Conditions: Psoriasis Vulgaris
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 210
Healthy volunteers: no

Brief summary:
The primary objective is to demonstrate added benefit of brodalumab versus a selected systemic comparator in treatment of moderate to severe plaque psoriasis in Germany in subjects who have not previously received systemic treatment for psoriasis.

Fumaric acid esters have been selected as the comparator because it is an established systemic treatment of psoriasis in Germany.

Detailed description:
A 24-week, randomised, open-label, active-controlled, parallel group, multi-centre trial with investigator-blinded efficacy assessments

Arms:
arm 1: Kyntheum® (brodalumab)

pre-filled syringe 210 mg/1.5 mL solution for subcutaneous injections.

First 3 injections are administered weekly, and hereafter every two weeks (Q2W). arm 2: Fumaderm® initial dose tablets (30 mg dimethyl fumarate, 67 mg ethyl hydrogen fumarate calcium salt, 5 mg ethyl hydrogen fumarate magnesium salt, 3 mg ethyl hydrogen fumarate zinc salt)

Fumaderm® tablets (120 mg dimethyl fumarate, 87 mg ethyl hydrogen fumarate calcium salt, 5 mg ethyl hydrogen fumarate magnesium salt, 3 mg ethyl hydrogen fumarate zinc salt)

Fumaderm® tablets are administered orally up to 3 times daily in accordance with the dosing scheme in the label.

Interventions: intervention 1: Brodalumab intervention 2: Fumaric acid esters
Intervention descriptions: intervention 1: Brodalumab is a recombinant fully human monoclonal immunoglobulin IgG2-antibody that binds with high affinity to human interleukin 17 receptor A (IL-17RA).

Blocking IL-17RA inhibits IL-17 cytokine-induced responses and results in reduced or normalised inflammation of the skin in subjects with psoriasis. intervention 2: Fumaric acid esters have been used to treat psoriasis since 1959. Systemic therapy with fumaric acid esters is based on an established dosing scheme with a gradual increase to improve tolerability, especially with regards to gastrointestinal side effects.

Protocol document:
Prot_SAP_000.pdf: 
Cover Page 
 
 
Official title: A Phase 4 Trial Comparing the Efficacy of Subcutaneous Injections of Brodalumab to Oral Administrations 
of Fumaric Acid Esters in Adults With Moderate to Severe Plaque Psoriasis 
LEO Pharma number: LP0160-1327 
NCT number: NCT03331835 
Date: 17-Apr-2018 


 
 
 
 
 
 
 
Clinical Trial Protocol LP0160-1327 
 
A phase 4 trial comparing the efficacy of subcutaneous injections of 
brodalumab to oral administrations of fumaric acid esters in adults with 
moderate to severe plaque psoriasis 
Phase 4 trial 
A 24-week, randomised, open-label, active-controlled, parallel group, multi-centre trial 
with investigator-blinded efficacy assessments 
 
 
 
 
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: 
LP0160-1327 
 
Date: 
17-Apr-2018 
 
EudraCT No: 
2016-003867-21 
 
Version: 
4.0 


T RI A L I D: L P 0 1 6 0 -1 3 2 7  
D A T E: 1 7 -A P R -2 0 1 8  
V E R SI O N: 4. 0  
P A G E 2  O F 1 0 8  
 
 
 
1  Cli nic al tri al  p r ot oc ol st ate me nt 
1. 1  
A p pr o v al st ate me nt L E O P h ar m a A/ S  
T he f oll o wi n g p ers o ns h a ve a p pr o ve d t his c li nical trial p r ot oc ol b y  usi n g el e ctr o nic si g nat ur es 
as prese nte d o n t he last p a ge of t his d oc u me nt:  
, M Sc Stat  
 
Bi ostatistics Lea d, Gl o bal Cli nical O perati o ns   
 
 
 
, M D 
 
Gl o bal Me dical Scie nce Direct or , Me di cal Scie nces 
a n d Safet y 
 
 
, M Sc P har m 
Cli nical O perati o ns Lea d, Gl o bal Cli nical O perati o ns  
 
 
1. 2  
A p pr o v al st ate me nt inter n ati o n al co or di n ati n g  in vesti g at or  
T he i nter nati o nal  c o or di nati n g i n vesti gat or a p pr o ves t he cli nical trial pr ot oc ol a n d 
c o ns oli date d cli nical trial pr ot oc ol(s) c o m prisi n g a n y s u bse q ue nt a me n d me nt(s) b y m a n uall y 
si g ni n g t he I nter n ati o nal C o or di nati n g I n vesti gat or Cli nical Trial Pr ot oc ol A p pr o val F or m, 
w hic h is a se parate d oc u me nt a dj oi ne d t o t his d oc u me nt.  
T he f oll o wi n g p ers o n has a p pr o ve d t his cli nica l tri al pr ot oc ol: 
Ulric h Mr o wietz, Pr of. Dr. me d.  
 
I nter nati o nal C o or di nati n g In v esti gat or  
 
 
1. 3  
A c k n o wle d ge me nt st ate me nt in vesti g at or(s)  
Eac h partici pati n g i n vesti gat or m ust a gree t o t he a p pr o ve d cli nical t rial p r ot oc ol a n d 
c o ns oli date d cli nical t rial p r ot oc ol(s) c o m prisi n g a n y s u bse q ue nt a me n d me nt(s) b y si g ni n g t he 
cli nical t rial pr ot oc ol ac k n o wle d ge me nt f or m  or a si milar d oc u me nt . 
 
 
P P D
P P D
P P D


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Protocol amendments and summary of changes tables 
Document history 
Document 
Date 
Amendment 2 (substantial), eTMF version 4.0 
17-Apr-2018 
Amendment 1 (substantial), eTMF version 3.0 
12-Oct-2017 
Original protocol including e-signature, eTMF version 2.0 
20-Jun-2017 
Original protocol, eTMF version 1.0 
20-Jun-2017 
Amendment 2 (17-Apr-2018) 
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. 
Overall rationale for the amendment 
The reason for the amendment is to clarify that exclusion criteria related to the PROs eC-
SSRS and PHQ-8 pertain to both the screening and the baseline visit. Also, the wording for 
the eC-SSRS criteria, and the described assessment hereof, has been updated to reflect the 
report from the eC-SSRS. The wording in eTMF version 3.0 of the protocol was based on the 
paper version of the C-SSRS. 
Substantial changes to the original protocol are provided in the table below. When applicable, 
original text is cited in quotation marks (‘’) with deletions as strike through, additions in bold, 
and descriptive comments in italics. Minor editorial revisions have also been applied during 
this amendment without further indication. 
Substantial changes in Amendment 2 
Affected 
Section(s) 
Rationale for change 
The header versioning (and front page) has been aligned 
with the eTMF versioning (the electronic archiving 
system). Hence, with this amendment the header version 
has been updated from version 2.0 to 4.0. 
All sections 
To align header versioning 
with the eTMF versioning. 
The “V11” column in the schedule of procedures is now 
marked “x” for the task “returning fumaric acid esters”. 
Panel 2 
This was missing by 
mistake. 


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Substantial changes in Amendment 2 
Affected 
Section(s) 
Rationale for change 
12. Any positive finding in history of suicidal behaviour 
(e.g., ‘actual suicide attempts’, ‘interrupted attempts’, 
‘aborted attempts’, or ‘preparatory actions’) based on 
the eC-SSRS questionnaire at screening or baseline. 
Subjects with a history of suicidal behaviour. 
13. Any positive finding in suicidal ideation of level 
severity 4 or 5 (‘some intent to act, no plan’ or ‘specific 
plan and intent’) based on the eC-SSRS questionnaire at 
screening or baseline. 
14. A PHQ-8 score of ≥10 corresponding to moderate to 
severe depression at screening or baseline. 
Sections 2, 6.6, 
9.3, 11.4.2.2, 
11.4.2.3, and 
Appendix 1 
Clarification that exclusion 
criteria related to the PROs 
eC-SSRS and PHQ-8 pertain 
to both the screening and the 
baseline visit. Also, the 
wording for the eC-SSRS 
criteria has been updated to 
reflect the report of the 
electronic version of the C-
SSRS. 
The described eC-SSRS assessment has been updated to 
reflect the report of the eC-SSRS. Appendixes 5C and 5D, 
containing the paper version of the C-SSRS, have been 
deleted. 
Section 11.4.2.3 
and Appendix 5 
Appendixes 5C and 5D in 
the previous version of the 
protocol were deleted since 
it was realized that they 
deviated slightly from the 
report of the electronic 
version of the C-SSRS (the 
eC-SSRS). Instead, further 
details from the eC-SSRS 
report format are included in 
the assessment description in 
Section 11.4.2.3. 
Psoriasis is a chronic inflammatory skin disease disorder 
associated with significant morbidity and mortality that 
occurs in approximately 2% of the population worldwide 
(Augustin et al. 2010, Gelfand et al. 2007, Rachakonda et 
al. 2014). 
Section 6.1 
Clarification that psoriasis is 
chronic and associated with 
significant morbidity and 
mortality 
Planned quarter of last subject last visit (LSLV): Q1 2019 
Q4 2018 
Section 8.1 
Updated planned time 
schedule due to recruitment 
challenges. 


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Substantial changes in Amendment 2 
Affected 
Section(s) 
Rationale for change 
No cases of overdose have been reported in clinical 
studies. Doses up to 700 mg intravenously have been 
administered in clinical studies with no evidence of dose 
limiting toxicity. In the event of an overdose, the subject 
should be monitored and treated symptomatically, and 
supportive measures instituted at the discretion of the 
investigator. 
 
Section 10.2.2 
Deleted since overdose has 
now been reported with use 
of brodalumab. The 
overdose did not lead to any 
adverse event.  
•Anaphylactic reaction or other severe systemic reaction to 
IMP injection. 
Section 10.8.1 
“injection” is deleted since 
this criterion for 
discontinuing IMP qualifies 
for both brodalumab and 
fumaric acid esters. 
Fumaric acid esters:  The subject must bring used, 
partly used, and unused IMP including empty 
packaging material at every site visit for compliance 
check. At every dispensing visit and at the end of 
treatment (visit 12), the subject must return all used, 
partly used, and unused IMP including empty 
packaging material to the site.  
 
Fumaric acid esters: The subject must bring used/partly 
used and unused including empty packaging material of 
fumaric acid esters at every site visit. From visit 3 until 
visit 11, the unused fumaric acid esters tablets must be 
taken back home by the subjects for further use. At the end 
of treatment (visit 12) the subject must return all 
used/partly used and unused IMP including empty 
packaging material of fumaric acid esters. 
 
Section 10.9.3 
The schedule for returning 
used, partially used, and 
unused fumaric acid esters 
has been updated to every 
dispensing visit. This change 
is implemented to minimise 
the risk of any accidental 
usage of expired IMP.  
11.4.2 Patient reported outcomes – Efficacy and safety 
Section 11.4.2 
The header is updated to 
clarify that the PROs 
address both efficacy (DLQI 
and PSI) and safety (eC-
SSRS and PHQ-8) 
The differences in response rates between treatment 
groups will be analysed using the Cochran-Mantel-
Haenszel test with stratification by and weight group 
(≥100 kg or <100 kg). 
Section 13.3.5 
Clarification of the primary 
analysis. 
A sensitivity analysis will be made where ineligible 
subjects randomised in error into the trial are excluded 
from the analysis. 
Section 13.3.5 
This sensitivity analysis is 
included to assess/limit 
inference based on ineligible 
subjects randomised in error 
into the trial. 
 


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Amendment 1 (12-Oct-2017) 
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. 
Overall rationale for the amendment 
The reason for the amendment is to implement requirements from the health authorities in 
Germany. 
Substantial changes to the original protocol are provided in the table below. When applicable, 
original text is cited in quotation marks (‘’) with deletions as strike through and additions in 
bold. 
Substantial changes in Amendment 1 
Affected 
Section(s) 
Rationale for change 
Sample size and analysis of primary endpoint updated. 
Endpoint structure updated as follows: 
‘Co-primary endpoints:  
 
At least 75% improvement from baseline at 
Week 24 in Psoriasis Area and Severity Index 
(PASI) 
 
Static Physician’s Global Assessment (sPGA) 
scale score of 0 or 1 at Week 24 
Secondary endpoints:  
 
At least 90% improvement from baseline at 
Week 24 in PASI 
 
100% improvement from baseline at Week 24 in 
PASI 
 
Change from baseline at Week 24 in PASI score 
 
PASI improvement (%) from baseline at Week 24 
 
Static Physician’s Global Assessment (sPGA) scale 
score of 0 or 1 at Week 24 
 
Change from baseline at Week 24 in affected body 
surface area (BSA)’ 
Protocol 
summary 
Section 7 
(Panel 3) 
Section 13.1 
13.3.5(sample 
size) 
Section 13.3.4 
(endpoints) 
Section  13.3.5 
(analysis of 
primary 
endpoint) 
To align with the health 
authorities request. 
Extra secondary endpoint introduced: ‘Burden of 
symptoms assessed as the normalised area under the 
curve (AUC) of PSI from baseline to the last available 
assessment’ 
Section 7 
(Panel 3) 
Section 13.3.4 
To align with the health 
authorities request. 
Inclusion criterion no. 8: 
‘Female subjects of childbearing potential must be willing 
to use highly effective contraception at trial entry and until 
15 weeks after end of treatment. For subjects randomised 
to fumaric acid esters: oral contraceptive pills must be 
used with an additional contraceptive method (e.g. 
condom by partner, diaphragm, contraceptive gel, 
vaginal ring, etc.)’ 
Section 9.2 
Appendix 1 
To avoid efficacy loss of 
oral contraceptive pills in 
case of subjects who may 
suffer from gastro-intestinal 
side effects. 
Exclusion criterion no. 2: 


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Substantial changes in Amendment 1 
Affected 
Section(s) 
Rationale for change 
Previous or current phototherapy PUVA (psoralens and 
ultraviolet A) therapy (UVA light therapy without 
psoralens, UVB light therapy, excimer laser, etc). 
Protocol 
summary 
Section 9.3 
Appendix 1 
To accommodate the change 
in the local health 
authorities’ interpretation of 
guidelines regarding 
phototherapy. 
Exclusion criterion no. 3: 
‘Have received phototherapy (UVA light therapy 
without psoralens, UVB light therapy, excimer laser, 
tanning beds, etc. within 4 weeks of baseline’ 
Exclusion criterion no. 6: 
‘Clinically significant abnormal laboratory values at 
screening within assessments of biochemistry, urine, 
and haematology (such as differential blood count and 
platelets) at the discretion of the investigator.’ 
Section 9.3 
Appendix 1 
To align with the side effects 
of Fumaderm® according to 
SmPC. 
Exclusion criterion no. 7: 
‘Subjects with any of the following laboratory 
abnormalities at screening: 
a) Leukocyte cell count below 3×109/L or 
lymphocyte count below 0.7×109/L. 
b) Aspartate aminotransferase (AST) or alanine 
transferase (ALT) > 2× ULN (upper level of 
normal limit). 
c) Absolute neutrophil count < 2× 109/L. 
d) Serum creatinine > ULN.’ 
Protocol 
summary, 
Section 9.3, and 
Appendix 1 
To align with the side effects 
of Fumaderm® according to 
SmPC. 
Exclusion criterion no. 12: 
‘Subjects with a history of suicidal behaviour (suicide 
attempt)’ 
Protocol 
summary, 
Section 9.3, 
and Appendix 
1 
To clarify that all subjects 
who have previously shown 
suicidal behaviour must be 
excluded, regardless of the 
behaviour having resulted in 
a suicide attempt or not. 
Updated criteria for previous anti-psoriatic therapy: 
‘All previous anti-psoriatic topical treatment used by the 
subjects to treat their psoriasis vulgaris over the past 2 
years prior to screening must be topical therapy (OTC 
topicals, topical non-steroid, topical steroids, topical 
combination etc.) and must be recorded. Any history of 
phototherapy must also be recorded.’ and must be 
recorded as such’ 
Section 10.5 
Clarification that previous 
anti-psoriatic topical 
treatment will be recorded 2 
years back in time, whereas 
any history of phototherapy 
must be recorded. 
‘Subjects should be discontinued from treatment with 
fumaric acid esters if any of the following applies: 
- 
Blood creatinine levels > ULN. 
Section 10.8.2 
To align with the side effects 
and discontinuation criteria 
according to the Fumaderm® 
SmPC. 


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Substantial changes in Amendment 1 
Affected 
Section(s) 
Rationale for change 
- 
Clinically significant changes in haematology 
values or confirmed proteinuria or haematuria 
not related to an ongoing urinary tract 
infection or renal calculus/nephrolith (at the 
discretion of the investigator).’ 
Clarification of the handling of fumaric acid esters. 
For fumaric acid esters, original kit cartons should be 
reused instead of new blank white kit cartons. 
Section 10.9.1 
The original kit cartons are 
not tamper sealed. 
Clarification on drug accountability for IMP 
‘Only used and empty packaging material of brodalumab 
must be returned by the subject. At end of treatment visit 
(visit 12) the subject should return all used/partly used and 
unused including empty packaging material of 
brodalumab.’ 
‘The subject must bring only unused and empty 
packaging material of brodalumab at every dispensing 
visit (visit 2, 8, 9, 10, and 11). Used syringes should be 
discarded in disposal containers. At end of treatment 
(visit 12) the subject must return all unused IMP, 
empty packaging material and disposal containers 
containing used IMP.’ 
Section 10.9.3 
To emphasise that the 
subjects need to bring 
unused and empty packaging 
material of brodalumab at 
every dispensing visit. 
Re-wording section regarding reporting of product 
complaints 
Section 10.11 
Clarification that product 
complaints related to the 
IMP itself and any device 
deficiency must be reported 
as product complaints.  
Clarification that critical 
complaints are subject to 
expedited reporting and that 
adverse events in connection 
with product complaints are 
to be reported as adverse 
events or serious adverse 
events as appropriate. 
Updated guidance text regarding calculation of body 
surface area (BSA) to state that the blinded assessor will 
use the surface area of the subject’s hand (palm and 
fingers) as a reference measurement to calculate the 
percentage of each body region that is affected by 
psoriasis. 
New BSA percentages introduced for head and neck 
(10%), upper extremities (20%), the trunk including the 
axillae and groin (30%), and lower extremities, including 
the buttocks (40%). 
Section 11.4.1.3 
To align with the Group for 
Research and Assessment of 
Psoriasis and Psoriatic 
Arthritis (GRAPPA) 
standard and to make the 
psoriatic assessment more 
feasible. 
Correction of blood volume drawn at each visit as well as 
the total volume of blood drawn during the trial 
Section 11.6.1.2 
Correction 


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Substantial changes in Amendment 1 
Affected 
Section(s) 
Rationale for change 
Added paragraph to statistical analysis of patient reported 
outcomes on how to calculate the AUC for PSI total 
scores: ‘The AUC for the PSI total score will be 
calculated for each subject…’ 
Section 13.3.7 
To accommodate the 
inclusion of the extra 
secondary endpoint related 
to PSI (see Panel 3). 
Added information about patient insurance and coverage: 
‘LEO has obtained taken out relevant a patient 
insurances as well as a travel accident insurance 
covering the subjects in the present clinical trial in 
accordance with national applicable laws and regulations. 
A copy of the conditions of the patient insurance as 
well as of the accident insurance will be handed out to 
the subject with the informed consent’ 
Appendix 4F 
Clarification of insurance 
coverage and note to 
investigator/ trial staff about 
copy of insurance conditions 
is to follow the inform 
consent form. 
Addition of DLQI instruction page, including information 
on scoring and how to interpret the results 
Appendix 5B 
Clarification regarding 
DLQI scoring and results 
interpretation. 
Minor editorial and document formatting revisions 
Throughout this 
document 
Minor, have therefore not 
been summarised. 
 
