Effect of Brodalumab Compared to Placebo on Vascular Inflammation in Moderate-to-severe Psoriasis
Phase: PHASE4
Conditions: Psoriasis
Sponsor: Aarhus University Hospital

Clinical Trial Protocol 
 
 
Effect of brodalumab compared to placebo on vascular inflammation in 
moderate-to-severe psoriasis 
 
 
A randomised, double-blind, placebo-controlled, trial to evaluate the efficacy  
of brodalumab monotherapy on vascular and systemic inflammation by 18F-FDG-
PET/CT in subjects with moderate-to-severe plaque-type psoriasis who are candidates 
for systemic therapy 
 
 
 
 This study protocol has been prepared in accordance with the guidelines for GCP (ICH-GCP and 
danish Executive Order number 695 of 12/06/2013). All aspects of the study including planning, 
completion and reporting are carried out in accordance with GCP as well as national and 
international legislation and provisions. The study is monitored by the GCP unit at Aarhus 
University Hospital.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Department of Dermatology 
Aarhus University Hospital 
 
 
 
Sponsors protokolkode 
PsoPET2 
 
Central Denmark Region 
Ethical Comittee No. 
1-10-72-386-17 
 
 
EudraCT No. 
2017-003697-14 
 
Danish Medicines Agency 
No. 
2017093879 
 
Date 
23.02.2018 

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1 Clinical Trial Approval Statement  
 
1.1 Approval statement sponsor 
 
The following person has approved this clinical trial protocol: 
 
 
Lars Iversen, MD, DMSc 
Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark  
 
1.2 Approval statement investigator 
 
The following persons has approved this clinical trial protocol: 
 
 
Anne Bregnhøj, MD, PhD 
Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark  
Trine Høgsberg, MD, PhD 
Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark  
 
1.3 Approval statement co-investigator 
 
The following person has approved this clinical trial protocol: 
 
 
Lars Christian Gormsen, MD, PhD 
Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, 
Denmark 
 
1.4 GCP responsibilty 
 
The following persons take responsibility for enabling GCP monitoring: 
 
Anne Bregnhøj, MD, PhD 
Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark  
Trine Høgsberg, MD, PhD 
Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark  

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2 Table of Contents 
1 Clinical Trial Approval Statement .................................................................................................. 2 
1.1 
Approval statement sponsor .................................................................................................................. 2 
1.2 
Approval statement investigator .......................................................................................................... 2 
1.3 
Approval statement co-investigator .................................................................................................... 2 
1.4 GCP responsibilty............................................................................................................................................ 2 
2 Table of Contents ................................................................................................................................. 3 
3 Trial Identification .............................................................................................................................. 6 
4 Trial location ......................................................................................................................................... 6 
5 Funding .................................................................................................................................................... 6 
6 List of abbreviations: .......................................................................................................................... 7 
6 Flow diagram of trial design ............................................................................................................ 9 
7 Schedule of procedures .................................................................................................................. 10 
8 Introduction, background, and rationale ................................................................................. 12 
8.1 
Psoriasis ....................................................................................................................................................... 12 
8.2 
Psoriasis and cardiovascular disease ................................................................................................ 12 
8.3 
18F−fluorodeoxyglucose positron emission tomography computed tomography ............ 13 
8.4 
Experience with experimental medicinal product ....................................................................... 14 
8.5 
Trial rationale and hypothesis ............................................................................................................. 15 
8.6 
Perspective .................................................................................................................................................. 16 
8.7 
Registration and publication ................................................................................................................ 16 
8.8 
Exposure to radiation .............................................................................................................................. 16 
8.9 
Benefit/risk assessment ......................................................................................................................... 17 
8.10 Ethical considerations ............................................................................................................................. 18 
9 Trial objectives and endpoints .................................................................................................... 19 
9.1 
Trial objectives and endpoints ............................................................................................................ 19 
10 Trial design ......................................................................................................................................... 20 
10.1 Overall trial design ................................................................................................................................... 20 
10.2 Number of subjects needed ................................................................................................................... 20 
10.3 End of trial definition .............................................................................................................................. 21 
10.4 Record keeping, monitoring, and data handling ........................................................................... 21 
11 Trial population and withdrawal ................................................................................................ 22 
11.1 Subject eligibility ...................................................................................................................................... 22 
11.2 Inclusion criteria ....................................................................................................................................... 22 
11.3 Exclusion criteria ...................................................................................................................................... 22 
11.4 Recruitment and informed consent procedures ........................................................................... 24 
11.4.1 Information collected from the medical records ................................................................................... 25 
11.5 Screening, screening failures, and randomisation ....................................................................... 25 
11.6 Discontinuation ......................................................................................................................................... 26 
11.7 Reimbursement ......................................................................................................................................... 26 

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11.8 Insurance ..................................................................................................................................................... 26 
12 Treatments .......................................................................................................................................... 26 
12.1 Trial product description ....................................................................................................................... 26 
12.2 Administration of investigational medicinal products ............................................................... 27 
12.3 Treatment assignment ............................................................................................................................ 28 
12.3.1 
Blinding ............................................................................................................................................................... 28 
12.3.2 
Emergency unblinding of individual subject treatment ................................................................. 29 
12.4 Background treatment (topical agents) ........................................................................................... 29 
12.5 Concomitant medication and procedures ........................................................................................ 29 
12.6 Prohibited medication and procedures ............................................................................................ 29 
12.7 Treatment logistics and accountability ............................................................................................ 30 
12.7.1 
Labelling and packaging of investigational medicinal products ................................................. 30 
12.7.2 
Storage of investigational medicinal products ................................................................................... 30 
12.7.3 
Drug accountability ........................................................................................................................................ 30 
12.7.4 
Trial product destruction ............................................................................................................................ 30 
12.7.5 
Treatment compliance .................................................................................................................................. 30 
12.8 Provision for subject care following trial completion ................................................................. 31 
12.9 Reporting product complaints ............................................................................................................. 31 
13 Trial schedule and assessments .................................................................................................. 31 
13.1 Overview ...................................................................................................................................................... 31 
13.2 Assessments performed only at screening/baseline ................................................................... 31 
13.2.1 
Demographics .................................................................................................................................................. 32 
13.2.2 
Medical history ................................................................................................................................................ 32 
13.2.3 
Height and weight ........................................................................................................................................... 32 
13.3 Psoriasis efficacy assessments ............................................................................................................. 33 
13.3.1 
Investigator assessments ............................................................................................................................ 33 
13.3.1.1 
Investigator’s Global Assessment ......................................................................................................................... 33 
13.3.1.2 
Psoriasis Area and Severity Index ........................................................................................................................ 33 
13.3.1.3 
Body surface area involvement ............................................................................................................................. 34 
13.3.1.4 
Quantitative nail assessment .................................................................................................................................. 34 
13.3.1.5 
Quantitative joint assessment ................................................................................................................................ 34 
13.3.2 
Subject assessments ...................................................................................................................................... 35 
13.3.2.1 
Dermatology Life Quality Index ............................................................................................................................ 35 
13.3.2.2 
Psoriasis Symptom Inventory (PSI) .................................................................................................................... 35 
13.3.2.3 
Visual Analog Scale for joint pain ......................................................................................................................... 35 
13.4 Clinical and laboratory assessments ................................................................................................. 36 
13.4.1 
Physical examination .................................................................................................................................... 36 
13.4.2 
Pregnancy test .................................................................................................................................................. 36 
13.4.3 
Laboratory testing .......................................................................................................................................... 36 
13.4.4 
Procedures ......................................................................................................................................................... 37 
13.4.5 
Research biobank ........................................................................................................................................... 37 
13.5 FDG-PET/CT assessments ...................................................................................................................... 37 
13.5.1 
Patient preparation ........................................................................................................................................ 37 
13.5.2 
FDG dose and circulation time .................................................................................................................. 38 
13.5.3 
Pre-scan fasting glucose ............................................................................................................................... 38 
13.5.4 
Image acquisition ............................................................................................................................................ 38 
13.5.5 
Reconstruction protocol .............................................................................................................................. 38 
13.5.6 
Quantification of radiotracer uptake in target tissue ...................................................................... 38 
14 Adverse events ................................................................................................................................... 39 
14.1 Collection and reporting of adverse events..................................................................................... 39 

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15 Statistical methods ........................................................................................................................... 40 
15.1 Sample size .................................................................................................................................................. 40 
15.2 Trial analysis sets ..................................................................................................................................... 41 
15.3 Statistical analysis .................................................................................................................................... 41 
15.3.1 
Disposition of subjects .................................................................................................................................. 41 
15.3.2 
Demographics and other baseline characteristics ............................................................................ 41 
15.3.3 
Treatment efficacy .......................................................................................................................................... 41 
15.4 Analysis of endpoints .............................................................................................................................. 41 
15.4.1 
Analysis of primary endpoints .................................................................................................................. 41 
15.4.2 
Analysis of secondary endpoints .............................................................................................................. 42 
15.4.3 
Analysis of other endpoints ........................................................................................................................ 42 
16 REFERENCES ....................................................................................................................................... 43 
17 Appendix .............................................................................................................................................. 48 
 
 

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3 Trial Identification 
 
The Danish Data Protection Agency 
Central Denmark Region Ethical Comittee 
1-10-72-386-17 
EudraCT 
 
 
 
2017-003697-14 
Danish Medicines Agency 
 
2017093879 
ClinicalTrials.gov 
4 Trial location 
 
Department of Dermatology 
Aarhus University Hospital 
P.P Ørums Gade 11 
DK-8000 Aarhus C 
Denmark 
Telephone: +45 
Email: annebreg@rm.dk / lars.iversen@clin.au.dk 
 
Department of Nuclear Medicine and PET Center 
Aarhus University Hospital 
DK-8000 Aarhus C 
Denmark 
5 Funding 
 
This investigator initiated clinical trial is supported by a grant provided by LEO Pharma. The 
investigational medicinal product (Brodalumab) is provided by LEO Pharma. LEO Pharma has 
no influence on the design of the study, the collection of data, and will have no influence on 
the interpretation of the results, the preparation of the manuscripts or the decision to submit 
for publication.  
The grant will be transferred to an account at Aarhus University Hospital. Trial related 
expenses will be paid from this account. The total amount received from LEO Pharma to cover 
trial related expenses in this investigator initiated study is 212.900 euro. 
 
 

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6 List of abbreviations: 
 
AE: 
Adverse events 
BMI: 
Body mass index 
CAC: 
Coronary artery calcium 
CAD: 
Coronary artery disease 
CCTA: 
Contrast-enhanced computed tomography angiography 
CD: 
Cluster of Differentation 
CI: 
Confidence interval 
eCRF: 
Electronic case report form 
CRP: 
C-reactive protein 
CT: 
Computed tomography 
DLQI: 
Dermatology Life Quality Index 
DMA: 
Danish Medicines Agency 
EANM: 
European Association of Nuclear Medicine 
ECG: 
Electrocardiogram 
EMA: 
European Medicines Agency 
EOW: 
Every other week 
FDG:  
18F−fluorodeoxyglucose 
GCP: 
Good Clinical Practice 
HCP: 
Health care professional 
HIV: 
Human immunodeficiency virus 
HLA: 
Human leukocyte antigen 
hs: 
High-sensitivity 
ICH: 
International Council for Harmonisation 
IGA: 
Investigator’s global assessment 
IL: 
Interleukin 
IFN: 
Interferon 
IgG: 
Immunoglobulin G 
IMP: 
Investigational Medicinal Product 
LDL: 
Low-density lipoprotein 
MBq: 
Megabecquerel 
MHC: 
Major histocompatibility complex 
MI: 
Myocardial infarction 
mSv: 
milliSievert 
NF: 
Nuclear Factor 
PASI: 
Psoriasis Area Severity Index 
PET: 
Positron emission tomography 
PsA: 
Psoriatic arthritis 
PSI: 
Psoriasis symptom inventory 
PUVA:  
Psoralen ultraviolet type A 
RA: 
Receptor A 
RCT: 
Randomised controlled trial 
ROI: 
Region of interest 
SAE: 
Serious adverse event 
Sv: 
Sievert 
SD: 
Standard deviation 

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SLR: 
Spleen-to-liver ratio 
SUV: 
Standardised uptake values 
TBR: 
Target-to-background ratio 
TNF: 
Tumour necrosis factor 
UVA: 
Ultraviolet type A 
UVB: 
Ultraviolet type B 
VAS: 
Visual analog scale 
VOI: 
Volume of interest 
 
 
 
 
 
 
 

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6 Flow diagram of trial design 
 
 
 
 
 
 
 

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7 Schedule of procedures 
 
Visit 
Screen 1 
Visit 2 
Visit 3 
Visit 4 
Week 
-4 
0 
6 
16 
Office visits 
 
 
 
 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Diagnosis of PsA 
X 
 
 
 
Smoking/alcohol consumption 
X 
 
 
 
Psoriasis: medical history / previous 
psoriasis therapies 
X 
 
 
 
Other medical history / treatments 
X 
 
 
 
Concomitant medications 
X 
X 
 
X 
Randomization 
X 
 
 
 
Collection of adverse events 
 
 
X 
X 
Physical examination 
 
 
 
 
General physical examination 
X 
 
 
X 
Height 
X 
 
 
 
Weight 
X 
 
 
X 
Hip circumference 
X 
 
 
 
Blood pressure, pulse 
X 
 
 
X 
PASI 
X 
X 
X 
X 
BSA 
X 
X 
X 
X 
IGA 
X 
X 
X 
X 
Quantitative nail assessment 
X 
X 
X 
X 
Quantitative joint assessment 
X 
X 
X 
 
DLQI 
X 
X 
X 
X 
PSI 
X 
X 
X 
X 
VAS (joints) 
X 
X 
X 
X 
Labs 
 
 
 
 
Serum electrolytes + renal panel 
X 
X 
X 
X 
Acute-phase proteins 
X 
X 
X 
X 
Lipids 
X 
X 
 
X 
Liver enzymes 
X 
X 
 
X 
Glucose metabolism 
X 
X 
X 
X 
T-spot 
X 
 
 
 
HIV I+II 
X 
 
 
 
Hepatitis serology 
X 
 
 
 
Treatment 
 
 
 
 
Initiation of treatment / placebo  
 
X 
 
 
Procedures 
 
 
 
 
FDG-PET/CT 
 
X 
 
X 
Chest X-ray 
X 
 
 
 
Optional punch biopsy 
 
X 
X 
 

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8 Introduction, background, and rationale 
 
8.1 Psoriasis 
 
Psoriasis is a common inflammatory disease of the skin and joints with a prevalence of 2%-
4% in the Western population with varying prevalence among different ethnic groups.1,2 
Accounting for 90% of cases, chronic-plaque psoriasis (henceforth “psoriasis”) is the most 
common form of the disease.  
Population-based studies report a genetic predisposition to psoriasis, showing a higher 
prevalence of psoriasis among first- and second-degree relatives than in the general 
population.3 
The characteristic clinical features of psoriasis are explained by the histopathological 
changes: Hyper-proliferation of the basal keratinocytes and the dermal infiltrate cause the 
skin to thicken; parakeratosis with premature maturation of keratinocytes and retention of 
nuclei in the stratum corneum cause scaling; and hyperaemia due to the dilated and winding 
capillaries in combination with inflammation causes the reddening of the skin.4 
Previous research has established that the disease is mainly a dendritic cell and T-cell-
mediated disease with complex feedback loops from antigen-presenting cells, neutrophilic 
granulocytes, keratinocytes, vascular endothelial cells and the cutaneous nervous system.5 
Traditionally, interleukin (IL)-12-stimulated T-helper lymphocyte (Th)-1 development has 
been viewed as an important driver for psoriasis pathogenesis, but in recent years it has 
become increasingly evident that the IL-23/Th-17 axis is of great importance.6 Once activated, 
Th-17 cells secrete various isoforms of IL-17 and IL-22, which constitute the link to epidermal 
hyper-proliferation. 
Overall, in the current models, the central features of immunogenicity in psoriasis are heavily 
based on IL-17 production by Th-17 cells and their IL-23-induced expansion and feedback 
loops, with TNF-α/NF-kappa beta signalling and signalling through Th22 and CD8+ Tc17 cells 
as other important contributing pathways.  
 
