.  
i) Only female subjects. If a urine pregnancy test (human chorionic gonadotropin) is positive, a serum pregnancy test has to be done to confirm the result. At screening, a serum 
pregnancy test is always performed regardless of the urine pregnancy result. 
j) In case of abnormal dipstick results, a urine sample will be sent to the central laboratory for microscopic examination (leukocytes, erythrocytes, and casts). 
k) Photography will require additional informed consent. If deemed necessary (e.g. in case of poor quality), photographs can be retaken. 
l) An end of treatment form must be completed in the electronic case report form (eCRF) for all randomised subjects, including subjects who permanently discontinue IMP treatment 
prematurely. 
m) An end of trial form must be completed in the eCRF for all randomised subjects, including subjects who permanently discontinue IMP treatment prematurely or withdraw from the 
trial, at their last trial visit. 
 
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j) Only applicable for home-based IMP administration; home-based administration of brodalumab is allowed (after proper training) at Week 18 (Day 127±3), Week 22 (Day 155±3), 
Week 24 (Day 169±3), Week 26 (Day 183±3), Week 30 (Day 211±3), Week 34 (Day 239±3), Week 38 (Day 267±3), Week 42 (Day 295±3), Week 46 (Day 323±3), and Week 50 
(Day 351±3). Subjects who refuse to do home-based IMP administration can have the IMP administered at the trial site at these weeks. 
k) Photography will require additional informed consent. If deemed necessary (e.g. in case of poor quality), photographs can be retaken. 
l) An end of treatment form must be completed in the eCRF for all randomised subjects, including subjects who permanently discontinue IMP treatment prematurely. 
m) An end of trial form must be completed in the eCRF for all randomised subjects, including subjects who permanently discontinue IMP treatment prematurely 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 disorder that occurs in approximately 
2% of the population worldwide (1, 2), and it affects 0.7 to 1.2% of children younger than 18 
years worldwide (3). 
It has been demonstrated that the psoriasis prevalence in children correlates in a linear manner 
with age. The prevalence is low in the age range of 0 to 6 years (4), and increasing during 
adolescence. Approximately 30 to 40% of adults with psoriasis report signs and symptoms 
before the age of 16 years (5). 
Psoriasis is a chronic polygenic inherited disease of uncontrolled cutaneous inflammation that 
manifests, in the majority of patients, as plaque psoriasis, clinically seen as sharply 
demarcated, elevated, scaly, erythematous plaques located predominantly on the scalp, 
extensor sides of elbows and knees, and the sacral region (6, 7, 8). The skin lesions can be 
painful, pruritic, and may cause significant emotional and physical discomfort (9). In general, 
childhood psoriasis presents in much the same way as in adults, typically with plaque-type 
lesions localised to the scalp, elbows, and knees (10). However, precipitating factors are more 
important in paediatric- than adult-onset psoriasis. For example, the appearance of psoriatic 
lesions may occur in uninvolved skin at sites of trauma (Koebner phenomenon), and 
psychological factors such as stress have also been reported to initiate paediatric psoriasis (11, 
12). In addition to skin manifestations, paediatric psoriasis is associated with multiple 
comorbidities. Increased rates of hyperlipidaemia, obesity, hypertension, diabetes mellitus, 
metabolic syndrome, polycystic ovarian syndrome, Crohn’s disease, and rheumatoid arthritis 
are found in adolescents with psoriasis (2, 13). Recently, a non-alcoholic fatty liver disease 
screening in children with psoriasis and excess adiposity has been proposed (14), 
acknowledging the fact of this comorbidity (13) and the importance of the early diagnose, 
when systemic treatment is indicated. Joint involvement with psoriatic arthritis is less 
common in younger psoriatic patients, but it does occur in 5-10% (15). When managing the 
paediatric psoriasis a significantly greater risk of anxiety and depression compared with the 
controls should be taken into consideration (16). 
Treatment options are similar to those of adults, but many therapeutic agents are not approved 
for use in children and guidelines are generally lacking for this population. Topical therapy in 
childhood is the recommended first-line treatment for skin-related diseases, and most children 
can be managed effectively with topical agents (e.g., emollients, corticosteroids, calcipotriol, 
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and coal tar). Approximately 8% of adolescents require phototherapy or systemic psoriasis 
therapy, which is typically reserved for patients with severe disease (5). 
5.2 Experience with investigational medicinal product 
Brodalumab is a recombinant fully human monoclonal immunoglobulin G (IgG)2 antibody 
that binds with high affinity to human interleukin (IL)-17 receptor A (IL-17RA), thereby 
blocking the IL-17 pathway. Brodalumab is currently approved in the EU, UK, UAE, Japan, 
Taiwan, Thailand, Hongkong, China, Canada, and the USA for treatment of moderate-to-
severe plaque psoriasis in adult patients who are candidates for systemic therapy. 
Blocking IL-17RA inhibits IL-17 cytokine-induced inflammatory responses and results in 
reduced or normalised inflammation of the skin in patients with psoriasis. Ixekizumab and 
secukinumab also target the IL-17 pathway by inhibiting the biological activity of IL-17A. 
But by blocking IL-17RA (the receptor), brodalumab also inhibits the biological activity on 
this receptor by other interleukins in the IL-17 family than IL-17A (namely, IL-17F, IL-17A/F 
heterodimer, and IL-17E also known as IL-25) (17). 
The approved dose regimen for brodalumab for the treatment of moderate-to-severe plaque 
psoriasis in adults is 210 mg by subcutaneous injection at Weeks 0, 1, and 2 followed by 
210 mg every 2 weeks. 
The efficacy of brodalumab for treatment of psoriasis in adults has been confirmed in 
3 placebo-controlled, clinical phase 3 trials, 2 of which also included an active comparator 
arm with ustekinumab. The overall benefit-risk profile of brodalumab was shown to be 
positive in the treatment of adults with moderate-to-severe plaque psoriasis regardless of 
baseline demographics and the subpopulations studied. 
In a population pharmacokinetic (PK) analysis of brodalumab, body weight was found to be a 
significant predictor of systemic exposure of brodalumab (expressed as area under the serum 
concentration-time curve [AUC] at Week 10–12) in the body weight range tested (39–234 kg) 
(18). Simulated systemic exposure across observed body weight quintiles shows a decrease of 
exposure with increasing body weight (Panel 4). 
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Panel 4: Simulated systemic exposure (AUC at Week 10-12 dosing Q2W+1) across 
observed body weight quintiles by dosing regime 
Dosage 
Weight group Median AUC 
(µg day/mL) 
90% prediction 
interval 
140 mg Q2W+1 
39 - 72 kg 
98.9 
[34.6, 315.6] 
72 - 83 kg 
57.8 
[23.2, 169.7] 
83 - 93 kg 
46.6 
[17.6, 141.7] 
93 - 107 kg 
34.9 
[12.6, 106.7] 
107 - 234 kg 
23.5 
[6.8, 68.9] 
210 mg Q2W+1 
39 - 72 kg 
293.3 
[109.9, 682.4] 
72 - 83 kg 
209.7 
[83.5, 478.3] 
83 - 93 kg 
171.6 
[62.6, 379.8] 
93 - 107 kg 
134.0 
[47.7, 338.6] 
107 - 234 kg 
91.5 
[31.3, 238.1] 
Abbreviation: AUC, area under the serum concentration-time curve; Q2W+1, dosing at Weeks 0, 1, 2, and every 
2 weeks thereafter. 
Based on the body weight distribution in the phase 3 trials, serum concentration-time profiles were simulated 
and systemic exposure (AUC at Week 10-12) was hereafter calculated. Summary statistics (median and 90% 
prediction interval) of the AUCs are provided for each body weight quintile. Source: 18.  
 
A lower systemic exposure is apparently associated with a lower frequency of static 
Physician’s Global Assessment (sPGA) response, both for sPGA 0/1 and sPGA 0 (Panel 5). 
Based on logistic regression, the AUC needed for 50% and 90% achievement of sPGA 0/1 at 
Week 12 are 34.8 and 159.8 μg*day/mL, respectively.  
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Panel 5: Week 12 sPGA response by quintiles of predicted AUCweek 10-12 for the phase 3 
population studied for 210 mg Q2W+1 brodalumab 
 
Abbreviations: AUC, area under the serum concentration-time curve; Q2W+1, dosing at Weeks 0, 1, 2, and 
every 2 weeks thereafter; PK, pharmacokinetics; sPGA, static Physician’s Global Assessment.  
Individual AUCs (Week 10-12) were calculated based on the individual population PK model parameter 
estimates and paired with the individual sPGA response. For each AUC quintile, the percentage of sPGA 0/1 and 
sPGA 0 were calculated. 
Comparing the Psoriasis Area and Severity Index (PASI) improvement versus body weight 
and dose (Panel 6) also shows a relationship between body weight and response at both dose 
levels of brodalumab (140 mg and 210 mg). Furthermore, data show that increasing the dose 
from 140 mg to 210 mg at Weeks 0, 1, 2, and every 2 weeks thereafter results in an increased 
mean PASI response for all body weight groups above 70 kg. For patients with a body weight 
below 70 kg, no statistical significant difference was seen between the PASI response in the 
140 mg and 210 mg dose groups. 
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Panel 6: Summary of mean PASI improvement from baseline (LOCF) at Week 12 by 
weight class and treatment (full analysis set) 
 
Abbreviations: LOCF, last observation carried forward; PASI, Psoriasis Area Severity Index. 
Source: Module 5.3.5.3 Summary of weight-based dosing, Table 6. 
5.3 Trial rationale and justification for dose 
5.3.1 
Trial rationale 
Brodalumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adult 
patients who are candidates for systemic treatment. Brodalumab’s mode of action is to bind to 
and block IL-17RA. It has been reported, that numbers of circulating Th17 cells in children 
with psoriasis are increased and positively correlated with the disease severity (19), indicating 
that brodalumab treatment might be as effective in the paediatric population as it is in adults. 
This trial is part of the paediatric investigational plan agreed with the Paediatric Committee 
(PDCO) and the European Medicines Agency (EMA) to investigate whether brodalumab is 
efficacious and safe in treating adolescents from 12 to 17 years of age with moderate-to-
severe plaque psoriasis. The PK data from this trial will be used to determine the appropriate 
dose of brodalumab to be used in a planned future trial with subjects from 6 to 11 years of 
age. 
Since vaccination programmes are an important part of health maintenance, the World Health 
Organization (WHO) as well as paediatric authorities worldwide recommend that infants, 
children, and adolescents follow a child vaccination schedule of the country of residence, it is 
therefore also relevant to investigate if brodalumab affects development of vaccination-
induced immune responses. This trial will assess immunisation responses against tetanus 
toxoid (TT)-containing vaccine (a combined tetanus, diphtheria, and acellular pertussis 
[hereinafter referred to as ‘Tdap’] vaccine or a combined tetanus, diphtheria vaccine 
[hereinafter referred to as ‘Td’] in adolescents with moderate-to-severe plaque psoriasis. The 
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selected types of T-cell-dependent vaccines are known to result in an immune response 
involving both T- and B-cells as well as other key cell types of the immune system. Further 
considerations regarding the vaccines are provided in Section 5.4. 
5.3.2 
Justification for dose 
The PK of brodalumab has been well-described in a population PK analysis including both 
healthy adults and adults with psoriasis, where body weight was found to be a significant 
predictor of brodalumab systemic exposure (18). Age was not found to be a significant 
predictor of brodalumab exposure, but due to the correlation between body weight and age in 
the paediatric population, a change in dose is warranted for the adolescent population.  
The planned dose levels of brodalumab in this trial are:  
• Subjects with a body weight of less than 70 kg will receive 140 mg at Weeks 0, 1, 2, and 
every 2 weeks thereafter.  
• Subjects with a body weight 70 kg or more will receive 210 mg at Weeks 0, 1, 2, and 
every 2 weeks thereafter. 
Due to the impact of body weight on systemic exposure, a dose level of 140 mg in subjects 
with a body weight below 70 kg will result in systemic exposures below the target exposure 
of an 80 kg adult subject. However, the efficacy data show no difference in efficacy between 
140 and 210 mg dose levels for adult subjects below 70 kg. Given that the PK of brodalumab 
in adolescent subjects has not yet been established, a conservative dosing strategy has been 
chosen, justifying a reduction in dose compared to what is recommend in the adult population.     
The brodalumab dose will be based on the subject’s body weight at baseline (Week 0, Day 1) 
and will not be changed during the trial. 
5.4 Ethical considerations  
The trial design chosen for this efficacy and safety trial with brodalumab is regarded as 
ethically justified and adherent with ethical requirements. 
Participation in this trial is voluntary and subjects can withdraw at any time. The subject’s 
legally authorised representative(s) will give informed consent, and subjects must give their 
informed consent (assent) as appropriate and according to national laws and regulations. No 
vulnerable subjects incapable of giving informed consent will be enrolled in this clinical trial. 
Furthermore, female subjects who are pregnant, breastfeeding, or trying to become pregnant 
will not be enrolled. Female subjects must agree to use highly effective methods of 
contraception, e.g., preferred in adolescents hormonal contraception associated with inhibition 
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of ovulation (oral, intravaginal, transdermal) or progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, implantable), to prevent pregnancy 
during the clinical trial and until 12 weeks after discontinuation of treatment with brodalumab 
or until 15 weeks after discontinuation of treatment with ustekinumab. In addition, all female 
subjects will have pregnancy tests performed before, during, and at end of trial to ensure that 
the administration of the investigational medicinal product (IMP) will be discontinued upon 
confirmation of pregnancy to minimise the exposure of the foetus to the IMP. 
To ensure safety of the trial subjects, investigators are informed only to enrol subjects they 
expect can complete wash out of previous psoriasis medications during the screening period 
without experiencing intolerable worsening of psoriasis symptoms. The subjects and/or their 
legally authorised representatives will be informed to contact the investigator if the subject’s 
psoriasis worsens.  
Paediatric plaque psoriasis is a chronic, relapsing disease that can cause significant morbidity, 
multiple somatic and psychiatric comorbidities (13, 20) and psychosocial stress for children 
and adolescents.  
Treatment with topical corticosteroids is the most commonly utilised treatment in children 
with psoriasis, and is typically sufficient to control mild skin disease, which is the majority of 
cases. For patients with moderate disease, combination therapy or phototherapy can be 
effective (21, 22). However, for some paediatric patients with moderate-to-severe plaque 
psoriasis who have widespread disease, or disease refractory to topical combination or 
phototherapy, there continues to be an unmet medical need.  
For many systemic agents, including some biologic therapies, efficacy and safety have not 
been established in paediatric patients and the treatments are not licensed for paediatric use. 
Biologic therapies, which are available or in development, offer the potential to address this 
deficit in the care of paediatric patients with plaque psoriasis. Currently, the approved 
therapies for paediatric psoriasis include: etanercept from age ≥6 years, ustekinumab from 
age ≥12 years, and adalimumab from age ≥4 years (EMA) (15). In adults, brodalumab is more 
effective in achieving clearance than ustekinumab, etanercept, and adalimumab (23, 24, 25); 
based on a direct comparison for ustekinumab and a systemic review and network meta-
analysis study for etanercept and adalimumab. Given that, brodalumab has the potential to 
improve the care of paediatric patients with psoriasis and provide a solid therapeutic benefit.  
The efficacy of brodalumab will be evaluated in this placebo-controlled trial in adolescents 
with moderate-to-severe plaque psoriasis who are otherwise healthy. Recognising that 
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prolonged placebo treatment is not optimal in this population, a 2:2:1:1 (brodalumab: 
ustekinumab:placebo followed by brodalumab:placebo followed by ustekinumab) 
randomisation is planned to increase the opportunity for subjects to receive active treatment. 
Subjects randomised to placebo will, after 12 weeks of treatment, receive active treatment 
with either brodalumab or ustekinumab. The placebo control is considered to provide the best 
design for an efficient assessment of both benefit and risk in adolescents. The placebo 
treatment from Week 0 until Week 12 will enable a formal test of superiority, comparing 
brodalumab with placebo in a double-blind manner. Demonstrating superiority to placebo will 
require fewer paediatric subjects than would be required to demonstrate superiority to an 
active comparator. This will enable to minimise the number of paediatric subjects required for 
the trial while maintaining a high statistical power. Minimising the number of subjects is an 
important ethical aspect, especially in the paediatric population, and this trial design is 
consistent with this requirement. In addition, all subjects in this trial may receive rescue 
treatment if the severity of their disease increases by more than 25% 4 weeks after baseline.  
The WHO guidelines recommend that a booster dose of TT-containing vaccine is given at age 
4 to 7 years (first booster) and another booster dose (second booster) is given in adolescence 
(i.e., at age 12 to 15 years). Immunisation guidelines for children and adolescents across 
European countries, USA, and Australia, developed by country-specific paediatric authorities, 
have implemented a second booster dose of an adult formulation of Tdap, which is routinely 
given between 9 and 17 years of age almost worldwide (26, 27). Tdap replaced the adolescent 
dose of Td to prevent increasing reports of pertussis among adolescents. The subjects to be 
enrolled in the current trial are between 12 and 17 years of age. To date, only few data on 
vaccination coverage of TT-containing vaccine in adolescents in Europe are available. A 
French study reports that 85% of school children aged 14 to 15 years are up-to-date for 
diphteria, tetanus, and pertussis (28). According to data from the Danish State Serum Institute, 
84% of children born in 2006 are covered with TT-containing vaccine (29). In the USA, up to 
52.1% of adolescents have received the Tdap vaccine (30). Thus, the subjects who have not 
yet received the scheduled adolescent dose of Td/Tdap will be vaccinated with a booster 
based on the subject’s previous history of vaccination with TT-containing vaccines and 
current local guidelines.   
The ethical considerations for including the subjects covered by Tdap have been thoroughly 
evaluated and are supported by available scientific data. It has been reported that 23% of 
healthy adolescents from 13 to 15 years of age who have received at least 6 doses of diphteria 
toxoid as a part of their scheduled vaccination programme were missing the protective level 
of diphteria antibodies. 68% had basic protection between 0.1-1.0 IU/mL and only 11% had 
high protection levels above 1.0 IU/mL, corresponding to a long-term protection (31). 
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Another study reports a diphteria antitoxin geometric mean level of 0.71 IU/mL in 88% of 
adolescents who had received 6 doses and the percentage of subjects with the protective levels 
of antibodies against diphteria decreases further after 20 years of age (32). An immediate 
booster vaccination is recommended when IgG levels of anti-diphteria toxoid antibodies are 
0.1-1.0 IU/mL (33). Moreover, children with autoimmune disorders receiving 
immunosuppressive medication show decreased in vitro lymphocyte proliferation in response 
to tetanus antigen (34) and a lower geometric mean concentration of antibodies against 
diphteria and tetanus is found in children suffering from juvenile idiopathic arthritis compared 
with healthy controls (35). Based on the above evidence, a booster dose of Td vaccine during 
the trial will ensure long-term protective levels of anti-diphteria and -tetanus antibodies, 
resulting in better protection against these diseases.    
The vaccination and withdrawal of blood samples planned in the trial expect to give no 
greater harm or discomfort than if done during routine diagnostic venipuncture procedure or 
scheduled vaccination. The amount of blood to be collected in the trial is calculated according 
to the current guidelines (36) and will not exceed 3% of total blood volume during a period of 
4 weeks and 1% at any single time for all trial subjects. Qualified trial personnel with 
experience in paediatric venipuncture will conduct the invasive procedures required in the 
trial. Furthermore, local anesthesia and/or “virtual reality” tools can be applied to reduce 
discomfort and/or pain that might be caused by venipuncture, unless the trial subjects do not 
want to use any.   
Suicidal ideation and behaviour (SIB) events, including completed suicide, have been 
reported in subjects treated with brodalumab. However, the majority of subjects with suicidal 
behaviour had a history of depression and/or SIB, and a causal association between treatment 
with brodalumab and increased risk of SIB is not indicated. Trial subjects will be monitored 
for depression and SIB by the Patient Health Questionnaire-9 modified for adolsecents 
without question number 9 (PHQ-A) and the Columbia-Suicide Severity Rating Scale 
questionnaires (C-SSRS). The investigator must discontinue subjects from trial treatment in 
case of C-SSRS suicidal ideation level 4 or 5, any suicidal behaviour, or a PHQ-A score ≥15, 
corresponding to moderate to severe depression (37). Furthermore, adolescents with a recent 
history of depression (within 2 years), C-SSRS suicidal ideation level 4 or 5 (that is, ‘some 
intent to act, no plan’ or ‘specific plan and intent’), or any suicidal behaviour (that is, ‘actual 
suicide attempt’, ‘interrupted attempt’, ‘aborted attempt’, or ‘preparatory actions’) are not 
allowed to participate in the trial since a history of prior depression and/or SIB are known risk 
factors for new SIB events. 
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In accordance with the current version of the ICH Good Clinical Practice (GCP) guidelines, 
qualified medical personnel employed by LEO Pharma A/S (hereafter referred to as LEO 
Pharma) will be readily available to advise on trial-related medical questions. Medical 
monitoring will be performed throughout the trial. In addition, an independent data 
monitoring committee (DMC, see Appendix 3H) is set up to review the clinical data ensuring 
safety of the trial subjects. 
5.5 Benefit/risk assessment 
There is an unmet medical need for highly effective new therapies for use in adolescents with 
moderate-to-severe psoriasis as currently approved immunosuppressive medications either 
have long-term toxicities or a less efficacious profile.   
Brodalumab is currently approved for adults in the EU, UK, UAE, Japan, Taiwan, Thailand, 
Hongkong, China, Canada, and the USA. Comprehensive efficacy, safety, and PK data related 
to the administration of brodalumab in adults with moderate-to-severe psoriasis are available. 
These data provide sufficient support to initiate this clinical phase 3 trial in adolescents with 
moderate-to-severe psoriasis with a body weight of 30 kg or above at baseline. For this trial, 
adolescents with a body weight below 30 kg are not allowed to participate. Based on the 
weight references for boys and girls between 12 and 17 years of age in Europe, it can be 
expected that 95% of the subjects will be in the weight range from 30 to 95 kg (38, 39). 
In the clinical phase 3 programme for brodalumab in adults, the only adverse events (AEs) 
that showed dose dependency were infections and neutropenia. These may occur with 
increased frequency in subjects receiving a higher dose of brodalumab. A PK modelling and 
simulation approach based on a population PK model for brodalumab in adults (18), 
combined with the efficacy results from the phase 3 trials in adults (see Panel 6), has been 
used to support the choice of the optimal brodalumab doses in adolescents. A lower dose of 
brodalumab has been chosen for adolescents with a body weight less than 70 kg to ensure the 
sufficient safety and optimal efficacy profile in this paediatric population (see Section 5.3.2). 
The active comparator (i.e., ustekinumab) is part of the standard treatment of moderate-to-
severe plaque psoriasis in adolescents from the age of 12 years who are inadequately 
controlled by, or intolerant to, other systemic therapies or phototherapies in Europe. All 
subjects, participating in the trial will receive effective biologic therapy (brodalumab or 
ustekinumab) during the maintenance period and it is expected that many will experience a 
significant reduction of psoriasis symptoms. The frequent clinical monitoring and contacts 
with trial site personnel will increase the quality of subject’s psoriasis care as well as the 
understanding of the disease. The subjects will also become familiar with self-injections. This 
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will enable a safe and effective home-based administration of any other biologic therapies in 
the future.  
The risk to subjects in this trial will be minimised by fulfilment of all eligibility criteria and 
by close clinical monitoring. Measures are in place in this trial as follows:   
• Exclusion of subjects with untreated systemic infections or low complete blood count (see 
Section 8.3).  
• Exclusion of subjects with active or latent tuberculosis (see Section 8.3). 
• Close safety monitoring of subjects throughout the treatment phase (see the schedule of 
trial procedures in Section 4).  
• Safety monitoring of the subjects after completed treatment phase (further details are 
given in Section 7.1.4).   
It is expected that many of the eligible subjects will have been immunised with Tdap within 
the past 5 years and thus should not be immunised with a Tdap booster during the trial. 
However, these subjects can safely receive a Td booster dose during the trial. The safety of 
Tdap and Td/TD administration at different intervals has been studied in 7156 children and 
adolescents. The study reports that Tdap can be safely administered at intervals as short as 
18 months after a previous Td/TD vaccine. Among the study subjects with most recent prior 
Td/TD vaccine, injection site erythema was slightly increased and swelling was significantly 
increased, however, no Arthus-like reactions or serious AEs were reported (40). The safety of 
Tdap vaccination less than 2 years following prior tetanus vaccination has also been evaluated 
among healthcare personnel and pregnant women. None of the studies found an increase rate 
of moderate-to-severe vaccine-related AEs in those vaccinated less than 2 years after the 
previous Td vaccine compared with those vaccinated 2 years or more after the previous Td 
vaccine (41, 42). The above-mentioned studies provide evidence that it is safe to include 
adolescents with a history of prior TT-containing vaccine, administered no later than 
18 months prior to the first dose of trial treatment. Tdap booster can be administered at 
intervals as short as 5 years since the initial Tdap booster and is well-tolerated and 
immunogenic in adolescents (43). The vaccination history of every single subject will be 
carefully evaluated by the investigator, and the appropriate TT-containing vaccine will be 
administered during the trial.  
Live vaccines will not be allowed during the trial. Inactivated or non-live vaccines, including 
COVID-19 vaccines, will be allowed from Week 12.  
Altogether, the risks associated with participating in this clinical trial are considered low and 
outweighed by the benefit of a potentially improved future treatment option for adolescents, 
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with a body weight of 30 kg or more, suffering from psoriasis. There is an opportunity for a 
positive treatment effect for the subjects participating in this clinical trial based on currently 
available clinical data. 
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6 Trial objectives and endpoints 
Panel 7: Primary objective and endpoints supporting the primary objective 
Primary objective 
Endpoints supporting the primary objective 
To determine the efficacy 
of subcutaneous 
administration of 
brodalumab compared with 
placebo in treating 
adolescents with moderate-
to-severe plaque psoriasis. 
 