 


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Table of contents 
1 Clinical trial protocol statement ............................................................................................ 2 
1.1 Approval statement LEO Pharma A/S ............................................................................... 2 
1.2 Approval statement international coordinating investigator ............................................. 2 
1.3 Acknowledgement statement investigator(s) .................................................................... 2 
Protocol amendments and summary of changes tables .............................................................. 3 
Table of contents ...................................................................................................................... 10 
List of panels ............................................................................................................................ 15 
List of abbreviations and definitions ........................................................................................ 15 
2 Protocol summary ................................................................................................................ 19 
3 Trial identification ............................................................................................................... 22 
4 Schematic of trial design ..................................................................................................... 22 
5 Schedule of procedures ........................................................................................................ 23 
6 Introduction and rationale .................................................................................................... 27 
6.1 Psoriasis vulgaris ............................................................................................................. 27 
6.2 Experience with investigational medicinal product ........................................................ 27 
6.2.1 
Brodalumab ................................................................................................................. 27 
6.2.2 
Fumaric acid esters ...................................................................................................... 29 
6.3 Trial rationale .................................................................................................................. 30 
6.4 Justification for dose ....................................................................................................... 30 
6.4.1 
Brodalumab ................................................................................................................. 30 
6.4.2 
Fumaric acid esters ...................................................................................................... 30 
6.5 Benefit-risk assessment ................................................................................................... 31 
6.6 Ethical considerations ...................................................................................................... 31 
7 Trial objectives and endpoints ............................................................................................. 32 
8 Trial design .......................................................................................................................... 33 
8.1 Overall trial design .......................................................................................................... 33 
8.2 Number of subjects needed ............................................................................................. 34 
8.3 Scientific rationale for trial design .................................................................................. 34 
8.4 End of trial definition ...................................................................................................... 35 
9 Trial population and withdrawal .......................................................................................... 35 


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9.1 Subject eligibility ............................................................................................................ 35 
9.2 Inclusion criteria .............................................................................................................. 35 
9.3 Exclusion criteria ............................................................................................................. 36 
9.4 Subject enrolment ............................................................................................................ 39 
9.5 Discontinuation ............................................................................................................... 40 
9.5.1 
Discontinuation rules and replacement ....................................................................... 40 
9.5.2 
Early termination assessments ..................................................................................... 40 
9.5.3 
Lost to follow-up ......................................................................................................... 40 
10 Treatments ........................................................................................................................... 42 
10.1 Investigational medicinal products description ............................................................... 42 
10.2 Administration of investigational medicinal products .................................................... 42 
10.2.1 Dosing scheme ............................................................................................................ 42 
10.2.2 Precautions/overdose ................................................................................................... 45 
10.3 Treatment assignment ...................................................................................................... 45 
10.3.1 Randomisation ............................................................................................................. 45 
10.3.2 Blinding ....................................................................................................................... 46 
10.3.3 Emergency unblinding of individual subject treatment ............................................... 46 
10.4 Concomitant medication and procedures ........................................................................ 46 
10.5 Previous anti-psoriatic therapy ........................................................................................ 47 
10.6 Prohibited medication and procedures ............................................................................ 47 
10.7 Rescue treatment ............................................................................................................. 47 
10.8 Dose modification and investigational medicinal product discontinuation rules ............ 48 
10.8.1 Reason for discontinuation of investigational medicinal product ............................... 48 
10.8.2 Specific to subjects allocated to fumaric acid esters ................................................... 48 
10.9 Treatment logistics and accountability ............................................................................ 49 
10.9.1 Labelling and packaging of investigational medicinal product ................................... 49 
10.9.2 Storage of investigational medicinal products ............................................................ 50 
10.9.3 Drug accountability ..................................................................................................... 50 
10.9.4 Investigational medicinal product destruction ............................................................ 51 
10.9.5 Treatment compliance ................................................................................................. 51 
10.10 Provision for subject care following trial completion ................................................. 52 
10.11 Reporting product complaints ......................................................................................... 52 
11 Trial schedule and assessments ........................................................................................... 53 
11.1 Overview ......................................................................................................................... 53 


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11.2 Assessments performed only at screening/baseline ........................................................ 53 
11.2.1 Demographics .............................................................................................................. 53 
11.2.2 Height .......................................................................................................................... 53 
11.2.3 Medical history ............................................................................................................ 54 
11.3 Concomitant medication and procedures ........................................................................ 54 
11.4 Efficacy assessments ....................................................................................................... 54 
11.4.1 Blinded assessments .................................................................................................... 54 
11.4.1.1 Psoriasis Area and Severity Index (PASI) ............................................................... 54 
11.4.1.2 Static Physician’s Global Assessment of disease severity (sPGA) ......................... 56 
11.4.1.3 Assessment of the body surface area involvement (BSA) ....................................... 57 
11.4.1.4 Nail Psoriasis Severity Index (NAPSI) .................................................................... 57 
11.4.2 Patient reported outcomes – Efficacy and safety ........................................................ 58 
11.4.2.1 Dermatology Life Quality Index (DLQI) ................................................................ 58 
11.4.2.2 Patient Health Questionnaire-8 (PHQ-8) ................................................................. 58 
11.4.2.3 Electronic self-rated version, Columbia-Suicide Severity Rating Scale (eC-SSRS)
 ................................................................................................................................. 59 
11.4.2.4 Psoriasis symptom inventory (PSI) ......................................................................... 60 
11.5 Safety assessments .......................................................................................................... 60 
11.5.1 Vital signs .................................................................................................................... 60 
11.5.2 Physical examination ................................................................................................... 61 
11.5.3 Weight .......................................................................................................................... 61 
11.5.4 Pregnancy test .............................................................................................................. 61 
11.5.5 Adverse events ............................................................................................................ 61 
11.6 Other safety assessments ................................................................................................. 62 
11.6.1 Laboratory testing ........................................................................................................ 62 
11.6.1.1 Safety laboratory blood analysis .............................................................................. 62 
11.6.1.2 Estimate of total blood volume collected ................................................................ 63 
11.6.1.3 Safety urinalysis ....................................................................................................... 63 
12 Adverse events ..................................................................................................................... 63 
12.1 Collection of adverse events ............................................................................................ 63 
12.2 Reporting of adverse events ............................................................................................ 64 
12.2.1 Actions taken as a consequence of an AE ................................................................... 64 
12.2.2 Reporting of serious adverse events ............................................................................ 64 
12.2.2.1 Investigator reporting responsibilities ..................................................................... 65 
12.2.2.2 LEO reporting responsibilities ................................................................................. 65 
12.3 Other events that require expedited reporting to LEO .................................................... 66 


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12.3.1 Pregnancy .................................................................................................................... 66 
12.3.2 Adverse events of special interest ............................................................................... 66 
12.4 Reporting of other events ................................................................................................ 67 
12.4.1 Overdose ...................................................................................................................... 67 
12.4.2 Medication error .......................................................................................................... 67 
12.4.3 Misuse ......................................................................................................................... 68 
12.4.4 Abuse ........................................................................................................................... 68 
12.4.5 Aggravation of condition ............................................................................................. 68 
12.4.6 Lack of efficacy ........................................................................................................... 68 
12.5 Follow-up for final outcome of adverse events ............................................................... 68 
12.6 Handling of an urgent safety measure ............................................................................. 69 
13 Statistical methods ............................................................................................................... 69 
13.1 Sample size ...................................................................................................................... 69 
13.2 Trial analysis sets ............................................................................................................ 70 
13.3 Statistical analysis ........................................................................................................... 71 
13.3.1 Disposition of subjects ................................................................................................ 71 
13.3.2 Demographics and other baseline characteristics ........................................................ 71 
13.3.3 Exposure and treatment compliance ............................................................................ 71 
13.3.4 Endpoints ..................................................................................................................... 71 
13.3.5 Analysis of primary endpoint ...................................................................................... 72 
13.3.6 Analysis of secondary efficacy endpoints ................................................................... 73 
13.3.7 Analysis of patient reported outcomes ........................................................................ 73 
13.3.8 Analysis of safety ........................................................................................................ 73 
13.3.8.1 Adverse events ......................................................................................................... 74 
13.3.8.2 Other specific safety assessments ............................................................................ 74 
13.3.8.3 Vital signs and physical examinations ..................................................................... 75 
13.3.8.4 Clinical laboratory evaluation .................................................................................. 75 
13.3.9 Interim analysis ........................................................................................................... 75 
13.3.10 General principles ........................................................................................................ 75 
13.3.11 Handling of missing values ......................................................................................... 76 
14 References ........................................................................................................................... 76 
15 List of appendices ................................................................................................................ 79 
Appendix 1 Abbreviated eligibility criteria in accordance with CDISC requirements ............ 80 
Appendix 2: Definitions of adverse events and serious adverse events ................................... 84 
Appendix 3: Classification of adverse events .......................................................................... 86 


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Appendix 4: Trial governance considerations .......................................................................... 88 
Appendix 4A: Regulatory and ethical considerations .............................................................. 88 
Appendix 4B: Informed consent process ................................................................................. 88 
Appendix 4C: Subject and data confidentiality ........................................................................ 89 
Appendix 4D: Record keeping, quality control, and data handling ......................................... 90 
Appendix 4E: Registration, reporting and publication policy .................................................. 94 
Appendix 4F: Insurance ........................................................................................................... 95 
Appendix 4G: Financial disclosure .......................................................................................... 95 
Appendix 4H: Trial and site closure ......................................................................................... 95 
Appendix 4I: Responsibilities .................................................................................................. 96 
Appendix 5 Questionnaires ...................................................................................................... 97 
Appendix 5A: Psoriasis Symptom Inventory (PSI) – 24 hours recall ............................... 97 
Appendix 5B: Dermatology Life Quality Index .................................................................. 98 
Appendix 5C: Patient Health Questionnaire-8 .................................................................. 100 
Appendix 6  Reference safety information ............................................................................ 101 
Appendix 7 Contact list .......................................................................................................... 107 
 


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List of panels 
Panel 1  Trial design ................................................................................................................. 22 
Panel 2  Schedule of trial procedures ....................................................................................... 23 
Panel 3  Objectives and endpoints............................................................................................ 32 
Panel 4  Identification of investigational medicinal products .................................................. 43 
Panel 5  Brodalumab dose scheme ........................................................................................... 44 
Panel 6  Fumaric acid esters dose scheme ................................................................................ 45 
Panel 7  Psoriasis area and severity index – Extent ................................................................. 55 
Panel 8  Psoriasis area and severity index – Severity .............................................................. 56 
Panel 9  Static physician’s global assessment of disease severity scale .................................. 57 
Panel 10  Analysts .................................................................................................................... 62 
Panel 11  Urine analysis ........................................................................................................... 63 
Panel 12  Adverse events of special interest ............................................................................ 67 
Panel 13  Estimated power by sample size and response rate (number of subjects per group) 70 
Panel 14  Transmission of electronic data ................................................................................ 93 
 
 
List of abbreviations and definitions 
AESI 
adverse events of special interest 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
 
 
BMI 
body mass index 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 


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CCDS 
company core data sheet 
CMO 
contract manufacturing organisation 
CONSORT 
Consolidated Standards of Reporting Trials 
CPM 
clinical project manager 
CRA 
clinical research associate 
CRO 
contract research organisation  
CRP 
C-reactive protein 
 
 
DLQI 
Dermatology Life Quality Index 
 
 
eCRF 
electronic case report form 
eC-SSRS 
electronic self-rated version, Columbia-Suicide Severity Rating Scale 
EDC 
electronic data capture 
ePRO 
electronic patient reported outcome 
 
 
FAS 
full analysis set  
FSFV 
first subject first visit 
 
 
GCP 
good clinical practice 
GPV 
global pharmacovigilance 
 
 
HIV 
human immunodeficiency virus 
 
 
ICH 
The International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
ICI 
international coordinating investigator 
IEC 
independent ethics committee 
IL-17(RA) 
interleukin 17 (receptor A) 
IMP 
investigational medicinal product 
IWRS 
interactive web response system 
 
 


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LSFV 
last subject first visit 
LSLV 
last subject last visit 
 
 
MACE 
major adverse cardiovascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measurements 
MTX 
methotrexate 
 
 
NAPSI 
Nail Psoriasis Severity Index 
 
 
PASI 
Psoriasis Area and Severity Index 
PASI 75 
responder cut-point defining responders as subjects with at least 75% 
improvement from baseline in PASI  
PASI 90 
responder cut-point defining responders as subjects with at least 90% 
improvement from baseline in PASI  
PASI 100 
responder cut-point defining responders as subjects with 100% 
improvement from baseline in PASI  
PHQ-8 
Patient Health Questionnaire-8 
PML 
progressive multifocal leukoencephalopathy 
PSI 
Psoriasis Symptom Inventory 
PUVA 
psoralens and ultraviolet A 
 
 
Q2W 
every two weeks (in this trial, this regimen includes an additional loading 
dose one week after initiation of brodalumab) 
 
 
RBC 
red blood cell count 
 
 
SAE 
serious adverse event 
SAPU 
statistical analysis plan update 
SAS 
safety analysis  
SC 
subcutaneous 
SIB 
suicidal ideation and behaviour 


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SmPC 
summary of product characteristics 
SOC 
system organ class 
sPGA 
static Physician’s Global Assessment 
SUSAR 
suspected unexpected serious adverse reaction 
 
 
TID 
three times a day 
 
 
ULN 
upper limit of normal 
UV A/B 
ultraviolet A/B 
 
 
WBC 
white blood cell count 
WMA 
World Medical Association 
 


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2 Protocol summary 
Trial ID 
LEO ID: LP0160-1327; EudraCT: 2016-003867-21 
Title of trial 
A phase 4 trial comparing the efficacy of subcutaneous injections of brodalumab to oral 
administrations of fumaric acid esters in adults with moderate to severe plaque psoriasis 
Trial rationale 
The rationale is to demonstrate added benefit of brodalumab versus a selected systemic 
comparator in treatment of moderate to severe plaque psoriasis in Germany in subjects who 
have not previously received systemic treatment for psoriasis.  
Fumaric acid esters have been selected as the comparator because it is an established 
systemic treatment of psoriasis in Germany. 
Primary 
objective 
To compare the efficacy of subcutaneous injections of brodalumab to oral administration of 
fumaric acid esters in subjects with moderate to severe plaque psoriasis who are naive to 
systemic treatment 
Endpoints for 
the primary 
objective 
Co-primary endpoints:  
 At least 75% improvement from baseline at Week 24 in Psoriasis Area and Severity 
Index (PASI) 
 Static Physician’s Global Assessment (sPGA) scale score of 0 or 1 at Week 24 
Secondary endpoints:  
 At least 90% improvement from baseline at Week 24 in PASI  
 100% improvement from baseline at Week 24 in PASI  
 Change from baseline at Week 24 in PASI score 
 PASI improvement (%) from baseline at Week 24 
 Change from baseline at Week 24 in affected body surface area (BSA) 
Trial design 
Randomised, open-label, active-controlled, parallel group, multi-centre trial with 
investigator-blinded efficacy assessments comparing the efficacy of subcutaneous injections 
of brodalumab to oral administration of fumaric acid esters in adults with moderate to severe 
plaque psoriasis. Eligible subjects will be randomised 1:1 to receive one of the following 
treatments, after stratification according to body weight (<100 kg or ≥100 kg): 
•
 


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Main criteria 
for inclusion 
 Men or women ≥18 years of age at the time of screening 
 Subjects with chronic plaque type psoriasis diagnosed for at least 6 months before 
randomisation 
 Subjects with moderate to severe plaque psoriasis in whom topical therapy only is not 
adequate and who are candidates for systemic therapy, defined at randomisation by 
PASI >10, affected BSA >10% and DLQI >10 
 Subject has no known history of active tuberculosis 
 Subject has a negative test for tuberculosis taken at screening (negative QuantiFERON 
test) 
 Subject and/or subject’s designee is/are capable of administering subcutaneous 
injections 
Main criteria 
for exclusion 
 Previous or current systemic treatment of plaque psoriasis or known contraindication 
for systemic therapy. 
 Previous or current PUVA (psoralens and ultraviolet A) therapy. 
 Washouts and non-permitted drugs: 
a) Have received phototherapy (UVA light therapy without psoralens, UVB light 
therapy, excimer laser, tanning beds etc. within 4 weeks of baseline. 
b) Have had topical psoriasis treatment within 2 weeks of baseline (exceptions: bland 
emollients without urea or beta or alpha hydroxy acids). 
c) Have received any biologic immune modulating treatment used for indication other 
than psoriasis within 4 weeks of baseline or within a period of 5 half-lifes of the 
received treatment, whichever is longer. 
d) Have received any other systemic immune modulating treatment (including but not 
limited to oral retinoids, methotrexate, calcineurin inhibitors, oral or parenteral 
corticosteroids etc. used for indication other than psoriasis) within 4 weeks of baseline 
or within a period of 5 half-lifes of the received treatment, whichever is longer. 
 
Subjects with any of the following laboratory abnormalities at screening: 
a) Leukocyte cell count below 3×109/L or lymphocyte count below 0.7×109/L. 
b) Aspartate aminotransferase (AST) or alanine transferase (ALT) > 2× ULN (upper 
level of normal limit). 
c) Absolute neutrophil count < 2× 109/L. 
d) Serum creatinine > ULN. 
 
History of depressive disorder within the last 2 years including current anti-depressive 
treatment. 
 
Any positive finding in history of suicidal behaviour (e.g., ‘actual suicide attempts’, 
‘interrupted attempts’, ‘aborted attempts’, or ‘preparatory actions’) based on the eC-
SSRS questionnaire at screening or baseline. 
 
Any positive finding in suicidal ideation of level 4 or 5 (‘some intent to act, no plan’ 
or ‘specific plan and intent’) based on the eC-SSRS questionnaire at screening or 
baseline. 
 
A PHQ-8 score of ≥10 corresponding to moderate to severe depression at screening or 
baseline. 
Investigational 
medicinal 
product(s) 
Brodalumab: 210 mg brodalumab in 1.5 mL solution for subcutaneous injection (140 
mg/mL). Each kit contains 2 syringes. 
Fumaric acid esters: 30 or 120 mg Fumaric acid tablets for oral administrations. Fumaderm® 
Initial package contains 40 tablets of 30 mg and Fumaderm® package contains 70 tablets of 
120 mg. 