8.2 Psoriasis and cardiovascular disease 
 
Studies in different populations in the Western world have repeatedly shown that psoriasis is 
associated with an increased risk of cardiovascular comorbidity. The data on which these 
studies build come from various sources, including nation-wide registers, large insurance 
databases, research databases and hospital cohorts.7-11 In moderate-to-severe psoriasis, the 
risk levels are broadly at a level corresponding to the risk found in rheumatoid arthritis, 
which was confirmed by at least one study that compared the risk of major cardiovascular 
events in psoriasis and rheumatoid arthritis.11 Several meta-analyses show that psoriasis is 
associated with an increased risk of cardiovascular disease.12-14 Taken together, this indicates 
that the relative risk of cardiovascular disease is increased in patients with severe disease and 
early disease onset, and that older patients with severe psoriasis have a high, absolute risk of 
cardiovascular disease. 
The inflammatory pathways of psoriasis are much similar to those identified in 
atherosclerosis. There is evidence of systemic inflammation in psoriasis,15,16 and an 
association between psoriasis and cardiovascular disease due to accelerated coronary artery 

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disease is suspected.17,18 It has been suggested that subcutaneous adipose tissue inflammation 
contributes to the pathogenesis of psoriasis, and there is evidence in support of an immune 
cell–adipocyte crosstalk in the pathogenesis of inflammatory diseases as well as in metabolic 
comorbidities. 
The concept of atherosclerosis as an inflammatory disease is based on observations of 
immune activation in human atherosclerotic lesions, recognition of inflammatory biomarkers 
as independent risk factors for cardiovascular events and evidence of immune activation 
induced by low-density lipoproteins.  
We have previously shown that 13 months of clinically effective treatment of psoriasis 
predominantly with anti-TNF drugs ameliorates the progression of CAD in patients with 
moderate-to-severe psoriasis.19 These data corroborate the results of other epidemiological 
and clinical studies. Taken together, there is emerging evidence that treatment of psoriasis 
with biologic agents is associated with a reduced risk of death and major cardiovascular 
events; and a reduction of surrogate markers such as endothelial dysfunction, insulin 
sensitivity, CRP and carotid intima thickness. Furthermore, recent data suggest an 
improvement of coronary flow reserve20 and improved myocardial function following 
treatment with biologic agents.21 
Interleukin (IL)-17 has been shown to be atherogenic in animal models and involved in the 
recruitment of inflammatory cells to atherosclerotic plaques, a process inhibited by depleting 
IL-17.22,23 However, the potential of IL-17 blocking agents to improve atherosclerosis in 
humans has only been sparsely investigated. One ongoing clinical study is investigating the 
effect of IL-17A antibodies compared to placebo on aortic vascular inflammation in subjects 
with moderate to severe plaque psoriasis (clinicaltrials.gov identifier: NCT02690701). 
Previous studies have shown that treatment with brodalumab, an IL-17 receptor A blocking 
agent (IL-17RA), resulted in a rapid and highly effective reduction in the signs and symptoms 
of psoriasis.24 
However, the effect of IL-17RA on vascular inflammation and cardiovascular outcomes is 
unknown.  
 
 
 
8.3 18F−fluorodeoxyglucose positron emission tomography computed tomography 
 
18F−fluorodeoxyglucose (FDG) positron emission tomography (PET) computed tomography 
(CT) provides a direct measure of metabolic activity in vessels and other tissues. FDG is a 
radiolabelled glucose analogue taken up in tissues with high metabolic activity such as 
inflammatory active tissue and tumour cells. Traditionally, FDG-PET/CT has been used in 
oncology, but given the focus of inflammation as a key player in atherosclerosis and the need 
to better diagnose active disease, vascular FDG-PET imaging has gained increasing interest as 
a promising tool for imaging atherosclerotic plaque inflammation and vulnerability.25 In early 
proof-of-concept studies it was shown that FDG accumulates in macrophage-rich 
atherosclerotic plaques and demonstrated that vascular macrophage activity can be 
quantified noninvasively with FDG-PET.26 In addition to visualizing atherosclerotic plaque 
inflammation, it has been shown that FDG uptake is associated with the severity of 
inflammation in atherosclerotic plaques.27, 28 Furthermore, arterial FDG uptake increases in 
proportion to atherosclerotic risk factors, with plaque morphological complexity, and after 

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atherothrombotic events. 29 It has been shown that FDG-PET/CT significantly improves 
cardiovascular disease prediction beyond that of traditional risk factor scoring and that FDG-
PET/CT imaging provides prognostic information adding to that which may be obtained using 
soluble biomarkers 30-33. 
We have previously conducted a clinical study evaluating vascular and subcutaneous adipose 
tissue inflammation from FDG-PET/CT.34 In this study we found that arterial inflammation 
was increased in psoriasis patients compared to controls (mean (SD) whole vessel maximal 
target-to-background ratio (TBRmax) 2.46 [0.31] versus 2.09 [0.36]; P=0.005). In psoriasis 
patients, higher FDG uptake values were observed for all aortic segments except the 
ascending aorta. Subcutaneous adipose tissue FDG uptake was increased in psoriasis patients 
compared with controls (mean TBRmax 0.49 [0.18] versus 0.31 [0.12]; P=0.002; and mean 
TBRmax-10pixels 0.39 [0.10] versus 0.28 [0.12]; P=0.01). Our results are corroborated by other 
studies.35,36  
Furthermore, we have recently conducted a study demonstrating increased splenic 
inflammation in patients with psoriasis compared with age-matched control subjects. 
Additionally, a significant association between splenic inflammation and aortic wall 
inflammation was found in psoriasis patients (unpublished data). Other exploratory studies 
indicate a role of the spleen in atherosclerosis-associated immunity,37,38 and cardiovascular 
clinical studies indicate that a cardio-splenic axis exists.39 Given the well-established role of 
the spleen in systemic inflammatory diseases, this provides evidence of systemic 
inflammation in psoriasis beyond that reported by biomarker studies.  
Recently, in an opel-label cohort of patients with mild-to-moderate psoriasis it was shown 
that reduction of skin inflammation by mixed interventions was associated with improvement 
in aortic wall inflammation assessed by FDG-PET/CT.40 This finding was not corroborated by 
two RCT’s assessing the effect of anti-TNF drug adalimumab on aortic wall inflamation as no 
significant difference was found after 16 weeks of treatment.41,42 However, a limitation of 
these studies were that the primary endpoint was changes in FDG-uptake in only the 
ascending part of aorta and not the entire vessel.43 Choosing the ascending aorta as the 
representative aortic segment may not always be the optimal approach. For example, Besson 
et. al. investigated the performance of different semiquantitative measures to distinguish 
controls from patients with large vessel vasculitis and found that TBR performed well in all 
segments of the aorta – except in the ascending aorta.44 In line with this, we also recently 
found increased aortic wall inflammation in psoriasis patients compared with controls 
without inflammatory diseases in all segments of the vessel except the ascending part.34 It has 
previously been suggested that whole-vessel aortic mean TBRmax is well suited as a marker 
of cardiovascular risk for assessment of global arterial inflammation.45  
Taken together, these studies establish FDG-PET/CT as a feasible technique for visualizing 
vascular inflammation and systemic inflammation as well as changes in vascular/systemic 
inflammation in psoriasis.  
 
 
8.4 Experience with experimental medicinal product 
 
Brodalumab is a recombinant fully human monoclonal immunoglobulin IgG2 antibody that 
binds with high affinity to human IL-17RA and blocks the biological activities of the pro 
inflammatory cytokines IL-17A, IL-17F, IL-17A/F heterodimer and IL-17C and IL-17E (IL-25). 

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Brodalumab is approved for the treatment of moderate to severe plaque psoriasis in adult 
patients who are candidates for systemic therapy. The trade name of brodalumab in Europe is 
Kyntheum and it is marketed by LEO Pharma A/S. Kyntheum is available as a 210 mg solution 
for injection.  
 
The approval of brodalumab is based on the results of three multicenter, randomized, double-
blind, controlled trials (AMAGINE 1, 2, and 3) that enrolled a total of 4373 subjects 18 years of 
age and older with at least a 6-month history of moderate to severe plaque psoriasis, defined 
as having a minimum affected body surface area (BSA) of 10%, a Psoriasis Area and Severity 
Index (PASI) score ≥ 12, a static Physician’s Global Assessment (sPGA) score ≥3 in the overall 
assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity 
scale of 0 to 5, and who were candidates for systemic therapy or phototherapy. In all three 
trials, subjects were randomized to subcutaneous treatment with placebo or brodalumab 210 
mg at Weeks 0, 1, and 2, followed by treatments every 2 weeks through Week 12. In the two 
active comparator trials (AMAGINE 2 and 3), subjects randomized to ustekinumab received a 
45 mg dose if their weight was less than or equal to 100 kg and a 90 mg dose if their weight 
was greater than 100 kg at Weeks 0, 4, and 16, followed by the same dose every 12 weeks.  
At week 12, the proportion of patients attaining a 75% improvement from the baseline 
Psoriasis Area and Severity Index (PASI 75) was similar among the three phase III trials 
(AMAGINE-1, 83%; AMAGINE-2, 86%; AMAGINE-3, 85%). Brodalumab remained efficacious 
through 52 weeks of treatment.46 
Most common adverse reactions (incidence ≥1%) were arthralgia, headache, fatigue, diarrhea, 
oropharyngeal pain, nausea, myalgia, injection site reactions, influenza, neutropenia, and 
tinea infections.  
Suicidal ideation and behavior, including 4 completed suicides, occurred in subjects treated 
with brodalumab in the psoriasis clinical trials. There were no completed suicides in the 12-
week placebo-controlled portion of the trials. Brodalumab users with a history of suicidality 
or depression had an increased incidence of suicidal ideation and behavior as compared to 
users without such a history. A causal association between treatment with brodalumab and 
increased risk of suicidal ideation and behavior has not been established.  
Brodalumab is contraindicated in patients with active Crohn’s disease and should be used 
with caution in patients with a history of Crohn’s disease because brodalumab may cause 
worsening of disease. 
Further details are available from the product description (Appendix I). 
 
 
8.5 Trial rationale and hypothesis 
 
We hypothesize that aortic wall inflammation is increased in subjects with moderate-to-
severe psoriasis and that this inflammatory process may be reduced by effectively treating 
psoriasis by brodalumab. Furthermore, we hypothesize that systemic inflammation, as 
indicated by increased splenic FDG uptake, may be reduced by brodalumab therapy, and that 
this reduction may be associated with reduced aortic wall inflammation. The rationale for the 
duration of follow-up is based on previous clinical trials showing a rapid and effective 
response to brodalumab on signs and symptoms of psoriasis. 
 

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The purpose of the study is to assess the effect of IL-17RA blockade by brodalumab on aortic 
wall inflammation and splenic inflammation in patients with moderate-to-severe psoriasis. 
 
8.6 Perspective 
 
The results of this study may advance the knowledge of vascular inflammation in psoriasis, 
which may be an important link between skin inflammation, systemic inflammation, and 
cardiovascular comorbidities. If vascular inflammation is abrogated by effectively treating 
psoriasis by anti-IL17RA agents, this may confirm a true link between psoriasis inflammation 
and cardiovascular comobidities. Furthermore, this may hold a large potential for reducing 
the risk of cardiovascular comorbidities in subjects with psoriasis and other IL-17 driven 
inflammatory diseases. 
 
8.7 Registration and publication 
 
Basic information of this clinical trial will be registered in the global data registry, 
www.clinicaltrials.gov and https://eudract.ema.europa.eu before the first subject enters into 
the trial. The trial may also become registered in other online data registries.  
The protocol will be registered with the Danish Data Protection Agency through the Central 
Denmark Region (Region Midt fællesanmeldelse) before initiation of the study. 
Results of this clinical trial will be submitted for publication in a peer-reviewed scientific 
journal and/or submitted for publication at an international scientfic congress. Positive, 
negative, and inconclusive results will be published. 
Results may also become reported in www.ClinicalTrials.gov and/or 
https://eudract.ema.europa.eu after clinical trial completion or premature termination. 
 
8.8 Exposure to radiation 
 
During FDG-PET/CT, the patients are exposed to ionising radiation in the amount of 4.8 mSv 
at each imaging procedure. In case of repeat scan after 16 weeks, this means that the subjects 
are exposed to a total amount of 9.6 mSv.  
To minimize the exposure to ionizing radiation a low radiation dose protocol of 200 Mbq FDG 
is used. To avoid loss of data quality the low radiation dose protocol is combined with an 
extended PET acquisition time. This particular PET protocol implies a radiation dose of 3.8 
mSv. Additionally, non-contrast low radiation dose CT is performed from just above the level 
of the aortic arch to the lower spleen level for attenuation correction and anatomical co-
registration. The radiation dose associated with this part of the procedure is 1.0 mSv.  
The total radiation dose for a subject completing the trial is thus: (2 x 3.8 mSv (PET) + 2 x 1.0 
mSv (CT)) = 9.6 mSv. Background radiation in Denmark is approximately 3 mSV per year. The 
exposure to radiation in this study corresponds to 3-4 years of average background radiation. 
The additional cancer risk associated with the radiation exposure in this study is 0.048%. An 
additional cancer risk of 0.048% is equal to approximately 1 in 2080 chances. In a healthy 
individual younger than 50 years of age, the exposure of 9.6 mSV will increase the lifetime risk 
of dying from cancer from 25% to 25.048%. 

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There is no risk of deterministic effects in this study. The risk of stochastic effects is estimated 
to category IIb. 
 
8.9 Benefit/risk assessment 
 
There is an unmet medical need to reduce the increased risk of cardiovascular disease in 
patients with psoriasis. Cardiovascular disease caused by premature atherosclerosis is the 
cause of morbidity and decreased quality of life as well as increased mortality in patients with 
psoriasis. Due to the high prevalence of the disease this is relevant to a large number of 
patients. Brodalumab targets IL-17RA which has been shown as a key receptor in psoriasis 
patogenesis and a promising target in atherosclerosis.  
 