 
Primary endpoint: 
• 
Having at least 75% improvement in Psoriasis Area and 
Severity Index (PASI) score from baseline 
(PASI 75 response), assessed at Week 12. 
Key secondary endpoints: 
• 
Static Physician’s Global Assessment (sPGA) score of 0 or 1, 
assessed at Week 12. 
• 
sPGA score of 0, assessed at Week 12. 
• 
PASI 90 response, assessed at Week 12. 
• 
PASI 100 response, assessed at Week 12. 
• 
Children’s Dermatology Life Quality Index (CDLQI) total 
score of 0 or 1, assessed at Week 12.  
Secondary endpoint: 
• 
Family Dermatology Life Quality Index (FDLQI) total score 
of 0 or 1, assessed at Week 12. 
Other endpoints: 
• 
Change from baseline in Adolescent Pruritus numeric rating 
scale (NRS) (weekly average), assessed at Week 12. 
• 
Improvement of at least 4 units in Adolescent Pruritus NRS 
(weekly average), assessed at Week 12. 
• 
Change from baseline in Itch-related Sleep NRS (weekly 
average), assessed at Week 12. 
Abbreviations: CDLQI, Children’s Dermatology Life Quality Index; FDLQI, Family Dermatology Life 
Quality Index; NRS, numeric rating scale; PASI, Psoriasis Area Severity Index; sPGA, static Physician’s 
Global Assessment.  
 
 
 
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Panel 8: Secondary objectives and endpoints supporting the secondary objectives 
Secondary objectives 
Endpoints supporting the secondary objectives 
To evaluate the efficacy 
of brodalumab 
compared with 
ustekinumab in treating 
adolescents with 
moderate-to-severe 
plaque psoriasis. 
Other endpoints: 
• 
PASI 75 response, assessed separately at Week 12 and Week 52. 
• 
PASI 90 response, assessed separately at Week 12 and Week 52. 
• 
PASI 100 response, assessed separately at Week 12 and Week 52. 
• 
sPGA score of 0 or 1, assessed separately at Week 12 
and Week 52. 
• 
sPGA score of 0, assessed separately at Week 12 and Week 52. 
• 
CDLQI total score of 0 or 1, assessed separately at Week 12 and 
Week 52. 
• 
FDLQI total score of 0 or 1, assessed separately at Week 12 
and Week 52. 
• 
Change from baseline in Adolescent Pruritus NRS (weekly 
average), assessed at Week 12 and Week 52. 
• 
Improvement of at least 4 units in Adolescent Pruritus NRS 
(weekly average), assessed separately at Week 12 and Week 52. 
• 
Change from baseline in Itch-related Sleep NRS (weekly 
average), assessed at Week 12 and Week 52. 
To evaluate the safety  
of brodalumab 
compared with placebo 
(until Week 12) and 
ustekinumab 
(throughout the trial) in 
adolescents with 
moderate-to-severe 
plaque psoriasis. 
Secondary endpoints: 
• 
Occurrence of adverse events (AEs) up to Week 60. 
• 
Presence of anti-drug antibodies (ADA), assessed at Weeks 4, 16, 
and 52. 
• 
Serum concentration of interleukin-17 (IL-17) and blood levels of 
T-cell subsets (CD4+ and CD8+), assessed at Weeks 8, 12, and 52. 
Other endpoints: 
• 
Laboratory toxicity, assessed at Weeks 4, 16, and 52. 
• 
Vital signs, assessed at Weeks 4, 16, and 52. 
• 
Blood levels of T-helper cells (Th1, Th17, and Th22), assessed at 
Weeks 8, 12, and 52. 
• 
Concentration of blood biomarkers, assessed at Weeks 8, 12, and 
52. 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) score up to 
Week 60. 
• 
Patient Health Questionnaire-9 modified for adolescents without 
question number 9 (PHQ-A) score up to Week 60.  
 
1 (2) 
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Panel 8: Secondary objectives and endpoints supporting the secondary objectives 
(continued) 
Secondary objectives 
Endpoints supporting the secondary objectives 
To evaluate the 
pharmacokinetics of 
brodalumab in adolescents 
with moderate-to-severe 
plaque psoriasis. 
Secondary endpoint: 
• 
Serum concentrations of brodalumab, assessed at Weeks 4, 8, 
10, 12, 16, 22, and 52. 
Other endpoint: 
• 
Area under the serum concentration-time curve at Weeks 10-
12, derived using all available concentrations in Weeks 0-52. 
To evaluate the 
immunogenicity of a 
tetanus toxoid (TT)-
containing vaccine in 
adolescents with moderate-
to-severe plaque psoriasis 
who are treated with 
brodalumab or placebo. 
Secondary endpoint:  
• 
Anti-tetanus toxoid antibodies (aTTA) ≥0.1 IU/mL, assessed 
at Week 12 (post-vaccination). 
Other endpoints: 
• 
Change from baseline in lymphocyte subsets (CD4+, CD8+, 
and CD19+), assessed at Week 12 (post-vaccination). 
• 
Change from baseline in aTTA, assessed at Week 12 
(post-vaccination). 
• 
Booster response to TT-containing vaccine, defined as: 
o 3-fold increase of aTTA, assessed at Week 12, if subject 
has an aTTA ≤1.0 IU/mL at Week 0. 
o ≥2.5 IU/mL increase of aTTA, assessed at Week 12, if 
subject has an aTTA>1.0 IU/mL at Week 0. 
• 
Change from baseline in aTTA, assessed at Week 8 
(pre-vaccination). 
Abbreviations: ADA, anti-drug antibodies; AEs, adverse events; aTTA, anti-tetanus toxoid antibodies;       2 (2) 
C-SSRS, Columbia-Suicide Severity Rating Scale; CDLQI, Children’s Dermatology Life Quality Index;  
FDLQI, Family Dermatology Life Quality Index; IL-17, interleukin-17; NRS, numeric rating scale; 
PASI, Psoriasis Area Severity Index; PHQ-A, Patient Health Questionnaire-9 modified for adolescents, 
without question number 9; sPGA, static Physician’s Global Assessment; Th, T-helper; TT, tetanus toxoid.                 
 
Estimands 
The applied estimands, addressing different aspects of the trial objectives, are defined and 
discussed in Section 14.3.6. 
 
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7 Trial design 
7.1 Overall trial design  
7.1.1 
Overview of the trial design 
This is a clinical phase 3, randomised, placebo-controlled and comparator-controlled trial 
designed to evaluate the efficacy, safety, tolerability, and PK of brodalumab treatment in 
adolescents (from 12 to 17 years of age) with moderate-to-severe plaque psoriasis.  
A schematic of the trial design is provided in Panel 1. The trial design includes 4 periods: 
• A screening period of up to 4 weeks (Week -4/-2 to Week 0).  
• An induction period of 12 weeks (Week 0 to Week 12 - treatment phase). 
• A maintenance period of 40 weeks (Week 12 to Week 52 - treatment phase). 
• A safety follow-up period of 8 weeks (Week 52 to Week 60 - off-treatment phase).  
The trial periods are further described in Sections 7.1.2, 7.1.3.3, and 7.1.4. Eligible trial 
participants will be randomised at Week 0 (Day 1) to 1 of the following 4 treatment arms in a 
2:2:1:1 ratio:  
• Brodalumab (brodalumab for 52 weeks of treatment). 
• Ustekinumab (ustekinumab for 52 weeks of treatment).  
• Placebo followed by brodalumab (brodalumab placebo for the first 12 weeks of treatment 
and brodalumab for the last 40 weeks). 
• Placebo followed by ustekinumab (brodalumab placebo for the first 12 weeks of treatment 
and ustekinumab for the last 40 weeks).  
The brodalumab arm and the placebo arms will be double-blinded until Week 12 (Week 0 to 
Week 12). The ustekinumab treatment will be open-label throughout the treatment phase 
(Week 0 to Week 52). The blinding is further described in Section 9.3.1. 
A schedule of all trial-specific assessments are provided in Panel 2 (screening and induction 
period) and Panel 3 (maintenance and safety follow-up periods), and all assessments are 
further described in Section 11. 
It will be recorded in the eCRF if a visit was performed. If not, a reason will be provided, 
including whether the reason for the missed visit was due to pandemic restrictions. 
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7.1.2 
Screening period (Week -4 to Week 0) 
A screening visit will occur within 28 days prior to initiation of the treatment phase in this 
trial. At the screening visit, the subjects’ eligibility to enter the trial will be checked. This 
could entail wash out of medications that are not allowed; all prohibited medications are listed 
in Panel 12. The eligibility criteria are listed in Section 8. 
7.1.3 
Treatment phase (Week 0 to Week 52) 
7.1.3.1 
Induction period (Week 0 to Week 12) 
The treatment phase begins with a 12-week induction period.  
Subjects randomised to the brodalumab arm or any of the placebo arms will receive 
subcutaneous injections of brodalumab or brodalumab placebo at Weeks 0, 1, 2, 4, 6, 8, and 
10. The dose will be determined by the subject’s body weight at Week 0 (Day 1): 
• Subjects weighing 30 to <70 kg will receive 140 mg brodalumab in 1.0 mL solution or 
brodalumab placebo in 1.0 mL solution. 
• Subjects weighing ≥70 kg will receive 210 mg brodalumab in 1.5 mL solution or 
brodalumab placebo in 1.5 mL solution. 
Subjects randomised to ustekinumab will receive subcutaneous injections of ustekinumab at 
Weeks 0 and 4. The ustekinumab dose will be determined by the subject’s body weight at 
each dosing visit: 
• Subjects weighing 30 to <60 kg will receive 0.75 mg ustekinumab per kg body weight. 
• Subjects weighing ≥60 and ≤100 kg will receive 45 mg ustekinumab. 
• Subjects weighing >100 kg will receive 90 mg ustekinumab.  
 
7.1.3.2 
Vaccination (Week 8) 
Subjects randomised to the brodalumab arm or any of the placebo arms will receive an 
intramuscular injection of 0.5 mL non-live T-cell-dependent TT-containing vaccine at Week 8 
to evaluate the vaccine response during treatment with brodalumab:  
• Subjects who have received either a combined tetanus and diphtheria (Td) vaccine for 
more than 18 months prior to the first dose of brodalumab or placebo or a combined 
tetanus, diphtheria, and pertussis (Tdap) vaccine for more than 5 years prior to the first 
dose of brodalumab or placebo will receive Tdap vaccine at Week 8 in this trial. 
• Subjects who have received Tdap vaccine more than 18 months but less than 5 years prior 
to the first dose of brodalumab or placebo will receive Td vaccine at Week 8 in this trial. 
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• Subjects who have not received the scheduled adolescent dose of Td/Tdap for the last 
5 years will be vaccinated with a booster based on the subject’s previous history of 
vaccination with TT-containing vaccines and current local guidelines. 
Subjects randomised to ustekinumab only will not receive the vaccination.  
7.1.3.3 
Maintenance period (Week 12 to Week 52) 
As psoriasis is a chronic disease requiring long-term treatment, it is also relevant to evaluate 
the efficacy and safety of brodalumab as a maintenance treatment. To assess the duration of 
response, the 12-week induction period will be followed by continued treatment until 
Week 52.  
Subjects randomised at Week 0 to either brodalumab or ustekinumab will continue on the 
allocated treatment throughout the maintenance period:  
• Subjects on brodalumab treatment will receive subcutaneous injections of brodalumab at 
Week 12 and every 2 weeks thereafter, with the last brodalumab dose administered at 
Week 50.   
• Subjects on ustekinumab treatment will receive subcutaneous injections of ustekinumab at 
Weeks 16, 28, and 40. 
Subjects randomised at Week 0 to the placebo arm followed by brodalumab will switch to 
brodalumab treatment in the maintenance period and receive subcutaneous injections of 
brodalumab at Weeks 12, 13, 14, and every 2 weeks thereafter, with the last brodalumab dose 
administered at Week 50. The brodalumab dose will be determined by the subject’s body 
weight at Week 0 (Day 1) in accordance with the rules described for the induction period 
(Section 7.1.3.1) and will not be changed even if the subject’s body weight crosses 70 kg. 
Subjects randomised at Week 0 to the placebo arm followed by ustekinumab will switch to 
ustekinumab treatment in the maintenance period and receive subcutaneous injections of 
ustekinumab at Weeks 12, 16, 28, and 40. The ustekinumab dose will be determined by the 
subject’s body weight at each dosing visit in accordance with the rules described for the 
induction period (Section 7.1.3.1). 
7.1.4 
Safety follow-up period (Week 52 to Week 60) 
All subjects will be followed in an off-IMP treatment period during a safety follow-up. The 
safety follow-up visit is scheduled at Week 60. However, in case of early termination (see 
Section 10), the safety follow-up visit will occur sooner. This 8-week safety follow-up period 
will allow for adequate wash out of brodalumab (covers 5 half-lives of brodalumab) and is 
appropriate for short-term safety evaluation after the treatment is completed. 
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7.2 Number of subjects needed 
This trial will be conducted at approximately 75 sites mainly in Europe and Russia. 
Assuming a screening failure rate of 25%, approximately 160 subjects will be screened and 
120 subjects will be randomly assigned to a treatment arm in the trial: 
• 40 subjects randomised to brodalumab. 
• 40 subjects randomised to ustekinumab. 
• 20 subjects randomised to placebo followed by brodalumab. 
• 20 subjects randomised to placebo followed by ustekinumab. 
The statistical power considerations for this sample size are described in Section 14.1. 
7.3 End of trial definition 
The end of the trial is defined as the date of the last visit of the last subject in the trial 
globally.  
A subject is considered to have finalised the trial if having concluded all periods of the trial 
including the safety follow-up visit, regardless of early IMP discontinuation or not.  
Final collection of data for the primary endpoint occurs at Week 12. However, the primary 
analysis and the safety evaluation will be done after the last subject has completed the trial at 
Week 60. 
 
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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 Panel 2. 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, 
and if not, it will be specified which criteria are violated. 
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. Signed and dated informed consent must be provided by the subject’s legal 
representative(s) and by the subject (as applicable according to national laws or 
regulations). 
2. Subject was diagnosed with chronic plaque psoriasis at least 6 months before 
randomisation as determined by the investigator. 
3. Subject has a diagnosis of moderate-to-severe plaque psoriasis as defined by PASI score 
≥12, sPGA score ≥3, and body surface area (BSA) ≥10% at screening and at baseline. 
4. Subject’s age is ≥12 to <18 years at baseline. 
5. Subject’s body weight is ≥30 kg at screening and at baseline. 
6. Subject, in whom topical therapy is not adequate, and who is candidate for systemic 
therapy. 
7. Subject has positive varicella zoster antibodies at screening. 
8. Subject has no evidence of active or latent tuberculosis according to local standard of care 
for patients requiring initiation of a biologic treatment. 
o A tuberculosis test can be performed at the central laboratory. 
o If a local laboratory test is performed to confirm this criterium, the local 
laboratory must be assessed before the local testing is performed. 
9. Female subjects must have a negative pregnancy test at screening and at baseline. 
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10. Female subject must agree to use a highly effective* form of birth control throughout the 
trial and during 15 weeks after last administration of ustekinumab (45) and 12 weeks after 
last administration of brodalumab.  
*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 (estrogen 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), vasectomised partner (given that the subject 
is monogamous). 
11. Subject and/or subject’s legally authorised representatives are capable of learning to 
administer subcutaneous injections. 
12. Subject is able and willing to follow protocol-required trial visits and trial procedures. 
 