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Duration of 
treatment 
Screening period up to 28 days, treatment period of 24 weeks, and follow-up period is 8 
weeks for brodalumab and 2 weeks for fumaric acid esters (approximately 5 half-lifes for 
each). 
Number of 
subjects 
A maximum of 204 subjects will be randomly assigned to study treatment such that more 
than approximately 102 evaluable subjects complete the trial. 
Number of  
trial sites  
Approximately 30 clinical sites in Germany 
Statistical 
methods 
The co-primary endpoints PASI 75 and sPGA (0 or 1) at Week 24 (end of treatment visit) 
will be evaluated on the FAS. 
Estimates and 95% confidence intervals (CI) for the response rates and treatment differences 
will be presented. The differences in response rates between treatment groups will be 
analysed using the Cochran-Mantel-Haenszel test and weight (≥100 kg or <100 kg). The 
null hypotheses of no difference in response rates between brodalumab and fumaric acid 
esters will be tested against the two-sided alternative that there is a difference on a 5% level. 
Subjects who drop-out of the trial before Week 24 (end of treatment visit) will be regarded 
as non-responders. 
As supportive analyses for the co-primary endpoints, a logistic regression model with 
baseline PASI or sPGA and weight group will be performed, and further, the mixed model 
for repeated measurements (MMRM) for PASI described below will be used to predict 
PASI 75 for subjects without assessments at Week 24 for an additional Cochran-Mantel-
Haenszel analysis. Finally subjects who drop-out of the trial before Week 24 will be LOCF 
imputed and analyzed using the Cochran-Mantel-Haenszel test.  
The trial is considered a success if superiority is confirmed for both primary endpoints.  
Coordinating 
investigator 
Ulrich Mrowietz, Prof. Dr. med. 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark 
For submission to IECs and/or regulatory authorities, attach schedule of trial procedures (Panel 2) 


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3   Trial identification 
EudraCT number: 2016-003867-21 
 
4 Schematic of trial design 
Panel 1  Trial design 
 
n: number of subjects randomised to each arm; SC: subcutaneous; TID: three times a day; Q2W: every two 
weeks (in accordance with the label, the brodalumab regimen includes an additional loading dose one week 
after the first administration) 
 


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5 Schedule of procedures 
Panel 2  Schedule of trial procedures 
 
Screening 
Treatment phase 
 
Follow-up 
Visit 
V1 
V21) 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
End of 
treatment 
Unscheduled 
visit2) or 
early 
termination 
visit3) 
V134) 
Visit Week/Day 
Up to 28 
days prior 
to V2 
0/0 
1/7 
2/14 
3/21 
4/28 
6/42 
8/56 
12/84 
16/112 
20/140 
24/168 
26/182 or 
32/2244) 
Visit window (days)5) 
 
  
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Trial population and eligibility (Sections 11.2.3 and 11.3) 
Informed consent6 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibillity criteria 
x 
x7 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, incl. 
concurrent illness 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous anti-psoreatic 
theraphy 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication/procedures 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
x 
Other investigator assessments only at screeing/baseline (Section 11.2) 
Demographics  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational medicinal product and randomisation (Section 10) 
Randomisation 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
IWRS 
x 
x 
 
 
 
 
 
x 
x 
x 
x 
 
(x) 
 
Handing out IMP: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brodalumab 
 
x 
 
 
 
 
 
x 
x 
x 
x 
 
(x) 
 
Fumaric acid esters 
 
x 
 
 
 
 
 
x 
x 
 
x 
 
(x) 
 
Treatment instruction 
x8 
x9 
x9 
 
 
 
 
 
 
 
 
 
 
 
Drug accountability/ 
Treatment compliance 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
 
Blinded assessments of efficacy Section 11.4.1) 
PASI 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
 
sPGA 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
 
BSA involvement 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
 
NAPSI 
 
x 
 
 
 
 
 
 
x 
 
 
x 
(x)* 
 


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Screening 
Treatment phase 
 
Follow-up 
Visit 
V1 
V21) 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
End of 
treatment 
Unscheduled 
visit2) or 
early 
termination 
visit3) 
V134) 
Visit Week/Day 
Up to 28 
days prior 
to V2 
0/0 
1/7 
2/14 
3/21 
4/28 
6/42 
8/56 
12/84 
16/112 
20/140 
24/168 
26/182 or 
32/2244) 
Visit window (days)5) 
 
  
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
e-PROs at clinic (Section 11.4.2):10 
DLQI 
x 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
(x)* 
 
eC-SSRS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
 
PHQ-8 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
(x)* 
 
e-PRO at home (Section 11.4.2.4): 
PSI (24h recall) 
 
Daily at home during entire treatment phase using a ePRO device 
 
 
Vital signs (Section 11.5.1): 
Blood pressure 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
x 
Heart rate 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
x 
Respiration rate 
 
x 
  
 
 
  
 
 
x 
 
 
x 
(x)* 
 
Temperature 
 
x 
 
 
 
 
 
 
x 
 
 
x 
(x)* 
 
Blood/urine sampling (Section 11.6.1): 
Serum pregnancy test11 
x 
 
 
 
 
 
 
 
 
 
 
 
(x) 
 
QuantiFERON-TB 
Gold 
x 
 
 
 
 
 
 
 
 
 
 
 
(x) 
 
Biochemistry12 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
(x)* 
 
Haematology13 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
(x)* 
 
Urine analysis14 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
(x)* 
 
Adverse events,physical examination and weight (Sections 12, 11.5.2, and 11.5.3): 
Adverse events15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
x 
Physical examination 
x 
x 
 
 
 
 
 
 
x 
 
 
x 
(x)* 
 
Weight 
x 
x 
 
 
 
 
 
 
x 
 
 
x 
(x)* 
 
Subject returning investigational medicinal product (Section 10.9.3): 
Brodalumab 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
(x)* 
 
Fumaric acid esters 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
 
End of trial form 
 
 
 
 
 
 
 
 
 
 
 
x 
(x)* 
 
Reminders 
Handout ID card 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Handout and instruct in 
ePRO device use 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening 
Treatment phase 
 
Follow-up 
Visit 
V1 
V21) 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
End of 
treatment 
Unscheduled 
visit2) or 
early 
termination 
visit3) 
V134) 
Visit Week/Day 
Up to 28 
days prior 
to V2 
0/0 
1/7 
2/14 
3/21 
4/28 
6/42 
8/56 
12/84 
16/112 
20/140 
24/168 
26/182 or 
32/2244) 
Visit window (days)5) 
 
  
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Reminders – Continued 
Dispense disposal 
containers for 
brodalumab syringes 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Handout cooler bag for 
transport of 
brodalumab 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Subject information 
folder 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Subject to bring ePRO 
device with them to site 
visit 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
 
Review ePRO device 
answers  
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)* 
 
Subject to return ePRO, 
disposal containers, and 
cooler bag to site 
 
 
 
 
 
 
 
 
 
 
 
x 
(x)* 
 
1) 
Subjects must be randomised within 28 days after screening or as soon as all inclusion and exclusion criteria are confirmed. Allow time for results from 
screening samples to be available from central lab. 
2) 
An unscheduled visit can be performed before the follow-up visit for the following purposes: By individual need at the discretion of the investigator, AE 
follow-up (and related concomitant medication/procedures, if applicable), re-instructing the subject in procedures for home treatment with the investigational 
medicinal product, re-collection of blood and/or urine samples in case of medical need of following up on specific test abnormalities, suspection of pregnancy, 
or in case of sampling or testing errors necessitating the colletion of new samples. Procedures are marked in brackets “(x)” since they are optional depending on 
the reason for the unscheduled visit. 


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3)  Subjects, who are withdrawn from the trial or discontinues trial treatment for any reason, should attend an early termination visit as soon as possible after last 
dose to have all early termination assessments performed. All mandatory assessments applicable for an early termination visit are marked with an asterix (*). If 
a subject discontinues trial treatment or withdraws at a visit, then all mandatory assessments for an early termination visit must be performed at this particular 
visit.  
4) 
Follow-up visit should be conducted no sooner than approximately 5 half-lifes after the last administration of investigational medicinal product. Hence, 
- at 8 weeks (±3 days) after Week 24 or early termination visit for subjects allocated to brodalumab; and 
- at 2 weeks (±3 days) after Week 24 or early termination visit for subjects allocated to fumaric acid esters. 
Additional follow-up visit(s) should be performed only in case an AE is ongoing at the initial follow-up visit and is either a non-serious AE classified as 
possibly or probably related to investigational medicinal product or an SAE. No data will be collected at the additional follow-up visit(s). Where the 
(sub)investigator considers it appropriate, any additional follow-up visit(s) may be performed as a telephone contact. 
5) 
All visit-dates should be scheduled relative to the baseline visit, except for the follow-up visit which should be scheduled relative to the date of end of treatment 
visit (captured at Week 24 or at an early treatment withdrawal visit) and the investigational medicinal product (see note 4). 
6) 
Informed consent must be signed both by subject and (sub)investigator (medically qualified) before any trial related procedures are carried out. 
7) 
Re-evaluation of in-/exclusion criteria, including review of results from the central laboratory of screening samples. 
8)  
At screening, all subjects will receive information that if they are randomised to brodalumab they will have to self-administer the subcutaneous injections. The 
subjects must confirm that he/she or the subject’s designated person will be able to administer the subcutaneous injections that randomisation to brodalumab 
would entail. 
9) 
The 2 first administered brodalumab doses, at baseline and Week 1, should be administered by the subject or designated person at the clinical trial site under 
supervision of the investigator or delegated person. After Week 1, IMP should be administered at home by subject or the subject’s designated person 
(subcutaneous injection if randomised to brodalumab and oral administration if randomised to fumaric acid esters). 
10) The DLQI should be completed by the subject prior to all other trial procedures and the electronic self-rated version, columbia-suicide severity rating scale (eC-
SSRS) and the patient health questionnaire-8 (PHQ-8) should be completed after all other assessments have been performed. 
11) Serum beta hCG test must be done in female subjects of childbearing potential (must also be done at visits after screening if a urine test is positive for 
pregnancy). 
12) Sodium, potassium, magnesium, bicarbonate, albumin, blood urea nitrogen (BUN), creatinine, uric acid, total bilirubin, direct bilirubin, Alk phosphatase, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), and C-reactive protein (CRP). 
13) RBC (red blood cell count), haemoglobin, haematocrit, platelets, white blood cell count (WBC), and differential (absolute count and %): neutrophils, 
lymphocytes, monocytes, eosinophils and basophils. 
14) Specific gravity, pH, occult blood, protein, glucose, leucocyte esterase, ketones, and urine pregnancy test. 
15) AEs will be collected from time of first trial related activity after the subject has signed the informed consent form. Pre-existing conditions identified as a result 
of the screening procedures should be reported as medical history. 
 


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6 Introduction and rationale 
6.1 
Psoriasis vulgaris 
Psoriasis is a chronic inflammatory disorder associated with significant morbidity and 
mortality that occurs in approximately 2% of the population worldwide (Augustin et al. 2010, 
Gelfand et al. 2007, Rachakonda et al. 2014). It is a chronic polygenic inherited disease of 
uncontrolled cutaneous inflammation that manifests, in the majority of subjects, as plaque 
type psoriasis, clinically seen as sharply demarcated, elevated, scaling, erythematous plaques 
located predominantly on the scalp, extensor sides of elbows and knees, and the sacral region 
(Griffiths and Barker 2007, Langley et al. 2005, Griffiths et al. 2007). These skin lesions can 
be painful, pruritic, and may cause significant emotional and physical discomfort (Dubertret 
et al. 2006). In addition to skin manifestations, psoriasis is associated with multiple 
comorbidities, for instance arthritis, cardiovascular disease, and psychiatric conditions such as 
depression and anxiety (Griffiths and Barker 2007, Gisondi et al. 2007). 
The majority of subjects with psoriasis has mild to moderate disease and can be treated with 
topical therapies (Menter et al. 2009). In subjects with moderate to severe psoriasis, 
phototherapy or systemic treatment, including biologic agents, are recommended (possibly 
adjunct to topical treatment) (Menter et al. 2009, Nast et al. 2012).  
6.2 
Experience with investigational medicinal product 
6.2.1 
Brodalumab 
Brodalumab is a recombinant fully human monoclonal immunoglobulin IgG2-antibody that 
binds with high affinity to human interleukin 17 receptor A (IL-17RA). Brodalumab is 
approved for the treatment of moderate to severe plaque psoriasis in adult patients who are 
candidates for systemic therapy in EU, Japan, and USA. 
Blocking IL-17RA inhibits IL-17 cytokine-induced responses and results in reduced or 
normalised inflammation of the skin in subjects with psoriasis. Ixekizumab and secukinumab 
share the same treatment target, 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 (namely, IL-17F, IL-17A/F heterodimer, and 
IL-17E also known as IL-25) (Gooderham et al. 2015). 
The dose regimen for brodalumab for the treatment of moderate to severe plaque psoriasis in 
adult patients is 210 mg by subcutaneous injection at Weeks 0, 1, and 2, and then 210 mg 
every 2 weeks (Q2W). 


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Brodalumab efficacy: 
The efficacy of brodalumab for the treatment of psoriasis has been confirmed in 3 pivotal 
phase 3 placebo-controlled clinical trials, in which 2 of the trials also included an 
ustekinumab comparator arm. The pivotal trials enrolled subjects of 18 to 75 years of age with 
stable moderate to severe plaque psoriasis diagnosed at least 6 months before the first dose of 
investigational medicinal product (IMP). At baseline, the enrolled subjects had plaque type 
psoriasis with Psoriasis Area and Severity Index (PASI) score of at least 12, static Physician’s 
Global Assessment (sPGA) score of at least 3, and at least 10% body surface area (BSA) 
involvement. In all 3 trials, brodalumab was superior to placebo (p<0.001) for the co-primary 
endpoints (PASI 75 and sPGA of 0 or 1) as well as the secondary endpoints at Week 12  
(PASI 100, sPGA of 0, and PSI). 
At Week 12, brodalumab 210 mg treated patients achieved response rates of 86% for PASI 75, 
80% for sPGA0/1, and 44% for PASI 100 (AMAGINE-2 trial, EU summary of product 
characteristics (SmPC)). 
Brodalumab safety: 
During the brodalumab development programme, the most commonly reported adverse 
reactions in brodalumab-treated subjects included arthralgia, headache, fatigue, diarrhoea, and 
oropharyngeal pain (see reference safety information in Appendix 6). There were no very 
common adverse reactions.  
During the brodalumab development programme, important identified and important potential 
risks have been identified to be further investigated after launch. These include serious 
infections, major adverse cardiovascular events (MACE), and malignancies. These important 
identified and important potential risks originate from the product’s immunomodulatory 
activity and are shared by biologics in general. Furthermore, suicidal ideation and behaviour 
(SIB) have been identified as an important potential risks based on rare events occurring 
during the brodalumab development programme. A causal relationship between brodalumab 
treatment and SIB has not been established, and there is no known mechanism of action by 
which brodalumab would be associated with triggers of self-injurious or suicidal behaviour, 
such as depression, mood disorders, and affective disorders or behaviours (Chiricozzi et al. 
2016).  
During the 12-week placebo-controlled trial period in plaque psoriasis, infections were 
reported in 25.4% of patients treated with brodalumab compared with 23.4% of patients 
treated with placebo. The majority of infections consisted of nasopharyngitis, upper 
respiratory tract infection, pharyngitis, urinary tract infections, bronchitis, and influenza, 
which did not necessitate treatment discontinuation. Serious infections occurred in 0.5% of 


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patients treated with brodalumab and in 0.2% of patients treated with placebo. Higher rates of 
fungal infections, primarily non-serious skin and mucosal candida infections were observed in 
brodalumab patients compared to placebo patients, 1.8% versus 0.9%, respectively. 
Antibodies to brodalumab developed in 2.7% (122/4461) of patients treated with brodalumab 
for up to 52 weeks in psoriasis clinical trials (0.3% of these patients had anti-brodalumab 
antibodies at baseline). Of these patients, none had neutralising antibodies. 
No evidence of altered pharmacokinetic profile, clinical response, or safety profile was 
associated with anti-brodalumab antibody development. 
For further details, please see the EU SmPC for Kyntheum®. 
6.2.2 
Fumaric acid esters 
Fumaric acid esters have been used to treat psoriasis since 1959. An oral preparation 
containing dimethyl fumarate and monoethyl fumarate salts, Fumaderm®, is licensed in 
Germany for treating adults with moderate to severe plaque psoriasis in whom topical therapy 
is not effective. It is available in two strengths, Fumaderm® Initial containing 30 mg dimethyl 
fumarate per tablet and Fumaderm® containing 120 mg dimethyl fumarate per tablet. 
Systemic therapy with fumaric acid esters is based on an established dosing scheme with a 
gradual increase to improve tolerability, especially with regards to gastrointestinal side 
effects. The dose is adjusted on an individual basis according to the response to therapy and 
the occurrence of side effects. 
Fumaric acid esters efficacy: 
The response rate for fumaric acid esters is expected to be lower than for brodalumab. In a 
systemic review, the rate is reported to be on par with methotrexate (Smith 2017). 
Methotrexate (MTX) for 24 weeks is reported to achieve at least PASI 75 in 51% of patients 
(Mrowietz and Warren et al. 2017).  
In the European Consensus, fumaric acid esters and MTX are considered slow-acting drugs 
and the endpoint should therefore be measured between Week 16 and Week 24 (Mrowietz and 
Szepietowski et al. 2017 ). In most reports on fumaric acid esters, clinical effects are from 
open studies and only few studies have been performed using evidence based criteria (Nast et 
al. 2012). For fumaric acid esters, the S3 guideline estimates a PASI 75 in 50 to 70% of 
patients at Week 16 (Nast et al. 2012). However, in a trial comparing fumarates versus MTX, 
only 39% of evaluable patients in the fumarates group had a ≥75% reduction in PASI at Week 
20 (the rate was 32% in the MTX group) (Fallah Arani et al. 2011).  


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In an observational study, mean PASI scores were reduced from 19.84 to 7.35 after 12 months 
(63% improvement) (Walker et al. 2014), and it was noted that several multi-centre trials had 
demonstrated the efficacy of fumaric acid esters in psoriasis with a PASI 75 in about 50% of 
patients.  
Fumaric acid esters safety: 
Very common adverse reactions include flushing, diarrhoea, and mild forms of 
lymphocytopenia and leukocytopenia. 
Common adverse reactions include gastrointestinal disorders (bloating, cramps, and 
flatulence), severe forms of lymphocytopenia, and transient eosinophilia. 
Trial treatment discontinuation criteria specific to subjects in the fumaric acid esters group, 
are provided in Section 10.8.2. 
For further details, see the SmPC for Fumaderm®. 
6.3 
Trial rationale 
The rationale is to demonstrate added benefit of brodalumab versus a selected systemic 
comparator in treatment of moderate to severe plaque psoriasis in Germany in subjects who 
have not previously received systemic treatment for psoriasis. 
Fumaric acid esters have been selected as the comparator because it is an established systemic 
treatment of psoriasis in Germany. 
6.4 
Justification for dose 
6.4.1 
Brodalumab 
210 mg 2QW brodalumab by subcutaneous injections is the recommended dose in the 
approved label. In the clinical development programme, this dose regimen demonstrated 
improved skin clearance across the key efficacy endpoints of PASI 75 response, PASI 100 
response, and sPGA success (0 or 1), relative to the comparator ustekinumab. 
The 210 mg brodalumab dose has been established as a well-tolerated dose with few and 
manageable AEs.  
6.4.2 
Fumaric acid esters 
Systemic therapy with fumaric acid esters is based on an established dosing scheme with a 
gradual increase in dosage to improve tolerability, especially with regards to gastrointestinal 


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side effects. The dose is adjusted on an individual basis according to the response to therapy 
and the occurrence of side effects, as described in the label. 
6.5 
Benefit-risk assessment 
A positive benefit-risk assessment of brodalumab and fumaric acid esters has been granted by 
relevant regulatory authorities via the market authorisation for each IMP in Germany. 
Further details on benefits and risks with each IMP are described in Section 6.2.  
6.6 
Ethical considerations 
The IMPs will be used according to the label in the indicated population, and therefore no 
ethical concern has been identified for this trial. The subjects will be followed using all 
relevant safety assessments for the duration of the trial. 
SIB, including completed suicide, has been reported in patients treated with brodalumab. The 
majority of patients with SIB had a history of depression and/or suicidal behaviour. A causal 
association between treatment with brodalumab and an increased risk of SIB events has not 
been established, and there is no known mechanism of action by which brodalumab would be 
associated with triggers of self-injurious or suicidal behaviour, such as depression, mood 
disorders, and affective disorders or behaviours (Chiricozzi et al. 2016).  
Subjects are monitored for depression and SIB by the Patient Health Questionnaire-8 (PHQ-8) 
and the electronic self-rated version of the Columbia-Suicide Severity Rating Scale 
questionnaires (eC-SSRS). The investigator must discontinue subjects from trial treatment in 
case of any positive finding of suicidal ideation of level 4 or 5, any positive finding in history 
of suicidal behaviour, or a PHQ-8 score ≥15 corresponding to moderately severe to severe 
depression (see Sections 11.4.2.2 and 11.4.2.3 for description of the PHQ-8 and eC-SSRS 
assessments).  
Subjects with a recent history of depression (within 2 years), any positive finding of suicidal 
ideation (eC-SSRS level 4 or 5), or any positive finding in history of suicidal behaviour 
(PHQ-8 score ≥10) are excluded from the trial. 