Brodalumab has already demonstrated high efficacy and a favorable safety profile in the 
treatment of moderate-to-severe psoriasis in clinical studies. The drug is approved for the 
treatment of moderate-to-severe psoriasis by EMA and DMA. 
In order to ensure appropriate treatment of the patients after they have completed the trial, 
the subjects will be treated at the investigator’s discretion or referred to other physicians 
according to clinical practice and national treatment guidelines. 
 
In patients undergoing FDG-PET/CT, it is well known that incidental focal lesions can be 
indicative of premalignant or malignant lesions.  For instance, studies have shown that FDG-
PET/CT reveals unexpected colonic FDG uptake in approximately 5% of patients and that a 
considerable number of these are diagnosed as premalignant or malignant.47-49 
A high frequency of incidental PET findings have previously been shown in psoriasis 
patients.50  
We found incidental focal colorectal FDG-uptake in one of 12 cases in our pilot study of aortic 
vascular inflammation in patients with moderate-to-severe psoriasis.34 This particular case of 
asymptomatic colorectal cancer was diagnosed earlier than would have been the case if the 
patient had not undergone FDG-PET/CT. The cancer was curably removed by surgery. 
In the current study, the low-dose FDG-PET/CT protocol will limit the area of interest to the 
thoracic and upper abdominal area. 
 
The main risk in this study is associated with the exposure to radiation. A low radiation dose 
PET protocol and a limited non-enhanced CT protocol has been adopted to reduce the 
radiation dose to a minimum without sacrificing data quality.51  
 
There is a risk that psoriasis may flare up during the wash-out period and during the study 
period for the patients included in the placebo group. Due to the relatively short duration of 
the study this is regarded as an acceptable risk and not associated with adverse outcomes. A 
similar period of treatment holiday may be seen during routine clinical practice when 
switching systemic treatments, in case of side-effects, travel, or when surgery must be 
performed. 
 
During the PET procedure an intravenous access is needed which can cause minor bruising. 
The same risk applies to the laboratory blood test performed. A very small risk of infection is 
associated with intravenous procedures. 

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Accordingly, the optional punch biopsy is associated with a small risk of bleeding, infection, 
and scaring. The use of approximately 1 mL/per injection 2% lidocaine with epinephrine 
solution is associated with a small risk of systemic allergic reactions. 
 
Some patients may experience claustrophobic sensations during the PET/CT procedure. 
 
Efficacy and safety of brodalumab has been shown previously and the drug is approved for 
routine clinical use. Any risk associated with brodalumab is comparable to other biologic 
agents approved for the treatment of psoriasis. Participating patients will be candidates for 
systemic treatment. 
 
In conclusion, the potential health-related benefits for the individual patient and for other 
psoriasis patients are considerable. Appropriate measures have been undertaken to reduce 
the risk for participating patients. The drug utilized is approved for clinical use and has 
documented high efficacy and a good safety profile. The current risk/benefit ratio is 
acceptable and supports the initiation of this study. 
 
 
8.10 
Ethical considerations 
 
The study is conducted in compliance with the principles of the Declaration of Helsinki.  
No children or other vulnerable subjects incapable of giving informed consent will be 
enrolled in this clinical trial. Furthermore, women who are pregnant, breastfeeding, or trying 
to become pregnant will not be enrolled in this clinical trial. Women of child-bearing potential 
have to agree to use a highly effective method of contraception to prevent pregnancy during 
the clinical trial. In addition, all female subjects of child-bearing potential will have a 
pregnancy test performed before treatment and study related procedures are commenced. 
Only psoriasis patients will be enrolled, meaning that only patient who may benefit from the 
results obtained in this trial is participating.  
Subjects are not reimbursed for participating in the trial, meaning that financial motivation 
will not lead to impaired judgment.  
 
 
The risk of developing solid cancers follows a linear pattern with increasing dose although the 
age at which exposure takes place is highly relevant. A decline in radiosensitivity does take 
place with age, making young individuals more susceptible to radiation-induced malignancies. 
Although the malignancy risk for the population as a whole is 5 %/Sv, this is higher in 
children and considerably lower in older individuals.  
The exposure to radiation restricts the age groups that may be enrolled to individuals > 40 
years of age to reduce the stochastic risk of malignancies. Furthermore, by chosing this age-
cutoff the study will include patients that may potentially benefit from incidental PET 
findings. Cardiovascular comorbidity and premature atherosclerotic disease associated with 
psoriasis are relevant for this age group. Younger indivuals more susceptible to radiation-
induced malignancies and with low absolute risk of incidental malignant findings and 
cardiovascular disease are excluded from participation. Moreover, the typical mean age of 

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patients with moderate-to-severe psoriasis included in clinical trials is approximately 40-50 
years. 
 
Altogether, the risks associated with participating in this clinical trial are considered low and 
outweighed by the benefit of achieving high-quality scientific knowledge regarding the 
potential of reducing premature cardiovascular disease in patients with moderate-to-severe 
psoriasis. 
 
In accordance with the current version of the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines and Danish Executive Order number 695 of 
12/06/2013, qualified medical personnel will be readily available to advise on trial-related 
medical questions. Medical monitoring will be performed by the GCP unit at Aarhus 
University throughout the trial.  
 
In conclusion, the trial design chosen for this trial investigating the effect of brodalumab on 
aortic vascular inflammation and systemic inflammation is regarded as ethically justified and 
adherent with ethical requirements. 
9 Trial objectives and endpoints 
 
9.1 Trial objectives and endpoints 
 
Objectives 
Endpoints 
Primary objective 
Primary endpoint 
To assess the change in aortic wall inflammation 
from baseline to week 16 in brodalumab treated 
psoriasis subjects compared to placebo. 
 
 
Change in the average of maximum TBR 
values (MeanTBRmax) of the entire aorta 
from baseline to week 16 
Secondary objectives 
Secondary endpoint 
To assess the change in splenic inflammation 
from baseline to week 16 in brodalumab treated 
psoriasis subjects compared to placebo. 
 
To assess the change in aortic wall subsegment 
inflammation from baseline to week 16 in 
brodalumab treated psoriasis subjects compared 
to placebo. 
 
To assess whether changes in skin inflammation 
is associated with changes in aortic wall 
inflammation and/or changes in splenic 
inflammation. 
 
Change in the spleen-to-liver ratio (SLR) 
based on splenic and liver mean 
standardised uptake values (SUVmean) 
 
 
Change in the average of maximum TBR 
values (MeanTBRmax) of the ascending, 
aortic arch, descending, suprarenal, and 
infrarenal aorta from baseline to week 
16 
 
 
Association between change in PASI and 
change in aortic wall MeanTBRmax  
 
 
Association between change in PASI and 
change in SLR 
Additional secondary objectives 
 
To assess the change in subcutaneous adipose 
tissue inflammation from baseline to week 16 in 
 
Change in the average of maximum SUV 
values (MeanSUVmax) of the abdomial 

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brodalumab treated psoriasis subjects compared 
to placebo and whether this change is associated 
with changes in skin inflammation. 
 
 
To assess the change in soluble inflammatory 
biomarkers from baseline to week 16 in 
brodalumab treated psoriasis subjects compared 
to placebo. 
 
To assess whether the change in aortic wall 
inflammation and/or splenic inflammation is 
associated with psoriasis-specific genotypes. 
 
 
To assess the change in gene expression and 
cytokine expression in paired lesional and non-
lesional psoriatic skin from baseline to week 16 
in brodalumab treated psoriasis subjects 
compared to placebo. 
subcutaneous adipose tissue from 
baseline to week 16 
 
Association between change in PASI and 
change in subcutaneous adipose tissue 
MeanSUVmax. 
 
 
Changes in acute phase proteins from 
baseline to week 16 
 
 
 
Correlation between changes in both 
aortic meanTBRmax and SLR and 
prescence of HLA-B*08, HLA-
C*06:02, HLA-B*27, HLA-B*38 and HLA-
B*39 
 
 
Changes in gene expression and cytokine 
expression in skin samples from baseline 
to week 16 
 
Correlation with changes in mean aortic 
TBRmax and SLR. 
 
10 Trial design  
10.1 
Overall trial design  
 
This is an investigator-initiated, single-center, randomized, double-blind (subjects, 
investigators, and nuclear medicine specialists and all staff involved in vascular imaging and 
analysis is blinded to group assignment) prospective, controlled study. Subjects are 
randomized and matched on sex and age (± 5 years) (stratified randomization). 
Subjects with moderate-to-severe psoriasis are enrolled consecutively and randomly assigned 
to either active treatment with brodalumab or placebo during the treatment period. Subjects 
are entered into a pre-study washout period, if needed, wherein all active anti-psoriatic 
topical and systemic therapies are discontinued according to pre-specified time frames. 
Psoriasis subjects are examined with FDG-PET/CT at baseline and again at end of study after 
16 weeks of brodalumab treatment or placebo, respectively.  
Baseline investigations include medical history, physical examination, and laboratory tests. 
 
10.2 
Number of subjects needed  
 
Assuming a screening failure rate of 20%, approximately 62 patients will be screened and 
50 patients will be included and randomly assigned to either brodalumab or placebo (1:1; 25 
patients in each arm).  
The statistical power calculation (section 14.1) includes the risk of drop-out before 
completion of the second FDG-PET/CT. 

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10.3 
End of trial definition 
 
A subject is considered to have completed the trial if they have completed all periods of the 
trial including the last FDG-PET/CT and end of study visit. 
The end of the trial is defined as the date of the last visit of the last subject in the trial. 
 
The Ethical committee and the Danish Medicines Agency will be notified ≤ 90 days after the 
end of the trial. Results will be posted in ”EudraCT Results” ≤ 12 months after the end of the 
trial.  
 
10.4 
Record keeping, monitoring, and data handling 
 
Case report forms 
Data will be collected by means of electronic data capture in an eCRF (REDCap).   
Personal data is protected according to the Act on Processing of Personal Data (lov om 
behandling af personoplysninger).  
 
Source data 
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 may be entered directly in the eCRF.  
 
Data entered directly in the eCRF are listed in appendix II. 
 
The following data will 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 the eligibility criteria 
are met. 
 The fact that the subject is participating in a clinical trial in psoriasis including 
treatment arms of brodalumab or placebo for 16 weeks  
 Other relevant medical information 
 
Trial monitoring 
 
The GCP unit at Aarhus University Hospital will be granted access to perform monitoring to 
confirm that the trial is being conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
 
In order to perform their role effectively, GCP unit staff involved in quality assurance and 
inspections will have direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. 
Upon request, inspectors from the Danish Medicines Agency will be granted the same access. 
 

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Data handling 
 
Subject data should be entered into the CRF as soon as possible after each visit. Patient-
reported data (data from questionnaires completed at the trial site) will be entered into the 
eCRF by the investigator. 
Data will be stored for at least 5 years as required according to Danish legislation. 
 
11 Trial population and withdrawal 
 
11.1 
Subject eligibility 
 
Eligible patients must fulfill all eligibility criteria and be expected to comply with the protocol. 
 
11.2 
Inclusion criteria  
 
1. Written informed consent obtained from the subject prior to performing any protocol-
related procedures. 
2. Age 40 and above. 
3. Diagnosis of chronic plaque psoriasis confirmed by a dermatologist  
4. PASI ≥ 10 
 
11.3 
Exclusion criteria  
 
1. Non-Danish speaking 
2. Known or suspected allergy or reaction to any component of the IMP formulation. 
3. History of inflammatory bowel disease, arthritis (not including psoriatic arthritis), 
systemic lupus erythematosus, and active inflammatory skin diseases. 
4. A history of malignancies within the past five years (excluding localized non-
melanoma skin cancer).  
5. Topical corticosteroid treatment (class III or stronger) and/or ultraviolet type B 
phototherapy within 2 weeks prior to randomization  
6. Treatment with psoralen plus ultraviolet type A photochemotherapy, methotrexate, 
cyclosporine, acitretin, or fumaric acid esters within 4 weeks prior to randomization.  
7. Treatment with adalimumab, etanercept, infliximab, cosentyx, or ixekizumab within 12 
weeks, ustekinumab within 24 weeks, or other immunosuppressive or anti-
inflammatory agents within 5 half-lives of the active substance prior to the FDG-
PET/CT, respectively.  
8. Scheduled surgery during the trial period (expect minor minimally invasive 
procedures). 
9. Systemic infection or fever within 7 days prior to FDG-PET/CT. 
10. Severe obesity (> 150 kg due to a PET/CT scanner limitation).  

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11. Presence of uncontrolled diabetes mellitus (HbA1c > 75 mmol/mol and/or blood sugar 
> 11.1 mmol/l and/or clinical judgment). 
12. History of coagulation defects (clinical judgment). 
13. Active or latent tuberculosis requiring treatment.  
14. Positive hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), 
hepatitis B core antibody (HBcAb) or hepatitis C virus antibody (anti-HCV) serology at 
screening. Subjects with positive HBsAb may be randomised provided they are 
hepatitis B vaccinated and have negative HBsAg and HBcAb. 
15. History of any known primary immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test at screening, or the subject taking antiretroviral 
medications as determined by medical history and/or subject’s verbal report. 
16. No history of varicella zoster infection and negative varicella antibody test (until 
varicella vaccination is completed). 
17. History of chronic alcohol or drug abuse within 12 months prior to screening, or any 
condition associated with poor compliance as judged by the investigator. 
18. History of intravenous drug use. 
19. History of attempted suicide or is at significant risk of suicide.  
20. Major surgery within the past 3 months. 
21. Pregnancy or lactation (Women of childbearing potential must use a highly effective* 
form of birth control (confirmed by the investigator) throughout the trial and until 12 
weeks after discontinuation of treatment with brodalumab. 
22. Claustrophobia. 
23. Reduced renal function (serum creatinine > 200 μmol/L or cr-EDTA clearance < 30 
ml/min) 
24. Any disorder, including but not limited to, cardiovascular, lung, gastrointestinal, 
hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, 
haematological, immunological, psychiatric, or major physical impairment that is not 
stable, in the opinion of the investigator, and could:  
o Affect the safety of the subject throughout the trial.  
o Influence the findings of the trial or their interpretations. 
o Impede the subject’s ability to complete the entire duration of trial. 
 
* A highly effective method of birth control is defined as one which results in a low failure rate 
(less than 1% per year) such as bilateral tubal occlusion, intrauterine device (IUD), 
intrauterine hormone-releasing system (IUS), combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal), progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, implantable), sexual abstinence (when this is in line 
with the preferred and usual life style of the subject), vasectomised partner (given that the 
subject is monogamous). The subjects must have used the contraceptive method continuously 
for at least 1 month prior to the pregnancy test. A female is defined as not being of child 
bearing potential if she is postmenopausal (at least 12 months with no menses without an 
alternative medical cause prior to screening), or surgically sterile (hysterectomy, bilateral 
salpingectomy or bilateral oophorectomy). 
 