8.3 Exclusion criteria 
Subjects must not enter the trial if any of the following exclusion criteria are fulfilled: 
Skin disease-related 
1. Subject is 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 subjects with plaque psoriasis. 
Tetanus vaccination-related 
2. Subject has been vaccinated with a TT-containing vaccine ≤18 months prior to the first 
dose of IMP. 
Subject has been vaccinated with a TT-containing vaccine within 5 years prior to the first 
dose of IMP - applicable for countries in EU + UK. 
3. Subject has developed Guillian-Barre syndrome within 6 weeks after a previous 
vaccination with TT-containing vaccine. 
4. Subject has a planned vaccination with other vaccines than the scheduled Tdap or Td 
vaccine during the trial. Inactivated and non-live vaccines, e.g. COVID-19 and human 
papillomavirus [HPV] vaccines, are allowed after completion of Visit 10 (Week 12). 
5. Subject has developed encephalopathy within 7 days of administration of a previous 
pertussis antigen-containing vaccine. 
6. Subject has experienced an Arthus-type hypersensitivity reaction following a previous 
dose of TT-containing vaccine. 
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7. Subject has developed transient thrombocytopenia or neurological complications 
following previous vaccinations against diphtheria or tetanus. 
8. Subject has a history of severe allergic reactions to either vaccine or vaccine components 
including, but not limited to, aluminium, formaldehyde, and latex. 
9. Subject has received vaccination with any vaccine within 1 month prior to first dose IMP, 
documented or subject reported.  
10. Subject has been treated with blood products within 3 months prior to screening. 
11. Subject has been treated with interferon within 3 months prior to screening. 
Other medical conditions 
12. Subject has a planned surgery, which, in the opinion of the investigator, will interfere with 
the planned IMP treatment (any planned surgery must be recorded). 
13. Subject has an active infection or history of infections, defined as: 
o Subject has had any active infection for which systemic anti-infectives were used 
within 4 weeks prior to first dose of IMP. 
o Subject has had a serious infection, defined as requiring hospitalisation or 
intravenous anti-infectives within 8 weeks prior to the first dose of IMP. 
o Subjects has recurrent or chronic infections or other active infections that, in the 
opinion of the investigator, might cause this trial to be detrimental to the subject. 
o Subject has a serious skin infection requiring parenteral (intravenous or 
intramuscular) antibiotics, antiviral, or antifungal medication. 
14. Subject has any systemic disease considered by the investigator to be uncontrolled and 
immunocompromising the subject and/or placing the subject at undue risk of intercurrent 
diseases*. 
*Such diseases include, but are not limited to, renal failure, heart failure, liver disease, 
diabetes, and anaemia. 
15. Subject has a known history of Crohn’s disease. 
16. Subject has positive hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B 
core antibody, hepatitis C virus antibody, or human immunodeficiency virus serology at 
screening. Subjects with positive hepatitis B surface antibody are eligible provided they 
have negative hepatitis B surface antigen and negative hepatitis B core antibody (blood 
pattern in hepatitis B vaccinated subjects). 
17. Subject has any active malignancy. 
18. 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.  
19. Subject has a history of suicidal behaviour (i.e., actual suicide attempt, interrupted 
attempt, aborted attempt or preparatory actions) based on the C-SSRS at screening or at 
baseline. 
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20. Subject has suicidal ideation of level 4 or 5 (some intent to act, no plan, or specific plan 
and intent) based on the C-SSRS at screening or at baseline. 
21. Subject has a PHQ-A (PHQ-9 modified for adolescents, without question number 9) score 
of ≥10, corresponding to moderate-to-severe depression at screening or at baseline. 
22. Subject has a history of depressive disorder with severe episode(s) within the last 2 years. 
Wash out and non-permitted medications/treatments 
23. Subject has used topical corticosteroids or topical anthralin/dithranol within 7 days prior 
to first dose of IMP (exceptions are specified*).  
*Topical corticosteroids class V-VII (WHO classification) are allowed on the face, axillae, 
and groin (see Section 9.6); bland emollients (without urea or alpha or beta hydroxy acids) 
and shampoo without steroids are permitted. 
24. Subject has received any of the following specified treatments# within 28 days prior to 
first dose 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; or 
oral or parenteral corticosteroids including intramuscular or intraarticular administration; 
or any other immune modulating therapy for psoriasis or any other indication (with the 
exception that: otic, nasal, ophthalmic, and inhaled corticosteroids within recommended 
doses are permitted). 
25. Subject has received any of the following biologic immune modulating therapies prior to 
first dose of IMP: 
Approved agents:  
• Within 2 weeks for etanercept.  
• Within 4 weeks for adalimumab.  
Other commercially available biologics: 
• Within 8 weeks for infliximab.  
Other experimental biologics:  
• Within 12 weeks or 5 half-lives whichever is longer.  
26. Subject has received anti-IL-12/23p40 within 12 months prior to the first dose of IMP.  
27. Subject has previously had an inadequate response to anti-IL-12/23p40 therapy. 
28. Subject has previously received anti-IL-17 therapy. 
29. 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 5 
half-lives of the active substance. 
30. Subject is undergoing other non-approved investigational procedures. 
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Laboratory abnormalities 
31. Subject has laboratory abnormalities at screening, including any of the following: 
o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x the 
upper limit of normal (ULN). 
o Serum direct bilirubin equal to or higher than 1.5 mg/dL (≥25.7 μmol/L). 
o White blood cell (WBC) count <3.00 x 109/L. 
o Absolute neutrophil count (ANC) <2.00 x 109/L. 
o Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2. 
General 
32. Subject has a known or suspected hypersensitivity to any component(s) of the IMPs (see 
Sections 9.1.1, 9.1.2, and 9.1.3). 
33. Female subject who is pregnant or lactating. 
34. Subject has any kind of disorder that, in the opinion of the investigator, may compromise 
the ability of the subject to give informed consent and/or to comply with all required trial 
procedures. 
35. Subject has any disorder* which, in the opinion of the investigator, is not stable and could: 
o Affect the safety of the subject throughout the trial. 
o Influence the findings of the trial. 
o Impede the subject’s ability to complete the trial. 
*Examples include, but are not limited to, cardiovascular, gastrointestinal, hepatic, renal, 
neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, 
immunological, and psychiatric disorders and major physical impairment. 
36. Subject has any abnormal finding# which, in the opinion of the investigator, may: 
o Put the subject at risk because of their participation in the trial. 
o Influence the results of the trial.  
o Influence the subject’s ability to complete the trial. 
#The abnormal finding must be clinically significant and observed during the screening 
period. Examples include abnormal findings in physical examination, vital signs, 
electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis. 
37. Subject or subject’s legally authorised representative(s) has a language barrier, mental 
incapacity, unwillingness, or lacking ability to understand the trial-related procedures 
38. 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. 
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39. Subject is employed at the trial site or directly involved with the planning or conduct of 
the trial, or immediate family member of such individuals. 
40. Subject has previously been randomised and dosed in this clinical trial. 
41. Subject is currently participating in any other interventional clinical trial. 
42. 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. 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 identification number 
(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.  
After informed consent is obtained, the screening may begin. The date of first screening 
activity could be on the same day or a later date than the informed consent was signed. At 
screening, a subject ID number will be assigned by a central interactive response technology 
(IRT) system. The subject ID will be used to identify the subject during the screening process 
and throughout trial participation. Subjects for whom the subject’s legally authorised 
representative(s) have given written informed consent for their participation in the trial 
(including subjects who have given written assent to participate in the trial, as appropriate and 
according to national laws and regulation) and who have been assigned a subject ID are 
considered ‘screened’ subjects. The investigator will maintain a log of all screened subjects 
(screening log). This log will be anonymous and will include the allocated subject ID and the 
reason(s) for not entering the trial, if applicable. 
8.4.2 
Screening failures 
Screening failures are defined as subjects who consent to participate in the trial, but are not 
subsequently assigned to trial treatment. A minimal set of screening failure information is 
required to ensure transparent reporting of screening failure subjects to meet the consolidated 
standards of reporting trials (CONSORT) publishing requirements (46) and to respond to 
queries from regulatory authorities.  
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The following data will be collected in the eCRF for screening failures: 
• Date of informed consent(s). 
• Demographics (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 Withdrawal by parent/guardian. 
o Other (specification is required). 
• Date of screening 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.  
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 exclusion 
criterion 19, 20, 21, or 22. In the event of re-screening, a new informed consent must be 
obtained and a new subject ID must be assigned. For subjects who are re-screened, the 
subject ID from the previous screening will be recorded in the eCRF. All screening 
assessments and laboratory samples must be repeated. Due to the blood volumes, re-screening 
is allowed no earlier than 2 months after the initial screening.   
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9 Treatments 
9.1 Trial product description 
9.1.1 
Brodalumab and placebo 
Brodalumab is a recombinant fully human monoclonal IgG2 antibody that binds with high 
affinity to the human interleukin-17 receptor A (IL-17RA) and blocks the interaction with IL-
17A, IL-17E, and IL-17F. 
Panel 9: Identification of brodalumab and placebo  
Investigational 
medicinal 
product 
Dosage form 
Active ingredient and 
concentration 
Pack size of 
primary 
packaging 
Manufacturer 
responsible 
for batch 
release 
Brodalumab        
140 mg 
brodalumab in 1 
mL solution  
Solution for 
subcutaneous 
injection. 
Brodalumab formulated at a 
nominal concentration of 
140 mg/mL including the 
following excipients: proline, 
glutamate, polysorbate 20, 
water for injections. 
1 pre-filled 
syringe with 
140 mg 
brodalumab in 
1 mL solution. 
LEO Pharma 
A/S. 
Placebo 
Solution for 
subcutaneous 
injection. 
Brodalumab placebo solution is 
similar to the active 
brodalumab solution except 
that it does not contain any 
active substance. 
1 pre-filled 
syringe with 
1 mL solution. 
LEO Pharma 
A/S. 
Brodalumab 
210 mg  
brodalumab in 
1.5 mL solution  
Solution for 
subcutaneous 
injection. 
Brodalumab formulated at a 
nominal concentration of 
140 mg/mL including the 
following excipients: proline, 
glutamate, polysorbate 20, 
water for injections. 
1 pre-filled 
syringe with 
210 mg 
brodalumab in 
1.5 mL solution. 
LEO Pharma 
A/S. 
Placebo 
Solution for 
subcutaneous 
injection. 
Brodalumab placebo solution is 
similar to the active 
brodalumab solution except 
that it does not contain any 
active substance. 
1 pre-filled 
syringe with 
1.5 mL solution. 
LEO Pharma 
A/S. 
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9.1.2 
Ustekinumab 
Ustekinumab is a human IgG1ĸ monoclonal antibody against the p40 subunit of the IL-12 and 
IL-23 cytokines. 
Panel 10: Identification of ustekinumab  
Investigational 
medicinal 
product 
Dosage form 
Active ingredient and 
concentration 
Pack size of 
primary 
packaging 
Source 
Ustekinumab  
Trade name: 
Stelara® 
Solution for 
subcutaneous 
injection. 
45 mg ustekinumab in 0.5 mL 
solution, including the following 
excipients: L-histidine and L-
histidine monohydrochoride 
monohydrate, polysorbate 80, 
sucrose, and water for injection. 
1 vial with 45 mg 
ustekinumab in 
0.5 mL solution. 
Janssen 
Biologics B.V. 
Commercially 
available; 
supplied by 
CMO. 
 
  Abbreviations: CMO, contract manufacturing organisation. 
 
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9.1.3 
Vaccines 
Panel 11: Identification of the vaccines 
Investigational 
medicinal 
product 
Dosage form 
Active ingredient and 
concentration 
Pack size of 
primary 
packaging 
Source 
Tdap vaccine 
Suspension 
for 
intramuscular 
injection  
Combined tetanus, diphtheria, and 
acellular pertussis vaccine 
(absorbed, reduced antigen 
content). Each 0.5 mL dose is 
formulated to contain: tetanus 
toxoid ≥20 IU, diphtheria toxoid 
≥2 IU and pertussis toxoid 20 µg. 
All antigens adsorbed on 
aluminium hydroxide, hydrated 
(0.5 mg Al). The other excipients: 
sodium chloride, sodium 
hydroxide and water for injections. 
May contain traces of 
formaldehyde, which are used 
during the manufacturing process. 
0.5 mL 
single-dose 
pre-filled 
syringes. 
Commercially 
available; 
supplied by 
CMO.  
Td vaccine 
Suspension 
for 
intramuscular 
injection  
Combined tetanus and diphtheria 
vaccine (absorbed, reduced antigen 
content). Each 0.5 mL dose is 
formulated to contain: tetanus 
toxoid ≥20 IU and diphtheria 
toxoid ≥2 IU, absorbed to 
aluminium hydroxide, hydrated, 
corresponding to 0.5 mg 
aluminium. The other excipients 
are: sodium hydroxide, sodium 
chloride, and water for injections. 
May contain traces of 
formaldehyde, which are used 
during the manufacturing process. 
0.5 mL 
single-dose 
pre-filled 
syringes. 
Commercially 
available; 
supplied by 
CMO.  
 
Abbreviations: CMO, contract manufacturing organisation; Td, tetanus and diptheria; Tdap, tetanus, diphteria, and pertussis. 
 
 
 
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9.2 Administration of IMP 
9.2.1 
Administration of brodalumab, placebo, and ustekinumab 
The IRT will assign the required kit number(s) for each subject at each 
dispensing/administration visit.  
Scheduled dispensing/administration (dosing) days are shown in Panel 2 and Panel 3. The 
first day of administration is considered Day 1 (Week 0). On administration visits, all other 
visit activities should be handled prior to administration of brodalumab, placebo, or 
ustekinumab. The last administration of brodalumab under this protocol will occur at Week 50 
and the last administration of ustekinumab under this protocol will occur at Week 40. 
Brodalumab, placebo, and ustekinumab must be injected subcutaneously.  
Brodalumab and placebo must be injected in the upper legs (thighs) or stomach area 
(abdomen) by the subject, the subject’s caregiver, or a qualified healthcare professional. The 
subject’s caregiver or the healthcare professional may also give injection(s) in the upper outer 
arm. Subsequent injections can be given to the same or different body regions. Each pre-filled 
syringe is for single-use only. Brodalumab and placebo should not be injected into areas 
where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis. The pre-filled 
syringe must not be shaken or heated.   
The subject will be kept under observation for 30 minutes following the first and second 
brodalumab injection. 
The trial site staff should encourage the subjects and/or the subjects’ caregiver to do the 
injections on their own, when properly trained. Please refer to Section 9.2.1.2 for information 
regarding home-based administration of brodalumab. 
Ustekinumab must be administered at the trial site according to the instructions for 
administration provided in current summary of product characteristics (SmPC) for 
ustekinumab.  
LEO Pharma does not recommend specific treatment for an overdose of brodalumab. The 
investigator will use clinical judgment to treat any overdose if necessary. See Section 13.6.1 
for further details regarding overdose. An overdose of ustekinumab must be handled in 
accordance with current SmPC.   
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9.2.1.1 
Conditions requiring rescheduling of administration of brodalumab, placebo, 
or ustekinumab 
If any of the following should occur, the investigator should reschedule the IMP 
administration (other scheduled visit assessments should be performed): 
• The subject has an intercurrent illness that, in the opinion of the investigator, may 
compromise the safety of the subject in the trial (e.g., viral illnesses). 
• The subject is febrile (defined as ≥38°C) within 72 hours prior to IMP administration. 
The rescheduled IMP administration will be reported in the eCRF as an unscheduled visit. 
The subseqent visit and IMP administration should be scheduled according to the schedule of 
the trial procedures and a minimum interval of 7 days must be kept between 2 administrations 
of brodalumab/placebo (except for Visit 3 and Visit 4, which are exempt from the 7-day gap 
requirement). If the trial visit cannot be rescheduled to maintain a minimum of 7 days to 
subsequent dose, the sponsor’s medical expert should be contacted.  
9.2.1.2 
Home-based administration of brodalumab 
Subjects randomised to the brodalumab arm or the placebo arm followed by brodalumab will 
be given the option to administer brodalumab at home at Weeks 18, 22, 24, 26, 30, 34, 38, 42, 
46, and 50 (Panel 3); the injections may be performed either by the subject (under supervision 
by the subject’s caregiver) or by the subject’s caregiver. The investigator should document 
that instructions for use for brodalumab and placebo have been given orally and/or in writing 
to the subject and the subject’s caregiver before any home-based administration. Subjects who 
refuse to do home-based administration can have the IMP administered at the trial site at these 
weeks.  
9.2.2 
Administration of vaccine 
At Week 8, subjects in the brodalumab, placebo followed by brodalumab, and placebo 
followed by ustekinumab arms will receive a TT-containing vaccine, either Tdap or Td. The 
type of vaccine each subject will receive is based on the subject’s previous history of 
vaccination with TT-containing vaccines and current local guidelines (see Section 7.1.3 for 
further details). The IRT will assign the required kit number for each subject. 
The vaccine will be administered by the trial staff on the same day the brodalumab/placebo 
injections are administered; the vaccine will be given first, then brodalumab or placebo will 
be given afterwards (see below). 
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The vaccine must be given intramuscularly (e.g., in the deltoid muscle of the upper arm). The 
injection site must be recorded in the source documents and in the eCRF. 
The subject will be kept under observation for 30 minutes following vaccination. After this 
observation period and when all other visit activities have been performed, the brodalumab or 
placebo injection will be given. Note that at Week 8, brodalumab/placebo injections must not 
be given in the same area as the vaccination. 
Syncope can occur in association with administration of the vaccines. Procedures should be in 
place to prevent falling injury and to restore cerebral perfusion following syncope. 
Appropriate drugs (such as epinephrine, antihistamines, corticosteroids, etc.) and medical 
equipment to treat acute anaphylactic reactions must be immediately available at the trial 
sites, and an appropriate treatment must be immediately provided according to local 
guidelines by site personnel.  
9.2.2.1 
Conditions requiring rescheduling of administration of the vaccine 
If the following should occur at the visit scheduled at Week 8 (i.e., Visit 7), the investigator 
should reschedule the vaccine administration: 
• The subject has an intercurrent moderate or severe acute illness with or without fever, that 
in the opinion of the investigator may compromise the safety of the subject in the trial. 
If the subject has recovered between Visit 7 and Day 64, the vaccine should be administered 
as soon as possible and no later than on Day 64. An extra visit for vaccine administration 
should be scheduled and reported in the eCRF as an unscheduled visit.    
9.2.3 
Reporting of IMP administration in eCRF 
The following data will be recorded in the eCRF for brodalumab, ustekinumab, and 
placebo: 
• Date of administration. 
• Time of administration, for selected visits. 
• Site of subcutaneous injection (thigh, abdomen, or upper outer arm). 
• Where the administration was performed, and by whom (on-site, by trial site staff; on-site, 
by subject’s caregiver; on-site, self-injection; at home, by subject’s caregiver; at home, 
self-injection). 
 
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The following data will be recorded in the eCRF for the vaccine: 
• Date and time of vaccine administration. 
• Site of intramuscular injection (left upper arm, right upper arm, or other site [will require 
a comment]). 
9.3 Treatment assignment  
Subjects who comply with all the inclusion criteria and who do not violate any of the 
exclusion criteria will be randomised centrally at Week 0 to receive treatment with 
brodalumab, ustekinumab, placebo followed by brodalumab, or placebo followed by 
ustekinumab, stratified by baseline body weight (<70 kg and ≥70 kg). The treatment 
assignment occurs on the basis of a computer-generated randomisation scheme in a 2:2:1:1 
ratio. 
The IRT will be used to control randomisation and stratification factors, along with IMP 
supply chain and expiry tracking. 
9.3.1 
Blinding 
Treatment allocation for the induction period (i.e., ‘ustekinumab’ or double-blind 
‘brodalumab/placebo’) will be revealed to the investigator at randomisation at Week 0. For 
subject on ‘brodalumab/placebo’ in the induction period, the treatment allocation for the 
maintenance period (i.e., ‘brodalumab’ or ‘ustekinumab’) will not be revealed before the visit 
scheduled at Week 12. 
It is not considered possible to differentiate between brodalumab and placebo visually, both 
solutions are colourless. For the induction period, the packaging and labelling will contain no 
evidence to distinguish brodalumab from placebo. For the maintenance period, treatment with 
brodalumab will be open-label and brodalumab will be labelled and packaged as such. 
Ustekinumab and the vaccine will be administered as the commercially available product and 
will not be blinded.  
When the IMP (brodalumab, placebo, ustekinumab, or vaccine) is administered at the trial 
site, it will be administered by site personnel not involved in the efficacy assessments. The 
efficacy assessments will be performed by an investigator (see Section 11.1) who is blinded to 
the treatment allocation and administration.  
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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, healthcare professionals 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. For a requester who is not a member of the trial staff and who does not have access to the 
IRT (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. 
9.4 Background treatment 
Not applicable. 
9.5 Rescue treatment 
Rescue treatment is allowed in all 4 treatment arms. From Week 4 and at all subsequent visits, 
rescue treatment is allowed in subjects with an increase of ≥25% in PASI score from baseline 
(Week 0, Day 1).  
Before the initiation of rescue treatment, investigators should make every attempt to conduct 
efficacy and safety assessments (for example, disease severity scores [PASI and sPGA] and 
safety labs). Unscheduled visit(s) may be used for this purpose, if necessary. 
Rescue treatment will consist of topical corticosteroids. Those topical corticosteroids with 
good therapeutic index e.g., hydrocortisone-17-butyrate, mometasone furoate, 
methylprednisolone aceponate should be preferred. However, it is allowed to use ultra-high 
potency (class I) to moderate potency (class V, IV), according to WHO classification (see 
Appendix 4), at the discretion of the investigator. The investigator is responsible for the 
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rescue treatment oversight and duration as well as switching and escalating to another therapy, 
when appropriate. However, it is recommended that the efficacy of the topical rescue 
treatment should be re-evaluated after 4 weeks of treatment and subjects who are still 
inadequately controlled (defined as a PASI score ≥150% of baseline PASI) might be escalated 
to an appropriate subsequent therapy (refer to Section 9.7 for prohibited medications and 
Section 10.2 for IMP discontinuation rules). 
Use of any rescue treatment must be recorded in the eCRF (see Section 9.6). 
9.6 Concomitant medication and concurrent procedures 
Any prior and concomitant medication or vaccine (except for vaccination as part of the trial) 
that the subject receives from 1 year prior to screening (if relevant) through safety follow-up 
must be recorded in the subject’s medical record and the eCRF along with details such as: 
• Medication or therapy (generic or brand name). 
• Indication. 
• Start and stop date of administration (it will also be recorded if the medication is 
ongoing). 
• Dosage information, including dose per administration, 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). 
Please also refer to Section 11.2.3 for specific details about history of psoriasis treatment. 
The following concomitant medications related to psoriasis treatment are permitted from 
screening through safety follow-up (Week 60): 
• Low potency topical corticosteroids (lower moderate potency [class V] to low potency 
[classes VI and VII] according to WHO classification [Appendix 4] may be used only on 
the face, axillae, and groin). 
• Bland emollients (without urea or alpha- or beta hydroxy acids). 
• Shampoo without steroids. 
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Concomitant medication for conditions other than psoriasis may be continued throughout the 
trial without any change in dosage whenever possible. 
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. 
9.7 Prohibited medications and procedures 
The medications listed in Panel 12 are prohibited during the trial.  
The following circumstances require permanent discontinuation of IMP:  
• Use of any other biologic immunomodulating agent than brodalumab and ustekinumab.  
• 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 action 
must be taken by the investigator to either discontinue the prohibited medication or 
discontinue the IMP. 
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Panel 12: Prohibited medications and procedures 
Prohibited medication or procedure 
Prohibited from 
Prohibited to 
Anti-IL-17 therapy other than brodalumab provided in this trial Ever used 
Week 52 
Anti-IL-12/23p40 therapy other than ustekinumab provided in 
this trial 
12 months prior to 
first dose of IMP 
Week 52 
Etanecept  
2 weeks prior to 
first dose of IMP 
Week 52 
Adalimumab  
4 weeks prior to 
first dose of IMP 
Week 52 
Infliximab 
8 weeks prior to 
first dose of IMP 
Week 52 
Other experimental or commercially available immune 
modulators (e.g., IL-23 inhibitors) and any IMP other than 
brodalumab/placebo and ustekinumab provided in this trial  
5 half-lives of 
active substance 
prior to first dose 
of IMP 
Week 52 
Ultraviolet A light therapy (with or without psoralen), 
ultraviolet B light therapy, eximer laser etc.  
4 weeks prior to 
first dose of IMP 
Week 52 
Oral retinoids; methotrexate; cyclosporine; systemically 
administered calcineurin inhibitors; azathioprine; thioguanine; 
hydroxyurea; fumarates; apremilast; or oral or parenteral 
corticosteroids including intramuscular or intraarticular 
administration (with the exception that: otic, nasal, ophthalmic, 
or inhaled corticosteroids within recommended doses are 
permitted) 
4 weeks prior to 
first dose of IMP 
Week 52 
Topical therapy for psoriasis e.g., calcineurin inhibitors, 
vitamin D analogues, class I-V (WHO classification) topical 
corticosteroids (TCS)  
• 
Use of TCS class V-VII (WHO classification) are allowed 
on the face, axillae, and groin through the trial (see 
Section 9.6) 
• 
Shampoos without steroids are permitted 
• 
Bland emollients without urea or beta or alpha hydroxy 
acids are permitted 
1 week prior to 
first dose of IMP 
Week 52 
Use of live vaccine 
4 weeks prior to 
first dose of IMP 
Week 52 
Use of any vaccine1. 
4 weeks prior to 
first dose of IMP 
Week 52 
Abbreviations: IL, interleukin; IMP, investigational medicinal product; SmPC, summary of product           1 (2) 
characteristics; TCS, topical corticosteroids; WHO, World Health Organization.  
1 For subjects in the placebo and brodalumab arms: inactivated or non-live vaccines, including COVID-19 
vaccines, are allowed from Week 12. For subjects in the ustekinumab arm: inactive or non-live vaccines are 
allowed according to ustekinumab's SmPC during the trial. 
 