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7 Trial objectives and endpoints 
Panel 3  Objectives and endpoints 
Objectives 
Endpoints 
Primary objective 
 
To compare the efficacy of subcutaneous 
injections of brodalumab to oral 
administration of fumaric acid esters in 
subjects with moderate to severe plaque 
psoriasis who are naive to systemic 
treatment. 
Co-primary endpoints:  
 
At least 75% improvement from baseline at Week 24 in 
Psoriasis Area and Severity Index (PASI) 
 
Static Physician’s Global Assessment (sPGA) scale 
score of 0 or 1 at Week 24 
Secondary endpoints:  
 
At least 90% improvement from baseline at Week 24 in 
PASI 
 
100% improvement from baseline at Week 24 in PASI 
 
Change from baseline at Week 24 in PASI score 
 
PASI improvement (%) from baseline at Week 24 
 
Change from baseline at Week 24 in affected body 
surface area (BSA) 
Secondary objectives 
 
To compare the effect on patient reported 
outcomes of subcutaneous injections of 
brodalumab to oral administration of fumaric 
acid esters in subjects with moderate to 
severe plaque psoriasis. 
Secondary endpoints: 
 
Psoriasis Symptom Inventory (PSI) responder at Week 
24 (total score ≤ 8, with no item scores > 1) 
 
PSI total score of 0 at Week 24 
 
Number of symptom-free days from randomisation to 
Week 24 (symptom-free day = daily total PSI of 0 on 
that day) 
 
Burden of symptoms assessed as the normalised area 
under the curve (AUC) of PSI from baseline to the last 
available assessment 
 
Change from baseline at Week 24 in Dermatology Life 
Quality Index (DLQI) total score 
 
DLQI total score of 0 or 1 at Week 24 
To evaluate the safety and tolerability of 
subcutaneous injections of brodalumab 
versus oral administration of fumaric acid 
esters in subjects with moderate to severe 
plaque psoriasis. 
Secondary point: 
 
Frequency of AEs and SAEs by preferred term 
Exploratory objective 
 
To explore the effect of subcutaneous 
injections of brodalumab versus oral 
administration of fumaric acid esters on nail 
involvement in subjects with moderate to 
severe plaque psoriasis and a NAPSI score 
of at least 6 on target nail.  
Other endpoint: 
 
Change from baseline at Week 24 in Nail Psoriasis 
Severity Index (NAPSI) total score 
Endpoints and analyses hereof are further described in Section 13.3 


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8 Trial design 
8.1 
Overall trial design 
Overview 
This is a randomised, open-label, active-controlled, parallel group, multi-centre trial with 
investigator-blinded efficacy assessments comparing the efficacy of subcutaneous injections 
of brodalumab to oral administration of fumaric acid esters in adults with moderate to severe 
plaque psoriasis. Eligible subjects will be randomised 1:1 to receive one of the following 
treatments, after stratification according to body weight (<100 kg or ≥100 kg): 
 
Brodalumab 210 mg, subcutaneous injections; or 
 
Fumaric acid esters, up to 240 mg dimethyl fumarate, oral administrations 
 
The clinical trial consists of 3 phases: 
The individual phases and visit structure are further described below and overviews of the 
trial design and scheduled procedures are displayed in Panel 1 and Panel 2. 
Screening phase (Week -4 to Week 0) 
A screening visit will take place up to a maximum of 28 days prior to the treatment phase. 
Before any trial related procedure is started, the subjects will receive the necessary written 
and verbal information and instructions, including the informed consent form (written 
informed consent) and the written subject information sheet. Each subject will receive a 
unique subject number and eligibility will be determined by clinical examination and 
confirmation of subject selection criteria. 
Treatment phase (Week 0 to Week 24) 
The start of the treatment phase is defined as Week 0 (baseline). At this visit, eligibility will 
be confirmed by re-checking the eligibility criteria in subjects who were eligible based on 
previous examinations and the lab results received from central lab for the samples taken at 
the screening visit. The investigator must ensure that lab values which are used to assess 
eligibility have been received and reviewed. If still eligible, the subject will continue in the 
trial and receive a unique randomisation number that determines the application scheme of 
IMP for the individual subject (see Section 10.3). 
Baseline, efficacy, and safety assessments during the trial are described in Section 11. 
Efficacy assessments are performed by an assessor blinded to treatment. 


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Follow-up phase (Week 24 to Week 26/32) 
The follow-up visit is scheduled approximately 5 half-lifes after last administration of IMP. 
 
If treated with brodalumab, the follow-up visit is scheduled at Week 32 (8 weeks 
after the end of treatment visit at Week 24). 
 
If treated with fumaric acid esters, the follow-up visit is scheduled at Week 26 
(2 weeks after the end of treatment visit at Week 24). 
Trial schedule 
The duration of the trial is planned as follows: 
 
Planned quarter of first subject first visit (FSFV): Q4 2017 
 
Planned quarter of last subject first visit (LSFV): Q2 2018 
 
Planned quarter of last subject last visit (LSLV): Q1 2019 
8.2 
Number of subjects needed 
Assuming a screening failure rate of 15%, approximately 240 subjects will be screened to 
obtain 204 randomised subjects. 
The statistical power considerations for this sample size (n=204) are described in 
Section 13.1. 
The trial will be conducted at approximately 30 sites in Germany. 
8.3 
Scientific rationale for trial design 
Randomised treatment allocation is applied as a methodology to reduce confounding by 
equalising factors (independent variables) not accounted for in the experimental design. 
Open-label treatment with blinded efficacy assessment is applied since the route of 
administration differs, and since the complexity of applying double dummy blinding is 
considered inappropriate due to the individual dose adjustment scheme of fumaric acid esters. 
A blinded assessor will perform all efficacy assessment not knowing the assigned treatment, 
while the investigator will be unblinded. The investigator is unblinded since dose adjustment 
may be necessary for subjects randomised to fumaric acid esters. 
A parallel design is applied to ensure correct temporal evaluation and to avoid any carry over 
effect from one treatment period to another, acknowledging the fact that, especially for 
biologic treatments, the effect may continue for weeks to months after treatment cessation. 


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8.4 
End of trial definition 
A subject is considered to have completed the trial if they have completed all periods of the 
trial, including the follow-up visit scheduled at Week 32 for brodalumab and at Week 26 for 
fumaric acid esters. The End of Trial Form must be completed for all randomised subjects. 
The filled form includes date of last dose, last attended scheduled visit number, and primary 
reason for withdrawal, if applicable. 
The end of the trial is defined as the date of the last visit of the last subject in the trial. 
9 Trial population and withdrawal 
9.1 
Subject eligibility 
The (sub)investigator must only randomise subjects who meet all eligibility criteria, who 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 checked according to the inclusion and 
exclusion criteria at the screening visit and the baseline visit. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial must be ensured and described in the documentation submitted to authorities/ethics 
committees, as applicable. 
9.2 
Inclusion criteria 
1. Signed and dated informed consent has been obtained 
2. Men or women ≥18 years of age at the time of screening 
3. Subjects with chronic plaque type psoriasis diagnosed at least 6 months before 
randomisation 
4. Subjects with moderate to severe plaque psoriasis in whom topical therapy only is not 
adequate and who are candidates for systemic therapy, defined at randomisation by 
PASI >10, affected BSA >10%, and DLQI >10 
5. Subject has no known history of active tuberculosis 
6. Subject has a negative test for tuberculosis taken at screening (negative QuantiFERON 
test) 


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7. A female subject of childbearing potential* is eligible to participate if she is not 
pregnant. This must be confirmed by a negative serum beta hCG pregnancy test at 
screening 
*Female subjects are considered of childbearing potential unless they have undergone 
hysterectomy, bilateral salpingectomy or bilateral oophorectomy, or have been post-
menopausal for at least one year prior to first visit. 
 
8. Female subjects of childbearing potential must be willing to use highly effective 
contraception* at trial entry and until 15 weeks after end of treatment. For subjects 
randomised to fumaric acid esters: oral contraceptive pills must be used with an 
additional contraceptive method (e.g. condom by partner, diaphragm, contraceptive 
gel, vaginal ring, etc.) 
*Highly effective contraception is defined as follows: 
• 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) 
• Bilateral tubal occlusion 
• An intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
9. Male subject with a female partner of childbearing potential who is willing to use 
adequate contraceptive methods*. Male subjects should not donate sperm in this 
period 
*Adequate contraceptive methods as required by local regulation or practice for at least 15 
weeks following last dose of investigational product. 
 
10. Subject and/or subject’s designee is/are capable of administering subcutaneous 
injections 
9.3 
Exclusion criteria 
1. Previous or current systemic treatment of plaque psoriasis or known contraindication 
for systemic therapy. 
2. Previous or current PUVA (psoralens and ultraviolet A) therapy. 
3. Washouts and non-permitted drugs: 


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a. Have received phototherapy (UVA light therapy without psoralens, UVB light 
therapy, excimer laser, tanning beds etc.) within 4 weeks of baseline. 
b. Have had topical psoriasis treatment within 2 weeks of baseline (exceptions: 
bland emollients without urea or beta or alpha hydroxy acids). 
c. Have received any biologic immune modulating treatment used for indication 
other than psoriasis within 4 weeks of baseline or within a period of 5 half-lifes 
of the received treatment, whichever is longer. 
d. Have received any other systemic immune modulating treatment (including but 
not limited to oral retinoids, methotrexate, calcineurin inhibitors, oral or 
parenteral corticosteroids etc. used for indication other than psoriasis) within 
4 weeks of baseline or within a period of 5 half-lifes of the received treatment, 
whichever is longer. 
4. Clinically important active infections or infestations, chronic, recurrent or latent 
infections, infestations or immunocompromised (e.g. HIV). 
5. Presence of significant uncontrolled cerebral, cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, haematologic, neurologic, or neuropsychiatric 
disorders. 
6. ‘Clinically significant abnormal values at screening within assessments of 
biochemistry, urine, and haematology (such as differential blood count and platelets) 
at the discretion of the investigator.’ 
7. Subjects with any of the following laboratory abnormalities at screening: 
a. Leukocyte cell count below 3×109/L or lymphocyte count below 0.7×109/L. 
b. Aspartate aminotransferase (AST) or alanine transferase (ALT) > 2× ULN 
(upper level of normal limit) 
c. Absolute neutrophil count < 2× 109/L 
d. Serum creatinine > ULN 
8. Subjects with severe gastrointestinal diseases including, but not limited to, ventricular 
and duodenal ulcers. 
9. Subject with a known history of Crohn’s disease or history of psoriatic arthritis with a 
need for treatment. 
10. Planned surgery, which in the opinion of the investigator would influence the planned 
treatment of the IMP. 


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11. History of depressive disorder within the last 2 years including current anti-depressive 
treatment. 
12. Any positive finding in history of suicidal behaviour (e.g., ‘actual suicide attempts’, 
‘interrupted attempts’, ‘aborted attempts’, or ‘preparatory actions’) based on the eC-
SSRS questionnaire at screening or baseline. 
13. Any positive finding in suicidal ideation of level 4 or 5 (‘some intent to act, no plan’ 
or ‘specific plan and intent’) based on the eC-SSRS questionnaire at screening or 
baseline. 
14. A PHQ-8 score of ≥10 corresponding to moderate to severe depression at screening or 
baseline. 
15. History of cancer: 
a. Subjects who have had basal cell carcinoma, localised squamous cell 
carcinoma of the skin or in situ carcinoma of the cervix are eligible provided 
that the subject is in remission and curative therapy was completed at least 
12 months prior to the date informed consent was obtained. 
b. Subjects who have had other malignancies are eligible provided that the 
subject is in remission and curative therapy was completed at least 5 years 
prior to the date informed consent was obtained. 
16. Known or suspected hypersensitivity to component(s) of the IMPs. 
17. Current participation in any other interventional clinical trial, ending another 
interventional clinical trial less than 4 weeks prior to screening visit, or receiving other 
investigational agents (based on interview of the subject). 
18. Subjects who have received treatment with any non-marketed drug substance (i.e. an 
agent which has not yet been made available for clinical use following registration) 
within the last 4 weeks prior to screening visit. 
19. Previously enrolled in this clinical trial. 
20. In the opinion of the (sub)investigator, the subject is unlikely to comply with the 
clinical trial protocol (e.g. due to alcoholism, drug addiction or psychotic state). 
21. Subjects in close affiliation with the trial personnel (e.g. immediate family member or 
subordinate), subjects being a member of the clinical trial personnel, or being an 
employee of the sponsor or a CRO involved in the trial. 


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22. Subjects under guardianship, hospitalised in a public or private institution, for a reason 
other than the research, or subject deprived of freedom. 
23. Female subjects who are pregnant or breastfeeding. 
24. Subject has any concurrent medical condition that, in the opinion of the investigator, 
could cause this trial to be detrimental to the subject. 
9.4 
Subject enrolment 
Trial participation begins once written informed consent is obtained (see Appendix 4B for 
details on the informed consent process). Once informed consent is obtained, a subject 
identification number (subject ID) will be assigned by a central interactive web response 
system (IWRS) and the screening evaluations to assess eligibility criteria may begin. The 
subject ID will be used to identify the subject during the screening process and throughout 
trial participation, if applicable. A master log of all consented subjects will be maintained at 
the trial site. 
Screening failures are defined as subjects who consent to participate in the trial but are not 
subsequently randomly assigned to trial treatment. A minimal set of screening failure 
information is required to ensure a transparent reporting that meets the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements (Schulz et al. 2010) and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screening failure details, eligibility criteria, and any AEs and SAEs. Follow up of SAEs must 
be carried out according to Section 12.5. 
Individuals who do not meet the criteria for participation in this trial (screening failures) may 
not be re-screened. However, if the reason for screening failure is administrative and not due 
to the subject failing to meet the eligibility criteria, re-screening may be permitted (this will 
require approval by the sponsor’s medical expert after thorough review of all data from the 
original screening visit in the electronic case report form (eCRF). Individuals who are allowed 
rescreening will get a new subject ID (old subject ID must be provided in a comment in the 
eCRF). 
The investigator will maintain a list of all randomised subjects at the trial site including each 
subject’s identity, date of enrolment and corresponding subject ID so that any subject may be 
identified if required for any reason. The list must not be copied or retained by LEO. 


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9.5 
Discontinuation 
9.5.1 
Discontinuation rules and replacement 
A subject may withdraw from trial or from treatment at any time (prior to first dose or during 
treatment period) at his/her own request. A subject may be withdrawn at any time at the 
discretion of the investigator. Discontinued subjects will not be replaced. 
Medical reasons for discontinuation of IMP are given in Section 10.8.1. 
9.5.2 
Early termination assessments 
Subjects who are withdrawn or discontinues trial treatment for any reason, should attend an 
early termination visit as soon as possible after last dose, to have all early termination 
assessments performed. Early termination assessments are identical to the assessments 
scheduled for the end of treatment visit (Week 24). 
If a subject discontinues IMP or withdraws from trial at a site visit, then this visit should be 
converted into an early termination visits and all applicable early termination assessments 
must be performed. The early termination is captured in the eCRF as an unscheduled visit by 
selecting the early termination option. 
The subjects should attend a follow-up visit 8 weeks after the early termination visit for 
brodalumab or 2 weeks after the early termination visit for fumaric acid esters. The 
investigator will review and follow up any AEs according to Section 12.5. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken that 
are not tested, and the investigator must document this in the site’s trial records. 
Reason(s) for discontinuation must be recorded in the medical records and the eCRF (lack of 
efficacy, AE, withdrawal by subject, lost to follow-up, death, other). 
9.5.3 
Lost to follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for 
scheduled/unscheduled visits and is unable to be contacted by the trial site. 
The following actions must be taken if a subject fail to return to the trial site for a required 
visit: 
 The trial site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 


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assigned visit schedule and ascertain whether or not the subject wishes to and/or 
should continue in the trial. 
 Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
 Should the subject continue to be unreachable, then the subject will be considered to 
have withdrawn from the trial with ‘lost to follow-up’ as the primary reason. 


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10  Treatments 
10.1 
Investigational medicinal products description 
Brodalumab and fumaric acid esters will be packaged in individually numbered kits. The 
brodalumab pack size includes 2 pre-filled syringes, while the fumaric acid esters pack sizes 
include 40 tablets per pack (fumaric acid esters initial; 4 blister packs each containing 
10 tablets) or 70 tablets per pack (fumaric acid esters; 7 blister packs each containing 10 
tablets). Refer to Panel 4 for further details. 
10.2 
Administration of investigational medicinal products 
The IWRS system will assign the required kits numbers for each subject at each dispensing 
visit. 
The first day of dosing is defined as Day 0 (baseline visit). 
10.2.1 
Dosing scheme 
Brodalumab 
Each brodalumab 210 mg dose will be given as 1 subcutaneous injection of a single-use pre-
filled syringe of 210 mg (1.5 mL) according to the dose scheme in Panel 5. 
Brodalumab must be injected in the upper legs (thighs) or stomach area (abdomen) by the 
subject or subject’s designee. The subject’s designee may also give injection(s) in the upper, 
outer arm. 
At baseline and Week 1, subjects randomised to brodalumab and/or their designated person 
must receive training on self administration of brodalumab. At these two visits, brodalumab 
should be administered by the subject or designated person at the clinical trial site under 
supervision of the investigator or delegated person. After Week 1, brodalumab should be 
administered at home by subjects or their designated person. However, assisted administration 
at trial site may be allowed at the discretion of the investigator if wished for by the subject. 


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Panel 4  Identification of investigational medicinal products 
Finished 
product 
brand name 
Dosage form 
Concentration and formulation 
Manufacturer 
Kyntheum® 
Each pre-filled 
syringe contains 210 
mg of brodalumab in 
1.5 mL solution for 
subcutaneous 
injection (140 mg/mL) 
Brodalumab formulated at a nominal 
concentration of 140 mg/mL including the 
following excipients:  
- Proline 
- Glutamate 
- Polysorbate 20 
- Water for injections 
Amgen Inc. 
Fumaderm® 
Initial 
Tablets for oral use 
Each tablet contains the following fumaric acid 
esters: 
- 30 mg dimethyl fumarate, 
- 67 mg ethyl hydrogen fumarate calcium salt, 
- 5 mg ethyl hydrogen fumarate magnesium salt, 
- 3 mg ethyl hydrogen fumarate zinc salt. 
Formulated as white gastro-resistant tablets with 
following excipients: Croscarmellose sodium, 
talc, magnesium stearate, titanium dioxide (E171), 
methacrylic acid - methyl methacrylate copolymer 
(1:1), methacrylic acid - ethyl acrylate copolymer 
(1:1), macrogol 6000, simethicone, povidone, 
triethyl citrate, microcrystalline cellulose, and 
highly dispersed silicon dioxide. 
Biogen GmbH 
Fumaderm® 
Tablets for oral use 
Each tablet contains the following fumaric acid 
esters: 
- 120 mg dimethyl fumarate, 
- 87 mg ethyl hydrogen fumarate calcium salt, 
- 5 mg ethyl hydrogen fumarate magnesium salt, 
- 3 mg ethyl hydrogen fumarate zinc salt. 
Formulated as blue gastro-resistant tablets with 
the following excipients: Croscarmellose sodium, 
talc, magnesium stearate, titanium dioxide (E171), 
indigo carmine (E132), methacrylic acid - methyl 
methacrylate copolymer (1:1), methacrylic acid - 
ethyl acrylate copolymer (1:1), macrogol 6000, 
simethicone, povidone, triethyl citrate, 
microcrystalline cellulose, and highly dispersed 
silicon dioxide. 
Biogen GmbH 
 


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Panel 5  Brodalumab dose scheme 
Route of administration 
Subcutaneous injections 
Dosing range  
210 mg 
Dosing frequency 
Weekly for the initial 3 doses and hereafter Q2W up to 
Week 24: 
Visit 
V2 V3 V4 V5 V6 V7 V8 
- 
V9 
- 
V10 
- 
V11 
- 
V12 
Week 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
Day 
0 
7 
14 
21 
28 
42 
56 
70 
84 
98 112 126 140 154 168 
Dosing  
x 
x 
x 
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
 
Daily maximum 
210 mg (1 dose) at scheduled treatment days 
Time of day for dosing 
Not defined 
 
Fumaric acid esters 
Fumaric acid esters tablets will be administered orally at home following the dose scheme in 
Panel 6. The first dose should be taken in the evening at day of the baseline visit (Day 0, 
visit 2).  
NOTE: The last tablet of fumaric acid esters initial (30 mg dimethyl fumarate tablets) should 
be taken in the evening of Day 19. Hereafter, the regimen must be shifted to fumaric acid 
esters, 120 mg dimethyl fumarate tablets, starting with 1 tablet once daily in the evening from 
Day 20 to Day 27 (Week 3 regimen, see Panel 6). 
Each subject will only receive one package of Fumaderm® Initial and this package will be 
used to up-titrate the subject to tolerate Fumaderm®, for which individual dosing can be 
performed. Experience has shown that the initial therapeutic effects with fumaric acid esters 
can be expected from Week 4 to Week 6 (see SmPC for Fumaderm®). 
The maximum daily dosage of 3×2 tablets must not be exceeded, and in many cases, 
administration of the maximum daily dose is not required as maintenance dose. 
The fumaric acid esters are gastro-resistant tablets and must be swallowed whole with plenty 
of liquid, during or immediately after meals. Generally, it is important to ensure that enough 
liquid is drunk over the course of the day (1½ to 2 litres). 