 

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11.4 
Recruitment and informed consent procedures 
 
Refer to Appendix IV for further details on recruitment and informed consent in Danish. 
 
Prospective study subjects: 
 Patients with moderate-to-severe psoriasis which is referred for treatment at 
Department of Dermatology, Aarhus University Hospital. 
 Patients with moderate-to-severe psoriasis which is currently being treated at 
Department of Dermatology, Aarhus University Hospital. 
 
Prospective study subjects are identified based on: 
 Physician referral letters 
 Medical records 
 Patient lists 
 
Typically, initial contact is made with a prospective subject during/before a scheduled routine 
appointment at the department of dermatology. The subjects will be invited for a formal 
informed consent dialogue by one of the investigators (KFH or LI) or another qualified HCP. 
Prospective subjects may be identified during the evaluation process of clinical physician 
referral letters. A recruitment letter (Appendix XI) may be sent to a prospective subject which 
is identified based on the referral letters. A contact may be performed by the investigators if 
the prospective subjects actively express a wish to learn more about the study. During this 
conversation, the prospective subject will be invited for a formal informed consent dialogue 
and a brief description of the trial will be provided. It is specifically emphasized that the 
dialogue and any further study participation is voluntarily and that standard clinical 
treatment is entirely possible at any stage. 
Written study information will be provided when date, time, and place for a formal informed 
consent dialogue has been arranged. 
The prospective subjects will be informed of the option to bring a family member or counselor 
at the formal dialogue. 
 
Enviroment: The environment where the process of consent is conducted will enable a 
period where a private, confidential, and “safe” setting is afforded to facilitate a constructive 
dialogue between the prospective subject and the investigator(s) involved in obtaining 
consent. A physician’s office or an examination room in the clinical research department will 
typically be used.  
 
Presentation of the Elements of Informed Consent: The required elements of informed 
consent will be presented and discussed with the prospective subject in a sequential manner 
utilizing the approved ”participant information” (appendix V) as a guide. The presentation 
will be structured to facilitate a dialogue with reinforcement and elaboration of important 
information (e.g., the risks of the research; radiation exposure, risk of flare). The 
investigator(s) involved in obtaining the subject’s consent will evaluate whether the process 
is achieving the goal which is obtainment of legally effective informed consent from the 
subject. Open-ended questions will be used in order to identify points of confusion which 
require clarification.  

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Use of a Delayed Consent Procedure: The amount of time allotted to the process of consent 
is individual and is decided at the subject’s discretion. A 24 hour delay is suggested. If the 
individual is uncomfortable or anxious about participating in the study they will be instructed 
to take the written material home for further review and consideration before deciding 
whether or not to participate in the research.  
 
Documentation of informed consent: The investigator who assumes responsibility for 
documentation of informed consent and the consenting subject should sign and date the 
informed consent form, preferably in each other’s presence.  
 
11.4.1 Information collected from the medical records 
 
The following information is passed on from the clinical medical records as part of the 
screening process (evaluation of elegibility criteria): 
 Age 
 Sex 
 Height and weight if available 
 Severity of psoriasis and PsA 
 Current treatment of psoriasis 
 
The following information is collected from the clinical medical records after informed 
consent: 
 Previous and current anti-psoriatic treatments 
 Concomitant medication, procedures and diagnoses 
 
 
11.5 
Screening, screening failures, and randomisation 
 
Trial participation begins once written informed consent is obtained. The screening 
evaluations to assess eligibility criteria may begin once informed consent is obtained. 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. The following information is recorded in 
case of screening failure:  demography, screening failure details, eligibility criteria, and any 
adverse events (AEs) and serious AEs (SAEs).  
 
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.  
Re-screening is permitted after a due washout period if screening failure is due to treatment 
with any of the substances listed in section 10.3. 
 

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11.6 
Discontinuation 
 
A subject may withdraw from trial or from treatment at any time (prior to FDG-PET/CT, 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 if 
baseline FDG-PET/CT has been performed. 
 
Assessments 
Subjects who permanently discontinue treatment for any reason will be invited to attend an 
early termination visit for data to be collected. The investigator will review any AEs which will 
be followed-up according to clinical guidelines, if the subject agrees. In order to ensure 
appropriate treatment of the subjects after they have discontinued the trial, the subjects will 
be treated at the investigator’s discretion or referred to other physicians according to clinical 
practice and national treatment guidelines. 
 
Lost to follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and is unable to be contacted by the trial site. 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 and/or “e-boks”). These contact attempts should be documented in 
the subject’s medical record.  
 
11.7 
Reimbursement 
 
Subjects are not reimbursed for participating in the trial. 
 
11.8 
Insurance 
 
Participating subjects are covered by The Patient Compensation Association as the study is 
conducted by authorized HCP’s at a public healthcare hospital. 
 
 
 
 
12 Treatments 
 
12.1 
Trial product description  
 
Brodalumab is a recombinant fully human monoclonal immunoglobulin IgG2 antibody that 
binds with high affinity to human IL-17RA and blocks the biological activities of the pro 

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inflammatory cytokines IL-17A, IL-17F, IL-17A/F heterodimer and IL-25. Brodalumab is 
approved for the treatment of moderate to severe plaque psoriasis in adult patients who are 
candidates for systemic therapy. The trade name of brodalumab is Kyntheum and it is 
marketed by LEO Pharma A/S. Kyntheum is available as a 210 mg solution for injection. 
Further details is available from the product description (Appendix I). 
 
Active substance: 
Brodalumab (Kyntheum) 210 mg in a pre-filled syringe. The prefilled syringe is a single use, 
disposable system that is designed to administer the labeled dose of the medicinal product to 
the subcutaneous space during 1 injection.  
Masking of the accessorised pre-filled syringes will be performed at the Central Denmark 
Region Hospital Pharmacy before delivery to the study site. 
 
Placebo: 
Placebo solution (1.5 mL Natriumklorid "Fresenius Kabi" 9 mg/ml solution)(Appendix XII) for 
injection in a pre-filled insulin-type syringe with a 30G-13 mm needle. The pre-filled injector 
is manufactered and masked at the Central Denmark Region Hospital Pharmacy before 
delivery to the study site. 
 
 
12.2 
Administration of investigational medicinal products  
 
Brodalumab (Kyntheum) will be provided by the funding body (LEO Pharma A/S). 
 
The first day of dosing is at visit 2 after completion of baseline FDG-PET/CT.  
 
Experimental arm: Brodalumab 
Eligible subjects will receive 210 mg of brodalumab administered by subcutaneous injection 
at Weeks 0, 1 and 2 followed by 210 mg every other week (EOW) thereafter.  
 
Placebo comparator: Placebo 
Eligible subjects will receive placebo doses administered by subcutaneous injection at Weeks 
0, 1 and 2 followed by placebo EOW thereafter.  
 
All subjects will be allowed to continue topical anti-psoriatic treatments as stated in section 
12.4. Other systemic and topical anti-psoriatic treatments are not allowed. 
 
The first dose of the investigational medicinal products is administered by a healthcare 
professional (HCP) at the trial site at visit 2. The investigational medicinal products will be 
administered by a qualified, unblinded HCP (see Section 11.3.1 for blinding details).  
For the first IMP dosing visit, subjects will be monitored after IMP administration for 
immediate drug reactions for a minimum of 15 minutes according to routine clinical practice. 
According to the investigators brochure (produktresume, appendix I) no monitoring is 
needed. However, the IMP is administered in the hospital setting where medication and 
equipment for acute life support is immediately available to physcians and nurses responsible 
for the treatment and monitoring of the subjects.  

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Subsequent doses will be administered as home-use by the subjects or the subject’s caregiver. 
Prior to self-administration at home, the individual who will be administering the injections 
(i.e., the subject and/or the caregiver) will receive proper training in subcutaneous (SC) 
injection technique and on procedures to be followed in the event of an emergency during or 
following home-use of brodalumab. This training will be conducted by an unblinded HCP. 
Patients who do not want to self-inject may have the staff at the trial site administer all the 
injections at the trial site if applicable. 
 
Subjects are instructed to contact the investigator/trial site in case of fever > 38°C within 72 
hours prior to injection. In case a clinically significant infection is suspected the following 
actions can be taken at the investigator’s discretion: 
 Rescheduled administration of placebo/brodalumab  
 Further work-up (e.g. laboratory tests) and concomitant treatment of infection  
 
Patients are instructed to contact the investigator/trial site in case of fever > 38°C within 1 
week prior to scheduled FDG-PET/CT. Rescheduling of FDG-PET/CT is at the investigator’s 
discretion. 
 
12.3 
Treatment assignment  
 
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria will be randomized at baseline (visit 2) to receive treatment with 
either brodalumab or placebo. Treatment assignment will be according to a computer 
generated randomization (REDCap, https://redcap.au.dk) in a 1:1 ratio. The method of 
randomization will be based on matched pairs design in which subjects will be matched on 
sex and age stratification (age decades; 40 – 49, 50 – 59, 60 – 69, 70 – 79, > 80). 
 
12.3.1 Blinding  
 
This is a double-blinded trial in which brodalumab and placebo are visually distinct from 
each other. The packaging and labelling of the products will contain no evidence of their 
identity. 
Since brodalumab and placebo are visually distinct, the products will be handled and 
administered by a qualified, unblinded HCP at the site. A blinded study physician at the site 
will perform clinical assessment of PASI, IGA, BSA, nails, and joints at visit 2, 3, and 4. 
Subjects are not informed of the visual differences between placebo and brodalumab. 
Syringes are masked and with no posibility of identifying the content. The only visual 
difference will be minor color differences. Therefor, subjects will not be aware of the 
treatment received. 
 
Subjects, investigators (except unblinded HCPs), and nuclear medicine specialists and all staff 
involved in vascular imaging and analysis is blinded to group assignment.  
 
The trial site will maintain a written plan detailing which staff members are 
blinded/unblinded. 

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12.3.2 Emergency unblinding of individual subject treatment  
 
Provisions are in place for 24 hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator can unblind a subject. Emergency 
envelopes of individual treatment allocation is maintained by the unblinded HCP’s at the trial 
site. For a requester without access to the trial site (e.g., an HCP not involved in the trial), a 24 
hour local contact number for the trial site is provided.  The requester will provide the subject 
ID (Danish CPR number) to the staff who will reveal the individual treatment allocation. If 
necessary, the staff will facilitate contact to the investigators.  
 
12.4 
Background treatment (topical agents)  
 
All subjects may use an additive-free, basic bland emollient twice daily and/or topical 
corticosteroid class II or weaker (danish classification of topical corticosteroids). Subjects are 
not allowed to start treatment with other prescription emollients including topical 
corticosteroids class III or stronger during the trial. Other topical and systemic anti-psoriatic 
treatments are not allowed. 
 
12.5 
Concomitant medication and procedures  
 
Concomitant medication and procedures (including diagnosis, intervention, and start and stop 
date) are recorded in the subject’s medical record and the eCRF. Investigators may prescribe 
concomitant medications or treatments to provide adequate supportive care as deemed 
necessary, except for medications listed in Section 11.6. 
Concomitant medication for conditions other than psoriasis may be continued throughout the 
trial without any change in dosage whenever possible. 
 
12.6 
 Prohibited medication and procedures  
 
The following medications are prohibited during the trial from inclusion through week 16: 
 
 Topical corticosteroid treatment (class III or stronger)  
 Other topical treatments for psoriasis such as calcipotriol 
 Ultraviolet type B phototherapy  
 Psoralen plus ultraviolet type A photochemotherapy 
 Methotrexate, cyclosporine, acitretin, and fumaric acid esters  
 Adalimumab, etanercept, infliximab, cosentyx, ixekizumab, and ustekinumab 
 Other immunosuppressive or anti-inflammatory agents including janus kinase 
inhibitors, interferon-gamma, or other biologics 
 Immunoglobulin or blood products 
 Systemic corticosteroids (nasal and inhaled corticosteroids are allowed) 
 Allergen immunotherapy 

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 Live (attenuated) vaccine 
 
12.7 
Treatment logistics and accountability  
12.7.1 Labelling and packaging of investigational medicinal products 
 
The investigational medicinal products will be packaged in individually numbered kits, each 
containing 1 syringe (brodalumab 210 mg or placebo). 
Primary and secondary packaging materials (syringe and outer carton, respectively) will be 
individually labelled. Labelling will not indicate whether the content of the syringe is 
brodalumab or placebo. 
 
12.7.2 Storage of investigational medicinal products 
 
Initial storage and relabeling of brodalumab are delegated to the Central Denmark Region 
Hospital Pharmacy. Products are subsequently delivered to the research facility at the 
Department of Dermatology, Aarhus University Hospital.  
All investigational medicinal products will be stored in a secure and restricted area under the 
conditions specified on the label and remain in the re-labelled original container until 
dispensed. 
The products will be stored at 2 to 8°C at the site. The temperature during storage will be 
monitored by a calibrated, stationary and continuously recording system.  
A temperature log will be kept to document the storage within the right temperature interval. 
Storage facilities will be checked at least every working day. 
Subject’s will be instructed to store Brodalumab for home-use at 2 to 8°C (refer to appendix I 
for details).  
 
12.7.3 Drug accountability  
 
An inventory (trial medication inventory log) will be kept of the investigational medicinal 
products administered/provided to each subject randomized in the trial. The trial medication 
inventory log will be available for inspection during monitoring visits. 
Subjects will be provided with sharps bins for used syringes. Filled sharps bins will be 
returned to the trial site. Subjects will return trial kit cartons, and any unused products at 
next trial visit. 
 
12.7.4 Trial product destruction  
 
Unused investigational medicinal products as well as used syringes returned to the site will be 
shipped for destruction by the Department of Dermatology according to local approved 
procedures. 
12.7.5 Treatment compliance  
 

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Subjects will record date and injection site for each administration in a log of drug 
administration; these data will then be transcribed into the eCRF by site staff at the next trial 
visit. Any non-compliance and the reason for it must be recorded in the eCRF. 
If the treatment has been interrupted for any reason (e.g. clinically significant infection) the 
final visit can be postponed at the investigator’s discretion with the number of weeks that the 
treatment was interrupted. 
All used and unused syringes must be returned to the trial site. 
 
12.8 
Provision for subject care following trial completion  
 
In order to ensure appropriate treatment of the subjects after they have completed the trial, 
subjects will be treated at the investigator’s discretion or referred to other physicians 
according to clinical practice and national treatment guidelines. This also applies to subjects 
that dropout or terminates the study before completing all visits. 
 
12.9 
Reporting product complaints  
 
Any defect with the brodalumab device will be reported to LEO Pharma A/S according to 
standard practice. 
 
13 Trial schedule and assessments  
 
13.1 
Overview  
 
Protocol approval (Danish Medicines Agency and Ethical Committee): by November 2017 
First patient first visit: December 2017 
Patient enrollment and investigational procedures: December 2017 – April 2019 
Last patient last visit: April 2019 
Data collection completion: May 2019 
Data analysis and publication of results: Until January 2020 
 
Evaluations to be done at each visit are shown in the schedule of procedures in Section 7. 
Refer to Section 10.1 for further details on the trial design. 
 