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Prohibited medication or procedure 
Prohibited from 
Prohibited to 
Blood products  
3 months prior to 
first dose of IMP 
Week 52 
Interferon 
3 months prior to 
first dose of IMP 
Week 52 
Abbreviations: IMP, investigational medicinal product.                                                                                2 (2)  
 
In case any prohibited treatments are used during the trial, they must be recorded as 
concomitant medication. 
As described in Section 9.5, some prohibited medications are allowed as rescue treatment for 
subjects with an increase of ≥25% in PASI score from baseline (Week 0, Day 1). Such 
instances of use of rescue treatment for the indication being investigated do not constitute a 
protocol deviation. If prohibited medications are used for reasons other than rescue treatment, 
they must be recorded as protocol deviations 
9.8 Treatment logistics and accountability  
9.8.1 
Labelling and packaging of trial products 
The IMP will be packaged in individually numbered kits.  
Primary and secondary packaging materials will be individually labelled. 
The labelling of IMPs will be in accordance with Annex 13, 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 (brodalumab, placebo, ustekinumab, and vaccines) 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. The temperature 
during storage should be monitored by a calibrated, stationary, and continuously recording 
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. 
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Note that in the cases listed below, site staff should not use the affected IMP and should 
immediately quarantine the IMP and contact their CRA for further guidance: 
• Temperature excursion upon receipt or during storage at the trial site. 
• Damaged kit, syringe, or vial. 
Damaged IMP should be documented in the IRT 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. 
9.8.3 
Drug accountability 
The investigator is fully responsible for the IMP at the trial site, for maintaining adequate 
control of the IMP, and for documenting all transactions with them. 
Dispensing of IMP may be delegated, e.g., to a hospital pharmacy, as locally applicable. 
An individual drug accountability form (or similar) must be kept of the IMP 
dispensed/administered to (and returned by, in case of home-based administration 
[Section 9.2.1.2]) each subject randomised in the trial. This individual drug accountability 
form should 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, 
where also inventory status of all IMP at the trial site will be maintained. 
The IMP dispensed for home-based administration should be stored in accordance with the 
label. If the IMP is administered at home (as described in Section 9.2.1.2), the used syringes 
will be discarded in disposal containers at home. The subject should return unused IMP and 
empty trial kit cartons at the next trial site visit (as shown in Panel 3). At end of treatment 
(Week 52), the subject must have returned all unused IMP, empty trial kit cartons, and 
disposal containers containing used IMP. Returned IMP (used or unused) can be stored at trial 
site at room temperature and must be stored separately from non-allocated IMP.  
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. No 
accountability is required for returned disposal containers; these can be disposed according to 
Section 9.8.5. 
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All unused IMP (including trial kit cartons) supplied by the contract manufacturing 
organisation (CMO) on behalf of LEO Pharma will be returned to the CMO. Prior to their 
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 on drug accountability forms and 
in the IRT. 
Please refer to the trial product handling manual for further details. 
9.8.4 
Treatment compliance 
The site staff will keep the drug accountability records up to date. Any non-compliance 
(subject received partial dose; subject received no dose) and the reason for the non-compliace 
will be recorded in the eCRF.  
If a subject with home-based IMP administration (see Section 9.2.1.2) is found to be non-
compliant, the investigator should remind the subject of the importance of following the 
instructions given, including using brodalumab as prescribed. 
9.8.5 
Trial product destruction 
Used IMP (and returned disposal containers) 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 return the used IMP to the CMO for destruction 
according to the trial product handling manual. 
Unused and used IMP returned to the CMO will be destroyed by the CMO according to 
approved procedures and any local requirements. 
9.9 Provision for subject care following trial completion  
In order to ensure appropriate treatment of the subjects after they have completed the trial or 
if they have been withdrawn from the trial or discontinued IMP treatment prematurely, 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 immediately reported to the CRA by the site. 
The CRA must contact Global Safety at LEO Pharma within 3 days of first knowledge.  
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Critical complaints (defined as any defect, issue, or device deficiency that has or potentially 
could have a serious impact for the subject [e.g., an SAE or large particles in the syringe]) 
must be reported to the Quality department via Global Safety within 24 hours of knowledge.  
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. 
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 7226 3287. 
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 or permanently discontinue trial treatment at any time 
(prior to first dose or during the treatment phase) if the subject, the subject’s legally 
authorised representative(s), the investigator, or LEO Pharma considers that it is not in the 
subject’s best interest to continue. 
In order to obtain the most representative efficacy and safety evaluation of brodalumab in 
adolescents, it is key to assess the efficacy status of each trial subject at the planned primary 
endpoint visit (i.e., at Week 12 [Panel 2]) and at the planned secondary endpoint visits at 
Week 16 and Week 52 (Panel 3), irrespective of whether the subject has discontinued IMP or 
not. Therefore, permanent discontinuation of IMP is evaluated as a separate occurrence that 
does not necessitate that the subject also withdraws from the trial. This is to enable selected 
subsequent trial visits to be conducted after early discontinuation of IMP.  
Permanent discontinuation of IMP and withdrawal from trial are considered to be 
2 (potentially) separate occurrences: 
• Permanent discontinuation of IMP occurs when all further trial treatment is stopped. The 
subject will continue to participate in selected trial visit activities as outlined in Section 
10.2.1. 
• Withdrawal from trial occurs when stop of all trial activities takes place before the 
planned safety follow-up visit at Week 60. This may happen either at the time of 
permanent discontinuation of IMP or later.  
Medical reasons for early discontinuation of IMP are given in Section 10.2.1. 
Reason(s) for discontinuation from IMP and withdrawal from the trial must be recorded in the 
medical records and the eCRF.  
Subjects who withdraw from the trial and subjects who permanently 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 if IMP is 
discontinued prematurely, the subject should be treated at the discretion of the investigator 
(Section 9.9). 
Throughout the protocol, last date of IMP administration is defined as date of the subject’s 
last dose of IMP. 
Subjects will permanently discontinue IMP in the event of: 
• An anaphylactic reaction or other severe systemic reaction to IMP.  
If the IMP is the vaccine, and the subject has received the last IMP (which is brodalumab 
or placebo) for more than 72 hours prior to the vaccine administration without any 
concerns or reactions, then the subject should continue in the trial. 
• An AE that, in the opinion of the investigator or sponsor’s medical expert, contraindicates 
further dosing (e.g., Crohn’s disease). 
• A diagnosis of malignancy during the trial, excluding carcinoma in situ of the cervix, or 
localised squamous or basal cell carcinoma of the skin. 
• Evidence of pregnancy. 
• Any infection that is opportunistic, such as active tuberculosis or 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-A score of ≥15 corresponding to moderately severe to severe depression. The 
subject must be referred to a mental health professional. 
• A need of concomitant therapies or treatments, which are prohibited throughout trial 
participation (see Section 9.7).  
• Any single measurement of ANC <0.50x103/µL. 
• Severe laboratory abnormalities:  
o ALT and/or AST values >3xULN with total bilirubin >2xULN (unless elevated 
bilirubin is related to Gilbert-Meulengracht Syndrome).  
o Confirmed AST and/or ALT >5xULN (for more than 2 weeks). 
Refer to Section 10.3 for details on the handling of subject discontinuation and to Panel 2 and 
Panel 3 for assessments to be performed in case of early discontinuation of IMP. 
 
 
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Data to be recorded in the eCRF 
The primary reason for early 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. 
• Withdrawal by parent/guardian. 
• Lost to follow-up. 
• Death. 
• Pregnancy. 
• Other. 
If ‘other’ is selected, a specification must be provided in the eCRF. If the discontinuation is 
related to an AE, the details of this must also be reported (Section 13). 
10.2.2 Reasons for temporary discontinuation of IMP 
Administration of IMP may 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. If the dosing window is 
missed (see Panel 2 and Panel 3) because of persistent infection, that dose should not be 
administered. Please refer to Sections 9.2.1 and 9.2.2 for rescheduling of IMP 
administration. 
• Other intercurrent illnesses or major surgery. The administration of the IMP should be 
withheld until the event has resolved in the opinion of the investigator. 
Administration of IMP must be temporarily suspended in the event of: 
• ANC ≥0.50x103/µL – ≤1.5x103/µL and fever (appropriate treatment must be initiated and 
blood samples/cultures and other appropriate specific cultures must be obtained according 
to the local paediatric guidelines). The administration of the IMP must be withheld until 
the infection has resolved in the opinion of the investigator and the ANC >1.5x103/µL. 
• Positive urine pregnancy test. The administration of the IMP must be withheld until a 
negative serum pregnancy test is available. 
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. 
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10.3 Early termination assessments 
Early permanent discontinuation of IMP 
All subjects who permanently discontinue IMP for any reason will be encouraged to continue 
in the trial for collection of scheduled efficacy and safety assessments or at least attend a visit 
at Week 12, Week 16, and Week 52 for collection of assessments related to primary and 
secondary endpoints.  
Subjects who permanently discontinue IMP before Week 12 will be asked to attend at least: 
• An early termination visit, as soon as possible and within 2 weeks of the last IMP 
administration, according to Panel 2. If discontinued at Week 10, the early termination 
visit should be aligned with the primary endpoint visit (12 weeks after randomisation).  
• A primary endpoint visit (12 weeks after randomisation).   
o A safety follow-up visit (8 weeks after the last IMP administration). 
o A secondary endpoint visit (16 weeks after randomisation). 
o A secondary endpoint visit (52 weeks after randomisation).  
Blood samples will only be collected at the early termination visit. At other visits, described 
above, the efficacy and safety will be evaluated, but no otherwise scheduled blood samples 
will be collected.  
Subjects who has received the last IMP at Week 12 and after will be asked to attend at least: 
• An early termination visit, as soon as possible and within 2 weeks of the last IMP 
administration, according to Panel 3. If discontinued at Week 50, the early termination 
visit should be aligned with the secondary endpoint visit (52 weeks after randomisation). 
• A safety follow-up visit (8 weeks after last administration of IMP). 
• A secondary endpoint visit (16 weeks after randomisation, if applicable). 
• A secondary endpoint visit (52 weeks after randomisation).  
Blood samples will only be collected at the early termination visit. At other visits, described 
above, the efficacy and safety will be evaluated, but no otherwise scheduled blood samples 
will be collected.  
Female subjects who permanently discontinue IMP will need to stay on contraceptives for 12 
weeks (for brodalumab) or 15 weeks (for ustekinumab) after last IMP administration. A urine 
pregnancy test (human chorionic gonadotropin) should be performed at the early termination 
visit, safety follow-up visit, and at 12 weeks (for brodalumab) or 15 weeks (for ustekinumab) 
after last IMP administration. This can be assessed at unscheduled visits, or at any of the 
above scheduled visits.  
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The investigator will review any AEs which will be followed-up according to Section 13.7, if 
the subject agrees. 
Early discontinuation from trial  
Randomised 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 and a safety follow-
up visit 8 weeks after last IMP administration. 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, after at least 3 attempts.    
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/or subject’s legally representatives 
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. 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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11Trial assessments and procedures 
11.1 Overview 
Evaluations to be done at each visit are shown in the schedule of trial procedures in Section 4: 
• Panel 2 includes all assessments during the screening period and the induction period of 
the treatment phase (including assessments to be performed in case of early termination, if 
applicable). 
• Panel 3 includes all assessments during the maintenance period of the treatment phase and 
the safety follow-up period (including assessments to be performed in case of early 
termination, if applicable). 
Refer to Section 7.1 for further details on the trial design. 
Assessments and procedures scheduled at each trial visit should be performed in the sequence 
shown in Panel 13, while laboratory assessments can be performed at any time prior to 
῾Patient-reported outcomes for safety assessments’. 
Panel 13: Sequence of assessments 
 
* Rater-administered C-SSRS and self-administered PHQ-A questionnaires. 
 
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 
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paediatric plaque psoriasis and have documented experience and/or training in use of the 
assessments required by the protocol and must be a physician. 
To reduce inter-rater variability, the same investigator/assessor should perform all the efficacy 
evaluations for a given subject throughout the entire trial period, if feasible.    
The blinded investigator performing the efficacy assessments should be qualified 
dermatologists preferably with experience in paediatric psoriasis.  
The site staff handling the IMP administration must not be involved in the efficacy 
assessments (Section 9.3.1). 
AEs must be assessed by a physician (Section 13.2). 
Review of the C-SSRS, PHQ-A, and other safety assessments must be performed by qualified 
physicians.  
Site staff administering the C-SSRS must be trained in the administration of the scale. The 
training certificate must be archived in the investigator trial file before any C-SSRS 
assessments.  
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 (requires a specification to be provided). 
• Ethnic origin (self-reported by the subject): Hispanic or Latino, not Hispanic or Latino. 
 
11.2.2 Trial disease (psoriasis, psoriatic arthritis, psoriatic arthropathy, and other 
immunoinflammatory diseases) 
The duration of psoriasis (to the nearest whole year) will be recorded in the eCRF. For 
subjects with current or previous psoriatic arthritis, psoriatic arthropathy, or other 
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immunoinflammatory diseases, the duration (to the nearest whole year) will be recorded in the 
eCRF. 
11.2.3 Trial disease treatment history 
It will be recorded in the eCRF if the subject has ever taken any psoriasis- and psoriatic 
arthritis-specific medication or medication for other immunoinflammatory diseases (including 
biologic and non-biologic systemic therapy and/or topical therapy) or had had any 
phototherapy or photochemotherapy at any time in the subject’s history. For these medications 
and therapies, 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, acitretin, ultraviolet A light therapy with psoralen, or ultraviolet B light therapy. 
Please also refer to Section 9.6 for recording of prior and concomitant medications. 
11.2.4 Medical history 
Other relevant past and concurrent medical illnesses, based on subject interview, will be 
recorded in the eCRF; the start date and stop date will be recorded; it will also be recorded if 
the condition, diagnosis, or treatment is ongoing. Please also 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 and alcohol consumption will be recorded in the eCRF. It will be 
recorded:  
• If the subject has ever consumed tobacco. If applicable, type, amount, and frequency of 
tobacco consumed and duration of the consumption 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 
The PASI is the most widely used tool in clinical practice and clinical trials to assess the 
severity and extent of psoriasis (47). The PASI score will be assessed according to the 
schedule of trial procedures (Panel 2 and Panel 3). The assessment will be based on the 
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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 PASI assessment will be recorded in the 
eCRF. 
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 14. It should be noted 
that ‘upper extremities’ includes arms and hands, ‘trunk’ includes the axilla and groin, and 
‘lower extremities’ includes legs, buttocks, and feet. 
The investigator will also assess the extent of psoriasis within each of the 4 body regions 
according to the area score scale shown in Panel 15. The assessment of extent is the 
percentage of that body region that is affected and not the percentage BSA affected. For 
example, if one arm and hand was totally affected, and the other arm and hand was totally 
unaffected, the extent assessment for the upper extremities would be 50% (half of that body 
region being affected). 
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 16). 
The investigator must evaluate subject eligibility in relation to inclusion criterion 3 for the 
PASI score at screening (Visit 1) and at baseline (Visit 2; Week 0). 
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Panel 14: 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) 
Abbreviations: PASI, Psoriasis Area and Severity Index. 
            Source: Modified from 47. 
Panel 15: 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 
Abbreviations: PASI, Psoriasis Area and Severity Index. 
Source: Modified from 47. 
 
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Panel 16: 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 
(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.  
Source: Modified from 47. 
 
11.3.2 Static Physician’s Global Assessment 
The sPGA is an instrument used in clinical trials to rate the severity of the subject’s global 
psoriasis and is based on a 6-point scale ranging from 0 (clear) to 5 (very severe) (Panel 17). 
The sPGA score will be assessed according to the schedule of trial procedures (Panel 2 and 
Panel 3). 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 sPGA score will be 
recorded in the eCRF. 
The investigator must evaluate subject eligibility in relation to inclusion criterion 3 for the 
sPGA score at screening (Visit 1) and at baseline (Visit 2; Week 0). 
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Panel 17: sPGA severity score scale 
Score 
Short descriptor 
Detailed descriptor 
0 
Clear 
No signs of psoriasis; post-inflammatory hyperpigmentation may be present. 
1 
Almost clear 
No thickening; normal to pink coloration; no to minimal focal scaling. 
2 
Mild 
Just detectable to mild thickening; pink to light red coloration; 
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 (marked) thickening with hard edges; bright to deep dark red 
coloration; severe/coarse scaling covering almost all lesions. 
5 
Very severe 
Very severe thickening with hard edges; deep dark red coloration; very 
severe/very coarse scaling covering all lesions. 
 