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Panel 6  Fumaric acid esters dose scheme 
Route of administration 
Oral administration 
Dosing range  
From 30 to 240 mg dimethyl fumarate per oral administration 
Dosing frequency 
1 to 3 times daily during titration with 30 and 120 mg dimethyl fumarate 
tablets (see scheme). After 9 weeks, the dose can be up to 2×120 mg 3 
times a day: 
 
30 mg dimethyl fumarate 
(No. of tablets per day) 
120 mg dimethyl fumarate 
(No. of tablets per day) 
Week 0 
0-0-1 
- 
Week 1 
1-0-1 
- 
Week 2 
1-1-1 
- 
Week 3 
- 
0-0-1 
Week 4 
- 
1-0-1 
Week 5 
- 
1-1-1 
Week 6 
- 
1-1-2 
Week 7 
- 
2-1-2 
Week 8 
- 
2-2-2 
Daily maximum  
720 mg (3 times 2 tablets) 
Time of day for dosing 
Morning, noon and evening 
 
10.2.2 
Precautions/overdose 
Brodalumab: Doses up to 700 mg intravenously have been administered in clinical studies 
with no evidence of dose limiting toxicity. In the event of an overdose, the subject should be 
monitored and treated symptomatically, and supportive measures instituted at the discretion of 
the investigator. 
Fumaric acid esters: For special warnings and precautions for use, please refer to the SmPC 
for Fumaderm® Initial/Fumaderm®. There are no known therapeutic interventions to enhance 
elimination of fumaric acid esters nor is there a known antidote. In the event of overdose, the 
subject should be monitored and treated symptomatically, and supportive measures instituted 
at the discretion of the investigator. 
10.3 
Treatment assignment 
10.3.1 
Randomisation 
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria will be randomised to receive treatment with either brodalumab or 


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fumaric acid esters. Treatment assignment will be pre-planned according to a computer 
generated randomisation schedule in a 1:1 ratio. 
Randomisation will be with stratification by body weight (<100 kg or ≥100 kg) using an 
IWRS system. 
Each investigator site will be supplied with sufficient IMPs for the trial on an ongoing basis 
controlled by the IWRS. 
10.3.2 
Blinding 
This is an open-label trial. Due to potential dose adjustments needed for subjects randomised 
to fumaric acid esters, the investigator and subject will need to know the treatment allocated. 
Furthermore, applying double dummy blinding is considered too demanding from a subject 
perspective, since home treatment would then involve both subcutaneous injections and oral 
administrations at varying time points. 
Blinded assessments of PASI, sPGA, BSA, and NAPSI will be performed. Blinded assessors 
who perform the assessment must be medically qualified physicians trained in the 
assessments. During the assessments, the subjects will be instructed not to reveal the 
treatment allocation and the blinded assessor must avoid asking questions that could reveal 
treatment allocation. All involved personnel will be instructed to desist from any discussions 
regarding safety, efficacy, treatment allocation of the study and subjects in the presence of the 
blinded assessor. In case a blinded assessor becomes unblinded, a new assessor should be 
appointed to perform the assessments of the subject going forward. 
If possible, each subject should have their assessments done by the same assessor throughout 
the trial. Extra care should be taken to ensure that the same blinded assessor performs the 
baseline and end of treatment visit (Week 24) assessments, where the co-primary endpoints 
are assessed. If necessary, trial visits may be rescheduled within the specified window to 
accommodate when the specific assessor will be available. 
10.3.3 
Emergency unblinding of individual subject treatment 
Not applicable. This is an open-label trial. 
10.4 
Concomitant medication and procedures 
Concomitant medication is defined as any medication used by a subject during the clinical 
trial apart from the IMP. 


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Use of concomitant treatment must be recorded in the subject’s medical record and the eCRF 
(e.g. treatment/drug name, indication, route of administration, dates of administration 
including start and stop dates, total daily dose, and frequency). 
10.5 
Previous anti-psoriatic therapy 
Previous anti-psoriatic topical treatment used by the subjects to treat their psoriasis vulgaris 
over the past 2 years prior to screening (OTC topicals, topical non-steroid, topical steroids, 
topical combination, etc.) must be recorded. Any history of phototherapy must also be 
recorded.  
10.6 
Prohibited medication and procedures 
The use of medications or procedures as defined in the exclusion criteria, is not permitted 
during the trial.  
Subjects who require use of a prohibited medication should be discontinued from IMP. The 
following concomitant therapies or treatments are prohibited throughout trial participation: 
1. Any phototherapy: ultraviolet A light therapy with or without psoralen, ultraviolet B 
light therapy, excimer laser etc. 
2. Any biologic immune modulator, including but not limited to etanercept, anakinra, 
adalimumab, infliximab, ustekinumab, and IL-17 inhibitors  
3. Any systemic therapy for psoriasis and other indications, including but not limited to 
oral retinoids, methotrexate, systemically administered calcineurin inhibitors (e.g. 
ciclosporin), or oral or parenteral corticosteroids 
4. Any topical therapy for psoriasis:  
a. Topical steroids of any strength  
b. Other topical therapies for psoriasis (e.g., calcineurin inhibitors and vitamin D 
analogues), with the exception that bland emollients without urea or beta or 
alpha hydroxy acids are allowed  
c. Shampoos with steroids  
10.7 
Rescue treatment 
No rescue medication is allowed. It will be at the discretion of the investigator to ensure 
treatment of subjects who discontinue the trial/IMP or ensuring that the subjects are referred 
to other physician(s) according to standard practice.  


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10.8 
Dose modification and investigational medicinal product 
discontinuation rules 
Please refer to Section 9.5 for general procedures related to IMP discontinuation. Medical 
reasons for IMP discontinuation are described below. 
10.8.1 
Reason for discontinuation of investigational medicinal product  
Subjects must be discontinued from IMP in the event of: 
 
Anaphylactic reaction or other severe systemic reaction to IMP. 
 
An AE that, in the opinion of the investigator or sponsor’s medical expert, 
contraindicates further dosing. 
 
Diagnosis of a malignancy during the trial, excluding carcinoma in situ of the cervix, 
or localised squamous or basal cell carcinoma of the skin. 
 
Evidence of pregnancy. 
 
Any infection that is opportunistic, such as active tuberculosis and other infections 
whose nature or course may suggest an immuno-compromised status. 
 
Severe laboratory abnormalities: 
a) ALT and/or AST values >3× ULN with total bilirubin >2× ULN  
(unless elevated bilirubin is related to Gilbert-Meulengracht Syndrome). 
b) Confirmed AST and/or ALT >5× ULN (for more than 2 weeks). 
 
If a subject is found to have any suicidal behaviour (actual suicide attempts, 
interrupted attempts, aborted attempts, or preparatory actions) or any suicidal 
ideation of level 4 (active suicidal ideation with some intent to act, without specific 
plan) or level 5 (active suicidal ideation with specific plan and intent) on any eC-
SSRS assessment, the subject must be discontinued and referred to a mental health 
professional. 
 
If a subject is found to have a PHQ-8 score of ≥15, corresponding to moderately 
severe to severe depression, the subject must be withdrawn and referred to a mental 
health professional. 
10.8.2 
Specific to subjects allocated to fumaric acid esters 
Progressive multifocal leukoencephalopathy (PML) cases have occurred with fumaric acid 
esters and other products containing fumarates in the setting of moderate to severe prolonged 


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lymphopenia. PML is an opportunistic infection caused by John-Cunningham virus, which 
may be fatal or result in severe disability. Hence: 
 
If the lymphocyte count drops below 0.7×109/L, the dose should be halved. If during 
a follow-up check after 4 weeks the lymphocyte count remains below this value, 
then treatment with fumaric acid esters must be discontinued.  
 
If the lymphocyte count drops below 0.5×109/L, treatment with fumaric acid esters 
must be discontinued. 
 
If the leukocyte cell count drops below 3×109/L, treatment with fumaric acid esters 
must be discontinued immediately. 
 
Subjects should be discontinued from treatment with fumaric acid esters if any of the 
following applies: 
a) Blood creatinine levels > ULN. 
b) Clinically significant changes in haematology values or confirmed proteinuria or 
haematuria not related to an ongoing urinary tract infection or renal 
calculus/nephrolith (at the discretion of the investigator). 
10.9 
Treatment logistics and accountability 
10.9.1 
Labelling and packaging of investigational medicinal product 
The labelling of IMPs will be in accordance with Annex 13, local regulations and trial 
requirements. Details are provided below: 
Brodalumab 
Brodalumab will be packaged in individually numbered kits. The brodalumab pack size 
includes 2 pre-filled syringes packed in blank white cartons.  
Each syringe will be labelled with a single panel label that allows the level of fluid in the 
syringe to be visible. 
Each kit carton will be labelled with one single panel label and tamper sealed. 
Fumaric acid esters  
Fumaric acid esters will be packaged in individually numbered kits. The Fumaric acid esters 
pack sizes include either 40 tablets per pack (Fumaderm® Initial; 4 blister packs each 
containing 10 tablets) or 70 tablets per pack (Fumaderm®; 7 blister packs each containing 
10 tablets) and both types are packed in original commercial cartons. 


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Each blister will be labelled with a single panel label. 
Each carton will be labelled with a single panel label and tamper sealed. 
10.9.2 
Storage of investigational medicinal products  
At clinical trial site 
All LEO supplied IMPs must be stored in a secure and restricted area under the conditions 
specified on the label and remain in the original container until dispensed. 
Brodalumab must be stored at 2-8°C (protected from light) and fumaric acid esters at ≤25°C 
at the site. The temperature during storage must 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.  
Temperature should be checked at least every working day. 
Transport from site to subject’s home 
The subjects’ randomised to brodalumab treatment will receive a cooler bag for transportation 
of brodalumab from site home of the subject.  
10.9.3 
Drug accountability  
The investigator is fully responsible for the accountability of IMPs at the trial site by 
continuously documenting all transactions using IWRS.  
Dispensing of IMPs may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
Fumaric acid esters: The subject must bring used, partly used, and unused IMP including 
empty packaging material at every site visit for compliance check. At every dispensing visit 
and at the end of treatment (visit 12), the subject must return all used, partly used, and unused 
IMP including empty packaging material to the site.  
Brodalumab: The subject must bring only unused and empty packaging material of 
brodalumab at every dispensing visit (visit 2, 8, 9, 10, and 11). Used syringes should be 
discarded in disposal containers. At end of treatment (visit 12), the subject must return all 
unused IMP, empty packaging material, and disposal containers containing used IMP.  
Returned IMP (used/partly used or unused IMP including empty packaging material) can be 
stored at room temperature and must be stored separately from non-allocated IMP. At end of 
treatment (visit 12), disposal containers and cooler bags must be returned by the subject.  


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All IMPs supplied by the contract manufacturing organisation (CMO) on behalf of LEO must 
be returned to the CMO. Prior to their return, they must be fully accounted for by the monitor 
with the help of the person responsible for dispensing the IMPs. Accountability must be 
documented by using drug accountability forms. The CRA will only do drug accountability by 
verifying the drug accountability performed by the investigator or designated site staff. 
IMPs may be returned from the trial site either to the CMO directly or via the LEO Pharma 
A/S affiliate or CRO responsible for running the clinical trial. 
10.9.4 
Investigational medicinal product destruction 
Used and unused IMP(s) will be destroyed by the CMO according to approved procedures. 
10.9.5 
Treatment compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures 
and requirements to ensure subject treatment compliance.  
Treatment compliance will be assessed by monitoring of drug accountability, see 
Section 10.9.3, and from interviewing the subjects. 
If a subject is found to be non-compliant, the (sub)investigator should remind the subject of 
the importance of following the instructions given, including taking the IMPs as prescribed. 
Compliance/non-compliance and the reason for it must be recorded in the eCRF. 
The date of first dose of IMP (baseline visit/Day 0) must be recorded in the eCRF.  
For subsequent visits in the treatment phase, the investigator must record the latest date of 
IMP administration and total daily dose relative to the specific visit in the eCRF. 
For subjects randomised to brodalumab: The investigator must ask the subject about each 
dose and whether the full dose was injected. This should be recorded in the eCRF as either 
full dose, partial dose, or no dose injected. If either partial or no dose was injected, a reason 
for not injecting the full dose must be provided. 
 
For subject randomised to fumaric acid esters: During the treatment phase (from baseline 
to Week 24), the investigator must record the prescribed total daily dose of fumaric acid esters 
in the eCRF. Based upon the effect and adverse events reported by the subject, the 
investigator should make individual dose adjustment. The investigator must also record 
whether or not the subject follows the prescribed dosing instruction. Reason for deviation 
from prescribed dose instructed to the subject must be recorded in the eCRF (AE, optimal 


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effect, or other). If the reason for deviation is an AE, this AE should be reported according to 
Section 12.2. 
10.10 
Provision for subject care following trial completion  
To ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice.  
10.11 
Reporting product complaints 
Any defects or issues with the IMP as well as any device deficiency (including malfunctions, 
use errors, and inadequate labelling) must be reported to Global Pharmacovigilance, LEO on 
the trial-specific (paper) Complaint Form within 3 days of first knowledge. 
Critical complaints (defined as any issue, defect, or device deficiency that has or potentially 
could have a serious impact for the subject [e.g., SAE or large particles in the syringe]) must 
be reported to Global Pharmacovigilance, LEO within 24 hours. 
Complaint forms should contain a detailed description of the defect, issue, or device 
deficiency, including whether it led to an AE. (S)AEs which occur due to a defect or issue 
with the IMP or due to a device deficiency will be reported by the investigator as described in 
Section 12.2. 
Refer to the pharmacy manual for information on how to update the kit status in the IWRS. 
During the investigation of the product complaint, the device must be stored at labelled 
conditions unless otherwise instructed; the trial site will be notified whether the device needs 
to be returned for further investigation or may be destroyed. 
Global Pharmacovigilance, LEO contact information for reporting product complaints: 
Fax number: +45 7226 3287 
E-mail address: drug.safety@leo-pharma.com 


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11  Trial schedule and assessments 
11.1 
Overview 
Overview of the assessments and procedures applicable to each visit is outlined in Panel 2. 
Specific details for each assessment and procedure are described in the following sections.  
During the course of the trial from screening to the follow-up visit (Week 26/32), unscheduled 
visits may be needed. It is at the discretion of the investigator to decide which assessments 
should be performed at an unscheduled visit.  
Assessments/procedures at any trial visit must be performed in the following order:  
 ePRO: DLQI must be completed by the subject prior to all other trial procedures 
 Investigator-blinded assessments (performed only by adequately trained investigators; 
the same investigator should perform all the evaluations for a given subject throughout 
the entire trial period) 
 Safety and laboratory assessments 
 Other assessments and procedures 
 ePRO: eC-SSRS and PHQ-8 should be completed by the subject after AE reporting has 
been completed. Investigator must review the questionnaires and take action, if required, 
before subject is sent home (see Section 11.4.2). 
11.2 
Assessments performed only at screening/baseline 
11.2.1 
Demographics  
At screening (visit 1) the following demographic details will be recorded: 
 Month and year of birth 
 Sex 
 Race: American Indian or Alaska Native; Asian, Black or African American; Native 
Hawaiian or Other Pacific Islander; White; Other 
 Ethnicity: Hispanic or Latino; Not Hispanic or Latino 
11.2.2 
Height  
The subject’s height must be measured in cm (without shoes). The height must be measured 
using a calibrated meter. 


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11.2.3 
Medical history 
Relevant past and concurrent medical illness must be recorded based on subject interview. 
The duration of psoriasis will be recorded (to the nearest whole year).  
11.3 
Concomitant medication and procedures 
Use of concomitant medication must be recorded in the subject’s medical record and the 
eCRF (e.g. treatment/drug name, route of administration, total daily dose, indication and dates 
of start and stop). 
For details about previous anti-psoriatic therapy see Section 10.5. 
11.4 
Efficacy assessments 
11.4.1 
Blinded assessments 
The blinded assessor must make the following assessments at visits specified in the schedule 
of trial procedures: PASI, sPGA, BSA and NAPSI (see Panel 2). The assessments will be 
captured in the eCRF. 
The blinded assessor who performs the assessments must be a medically qualified physician 
trained in the assessments and must remain blinded towards treatment of the subject through 
the course of the trial. If possible, each subject should have their assessments done by the 
same assessor throughout the trial. Extra care should be taken to ensure that the same assessor 
performs the baseline and end of treatment assessments (Week 24), where the co-primary 
endpoints data is collected. If necessary, trial visits may be rescheduled within the specified 
window to accommodate when the specific assessor will be available. 
The trial site will maintain a written plan detailing which staff members are blinded/unblinded 
and the process of IMP administration used to maintain the blind. 
11.4.1.1 Psoriasis Area and Severity Index (PASI) 
The blinded assessor will assess the extent of psoriasis and the severity of the clinical signs 
(redness, thickness and scaliness) by body region (head and neck, upper extremities, trunk, 
and lower extremities).  
The extent of psoriatic involvement will be recorded for each of the four regions (head and 
neck, upper extremities, trunk, and lower extremities) using the following scale: 


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Panel 7  Psoriasis area and severity index – Extent 
Score 
Extent of psoriatic 
involvement 
0 
No involvement 
1 
<10% 
2 
10 - 29% 
3 
30 - 49% 
4 
50 - 69% 
5 
70 - 89% 
6 
90 - 100% 
 
This assessment of extent is the percentage of that body region that is affected and not the 
percentage BSA affected. For example, if one arm was totally affected, and the other arm was 
totally unaffected, the extent assessment for the arms would be 50% (half of the arms 
affected). 
Note: 
‘head and neck’ includes head and neck 
‘upper extremities’ includes arms and hands 
‘trunk’ includes the axilla and groin 
‘lower extremities’ includes legs including the buttocks and feet 
The severity of the psoriasis in each of the four regions (head and neck, upper extremities, 
trunk, and lower extremities) will be recorded for each of the signs of redness, thickness and 
scaliness. For each clinical sign, a single score reflecting the average severity of all psoriatic 
lesions on the given body region will be determined according to the scale below: 


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Panel 8  Psoriasis area and severity index – Severity 
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)] 
 
Based upon the PASI score at randomisation the investigator must evaluate eligibility, see 
inclusion criterion 4. 
11.4.1.2 Static Physician’s Global Assessment of disease severity (sPGA) 
The blinded assessor will make a global assessment of the disease severity of psoriasis using 
the 6-point scale below. This assessment will represent the average lesion severity on the 
trunk and limbs. 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. 


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Panel 9  Static physician’s global assessment of disease severity 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 chickening; 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 
 
11.4.1.3 Assessment of the body surface area involvement (BSA) 
The investigator must first evaluate eligibility of the inclusion criterion for the BSA before 
evaluating the total psoriatic involvement on the head and neck, upper extremities, trunk, and 
lower extremities.  
The blinded assessor will use the surface area of the subject’s hand (palm and fingers) as a 
reference measurement to calculate the percentage of each body region that is affected by 
psoriasis. One hand is approximately equal to 1% total BSA. 
Furthermore, the complete body surface area (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%).  
11.4.1.4 Nail Psoriasis Severity Index (NAPSI) 
The NAPSI scale is an objective, numeric, and reproducible grading system for nail psoriasis 
that incorporates the many different features of nail psoriasis. For assessments in this trial 
(including selection of target nail), a nail is graded using the NAPSI scale by first dividing the 
nail area with imaginary horizontal and vertical lines into 4 quarters. The following 8 clinical 
features of nail psoriasis are then scored based on the number of quarters in which the feature 
is present (0 to 4) to arrive at a NAPSI score of 0 to 32 for each nail: 
 pitting 
 leukonychia 
 red spots in lunula 


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 nail plate crumbling 
 oil drop (salmon patch) discoloration 
 onycholysis 
 nail bed hyperkeratosis 
 splinter haemorrhages 
In randomised subjects with nails involved with psoriasis, each nail will be scored at baseline 
to determine the worst nail (i.e., the nail with the highest NAPSI score). Those subjects whose 
nail with the highest NAPSI score is 6 or above at baseline visit will have this nail (the target 
nail) followed for the remainder of the trial. If multiple nails have the same highest score, 
only 1 target nail will be followed. Subjects whose nail with the highest NAPSI score is 5 or 
less will not have a designated target nail. 
11.4.2 
Patient reported outcomes – Efficacy and safety 
The subject must make self-assessments at visits specified in the schedule of trial procedures 
(Panel 2). 
The following assessments will be done by the subject and must be completed prior to any 
other procedure at the applicable visit. An ePRO tablet will be provided to the sites for the 
subject to use when answering the PROs at site. 
11.4.2.1 Dermatology Life Quality Index (DLQI) 
The DLQI is a validated questionnaire with content specific to subjects with dermatology 
conditions (Finlay and Khan, 1994; Appendix 5B). It consists of 10 items addressing the 
subject’s perception of the impact of their skin disease on different aspects of their quality of 
life over the last week such as dermatology-related symptoms and feelings, daily activities, 
leisure, work or school, personal relationships, and the treatment. Each item is scored on a 4 
point Likert scale (0 = not at all ⁄not relevant; 1 = a little; 2 = a lot; 3 = very much). The total 
score is the sum of the 10 items (0 to 30); a high score is indicative of a poor quality of life. 
The DLQI takes about 2 minutes to complete. 
The investigator must evaluate eligibility of the inclusion criterion for the DLQI. 
11.4.2.2 Patient Health Questionnaire-8 (PHQ-8) 
The PHQ-8 is a validated and widely used 8 item version of the Patient Health Questionnaire 
depression scale designed to clinically assess patients for symptoms and signs of depression 
(Kroenke et al. 2009; Appendix 5C). 