During the course of the trial, subjects may need to be seen at unscheduled visits. The 
assessments to be performed at an unscheduled visit are left to the investigator’s discretion. 
Assessment of psoriasis disease severity (PASI, IGA, BSA, nail count, and joint count) after 
randomization will be performed only by the blinded assessor. 
13.2 
Assessments performed only at screening/baseline  
 
Assessments performed only at the screening and/or baseline visit include: assessment of 

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elegibility criteria, demographics, medical history, height, and weight. These are described in 
further detail below. Laboratory tests include hepatitis B, hepatitis C, HIV-1, HIV-2, T-spot, 
and serum pregnancy test. Varicella zoster antibody analysis may be relevant in some 
subjects. Procedures include chest X-ray.  
A pre-treatment chart is completed before initiation of treatment according to national 
guidelines (Appendix III) 
 
13.2.1 Demographics  
 
The following demographic data will be recorded: 
year of birth 
 
ian, Black or African American, Middle East and North Africa, White, Other 
 
13.2.2 Medical history  
 
Relevant past and concurrent medical history must be recorded and includes: 
 
 Psoriasis medical history: all past and current history including: 
o Duration of psoriasis in years 
o Severity of psoriasis 
o Previous psoriasis treatments 
o Psoriasis clinical manifestations (plaque, scalp, nails, genital/flexural) 
o Family history of psoriasis 
o Co-morbidities including psoriatic arthropathy*, obesity, diabetes mellitus, 
arterial hypertension, hypercholesterolemia, stroke, ischemic heart disease, and 
depresion 
 
 Other medical and surgical history including concurrent diagnoses. 
 
Relevant medical history includes also diseases which are specifically listed as exclusion 
criteria and diseases for which specific treatments are listed as exclusion criteria. 
 
*Psoriatic arthropathy: history of formal psoriatic arthritis diagnosis or; pain, stiffness for >30 
minutes in the morning / after prolonged inactivity. Improves with activity. Peripheral or 
with axial involvement – inflammatory back pain and stiffness that improve with activity. 
Night symptoms.  
13.2.3 Height and weight  
 
The subject’s height must be measured (without shoes) and weight must be determined (in 
indoor clothing and without shoes). 

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13.3 
Psoriasis efficacy assessments  
13.3.1 Investigator assessments  
13.3.1.1 
Investigator’s Global Assessment  
 
The IGA is an instrument used in clinical trials to rate the severity of the subject’s global 
psoriasis and is based on a 5-point scale ranging from 0 (clear) to 4 (severe).52 The IGA score 
will be assessed according to the Schedule of procedures (Section 6). 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 (static form of IGA). Assessment at screening is performed by a 
trained investigator. Assessment at baseline (visit 2) and follow-up (visit 3 and 4) will be 
performed by a blinded assessor only. 
 
Investigator’s Global Assessment 
Score  
Disease severity 
0  
 
Clear 
1 
Almost clear 
2 
Mild disease 
3 
Moderate disease 
4 
Severe disease 
 
13.3.1.2 
Psoriasis Area and Severity Index  
 
The most widely used and best validated instrument for assessment of psoriasis disease 
severity is the Psoriasis Area Severity Index (PASI).53-55 The PASI score rests on a physician’s 
evaluation of the skin area involved, erythema, induration and scaling; and scores range from 
0 to 72. Treatment response is assessed as PASI reduction in percentage. Even though there is 
no definite consensus, moderate-to-severe psoriasis is often defined as a PASI score ≥ 10.56 
Assessment at screening is performed by a trained investigator. Assessment at baseline (visit 
2) and follow-up (visit 3 and 4) will be performed by a blinded assessor only. 
 
 

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13.3.1.3 
Body surface area involvement 
 
The total BSA affected by psoriasis will be assessed. 
Assessment at screening is performed by a trained investigator. Assessment at baseline (2) 
and follow-up (visit 3 and 4) will be performed by a blinded assessor only. 
 
13.3.1.4 
Quantitative nail assessment 
 
The total number of nails affected by psoriasis will be assessed. The nails are assessed for 
both nail matrix psoriasis and nail bed psoriasis. Features of nail matrix psoriasis includes 
nail pitting, leukonychia, red spots in the lunula, and crumbling of the nail. Features of nail 
bed psoriasis includes onycholysis, oil drop (salmon patch), dyschromia, splinter 
hemorrhages, and nail bed hyperkeratosis. 
 
Assessment at screening is performed by a trained investigator. Assessment at baseline (visit 
2) and follow-up (visit 3 and 4) will be performed by a blinded assessor only. 
 
13.3.1.5 
Quantitative joint assessment 
 
Joints are palpated for the purpose of determining if they are tender and/or swollen, the latter 
implying the presence of active synovitis, and both implying the presence of inflammation.57  
Joint swelling is defined as soft tissue swelling of the joint which is detectable along the joint 
margins. A synovial effusion invariably means that the joint is swollen. Fluctuance is a 
characteristic feature of swollen joints; neither bony enlargement nor deformity of the joint 

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constitutes “swelling”. Joint swelling may influence the range of joint motion, which can be 
useful to recognize the presence of swelling.58   
Joint tenderness is defined as pain at rest that is induced by pressure at examination of some 
joints such as the metacarpophalangeal (MCP) and wrist joints. The assessor should use 
his/her thumb and index finger to exert pressure that is sufficient to cause whitening in the 
assessors nailbed, which is called the “rule of thumb”.58   
The total number of swollen and the total number of tender joints will be recorded. 
 
13.3.2 Subject assessments 
13.3.2.1 
Dermatology Life Quality Index 
 
The Dermatology Life Quality Index (DLQI) is a validated questionnaire with content 
specific to those with dermatology conditions. It consists of 10 items addressing the subject’s 
perception of the impact of their skin disease on different aspects of their quality of life (QoL) 
over the last week such as dermatology-related symptoms and feelings, daily activities, 
leisure, work or school, personal relationships, and the treatment.59 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 QoL. The DLQI 
will be completed according to the Schedule of procedures in Section 7 and at each self-
injection during home-use of the investigational medicinal product. The DLQI is included in 
the appendix. 
 
13.3.2.2 
Psoriasis Symptom Inventory (PSI) 
 
The Psoriasis Symptom Inventory (PSI) is an eight-item psoriasis-specific, patient-reported 
outcome measure used in assessing the severity of psoriasis symptoms.60 The PSI has 
demonstrated excellent internal consistency, test–retest reliability, validity, and 
responsiveness in moderate to severe plaque psoriasis, based on a pooled analysis of data 
from a phase II clinical study (n = 198) to evaluate the efficacy of brodalumab in moderate to 
severe chronic plaque psoriasis.61 The PSI consists of 8 items: itching, redness, scaling, 
burning, stinging, cracking, flaking, and pain. Patients were asked to complete the 24-hour 
and 7-day recall version of the PSI by rating the severity of each symptom on a 5- point 
categorical rating scale, ranging from not at all to very severe. The PSI can use a 24-hour recall 
and 7- day recall, and both versions have been found to yield comparable data.60 A PSI total 
score is defined for each version as the sum of all 8 items and ranges from 0–32, with higher 
scores indicating greater severity.  
The PSI will be completed according to the Schedule of procedures in Section 7 and at each 
self-injection during home-use of the investigational medicinal product. The PSI is included in 
the appendix. 
 
 
 
13.3.2.3 
Visual Analog Scale for joint pain 
 

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The pain is a unidimensional measure of pain intensity, which has been widely used in diverse 
adult populations, including those with rheumatic diseases.  
A subjective assessment of the average joint pain over the last 3 days/nights is recorded by 
the subject on a visual analogue scale, where 0 is no pain and 100 is the worst imaginable 
joint pain. 
 
13.4 
Clinical and laboratory assessments  
13.4.1 Physical examination 
 
A thorough physical examination of the subject including whole body inspection of the skin 
and auscultation of heart, lungs and abdomen; palpation of the abdominal organs and basic 
neurological status will be performed at the screening visit. 
 
Height, weight, hip circumference, blood pressure, and pulse will be assessed according to the 
Schedule of procedures in Section 6. 
 
Blood pressure and pulse (vital signs) will be measured in supine position following at least 5 
minutes rest. 
If an abnormal vital sign at screening is considered by the investigator to be clinically 
significant, it will be up to the investigator’s discretion if the subject should be randomized 
into the trial. 
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later with subjects resting in a supine position to verify the first measurement. 
Should the repeated measurement result in a normal value, the measurement must be 
repeated once more. If the third measurement verifies the second (normal) value, the first 
measurement will be considered as false. If the third measurement confirms the first 
measurement (abnormal) the second measurement will be considered as false. Only the last 
value measured and considered as correct will be recorded in the eCRF. 
 
13.4.2 Pregnancy test  
 
A urine pregnancy test (human chorionic gonadotropin; dipstick) will be performed at the 
trial site at screening prior to randomization in female subjects of child-bearing potential. 
 
13.4.3 Laboratory testing  
 
The following analyses will be performed at the Biochemical laboratory Aarhus University 
Hospital: Sodium, Potassium, Creatinine, C-reactive protein, Alkaline phosphatase, Alanine 
aminotransferase, Gamma glutamyl transferase, Cholesterol, LDL cholesterol, HDL 
cholesterol. Triglycerides, Glucose (non-fasting), Hba1c, Albumin, Hemoglobin, Leukocytes, 
Neutrophils, (neutrophils/total cells), Lymphocytes (lymphocytes/total cells) Monocytes 
(monocytes/total cells), Eosinophils (eosinophils/total cells), Basophils (basophils/total 
cells), Thrombocytes, Urinalysis (Protein, Glucose, Ketones, Occult blood, Leukocytes, Nitrite). 

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Analysis of hepatitis serology and HIV 1+2 will be performed according to institutional 
protocols. Analysis of varicella zoster antibodies will be performed in case of no history of 
previous varicella zoster infection. These tests are standard procedures before commencing 
treatment with biologic agents. 
A sample of 4 mL blood in an EDTA-tube is collected for storage at visit 1 (screening) and visit 
3 (week 6). Plasma is separated from erythrocytes by centrifugation and stored at -150°C for 
later analysis of inflammatory markers. 
 
13.4.4 Procedures 
 
Chest X-ray will be performed at a collaborating radiology imaging facility as part of the 
screening. If a chest X-ray result is abnormal and considered by the investigator to be 
clinically significant, it will be up to the investigator’s discretion if the subject should be 
enrolled into the trial.  
The procedure may be omitted if a chest x-ray has been performed within 6 months before 
screening and the result is accessible and normal. 
 
Punch biopsies will be performed as optional procedures. A supplementary informed consent 
form must be signed. A lesional and a non-lesional 4 mm punch biopsy will be performed in 
local anesthesia (approximately 1 mL/per injection 2% lidocaine with epinephrine solution) 
according to institutional guidelines. The punch biopsies will be performed at baseline and at 
visit 3 / 6 Weeks. Subjects will have the option to accept or decline punch biopsies. The 
acceptance or rejection of this procedure does not otherwise affect the eligibility of subjects. 
Punch biopsies will be snap frozen in liquid nitrogen and stored at -150°C for later analysis of 
IL-17 downstream pro-inflammatory marker genes (e.g. Nfkbiz, CCL20, Defb4) by qPCR. 
 
13.4.5 Research biobank 
 
Samples of plasma (4 mL) are collected for storage in a research biobank at visit 1 (screening) 
and visit 3 (week 6). Optional skin punch biopsies are collected at baseline and visit 3 (week 
6).   
Purpose of the research biobank is to store the biological material safely until analysis of 
inflammatory markers can be performed in all samples. 
Termination of the research biobank: January 2020. 
Any remaining biological materials after this date will be anonymized or destroyed.  
  
13.5 
FDG-PET/CT assessments  
13.5.1 Patient preparation 
 
FDG-PET/CT will be performed after an overnight fast using a combined PET/CT scanner 
(Siemens Biograph 64 PET/CT (Siemens, Germany)). FDG will be administered intravenously 
(approximately 200 MBq) and patients will rest comfortably for approximately 90 to 120 min 
in a well-tempered environment. 

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13.5.2 FDG dose and circulation time 
 
For arterial imaging with PET, longer delays between FDG injection and PET imaging than 
those used for oncology are recommended to allow sufficient FDG accumulation in the arterial 
wall and to reduce the intensity of FDG signal in the blood. The FDG circulation time is critical 
as optimal contrast between the target (plaque, arterial wall) and the background (blood) is 
essential to ensure accurate quantification of plaque FDG uptake. Based on previous results 
and current recommendations,45 the acquisition of PET images is performed 2 hours after 
injection. This imaging delay represents the best compromise between a low background 
signal in blood and an acceptable duration of the PET study for patients. 
To obtain a radiation dose as low as reasonably achievable, a 200 MBq protocol has been 
adopted. It has previously been shown that low-radiation-dose protocols can be used in 
arterial FDG-PET imaging without undue degradation of either image quality or lesion 
quantification.62 
 
13.5.3 Pre-scan fasting glucose 
 
Fasting glucose will be assessed before FDG-PET/CT. Vascular imaging should ideally be 
performed in patients with prescan glucose levels lower than approximately 7.0 – 7.2 
mmol/l). In patients in whom these blood glucose levels cannot be achieved, correction of the 
vascular FDG uptake according to the EANM recommendations for oncological PET imaging 
will be considered at the discretion of the nuclear medicine expert investigator. 
 
13.5.4 Image acquisition 
 
A low dose CT from the skull base level to the lower spleen level will be performed first for 
attenuation correction and anatomical co-registration. Imaging of the entire aorta, spleen and 
truncal adipose tissue will be performed next over 15–30 min (1 or 2 bed positions) 
acquisition time depending on the patient’s anatomy. 
 
 
13.5.5 Reconstruction protocol 
 
Reconstruction of attenuation-corrected images will be done using an ordered subset 
expectation maximization algorithm with point-spread function (PSF) and time-of-flight 
(three iterations, 24 subsets, matrix size 192 x 192, 4-mm Gaussian postprocessing filter). 
 