11.3.3 Body surface area involvement 
The investigator will assess the total psoriatic involvement on the arms, trunk, and legs 
(excluding any involvement on skin folds and genitals) as a percentage of the total BSA. As a 
guidance for this estimate, the surface of a full, flat palm (including the 5 fingers) of an 
adolescent subject corresponds to approximately 1% of the total BSA. 
As an additional guidance for assessment of the full BSA with psoriatic involvement, the 
complete BSA (100%) can be divided into regions that approximates percentages of BSA as 
follows: head and neck (10%), upper extremities (20%), the trunk including the axillae and 
groin (30%), and finally the lower extremities, including the buttocks (40%). 
The BSA will be assessed and recorded in the eCRF in accordance with the schedule of trial 
procedures in Panel 2 and Panel 3.  
The investigator must evaluate subject’s eligibility in relation to inclusion criterion 3 for the 
BSA at screening (Visit 1) and at baseline (Visit 2; Week 0). 
11.3.4 Patient-reported outcomes for efficacy and health-related quality of life 
The subjects will receive an electronic diary (eDiary) device and eDiary training at screening 
(Visit 1). The eDiary should be returned at the last visit at the latest. 
Each subject and subject’s parent/legally authorised representative 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 his or her efficacy assessments. The 
investigator should not question the subject’s answers for any of the patient-reported 
outcomes. The investigator must review the data for timeliness and completeness. 
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Symptoms reported in the patient-reported outcomes 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 Patient Health Questionnaire-A (see Section 11.7.1). 
11.3.4.1 Children’s Dermatology Life Quality Index 
The Children’s Dermatology Life Quality Index (CDLQI) questionnaire is designed and 
validated in subjects with dermatological conditions from 5 to 16 years (48).  
The CDLQI is available in text and cartoon versions. The text version (48) will be used in this 
trial. It consists of 10 items addressing the subject’s perception of the impact of their skin 
disease on various aspects of their quality of life over the last week such as dermatology-
related symptoms and feelings, leisure, school or holidays, personal relationships, sleep, and 
the treatment (48). Each item is scored on a 4-point Likert scale (0 = ‘not at all’; 1 = ‘only a 
little; 2 = ‘quite a lot’; 3 = ‘very much’). The item on school time (item 7) has an additional 
response category ‘prevented school’, which is also scored ‘3’. 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 CDLQI will be completed by the subjects at the trial site according to the schedule of 
trial procedures in Panel 2 and Panel 3.  
11.3.4.2 Family Dermatology Life Quality Index 
The Family Dermatology Life Quality Index (FDLQI) questionnaire is designed and validated 
to evaluate the impact of the subject’s skin disease on the quality of life of the subject’s 
relative (49, 50).  
The FDLQI is available as a text version. It consists of 10 items addressing the subject’s 
relative perception of the impact of the subject’s skin disease on various aspects of his/her 
quality of life over the last month such as: emotional distress, social life, job and leisure 
activities, physical well-being, time spent on helping the subject with e.g., treatment 
procedures, extra housework, and routine household expenditure (49, 50). Each item is scored 
on a 4-point Likert scale (0 = ‘not at all’; 1 = ‘only a little; 2 = ‘quite 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 FDLQI must be completed by the same relative of the subject throughout the trial. The 
FDLQI will be completed at the trial visits, or 1 day before the trial visits, according to the 
schedule of trial procedures in Panel 2 and Panel 3. 
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11.3.4.3 Adolescent Pruritus NRS  
Subjects will assess their worst itch over the past 24 hours using an 11-point numeric rating 
scale (NRS) (Adolescent Pruritus NRS) with 0 indicating ‘no itch’ and 10 indicating ‘worst 
itch possible’. Subjects will complete the Adolescent Pruritus NRS as part of the eDiary 
(Section 11.3.4) from at least 7 days before the baseline visit at Week 0 until Week 52. The 
eDiary should be completed each day, preferably in the evening. 
11.3.4.4 Itch-related Sleep NRS 
Subjects will rate how much their psoriasis interfered with their sleep the last night using an 
11-point NRS (Itch-related Sleep NRS) with 0 indicating that it ‘did not interfere’ and 10 
indicating that it ‘completely interfered’. Subjects will complete the Itch-related Sleep NRS as 
part of the eDiary (see Section 11.3.4) from at least 7 days before the baseline visit at Week 0 
until Week 52. The eDiary should be completed each day, preferably in the evening.  
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). Vital signs will be measured in a supine 
position following at least 5 minutes of rest. 
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 if the subject should be randomised 
into the trial (respecting exclusion criterion 36). 
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later with subjects resting in a supine position 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. 
The 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 will 
be reported as an AE in accordance with Section 13.3. 
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11.4.2 Physical examination 
A thorough physical examination of the subject including whole body inspection of the skin, 
auscultation of heart, lungs, and abdomen, palpation of the abdominal organs, inspection of 
regional lymph nodes, and neurological status must be performed according to the schedule of 
trial procedures (Section 4). 
If an unacceptable abnormal finding is identified during the physical examination at the 
screening visit, the subject must not be randomised into the clinical trial (respecting exclusion 
criterion 36). 
If an abnormal finding at any other visit than the screening visit is considered by the 
investigator to be clinically significant, it will be reported as an AE in accordance with the 
principles for data entry in Section 13.3. 
At least 1 physical examination should be done if the subject terminates the trial before 
Week 52 for any reason and if the subject accepts this procedure.   
It will be recorded in the eCRF if a physical examination was performed and 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 will be 
reported as an AE in accordance with Section 13.3. 
11.4.3 Electrocardiogram 
A single 12-lead resting digital ECG will be recorded after the subject has been supine for at 
least 5 minutes at the visits indicated in the schedule of trial procedures (Section 4). 
A pre-evaluation of the ECG will be performed by the investigators to evaluate immediate 
subject safety. At a minimum, the date of ECG collection will be recorded in the source 
documents. 
The ECG data will be transferred to a central ECG service company for central evaluation. A 
cardiologist at the ECG service company will analyse and interpret the ECG data. The ECG 
service company will provide ECG evaluation reports to the trial sites. The collection and 
transmission of ECG data will be described in a separate ECG manual. 
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The investigator must evaluate all abnormal ECG results (‘clinically significant’ or ‘not 
clinically significant’) and sign and date when the evaluation is performed. The investigator 
has the final decision on the clinical significance of ECG abnormalities. 
Subjects should not be randomised before the evaluation report from the ECG service 
company of the ECG performed at Visit 1 is received at site. If the Visit 1 ECG is evaluated as 
abnormal and considered by the investigator to be clinically significant, it will be at the 
investigator’s discretion if the subject should be randomised into the trial (respecting 
exclusion criterion 36); if such a subject is randomised, the investigator should provide a 
justification in the medical record.  
It will be recorded in the eCRF if an ECG was performed and the investigator’s assessment of 
ECG results (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically 
significant’); if an ECG 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 will 
be reported as an AE in accordance with Section 13.3.   
11.4.4 Body measurements: height and weight 
The subject’s height (without shoes) will be measured; the subject’s weight (in indoor 
clothing and without shoes) will be measured. The subject’s height and weight will be 
recorded in the eCRF according to the schedule of trial procedures (Section 4). 
11.4.5 Laboratory testing 
11.4.5.1 Overview of all laboratory tests 
Blood and urine samples will be collected according to the schedule of trial procedures 
(Section 4).  
See Panel 18 for an overview of all laboratory tests to be conducted in this trial. 
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11.4.5.2 Investigator evaluation of laboratory tests 
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 to confirm the abnormality. 
The site staff will record in the eCRF if a blood sample was taken as well as the investigator’s 
assessment of the results (‘normal’, ‘abnormal, not clinically significant’, or ‘abnormal, 
clinically significant’). 
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 take an additional sample in order to 
reject or confirm the initial finding within 28 days, and if normalised, be randomised into the 
trial.  
Urine samples will be tested at the trial site with a dipstick and it will be recorded in the eCRF 
if the result was normal or abnormal. If dipstick sampling was not performed, a reason will be 
given. If a urine 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 local 
assessment of significance. The investigator’s assessment of the central laboratory analysis 
result (‘normal’, ‘abnormal, not clinically significant’, or ‘abnormal, clinically significant’) 
must also be recorded in the eCRF. 
Female subjects will have a serum pregnancy test performed at screening and a urine 
pregnancy test performed both at screening and baseline prior to randomisation. The test will 
be repeated at the visits stated in the schedule of trial procedures in Section 4. The date and 
the outcome of the urine pregnancy test will be recorded in the eCRF (‘positive’, ‘negative’). 
If a urine pregnancy test is positive, the result must be confirmed by a serum pregnancy test. 
Any 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 as well as any new clinically significant sign, 
symptom or illness will be reported as an AE in accordance with Section 13.3. 
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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. 
11.4.6 Blood sampling for analysis of vaccine antibodies 
Blood samples will be collected to determine levels of anti-tetanus toxoid antibodies (aTTA) 
at pre-determined time points according to the schedule of trial procedures (Section 4). It will 
be recorded in the eCRF if the sample was taken; if not, a reason will be provided. 
Blood sampling times must be recorded on the laboratory requisition forms (‘date and hours’). 
Collection, handling, and shipment instructions for blood samples for analysis of aTTA levels 
are provided in a laboratory manual. 
11.4.7 Blood sampling for analysis of ADA 
Blood samples will be collected to determine anti-drug antibody (ADA) levels at 
pre-determined time points according to the schedule of trial procedures (Section 4). It will be 
recorded in the eCRF if the sample was taken; if not, a reason will be provided. 
Blood sampling times must be recorded on the laboratory requisition forms (‘date and hours’). 
Collection, handling, and shipment instructions for blood samples for analysis of ADA levels 
are provided in a laboratory manual. 
Serum samples for determination of presence or absence ADA will be analysed by a 
laboratory using a validated bioanalytical method. A tiered testing scheme will be employed, 
with the first step being screening. Samples found positive in the screening step will be tested 
in the confirmatory step. Samples confirmed positive for ADA in the confirmatory step will 
be analysed for the presence of neutralising antibodies. Details of the analytical method used 
will be described in an ADA bioanalytical report. 
11.5  Pharmacokinetic assessments 
11.5.1 Blood sampling for analysis of brodalumab concentration for PK assessments 
A blood sample for analysis of brodalumab concentration for PK assessments will be 
collected at the time points specified in the schedule of trial procedures (Section 4). It will be 
recorded in the eCRF if the blood samples for PK assessments were taken; if not, a reason 
will be provided. 
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Blood sampling times must be recorded on the laboratory requisition forms (‘date and hours’). 
Collection, handling, and shipment instructions for the blood samples for PK assessments will 
be provided in a laboratory manual. 
Serum samples for determination of brodalumab concentrations will be analysed by a 
laboratory using a validated bioanalytical method. Details of the analytical method used will 
be described in the bioanalytical report. 
11.6 Pharmacodynamics 
11.6.1 Overview 
Treatment with brodalumab is known to increase the serum levels of IL-17 as a result of 
IL-17R blockade. Consequently, as part of the assessment of the pharmacodynamic effects of 
brodalumab treatment, the level of IL-17 and lymphocyte subsets will be measured. Blood 
biomarkers and lymphocyte subsets will be measured to assess the effect of brodalumab as 
well as the vaccination on the immune system in adolescents with psoriasis treated with 
brodalumab. 
11.6.2 Blood sampling for analysis of IL-17 and other blood biomarkers 
Blood samples for analysis of IL-17 and other immunological and inflammatory biomarkers 
that reflect the effect of the vaccination and the psoriasis severity will be collected at the time 
points specified in the schedule of trial procedures (Section 4). It will be recorded in the eCRF 
if the blood samples were taken; if not, a reason will be provided. 
Blood sampling times must be recorded on the laboratory requisition forms (‘date and hours’). 
Collection, handling, and shipment instructions for the blood biomarker samples will be 
provided in a separate laboratory manual.  
Biomarkers to be analysed include IL-17, IL-10, IL-6, CXCL9, CCL20, S100-A12, and 
Caspase-8; additional biomarkers of relevance to psoriasis may be analysed from these 
samples to serve as pharmacodynamic markers of drug effect, if deemed relevant. 
11.6.3 Blood sampling for analysis of T- and B-lymphocyte subsets 
Blood samples for analysis of T- and B-lymphocyte subsets (including CD4+, CD8+, T-helper 
(Th)1, Th17, Th22, and CD19+ cells) will be collected at the time points specified in the 
schedule of trial procedures (Section 4). It will be recorded in the eCRF if the blood samples 
were taken; if not, a reason will be provided. 
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Blood sampling times must be recorded on the laboratory requisition forms (‘date and hours’). 
Collection, handling, and shipment instructions for the blood samples for measurement of T- 
and B-lymphocyte subsets will be provided in a separate laboratory manual.  
11.7 Other assessments 
11.7.1 Patient-reported outcomes for safety assessments 
The C-SSRS and PHQ-A 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. 
11.7.1.1 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 (52). The C-SSRS defines 5 subtypes of SIB 
in addition to self-injurious behaviour with no suicidal intent. 
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. 
• 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. 
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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 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 19 and 
20 for the C-SSRS components ‘history of suicidal behaviour’ and ‘suicidal ideation’ at 
screening (Visit 1) and at 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 other visits. The C-SSRS assessments will be transcribed into 
the eCRF. 
Suicidal ideation of category 4 or 5 or any suicidal behaviour must be reported as an AE. In 
addition, these subjects must be referred to a mental health professional and be discontinued 
from IMP. 
11.7.1.2 Patient Health Questionnaire, adjusted for adolescents 
PHQ-A is a severity measure for depression in children 11 to 17 years of age. PHQ-A is 
adapted from PHQ-9 and modified for adolescents (53). The PHQ-A is a validated and widely 
used 9-item version of the Patient Health Questionnaire depression scale designed to 
clinically assess subjects for symptoms and signs of depression (53).  
Eight questions of the questionnaire will be applied in this trial. Question number 9: 
“Thoughts that you would be better off dead, or of hurting yourself in some way?” will be 
removed. The PHQ-9 and PHQ-8 have a similar sensitivity and specificity to detect major 
depression (54). Furthermore, the removed question number 9 will be adequately covered by 
the C-SSRS, described above. Each question is rated on a 4-point scale (0=Not at all; 
1=Several days; 2=More than half the days; and 3=Nearly every day). The total score of 
8 questions can range from 0-24. The subject must complete all 8 questions.  
The PHQ-A (i.e., PHQ-9 adopted for adolescents, without question number 9) takes 
approximately 3 minutes to complete. 
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PHQ-A scores ≥10 must be reported as an AE and the subject referred to a mental health 
professional (score ≥10 is cut-point for defining current depression) (53). Subjects scoring 
≥15 must in addition be discontinued from IMP. 
11.7.2 Photography (selected trial sites) 
Subjects at selected trial sites will be asked to participate in a voluntary photography 
component of the trial which involves digital photography assessments to show disease 
progression over time. Participation in this photography component requires that the subject 
and the legal authorised representative provide additional informed consent with the 
possibility to choose for which purpose (scientific and/or commercial) the photographs can be 
used. It is estimated that photos will be taken of approximately 40 subjects. 
Digital colour photographs will be taken of the legs including feet (dorsal and ventral image), 
torso including arms (dorsal and ventral image), and head (anterior image) according to the 
schedule of trial procedures (Section 4). The photographs must always be taken with 
underwear (modesty garments, provided by the central photography vendor) and female 
subjects should have their breasts hidden. All faces (eyes and mouth) will be anonymised 
upon receipt of the images by the central photography vendor. It will be recorded in the eCRF 
if the photograph(s) was taken; if not, a reason should be provided. If deemed necessary (e.g. 
in case of poor quality), photographs can be retaken at the next visit. 
Photography equipment, standards, and procedures are provided to the trial sites by the 
central photography vendor. Instructions for photography will be provided to the sites in a 
photography manual. 
The photographs will have no other subject identifier than the subject ID, year of birth, visit 
number, and date, and will be transmitted electronically to the photography vendor using a 
secure file transfer protocol. 
The photographs must be included as part of the individual subject source documentation. 
Depending on the subject’s consent, LEO Pharma may use the photographs in publications, 
posters, and similar types of information material or media targeting patients and healthcare 
professionals. The photographs may also be part of training material used for training and 
educational purposes. Steps will be taken to ensure that the identity of the subject is protected 
by blinding or covering any potential identifying features in the photographs. 
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11.8 Estimate of total blood volume collected 
Blood samples will be drawn in this trial as indicated in Panel 2 and Panel 3. The blood 
volume to be collected will not exceed 72 mL during a period of 4 weeks, or 24 mL at any 
single time throughout the trial. This is in compliance with the current ethical guidelines on 
trial-related blood loss in children (36). The above volumes are acceptable for the subject with 
the body weight of 30 kg and total blood volume of 2400 mL (36). The total volume of blood 
to be drawn in the trial corresponds to approximately 33% of blood volume drawn during a 
single blood donation (approximately 500 mL). 
11.9 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. 
11.9.1 End of treatment form 
An end of treatment form will be completed in the eCRF for all subjects when they have had 
their last administration of IMP. This form will also be completed for subjects who 
discontinue IMP prematurely 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 period 
and, if not, whether the reason for not completing the treatment period was related to 
pandemic restrictions (e.g. 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 the supply chain of IMP). If the subject did not complete the 
treatment, the date of last administration of IMP and the primary reason for permanent 
discontinuation of IMP must be recorded (see Section 10.2.1).  
11.9.2 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:  
• Last scheduled visit number for which data is recorded. 
• If the subject completed the trial. If not, the primary reason for early termination and 
whether the reason for not completing the trial was related to pandemic restrictions (e.g. 
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 the supply chain of IMP) must be recorded. 
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• Date of last contact. 
• Primary reason for withdrawal from trial (lack of efficacy, adverse event, withdrawal by 
subject, withdrawal by parent/guardian, lost to follow-up, death, pregnancy, other). 
o 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 their last visit, that is, the 
safety follow-up visit at Week 60, or earlier in case of early trial termination (see Section 10). 
11.10 
Storage of biological samples 
Blood samples collected for PK, aTTA, and biomarkers will be retained for as long as the 
quality of the material permits evaluation, but will be discarded after completion of the 
clinical trial report (CTR). 
Blood samples collected for analysis of ADA and nAb will be stored in the biobank 
established by LEO Pharma for no longer than 10 years after completion of the CTR.  
 
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12 Scientific rationale for trial design and appropriateness of assessments 
12.1 Scientific rationale for trial design 
This trial is the first clinical trial in the LEO Pharma paediatric investigational plan for 
brodalumab, which has been agreed with PDCO and EMA.   
The trial population will comprise both male and female subjects to explore differences in 
effects between genders and across the adolescent age range. Psoriasis prevalence in children 
correlates in a linear manner with age with a low prevalence in the age range from 0 to 6 years 
and a higher prevalence in the age range from 11 to 18 years (2). The paediatric 
investigational plan for brodalumab is designed to follow the safety principle, i.e., the 
adolescent trial must be conducted before the trial in children, aged 6 to 11 years. Thus, 
children will not be exposed to brodalumab before efficacy, safety, and PK data from the 
adolescent trial have been analysed and indicated that it is appropriate to initiate the trial in 
children. Furthermore, the adolescent population is more comparable with adults with fewer 
differences in pharmacokinetic and safety profiles (55). This enables extrapolation of 
brodalumab PK, pharmacodynamics, and safety data from the completed development 
programme in adults to this adolescent trial.  
The most important inclusion criterion for entry into the trial is a diagnosis of chronic plaque 
psoriasis for at least 6 months before randomisation to ensure correct diagnosis and rule out 
differential diagnosis. Furthermore, the subject must be a suitable candidate for systemic 
treatment. Subjects diagnosed with erythrodermic psoriasis, pustular psoriasis, guttate 
psoriasis, medication-induced psoriasis, or other skin conditions are not allowed to participate 
in the trial to ensure a homogenous disease population and interpretability of efficacy results. 
The number of paediatric patients available for clinical trials is often limited, which poses a 
challenge for including a sufficient number of subjects in the trial. Moreover, administration 
of IMP by injection, the mandatory trial-specific blood sampling, and the additional 
vaccination may further impact the recruitment of adolescents for this trial. 
Minimising the number of trial subjects is an important ethical aspect, especially in paediatric 
trials. Inclusion of a double-blind placebo arm from Week 0 to Week 12 will enable a formal 
test of superiority of brodalumab compared to placebo, and demonstrating superiority of 
brodalumab to placebo will require fewer paediatric subjects than would be required to 
demonstrate superiority of brodalumab to an active comparator. Thus, inclusion of a placebo 
arm in this trial will minimise the number of paediatric subjects required for the trial while 
maintaining a high statistical power. 
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The open-label ustekinumab arm will enable a safety evaluation and a descriptive efficacy 
comparison of brodalumab to ustekinumab. No formal hypotheses regarding brodalumab vs 
ustekinumab or placebo vs ustekinumab will be tested. Ustekinumab is part of the standard 
treatment of moderate-to-severe plaque psoriasis in adolescents (from the age of 12 years), 
who are inadequately controlled by, or intolerant to, other systemic therapies or 
phototherapies. The administration of ustekinumab in an open-label manner will significantly 
reduce the number of injections. According to the SmPC of Stelara® (45), ustekinumab must 
be administered at Weeks 0, 4, and then every 12 weeks. The blinding of ustekinumab until 
Week 12 would require a double dummy design, leading to a significant increase in the 
number of subcutaneous injections. Furthermore, to adequately power a formal statistical test 
of superiority comparing brodalumab to ustekinumab would require a significantly larger 
sample size. In light of the previously described potential challenges of recruitment of 
adolescent subjects, this would impact the feasibility of the trial design. 
The double-blind induction period (Week 0 to Week 12) is considered appropriate for 
evaluating the primary objective of the trial as double-blinding of the subject’s treatment 
(brodalumab or placebo) is maintained and the possible observer bias regarding treatment 
effects is minimised. All efficacy assessments will be performed by an investigator, who is 
blinded to the treatment allocation (brodalumab/placebo, ustekinumab, and vaccine) 
throughout the trial, which will minimise observer bias also in the open-label ustekinumab 
arm.  
Psoriasis is a chronic condition, requirering a long-term therapy. Therefore, it is important to 
evaluate the efficacy and safety of brodalumab as maintenance treatment. To allow for 
assessment of the duration of treatment response, the 12-week induction period will be 
followed by continued 40 weeks treatment until Week 52. Subjects, who are initially treated 
with placebo will switch to either brodalumab or ustekinumab, and will thus receive 40 weeks 
of active treatment in the maintenance period. The duration of the treatment phase (induction 
and maintenance periods) is the same as those in the pivotal clinical phase 3 trials in adults, 
and is also considered sufficient for evaluation of the duration of treatment response in 
adolescents.  
12.2 Appropriateness of assessments 
The clinical efficacy of brodalumab treatment will be assessed by PASI and sPGA: 
• PASI is the most thoroughly validated and the most extensively studied psoriasis clinical 
severity score, which assesses the extent of psoriasis at 4 anatomic sites with the signs of 
erythema, scale, and elevation (56). 
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• sPGA is a validated and standardised global score of the patient’s overall disease severity, 
and can be used in conjunction with PASI for assessment of clinical efficacy (57). 
The efficacy endpoints sPGA score of 1 or 0 and PASI 75 are recommended by both EMA 
and the United States Food and Drug Administration (FDA) for assessment of clinical 
efficacy (57, 58) and recognised as important endpoints in clinical trials in psoriasis by 
regulatory authorities in the EU. 
Validated patient-reported questionnaires (CDLQI, FDLQI) have also been included to assess 
the efficacy of brodalumab on patient-reported outcomes and health-related quality of life.  
Blood concentrations of brodalumab will be analysed using validated bioanalytical methods. 
To minimise the number of blood samples, a population PK approach will be used to quantify 
the systemic brodalumab exposure in adolescents.  
The trial will evaluate the percentage of subjects with seroprotective aTTA at Week 12, 
defined as aTTA ≥0.1 IU/mL at Week 12 (43, 59) and whether the subjects achieve a booster 
response at Week 12, defined as a 3-fold increase in IgG at Week 12 if IgG ≤1.0 IU/mL at 
baseline, or IgG ≥2.5 IU/mL if IgG >1.0 IU/mL at baseline. These response criteria were 
developed based on the criteria for positive vaccine response in the assays used for 
determining aTTA. The aTTA booster response definition takes into account that some 
subjects may have high pre-vaccination anti-tetanus IgG levels and may therefore not be able 
to elicit the same increase in anti-tetanus IgG levels as those with low pre-vaccination IgG 
levels. It has also been reported, that antigen-specific B- and T-cells and IL-17 are increased 
after vaccination and remain above the baseline for more than 4 weeks after the vaccination 
(60). The vaccine-induced changes in B- and T-cells and IL-17 levels will therefore be 
evaluated at Week 12 in this trial.  
Subjects who do not achieve clinical response and subjects who loose clinical response will 
not be excluded from further participation in the trial. This approach has been chosen to 
increase the likelihood that subjects from the placebo arm will stay in the trial until 
administration of the vaccine at Week 8 and evaluation of the vaccine responses at Week 12.  
It has been reported that IL-17-producing Th17 cells are increased and positively correlated 
with disease severity in children with psoriasis (19). Brodalumab treatment in adult patients, 
who received a constant 140 mg or 210 mg dose of brodalumab every 2 weeks through the 
treatment period increased the median serum IL-17A levels by 3- to 4-fold relative to baseline 
(61). IL-17 cytokines play a role in several homeostatic and pathogenic processes. Scientific 
literature suggests that IgG antibodies can cross the blood-brain barrier, albeit in low amounts, 
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and that the Th17/IL-17 axis may potentially play a role in depression (62, 63, 64, 65). 
However, the observed brodalumab plasma concentrations in patients with SIB events were 
similar to the overall subject population in the individual trials (61, 66, 67) and there is no 
clear evidence of a relationship between brodalumab (systemic exposure) and SIB events 
(68). The current trial will evaluate the serum IL-17 levels in adolescents treated with 
brodalumab by use of an established assay. 
Data on antibodies against brodalumab (ADAs) will be collected and the potential for 
immunogenicity will be evaluated throughout the trial.   
Furthermore, safety will be assessed using standard clinical methods of subject evaluations, 
such as AE monitoring, ECG, vital signs, and clinical laboratory measurements. 
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13 Adverse events 
13.1 Definition and classification of adverse events 
Adverse events (AEs) and serious adverse events (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, placebo, ustekinumab, and 
vaccine). 
13.2 Collection of adverse event reports 
AEs must be collected from time of first trial-related activity after the subject has signed the 
informed consent form until subject´s completion of the clinical trial (defined in Section 7.3). 
AEs must be assessed by a physician. 
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 11.4.5 for principles for data entry in the eCRF. 
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, unless 
the event is ongoing. If the event is ongoing, it will be marked as ongoing. In addition, it will 
be recorded if the AE started prior to first administration of the IMP. 
AEs must be classified in terms of severity, causality, and outcome according to the 
definitions in Appendix 2. 
Action taken with IMP: any action taken with IMP as a consequence of the AE must be 
recorded, e.g., dose not changed, dose reduced, dose increased, drug interrupted, drug 
withdrawn, not applicable, unknown. 
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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 immediately, without 
undue delay and no later than 24 hours of obtaining knowledge. This report should contain 
amongst others an assessment of available information on seriousness, severity, causal 
relationship to IMPs, device, or trial procedure, the action taken, the outcome to date, and a 
narrative description of the course of the event. For more details regarding reporting of any 
SAE, please see the guidance text on the SAE form. 
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 7226 3287. 
If relevant, the investigator will enclose other information with the SAE form, such as 
anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
Additionally, Global Safety at LEO Pharma may request further information in order 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). 
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The investigator must notify the IEC(s) of SAEs, as required by current applicable legislation 
for the concerned country. 
SAEs occurring after the completion of the clinical trial including any protocol required 
post-treatment follow-up period, should not be routinely sought or recorded. However, such 
events should be reported immediately without undue delay and no later than 24 hours of 
obtaining knowledge 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 the IMP (brodalumab/placebo), the current edition of the Investigator’s Brochure, 
edition 13 and subsequent updates.  
• For the comparator (ustekinumab), the current SmPC in the EU. 
• For Td and Tdap vaccines, the current SmPC in the EU. 
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.  
The following reporting requirements apply: all SAEs which are assessed as causally related 
to the IMP(s) by either the investigator or LEO Pharma (78), 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 (AESI) have been defined: suicidal ideation and 
behaviour (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 immune modulating 
biologics used for psoriasis. AESIs must be reported to LEO Pharma as described in  Panel 19. 
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 Panel 19: 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). 
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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. 
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. Broadly, medication errors fall into 3 categories: wrong medication, wrong dose 
(including overdose, form, concentration, amount), and 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 the 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). 
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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. 
Plaque psoriasis is a fluctuating disease with possible periods of remission. In case of 
relapses/recurrences, only aggravations/exacerbations exceeding normal disease fluctuation or 
lesions appearing in a body area normally not affected by plaque psoriasis should be reported 
as an AE.  
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). Once a subject leaves the clinical trial, the investigator should follow-up on the 
outcome of all non-serious AEs classified as of possibly/probably related to the IMP for 
2 weeks or until the final outcome is determined, whichever comes first. 
All 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 
from which the subject cannot be expected to recover during the trial or the safety follow-up 
periods, for example chronic or stabilised conditions, the final outcome should be reported as 
‘recovering/resolving’ or ‘not recovered/not resolved’ at the investigator´s discretion. In 
addition, a statement detailing why the subject cannot be expected to recover during the trial, 
e.g. 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.” (69). 
If the investigator becomes aware of information that necessitates an immediate change in the 
clinical trial procedure or a temporary halt to the clinical trial in order 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. 
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The investigator must immediately inform LEO Pharma – by contacting the clinical project 
manager or medical expert – of this change in the clinical trial procedure or of the temporary 
halt providing 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 endpoint for this trial is the PASI 75 response status at Week 12. Denoting the 
Week 12 PASI 75 responder rates for the adolescent brodalumab dosing regimen and pooled 
placebo arms by πbroda and πplacebo respectively, the following null hypothesis,  
H0: πbroda – πplacebo ≤0, 
will be tested versus the 1-sided alternative, 
H1: πbroda – πplacebo >0, 
by assessing if the lower limit of the 95% confidence interval (CI) for the difference in 
responder rates is >0 and by comparing the 2-sided p-value with the 5% significance level.   
For the purposes of this trial, the PASI 75 composite endpoint is defined as achieving a 
PASI 75 response without prior discontinuation of IMP treatment or previously satisfying the 
requirements for rescue treatment. Under the assumption that the Week 12 response rates for 
the PASI 75 composite endpoint in the adolescent brodalumab dosing regimen and pooled 
placebo arms are 80% and 15% respectively, a sample size of 40 subjects per arm, will 
provide >99% power to detect a significant treatment difference.  
In addition to the primary endpoint, the precision of the estimate of the difference in vaccine 
response rates between the adolescent brodalumab dosing regimen and pooled placebo arms, 
was taken into consideration when arriving upon a final sample size.   
For the purposes of the sample size calculation, the precision was taken to be half the width of 
the associated 95% CI for the estimated difference in the Week 12 vaccine response rates 
between the adolescent brodalumab dosing regimen and pooled placebo arms. Panel 20 
provides the 95th percentile for the precision of the estimated difference in vaccine response 
rates, from 100 000 simulations assuming the rate of vaccine response is equal in the 2 arms. 
The 95% CIs were calculated based on 
 