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The PHQ-8 takes approximately 3 minutes to complete. 
PHQ-8 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; Kroenke et al. 2009). 
Subjects scoring ≥15, corresponding to moderately severe to severe depression, must in 
addition be withdrawn from the trial, see Section 10.8.1. 
11.4.2.3 Electronic self-rated version, Columbia-Suicide Severity Rating 
Scale (eC-SSRS) 
The eC-SSRS is a standardized and validated instrument developed for the assessment of the 
severity and frequency of SIB (Mundt et al. 2010, Posner et al. 2011).  
The eC-SSRS divides SIB into suicidal ideation (level 1-5), suicidal behaviour, and non-
suicidal self-injurious behaviour: 
Suicidal ideation 
 Level 1: Wish to be dead or not to wake up 
 Level 2: Non-specific thoughts 
 Level 3: Specific thoughts of method 
 Level 4: Some intent to act, no plan 
 Level 5: Specific plan and intent 
Suicidal behaviour  
 Actual suicide attempts 
 Interrupted attempts 
 Aborted attempts 
 Preparatory actions 
Non-suicidal self-injurious behaviour 
  Non-suicidal self-injurious behaviours 
 
The eC-SSRS takes approximately 3 to 10 minutes to complete.  
At all visits with scheduled assessment of SIB, using the eC-SSRS, the questionnaire must be 
filled by the subject after all other visit activities have been completed.  


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Any positive finding in suicidal ideation of level 4 or 5 or any positive finding in history of 
suicidal behaviour must be reported as an AE and the subject referred to a mental health 
professional and withdrawn from the trial, see Section 10.8.1.  
Documentation of the training and certification must be archived in the investigator trial file. 
This documentation must be in place before any eC-SSRS results are evaluated by the 
investigator. 
11.4.2.4 Psoriasis symptom inventory (PSI) 
Subjects will use an ePRO device to record their daily psoriasis symptoms using the PSI, a 
psoriasis specific patient reported outcome measure that has been developed on the basis of a 
literature review, in-depth physician interviews, psoriasis patient focus groups, and cognitive 
interviews (Bushnell et al. 2013; Appendix 5A).  
The PSI consists of eight psoriasis-specific questions. Subjects will be requested to rate the 
severity of their symptoms in the last 24 hours from ‘not at all’ to ‘very severe,’ ranging from 
0 to 4. Total scores range from 0 to 32 with higher scores indicating worse symptoms.  
The PSI takes about 3 minutes to complete.  
Site staff will train the subject on the proper use of the ePRO device at the baseline visit. 
Subjects should be instructed to complete the PSI once per day. The ePRO must be completed 
in the evening within a specified time window (for the early termination visit only, the PSI 
may be completed earlier in the day). 
The investigator should not question the subject’s answers. The investigator must review the 
data for timeliness and completeness. 
Symptoms reported on the PSI 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?” All data collected as part of the PSI will be reported in the trial 
report. 
11.5 
Safety assessments 
11.5.1 
Vital signs 
Following vital signs must be measured:  


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e) Blood pressure (BP), systolic and diastolic (mmHg) 
f) Heart rate (beats per minute) 
g) Temperature (Celsius with one decimal)  
h) Respiration rate (beats per minute) 
 
The vital signs must be assessed after approximately 5 minutes in a resting position.  
 
Clinically significant abnormal vital signs at the screening visit will be documented as 
medical history in the eCRF (see Appendix 4D). If an abnormal vital sign 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 12.2. 
11.5.2 
Physical examination 
An abbreviated physical examination will be performed by the investigator and must include:  
i) General appearance 
j) Lymph nodes 
k) Dermatologic examination of the skin  
 
Clinically significant abnormal findings at the screening visit will be documented as medical 
history in the eCRF (see Appendix 4D). 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 12.2. 
11.5.3 
Weight 
The subjects must be wearing indoor clothing without shoes when weight is determined 
(kilograms, one decimal).  
11.5.4 
Pregnancy test 
Female subjects of childbearing potential must have a serum beta hCG performed at the trial 
site at the screening visit (visit 1). An urine pregnancy test must be performed at visits 
described in the schedule of trial procedures (see Panel 2). In case of a positive urine test, a 
serum beta hCG must be performed for the purpose of confirmation. 
11.5.5 
Adverse events 
AEs must be assessed and recorded as specified in Section 12. 


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11.6 
Other safety assessments 
11.6.1 
Laboratory testing 
11.6.1.1 Safety laboratory blood analysis 
Blood samples will be drawn for analysis of laboratory parameters according to the schedule 
of trial procedures (Panel 2). 
The following blood sample tests will be analysed at central laboratory: serum chemistry, 
haematology, serum pregnancy, urinalysis (incl. urine pregnancy tests). 
The central laboratory will provide a trial specific laboratory manual that outlines handling, 
labelling, and shipping procedures for all samples. All blood samples will be obtained by 
venepuncture before IMP administration. The date and time of sample collection will be 
recorded in the source documents at the site.  
The serum chemistry, haematology and other tests are listed below: 
Panel 10  Analysts 
Chemistry  
Haematology and differential 
Other 
Sodium 
Potassium 
Magnesium 
Bicarbonate 
Albumin 
BUN 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alk phosphatase 
AST 
ALT 
CRP 
RBC 
Haemoglobin 
Haematocrit 
Platelets 
WBC 
Differential (absolute count and %):  
 
- 
Neutrophils 
- 
Lymphocytes 
- 
Monocytes 
- 
Eosinophils 
- 
Basophils 
Serum beta hCG 
QuantiFERON-TB Gold  
 
The investigator must evaluate all results outside the reference range (‘clinically significant’ 
or ‘not clinically significant’) and sign and date. The signed and dated version of the lab 
results will be filed with the investigator’s trial documentation. If a laboratory result is 
abnormal and of clinical significance, it will be up to the investigator’s discretion to decide if 
the subject should be enrolled into the trial.  
Clinically significant abnormal laboratory results at the screening visit will be documented as 
medical history in the eCRF (see Appendix 4D). If an abnormal laboratory results are found at 
any other visit than the screening visit is considered by the investigator to be clinically 


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significant, it will be reported as an AE in accordance with the principles for data entry in 
Section 12.2. 
The laboratory provides results to the trial sites in SI units. 
Handling, storage, destruction and shipment instructions are provided in a separate laboratory 
manual. 
11.6.1.2 Estimate of total blood volume collected 
Blood samples will be drawn for haematology, biochemistry and other tests. The blood 
volume at each visit depends on the visit and will vary from 6.0 mL to 12.0 mL. The total 
volume of blood drawn over the entire trial duration will be approximately 60 mL, which is 
less than the volume of blood drawn during a single blood donation (approximately 500 mL). 
11.6.1.3 Safety urinalysis 
Urine samples will be taken for analysis of the parameters listed below, at the visits specified 
in the schedule of trial procedures (Panel 2). 
Panel 11  Urine analysis 
Urine:  
-Specific gravity 
-pH 
-Occult blood 
-Protein 
-Glucose 
-Leucocyte esterase 
-Ketones  
-Urine pregnancy tests 
 
12  Adverse events 
 
AEs and serious adverse events (SAEs) are defined in Appendix 2: Definitions of 
adverse events and serious adverse events. 
 
Classification of AEs in terms of severity, causality and outcome are defined in 
Appendix 3: Classification of adverse events. 
12.1 
Collection of adverse events 
AEs must be collected from time of first trial related activity after the subject has signed the 
informed consent form until completion of the clinical trial. Hence, until the follow-up visit 


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scheduled at Week 32 for subjects allocated to brodalumab and at Week 26 for subjects 
allocated to fumaric acid esters. 
AEs must be assessed by medically qualified personnel. 
At all visits, the subject will be asked a non-leading question by the (sub)investigator about 
AEs, for example: “How have you felt since I saw you last?” No specific symptoms should be 
asked for.   
12.2 
Reporting of adverse events  
AEs reported by the subject or observed by the (sub)investigator must be recorded on the AE 
form of the eCRF and should be described in the following manner: 
The AE term will be in precise English medical terminology (i.e. 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. In 
addition, it must be recorded whether the AE started prior to start of IMP. 
AEs must be classified in terms of severity, causality and outcome according to the definitions 
in Appendix 3: Classification of adverse events. 
12.2.1 
Actions taken as a consequence of an AE 
Action taken with trial treatment: Any action taken with IMP as a consequence of the AE 
must be recorded (dose not changed, dose reduced, dose increased, drug interrupted, drug 
withdrawn, not applicable or unknown). 
Other action taken: any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concomitant procedure). 
Withdrawn due to AE: it must be recorded whether the AE leads to withdrawal from the trial. 
12.2.2 
Reporting of serious adverse events 
The criteria that define an AE as serious (i.e. an SAE) are defined in Appendix 2: Definitions 
of Adverse Events and Serious Adverse Events 


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12.2.2.1 Investigator reporting responsibilities 
Any SAE must be reported to LEO on the (paper) ‘SAE Form – Clinical Trials’ within 24 
hours of first knowledge. This report should contain an assessment of available information 
on seriousness, severity, causal relationship to the IMP, comparator or trial procedure, the 
action taken, the outcome to date, and a narrative description of the course of the event. 
The completed SAE form must be faxed or scanned and e-mailed to Global 
Pharmacovigilance LEO, using the following fax number or e-mail address: 
 
E-mail address: drug.safety@leo-pharma.com 
 
Fax number: +45 7226 3287  
It may be relevant for the (sub)investigator to enclose other information with the SAE form, 
such as anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
Additionally, Global Pharmacovigilance LEO may request further information in order to 
fully assess the SAE. The (sub)investigator must forward such information to Global 
Pharmacovigilance, LEO upon request by fax or e-mail (see contact details above). 
The investigator must notify the local independent ethics committee(s) (IEC(s)) of SAEs as 
required by current applicable legislation for the concerned country. 
SAEs occurring after the completion of the clinical trial (i.e. after the safety follow-up visit 
defined in Section 11.1) should not be routinely sought or collected. However, such events 
must be reported, without undue delay, to Global Pharmacovigilance LEO (see contact details 
above) if the investigator becomes aware of them.  
12.2.2.2 LEO reporting responsibilities 
Global Pharmacovigilance, LEO is responsible for assessing whether or not an SAE is 
expected. The relevant reference documents for this clinical trial are:  
 For brodalumab, the latest version of the company core safety information  
 For fumaric acid esters, the latest version of the SmPC for Fumaderm® 
  
The reference safety information for brodalumab (Appendix 6) is based on the company core 
data sheet (CCDS). The CCDS is chosen to ensure consistency in case evaluation and 
assessment of listedness/expectedness for different trials and spontaneous reporting. Further, 
changes to the safety profile are implemented in the CCDS immediately. 


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Global Pharmacovigilance, LEO will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation in Germany. 
The IEC(s) will be notified of SAEs according to the current applicable legislation in 
Germany.  
All SAEs which are assessed as causally related to the IMP(s) by either the investigator or 
LEO, as described in the ICH E2A guideline, 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 Germany. 
Investigators will be notified of these on an ongoing basis. 
12.3 
Other events that require expedited reporting to LEO 
12.3.1 
Pregnancy 
Any pregnancy occurring during the clinical trial must be reported to LEO within 24 hours of 
first knowledge using the (paper) Pregnancy Follow-up Form (Part I). All such pregnancies 
must be followed up until delivery or termination and final outcome must be reported on the 
(paper) Pregnancy Follow-up Form (Part II) within 24 hours of first knowledge. 
The completed Pregnancy Follow-up Forms must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO (see Section 12.2.2.1 for contact details).  
Pregnant subjects must discontinue IMP. 
12.3.2 
Adverse events of special interest 
The following four adverse events of special interest (AESI) have been defined: SIB, serious 
infections, MACE defined as stroke, myocardial infarction, or cardiovascular death), and 
malignancy. These 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. 
The events might require that the investigator provides additional information to LEO (see 
Panel 12). 
All AESI must be reported to LEO within 24 hours (see Section 12.2.2.1) 


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Panel 12  Adverse events of special interest 
Adverse event of special interest 
Additional information to be provided 
SIB 
This AESI may be serious or non-serious. A specific adverse event 
form will need to be filled out whenever a SIB event is reported. 
This form will also include specific event related questions.  
Serious infections 
No additional information except for the described procedure for 
serious adverse event. 
MACE 
No additional information except for the described procedure for 
serious adverse event. 
Malignancy diagnosed after 
randomisation (except basal cell 
carcinoma, squamous cell 
carcinoma, and cervical carcinoma in 
situ)  
Procedure as described for serious adverse event including: 
Histology report 
Oncology assessment 
Treatment (surgery, radiation, chemotherapy, other) 
 
12.4 
Reporting of other events  
12.4.1 
Overdose 
An overdose is defined as a subject receiving a dose of IMP in excess of that specified in this 
protocol. 
The term overdose must be documented on the AE form of the eCRF. In addition, AEs 
originating from overdose must be documented on a separate line. If the AE originating from 
overdose is serious expedited reporting is required (see Section 11.2.2.1). 
In the event of an overdose, the patient should be monitored and treated symptomatically, and 
supportive measures instituted to the discretion of the investigator  
12.4.2 
Medication error 
Medication error refers to any unintentional error in the dispensing or administration of a 
medicinal product while in the control of the (sub)investigator or subject. Broadly, medication 
errors fall into four categories: wrong medication, wrong dose (including strength, form, 
concentration, and amount), wrong route of administration, or wrong subject. 
The medication error specifying the category of error (see definitions above) must be 
documented on the AE form of the eCRF. In addition, AEs originating from a medication 
error must be documented on a separate line. If the AE originating from medication error is 
serious expedited reporting is required (see Section 12.2.2.1). 


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12.4.3 
Misuse 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
The term misuse must be documented on the AE form of the eCRF. In addition, AEs 
originating from misuse must be documented on a separate line. If the AE originating from 
misuse is serious expedited reporting is required (see Section 12.2.2.1). 
12.4.4 
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 documented on the AE form of the eCRF. In addition, AEs 
originating from abuse must be documented on a separate line. If the AE originating from 
abuse is serious expedited reporting is required (see Section 12.2.2.1). 
12.4.5 
Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s), 
compared to baseline, must be reported as an AE. If the AE originating from aggravation of 
condition is serious expedited reporting is required (see Section 12.2.2.1). 
12.4.6 
Lack of efficacy 
Not applicable.  
12.5 
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 possible/probable related to the investigational 
product for 8 weeks after last treatment for brodalumab or for 2 weeks after last treatment for 
fumaric acid esters, or until the final outcome is determined, whichever comes first. SAEs 
must be followed up until a final outcome has been established, i.e. the follow-up may 
continue beyond the end of the clinical trial. For SAEs which have stabilised and cannot be 
expected to recover during trial or safety follow-up periods, for example chronic illnesses, the 
final outcome should be considered recovered and a statement that the SAE has stabilised 
should be added to the narrative in the SAE form. Please note that the event should not be 
reported as 'recovered' in the eCRF and on the SAE form. 


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12.6 
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 within the EU Directive 2001/20/EC 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.” (EU 2001/20/EC, article 10).  
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, regulatory authority(ies), or IEC(s). 
The investigator must immediately inform LEO - 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 must act immediately upon receipt of the urgent safety measure notification in 
accordance with the internal procedures, which are based on the EU guideline. 
13  Statistical methods 
13.1 
Sample size 
The effect on psoriasis symptoms of subcutaneous injections of brodalumab will be compared 
to oral administration of fumaric acid esters in subjects with moderate to severe plaque 
psoriasis who are naïve to systemic treatment.  
Formally, this will be formulated by testing the null hypotheses of equality of proportion of 
PASI 75 response and sPGA (0 or 1) success to treatment with brodalumab compared with 
treatment with fumaric acid esters; against the alternative hypothesis that the two proportions 
differ. 
The sample size is determined using Fisher's exact test for the two independent proportions 
under the assumption of a two-sided test of size 5%. Based on experience from previous trials 
with brodalumab and fumaric acid esters in subjects with moderate to severe psoriasis, 
conservative estimates for the proportion of PASI 75 responders of 80% for brodalumab and 
between 50% and 70% for fumaric acid esters (Nast et al. 2012) are used in the sample size 
calculation (using Proc Power in SAS version 9.4). Assuming a dropout rate of 50% for 


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fumaric acid esters, a PASI 75 response rate combined with NRI will correspond to a total rate 
of responders of 25%. A dropout rate of less than 40% with brodalumab, a PASI 75 response 
rate will correspond to a total rate of responders of 48%. 
For sPGA, the expected rate of sPGA success is 37.4% with fumaric acid esters (Mrowietz 
and Szepietowski et al. 2017), while varying rates above 60% has been seen in the previous 
brodalumab trials. 
An overview of the estimated power within the given spread of response rates, is presented in 
Panel 13. 
Panel 13  Estimated power by sample size and response rate (number of subjects per 
group) 
 
PASI 75 Fumaric acid 
esters response rate = 
50% (total response 
rate = 25%) 
PASI 75 Fumaric acid 
esters response rate = 
60% (total response 
rate = 30%) 
PASI 75 Fumaric acid 
esters response rate = 
70% (total response 
rate = 35%) 
sPGA success 
Fumaric acid 
esters response 
rate = 37.4% 
N = 91 
0.873 
0.652 
0.372 
0.833 
N = 102 
0.910 
0.708 
0.416 
0.876 
N = 118 
0.947 
0.776 
0.476 
0.921 
N = 144 
0.978 
0.858 
0.566 
0.963 
 
Assuming independence between PASI 75 and sPGA the power to show superiority of 
brodalumab compared to fumaric acid esters will be 0.91*0.876 = 80% with 102 subjects in 
each treatment arm. 
13.2 
Trial analysis sets 
All subjects enrolled in the trial (i.e. subjects for whom informed consent has been obtained 
and who have been registered in the trial) will be accounted for in the clinical trial report. 
All subjects randomised are included in the full analysis set (FAS) and will be used for 
efficacy analyses. Exclusions from the FAS can be considered in special cases as described in 
ICH E9, Section 5.2.1. If it is decided to exclude a randomised subject from the FAS, a 
justification addressing ICH E9 will be given. Subjects contribute to the evaluation ‘as 
randomised’. 
A safety analysis (SAS) set will be defined as subjects receiving treatment with IMP. The 
decisions regarding inclusion/exclusion of subjects and/or subject data from the trial analysis 
sets will be documented in the statistical analysis plan update before breaking the 


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randomisation code/clinical trial report. Subjects in the safety analysis set contribute to the 
evaluation ‘as treated’.  
13.3 
Statistical analysis 
13.3.1 
Disposition of subjects 
A subject disposition will be made including information of number of subjects screened, 
randomised, exposed, completing and withdrawn (and reason for withdrawal), by treatment 
group and in total. This will also include number of subjects included in the FAS and safety 
analysis set, by treatment group and in total. 
13.3.2 
Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects by treatment group. Presentations of age, sex, ethnicity, race, and 
baseline efficacy assessment by treatment will also be given by centre. 
Demographics include age, sex, race, and ethnicity. Other baseline characteristics include vital 
signs (including height, weight, BMI), duration of psoriasis, concurrent diagnoses (from 
medical history and indications for concomitant medication), concomitant medication, and 
previous anti-psoriatic therapy.  
13.3.3 
Exposure and treatment compliance 
Relevant exposure, compliance and drug accountability data will be tabulated. 
13.3.4 
Endpoints 
In support of the objectives stated in Panel 3, the endpoints of the trial are prioritised as 
follows:  
Co-primary endpoints: 
 
At least 75% improvement from baseline at Week 24 in Psoriasis Area and Severity Index 
(PASI) 
 
Static Physician’s Global Assessment (sPGA) scale score of 0 or 1 at Week 24 
Secondary endpoints:  
 
At least 90% improvement from baseline at Week 24 in PASI 
 
100% improvement from baseline at Week 24 in PASI 
 
Change from baseline at Week 24 in PASI score 


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 
PASI improvement (%) from baseline at Week 24 
 
Change from baseline at Week 24 in affected body surface area (BSA) 
 
Psoriasis Symptom Inventory (PSI) responder at Week 24  
(total score ≤ 8, with no item scores > 1) 
 
PSI total score of 0 at Week 24 
 
Number of symptom-free days from randomisation to Week 24 (symptom-free day = daily 
total PSI of 0 on that day)  
 
Burden of symptoms assessed as the normalised area under the curve (AUC) of PSI from 
baseline to the last available assessment 
 
Change from baseline at Week 24 in Dermatology Life Quality Index (DLQI) total score 
 
DLQI total score of 0 or 1 at Week 24 
 
Frequency of AEs and SAEs by preferred term 
Other endpoints:  
 
Change from baseline at Week 24 in Nail Psoriasis Severity Index (NAPSI) total score 
13.3.5 
Analysis of primary endpoint 
The co-primary endpoints PASI 75 and sPGA (0 or 1) at Week 24 (end of treatment visit) will 
be evaluated on the FAS. 
Estimates and 95% confidence intervals (CI) for the response rates and treatment differences 
will be presented. The differences in response rates between treatment groups will be analysed 
using the Cochran-Mantel-Haenszel test with stratification by weight group (≥100 kg or <100 
kg). The null hypotheses of no difference in response rates between brodalumab and fumaric 
acid esters will be tested against the two-sided alternative that there is a difference on a 5% 
level. Subjects who drop-out of the trial before Week 24 (end of treatment visit) will be 
regarded as non-responders. A sensitivity analysis will be made where ineligible subjects 
randomised in error into the trial are excluded from the analysis. 
As supportive analyses for the co-primary endpoints, a logistic regression model with baseline 
PASI or sPGA and weight group will be performed, and further, the mixed model for repeated 
measurements (MMRM) for PASI described below will be used to predict PASI 75 for 
subjects without assessments at Week 24 for an additional Cochran-Mantel-Haenszel analysis. 
Finally, subjects who drop-out of the trial before Week 24 will be LOCF imputed and 
analysed using the Cochran-Mantel-Haenszel test.  