13.5.6 Quantification of radiotracer uptake in target tissue 
 
PET and CT data will be fused and analysed with PMOD v3.703 (PMOD Technologies, Zurich, 
Switzerland). CT and PET images will be reviewed for quality and the images are manually co-

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registered to ensure optimal anatomical correlation. Image analysis will be performed in 
accordance with recent nuclear medicine imaging guidelines by one expert observer. For the 
aorta, measurements are made every 3 mm, starting above the aortic valve level and 
continuing to the aortic bifurcation, approximately 200 slices per patient. Measurements are 
made in the axial planes by drawing a region of interest (ROI) containing the arterial wall and 
the lumen in each slice. The maximum standardized uptake values (SUVmax) of FDG within 
each ROI are recorded as a time- and dose-corrected tissue radioactivity divided by body 
weight. 
Blood SUVmean are measured by drawing small ROIs in the superior vena cava and then 
averaged to approach one single most accurate value for the circulating blood-pool signal in 
each individual. The target-to-background ratio (TBR) will be calculated from the ratio of the 
SUV of the artery compared with background venous activity. Aortic FDG uptake will be 
assessed using the average TBRmax. Subcutaneous adipose tissue inflammation will be 
assessed and compared as SUVmax and TBR based on SUVmax. Targets are truncal 
subcutaneous adipose tissue localized beneath psoriatic plaques as indicated by the 
investigator. 
Splenic inflammation is measured using mean standardised uptake values (SUVmean) and the 
spleen-to-liver ratio (SLR) in accordance with current recommendations and previously 
published methodology 63-66. Spleen volume of interst (VOI)s are drawn on five adjacent axial 
slices covering the central part of the organ, whereas liver VOIs are drawn on six adjacent 
axial slices in the right lobe. 
 
14 Adverse events  
14.1 
Collection and reporting of adverse events  
 
AEs1 will be be collected from time of first dosing of IMP until completion of the clinical trial. 
At all visits, the subject will be asked a non-leading question by the investigator about AEs, for 
example: “How have you felt since I saw you last?” No specific symptoms will be asked for. It 
is important that the investigator also observes the subject for any changes not reported by 
the subject and records these changes.  
SUSARs (Suspected, Unexpected Serious Adverse Reactions2) will be immediately reported 
directly to the Danish Medicines Agency in accordance with Danish legislation.  
All SAEs3 (Serious Adverse Events) and applicable AEs will be recorded in the medical record 
and the eCRF. 
Section 4.8 in the Product Information (appendix I) serves as reference for determining the 
relevance of events/reactions. 
It is the responsibility of the investigators to forward an annual safety report including a list 
of SAEs to the Ethical committee and the Danish Medicines Agency. 
All serious adverse reactions (SARs) from the entire trial must appear from the annual report 
on the trial subjects’ safety. This includes expected as well as unexpected serious adverse 
reactions (SARs and SUSARs) 
All important adverse events from the trial must appear from the final reporting of trial 
results in the EudraCT database in accordance with the EU guideline 2008/C168/02. 
 

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1 Adverse event: Medical occurrence temporally associated with the use of a medicinal 
product, but not necessarily causally related 
 
2Adverse reaction: All untoward and unintended responses to an investigational medicinal 
product related to any dose administered.  
 The definition covers also medication errors and uses outside what is foreseen in the 
protocol, including misuse and abuse of the product.  
 The definition implies a reasonable possibility of a causal relationship between the 
event and the IMP. This means that there are facts (evidence) or arguments to suggest 
a causal relationship.  
 An untoward and unintended response to a non-IMP which does not result from a 
possible interaction with an IMP is, by definition, not a SUSAR  
‘Serious’ adverse reaction: 
Regarding the criterion of ‘seriousness’, reference is made to footnote 3. 
 
3An 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 fulfill the 
criteria for being an SAE but should be documented in the subject’s medical 
record). 
 results in persistent or significant disability/incapacity. 
 is a congenital anomaly/birth defect. 
 is a medically important condition. Events that may not be immediately lifethreatening 
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 hospitalization, development of drug dependency or drug abuse. 
 
15 Statistical methods  
15.1 
 Sample size  
 
Derived from our investigations of vascular inflammation in psoriasis patients and control 
subjects, we expect a mean aortic TBRmax of 2.4 with a standard deviation of 0.35 in the 
psoriasis subjects. After succesful treatment with biologic agents, we expect the MeanTBRmax 
in the psoriasis subjects to be reduced to 2.1 with SD 0.35. Based on these assumptions and an 
alpha-level of 0.05 we calculate that 22 psoriasis subjects in each study arm will provide a 
power of 80% to detect a difference between the groups. By choosing a sample size of 25 
psoriasis subjects we allow for a dropout of 3 subjects at follow-up without reducing power 
significantly. 
 

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15.2 
Trial analysis sets  
 
A per protocol analysis set will be used as the main efficacy measure for the analysis of the 
endpoints at week 16. 
The per protocol analysis set will be defined by excluding subjects for whom any of the 
following conditions apply: 
 major protocol violations (e.g. did not receive treatment with investigational medicinal 
product) 
 are known to have initiated prohibited medicine (section 11.6) during the trial 
 follow-up FDG-PET/CT not completed  
 
 
15.3 
Statistical analysis  
15.3.1 Disposition of subjects  
 
For all randomised subjects the reasons for leaving the trial in the follow-up period will be 
presented by last visit attended and last week completed for each group, respectively. 
 
15.3.2 Demographics and other baseline characteristics  
 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects. The presentations will be by treatment group. 
Demographics include age, sex, and race. Other baseline characteristics include height, weight, 
body mass index, waist circumference, duration of psoriasis, PASI, nail and joint involvement, 
DLQI, concurrent diagnoses, concomitant medication, and previous psoriasis treatments. 
 
15.3.3 Treatment efficacy 
 
Efficacy of brodalumab on skin, nails, and joints compared to placebo will be shown as 
reduction in PASI, IGA, DLQI, VAS, joint count, and nail count at week 16 for both groups. 
 
15.4 
Analysis of endpoints  
15.4.1 Analysis of primary endpoints  
 
The primary endpoint, change in the average of maximum TBR values (MeanTBRmax) of the 
entire aorta from baseline to week 16, will be analysed for the per protocol analysis set. The 
endpoint will be analysed using a repeated measurements model. 
Estimates and 95% confidence intervals (CIs) or standard deviations (SDs) for the change in 
meanTBRmax and treatment differences will be presented. Values for the entire aorta and 
aortic subsegments will be presented. The difference in efficacy between treatment groups 
will be analysed. The null hypothesis of no difference in change in meanTBRmax between 

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brodalumab and placebo will be tested against the two-sided alternative that there is a 
difference. 
If applicable, a supportive multivariate analysis will be performed to test the effect of the 
continuous covariates age, body mass index, statin treatment and categorical variables gender 
and smoking status on the difference in vascular FDG uptake at week 16. 
 
15.4.2 Analysis of secondary endpoints  
 
The 4 secondary efficacy endpoints evaluate the impact of 16 weeks of treatment on (I) 
change in SLR, (II) change in the average of maximum TBR values (MeanTBRmax) of each 
aortic subsegment (ascending, aortic arch, descending, suprarenal, and infrarenal aorta), (III) 
association between change in PASI and change in aortic wall FDG-uptake, (IV) association 
between change in PASI and change in SLR. 
These endpoints will be evaluated by testing the hypothesis of no difference between 
brodalumab and placebo. The endpoints will be analysed and presented for the per protocol 
analysis set. 
The change from baseline to Week 16 in SLR and aortic subsegment FDG-uptake are 
continuous endpoints and will be analysed using a repeated measurements model. 
If applicable, a supportive multivariate analysis will be performed as described in section 
12.4.1. 
 
15.4.3 Analysis of other endpoints  
 
Change in acute phase proteins at week 16 between groups and change in abdominal 
subcutaneous adipose tissue FDG-uptake will be analysed using a repeated measures model. 
Changes in cytokine expression and gene expression in optional skin samples will be analysed 
using a repeated measures model. Association between change in PASI and change in 
subcutaneous adipose tissue as well as the association between change in TBR/SLR and 
psoriasis-specific genotypes will be computed using applicable correlation coefficients.  
 
 
 
 
 

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16  
REFERENCES 
 
 
 
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Rominger A, Saam T, Wolpers S, et al. 18F-FDG PET/CT identifies patients at risk for 
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34. 
Hjuler KF, Gormsen LC, Vendelbo MH, Egeberg A, Nielsen J, Iversen L. Increased global 
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Naik HB, Natarajan B, Stansky E, et al. Severity of Psoriasis Associates With Aortic 
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Grasset EK, Duhlin A, Agardh HE, et al. Sterile inflammation in the spleen during 
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response. Proc Natl Acad Sci U S A. 2015;112(16):E2030-2038. 
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van der Laan AM, Ter Horst EN, Delewi R, et al. Monocyte subset accumulation in the 
human heart following acute myocardial infarction and the role of the spleen as 
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Emami H, Singh P, MacNabb M, et al. Splenic metabolic activity predicts risk of future 
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Dey AK, Joshi AA, Chaturvedi A, et al. Association Between Skin and Aortic Vascular 
Inflammation in Patients With Psoriasis: A Case-Cohort Study Using Positron Emission 
Tomography/Computed Tomography. JAMA Cardiol. 2017. 
41. 
Bissonnette R, Harel F, Krueger JG, et al. TNF-alpha Antagonist and Vascular 
Inflammation in Patients with Psoriasis Vulgaris: A Randomized Placebo-Controlled 
Study. J Invest Dermatol. 2017;137(8):1638-1645. 
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Bissonnette R, Tardif JC, Harel F, Pressacco J, Bolduc C, Guertin MC. Effects of the tumor 
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Hjuler KF, Gormsen LC, Iversen L. Using FDG-PET/CT to Detect Vascular Inflammation 
in Patients with Psoriasis: Where to Look? And for What?? J Invest Dermatol. 2017. 
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Besson FL, de Boysson H, Parienti JJ, Bouvard G, Bienvenu B, Agostini D. Towards an 
optimal semiquantitative approach in giant cell arteritis: an (18)F-FDG PET/CT case-
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2014;41(1):155-166. 
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Bucerius J, Hyafil F, Verberne HJ, et al. Position paper of the Cardiovascular Committee 
of the European Association of Nuclear Medicine (EANM) on PET imaging of 
atherosclerosis. European journal of nuclear medicine and molecular imaging. 
2016;43(4):780-792. 
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Farahnik B, Beroukhim K, Abrouk M, et al. Brodalumab for the Treatment of Psoriasis: 
A Review of Phase III Trials. Dermatol Ther (Heidelb). 2016;6(2):111-124. 
47. 
Fleming M, Knox M, Kennedy MJ. Incidental detection of colorectal malignancies using 
FDG PET-CT. Ir Med J. 2013;106(5):151-153. 
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Kunawudhi A, Wong AK, Alkasab TK, Mahmood U. Accuracy of FDG-PET/CT for 
Detection of Incidental Pre-Malignant and Malignant Colonic Lesions - Correlation with 

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Colonoscopic and Histopathologic Findings. Asian Pac J Cancer Prev. 2016;17(8):4143-
4147. 
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van Hoeij FB, Keijsers RG, Loffeld BC, Dun G, Stadhouders PH, Weusten BL. Incidental 
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and molecular imaging. 2015;42(1):66-71. 
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Civelek A, Rana A, Malayeri A, et al. Incidental findings of 94 consecutive patients with 
psoriasis detected by FDG PET-MRI and PET-CT. Journal of Nuclear Medicine. 
2017;58(supplement 1):1234. 
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Bucerius J, Mani V, Moncrieff C, et al. Optimizing 18F-FDG PET/CT imaging of vessel 
wall inflammation: the impact of 18F-FDG circulation time, injected dose, uptake 
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52. 
Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. The 5-point 
Investigator's Global Assessment (IGA) Scale: A modified tool for evaluating plaque 
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Berth-Jones J, Grotzinger K, Rainville C, et al. A study examining inter- and intrarater 
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Puzenat E, Bronsard V, Prey S, et al. What are the best outcome measures for assessing 
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Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 
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Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to 
severe psoriasis: a European consensus. Arch Dermatol Res. 2011;303(1):1-10. 
57. 
Mease PJ. Measures of psoriatic arthritis: Tender and Swollen Joint Assessment, 
Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), 
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(MEI), Leeds Enthesitis Index (LEI), Spondyloarthritis Research Consortium of Canada 
(SPARCC), Maastricht Ankylosing Spondylitis Enthesis Score (MASES), Leeds Dactylitis 
Index (LDI), Patient Global for Psoriatic Arthritis, Dermatology Life Quality Index 
(DLQI), Psoriatic Arthritis Quality of Life (PsAQOL), Functional Assessment of Chronic 
Illness Therapy-Fatigue (FACIT-F), Psoriatic Arthritis Response Criteria (PsARC), 
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Bushnell DM, Martin ML, McCarrier K, et al. Validation of the Psoriasis Symptom 
Inventory (PSI), a patient-reported outcome measure to assess psoriasis symptom 
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61. 
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Ahn SS, Hwang SH, Jung SM, et al. Evaluation of spleen glucose metabolism in patients 
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Dunford A, Keramida G, Anagnostopoulos CD, Michael Peters A. The cardiosplenic axis: 
another obscure pathophysiological function of the spleen and its investigation using 
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Nam HY, Kim SJ, Kim IJ, Kim BS, Pak K, Kim K. The clinical implication and prediction of 
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Rao L, Wang X, Zong Z, et al. PET-CT for Evaluation of Spleen and Liver 18F-FDG 
Diffuse Uptake Without Lymph Node Enlargement in Lymphoma. Medicine (Baltimore). 
2016;95(20):e3750. 
 
 
 

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17 Appendix 
 
Please find the following appendices enclosed: 
 
Appendix I:   
Investigators brochure (Kyntheum produktresume in danish) 
Appendix II:  
List of source data captured in the eCRF 
Appendix III: 
Screening chart 
Appendix IV: 
Protokolresume in danish 
Appendix V:  
Deltagerinformation in danish 
Appendix VI: 
Informed consent 
Appendix VII: 
DLQI 
Appendix VIII: 
VAS score 
Appendix IX: 
Subject Logbog 
Appendix X:  
PSI – Patient symptomliste 
Appendix XI: 
Recruitment letter (rekrutteringsbrev) 
Appendix XII: 
Produktresume in danish Natriumklorid "Fresenius Kabi" 9 mg/ml 
 
 

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Deltagerformation og samtykkeerklæring vedrørende deltagelse i et  
sundhedsvidenskabeligt forsøg. 
 
Effekten af brodalumab sammenlignet med placebo på 
inflammation i hovedpulsåren hos patienter med moderat 
til svær psoriasis 
 
Originale titel: 
Effect of brodalumab compared to placebo on vascular inflammation in 
moderate-to-severe psoriasis 
 
A randomised, double-blind, placebo-controlled, trial to evaluate the efficacy  
of brodalumab monotherapy on vascular and systemic inflammation by 18F-FDG-PET/CT 
in subjects with moderate-to-severe plaque-type psoriasis who are candidates for systemic 
therapy 
 
 
 
Projekt nr. 2017-003697-14 
Godkendt den  
 
 
 
 
Projekt ansvarlige: 
Anne Bregnhøj, afdelingslæge, PhD 
Hud- og Kønssygdomme 
Aarhus Universitetshospital 
 
Lars Iversen, Klinisk Professor, overlæge, dr.med. 
Hud- og Kønssygdomme 
Aarhus Universitetshospital 
 
Trine Høgsberg, afdelingslæge, PhD 
Hud- og Kønssygdomme 
Aarhus Universitetshospital 
 
 
Lars Gormsen, overlæge, PhD 
Nuklearmedicin og PET 
Aarhus Universitetshospital 

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Vil du deltage i et sundhedsvidenskabeligt forsøg, som skal belyse, om det 
biologiske behandlingsmiddel ”brodalumab” (Kyntheum) kan mindske 
betændelsesgraden i hovedpulsåren og kroppen generelt hos psoriasis 
patienter? 
 