where 
 and 
 are the estimated Week 12 vaccine response rates for the 
adolescent brodalumab dosing regimen and pooled placebo arms respectively, and nbroda and 
nplacebo are the number of subjects randomised to the respective arms. Therefore, for a given 
set of assumptions regarding the sample size and response rates provided in Panel 20, we 
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would expect that the probability of obtaining a 95% CI for the difference in response rates 
less precise than the corresponding value in Panel 20 to be ≤5%.     
Panel 20: Estimated one-sided 95% upper confidence limit for the precision of the 
estimated difference in vaccine response between the brodalumab dosing 
regimen and placebo arms assuming the probability of vaccine response is 
equal in the 2 arms 
 
Probability of vaccine response 
Sample size/arm 
70% 
80% 
30 
24.6% 
22.8% 
35 
22.8% 
20.8% 
40 
21.2% 
19.5% 
 
14.2 Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
All randomised subjects will be included in the full analysis set (FAS) and will be analysed 
for efficacy up to Week 12. Analyses based on the FAS, will be analysed according to the 
randomised treatment allocation. Exclusions from the FAS can be considered in special cases 
as described in ICH E9, Section 5.2.1., Full Analysis Set. If it is decided to exclude a 
randomised subject from the FAS, a justification addressing ICH E9 will be given. 
A safety analysis set will be defined as all subjects who received IMP and will be analysed 
according to the actual treatment received.    
A PK analysis set will be defined as all subjects who received brodalumab, who have at least 
1 PK sample. 
A population PK analysis set will be defined as all subjects in the PK analysis set, who have 
at least 1 sample with a quantifiable concentration. 
The decisions regarding inclusion/exclusion of subjects or subject data from the trial analysis 
sets will be documented in the analysis set definition document before breaking the 
randomisation code. 
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14.3 Statistical analysis 
14.3.1 General principles 
Unless otherwise stated, significance tests will be two-sided with a significance level of 5%. 
CIs will be presented with 95% degree of confidence. Efficacy analyses will be based on the 
FAS. Safety analyses will be based on the safety analysis set.  
The presentation of sensitivity analyses and the secondary estimand will be reserved for 
primary and key secondary endpoints only.   
For induction period-related endpoints, i.e., endpoints assessed at or over the initial 12-week 
treatment phase, separate treatment contrasts comparing the adolescent brodalumab dosing 
regimen to the pooled placebo (consisting of subjects randomised to either of the treatment 
arms scheduled to receive placebo for the first 12 weeks) and the ustekinumab arm will be 
presented.   
For maintenance period-related endpoints, i.e., endpoints assessed at or over the entire 52-
week treatment phase, 2 separate analyses comparing the adolescent brodalumab dosing 
regimen versus ustekinumab will be presented:  
• Brodalumab (consisting of subjects randomised to the brodalumab arm [a constant 
brodalumab arm]) versus ustekinumab (consisting of subjects randomised to the 
ustekinumab arm [a constant ustekinumab arm]). 
• Pooled brodalumab (consisting of all subjects randomised to receive brodalumab during 
the maintenance period [a mixed brodalumab arm]) versus pooled ustekinumab 
(consisting of all subjects randomised to receive ustekinumab during the maintenance 
period [a mixed ustekinumab arm]). 
For the purposes of stratified analyses, the strata defined by baseline body weight (<70 kg and 
≥70 kg) may be pooled in order to ensure there is a sufficient number of subjects in every 
stratum. In the event that all strata are pooled into a single stratum, inference based on the 
general association test statistics for the Cochran-Mantel-Haenszel (CMH) test, simplifies to 
, where 
 is the test statistic for the Pearson chi-square test, and n is the sample size.   
Imputation algorithms specified in Section 14.3.2.1 will be implemented using PROC MI. 
Inference based on multiple imputation methods will consist of n=250 imputed data sets to 
ensure that the between-imputation variance is estimated with adequate precision. For the 
analysis of binary endpoints using the CMH test and relying on multiple imputation methods 
to address missing data, the test-statistics will be pooled based on the procedure proposed by 
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Li et al (70) and outlined by Ratitich, Lipkovich, and O’Kelly (71) in order to derive the final 
p-value. Additionally, the common risk differences and associated standard errors will be 
pooled directly, based on Rubin’s rules, in order to quantify the potential treatment benefit. In 
the event of a potential disagreement between the pooled p-value and 95% CI for the 
estimated common risk difference, inference will be based on the pooled p-value. For the 
analysis of multiply imputed data sets using generalised estimating equation (GEE) or 
analysis of covariance (ANCOVA), the estimated regression coefficients and associated 
standard errors will be pooled directly using Rubin’s rules.   
LSMeans will be estimated based on the observed margins. For analyses that rely on the 
missing at random assumption, the observed margins dataset should contain data entries 
corresponding to missed visits.  
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, 1st quartile, 3rd quartile, 
standard deviation (SD), minimum, and maximum values.  
The analyses specified in the protocol will be reviewed in relation to the blinded data. If a 
statistical analysis plan is required, it will be finalised before breaking the blind. 
Any changes from the statistical analyses planned in this clinical trial protocol will be 
described and justified in a protocol amendment, the statistical analysis plan and/or in the 
CTR depending on the ramifications of the proposed changes. 
14.3.2 Handling of missing values 
Likelihood methods, as well as single and multiple imputation methods will be implemented 
in order to account for the presence of missing data in the statistical analysis of the primary 
and secondary endpoints. The missing data methods specified in Sections 14.3.6.1 and 
14.3.6.2 are designed to assess the robustness of the results of the primary analysis, with 
respect to the assumptions made regarding missing data. For imputation-based methods, non-
monotone missing data will be imputed based on a Markov Chain Monte Carlo (MCMC) 
method, assuming an underlying multi-variate normal distribution for continous endpoints 
and the fully-conditional specification method for binary or ordinal endpoints.  
Multiple impupation methods that will be implemented as a part of the sensitivity analyses of 
the primary and key secondary endpoints include the ‘control-based’ pattern mixture model 
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outlined by Ratitich and O’Kelly (72), as well as imputation models assuming that missing 
data is missing at random (MAR) within the randomised treatment arms.   
The ‘control-based’ pattern mixture model assumes that the mean response value among 
subjects no longer receving active treatment is given by the mean response among the 
reference/placebo arm. Missing data in subjects receiving either active or reference treatment 
at a given time point is imputed based on the distribution of the conditional mean fitted to the 
observed data amongst the appropriate reference arm.        
14.3.2.1 Endpoint-specific considerations for multiple imputation algorithms 
PASI 
Imputation of missing binary PASI 75/90/100 data between Week 2 and Week 52 will be 
based on imputating the underlying PASI scores (range 0-72). The relevant assumptions and 
groups are dependent on the specified multiple imputation algorithm. Intermittent missing 
values will be imputed in each relevant group based on a MCMC method to obtain 
n=250 copies of the data set with a monotone missing data pattern (seed=992051). 
Imputation of monotone missing data for each relevant patient population defined by the 
specified multiple imputation procedure will be based on the following 4 steps: 
1. Fitting an ANCOVA model to the Week 2 PASI score including the effects of baseline 
PASI as a covariate, and baseline body weight (<70 kg and ≥70 kg) as a factor. The 
estimated parameters, and their variances, will be used to impute missing PASI scores at 
Week 2 in each of the n=250 copies of the dataset generated above (seed=485741). 
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. 
2. For each of the 250 copies of the dataset, missing PASI scores at Week 4 will be imputed 
in the same manner as for missing Week 2 values in step 1. The imputations will be based 
on the same ANCOVA model with the effects of baseline and Week 2 PASI scores as a 
covariate, and baseline body weight (<70 kg and ≥70 kg) as a factor. Again, negative 
imputed values will be replaced by 0, and imputed values larger than 72 will be replaced 
by 72. 
3. This stepwise procedure will then be repeated sequentially through Week 52, with the 
modification that only the PASI scores from the preceding 2 visits be included as 
covariates in the ANCOVA model.  
4. The missing binary PASI 75/90/100 response values over the 52-week treatment phase, 
will be derived from the underlying imputed PASI scores. 
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Ordinal variables (sPGA, CDLQI, FDLQI) 
The analysis of sPGA, CDLQI, and FDLQI are based on perceived subject relevant 
dichotomisations, e.g., the proportion of subjects with sPGA score ≤1 at Week 12. The 
imputation of missing binary values for these dichotomisations, will be based on imputing the 
values on the underlying scales, e.g., 5-point scale for sPGA. 
Imputation of missing data for each relevant trial population, defined by the specified multiple 
imputation procedure, will be based on the following steps: 
1. In each group, missing ordinal data from Week 2 to Week 52 will be imputed based on the 
FCS logistic regression model. The logit link option should be specified in order to impute 
missing values based on an ordinal logistic regression model assuming proportional odds. 
Separate conditional specifications will be specified for visits with missing values. The 
imputation model at a given visit should depend on the values from the preceding and 
subsequent 2 visits (exceptions being baseline and Weeks 2, 48, and 52) as well as the 
stratifying factor, baseline body weight (<70 kg and ≥70 kg). n=250 complete data sets 
will be generated (seed=657337). 
2. The missing binary response variables will be derived from the corresponding underlying 
imputed ordinal values. 
aTTA and lymphocyte subset 
Intermittent missing values will be imputed in each relevant group based on a MCMC method 
in order to obtain n=250 copies of the data set with a monotone missing data pattern 
(seed=875806). 
Imputation of monotone missing data for each relevant patient population defined by the 
specified multiple imputation procedure will be based on the following 2-step process: 
1. Fitting an ANCOVA model to the Week 8 lab value including the effects of baseline lab 
value as a covariate, and baseline body weight (<70 kg and ≥70 kg) as a factor. The 
estimated parameters, and their variances, will be used to impute missing lab values at 
Week 8 in each of the n=250 copies of the dataset generated above (seed=604006).  
2. For each of the 250 copies of the dataset, missing lab values at Week 12 will be imputed 
in the same manner as for missing Week 8 values in step 1. The imputations will be based 
on the same ANCOVA model with the effects of baseline and Week 8 lab values as a 
covariate, and baseline body weight (<70 kg and ≥70 kg) as a factor.  
For the booster response endpoint, missing binary response values at Week 8 and Week 12 
will be derived from the imputed aTTA values. 
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, satisfying the 
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inadequate responder criteria during the induction period, completing IMP, discontinuing 
IMP, and withdrawal from trial by treatment arm and overall. Within the overall summary, the 
number of exposed, completing IMP, discontinuing IMP, and withdrawal from trial will be 
presented for the 12-week induction period as well as the entire 52-week treatment phase. The 
reasons for permanent discontinuation of IMP and withdrawal from trial will be presented for 
all randomised subjects by last visit attended, treatment arm, and reason for discontinuation of 
IMP and/or withdrawal from trial.   
In addition to the above, the number of subjects included in the FAS, the safety analysis set, 
and the PK analysis set will be summarised by treatment arm and in total. 
Cumulative incidence plots of the time to early termination, stacked by reason for early 
termination and time to initiation of rescue treatment will be presented by treatment arm over 
the duration of the treatment phase.   
14.3.4 Demographics and other baseline characteristics 
Descriptive statistics of demographics and baseline characteristics will be presented for all 
randomised subjects 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, aTTA, and lymphocyte subsets. In addition to 
the above specified baseline characteristics, the following baseline measures of disease 
severity will be presented: PASI, sPGA, CDLQI, FDLQI, and the baseline weekly average 
itch severity and itch-related sleep 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 
14.3.5.1 Exposure 
The exposure to treatment will be tabulated by treatment arm and visit for the FAS. Separate 
tabulations will be presented for the 12-week induction period and the entire 52-week 
treatment phase. 
14.3.5.2 Treatment compliance 
Treatment compliance will be presented from data listings. Subjects not receiving the 
scheduled dose will be listed by trial site, sorted by treatment arm and subject number. 
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14.3.6 Estimand strategy 
For each endpoint associated with a trial objective, a primary estimand will be pre-specified, 
and the secondary estimand will be used to further aid in the interpretation of the results. The 
estimands are described in a general manner to allow for the use of the same estimand for 
different endpoints.  
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 
underpinning the associated models/estimators.         
Description of intercurrent events  
An intercurrent event refers to a post-randomisation event that affects either the interpretation 
or the existence of the measurements of an endpoint. For the purposes of this trial, the 
following 3 intercurrent events were defined: 
I. 
Initiation of rescue treatment: Defined as satisfying the requirements for the initiation 
of rescue treatment specified in Section 9.5. This intercurrent event is handled without 
assessing relatedness to pandemic restrictions. 
II. Permanent discontinuation of IMP not due to pandemic restrictions: This event 
occurs when a subject permanently discontinues IMP for reasons not related to pandemic 
restrictions. Permanent discontinuation of IMP due to sickness with COVID-19 (an AE) 
will be interpreted as permanent discontinuation of IMP not due to 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 defined in the SAP. 
III. Permanent discontinuation of IMP due to pandemic restrictions: 
This event occurs when a subject permanently discontinues IMP for reasons related to 
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 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 the supply chain of IMP. The timing of the event will be defined in the 
SAP. 
Note, there is a distinction between permanent discontinuation of IMP (an intercurrent event) 
and withdrawal from trial and/or lost to follow-up. Withdrawal from trial and lost to follow-
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up, which are not intercurrent events, will be addressed when specifying methods and/or 
assumptions for handling missing data. If the withdrawal from trial is related to the pandemic 
restrictions, missing data will be handled as missing data related to the pandemic restrictions.  
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.  
The ‘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.  
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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14.3.6.1 Estimand strategy for binary endpoints 
14.3.6.1.1 Primary estimand for binary endpoints 
The primary estimand will assess the expected difference in response rate achieved without 
initiation of rescue treatment or permanent discontinuation of IMP not due to pandemic 
restriction, as if the conduct of the trial was not impacted by pandemic related restrictions.  
This implies an underlying composite strategy, assuming that the need for rescue treatment or 
permanent discontinuation of IMP not due to pandemic restrictions is indicative of treatment 
failure. But, also implied is a hypothetical strategi for mitigating any untoward influences the 
pandemic might have on the trial. 
With the composite strategy subjects who have either permanently discontinued treatment not 
due to pandemic restrictions or have initiated rescue treatment prior to the endpoint visit will 
be defined as non-responders, reflecting an assumption that initiation of rescue treatment and 
permanent treatment discontinuation not due to pandemic restrictions indicates failure of the 
randomised treatment to achieve response. 
A hypothetical strategy, in the form of a multiple imputation method, will be used to address 
permanent discontinuation of IMP due to pandemic restrictions. For subjects who have 
permanently discontinued IMP due to pandemic restrictions prior to the endpoint visit, data 
collected after treatment discontinuation will be excluded (including the occurrence of 
subsequent intercurrent events) and will be 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, assuming a similar course of 
events as experienced by subjects from the same treatment arm who have not discontinued 
IMP due to pandemic restrictions. With this purpose in mind two questions naturally arise 
because of the composite strategy used to address permanent discontinuation of IMP not due 
to pandemic restrictions: 
a) Would the subject still have been on treatment at the endpoint visit without rescue 
treatment as opposed to having permanently discontinued IMP not due to pandemic 
restrictions or initiated rescue treatment beforehand? 
b) If yes, would the subject have been a responder at the endpoint visit? 
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. In 
addition to outlining the hypothetical strategy for addressing permanent discontinuation of 
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IMP due to pandemic restrictions, Panel 22 specifies the handling of missing data in the 
primary analysis of the primary estimand. 
Panel 22: Hypothetical strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions and handling of missing data in the primary 
analysis of the primary estimand for binary endpoints 
Step no. 
Description 
Subjects in scope for imputation 
Purpose 
1 
Impute responder 
status at the 
endpoint visit under 
MAR assumptions 
Subjects who have permanently discontinued IMP due 
to pandemic restrictions prior to the endpoint visit 
Hypothetical 
strategy 
Subjects who have not experienced an intercurrent 
event prior to the endpoint visit and whose score at the 
endpoint visit is missing due to pandemic restrictions 
Handling of 
missing data 
2 
Impute responder 
status at the 
endpoint visit based 
on NRI 
Subjects who have not experienced an intercurrent 
event prior to the endpoint visit and whose score at the 
endpoint visit is missing for reasons other than 
pandemic restrictions 
Handling of 
missing data 
3 
Impute treatment 
adherence status at 
the endpoint visit 
Subjects who have permanently discontinued IMP due 
to pandemic restrictions prior to the endpoint visit 
Hypothetical 
strategy 
Abbreviations: IMP, investigational medicinal product; MAR, missing at random; NRI, non-responder 
imputation. 
 