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The trial is considered a success if superiority is confirmed for both primary endpoints.  
13.3.6 
Analysis of secondary efficacy endpoints 
All binary endpoints will be analysed in a similar manner as the co-primary endpoints, by 
analysing the difference in response rates between treatment groups using the Cochran-
Mantel-Haenszel test.  
Continuous endpoints like absolute PASI score, % PASI improvement, and NAPSI 
improvement will be modelled by MMRM to compare treatments through Week 24. The 
mixed model will include treatment group, week, interaction between treatment and time, 
baseline PASI/NAPSI score, and baseline weight group as fixed factors. Within subject 
covariance will be estimated by an unstructured covariance matrix (if possible). 
Number of symptom-free days will be summarised.  
13.3.7 
Analysis of patient reported outcomes 
The PROs will be summarised by treatment and stratification group. Further DLQI, change 
from baseline will be compared between treatments by MMRM including treatment group, 
week, interaction between treatment and time, baseline DLQI score and baseline weight group 
as fixed factors. Within subject covariance will be estimated by an unstructured covariance 
matrix (if possible). DLQI total score of 0 or 1 will be analysed by a Cochran-Mantel-
Haenszel model adjusting for baseline weight group. 
The AUC for the PSI total score will be calculated for each subject using the standard 
trapezoidal rule. The AUC will be normalised by dividing with the time period from baseline 
to the last available assessment of the PSI total score. The normalisation converts the AUC to 
the original scale of the PSI total score. Missing assessments of the PSI total score in-between 
non-missing assessments will not be imputed, which corresponds to linear interpolation 
between the non-missing assessments of the PSI total score. The normalised AUCs will be 
analysed using an analysis of covariance (ANCOVA) with treatment group, baseline weight 
group and the baseline PSI total score as explanatory variables. 
13.3.8 
Analysis of safety 
The analysis of safety will be based on the safety analysis set. 


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13.3.8.1 Adverse events 
AEs will be coded during the trial according to the most recent version of Medical Dictionary 
for Regulatory Activities (MedDRA). All AEs will be presented by preferred terms (PT) and 
primary system organ class (SOC). 
Treatment-emergent AEs (TEAEs) will be summarised, however, all AEs recorded during the 
course of the trial will be included in the subject data listings. An event will be considered 
treatment-emergent if started on or after the first day of IMP and no later than 5 half-lifes after 
the last day on randomised treatment, or if started before the first use of IMP and worsened in 
severity thereafter. The tabulations described in the following will only include the treatment-
emergent events. 
An overall summary of the number of subjects with any TEAEs, the percentage of subjects 
with at least one event, the number of events and the event rate per 100 years will be 
presented. These summaries are done by SAEs, discontinuations from the trial due to AEs, 
treatment-related AEs, severe AEs, relation to device, outcome and AESIs. 
Where there are several recordings of a specific AE within a subject, severity will be taken as 
the most severe recording for that specific AE. If a subject experience more than one AE of 
the same type, all severity evaluations should be recorded. 
Where there are several recordings of causal relationship to a specific AE within a subject, 
causal relationship will be taken as the most-related recording from the last report of that AE.  
Related AEs are defined as AEs for which the (sub)investigator has not described the causal 
relationship to IMP as ‘not related’.  
Summary tables based on SOC and PT are made for all TEAEs, serious TEAEs, related AEs, 
severe TEAEs, TEAEs reported as AESIs, AEs leading to withdrawal, and TEAEs with 
preferred term that are experienced by at least 5% of the subjects in any treatment arm or by 
at least 5% of all subjects. 
Finally, relevant AE listings will be created. 
13.3.8.2 Other specific safety assessments 
Adverse events reported as injection site reactions will be summarised separately based on 
SOC and PT. Furthermore, a corresponding list will be created. 


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13.3.8.3 Vital signs and physical examinations 
The change in vital signs (BP, heart rate, body temperature and respiration rate) from baseline 
to Week 24 will be summarised as mean, standard deviation (SD), median, minimum and 
maximum values for each treatment group. 
Furthermore, a shift table for vital signs showing the change from baseline to Week 24 in 
clinical assessments (normal; abnormal, not clinical significant; abnormal, clinical significant) 
will be performed. 
Finally, a shift table for physical examinations (general appearance, lymph nodes and 
dermatologic examination) showing the change from baseline to Week 24 in clinical 
assessments (normal; abnormal, not clinical significant; abnormal, clinical significant) will be 
performed. 
13.3.8.4 Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline to Week 24 will be 
summarised as mean, SD, median, minimum and maximum values for each treatment group. 
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 Week 24. Subjects with 
laboratory parameters outside the reference range will be listed. 
13.3.9 
Interim analysis 
No interim analyses are planned. 
13.3.10 
General principles 
All statistical analyses of efficacy endpoints will be based on the FAS and safety endpoints on 
the safety analysis set (SAS). All significance tests will be two-sided using the 5% 
significance level. All CIs will be presented with 95% degree of confidence. No corrections 
for multiplicity will be performed. 
If not mentioned otherwise, endpoints will be summarised descriptively at each visit by 
treatment and in total. 
An observed-cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects who attended each specific visit). For categorical endpoints number of subjects 
not attending each specific visit will also be added. 


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Categorical data will be summarised using the number and percentage of subjects in each 
category. Continuous data will be summarised using the mean, median, SD, minimum, and 
maximum values. 
In general, for endpoints evaluated as change from baseline and/or where a baseline 
adjustment is applied, baseline is defined as information collected at the randomisation visit 
(Visit 2), if not otherwise stated. If the assessment is not available at the randomisation visit 
but at the screening visit (Visit 1) then this will be used instead. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
obtained and the statistical analysis plan update will be finalised before breaking the 
randomisation code. 
Any changes from the statistical analysis planned in this clinical trial protocol will be 
described and justified in the statistical analysis plan update (SAPU) and/or in the clinical trial 
report dependent on the type of deviation. 
For endpoints evaluated over time, plots will be made to explore the trajectory with time. 
13.3.11 
Handling of missing values 
Missing data for categorical endpoints will be imputed with non-responder imputation. 
Missing data for continuous endpoints will be dealt with by a mixed model for repeated 
measurements. 
14  References  
Augustin M, Reich K, Glaeske G, Schaefer I, Radtke M. Co-morbidity and age-related 
prevalence of psoriasis: Analysis of health insurance data in Germany. Acta Derm Venereol. 
2010;90(2):147-51. 
Bushnell DM, Martin ML, McCarrier K, Gordon K, Huang X et al Validation of the Psoriasis 
Symptom Inventory (PSI), a patient-reported outcome measure to assess psoriasis symptom 
severity. J Dermatolog Treat. 2013;24(5):356-60. 
Chiricozzi A, Romanelli M, Saraceno R, Torres T. No meaningful association between 
suicidal behavior and the use of IL-17A-neutralizing or IL-17RA-blocking agents. Expert 
Opin Drug Safety. 2016;15(12):1653-1659. 
Dubertret L, Mrowietz U, Ranki A, van de Kerkhof PC, Chimenti S, et al. EUROPSO Patient 
Survey Group. European patient perspectives on the impact of psoriasis: the EUROPSO 
patient membership survey. Br J Dermatol. 2006;155(4):729-36. 


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Fallah Arani S, Neumann H, Hop WCJ, Thio HB. Fumarates vs. methotrexate in moderate to 
severe chronic plaque psoriasis: a multicentre prospective randomized controlled clinical trial. 
Br J Dermatol. 2011;164(4):855–861. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure 
for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-6. 
Gisondi P, Tessari G, Conti A, Piaserico S, Schianchi S, et al. Prevalence of metabolic 
syndrome in patients with psoriasis: a hospitalbased case-control study. Br J Dermatol. 
2007;157(1):68-73. 
Gooderham M, Posso-De Los Rios CJ, Rubio-Gomez GA, Papp K. Interleukin-17 (IL-17) 
inhibitors in the treatment of plaque psoriasis: a review. Skin Therapy Lett. 2015;20(1):1-5. 
Gelfand JM, Troxel AB, Lewis JD, Kurd SK, Shin DB, et al. The Risk of Mortality in Patients 
With Psoriasis: Results From a Population-Based Study. Arch Dermatol. 2007; 143(12):1493-
1499. 
Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis.Lancet. 
2007;370(9583):263-71. 
Griffiths CE, Christophers E, Barker JN, Chalmers RJ, Chimenti S, et al. A classification of 
psoriasis vulgaris according to phenotype. Br J Dermatol. 2007;156(2):258-62. 
Kroenke K, Strine TW, Spitzer RL, Williams JBW, Berry JT, et al. The PHQ-8 as a measure 
of current depression in the general population. J Affect Disord. 2009;114(1–3):163–73. 
Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality 
of life. Ann Rheum Dis. 2005;64(Suppl 2):ii18-23;discussion II24-5. 
Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, et al. American Academy of 
Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis. 
Section 3. Guidelines of care for the management and treatment of psoriasis with topical 
therapies. J Am Acad Dermatol. 2009;60(4):643-59. 
Mrowietz U, Szepietowski JC, Loewe R, van de Kerkhof P, Lamarca R, Ocker WG, Tebbs 
VM, Pau-Charles I. Efficacy and safety of LAS41008 (dimethyl fumarate) in adults with 
moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, Fumaderm® - and 
placebo-controlled trial (BRIDGE). Br J Dermatol. 2017;176(3):615-623. 
Mrowietz U, Warren RB, von Kiedrowski R et al. An intensified dosing schedule of 
subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis 
(METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 
trial. Lancet. 2017;389(10068):528-537. 


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Mundt JC, Greist JH, Gelenberg AJ, Katzelnick DJ, Jefferson JW, Modell JG. Feasibility and 
validation of a computer-automated Columbia-Suicide Severity Rating Scale using interactive 
voice response technology. J Psychiatr Res. 2010;44(16):1224-8. 
Nast A, Boehncke W-HH, Mrowietz U, et al. (2012) S3 - Guidelines on the treatment of 
psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges. 2012;10(Suppl 2):S1–95. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, et al. The Columbia-Suicide 
Severity Rating Scale: initial validity and internal consistency findings from three multisite 
studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-77. 
Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the 
United States. J Am Acad Dermatol. 2014;70(3):512-6. 
Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: updated 
guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18. 
Smith D. Fumaric acid esters for psoriasis: a systematic review. Ir J Med Sci. 
2017;186(1):161-177. 
Walker F, Adamczyk A, Kellerer C, Belge K, Brück J, et al. Fumaderm® in daily practice for 
psoriasis: dosing, efficacy and quality of life. Br J Dermatol. 2014;171(5):1197–205. 


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15  List of appendices 
Appendix 1 Abbreviated eligibility criteria in accordance with CDISC requirements 
Appendix 2: Definitions of adverse events and serious adverse events 
Appendix 3: Classification of adverse events 
Appendix 4: Trial governance considerations 
Appendix 5 Questionnaires 
Appendix 6  Reference safety information 
Appendix 7 Contact list of LEO, protocol authors, vendors, trial committees and coordinating 
investigators 


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Appendix 1 Abbreviated eligibility criteria in accordance with CDISC 
requirements 
Inclusion criteria in accordance with CDISC requirements 
(see Section 9.2 and 9.3 for full eligibility criteria) 
# 
Short definition 
Detailed description 
1 
Signed and dated informed consent has been 
obtained. 
 
2 
Men or women ≥18 years of age at the time of 
screening. 
 
3 
Subjects with chronic plaque type psoriasis 
Chronic plaque type psoriasis means diagnosed for 
at least 6 months before randomisation   
 
4 
Subjects with moderate to severe plaque 
psoriasis in whom topical therapy only is not 
adequate and who are candidates for systemic 
therapy at randomisation 
Defined at randomisation by: 
- PASI >10 and  
- Affected BSA >10% and 
- DLQI >10 
5 
Subject has no known history of active 
tuberculosis. 
 
6 
Subject has a negative test for tuberculosis taken 
at screening (negative QuantiFERON test). 
 
7 
A female subject of childbearing potential is 
eligible to participate if she is not pregnant. This 
must be confirmed by a negative serum beta 
hCG pregnancy test at screening. 
Female subjects are considered of childbearing 
potential unless they have undergone hysterectomy, 
bilateral salpingectomy or bilateral oophorectomy, or 
have been post-menopausal for at least one year 
prior to first visit. 
8 
Female subjects of childbearing potential must 
be willing to use highly effective contraception 
at trial entry and until 15 weeks after end of 
treatment.  
For subjects randomised to fumaric acid esters: 
oral contraceptive pills must be used with an 
additional contraceptive method (e.g. condom by 
partner, diaphragm, contraceptive gel, vaginal 
ring, etc.) 
 
Highly effective contraception is defined as follows: 
• 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) 
• Bilateral tubal occlusion 
• An intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Combined (oestrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal) 
• Progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, 
injectable, implantable) 
9 
Male subject with a female partner of 
childbearing potential who is willing to use 
adequate contraceptive methods. Male subjects 
should not donate sperm in this period. 
Adequate contraceptive measures as required by 
local regulation or practice for at least 15 weeks 
following last dose of investigational product. 
10 
Subject and/or subject’s designee is/are capable 
of administering subcutaneous injections. 
 
 


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Exclusion criteria in accordance with CDISC requirements 
(see Section 9.2 and 9.3 for full eligibility criteria) 
# 
Short Definition 
Detailed description 
1 
Previous or current systemic treatment of plaque 
psoriasis or known contraindication for systemic 
therapy. 
 
2 
Previous or current PUVA (psoralens and 
ultraviolet A) therapy. 
 
3 
Washouts and non-permitted drugs:  
a) Have received phototherapy (UVA light therapy 
without psoralens, UVB light therapy, excimer 
laser, tanning beds etc.) within 4 weeks of 
baseline. 
b) Have had topical psoriasis treatment within 2 
weeks of baseline (exceptions: bland emollients 
without urea or beta or alpha hydroxy acids). 
c) Have received any biologic immune modulating 
treatment used for indication other than psoriasis 
within 4 weeks of baseline or within a period of 5 
half-lifes of the received treatment, whichever is 
longer. 
d) Have received any other systemic immune 
modulating treatment (including but not limited to 
oral retinoids, methotrexate, calcineurin inhibitors, 
oral or parenteral corticosteroids etc. used for 
indication other than psoriasis) within 4 weeks of 
baseline or within a period of 5 half-lifes of the 
received treatment, whichever is longer. 
4 
Clinically important active infections or 
infestations, chronic, recurrent or latent 
infections, infestations or immunocompromised 
(e.g. HIV). 
 
5 
Presence of significant uncontrolled cerebral, 
cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, haematologic, 
neurologic, or neuropsychiatric disorders.  
 
6 
Clinically significant abnormal values at 
screening within assessments of biochemistry, 
urine, and haematology (such as differential 
blood count and platelets) at the discretion of the 
investigator. 
 


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Exclusion criteria in accordance with CDISC requirements 
(see Section 9.2 and 9.3 for full eligibility criteria) 
# 
Short Definition 
Detailed description 
7 
Subjects with any of the following laboratory 
abnormalities at screening: 
a) Leukocyte cell count below 3×109/L or 
lymphocyte count below 0.7×109/L. 
b) Aspartate aminotransferase (AST) or 
alanine transferase (ALT) > 2× ULN 
(upper level of normal limit). 
c) Absolute neutrophil count < 2× 109/L. 
d) Serum creatinine > ULN. 
 
8 
Subjects with severe gastrointestinal diseases 
including, but not limited to, ventricular and 
duodenal ulcers. 
 
9 
Subject with a known history of Crohn’s disease 
or history of psoriatic arthritis with a need for 
treatment. 
 
10 
Planned surgery, which in the opinion of the 
investigator would influence the planned 
treatment of the IMP. 
 
11 
History of depressive disorder within the last 2 
years including current anti-depressive treatment. 
 
12 
Any positive finding in history of suicidal 
behaviour based on the C-SSRS questionnaire at 
screening or baseline. 
 
13 
Any positive finding in suicidal ideation of level 
4 or 5 based on the C-SSRS questionnaire at 
screening or baseline. 
 
14 
A PHQ-8 score of ≥10 corresponding to 
moderate to severe depression at screening or 
baseline. 
 
15 
History of cancer. 
a. Subjects who have had basal cell carcinoma, 
localised squamous cell carcinoma of the skin or in 
situ carcinoma of the cervix are eligible provided 
that the subject is in remission and curative therapy 
was completed at least 12 months prior to the date 
informed consent was obtained.  
b. Subjects who have had other malignancies are 
eligible provided that the subject is in remission 
and curative therapy was completed at least 5 years 
prior to the date informed consent was obtained. 
16 
Known or suspected hypersensitivity to 
component(s) of the IMPs. 
 


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Exclusion criteria in accordance with CDISC requirements 
(see Section 9.2 and 9.3 for full eligibility criteria) 
# 
Short Definition 
Detailed description 
17 
Current or recent involvement in other 
interventional clinical trial.  
Current participation in any other interventional 
clinical trial, ending another interventional clinical 
trial less than 4 weeks prior to screening visit, or 
receiving other investigational agents (based on 
interview of the subject). 
18 
Current or recent treatment with any non-
marketed drug substance. 
Subjects who have received treatment with any 
non-marketed drug substance (i.e. an agent which 
has not yet been made available for clinical use 
following registration) within the last 4 weeks 
prior to screening visit 
19 
Previously enrolled in this clinical trial. 
 