I det følgende er beskrevet, hvad forsøget går ud på, og hvad det indebærer. Først når du 
er blevet informeret af en læge og har læst og forstået det følgende, skal du afgøre, om du 
vil deltage.  
 
Du har krav på betænkningstid og på at få mundtlig information sammen med en bisidder, 
hvis du ønsker det. Vi beder dig endvidere om at læse den vedlagte brochure  ”Før du 
beslutter dig”, som er udgivet af Den Nationale Videnskabsetiske Komité.  
 
Din deltagelse er frivillig, og du kan altid fortryde og vælge at udgå af projektet, uden at det 
får konsekvenser for din videre behandling. Du vil fortsat blive undersøgt, behandlet, og 
kontrolleret efter afdelingens sædvanlige procedurer. 
  
Dette videnskabelige forsøg foregår i et samarbejde mellem Hud- og Kønssygdomme på 
Aarhus Universitetshospital og Nuklearmedicin og PET, Aarhus Universitetshospital.  
I perioden fra december 2017 til og med marts 2019 vil vi gerne undersøge 50 patienter 
med moderat-til-svær psoriasis – hver patient vil blive fulgt gennem en 16 ugers periode. 
Halvdelen vil modtage behandling med brodalumab. Den anden halvdel vil modtage 
behandling med et blindpræparat (placebo). 
 
Den projekt ansvarlige er afdelingslæge, PhD Anne Bregnhøj, og de øvrige 
projektansvarlige er professor Lars Iversen på Hud- og Kønssygdomme, Aarhus 
Universitetshospital, afdelingslæge, PhD Trine Høgsberg på Hud- og Kønssygdomme, 
Aarhus Universitetshospital og overlæge, PhD Lars Gormsen på Nuklearmedicin og PET, 
Aarhus Universitetshospital. 
 
Det videnskabelige forsøg vil bidrage med viden om den forøgede risiko for 
hjertekarsygdom, der knytter sig til psoriasis, og kan være med til at afklare, om effektiv 
behandling af psoriasis kan bremse de processer i kroppen, der fører til fremskyndet 
åreforkalkningssygdom. 
 
 
Baggrund 
Psoriasis er en kronisk inflammatorisk (betændelses) sygdom. Ved et psoriasis udbrud er 
der inflammation i huden, som er en betændelsesreaktion uden bakterier. Inflammationen i 
huden, som resulterer i psoriasis, er en kompliceret proces, som involver både kroppens 
immunforsvar og cellerne i huden.   
 

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Igennem de senere år har forskning vist, at mennesker med psoriasis har større risiko for 
at få sukkersyge, forhøjet blodtryk, forhøjet kolesterol og fedme. Samtidig ved man, at 
disse sygdomme giver en større risiko for at få hjertekarsygdomme med blodpropper i 
hjertet eller hjernen. Desuden har forskningsresultater vist, at psoriasis i sig selv er 
forbundet med en forøget risiko for hjertekarsygdomme og hjertedød uafhængigt af de 
klassiske risikofaktorer for hjertekarsygdom. Denne sammenhæng menes at skyldes, at 
åreforkalkning også er en tilstand, hvor betændelseslignende reaktioner spiller en stor 
rolle. Der er mange fællestræk mellem betændelsesreaktionen ved psoriasis, og den der 
foregår i blodkar med åreforkalkning. Betændelsesreaktionen ved psoriasis forårsager 
formentlig en forøget grad af betændelse i blodkarrene, hvilket fører til en øget risiko for 
hjertekarsygdomme.  
Denne sammenhæng mellem psoriasis i huden og sygdomme i kroppens indre organer, 
har medført, at man nu betragter psoriasis som en systemisk inflammatorisk sygdom, der 
kan påvirke hele kroppen.  
Et begrænset antal studier har indikeret, at man kan bremse den fremskyndende 
åreforkalkningsproces ved at behandle moderat til svær psoriasis effektivt, men man ved 
endnu ikke meget om denne sammenhæng, og man ved ikke om moderne biologiske 
præparater kan nedbringe graden af betændelse i de store blodkar.  
Studiet er vigtigt for at afklare, om effektiv behandling af psoriasis med biologiske 
præparater som brodalumab (Kyntheum) kan nedbringe inflammationsgraden i 
karsystemet og kroppen generelt, og dermed mindske den fremskyndede 
åreforkalkningsproces.  
 
Formål 
I dette projekt vil vi undersøge, om behandling med det biologiske præparat brodalumab 
(Kyntheum) kan nedbringe graden af betændelse i hovedpulsåren, betændelse generelt i 
kroppen og betændelse i fedtvævet hos mennesker med moderat-til-svær psoriasis.  
 
Metode: 
Til at måle inflammation i kroppen anvendes en såkaldt PET/CT skanning. Ved denne 
undersøgelse får forsøgspersonen indsprøjtet en lille mængde radioaktivt mærket 
sukkerstof i blodåren, som optages særligt i inflammatoriske (betændelseslignende) celler. 
PET/CT-skanneren kan derefter måle radioaktiviteten i kroppen med stor følsomhed og 
derved påvise, hvor og i hvor høj grad der er inflammation.   
 
Du vil blive skannet ved starten af studiet og igen ved afslutningen af din deltagelse efter 
16 uger. Skanningsresultaterne fra de første skanninger vil herefter kunne sammenlignes 
med de afsluttende skanninger, for at afgøre, om præparatet brodalumab kan mindske 
graden af betændelse sammenlignet med placebo.   
 
Du vil blive tildelt enten aktiv behandling med brodalumab eller behandling med placebo 
efter et tilfældighedsprincip. Det personale, der står for skanningerne på Nuklarmedicin og 

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4
PET, vil ikke vide, hvilken gruppe du tilhører. Når hele forsøget er afsluttet, vil du kunne få 
at vide, hvilken behandling du har fået. Du kan få oplyst om dine skanninger har vist tegn 
på sygdom efter ca. en uge. 
 
Det aktive præparat, der anvendes, er ”brodalumab”, handelsnavn i Europa ”Kyntheum”. 
Brodalumab tilhører gruppen af biologisk medicin godkendt til behandling af moderat til 
svær psoriasis. Der er tale om et antistof, der blokerer de signalveje i immunsystemet, 
som er opreguleret i for høj grad hos mennesker med bl.a. psoriasis. Præparatet justerer 
med andre ord på den ubalance i immunsystemet, der giver anledning til psoriasis. 
Undersøgelser har vist, at brodalumab er sikkert at bruge, og det har en hurtigt 
indsættende og effektiv virkning på psoriasis. Brodalumab (Kyntheum) anvendes i sin 
standarddosering, som er 210 mg. 
 
Hvis du får lysbehandling eller tablet behandling for din psoriasis og gerne vil deltage, kan 
det være nødvendigt at stoppe din behandling i 2-4 uger forud for PET/CT skanningen. 
Hvis du får indsprøjtninger med biologiske lægemidler, kan behandlingspausen være 
længere. Inden du beslutter, om du vil deltage i projektet, vil vi oplyse dig om, hvor lang 
behandlingspause der er behov for i dit tilfælde. Umiddelbart efter den afsluttende 
PET/CT-skanning vil der blive lavet en behandlingsplan for den videre behandling af din 
psoriasis i forløbet efter forskningsundersøgelsen. Den videre behandling vil følge de 
almindelige retningslinjer for behandling af psoriasis og bl.a. afhænge af sværhedsgraden 
af din hudsygdom og om der er tegn på psoriasisgigt. 
 
Brodalumab (Kyntheum) er godkendt til behandling af moderat til svær plaque psoriasis. 
Standardbehandlingen af psoriasis afhænger af en række forhold, herunder sværhedsgrad 
af sygdommen, tilstedeværelse af eventuelle følgesygdomme og tidligere forsøgte 
behandlinger. Såfremt du ikke ønsker at deltage i studiet, vil du have mulighed for at 
modtage behandling i henhold til de almindelige retningslinjer for behandling af psoriasis.  
 
Graviditet og amning 
Hvis du er gravid eller ammer, har mistanke om, at du er gravid, eller planlægger at blive 
gravid, har du ikke mulighed for at deltage i forsøget. Brodalumab (Kyntheum) er ikke 
blevet testet hos gravide kvinder, og det vides ikke, om lægemidlet kan skade dit ufødte 
barn. Du bør derfor undgå brugen af Kyntheum under graviditeten. Endvidere bør PET/CT 
skanninger undgåes under graviditeten grundet udsættelse for stråling. Hvis du er en 
kvinde i den fødedygtige alder, skal du undgå at blive gravid, og du skal bruge sikker 
prævention, mens du er i behandling med forsøgslægemidlet og i mindst 12 uger efter den 
sidste dosis forsøgslægemiddel.  
Følgende svangerskabsforebyggende midler anses som sikker prævention: Spiral eller 
hormonel prævention (p-piller, implantat, transdermal depotplastre, vaginalring eller 
depotinjektion). Sterile eller ikke fertile forsøgsdeltagere er fritaget for kravet om brug af 
prævention. For at betragtes som steril eller ikke fertil, må man almindeligvis være 
kirurgisk steriliseret eller være postmenopausal, defineret som udebleven menstruation i 

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mindst 12 måneder før studie indrullering. Kirurgisk sterilisation af fast mandlig partner kan 
være tilstrækkelig prævention. 
Det vides ikke, om brodalumab udskilles i modermælken. Du har ikke mulighed for at 
deltage i studiet, hvis du ammer eller planlægger at amme.  
 
Plan for forsøget: 
Der indgår 4 besøg på hudafdelingen, hvoraf det første besøg består af en konsultation og 
undersøgelse samt screening for, om du opfylder kriterierne for at deltage i forsøget. Selve 
behandlingsperioden strækker sig over 16 uger. De resterende 3 besøg på hudafdelingen 
vil blive i løbet af denne periode; ved påbegyndelse af behandlingen, efter 6 ugers 
behandling og efter 16 ugers behandling. Der indgår 2 besøg på Nuklearmedicin og PET, 
hvor du får foretaget PET/CT-skanningerne. De 2 besøg på Nuklearmedicin og PET vil så 
vidt muligt blive planlagt til samme dag som 2 af besøgene på hudafdelingen.  
 
Hvis du deltager i den videnskabelige undersøgelse, vil den første del af forløbet minde 
meget om det almindelige program for forundersøgelse til biologisk behandling af 
psoriasis.  
 Som en almindelig del af en ambulant konsultation for psoriasis på Hud- og 
Kønssygdomme vil du få en lægelig samtale og undersøgelse.  
 Du vil også få taget en blodprøve fra armen. Blodprøven bliver taget af en erfaren 
medarbejder på afdelingens laboratorium. Blodprøven består af 2-5 blodprøveglas 
a 3-5ml. Blodet skal bruges til rutine undersøgelser af infektionstal, væsketal, 
levertal, blodsukker, kolesteroltal og screening for leverbetændelse, HIV og 
tuberkulose. Herudover vil der blive analyseret for enkelte markører på systemisk 
betændelse (inflammation). Når blodprøverne er analyseret, indgår resultaterne i 
din patientjournal og i den database, der anvendes i forskningsprojektet. En mindre 
del af blodet vil blive frosset ned og opbevaret i en periode i en fryser godkendt til 
formålet, idet nogle analyser ikke kan foretages med det samme på den friske 
blodprøve, men vil blive udført senere, når alle blodprøver fra alle forsøgsdeltagere 
foreligger. Se ”biologisk materiale” for nærmere oplysninger. 
 Der tages eventuelt en hudprøve fra et område med psoriasis og fra et raskt 
hudområde. Det drejer sig om stansebiopsier der er 4 mm i diameter og ca 4-5 mm 
i dybden. Prøverne tages inden påbegyndelse af projektmedicin og igen efter 6 
uger. Det er frivilligt, om du vil indgå i denne del af studiet. Hvis du ikke ønsker at 
donere vævsprøver, kan du fortsat deltage i resten af forskningsundersøgelsen. 
 Du vil blive henvist til at få foretaget et røntgen billede af lungerne, medmindre du 
for nyligt har fået foretaget en sådan undersøgelse. Denne undersøgelse er 
ligeledes standard inden påbegyndelse af biologisk behandling af psoriasis.   
 Til forskningsprojektet skal vi bruge oplysninger om din sygdomshistorie, 
medicinske behandling, andre sygdomme, højde, vægt, taljemål, blodtryk, nyretal, 
infektionstal, kolesterol, blodsukker, samt tobak og alkohol forbrug. Resultaterne af 
din undersøgelse og oplysninger vil i anonymiseret form indgå i sammenligningen 
af de to behandlingsgrupper i forsøget. 

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 Kvinder i den fertile alder skal anvende sikker kontraception (beskyttelse) under 
behandlingen og i mindst 12 uger efter behandlingen. 
 Når de forskellige forundersøgelser er gennemført og resultaterne foreligger, vil du 
få besked om hvad undersøgelserne har vist, og om du kan fortsætte i studiet eller 
om prøveresultaterne evt. har givet anledning til at foretage yderligere 
undersøgelser (f.eks. ved unormale blodprøver eller lignende). 
 Hvis forundersøgelserne er upåfaldende, vil du blive henvist til PET/CT-skanning, 
og du vil få en tid umiddelbart efter i forskningsambulatoriet på Hud- og 
Kønssygdomme. Du vil her modtage den første behandling med projektmedicin 
(brodalumab (Kyntheum) eller placebo) og få yderligere medicin med hjem til 
hjemmebehandling.  
 Du vil ikke kunne se på medicinen om indholdet er det aktive stof eller placebo. 
 Du vil blive lært op i at injicere dig selv med medicinen. Injektionen minder meget 
om den måde, hvorpå sukkersyge-patienter injicerer sig selv med insulin. 
 Oplæring i hjemmebehandling og forholdene omkring hjemmebehandling følger de 
normale retningslinjer og er standard ved de fleste biologiske behandlinger af 
psoriasis. 
 Du vil få en injektion på Hud- og Kønssygdomme ved kontrollen umiddelbart efter 
PET/CT-skanningen. Herefter vil du derhjemme skulle injicere dig efter 1 og 2 uger, 
og derefter fast hver 2. uge. 
 Du vil få en tid til kontrol i forskningsambulatoriet efter 6 uger og igen efter 16 uger. 
 Den afsluttende PET/CT-skanning vil ligeledes blive udført efter 16 uger. 
 I forbindelse med den afsluttende kontrol i forskningsambulatoriet aftales, hvordan 
den videre behandling af din psoriasis skal forløbe. Efter aftale med dig planlægges 
anden behandling evt. med det samme. 
 Umiddelbart efter at din deltagelse i studiet er slut, vil du kunne få svar på om 
PET/CT-skanningerne har vist tegn til anden sygdom. Der vil typisk gå ca. en uge 
fra den sidste undersøgelse er udført, til skanningerne er blevet gennemgået for 
tegn på anden sygdom. Ved mistanke om alvorlig sygdom som eksempelvis kræft 
vil du dog blive orienteret indenfor ca. en uge efter den første PET/CT-skanning. 
 