When performing Step no. 1 in Panel 22, data collected after initiation of rescue treatment or 
permanent discontinuation of IMP will not be applied, regardless of the reason for treatment 
discontinuation. This is well aligned with the composite strategy described above for 
addressing permanent discontinuation of IMP not due to pandemic restrictions and initiation 
of rescue treatment, where data collected after treatment discontinuation or initiation of rescue 
treatment is irrelevant for the value of the estimand’s variable.  
For subjects who prior to the endpoint visit have permanently discontinued IMP due to 
pandemic restrictions the values imputed in Step no. 1 may be thought of as the responder 
status at the endpoint visit, conditional on treatment adherence, thereby addressing the 
hypothetical question b) stated above. Similarly, Step no. 3 in Panel 22 may be thought of as 
addressing the hypothetical question a) for these subjects. 
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Impute responder status at the endpoint visit under MAR assumptions 
The imputation of responder status at the endpoint visit under MAR assumptions will be 
carried out as outlined in Section 14.3.2.1. 
Impute responder status at the endpoint visit based on NRI 
For each of the 250 copies of the dataset generated in the previous step, NRI will be carried 
out by imputing subjects in scope as non-responders. 
Impute treatment adherence status at the endpoint visit 
For each treatment arm, a Cox proportional hazards regression model will be fit for the hazard 
rate of permanent discontinuation of IMP not due to pandemic restrictions. The models will 
be stratified by baseline body weight (<70 kg and ≥70 kg), and will include baseline PASI 
score as a continuous covariate. The time to permanent discontinuation of IMP not due to 
pandemic restrictions or initiation of rescue treatment 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 the endpoint visit, say at time 𝑡, the model will provide an estimated probability 
𝑝̂(𝑡, treatment arm, baseline body weight, baseline PASI score) 
of being on treatment at the endpoint visit conditional on being on treatment at the earlier time 
𝑡 in the hypothetical 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 the endpoint visit divided by the same function evaluated at 
time 𝑡. 
For each subject having discontinued treatment prior to the endpoint visit due to pandemic 
restrictions and each of the 250 copies of the dataset a Bernoulli trial with the subject-specific 
success probability 𝑝̂ will be performed (seed=183511) 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) stated above.  
The imputed value of the estimand’s variable will be derived from the responder status at the 
endpoint visit, 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 not due to pandemic restrictions and initiation 
of rescue treatment. 
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Primary analysis  
The null hypothesis, that the response rate associated with the adolescent brodalumab dosing 
regimen is less than or equal to the rate in the placebo arm, will be tested againist the 
alternative that brodalumab is superior to placebo. For each of the 250 complete data sets, the 
difference in response rates between treatment arms will be analysed using the 
Cochran-Mantel-Haenszel (CMH) test stratified by baseline body weight (<70 kg and ≥70 kg) 
for the composite endpoint. The estimated common risk difference, across the strata defined 
by baseline body weight (<70 kg and ≥70 kg), between treatment arms and the corresponding 
standard errors from the 250 analyses will be pooled to one estimated treatment difference 
and associated standard error using Rubin’s rule to draw inference. From these pooled 
estimates, the 95% CI for the treatment difference will be calculated.  
The test-statistics will be pooled based on the procedure proposed by Li et al (70) and 
outlined by Ratitich, Lipkovich, and O’Kelly (71) in order to derive the final p-value. 
In the event of a potential disagreement between the pooled p-value and 95% CI for estimated 
treatment difference, inference will be based on the pooled p-value. 
Sensitivity analysis 
The sensitivity analysis will be conducted based on the stratified CMH test, specified for the 
primary analysis. The sensitivity analysis will assess the robustness of the results of the 
primary analysis with respect to the NRI.    
Subjects for whom no data for the primary endpoint has been collected at the endpoint visit 
for reasons other than pandemic restrictions will be imputed as in Step no. 1 rather than Step 
no. 2 of Panel 22, corresponding to imputation of all missing responder status data at the 
endpoint visit under MAR assumptions. 
14.3.6.1.2 Secondary estimand for binary endpoints 
The secondary estimand will assess the expected difference in response rates irrespective of 
initiation of rescue treatment or permanent discontinuation of IMP not due to pandemic 
restrictions, as if the conduct of the trial was not impacted by pandemic related restrictions. 
With the “treatment-policy” strategy, the initiation of rescue treatment or permanent 
discontinuation of IMP not due to pandemic restrictions will be ignored, i.e., observations 
occurring after these intercurrent events will be incorporated into the analysis.  
Missing data at the endpoint visit will be imputed assuming missing at random.  
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Permanent discontinuation of IMP due to pandemic restrictions will be addressed by the same 
hypothetical strategy as for the primary estimand, with the exceptions that: 
• Data collected from subjects who have permanently discontinued IMP not due to 
pandemic restrictions or initiated rescue treatment prior to the endpoint visit will be 
included when performing Step no. 1 of the multiple imputation method, and 
• Step no. 2 and 3 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 not due to pandemic restrictions, which simply ignores 
treatment discontinuations of that nature. Panel 23 summarises the procedure. 
Panel 23: Hypothetical strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions and handling of missing data in the primary analysis of 
the secondary estimand for binary endpoints 
Step no. 
Description 
Subjects in scope for imputation 
Purpose 
1 
Impute responder 
status at the 
endpoint visit under 
MAR assumptions 
Subjects who have permanently discontinued IMP due 
to pandemic restrictions prior to the endpoint visit 
Hypothetical 
strategy 
Subjects whose score at the endpoint visit is missing 
Handling of 
missing data 
Abbreviations: IMP, investigational medicinal product; MAR, missing at random. 
 
The analysis will be done as specified for the primary analysis of the primary estimand for 
binary endpoints. 
Sensitivity analyses 
Additional analyses of this estimand will assess the robustness of the imputation method for 
subjects with missing data at  the endpoint visit for reasons other than pandemic restrictions. 
Imputation methods to be used for these analyses include: 
• ‘Control-based’ pattern mixture model. 
• NRI. 
The hypothetical strategy and the handling of missing data for the sensitivity analyses are 
outlined in Panel 24. 
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Panel 24: Hypothetical strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions and handling of missing data in the sensitivity analyses 
of the secondary estimand for binary endpoints 
Step no. 
Description 
Subjects in scope for imputation 
Purpose 
1 
Impute responder 
status at the 
endpoint visit under 
MAR assumptions 
Subjects who have permanently discontinued IMP due 
to pandemic restrictions prior to the endpoint visit 
Hypothetical 
strategy 
Subjects who have not experienced an intercurrent 
event and whose score at the endpoint visit is missing 
due to pandemic restrictions 
Handling of 
missing data 
2 
Impute responder 
status at the 
endpoint visit based 
on ‘control-based’ 
pattern mixture 
model or NRI 
Subjects who have not experienced an intercurrent 
event and whose score at the endpoint visit is missing 
for reasons other than pandemic restrictions 
Handling of 
missing data 
Abbreviations: IMP, investigational medicinal product; MAR, missing at random; NRI, non-responder 
imputation. 
 
14.3.6.1.3 Supplemental analyses 
For binary endpoints assessed over the duration of the trial, from Week 0 to Week 52, a 
supplementary analysis based on a GEE model will be carried out to illustrate the trajectory of 
the treatment response over the duration of the trial. The GEE model for longitudinal binary 
data will be based on specifying the logit link function and visit, visit by treatment interaction, 
baseline value, and baseline body weight (<70 kg and ≥70 kg) as fixed effects. The working 
correlation matrix will be specified as having an unstructured form. In the event that this 
model fails to converge, the model should be fit using a compound symmetry working 
correlation matrix.   
The results of the GEE model will be presented as a figure, displaying the estimated response 
rates over the duration of the trial for the 4 treatment arms, along with tables providing the 
least squares (LS)-mean estimated response rates, difference in LS-mean response rates and 
associated approximate 95% CI based on the Delta-method, odds ratio and associated 95% CI 
and p-value. The analysis will be performed for the FAS. Subjects who initiate rescue 
treatement or permanently discontinue IMP not due to pandemic restrictions will be defined 
as non-responders. Monotone missing data for reasons other than pandemic restrictions will 
be imputed using NRI. Subjects who permanently discontinue IMP due to pandemic 
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restrictions, intermittent missing data, and monotone missing data due to pandemic 
restrictions will be assumed missing completely at random. 
For the Week 12 PASI, sPGA, CDLQI, and FDLQI responder endpoints, the estimated 
cumulative incidence functions for the time from randomisation to first satisfying the 
responder criteria for the brodalumab, ustekinumab, and pooled placebo arms will be 
presented based on the Aalen-Johansen estimator. The analysis will account for the competing 
risks, IMP discontinuation and initiation of rescue treatment. p-values based on Gray’s test for 
the cumulative incidence of satisfying the responder thresholds will be presented for the 
pairwise comparisons, brodalumab vs pooled placebo and brodalumab vs ustekinumab.      
14.3.6.2 Estimand strategy for continuous endpoints 
14.3.6.2.1 Primary estimand for continuous endpoints 
The estimand is defined as the treatment difference in the LS-mean change from baseline at 
the endpoint visit irrespective of initiation of rescue treatment or permanent discontinuation of 
IMP not due to pandemic restrictions, as if the conduct of the trial was not impacted by 
pandemic related restrictions. 
With the treatment policy strategy, subjects who have permanently discontinued IMP not due 
to pandemic restrictions or initiated rescue treatment prior to the endpoint visit will be 
included in the analysis with the observed score at this visit. 
Permanent discontinuation of IMP due to pandemic restrictions will be addressed by a 
hypothetical strategy. Data collected after such an event will not be applied in the analysis. 
The hypothetical scenario envisaged is that permanent discontinuation of IMP due to 
pandemic restrictions would not occur, assuming that subjects who have experienced this 
event would respond like subjects from the same treatment arm who have not experienced it. 
The hypothetical strategy and the handling of missing data in the primary analysis are 
outlined in Panel 25. 
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Panel 25: Hypothetical strategy for addressing permanent discontinuation of IMP due to 
pandemic restrictions and handling of missing data in the primary analysis of 
the primary estimand for continuous endpoints 
Step no. 
Description 
Subjects in scope for imputation 
Purpose 
1 
Impute score at the 
endpoint visit under 
MAR assumptions 
Subjects who have permanently discontinued IMP due 
to pandemic restrictions prior to the endpoint visit 
Hypothetical 
strategy 
Subjects whose score at the endpoint visit is missing 
Handling of 
missing data 
Abbreviations: IMP, investigational medicinal product; MAR, missing at random.  
 
The imputation of scores will be carried out like the imputation of PASI scores for the 
secondary estimand for binary endpoints. Data collected from subjects who have permanently 
discontinued IMP not due to pandemic restrictions or initiated rescue treatment will be 
included when applying this multiple imputation method, in alignment with the treatment 
policy strategy used for addressing occurrences of that intercurrent event. 
Primary analysis 
For each of the 250 datasets, analysis will be based upon an ANCOVA model including 
treatment arm and baseline body weight as factors and adjusting for baseline score as 
covariate. 
The pooled estimated difference in the LS-mean change from baseline at the endpoint visit, 
and the associated 95% CIs and nominal p-values will be presented based on applying 
Rubin’s rule to the estimates and standard errors from the aforementioned ANCOVA analyses 
of the imputed datasets. 
14.3.6.3 Estimand strategy for vaccine-related endpoints 
14.3.6.3.1 Estimand for binary vaccine-related endpoints 
The hypothetical estimand is defined as the treatment difference in the response rates if all 
subjects adhered to the treatment regimen, in the sense that they did not discontinue IMP 
treatment (regardless of relation to pandemic restrictions) and rescue treatment was not made 
available prior to endpoint visit.  
For this approach, data collected following discontinuation of IMP or the initiation of rescue 
treatment, is excluded from the analysis. Instead, missing data is imputed based on a multiple 
imputation algorithm outlined in Section 14.3.2.1, assuming that missing data is MAR within 
each treatment arm.   
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In order to account for the use of different vaccines, depending on the adolescents’ vaccine 
history, the analysis will be performed by fitting a logistic regression model, including fixed 
effects for baseline, treatment, baseline body weight (<70 kg and ≥70 kg), and vaccine type. 
In the event that issues arise fitting the model(s) due to the fixed effects for baseline and 
vaccine type, the model(s) will be re-fit excluding the relevant term(s). The logistic regression 
model will be used to estimate the risk difference and associated 95% confidence interval 
based on the standardised estimator presented in Ge et al (76). 
14.3.6.3.2 Estimand for continuous vaccine-related endpoints 
The estimand is defined as the treatment difference in the LS-mean change from baseline at 
the endpoint visit if all subjects adhered to the treatment regimen, in the sense that they did 
not permanently discontinue IMP and rescue treatment was not given prior to the endpoint 
visit. 
Permanent discontinuation of IMP or initiation of rescue treatment will be addressed by a 
hypothetical strategy that depends on the reason for treatment discontinuation. Data collected 
after permanent discontinuation of IMP or initiation of rescue treatment will not be applied in 
the analysis. The hypothetical scenario envisaged is that permanent discontinuation of IMP or 
rescue treatment would not occur, assuming that subjects who have permanently discontinued 
IMP (regardless of relation to the pandemic) or initiated rescue medication would respond like 
subjects having remained on treatment from the same treatment arm without initiation of 
rescue treatment. 
The hypothetical strategy is outlined in Panel 26, together with the handling of missing data in 
the analysis. 
Panel 26: Hypothetical strategy for addressing permanent discontinuation of IMP and 
rescue treatment and handling of missing data in the analysis of the secondary 
estimand for continuous secondary endpoints 
Step no. 
Description 
Subjects in scope for imputation 
Purpose 
1 
Impute score at the 
endpoint visit under 
MAR assumptions 
Subjects who have permanently discontinued IMP 
(regardless of relation to the pandemic) or who have 
initiated rescue treatment prior to the endpoint visit 
Hypothetical 
strategy 
Subjects whose score at the endpoint visit is missing 
Handling of 
missing data 
Abbreviations: IMP, investigational medicinal product; MAR, missing at random. 
 
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For each of the 250 datasets, analysis will be based upon an ANCOVA model including 
treatment arm and baseline body weight as factors and adjusting for baseline score as 
covariate. 
The pooled estimated difference in the LS-mean change from baseline at the endpoint visit, 
and the associated 95% CIs and nominal p-values will be presented based on applying 
Rubin’s rule to the estimates and standard errors from the aforementioned ANCOVA analyses 
of the imputed datasets. 
14.3.7 Testing Strategy 
To control the familywise error rate of the analysis of the pre-specified primary and key 
secondary endpoints, the following hierarchical testing procedure, illustrated in Panel 27, has 
been defined. The hierarchial testing procedure, will assess the difference in the response rates 
between the adolescent brodalumab dosing regimen and pooled placebo arms at Week 12, 
with respect to the specified endpoints. For the purposes of controlling the familywise error 
rate, the test of the null hypothesis will be based on the primary analysis of the primary 
estimand for binary endpoints. As stated in Section 14.3.1, the hypotheses in Panel 27 will be 
tested at a 5% significance level. The initial weight allocated to each hypothesis test is 
specified in Panel 27. Initially, 100% of the weight is allocated to the hypothesis test of the 
primary endpoint. If a given hypothesis is rejected, the arrows in Panel 27 specify how the 
allocated alpha for the rejected hypothesis is redistributed among the remaining hypothesis 
tests. 
Panel 27: Hierarchical testing procedure to control the familywise error rate for the pre-
specified primary and key secondary endpoints 
 
 
Abbreviations: CDLQ, Children’s Dermatology Life Quality Index; PASI, Psoriasis Area and Severity Index; 
sPGA, static Physician’s Global Assessment. 
14.3.8 Analysis of efficacy endpoints 
An overview of the analyses for efficacy endpoints can be found in Panel 28. 
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Panel 28: Overview of statistical analyses 
Endpoint 
Type of 
endpoint  
Primary estimand 
Comparison 
Primary endpoint  
PASI 75 response at Week 12. 
Binary.    
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
placebo. 
Key secondary endpoints 
sPGA score of 0 or 1 at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
placebo. 
sPGA score of 0 at Week 12. 
Binary. 
Primaryestimand 
for binary 
endpoints. 
Brodalumab vs 
placebo. 
PASI 90 response at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
placebo. 
PASI 100 response at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
placebo. 
CDLQI score of 0 or 1 at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
placebo. 
Secondary and other endpoints 
FDLQI score of 0 or 1 at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
placebo. 
PASI 75 response at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
PASI 75 response at Week 52. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
PASI 90 response at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
PASI 90 response at Week 52. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
PASI 100 response at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
PASI 100 response at Week 52. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
 
 
 
1 (3) 
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Endpoint 
Type of 
endpoint  
Primary estimand 
Comparison 
sPGA score of 0 or 1 at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
sPGA score of 0 or 1 at Week 52. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
sPGA score of 0 at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
sPGA score of 0 at Week 52. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
CDLQI score of 0 or 1 at Week 12 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
CDLQI score of 0 or 1 at Week 52. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
FDLQI score of 0 or 1 at Week 12. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
FDLQI score of 0 or 1 at Week 52. 
Binary. 
Primary estimand 
for binary 
endpoints. 
Brodalumab vs 
ustekinumab. 
aTTA ≥0.1 IU/mL at Week 12. 
Binary. 
Estimand for binary 
vaccine-related 
endpoints. 
Brodalumab vs 
placebo. 
Change from baseline in aTTA at Week 8 and 
Week 12. 
Continuous. 
Estimand for 
continuous vaccine-
related endpoints. 
Brodalumab vs 
placebo. 
Change from baseline in lymphocyte subsets at 
Week 12. 
Continuous. 
Estimand for 
continuous vaccine-
related endpoints. 
Brodalumab vs 
placebo. 
Booster response to TT-containing vaccine, 
defined as: 
• 3-fold increase in aTTA at Week 12, if the 
subject has a baseline aTTA ≤1.0 IU/mL. 
• ≥2.5 IU/mL increase in aTTA at Week 12, if 
the subject has a baseline aTTA >1.0 IU/mL. 
Binary. 
Estimand for binary 
vaccine-related 
endpoints. 
Brodalumab vs 
placebo. 
Change from baseline in average weekly itch 
severity. 
Continuous. 
Primary estimand 
for continuous 
endpoints. 
Brodalumab vs 
placebo. 
Brodalumab vs 
ustekinumab. 
 
 
 
2 (3) 
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Endpoint 
Type of 
endpoint  
Primary estimand 
Comparison 
Improvement of at least 4 units in average weekly 
itch severity. 
Binary. 
GEE analysis based 
on the average 
weekly itch severity 
scores calculated 
for the continuous 
endpoint. 
Brodalumab vs 
placebo. 
Brodalumab vs 
ustekinumab. 
Change from baseline in average weekly itch-
related sleep. 
Continuous. 
Primary estimand 
for continuous 
endpoints. 
Brodalumab vs 
placebo. 
Brodalumab vs 
ustekinumab. 
Abbreviations: aTTA, anti-tetanus toxoid antibodies; CDLQ, Children’s Dermatology Life                     3 (3) 
       Quality Index; FDLQI, Family Dermatology Quality Index; GEE, generalised estimating equation; 
PASI, Psoriasis Area and Severity Index; sPGA, static Physician’s Global Assessment; TT, tetanus 
toxoid. 
 