20 
In the opinion of the (sub)investigator, the 
subject is unlikely to comply with the clinical 
trial protocol (e.g. due to alcoholism, drug 
addiction or psychotic state). 
 
21 
Subjects being the member of or being in close 
affiliation with trial personnel, sponsor or CRO. 
Subjects in close affiliation with the trial personnel 
(e.g. immediate family member or subordinate), 
subjects being a member of the clinical trial 
personnel, or being an employee of the sponsor or 
a CRO involved in the trial. 
22 
Subjects under guardianship, hospitalised in a 
public or private institution, for a reason other 
than the research, or subject deprived of freedom. 
 
23 
Female subjects who are pregnant or 
breastfeeding. 
 
24 
Subject has any concurrent medical condition 
that, in the opinion of the investigator, could 
cause this trial to be detrimental to the subject 
 


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Appendix 2: 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. (ICH Harmonized Tripartite Guideline for Good Clinical Practice, 
E6 (R1)). 
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, or reasons for admission to hospital or surgical 
procedures unless these were planned before enrolment. It also includes AEs 
commonly observed and AEs anticipated based on the pharmacological effect of the 
IMP. In addition, any laboratory abnormality assessed as clinically significant by the 
(sub)investigator must be recorded as an AE. 
Serious adverse event definition 
An SAE is any untoward medical occurrence that 
 
results in death 
 
is life-threatening 
 
requires inpatient hospitalisation or prolongation of existing hospitalisation. Planned 
hospitalisation or planned prolonged hospitalisation do not fulfil the criteria for being 
an SAE but should be documented in the subject’s medical record 
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect 
or  


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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. 


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Appendix 3: Classification of adverse events 
Severity 
The severity of the AE should be described in terms of mild, moderate or severe according to 
the (sub)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. For the AE that worsens, a 
stop date should be entered in the eCRF and the outcome should be categorized as "not 
recovered / not resolved".  
Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probable, 
possible or not related according to the following: 
Probably 
related 
 
Follows a reasonable temporal sequence from administration of the IMP. 
Could not be reasonably explained by the subject’s clinical state, environmental or toxic 
factors or other therapies administered to the subject. 
Follows a known pattern of response to the IMP. 
Disappears or decreases on cessation or reduction in dose of the IMP. 
Reappears or worsens upon re-challenge. 
Possibly 
related 
 
Follows a reasonable temporal sequence from the administration of the IMP. 
Could also be reasonably explained by the subject’s clinical state, environmental or toxic 
factors or other therapies administered to the subject. 
Follows a known pattern of response to the IMP. 
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 should be classified and handled as follows: 
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/resol
ved 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 (sub)investigator, e.g. subject lost to follow-up. 
 


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Appendix 4: Trial governance considerations 
Appendix 4A: 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 and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. 
 Current version of applicable ICH-GCP guidelines. 
 Applicable laws and regulations. 
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial as 
required.  
The protocol, protocol amendments, subject information leaflet including the informed 
consent form (ICF), Investigator’s Brochure, and other relevant documents (for example 
advertisements) must be submitted to an IEC by the investigator (in collaboration with LEO, 
if applicable) and reviewed and approved by the IEC prior to enrolment of subjects.  
Any amendments to the protocol must be approved by/receive favourable opinion from 
relevant regulatory authorities and IECs as required prior to the implementation. 
The investigator will be responsible for the following: 
 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 adherence to 
applicable national and international legislation. 
Appendix 4B: Informed consent process 
Subjects shall receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 


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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. The authorised person obtaining the 
informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the trial.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.  
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. 
Appendix 4C: 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 and shall not be used by the 
investigator for purposes other than this clinical trial. 
The investigator agrees that LEO 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. 
Subjects will be assigned a unique identifier (subject ID) by LEO. Any subject’s records or 
datasets that are transferred to LEO will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.  
Subjects must be informed that their personal trial related data will be used by LEO in 
accordance with local data protection law.   
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by LEO, by appropriate 
IEC members, and by inspectors from regulatory authorities. 


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Processing of personal data 
This protocol specifies the personal data on trial subjects (for example age, gender, health 
condition, height, 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 and third parties acting on behalf of LEO. 
Processing of personal data on behalf of LEO requires a written agreement between LEO 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. 
Investigators and LEO must ensure that collection, processing and transfer of personal data 
are in compliance with applicable legislation on data protection and privacy. 
Subjects (or their legally acceptable representative) 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 has obtained the necessary authorisations for the processing of personal data collected in 
the trial. 
Appendix 4D: Record keeping, quality control, and data handling 
Case report forms 
Data will be collected by means of electronic data capture unless transmitted to LEO or 
designee electronically (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 
to the trial site and LEO 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 the 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. 


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Principles for data entry 
Clinically significant abnormal findings at the (first) screening visit will be documented as 
medical history in the eCRF. 
If an abnormal finding (vital signs, physical examination, laboratory tests) at any other visit 
than the (first) screening visit is considered by the investigator to be clinically significant, it 
will be reported as an AE in accordance with Section 12.2. Further, any clinically significant 
deterioration of a pre-existing condition as well as any new clinically significant sign, 
symptom or illness observed after screening will be reported as an AE in accordance with 
Section 12.2. 
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 one 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 by medically qualified investigators.  
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 
 
Date(s) of conducting the informed consent process, including date of provision of 
subject information. 
 
A statement from the investigator to verify that each of the eligibility criteria are met. 
 
Subject ID. 
 
The fact that the subject is participating in a clinical trial in psoriasis including 
treatment with brodalumab or fumaric acid esters for 24 weeks with a follow-up 
period of 2 or 8 weeks depending on treatment group. 
 
Other relevant medical information. 
Trial monitoring 
During the course of the trial the CRA(s) will visit the trial site. These visits have the 
following objectives: (i) to perform ongoing source data verification to confirm that data 
entered into the CRF 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; 


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and (iii) to confirm that the trial is being conducted in accordance with the currently approved 
protocol and any other trial agreements, ICH-GCP, and all applicable regulatory 
requirements. 
The monitoring visit intervals will depend on the trial site’s recruitment rate, the compliance 
of the trial site with the protocol and GCP. 
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 and included in the clinical trial report. 
Sponsor audits, IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO 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 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 must be notified 
immediately. 
Data handling 
Subject data should be entered into the CRF as soon as possible after each visit in accordance 
with the requirements described in the Clinical Trial Agreement, if applicable. 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 PRO (ePRO) solution will be used to capture patient reported data (data from 
questionnaires completed at the trial site and ePRO device data). By the use of an ePRO, data 


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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 will be transmitted and handled via a secure file 
transfer protocol site.  
Transmissions of electronic data from external data providers and of ePRO data to the clinical 
database are illustrated in Panel 14. 
Panel 14  Transmission of electronic data 
 
   
CTR: clinical trial report; ECG: electrocardiogram; eCRF: electronic case report form; ePRO: 
electronic patient reported outcome. 
 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents including the investigator trial file (ICH-GCP E6 guideline) until LEO 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. 


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No records may be destroyed during the retention period without the written approval of 
LEO. No records may be transferred to another location or party without written acceptance 
from LEO. 
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 a copy of the eCRFs and 
ePRO data for all subjects enrolled 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, from regulatory authorities and/or IECs. 
Appendix 4E: Registration, reporting and publication policy 
Basic information of this clinical trial will be registered in the global data registry, 
www.clinicaltrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Results of this clinical trial will be posted on the corporate website of LEO in accordance with 
LEO’s Position on Public Access to Clinical Trial Information, latest 12 months after trial 
completion. 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.   
In the case of a multi-centre trial the first publication will be a joint multi-centre publication. 
Multi-centre publications will be prepared in collaboration between LEO and the members of 
a writing group, which shall be appointed by LEO. 
Publication by an investigator of his/her trial results shall not be made public before the first 
multi-centre publication. 
If no multi-centre publication has been 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, 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 submitting or presenting a manuscript relating to the clinical trial to a publisher, 
reviewer or other outside person, the investigator shall provide to LEO a copy of all such 
manuscripts, and LEO shall have rights to review and comment. Upon the request of LEO, the 


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investigator shall 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, delay the publication or presentation to allow LEO to protect its 
inventions and other intellectual property rights described in any such manuscripts. In case the 
first multi-centre publication is still ongoing and has not been made public at the time of 
notification, LEO 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. 
LEO complies with recommendations from the International Committee of Medical Journal 
Editors and with the positions of the International Federation of Pharmaceutical 
Manufacturers & Associations (IFPMA), European Federation of Pharmaceutical Industries 
and Associations (EFPIA), Japan Pharmaceutical Manufacturers Association (JPMA) and 
Pharmaceutical Research and Manufacturers of America (PhRMA) on disclosure of 
information about clinical trials, trial results and authorship. 
Appendix 4F: Insurance 
LEO has obtained a patient insurance as well as a travel accident assurance covering the 
subjects in the present clinical trial in accordance with the national law and regulations. A 
copy of the conditions of the patient insurance as well as of the accident insurance will be 
handed out to the subject with the informed consent. 
Appendix 4G: Financial disclosure 
Investigators will provide LEO with sufficient, accurate financial information as requested to 
allow LEO to submit complete and accurate financial certification or disclosure statements to 
the appropriate regulatory authorities. Investigators are responsible for providing information 
on financial interests during the course of the clinical trial and for app. 1 year after completion 
of the clinical trial, or for a longer period of time if required by local legislation. 
Appendix 4H: Trial and site closure 
Premature termination of trial or trial site 
LEO, the investigator, the IECs or competent authorities may decide to stop the clinical trial, 
part of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained. 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 


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regulatory requirements, the investigator or LEO must promptly inform IECs and provide a 
detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit:risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
Reasons for the early closure of a trial site by LEO 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’s procedures, or GCP guidelines. 
 
Inadequate recruitment of subjects by the investigator. 
 
Discontinuation of further IMP development. 
Completion of trial 
Investigators will be informed when subject recruitment is to cease. Trial enrolment 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 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. 
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 4I: Responsibilities 
The international coordinating investigator (ICI) is responsible for the approval of the 
clinical trial protocol, including any amendment(s) and the CTR on behalf of all clinical trial 
investigators and as agreed to in an International 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 Questionnaires 
Appendix 5A: Psoriasis Symptom Inventory (PSI) – 24 hours recall 
 
 
 


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Appendix 5B: Dermatology Life Quality Index 
 
 
 


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‘ 
Appendix 5C: Patient Health Questionnaire-8 
 


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Appendix 6  Reference safety information 
This reference safety information document is based on the current version of the company 
core safety document that is version 1.0 of the CCDS.  
CONTRAINDICATIONS 
Hypersensitivity to the active substance or to any of the excipients: 
 
Proline 
 
Glutamate 
 
Polysorbate 20 
 
Water for injections 
Active Crohn’s disease. 
Clinically important active infections (e.g. active tuberculosis; see Section below). 
SPECIAL WARNING AND SPECIAL PRECAUTIONS FOR USE 
Crohn’s Disease 
There is limited data in patients with a history of Crohn’s disease. Exercise caution when 
prescribing Kyntheum® to patients with a history of Crohn’s disease. Patients with a history 
of Crohn’s disease should be followed for signs and symptoms of active Crohn’s disease. If 
patients develop active Crohn’s disease, treatment should be discontinued permanently. 
Suicidal ideation and behaviour 
Suicidal ideation and behaviour, including completed suicide, have been reported in patients 
treated with Kyntheum®. The majority of patients with suicidal behaviour had a history of 
depression and/or suicidal ideation or behaviour. A causal association between treatment with 
Kyntheum® and increased risk of suicidal ideation and behaviour has not been established. 
Carefully weigh the risk and benefit of treatment with Kyntheum® for patients with a history 
of depression and/or suicidal ideation or behaviour, or patients who develop such symptoms. 
Patients, caregivers, and families should be advised of the need to be alert for the emergence 
or worsening of depression, suicidal ideation, anxiety, or other mood changes, and they should 
contact their healthcare provider if such events occur. 
Infections 
Kyntheum® may increase the risk of infections. 


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During the 12-week placebo-controlled clinical trial period in patients with psoriasis, serious 
infections were observed in 0.5% of patients receiving Kyntheum® (see Section on 
undesirable effects). 
Caution should be exercised when considering the use of Kyntheum® in patients with a 
chronic infection or a history of recurrent infection. Patients should be instructed to seek 
medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a 
serious infection, the patient should be closely monitored and Kyntheum® should not be 
administered until the infection resolves. 
No cases of active tuberculosis were reported from clinical trials. However, Kyntheum® 
should not be given to patients with active tuberculosis. Anti-tuberculosis therapy should be 
considered prior to initiation of Kyntheum® in patients with latent tuberculosis. 
Vaccinations 
It is recommended that patients be brought up-to-date with all immunisations in accordance 
with local immunisation guidelines prior to initiation of treatment with Kyntheum®. Live 
vaccines should not be given concurrently with Kyntheum® (see Section below). No data are 
available on the response to live vaccines or the risk of infection, or transmission of infection 
after the administration of live vaccines in patients receiving Kyntheum®. 
Vaccination of infants 
Vaccination of infants with live vaccines following third trimester exposure to Kyntheum® 
should be discussed with a physician (see also Section on fertility, pregnancy and lactation). 
Concomitant immunosuppressive therapy 
The safety and efficacy of Kyntheum® in combination with immunosuppressants, including 
biologics, or phototherapy have not been evaluated. 
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF 
INTERACTIONS 
Live vaccines should not be given concurrently with Kyntheum® (see Section on special 
warning and precautions for use). 
The formation of CYP450 enzymes can be altered by increased levels of certain cytokines 
(e.g. IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Although a role for 
interleukin (IL)-17A and IL-17RA in the regulation of CYP450 enzymes has not been 
reported, the effect of brodalumab on CYP3A4/3A5 activity was evaluated in a disease-drug- 
drug interaction study. 


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In patients with moderate to severe plaque psoriasis, a single subcutaneous dose of 210 mg 
brodalumab increased the exposure of midazolam, a CYP3A4/3A5 substrate by 24%. Based 
on the magnitude of change in exposure of midazolam, no dose adjustment of CYP3A4/3A5 
substrates is necessary when administered concomitantly with Kyntheum®. 
FERTILITY, PREGNANCY AND LACTATION 
Women of childbearing potential 
Women of childbearing potential should use an effective method of contraception during 
treatment and for at least 12 weeks after treatment. 
Pregnancy 
There are no or limited amount of data from the use of brodalumab in pregnant women. 
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive 
toxicity. 
Human IgG2 is known to cross the placental barrier and brodalumab is a human IgG2, 
therefore, brodalumab has the potential to be transmitted from the mother to the developing 
foetus. As a precautionary measure, it is preferable to avoid the use of Kyntheum® in 
pregnancy. 
As the metabolism of brodalumab is unknown in infants, benefit risk for exposure of the 
infant to live vaccines following third trimester exposure to Kyntheum® should be discussed 
with a physician. 
Breast-feeding 
It is unknown whether brodalumab is excreted in human milk. Brodalumab is a monoclonal 
antibody and is expected to be present in the first milk and at low levels afterwards. 
A risk to the newborn/infant cannot be excluded. 
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from 
Kyntheum® therapy taking into account the benefit of breast-feeding for the child and the 
benefit of therapy for the woman. 
Fertility 
No data are available on the effect of brodalumab on human fertility. Animal studies did not 
show any effects on male and female reproductive organs and on sperm count, motility and 
morphology. 


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EFFECTS ON ABILITY TO DRIVE AND USE MACHINES 
Kyntheum® has no or negligible influence on the ability to drive and use machines. 
UNDESIRABLE EFFECTS 
Summary of the safety profile 
The most commonly reported adverse reactions in all Kyntheum®-treated patients were 
arthralgia, headache, fatigue, diarrhoea and oropharyngeal pain. 
Tabulated list of adverse reactions 
Adverse reactions from clinical trials (Table1) are listed by MedDRA system organ class 
(SOC). Within each SOC, the adverse reactions are ranked by frequency, with the most 
frequent reactions first. Within each frequency grouping adverse reactions are presented in 
order of decreasing seriousness. In addition, the corresponding frequency category for each 
adverse reaction is based on the following convention: very common (≥1/10), common 
(≥1/100 to < 1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very 
rare (<1/10,000). 
List of adverse reactions in clinical trials 
System Organ Class 
Frequency 
Adverse Reaction 
Infections and infestations 
Common 
Influenza 
Tinea infections (including tinea pedis, 
tinea versicolor, tinea cruris) 
Uncommon 
Candida infections (including oral, genital, 
and oesophageal infections) 
Blood and lymphatic system 
disorders 
Common 
Neutropenia 
Nervous system disorders 
Common 
Headache 
Eye disorders 
Uncommon 
Conjunctivitis 
Respiratory, thoracic and 
mediastinal disorders 
Common 
Oropharyngeal pain 
Gastrointestinal disorders 
Common 
Diarrhoea 
Nausea 
Musculoskeletal and 
connective tissue disorders 
Common 
Arthralgia 
Myalgia 
General disorders and 
administration site 
conditions 
Common 
Fatigue 
Injection site reactions (including injection 
site erythema, pain, pruritus, bruising, 
haemorrhage) 
 


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Description of selected adverse reactions 
Infections 
During the 12-week placebo-controlled trial period in plaque psoriasis, infections were 
reported in 25.4% of patients treated with Kyntheum® compared with 23.4% of patients 
treated with placebo. The majority of infections consisted of nasopharyngitis, upper 
respiratory tract infection, pharyngitis, urinary tract infections, bronchitis, and influenza, 
which did not necessitate treatment discontinuation. Serious infections occurred in 0.5% of 
patients treated with Kyntheum® and in 0.2% of patients treated with placebo. Higher rates of 
fungal infections, primarily non-serious skin and mucosal candida infections, were observed 
in Kyntheum® patients compared to placebo patients, 1.8% vs 0.9%, respectively. One serious 
case of cryptococcal meningitis and one serious case of coccidioidies infection were observed 
in clinical trials (see Section on special warning and precautions for use). 
Through week 52, the exposure-adjusted event rates (per 100 patient-years) for infections 
were 114.6 for patients treated with Kyntheum® and 118.1 for patients treated with 
ustekinumab. The exposure-adjusted event rates (per 100 patient-years) for serious infections 
were 1.3 for patients treated with Kyntheum® and 1.0 for patients treated with ustekinumab. 
Reduced absolute neutrophil count 
During the 12-week placebo-controlled clinical trial period in patients with psoriasis, a 
decrease in absolute neutrophil count (ANC) was observed in 5.6% of patients receiving 
Kyntheum® , which was generally transient and reversible. Grade 3 and 4 have been observed 
occasionally. None of the Grade 3 or 4 ANC decreases in the psoriasis subset overall were 
associated with a serious infection. 
Neutropenia 
During the 12-week placebo-controlled period of clinical trials, neutropenia was reported in 
0.8% of patients treated with Kyntheum® compared with 0.5% of patients treated with 
placebo. Most adverse reactions of Kyntheum®-associated neutropenia observed were mild, 
transient and reversible. 
Neutropenia Grade 3 and 4 were reported in 0.4% of patients receiving Kyntheum compared 
to 0.2% of patients who received ustekinumab and none in patients receiving placebo. No 
serious infections were associated with neutropenia. 
Immunogenicity 
Antibodies to brodalumab developed in 2.7% (122/4461) of patients treated with Kyntheum® 


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for up to 52 weeks in psoriasis clinical trials (0.3% of these patients had anti-brodalumab 
antibodies at baseline). Of these patients, none had neutralising antibodies. 
No evidence of altered pharmacokinetic profile, clinical response, or safety profile was 
associated with anti-brodalumab antibody development. 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is 
important. It allows continued monitoring of the benefit/risk balance of the medicinal product. 
Healthcare professionals are asked to report any suspected adverse reactions. 
When reporting a suspected adverse reaction of a biological medicine, the name of the 
medicine and the batch number should be included. 
OVERDOSE 
Doses up to 700 mg intravenously have been administered in clinical trials with no evidence 
of dose limiting toxicity. In the event of overdose, it is recommended that the patient be 
monitored for any signs or symptoms of adverse reactions and appropriate symptomatic 
treatment be instituted immediately. 


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