I dette studie afprøves ikke nye lægemidler, idet brodalumab (Kyntheum) er en godkendt 
behandling til psoriasis. Der undersøges dog for nye effekter af dette præparat i forhold til 
at mindske graden af betændelse i karsystemet og kroppen generelt. Der indgår som 
anført tilfældig fordeling (randomisering) og et blindpræparat (placebo).  
 
PET/CT-skanning er en almindelig anerkendt undersøgelse metode, som anvendes 
rutinemæssigt på PET-Centret, Nuklearmedicinsk afd., Aarhus Universitetshospital. 
PET/CT-skanninger anvendes normalt til undersøgelse for bl.a. infektionssygdomme, 
kræftsygdomme og andre inflammatoriske sygdomme.  
 
Biologisk materiale: 

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Da ikke alle analyser straks kan udføres oprettes en forskningsbiobank.  
 Der udtages ca. 4 ml blod ved den almindelige blodprøvetagning ved 
screeningsbesøget og igen efter 6 uger. Disse 4 ml blod nedfryses i en fryser, der 
er placeret i et aflåst rum i forskningsfaciliteterne tilknyttet Hud og Kønssygdomme. 
 Herudover indgår eventuelt en hudprøve fra et område med psoriasis og fra et raskt 
hudområde. Det drejer sig om stansebiopsier der er 4 mm i diameter og ca 4-5 mm 
i dybden. Prøverne tages inden påbegyndelse af projektmedicin og igen efter 6 
uger. Det er frivilligt, om du vil indgå i denne del af studiet. Hvis du ikke ønsker at 
donere vævsprøver, kan du fortsat deltage i resten af forskningsundersøgelsen. 
Vævsprøverne nedfryses i afdelingens forskningsfaciliteter og analyseres for 
signalmolekyer som er involveret i sygdomsmekanismen ved psoriasis. Disse 
signalmolekyler antages at blive blokeret af Kyntheum (brodalumab). 
 Ved blodprøvetagningen er der risiko for let ubehag ved selve indstikket, ligesom 
der er en risiko for et lille blår mærke ved indstiksstedet. Enkelte personer kan føle 
alment ubehag ved at få taget blodprøver. 
 Ved de frivillige hudbiopsier kan der være kortvarigt let til moderat svie i huden ved 
lokalbedøvelse af området. Selve udtagningen af hudbiopsierne er som regel 
smertefrit. Efterfølgende er der risiko for let blødning fra området og en lille risiko for 
infektion. Du vil i forbindelse med hudbiopsierne få forklaret tegnene på infektion og 
hvordan du skal forholde dig ved blødning fra området eller ved infektionstegn. Der 
kan opstå et lille ar, de steder hvor der er udtaget hudprøver. 
 Formålet med forskningsbiobanken er at samle alle blodprøver og vævsprøver, idet 
analyserne for biomarkører på inflammation skal foretages samlet, når alle 
prøverne foreligger. 
 Alle analyser på materialet forventes at være afsluttede i januar 2020. 
 Hvis der er materiale til overs efter denne dato, vil det blive anonymiseret, hvis det 
skal opbevares i længere tid. 
 
 
Procedure ved PET/CT-skanningen:  
Du skal faste 6 timer forud for PET/CT- skanningen, men må gerne drikke vand, kaffe/the 
uden sukker eller mælkeprodukter. Når skanningen begyndes, får du anlagt en nål i en 
blodåre, som derefter skal bruges til indsprøjtning af en lille mængde radioaktivt mærket 
sukkerstof. Efter ca. 90-120 minutters ventetid kan skanningen begynde. Til skanningen 
skal du ligge på et leje på ryggen, imens du bliver kørt igennem hullet på skanneren, som 
består af to sammenbyggede ringe.  Selve PET/CT-skanningen tager ca. 40 minutter, og 
du skal regne med at være i afdelingen i ca. 2,5-3 timer i alt. Efter skanningen kan du få 
noget at spise og drikke, inden du tager hjem. 
 
Der er vedlagt kopi af ”patientinformationen” for PET/CT-skanning fra PET-Centret, 
Nuklearmedicinsk og PET, Aarhus Universitetshospital. 
 

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Mulig nytte ved forsøget  
Hvis du efter tilfældighedsprincippet tildeles aktiv behandling med brodalumab 
(Kyntheum), kan du forvente, at din psoriasis med stor sandsynlighed afglattes helt eller 
stort set helt. På sigt kan deltagelsen for dig og andre psoriasis patienter betyde en bedre 
behandling af både psoriasis i huden men muligvis også af de inflammatoriske processer, 
som påvirker andre organer. Resultaterne kan også medføre, at patienter i højere grad 
kan tilbydes individualiseret behandling ud fra kendskab til flere markører for 
sygdomsaktivitet og følgesygdomme. Studiet forventes at bidrage med viden, der kan 
afklare, om den forøgede risiko for hjertekarsygdom hos psoriasispatienter vil kunne 
mindskes ved effektiv behandling af psoriasis. Samtidig vil studiet kunne bidrage med 
viden omkring den rolle, som inflammation spiller ved åreforkalkningssygdom generelt. Det 
er desuden muligt, at PET/CT-skanningerne påviser tegn på andre sygdomme, som endnu 
ikke har givet dig symptomer. F.eks. er det kendt fra flere internationale studier og fra 
kliniske erfaringer, at der hos nogle patienter kan opdages ondartede knuder i bl.a. 
tarmsystemet, som endnu ikke har givet symptomer. Med mindre du i situationen tydeligt 
frabeder dig dette, vil du i så fald straks blive henvist til yderligere undersøgelse og 
behandling. De forsøgsansvarlige læger og De Videnskabs Etiske Komitéer har vurderet, 
at nytteværdien ved forsøget opvejer den risiko, som forsøget indebærer.   
 
 
Bivirkninger ved PET/CT skanning: 
I forbindelse med passagen igennem hullet i skanneren oplever personer med klaustrofobi 
nogle gange ubehag.   
 
Mængden af indsprøjtet radioaktivt sukkerstof og stråler fra PET/CT-skanning er lille og 
svarer til ca. 3-4 års baggrundsstråling. Strålingen medfører en meget lille øget risiko for at 
udvikle en uhelbredelig kræftsygdom - teoretisk stiger livstidsrisikoen for at udvikle kræft 
fra ca. 25 procent til 25.048 procent for personer under 50. For personer over 50 år 
reduceres denne risiko for at dø af en stråle udløst kræftsygdom, da varigheden til 
udvikling af kræft er mangeårig, og følsomheden for stråling falder med alderen.   
 
 
Ulemper ved at deltage i forsøget 
Du kan evt. opleve forværring i din psoriasis sygdom, hvis du skal holde en pause fra din 
behandling inden påbegyndelse af det videnskabelig forsøg, og hvis du bliver 
randomiseret til at modtage placebo (blindpræparat) i behandlingsperioden. I forbindelse 
med de første undersøgelser vil forløbet omkring behandlingspause blive aftalt. Du vil altid 
have mulighed for at komme i kontakt med personalet i forskningsafdelingen og med de 
forsøgsansvarlige, mens du deltager i forsøget. Det er ikke tilladt at anvende stærke 
lokalsteroid (binyrebarkhormon) cremer under studiet, da dette vil kunne forstyrre 
resultatet. Det er dog tilladt at anvende almindelige fugtighedscremer, svage og 

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middelstærke binyrebarkhormon cremer for at mildne generne fra din psoriasis. Der kan 
således anvendes en gruppe II steroid creme efter nærmere aftale med de 
projektansvarlige læger.  
 
I forbindelse med PET/CT-skanningen kan der være gener i form af sult fornemmelse pga. 
6-timers faste forud for skanningen. Dertil er der tidsforbrug i forbindelse med selve 
skanningen og transport til og fra skanningen. Der kan forekomme ekstra ventetid pga. 
tekniske problemer ved fremstilling af det radioaktivt mærkede sukkerstof.  
 
Brodalumab (Kyntheum) er som anført et godkendt lægemiddel til behandling af moderat 
til svær psoriasis. De kendte bivirkninger ved brodalumab omfatter ledsmerter, hovedpine, 
træthed, diarré, smerter i mund/svælg, infektion og svampeinfektioner. Sjældent kan der 
opstå tendes til et lavt antal hvide blodlegemer (neutropeni).  
 
 
Registrering og brug af oplysninger i forsøget  
I forbindelse med forsøget og kontrol af dette, kan særligt bemyndigede personer, der har 
tilknytning til forsøget, monitor (GCP-enheden ved Aarhus Universitet), samt 
Lægemiddelstyrelsen, få direkte adgang til oplysninger i din journal. Disse personer har 
tavshedspligt og vil behandle dine personlige data strengt fortroligt. Der vil på intet 
tidspunkt blive udleveret oplysninger, som kan henføres til dig personligt. Oplysningerne vil 
blive registreret og opbevaret i 5 år efter forsøgets afslutning. Resultaterne af forsøget vil 
senere indgå i en videnskabelig opgørelse. 
 
 
Transport  
Udgifter til transport i forbindelse med ambulante besøg til lægesamtaler og PET/CT-
skanninger refunderes i henhold til gældende retningslinjer. Der gives ikke i øvrigt 
økonomisk kompensation for deltagelse i forsøget. 
 
 
Udgang fra forsøget 
Lægen, der er ansvarlig for forsøget, kan på et hvilket som helst tidspunkt afslutte 
forsøget, fx hvis der foreligger en medicinsk begrundelse, en sundhedsrisiko eller et krav 
fra myndighederne.  
 
 
Økonomisk forhold: 
Projektet er initieret af afdelingslæge Anne Bregnhøj, afdelingslæge Trine Høgsberg  og 
professor, overlæge Lars Iversen, Hud og Kønssygdomme, Aarhus Universitetshospital. 
De projektansvarlige har ingen økonomiske interesse i studiet.  
 

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Driftsomkostninger til gennemførsel af studiet dækkes af en bevilling fra LEO Pharma A/S 
som administreres via en forskningskonto på Aarhus Universitetshospital. Desuden 
sponsorerer LEO Pharma A/S den brodalumab (Kyntheum) der anvendes i studiet. LEO 
Pharma A/S har ikke indflydelse på designet af forsøget, udførelsen af forsøget eller 
tolkningen af forsøgsresultaterne. Den samlede økonomiske støtte til dækning af 
ovennævnte udgifter fordelt over hele forsøgsperioden er 212.900 euro (ca. 1.607.000 kr). 
 
 
Det er frivilligt at deltage i forsøget 
Meningen med denne skriftlige information er, at du skal overveje, om du vil deltage i 
forskningsprojektet. Det er godt at drøfte informationerne med din nærmeste. 
Det er din egen frivillige beslutning, om du vil deltage i forsøget. Hvis du beslutter dig for at 
deltage i forsøget, kræver dansk lov, at du bekræfter dette ved at skrive under på 
samtykkeerklæringen.   
 
Ved  at skrive under giver du tilladelse til, at vi må bruge og videregive resultaterne fra din 
PET/CT-skanning samt oplysninger i din journal, mellem lægerne og afdelingerne som er 
involveret i projektet. Dine personlige oplysning vil blive behandlet strengt fortroligt og vil 
kun blive anvendte til dette projekt. Der vil ikke blive offentliggjort personhenførbare 
oplysninger. 
 
Føler du, at der bliver lagt pres på dig, råder vi dig til at udskyde afgørelsen. Vælger du at 
deltage, kan du i øvrigt, når som helst og uden begrundelse, tilbagekalde dit samtykke. 
Uanset om du siger ja, nej, eller fortryder senere, vil vi give dig den bedst mulige 
behandling af din sygdom.  
 
Forsøget er godkendt af De Videnskabsetiske Komitéer, Lægemiddelstyrelsen og 
Datatilsynet. Den Videnskabsetiske Komités hovedopgave er at beskytte forsøgspersoner, 
der deltager i biomedicinske forsøg og sikre, at man som forsøgsperson frit kan vælge, om 
man vil deltage.  
 
Hvis du har spørgsmål til projektet, er du velkommen til at kontakte projektets 
kontaktperson og forsøgsansvarlige.  
 
Vi vil opfordre dig til at læse pjecen "Forsøgspersoners rettigheder i 
sundhedsvidenskabelige forskningsprojekter" som er vedlagt deltagerinformationen. 
 
 
 
 
 
 
 

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Kontaktperson og forsøgsansvarlig 
Anne Bregnhøj, Afdelingslæge, PhD  
Hud- og Kønssygdomme 
Aarhus Universitetshospital,  
P.P. Ørumsgade 11 
8000 Aarhus C 
Mobile: 21835710   
E-mail: annebreg@rm.dk 
 
Kontaktperson i de kliniske forskningsfaciliteter: 
Mette Thorup, sygeplejerske 
Hud- og Kønssygdomme 
Aarhus Universitetshospital,  
P.P. Ørumsgade 11 
8000 Aarhus C 
Mobile:  24244900 
E-mail: annthoru@rm.dk 

 
 
Informeret samtykke til deltagelse i et sundhedsvidenskabeligt forskningsprojekt. 
 
Forskningsprojektets titel: Effekten af brodalumab sammenlignet med placebo på inflammation i 
hovedpulsåren hos patienter med moderat til svær psoriasis 
 
 
Erklæring fra forsøgspersonen: 
Jeg har fået skriftlig og mundtlig information og jeg ved nok om formål, metode, fordele og  
ulemper til at sige ja til at deltage.  
Jeg ved, at det er frivilligt at deltage, og at jeg altid kan trække mit samtykke tilbage uden at miste mine 
nuværende eller fremtidige rettigheder til behandling.  
 
Jeg giver samtykke til, at deltage i forskningsprojektet og til, at mit biologiske materiale udtages  
med henblik på opbevaring i en forskningsbiobank. Jeg har fået en kopi af dette samtykkeark samt  
en kopi af den skriftlige information om projektet til eget brug.      
 
Forsøgspersonens navn: ________________________________________________________ 
 
Dato: _______________   Underskrift: ____________________________________________ 
 
Ønsker du at blive informeret om forskningsprojektets resultat samt eventuelle konsekvenser for dig?: 
 
Ja _____ (sæt x)         Nej _____ (sæt x) 
 
Erklæring fra den, der afgiver information: 
Jeg erklærer, at forsøgspersonen har modtaget mundtlig og skriftlig information om forsøget. 
 
Efter min overbevisning er der givet tilstrækkelig information til, at der kan træffes beslutning om 
deltagelse i forsøget.   
Navnet på den, der afgiver information: Forsøgsansvarlige: 
 
Dato: _______________   Underskrift: ____________________________________________ 
 
 
 
 
Projektidentifikation:  
 
EudraCT 2017-003697-14 
 
Deltagerinformation ver. nr.: 2.1, 12.12.2017