14.3.9 Analysis of other endpoints 
Itch severity and itch-related sleep loss will be assessed daily, based on an 11-point NRS, with 
‘0’ indicating ‘no itch’ / ’itch did not interfere’ up to ‘10’ indicating ‘worst itch possible’ / 
’completely interfered’. The analysis will be based on assessing the difference in the LS-mean 
change from baseline in the average weekly itch severity and itch-related sleep loss. The 
baseline average weekly itch assessments will be based on the assessments recorded between 
Day -6 and Day 0 (pre-dose). The daily itch assessments used to calculate the average weekly 
itch severity and itch-related sleep loss will be anchored to the date of randomisation. For 
example, assessments recorded on Day 1 through Day 7 will be used to calculate the average 
itch during Week 1, assessments recorded on Day 8 through Day 14 will be used to calculate 
the average itch during Week 2, etc. In order to assess the average weekly itch 
severity/itch-related sleep loss, a minimum of 4 out of the 7 planned assessments must be 
recorded. Otherwise, the average weekly itch severity/itch-related sleep loss score will be 
considered missing. The primary estimand for continuous endpoints will be applied for this 
endpoint.  
Moreover, the differences in the LS-mean change from baseline at Week 12 between 
adolescent brodalumab dosing regimen and the pooled placebo arms, as well as from baseline 
to Week 12 and Week 52 between the adolescent brodalumab dosing regimen and 
ustekinumab arms, will be presented along with the corresponding 95% CIs and nominals p-
values, based on an MMRM, with an unstructured covariance matrix, the Kenward-Roger 
approximation for estimating the denominator degrees of freedom and the following mean 
model: 
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• Change from baseline = treatment + week + treatment × week + baseline body weight + 
baseline value.   
Baseline body weight will be included in the mean model as a fixed effect factor, based on the 
levels defined by the randomisation strata. Plots of the LS-mean change from baseline in 
average weekly itch severity and itch-related sleep loss will be presented over the entire 
52-week treatment phase for each treatment arm, based on the above MMRM.  
In addition to the above MMRM analysis of the mean change from baseline in average 
weekly itch severity and itch-related sleep loss, a responder analysis will also be conducted 
for the weekly average itch severity endpoint among the subset of subjects with a weekly 
average itch severity of at least 4 units at baseline. A GEE model with logit link function will 
be used to assess the proportion of subjects who have achieved a reduction of at least 4 units 
in average weekly itch severity over the 52-week assessment period. The working correlation 
matrix for the GEE model will have an unstructured form and the linear predictor will take the 
same form, as the above MMRM for the mean change from baseline in average weekly itch 
severity and itch-related sleep loss. Subjects who initiate rescue treatement or permanently 
discontinue IMP not due to pandemic restrictions will be defined as non-responders. 
Monotone missing data for reasons other than pandemic restrictions will be imputed using 
NRI. Subjects who permanently discontinue IMP due to pandemic restrictions, intermittent 
missing data, and monotone missing data due to pandemic restrictions will be assumed 
missing completely at random. The estimated proportion and difference in proportion of 
subjects achieving the responder status will be presented at Week 12 and Week 52, along with 
corresponding CIs and nominal p-values along with plots showing the responder rate over the 
entire treatment phase, for all treatment arms. In the event that either model fails to converge, 
the model will be fit assuming a compound symmetry working correlation matrix/covariance 
matrix. 
14.3.10 Analysis of safety 
The analysis of safety will be based on the safety analysis set. The reporting of safety data 
will be presented for the 12-week induction period and the entire 52-week treatment phase 
separately. For the summaries of the 52-week treatment phase, data will only be presented for 
the pooled brodalumab and ustekinumab arms. In other words, subjects initially on placebo, 
will only contribute data to the 52-week safety summaries after they initiate active treatment 
at Week 12.     
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14.3.10.1 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 terms (PTs) and primary 
system organ class (SOC). 
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 dosing; if outcome is missing, and no date of 
outcome is present, the outcome is regarded as ‘not recovered’. 
Treatment-emergent AEs (TEAEs) 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 started after the first use of IMP or if started before the first use of IMP 
and worsened in severity after first dose of IMP. The tabulations described in the following, 
will only include treatment-emergent events reported prior to or at the Week 60 safety follow-
up visit. Tabulations of TEAEs will be presented for the following 2 scenerios: 
• “While exposed to IMP”, defined as TEAEs occurring within 5 x half-lifes of the most 
recent date of IMP administration (body weight specific half-lifes for brodalumab are 
based on PK modelling): 
o Brodalumab and baseline weight ≥30 kg up to but not including 50 kg – 55 days. 
o Brodalumab and baseline weight ≥50 kg up to but not including 70 kg – 35 days. 
o Brodalumab and baseline weight ≥70 kg – 55 days. 
o Ustekinumab – 105 days. 
• “While in trial”, defined as all TEAEs observed during the duration of the trial.  
In order to facilitate a comparison versus placebo for the ‘while exposed to IMP’ scenario, the 
same baseline body weight specific time-periods specified for the brodalumab arm will be 
used for the placebo arm. In each of the tabulations, AEs are defined by MedDRA PTs within 
primary SOC. 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, premature discontinuations due to AEs, treatment-
related AEs, and severe AEs will be presented. 
The number and percentage of subjects reporting an event along with the number of events 
and the event rate per 100 subject-years for each type of AE, will be tabulated and presented 
by treatment arm.  
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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.  
The causal relationship to vaccine for each type of AE will be tabulated by treatment group 
for the induction phase. AEs related to the vaccine are defined as AEs for which the 
investigator has not described the causal relationship to vaccine as ‘not related’. The number 
AEs related to the vaccine, the number of subjects with each type of AE related to the vaccine, 
and the event rate per 100 subject-years for each type of 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. No narratives will be given. 
Other events (medication error, misuse, and abuse of IMP) will be tabulated and listed. No 
narratives will be given. 
14.3.10.2 Adverse events of special interest 
The adverse events of special interest (AESI) for the trial are classified as important identified 
and important potential risks. The AESI will be tabulated and listed by treatment arm for the 
12-week induction period and the entire 52-week treatment phase separately according to the 
safety analysis set. Panel 29 provides search criteria for the AESI. 
Panel 29: Search criteria for AESI 
Adverse events of special interest 
Search criteria 
Important identified risk 
Serious infections 
MedDRA SOC: Infections and infestations; only events classified 
as SAE. 
Important potential risks 
Suicidal ideation and behaviour 
MedDRA SMQ: Suicide/self-injury (narrow). 
MACE 
MedDRA SMQ: Ischaemic heart disease (narrow). 
MedDRA SMQ: Ischaemic central nervous system vascular 
conditions (narrow). 
Malignancy 
MedDRA SMQ: Malignant or unspecified tumours (narrow). 
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Adverse events of special interest 
Search criteria 
Abbreviations: MACE, major adverse cardiac events; MedDRA, medical dictionary for regulatory activities; 
SMQ, standardised MedDRA queries; SOC, system organ class. 
14.3.10.3 Vital signs  
The change in vital signs (blood pressure, pulse, body temperature) from baseline to each visit 
will be summarised by visit and treatment arm as mean, SD, median, 1st quartile, 3rd quartile, 
minimum, and maximum values for the safety analysis set. 
14.3.10.4  Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline to each visit will be 
summarised by visit and treatment arm as mean, SD, median, 1st quartile, 3rd quartile, 
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. 
14.3.10.5 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The most severe CSSRS 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. 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. Prepatory acts or behaviour. 
7. Aborted attempt. 
8. Interrupted attempt. 
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: 
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• 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.  
Separate tables for the 12-week induction period and the overall treatment phase will be 
presented. For the induction period, a pooled placebo arm will be presented along with the 
brodalumab and ustekinumab arms. For the overall treatment phase, only the pooled 
brodalumab and ustekinumab arms will be presented. 
14.3.10.6 Patient Health Questionnaire-A (PHQ-A) 
The most severe PHQ-A 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. 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). 
Separate tables for the 12-week induction period and the overall treatment phase will be 
presented. For the induction period, a pooled placebo arm will be presented along with the 
brodalumab and ustekinumab arms. For the overall treatment period, only the pooled 
brodalumab and ustekinumab arms will be presented. 
14.3.11 Anti-drug antibodies 
ADA status (positive, negative, missing assessment) will be summarised according to the 
number and percentage of subjects in each category, by treatment arm for the safety analysis 
set at Weeks 0, 4, 16, and 52. 
14.3.12 Pharmacokinetics 
The following PK parameters will be derived based on the PK analysis set:  
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Ctrough 
Trough (pre-dose) serum concentrations at Weeks 4, 8, 12, 16, and 52 (for 
brodalumab arm) and Weeks 4 and 40 (for placebo followed by brodalumab 
arm). 
CW10 
Serum concentration sampled during Week 10 (for brodalumab arm) and 
during Week 22 (for placebo followed by brodalumab arm). 
CW22 
Serum concentration sampled during Week 22 (for brodalumab arm). 
The following PK parameter will be estimated based on the population PK analysis set: 
AUCW10-12 Area under the serum concentration-time curve at Week 10-12. 
Due to sparse blood sampling, the AUC at Week 10-12 for the individual subjects will be 
estimated using a population PK analysis approach (77). Overall, the population PK model 
developed based on adult data from healthy subjects and subjects with plaque psoriasis will be 
used to derive individual model parameter estimates for the adolescents who have received 
brodalumab. Individual AUCs at Week 10-12 will be determined based on the individual 
model parameters. The details of the analysis will be specified in a population PK analysis 
plan prior to trial unblinding. 
AUC will be listed and summarised per treatment arm (brodalumab arm and placebo followed 
by brodalumab arm) and combined. For subjects in the PK analysis set who have no 
quantifiable concentration, the AUC will be set to ‘not calculated’ and included in the listing, 
but excluded from the summary statistics. Ctrough will be listed and summarised per treatment 
arm and combined (Week 4 [for brodalumab arm] and Week 16 [for placebo followed by 
brodalumab arm]). CW10 and CW22 will be listed. In the summary statistics, values below lower 
limit of quantification (LLOQ) will be set to 0.5*LLOQ. 
14.3.13 Interim analysis 
No interim analysis is planned. 
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15 References 
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14. Waldman A, Sirlin C, Sy E, Diep D, Schwimmer JB, Tom WL. Non-alcoholic fatty liver 
disease (NAFLD) and metabolic dysfunction in children with psoriasis. Pediatric 
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54. Razycov I, Ziegelstein RC, Whooley MA, Thombs BD. The PHQ-9 versus the PHQ-8--is 
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61. Amgen. Clinical study report: 20120102. A phase 3 study to evaluate the efficacy, safety, 
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66. Amgen. Clinical study report: 20120103. A phase 3 study to evaluate the efficacy and 
safety of induction and maintenance regimens of brodalumab compared with placebo and 
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date: 15 Mar 2015. 
67. Amgen. Clinical study report: 20120104. Phase 3 study to evaluate the efficacy and safety 
of induction and maintenance regimens of brodalumab compared with placebo and 
ustekinumab in subjects with moderate to severe plaque psoriasis: AMAGINE-3. Report 
date: 27 Mar 2015. 
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69. European Parliament and Council of The European Union. Directive 2001/20/EC of 
4 April 2001 on the approximation of the laws, regulations and administrative provisions 
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Differences. Drug Information Journal. 2011;45(4):481-493.  
77. EMA. 2007. Guideline on the role of pharmacokinetics in the development of medicinal 
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78. International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
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Assembly, Fortaleza, Brazil. 2013. 
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80. International Ethical Guidelines for Health-related Research Involving Humans, Fourth 
Edition. Geneva. Council for International Organizations of Medical Sciences (CIOMS); 
2016.  
81. International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) 2016. Integrated addendum to ICH E6(R1): Guideline for good 
clinical practice E6(R2).  
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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 (78). 
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*. 
• AEs commonly observed and AEs anticipated based on the pharmacological effect of the 
IMP.  
• Any laboratory abnormality assessed as clinically significant by the investigator (see 
Section 11.4.5.2). 
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). 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation*.  
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
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• 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 broncospasm, blood dyscrasias and 
convulsions that do not result in hospitalisation, development of drug dependency, or drug 
abuse. 
 
*Hospitalisation for procedures or treatments planned prior to the subject consented to trial 
participation does not constitute an AE and should therefore not be reported as an AE or SAE. 
*Hospitalisation for elective treatment of a pre-existing condition which did not worsen from 
the subject consented to trial participation is not considered an AE and should therefore not be 
reported as an AE or SAE, even if not planned before consent to trial participation. 
*Hospitalisation for routine scheduled treatment or monitoring of the studied indication not 
associated with any aggravation of the condition does not constitute an AE and should 
therefore not be reported as an AE or SAE. 
*Hospitalisation for administrative, trial-related, or social purpose does not constitute an AE 
and should therefore not be reported as an AE or SAE. 
*Complications that occur during hospitalisation are (S)AEs. If a complication prolongs 
hospitalisation, the event is an SAE. 
*When in doubt as to whether hospitalisation occurred or was necessary, the AE should be 
considered serious. 
 
AEs of special interest 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. The categories are 
defined below. 
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. 
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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. 
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. 
 
 
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Outcome 
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below. Follow-up on an event is required until final outcome is 
established as described in Section 13.7. 
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”. 
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. 
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In summary, the definitions used by LEO Pharma are more conservative than those used by 
CDISC. 
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 (79) and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines (80). 
• Current version of applicable International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guidelines (81). 
• EU’s 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 IECs may need to fulfil their responsibilities (such as the trial 
protocol, protocol amendments, investigator’s brochure, subject information sheet and 
informed consent/assent form(s), or advertisements) will be submitted to the IECs. These 
documents must be reviewed and approved by the IECs 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. 
Appendix 3B: Informed consent process  
Subjects and the subject’s legally authorised representative(s) 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 and the subject’s legally authorised representative(s) will 
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be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 
The subject’s legally authorised representatives’ signed and dated informed consent to 
participate in the clinical trial must be obtained prior to any clinical trial-related procedure 
being carried out in accordance with ICH GCP (4.8) and all applicable laws and regulations. 
The authorised person obtaining the informed consent must also sign the informed consent 
form. The subject’s decision not to participate or to withdraw will be respected, even if 
consent is given by the subject’s legally authorised representative(s).  
The subject’s legally authorised representatives’ will be re-consented to the most current 
version of the informed consent form(s) during the trial, if applicable.  
A copy of the informed consent form(s) must be provided to the subject’s legally authorised 
representative(s).  
Subjects must give their written assent or consent as appropriate according to national laws 
and regulation. The subject’s signed and dated informed consent to participate in the clinical 
trial must be obtained prior to any clinical trial-related procedure being carried out in 
accordance with ICH GCP (4.8) and all applicable laws and regulations. Subject will be re-
consented to the most current version of the informed consent form(s) during the trial, if 
applicable and in accordance with national laws and regulations. A copy of the informed 
consent form(s) must be provided to the subject in accordance with national laws and 
regulations.  
Subjects who become of legal age during the trial, will be consented to the most current 
version of the informed consent form for the subject’s legally authorised representative, if 
required by national laws or regulations. Subsequently, these subjects will be re-consented to 
the most current version of the informed consent form for the subject’s legally authorised 
representative during the trial, if applicable. 
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. 
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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.  
Trial subjects must be informed and consent to 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, 
gender, 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. In certain cases, an agreement on transfer of personal data 
may also be required. 
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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 (or their legally acceptable representative[s]) 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. 
Appendix 3D: Record keeping, quality control, and data handling 
Source data 
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 a physician.  
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 ustekinumab for 52 weeks or placebo for 12 weeks followed by 
brodalumab or ustekinumab for 40 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 
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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, e.g., medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit 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 important 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 eCRFs. Data recorded in the eCRFs will be accessible 
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to the trial site and LEO Pharma personnel immediately after entry. The eCRFs 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 eCRFs 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 
electronic data capture system. This systematic validation will ensure that a clean and 
consistent database is provided for the statistical analysis. 
An electronic patient-reported outcome (ePRO) solution will be used to capture some of the 
patient-reported data. By the use of an ePRO solution, data will be available immediately after 
data entry and available for monitors and site personnel, including the investigator, with read 
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.  
Transmission of data is documented in more detail in the trial-specific data flow plan, which 
is part of the trial master file. 
Software 
CDISC controlled terminology version 30-Mar-2018 or newer 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 1.5 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 (81). Essential trial documents must be stored 
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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. 
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 leopharmatrials.com in accordance with our 
Position on Public Access to Clinical Trial Information no later than 6 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 
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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 investigator 
in accordance with the process described here. 
A multi-centre 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-centre publication is made 
public, or if no multi-centre 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. 
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-centre 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-centre publication. 
In case of publications made by the investigator after the first multi-centre 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 
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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 (46). 
Appendix 3F: Insurance 
LEO Pharma A/S has taken out relevant insurances covering the participants in this 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 
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: Data monitoring committee structure 
Safety of the subjects will be carefully assessed by an independent DMC. All members will 
be independent of the trial (that is, they will not be participating investigators or employees at 
participating sites) and of LEO Pharma (that is, they will not be LEO Pharma employees). 
The DMC members are experienced with clinical trials and will be responsible for assessing 
the safety of the subjects through assessment of the safety of the treatment regimen during the 
trial and through monitoring the overall conduct of the trial.  
The DMC will review data on a regular basis. Additional meetings may also be called on an 
ad hoc basis, as requested by the DMC or LEO Pharma. All data collected at the time of the 
data cut-off/scheduled meetings will be included in the summaries for the DMC, including 
data from subjects still ongoing in the trial. The DMC will examine summaries and listings of 
AEs, specific laboratory parameters and subject disposition data as detailed in the DMC 
charter. Full details of the analyses to be presented to the DMC will be specified in a separate 
DMC statistical analysis plan.  
The DMC will have an independent statistician and an independent administrator who will 
remain independent of the trial management team.  
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The chairman of the DMC, in conjunction with the other members, will communicate their 
recommendations to LEO Pharma A/S after each meeting. The chairman of the DMC will 
provide written reports to LEO Pharma after each formal review to indicate the committee’s 
recommendation regarding safety concerns and trial continuation. Further details on all 
aspects relating to the DMC are provided in the DMC charter. 
Appendix 3I: Trial and site closure 
Premature termination of trial or trial site 
LEO Pharma, the investigator, the IECs, or the 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 the 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´s 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 5: Contact list 
Contact details for the clinical project manager, national lead 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 
Signatory investigator 
 
 
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Appendix 6: Protocol amendment history 
The Protocol amendment summary of changes table for the current amendment is located 
directly before the table of contents. 
Amendment 1 (10-Jun-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. 
Overall rationale for the amendment: 
The main reasons for this amendment, based on comments received during the Voluntary 
Harmonisation Procedure, were to:  
• Extend the interval of prior tetanus-toxoid containing vaccination for inclusion into the 
trial in countries in EU + UK.  
• Include additional blood sampling at Weeks 28, 36, and 44 for analysis of haematology 
and chemistry parameters. 
• Include a recommendation regarding rescue treatment in case of inadequate disease 
control.  
Furthermore, exclusion criteria #16 and #31 were updated and additional changes included in 
the amendment are presented in the table below. The table on the following pages describes 
the changes in each section, summarised as plain text, and/or 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 
Synopsis – Main criteria 
for exclusion – 2nd bullet 
point; 
Section 8.3 Exclusion 
criteria – Exclusion 
criterion number 2. 
Exclusion criterion number 2 has been updated 
with the following change: 
Subject has been vaccinated with a TT-
containing vaccine ≤18 months prior to first 
dose of investigational medicinal product 
(IMP).  
Subject has been vaccinated with a TT-
containing vaccine within 5 years prior to the 
first dose of IMP - applicable for countries in 
EU + UK. 
Updated to extend the 
interval of prior tetanus-
toxoid containing 
vaccination for inclusion 
into the trial in countries in 
EU + UK. 
Section 4 Schedule of 
trial procedures, Panel 3. 
Panel 3 has been updated as additional 
haematology and chemistry blood samples will 
be collected at Visits 16, 18, and 20. 
Updated to be able to 
monitor laboratory values 
between Week 22 and 
Week 52. 
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Section no. and name 
Description of change 
Brief rationale 
Section 5.1 Plaque 
psoriasis. 
The definition of psoriasis has been rephrased: 
Psoriasis is a chronic, immune-mediated 
inflammatory disorder an inflammatory skin 
disease 
Updated to clarify that 
psoriasis is not just a skin 
disease.  
Section 5.4 Ethical 
considerations. 
This section has been updated with the 
following change: 
Thus, the subjects who have received the 
adolescent dose of Td or have not yet received 
the scheduled adolescent dose of Td/Tdap will 
be vaccinated with a booster based on the 
subject’s previous history of vaccination with 
TT-containing vaccines and current local 
guidelinesdose of Tdap in this trial, which is in 
compliance with the current recommendations 
on prevention of pertussis infection. The 
subjects who have received the adolescent dose 
of Tdap vaccine will be vaccinated with a dose 
of Td in the trial.  
Updated to reflect the 
change in exclusion 
criterion number 2. 
 
Section 7.1.3.2 
Vaccination (Week 8). 
The following text has been added in this 
section: 
• 
Subjects who have not received the 
scheduled adolescent dose of 
Td/Tdap for the last 5 years will be 
vaccinated with a booster based on 
the subject’s previous history of 
vaccination with TT-containing 
vaccines and current local 
guidelines. 
Updated to reflect the 
change in exclusion 
criterion 2. 
 
Section 8.3 Exclusion 
criteria, Exclusion 
criterion 16. 
Exclusion criterion number 16 has been updated 
with the following: 
Subject has positive hepatitis B surface antigen, 
hepatitis B surface antibody, hepatitis B core 
antibody, hepatitis C virus antibody, or human 
immunodeficiency virus serology at screening. 
Subjects with positive hepatitis B surface 
antibody are eligible provided they have 
negative hepatitis B surface antigen and 
negative hepatitis B core antibody (blood 
pattern in hepatitis B vaccinated subjects). 
Updated to clarify the 
exclusion criterion for 
subjects with positive 
hepatitis B surface 
antibodies. 
Section 8.3 Exclusion 
criteria, Exclusion 
criterion 31. 
The following bullet point has been added in 
exclusion criterion number 31: 
• 
Estimated glomerular filtration rate 
(eGFR) <45 mL/min/1.73 m2. 
Updated to clarify the 
threshold for eGFR. 
Section 9.2.2 
Administration of 
vaccine. 
This section has been updated with the 
following change: 
The type of vaccine each subject will receive is 
based on the subject’s previous history of 
vaccination with TT-containing vaccines and 
Updated to reflect the 
change in exclusion 
criterion 2. 
 
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Section no. and name 
Description of change 
Brief rationale 
current local guidelines (see Section 7.1.3 for 
further details). 
Section 9.5 Rescue 
treatment. 
This section has been updated with the 
following change: 
The investigator is responsible for the rescue 
treatment oversight and duration as well as 
switching and escalating to another appropriate 
therapy, when appropriateindicated. However, 
it is recommended that the efficacy of the 
topical rescue treatment should be re-
evaluated after 4 weeks of treatment and 
subjects who are still inadequately controlled 
(defined as a PASI score ≥150% of baseline 
PASI) might be escalated to an appropriate 
subsequent therapy (refer to Section 9.7 for 
prohibited medications and Section 10.2 for 
IMP discontinuation rules). 
Updated to clarify that 
investigator is responsible 
for the oversight of rescue 
treatment and to include 
recommendations for the 
use of rescue treatment in 
case of inadequate disease 
control. 
Section 11.4.5.1 
Overview of all 
laboratory tests, Panel 18. 
eGFR and a reference to the Schwartz formula 
have been added in Panel 18: 
Estimated glomerular filtration rate (eGFR)2 
2 Measured at screening only. The eGFR will 
be calculated using the Schwartz formula 
(52). 
Updated to reflect the 
updated exclusion criterion 
number 31. 
Section 11.8 Estimate of 
total blood volume 
collected. 
This section has been updated with the 
following change: 
The total volume of blood to be drawn in the 
trial corresponds to approximately 2733% of 
blood volume drawn during a single blood 
donation (approximately 500 mL). 
Updated to be able to 
monitor laboratory values 
between Week 22 and 
Week 52. 
Throughout  
Minor editorial revisions. 
Minor, and are therefore not 
summarised. 
 
 
TMF-000115641 - Version
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TMF-000115641 - Version
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SAP_003.pdf: 
 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Study title: Efficacy and safety of brodalumab in adolescents from 12 to 17 years of age with moderate-
to-severe plaque psoriasis; EMBRACE 1 
LEO Pharma number: LP0160-1396 
NCT number: NCT04305327    
Date: 26-Jun-2023 
 






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